European Resuscitation Council and European Societ

RESUSCITATION 161 (2021) 220 269
Available online at www.sciencedirect.com
Resuscitation
journal homepage: www.elsevier.com/locate/resuscitation
European Resuscitation Council and European

Society of Intensive Care Medicine Guidelines 2021:
$
Post-resuscitation care
Jerry P. Nolan a,b,1, * , Claudio Sandroni c,d,1 , Bernd W. Böttiger e, Alain Cariou f ,
Tobias Cronberg g , Hans Friberg h , Cornelia Genbrugge i,j , Kirstie Haywood k ,
Gisela Lilja l , Véronique R.M. Moulaert m, Nikolaos Nikolaou n ,
Theresa Mariero Olasveengen o , Markus B. Skrifvars p , Fabio Taccone q, Jasmeet Soar r
a
University of Warwick, Warwick Medical School, Coventry CV4 7AL, UK
b
Royal United Hospital, Bath, BA1 3NG, UK
c
Department of Intensive Care, Emergency Medicine and Anaesthesiology, Fondazione Policlinico Universitario A. Gemelli-IRCCS, Rome, Italy
d
Institute of Anaesthesiology and Intensive Care Medicine, Università Cattolica del Sacro Cuore, Rome, Italy
e
University Hospital of Cologne, Kerpener Straße 62, D-50937 Cologne, Germany
f
Cochin University Hospital (APHP) and University of Paris (Medical School), Paris, France
g
Department of Clinical Sciences, Neurology, Lund University, Skane University Hospital, Lund, Sweden
h
Department of Clinical Sciences, Anaesthesia and Intensive Care Medicine, Lund University, Skane University Hospital, Lund, Sweden
i
Acute Medicine Research Pole, Institute of Experimental and Clinical Research (IREC) Université Catholique de Louvain, Brussels, Belgium
j
Emergency Department, University Hospitals Saint-Luc, Brussels, Belgium
k
Warwick Research in Nursing, Room A108, Division of Health Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
l
Lund University, Skane University Hospital, Department of Clinical Sciences Lund, Neurology, Lund, Sweden
m
University of Groningen, University Medical Center Groningen, Department of Rehabilitation Medicine, Groningen, The Netherlands
n
Cardiology Department, Konstantopouleio General Hospital, Athens, Greece
o
Department of Anesthesiology, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo, Norway
p
Department of Emergency Care and Services, University of Helsinki and Helsinki University Hospital, Finland
q
Department of Intensive Care, Hôpital Erasme, Université Libre de Bruxelles, Route de Lennik, 808, 1070 Brussels, Belgium
r
Southmead Hospital, North Bristol NHS Trust, Bristol BS10 5NB, UK
Abstract
The European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM) have collaborated to produce these post-
resuscitation care guidelines for adults, which are based on the 2020 International Consensus on Cardiopulmonary Resuscitation Science with
Treatment Recommendations. The topics covered include the post-cardiac arrest syndrome, diagnosis of cause of cardiac arrest, control of
oxygenation and ventilation, coronary reperfusion, haemodynamic monitoring and management, control of seizures, temperature control, general
intensive care management, prognostication, long-term outcome, rehabilitation, and organ donation.
$
This article is co-published in the journals Intensive Care Medicine and Resuscitation.
* Corresponding author at: University of Warwick, Warwick Medical School, Coventry, CV4 7AL.
E-mail address: [email protected] (J.P. Nolan).
1
Joint first authors.
https://doi.org/10.1016/j.resuscitation.2021.02.012
0300-9572/© 2021 European Resuscitation Council and European Society of Intensive Care Medicine. Published by Elsevier B.V. All rights reserved
RESUSCITATION 161 (2021) 220 269 221
representation and diversity (gender, physician and non-physician,

Introduction and scope and geography (Northern and Southern Europe).
These ERC-ESICM guidelines on post-resuscitation care for
In 2015 the European Resuscitation Council (ERC) and the European adults are based mainly on the Advanced Life Support section of the
Society of Intensive Care Medicine (ESICM) collaborated to produce 2020 CoSTR document and represent consensus among the writing
their first combined post-resuscitation care guidelines, which were co- group, which included representatives of the ERC and the ESICM.9
published in Resuscitation and Intensive Care Medicine.1,2 These Where treatment recommendations are provided by ILCOR, these
post-resuscitation care guidelines have been extensively updated for have been adopted by the ERC and ESICM. In the absence of an
2020 and incorporate the science that has been published since 2015. ILCOR recommendation, ERC-ESICM guidance was based on
The topics covered include the post-cardiac arrest syndrome, control review and discussion of the evidence by the working group until
of oxygenation and ventilation, haemodynamic targets, coronary consensus was achieved. The writing group chairs ensured that
reperfusion, targeted temperature management, control of seizures, everyone on the working group had the opportunity to present and
prognostication, rehabilitation, and long-term outcome. debate their views and ensured that discussions were open and
constructive. All discussions took place during eight 2-h Zoom
videoconferences that were held between January 2020 and
Methods November 2020. Consensus was achieved by all 15 writing group
members on all the treatment recommendations using an open
A comprehensive description of the guideline development process is process.
provided in an electronic supplement. These guidelines were drafted and agreed by the Post-
Resuscitation Care Writing Group members before posting on the
The international consensus on cardiopulmonary ERC website for public comment between 21 October and 5 Novem-
resuscitation science evidence review process ber 2020. The opportunity to comment on the guidelines was
advertised through social media (Facebook, Twitter) and the ERC
The International Liaison Committee on Resuscitation (ILCOR, www. network of 33 national resuscitation councils. Nine individuals from
ilcor.org) includes representatives from the American Heart Associa- four countries made 25 comments. One of these individuals was a lay
tion (AHA), the European Resuscitation Council (ERC), the Heart and person. Review of these comments led to eight changes.
Stroke Foundation of Canada (HSFC), the Australian and New
Zealand Committee on Resuscitation (ANZCOR), the Resuscitation
Council of Southern Africa (RCSA), the Inter-American Heart Summary of the key changes
Foundation (IAHF), and the Resuscitation Council of Asia (RCA).
From 2000 to 2015 researchers from the ILCOR member councils A summary of the main changes from the 2015 ERC-ESICM Post-
evaluated resuscitation science in 5-yearly cycles. After publication of resuscitation care guidelines is set out in Table 1.
the 2015 International Consensus on CPR and ECC Science with Key messages from the section are presented in Fig. 1.
Treatment Recommendations (2015 CoSTR),3 ILCOR committed to a
continuous evidence-evaluation process, with topics prioritised for
review by the task forces and with CoSTR updates published annually. Concise guidelines for clinical practice
4 6
For the 2020 CoSTR, the six ILCOR task forces performed three
types of evidence evaluation: the systematic review, the scoping This section includes only a summary of the main recommendations.
review, and the evidence update, which covered 184 topics in total.7 It The evidence underpinning each recommendation is detailed in the
was agreed that only systematic reviews (these used Grading of section on ‘evidence informing the guidelines’.
Recommendations Assessment, Development, and Evaluation
(GRADE) methodology) could result in new or modified treatment Immediate post-resuscitation care
recommendations.8 The data analysis from each systematic review
was presented to the task force, and the task force drafted the Post-resuscitation care is started immediately after sustained
summary consensus on science and the treatment recommendations. ROSC, regardless of location (Fig. 2).
Each treatment recommendation indicated the strength of the For out-of-hospital cardiac arrest consider transport to a cardiac
recommendation (recommends = strong, suggests = weak) and the arrest centre.
certainty of the evidence. Draft 2020 CoSTRs were posted on the
ILCOR website (ilcor.org) for a 2-week comment period after which Diagnosis of cause of cardiac arrest
final wording of science statements and treatment recommendations
were completed by the task forces and published in Resuscitation and If there is clinical (e.g. haemodynamic instability) or ECG evidence
Circulation as the 2020 Consensus on Science and Treatment of myocardial ischaemia, undertake coronary angiography first.
Recommendations (CoSTR). This is followed by CT brain and/or CT pulmonary angiography if
coronary angiography fails to identify causative lesions.
The European Resuscitation Council and European Society Early identification of a respiratory or neurological cause can be
for intensive care medicine process for developing post- achieved by performing a brain and chest CT-scan at hospital
resuscitation care guidelines admission, before or after coronary angiography (see coronary
reperfusion).
Fifteen individuals were selected for the ERC-ESICM Post-Resusci- If there are signs or symptoms pre-arrest suggesting a
tation Care Writing Group based on their expertise, ERC and ESICM neurological or respiratory cause (e.g. headache, seizures or
222 RESUSCITATION 161 (2021) 220 269
Table 1 – Summary
neurological deficits, shortness of breath
of changes sinceor the
documented hypo-
2015 Guidelines on Post-resuscitation care.
xaemia in patients with known respiratory disease), perform a CT
2015 Guidelines 2021 Guidelines Rationale for change
brain and/or a CT pulmonary angiogram.
Coronary angiography
It is reasonable to discuss and consider emergent cardiac In patients with ROSC after OHCA without ST- A randomised controlled trial showed no
catheterisation laboratory evaluation after ROSC in elevation on the ECG, emergent cardiac catheter- difference in 90-day survival following out of
patients with the highest risk of a coronary cause for their isation laboratory evaluation should be considered if hospital VF cardiac arrest among patients
cardiac arrest there is an estimated high probability of acute without ST-elevation on the ECG allocated to
coronary occlusion (e.g. patients with haemody- immediate coronary angiography versus de-
namic and/or electrical instability). layed angiography.10 Recent ESC guidelines
state that ‘Delayed as opposed to immediate
angiography should be considered in haemo-
dynamically stable patients without ST-seg-
ment elevation successfully resuscitated after
an out-of-hospital cardiac arrest’.11
Blood pressure target

Target the mean arterial blood pressure to achieve an Avoid hypotension (<65 mmHg). Target MAP to Several studies show that hypotension
adequate urine output (1 mL kg 1 h 1) and normal or achieve adequate urine output (>0.5 mL kg 1 h 1) (<65 mmHg) is consistently associated with
decreasing plasma lactate values, taking into and normal or decreasing lactate. poor outcome. Although we have stated a
consideration the patient’s normal blood pressure, the threshold value for blood pressure, optimal
cause of the arrest and the severity of any myocardial MAP targets are likely to need to be
dysfunction. individualised.
Treatment of seizures
Treat [seizures] with sodium valproate, levetiracetam, To treat seizures after cardiac arrest, we suggest In a recently reported trial, valproate, levetir-
phenytoin, benzodiazepines, propofol, or a barbiturate. levetiracetam or sodium valproate as first-line acetam and fosphenytoin were equally effective
antiepileptic drugs in addition to sedative drugs. in terminating convulsive status epilepticus but
fosphenytoin caused more episodes of
hypotension.12
Temperature control
Maintain a constant, target temperature between We recommend TTM for adults after either A recent randomised controlled trial of both
32 C and 36 C for those patients in whom tempera- OHCA or IHCA (with any initial rhythm) who IHCA and OHCA patients with initial non-
ture control is used (strong recommendation, moder- remain unresponsive after ROSC. shockable rhythms showed a higher percent-
ate-quality evidence). Maintain a target temperature at a constant age of patients survived with a favourable
Whether certain subpopulations of cardiac arrest value between 32 C and 36 C for at least 24 h. neurological outcome when treated with TTM at
patients may benefit from lower (32 34 C) or higher Avoid fever (>37.7 C) for at least 72 h after 33 C versus 37 C.13 This has enabled the
(36 C) temperatures remains unknown, and further ROSC in patients who remain in coma. recommendation to be extended to all rhythms
research may help elucidate this. and locations.
TTM is recommended for adults after OHCA with an The definition of fever (>37.7 C) is consistent
initial shockable rhythm who remain unresponsive with that used in the TTM2 trial.14
after ROSC (strong recommendation, low-quality
evidence).
TTM is suggested for adults after OHCA with an initial
non-shockable rhythm who remain unresponsive after
ROSC (weak recommendation, very low-quality
evidence).
TTM is suggested for adults after IHCA with any initial
rhythm who remain unresponsive after ROSC (weak
recommendation, very low-quality evidence).
If targeted temperature management is used, it is
suggested that the duration is at least 24 h (weak
recommendation, very low-quality evidence).
General intensive care management

Short-acting drugs (e.g., propofol, alfentanil, remifentanil) Use short acting sedatives and opioids. The 2015 guidelines included very few state-
will enable more reliable and earlier neurological Avoid using a neuromuscular blocking drug ments on general intensive care management.
assessment and prognostication routinely in patients undergoing TTM, but it may For 2020 we have several best practice state-
Following ROSC maintain the blood glucose at be considered in case of severe shivering ments based mainly on data extrapolated from
10 mmol L 1 (180 mg dL 1) and avoid hypoglycaemia. during TTM. other critically ill patient groups.
Provide stress ulcer prophylaxis routinely in
cardiac arrest patients.
Provide deep venous thrombosis prophylaxis.
Target a blood glucose of 7.8 10 mmol L 1
(140 180 mg dL 1) using an infusion of insulin if
required; avoid hypoglycaemia (<4.0 mmol L 1
(<70 mg dL 1).
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Table 1 (continued)
2015 Guidelines 2021 Guidelines Rationale for change
Start enteral feeding at low rates (trophic
feeding) during TTM and increase after re-
warming if indicated. If TTM of 36 C is used as
the target temperature, trophic gastric feeding
rates may be increased early during TTM.
We do not recommend using prophylactic
antibiotics routinely.
Prognostication
The prognostication strategy algorithm is applicable to all In a comatose patient with M 3 at 72 h from There has a very large amount of data published
patients who remain comatose with an absent or extensor ROSC, in the absence of confounders, poor on prognostication since the 2015 guidelines. A
motor response to pain at 72 h from ROSC. Results of outcome is likely when two or more of the following recent systematic review identified 94 studies
earlier prognostic tests are also considered at this time predictors are present: that included over 30,000 patients, all published
point. no pupillary and corneal reflexes at 72 h, since January 2013.15
One or both of the following indicate that a poor outcome is bilaterally absent N20 SSEP wave at 24 h, The two-stage prognostication algorithm in the
very likely (FPR < 5%, narrow 95% CIs): highly malignant EEG (suppressed background 2015 guidelines has been simplified so that a
No pupillary and corneal reflexes or burst-suppression) at >24 h, poor outcome is considered likely when two or
Bilaterally absent N20 SSEP wave NSE >60 mg L 1 at 48 h and/or 72 h, more of the listed predictors are present. The
Two or more of the following indicate that a poor outcome status myoclonus 72 h, algorithm is valid for comatose patients with a
is likely: or a diffuse and extensive anoxic injury on brain Glasgow Motor Score 3 (compared with 2 in
Status myoclonus 48 h after ROSC CT/MRI. the 2015 version). A threshold value for NSE is
High NSE levels now stated. The EEG patterns suppression and
Unreactive burst-suppression or status epilepticus on burst-suppression are the most consistent
EEG predictors of poor neurological outcome. Con-
Diffuse anoxic injury on brain CT/MRI versely, absence of EEG reactivity has been
only inconsistently associated with poor neu-
rological outcome in recent studies.
We suggest using the 2021 ACNS terminology
when assessing these patterns for prognosti-
cation, to ensure an unequivocal identification.
Rehabilitation
Follow-up care should be organised systematically and Perform functional assessments of physical The authorship of the 2021 guidelines now
can be provided by a physician or specialised nurse. It and non-physical impairments before dis- includes 3 individuals with expertise on long-
includes at least the following aspects: charge from the hospital to identify early term outcomes and rehabilitation after cardiac
Screening for cognitive impairments rehabilitation needs and refer to rehabilitation arrest compared with one author in 2015. The
Screening for emotional problems if necessary. 2021 guidelines include greater emphasis on
Provision of information Organise follow-up for all cardiac arrest survi- functional assessments of physical and non-
vors within 3 months after hospital discharge, physical impairments before discharge and
including: long-term follow up and rehabilitation. There is
1. Screening for cognitive problems. greater recognition of the importance of survi-
2. Screening for emotional problems and fatigue. vorship after cardiac arrest. The recommen-
3. Providing information and support for survivors dations in this section are all best practice
and family members. statements
Cardiac arrest centres

No specific recommendation Adult patients with non-traumatic OHCA should be An expert consensus paper published by
considered for transport to a cardiac arrest centre several European organisations including the
according to local protocol. Association of Acute Cardiovascular Care
(ACVA) of the European Society of Cardiology
(ESC), the ERC and the ESICM, states that the
minimum requirements for a cardiac arrest
centre are 24/7 availability of an on-site
coronary angiography laboratory, an emer-
gency department, an ICU, imaging facilities,
such as echocardiography, CT, and MRI.16
Based on evidence from a systematic review,
ILCOR suggests that wherever possible, adult
patients with non-traumatic OHCA cardiac
arrest should be cared for in cardiac arrest
centres.17
ACNS American Clinical Neurophysiology Society; CT computed tomography; ESC European Society of Cariology; EEG electroencephalogram; FPR false
positive rate; ILCOR International Liaison Committee on Resuscitation; IHCA in-hospital cardiac arrest; MAP mean arterial pressure; MRI magnetic resonance
imaging; NSE neuron specific enolase; OHCA out-of-hospital cardiac arrest; ROSC return of spontaneous circulation; SSEP somatosensory evoked potential;
TTM targeted temperature management; VF ventricular fibrillation.
224 RESUSCITATION 161 (2021) 220 269
Fig. 1 – Post-resuscitation care infographic summary.
Airway and breathing

Patients who remain comatose following ROSC, or who have
another clinical indication for sedation and mechanical ventilation,

Airway management after return of spontaneous circulation should have their trachea intubated if this has not been done
Airway and ventilation support should continue after return of already during CPR.
spontaneous circulation (ROSC) is achieved. Tracheal intubation should be performed only by experienced
Patients who have had a brief period of cardiac arrest and an operators who have a high success rate.
immediate return of normal cerebral function and are breathing Correct placement of the tracheal tube must be confirmed with
normally may not require tracheal intubation but should be given waveform capnography.
oxygen via a facemask if their arterial blood oxygen saturation is In the absence of personnel experienced in tracheal intubation,
less than 94%. it is reasonable to insert a supraglottic airway (SGA) or
RESUSCITATION 161 (2021) 220 269 225
Fig. 2 – Post resuscitation care algorithm.

SBP Systolic blood pressure; PCI Percutaneous coronary intervention; CTPA Computed tomography pulmonary angiogram; ICU Intensive care
unit; EEG electroencephalography; ICD implanted cardioverter defibrillator.
226 RESUSCITATION 161 (2021) 220 269
maintain the airway with basic techniques until skilled Consider mechanical circulatory support (such as intra-aortic
intubators are available. balloon pump, left-ventricular assist device or arterio-venous
extra corporal membrane oxygenation) for persisting cardio-
Control of oxygenation genic shock from left ventricular failure if treatment with fluid
After ROSC, use 100% (or maximum available) inspired oxygen resuscitation, inotropes, and vasoactive drugs is insufficient.
until the arterial oxygen saturation or the partial pressure of arterial Left-ventricular assist devices or arterio-venous extra corporal
oxygen can be measured reliably. membrane oxygenation should also be considered in haemo-
After ROSC, once SpO2 can be measured reliably or arterial blood dynamically unstable patients with acute coronary syndromes
gas values are obtained, titrate the inspired oxygen to achieve an (ACS) and recurrent ventricular tachycardia (VT) or ventricular
arterial oxygen saturation of 94 98% or arterial partial pressure of fibrillation (VF) despite optimal therapy.
oxygen (PaO2) of 10 13 kPa or 75 100 mmHg (Fig. 3).
Avoid hypoxaemia (PaO2 < 8 kPa or 60 mmHg) following ROSC. Disability (optimising neurological recovery)
Avoid hyperoxaemia following ROSC.
Control of seizures
Control of ventilation We recommend using electroencephalography (EEG) to diag-
Obtain an arterial blood gas and use end tidal CO2 in mechanically nose electrographic seizures in patients with clinical convulsions
ventilated patients. and to monitor treatment effects.
In patients requiring mechanical ventilation after ROSC, adjust To treat seizures after cardiac arrest, we suggest levetiracetam or
ventilation to target a normal arterial partial pressure of carbon sodium valproate as first-line antiepileptic drugs in addition to
dioxide (PaCO2) i.e. 4.5 6.0 kPa or 35 45 mmHg. sedative drugs.
In patients treated with targeted temperature management (TTM) We suggest that routine seizure prophylaxis is not used in post-
monitor PaCO2 frequently as hypocapnia may occur. cardiac arrest patients.
During TTM and lower temperatures use consistently either a
temperature or non-temperature corrected approach for measur- Temperature control
ing blood gas values. We recommend targeted temperature management (TTM)
Use a lung protective ventilation strategy aiming for a tidal volume for adults after either OHCA or in-hospital cardiac arrest
of 6 8 mL kg 1 ideal body weight. (IHCA) (with any initial rhythm) who remain unresponsive after
ROSC.
Circulation Maintain a target temperature at a constant value between 32 C
and 36 C for at least 24 h.
Coronary reperfusion Avoid fever (>37.7 C) for at least 72 h after ROSC in patients who
Emergent cardiac catheterisation laboratory evaluation (and remain in coma.
immediate PCI if required) should be performed in adult patients Do not use pre-hospital intravenous cold fluids to initiate
with ROSC after cardiac arrest of suspected cardiac origin with hypothermia.
ST-elevation on the ECG.
In patients with ROSC after out-of-hospital cardiac arrest (OHCA) General intensive care management
without ST-elevation on the ECG, emergent cardiac catheter-
isation laboratory evaluation should be considered if there is an Use short acting sedatives and opioids.
estimated high probability of acute coronary occlusion (e.g. Avoid using a neuromuscular blocking drug routinely in patients
patients with haemodynamic and/or electrical instability). undergoing TTM, but it may be considered in case of severe
shivering during TTM.
Haemodynamic monitoring and management Provide stress ulcer prophylaxis routinely in cardiac arrest
All patients should be monitored with an arterial line for continuous patients.
blood pressure measurements, and it is reasonable to monitor Provide deep venous thrombosis prophylaxis.
cardiac output in haemodynamically unstable patients. Target a blood glucose of 7.8 10 mmol L 1 (140 180 mg dL 1)
Perform early (as soon as possible) echocardiography in all using an infusion of insulin if required; avoid hypoglycaemia
patients to detect any underlying cardiac pathology and quantify (<4.0 mmol L 1 (<70 mg dL 1).
the degree of myocardial dysfunction. Start enteral feeding at low rates (trophic feeding) during TTM and
Avoid hypotension (<65 mmHg). Target mean arterial pressure increase after rewarming if indicated. If TTM of 36 C is used as the
(MAP) to achieve adequate urine output (>0.5 mL kg 1 h 1) and target temperature, gastric feeding rates may be increased early
normal or decreasing lactate (Fig. 3). during TTM.
During TTM at 33 C, bradycardia may be left untreated if blood We do not recommend using prophylactic antibiotics routinely.
pressure, lactate, ScvO2 or SvO2 is adequate. If not, consider
increasing the target temperature, but to no higher than 36 C. Prognostication
Maintain perfusion with fluids, noradrenaline and/or dobutamine,
depending on individual patient need for intravascular volume, General guidelines
vasoconstriction or inotropy. In patients who are comatose after resuscitation from cardiac
Do not give steroids routinely after cardiac arrest. arrest, neurological prognostication should be performed using
Avoid hypokalaemia, which is associated with ventricular clinical examination, electrophysiology, biomarkers, and imaging,
arrhythmias. to both inform patient's relatives and to help clinicians to target
RESUSCITATION 161 (2021) 220 269 227
Fig. 3 – Haemodynamic, oxygenation and ventilation targets.

treatments based on the patient's chances of achieving a Index tests for neurological prognostication are aimed at
neurologically meaningful recovery (Fig. 4). assessing the severity of hypoxic-ischaemic brain injury. The
No single predictor is 100% accurate. Therefore, a multimodal neurological prognosis is one of several aspects to consider in
neuroprognostication strategy is recommended. discussions around an individual's potential for recovery.
When predicting poor neurological outcome, a high
specificity and precision are desirable, to avoid falsely pessimistic Multimodal prognostication
predictions. Start the prognostication assessment with an accurate clinical
The clinical neurological examination is central to prognostication. examination, to be performed only after major confounders
To avoid falsely pessimistic predictions, clinicians should avoid (e.g. residual sedation, hypothermia) have been excluded
potential confounding from sedatives and other drugs that may (Fig. 5).
confound the results of the tests. In a comatose patient with M 3 at 72 h from ROSC, in the
When patients are treated with TTM, daily clinical examination is absence of confounders, poor outcome is likely when two or more
advocated but final prognostic assessment should be undertaken of the following predictors are present: no pupillary and corneal
only after rewarming. reflexes at 72 h, bilaterally absent N20 SSEP wave at 24 h,
Clinicians must be aware of the risk of a self-fulfilling prophecy highly malignant EEG at >24 h, neuron specific enolase (NSE)
bias, occurring when the results of an index test predicting poor >60 mg L 1 at 48 h and/or 72 h, status myoclonus 72 h, or a
outcome is used for treatment decisions, especially regarding life- diffuse and extensive anoxic injury on brain CT/MRI. Most of these
sustaining therapies. signs can be recorded before 72 h from ROSC, however their
228 RESUSCITATION 161 (2021) 220 269
Fig. 4 – Prognostication modes. EEG electroencephalography; NSE neuron specific enolase; SSEP somatosensory
evoked potential.
results will be evaluated only at the time of clinical prognostic The presence of unequivocal seizures on EEG during the first 72 h
assessment. after ROSC is an indicator of a poor prognosis.
Absence of background reactivity on EEG is an indicator of poor
Clinical examination prognosis after cardiac arrest.
Clinical examination is prone to interference from sedatives, Bilateral absence of somatosensory evoked cortical N20-
opioids or muscle relaxants. A potential confounding from residual potentials is an indicator of poor prognosis after cardiac arrest.
sedation should always be considered and excluded. Always consider the results of EEG and somatosensory evoked
A Glasgow Motor Score of 3 (abnormal flexion or worse in potentials (SSEP) in the context of clinical examination findings
response to pain) at 72 h or later after ROSC may identify patients and other tests. Always consider using a neuromuscular
in whom neurological prognostication may be needed. blocking drug when performing SSEP.
In patients who remain comatose at 72 h or later after ROSC the
following tests may predict a poor neurological outcome: Biomarkers
The bilateral absence of the standard pupillary light reflex. Use serial measurements of NSE in combination with other
Quantitative pupillometry methods to predict outcome after cardiac arrest. Increasing values
The bilateral absence of corneal reflex between 24 and 48 h or 72 h in combination with high values at 48
The presence of myoclonus within 96 h and, in particular, status and 72 h indicate a poor prognosis.
myoclonus within 72 h
We also suggest recording the EEG in the presence of myoclonic Imaging
jerks to enable detection of any associated epileptiform activity or Use brain imaging studies for predicting poor neurological
EEG signs, such as background reactivity or continuity, suggest- outcome after cardiac arrest in combination with other
ing a potential for neurological recovery. predictors, in centres where specific experience in these studies
is available.
Neurophysiology Use presence of generalised brain oedema, manifested by a
Perform an EEG in patients who are unconscious after the arrest. marked reduction of the grey matter/white matter ratio on brain CT,
Highly malignant EEG-patterns include suppressed background or extensive diffusion restriction on brain MRI to predict poor
with or without periodic discharges and burst-suppression. We neurological outcome after cardiac arrest.
suggest using these EEG-patterns after the end of TTM and after Always consider findings from imaging in combination with other
sedation has been cleared as indicators of a poor prognosis. methods for neurological prognostication.
RESUSCITATION 161 (2021) 220 269 229
Fig. 5 – Prognostication strategy algorithm.

EEG electroencephalography; NSE neuron specific enolase; SSEP somatosensory evoked potential; ROSC return of spontaneous circulation.
230 RESUSCITATION 161 (2021) 220 269
Fig. 6 – Recommendations for in-hospital functional assessments, follow-up and rehabilitation after cardiac arrest.
Withdrawal of life-sustaining therapy

1. Screening for cognitive problems.
Separate discussions around withdrawal of life-sustaining therapy 2. Screening for emotional problems and fatigue.
(WLST) and the assessment of prognosis for neurological 3. Providing information and support for survivors and family
recovery; WLST decisions should consider aspects other than members.
brain injury such as age, co-morbidity, general organ function and
the patients’ preferences. Organ donation
Allocate sufficient time for communication around the level-of-
treatment decision within the team and with the relatives. All decisions concerning organ donation must follow local legal
and ethical requirements.
Long-term outcome after cardiac arrest Organ donation should be considered in those who have achieved
ROSC and who fulfil neurological criteria for death (Fig. 7).
Perform functional assessments of physical and non-physical In comatose ventilated patients who do not fulfil neurological
impairments before discharge from the hospital to identify early criteria for death, if a decision to start end-of-life care and
rehabilitation needs and refer to rehabilitation if necessary (Fig. 6). withdrawal of life support is made, organ donation should be
Organise follow-up for all cardiac arrest survivors within 3 months considered for when circulatory arrest occurs.

after hospital discharge, including:
RESUSCITATION 161 (2021) 220 269 231
Fig. 7 – Organ donation after cardiac arrest algorithm.
Cardiac arrest centres deaths.23,26,27 Post-cardiac arrest hypoxic-ischaemic brain injury is

associated with hypotension, hypoxaemia, hyperoxaemia, pyrexia,
Adult patients with non-traumatic OHCA should be considered for hypoglycaemia, hyperglycaemia and seizures. Significant myocardial
transport to a cardiac arrest centre according to local protocol. dysfunction is common after cardiac arrest but typically starts to
recover by 2 3 days, although full recovery may take significantly
longer.28 33 The whole-body ischaemia/reperfusion of cardiac arrest,
Evidence informing the guidelines CPR and ROSC activates immune and coagulation pathways
contributing to multiple organ failure and increasing the risk of
Post-cardiac arrest syndrome infection.34 43 Thus, the post-cardiac arrest syndrome has many
features in common with sepsis, including intravascular volume
The post-cardiac arrest syndrome comprises post-cardiac arrest depletion, vasodilation, endothelial injury and abnormalities of the
hypoxic-ischaemic brain injury, post-cardiac arrest myocardial microcirculation.44 53
dysfunction, the systemic ischaemia/reperfusion response, and the
persistent precipitating pathology.18 21 The severity of this syndrome Diagnosis of cause of cardiac arrest
will vary with the duration and cause of cardiac arrest. It may not occur
at all if the cardiac arrest is brief. Among patients surviving to intensive These guidelines are informed by expert consensus.
care unit (ICU) admission but subsequently dying in-hospital, Cardiac causes of OHCA have been studied extensively in the last
withdrawal of treatment following prognostication of poor neurological few decades; conversely, little is known about non-cardiac causes.
outcome is the cause of death in approximately two-thirds after Early identification of a respiratory or neurological cause would enable
OHCA and approximately 25% after in-hospital cardiac arrest.22 26 transfer of the patient to a specialised ICU for optimal care. Improved
Cardiovascular failure accounts for most deaths in the first three days, knowledge of prognosis also enables discussion about the appropri-
while, in many countries, WLST based on a prognostication of severe ateness of specific therapies, including TTM. Several case series
hypoxic-ischaemic brain injury accounts for most of the later showed that this strategy enables diagnosis of non-cardiac causes of
232 RESUSCITATION 161 (2021) 220 269
arrest in a substantial proportion of patients.54,55 There is consider- oxygenation targets for varying durations immediately and up to
able regional variation in the incidence of sub-arachnoid haemorrhage 48 h after ROSC.74 79 A sub-group analysis of a large RCT targeting
as a cause of cardiac arrest among those with sustained ROSC at an arterial blood oxygen saturation of 90 97% compared with 90
hospital admission. Published case series report 16.2% in Japan,56 100% showed that in patients at risk of hypoxic-ischaemic brain
11.4% in Korea57 and 7% in France.58 In those with cardiac arrest injury 180-day mortality was lower in the lower oxygen target group74 ;
associated with trauma or haemorrhage a whole-body CT scan is however, this difference was no longer statistically significant when
likely indicated.9,59,60 adjusted for baseline differences.80 A pilot RCT targeting a PaO2 of
10 15 kPa compared with 20 25 kPa showed no difference in the
Airway and breathing values of biomarkers of neurological injury.75 Overall, the evidence is
mixed but suggests targeting normal oxygenation rather than
Airway management after return of spontaneous circulation hyperoxaemia. Observational data suggests avoiding hypoxaemia
These guidelines are informed by expert consensus. but there are no RCTs on this topic.
Patients can have their trachea intubated before, during or following In most post-cardiac arrest patients, controlled oxygenation will
cardiac arrest depending on the setting or particular circumstances.61 require tracheal intubation and mechanical ventilation for at least
Following most cardiac arrests tracheal intubation will occur during CPR 24 72 h. The exception being the completely conscious patient with a
or if the patient remains comatose after ROSC.62 patent airway who should be treated with an oxygen mask or non-
Tracheal intubation following ROSC in comatose patients will invasive ventilation targeting a peripheral oxygen saturation (SpO2) of
facilitate post-resuscitation care that includes controlled oxygen- 94 98%. During cardiac arrest, patients’ lungs are ventilated with the
ation and ventilation, protection of the lungs from aspiration of maximum feasible inspired oxygen, which is usually 100% during
stomach contents, control of seizures, and TTM see below for advanced resuscitation.9 After ROSC the goal should be to monitor
further details. oxygenation either with a pulse oximeter or preferably with an early
Post ROSC patients are haemodynamically unstable and, arterial blood gas sample. Oxygenation measured early after ROSC is
depending on their level of consciousness, may require drug assisted highly variable, varying from hypoxaemia to extreme hyperoxaemia.81
tracheal intubation. The same level of care should be provided as for Thus, it is appropriate to titrate the inspired oxygen by adjusting either
any other critically ill patient in terms of skills of the provider, the oxygen flow if using bag-mask ventilation or the fraction inspired
monitoring, and choice of drugs.63,64 There are no recommendations oxygen (FiO2) if using a mechanical ventilator.82 Prolonged use of
for a specific drug combination,65 but use of a low dose of a sedative, 100% inspired oxygen, for example during transport, will lead
an analgesic and a rapid onset neuromuscular blocking drug is commonly to extreme hyperoxaemia.83 Another method for monitor-
probably optimal. ing is using cerebral oxygen monitoring with near infrared spectros-
copy, but its role during post resuscitation care is uncertain.84,85
Control of oxygenation
These guidelines are informed by the ILCOR systematic review on Control of ventilation
oxygenation and ventilation targets after cardiac arrest, which These guidelines are informed by the same ILCOR systematic review
identified seven RCTs and 36 observational studies.66 and CoSTR.9 noted in the section on oxygenation.9,66 The ILCOR treatment
The ILCOR treatment recommendations in relation to oxygenation recommendations in relation to ventilation are:
are: There is insufficient evidence to suggest for or against targeting
We suggest the use of 100% inspired oxygen until the arterial mild hypercapnia compared with normocapnia in adults with
oxygen saturation or the partial pressure of arterial oxygen can be ROSC after cardiac arrest.
measured reliably in adults with ROSC after cardiac arrest in any We suggest against routinely targeting hypocapnia in adults with
setting (weak recommendation, very low-certainty evidence). ROSC after cardiac arrest. (weak recommendation, low-certainty
We recommend avoiding hypoxaemia in adults with ROSC after evidence).
cardiac arrest in any setting (strong recommendation, very low-
certainty evidence). After ROSC, blood carbon dioxide values (PaCO2) are commonly
We suggest avoiding hyperoxaemia in adults with ROSC after increased because of intra-arrest hypoventilation and poor tissue
cardiac arrest in any setting (weak recommendation, low-certainty perfusion,86 causing a mixed respiratory acidosis and metabolic
evidence). acidosis.87 Carbon dioxide is a well-known regulator of blood vessel
tone and cerebral blood flow.88 Increased PaCO2 (hypercapnia)
From a pathophysiological perspective, post cardiac arrest increases cerebral blood flow, cerebral blood volume and intracere-
patients are at risk of developing hypoxic-ischaemic brain injury bral pressure. Hypocapnia causes vasoconstriction that may
and accompanying organ dysfunction.9,21,67,68 The role of blood decrease blood flow and cause cerebral ischaemia.89
oxygen values in the disease process is poorly understood.69 Studies The main method for controlling PaCO2 in a mechanically
show that cerebral ischaemia in post cardiac arrest patients is ventilated patient is adjusting the minute volume by changing the
associated with poor outcome.70 Administering more oxygen can ventilation frequency and or tidal volume. In general, limiting the tidal
increase brain oxygenation.71 On the other hand, higher oxygen volume and using a lung protective ventilation strategy is the standard
values would logically cause an increase in harmful oxygen free of care, especially in patients with acute respiratory distress syndrome
radicals.72 It is also likely that the effect of oxygen values varies (ARDS).9,90,91 Acute respiratory distress syndrome is not uncommon
between different organs such as the heart and brain. in cardiac arrest patients and is associated with worse out-
Numerous experimental studies have assessed the impact of comes.9,92,93 Low lung compliance predicts poor functional outcome
hyperoxaemia on neurological injury with mixed findings.73 Six in OHCA patients94 ; however, ventilation with lower tidal volumes is
randomised controlled trials (RCTs) have compared different not standard practice in neurointensive care.95
RESUSCITATION 161 (2021) 220 269 233
Two pilot studies have compared different carbon dioxide targets recommend emergency cardiac catheterisation laboratory evaluation
during post resuscitation care.75,96 One study found targeting mild in comparison with cardiac catheterisation later in the hospital stay or no
hypercapnia (50 55 mmHg) compared with normocapnia (35 45 catheterization in select adult patients with ROSC after OHCA of
mmHg) resulted in lower neuron specific enolase (NSE) values, a suspected cardiac origin with ST elevation on ECG (strong recommen-
marker of the magnitude of neurological injury.96 Another pilot study dation, low-quality evidence). The 2017 European Society of
compared the lower and higher end of the range for normocapnia (33 Cardiology Guidelines for the management of acute myocardial
45 mmHg) for the first 36 h of post resuscitation care and found no infarction with ST-segment elevation state that ‘a primary PCI strategy
difference in markers of neurological injury.75 Both of these studies is recommended in patients with resuscitated cardiac arrest and an
showed that a higher PaCO2 was associated with higher cerebral ECG consistent with STEMI’.113
oxygenation measured with near infrared spectroscopy (NIRS), but the
clinical implications of this are uncertain.85 Several large observational [5_TD$IF]Percutaneous coronary intervention following ROSC without
studies have aimed to define the optimal CO2 during post-cardiac arrest ST-elevation
care.97 102 The results are mixed, with some studies indicating harm [6_TD$IF]In OHCA patients without ST segment elevation, several large
from both hypo- and hypercapnia and some suggesting better outcome observational series showed that absence of ST segment elevation
with mild hypercapnia. Recent UK observational data suggest a does not completely exclude the presence of a recent coronary
relationship between arterial oxygen and carbon dioxide. Data from the occlusion.114 Therefore, the decision for early CAG should be based
first 24 h of post resuscitation care observed a combination of hypoxia on meticulous patient assessment for the presence of haemodynamic
and hypocapnia was associated with a worse outcome and did not or electrical instability and ongoing myocardial ischaemia taking into
report harm from hyperoxia.103 Previous observational data from account multiple factors including previous medical history, warning
Finnish ICUs reported similar findings.97 symptoms before arrest, initial cardiac rhythm for CA,115 ECG pattern
Observational data suggest that patients undergoing TTM are prone post ROSC, and echocardiography, as well as comorbidities. When
to hypocapnia.104 This may be avoided by frequent measurement of an ischaemic cause is considered likely, a similar approach as for
carbon dioxide with arterial blood gas analysis and use of end tidal CO2 patients with STEMI should be followed. In patients with a low
monitoring. In patients undergoing TTM with lower temperature targets, probability of an ischaemic cause of cardiac arrest, delaying CAG for
PaCO2 management including measurement is particularly challeng- few hours or days may buy time for initial management in ICU,
ing.105 There is limited evidence to support a particular method for enabling early initiation of post-resuscitation care (haemodynamic
measuring PaCO2 during hypothermia, therefore the guidance to use optimisation, protective ventilation, TTM) and prognostication. This
either a temperature or non-temperature corrected approach for ‘wait and see’ management may also avoid performing CAG in
measuring blood gases is based on expert opinion.106 patients with the lowest probability of an acute coronary lesion. These
The recommendation for tidal volume is based on current guidance two strategies (early versus delayed CAG) were evaluated in patients
for lung protective ventilation in the ICU107 and limited observational with VF arrest and without shock in an RCT that showed no difference
data from post cardiac arrest patients.108 One observational study in 90-day survival, the primary outcome (odds ratio 0.89; 95%
suggests that using a tidal volume of 6 8 mL kg 1 to ventilate the confidence interval [CI], 0.62 to 1.27; P = 0.51),10 In this study, the
lungs of post-cardiac arrest patients may be associated with improved median time to target temperature was 5.4 h in the immediate
outcome.108 This study also showed that by using higher ventilation angiography group and 4.7 h in the delayed angiography group (ratio
frequency normocapnia may be achieved.108 of geometric means, 1.19; 95% CI, 1.04 to 1.36). Another recently
published pilot RCT comparing early with delayed CAG also showed
Circulation no difference in the primary outcome, which was a composite of
efficacy and safety measures.116 Further trials testing the same
Coronary reperfusion hypothesis are ongoing (DISCO NCT02309151, COUPe
NCT02641626, TOMAHAWK NCT02750462, EMERGE
Percutaneous coronary intervention following ROSC with NCT02876458). The 2020 European Society of Cardiology Guide-
ST-elevation lines for the management of acute coronary syndromes in patients
[4_TD$IF]Arrhythmia caused by myocardial ischaemia is the commonest cause of without persistent ST-segment elevation state that ‘delayed as
sudden cardiac death (SCD) in adults.109,110 Immediate reperfusion opposed to immediate angiography should be considered in
using percutaneous coronary intervention (PCI) of the culprit coronary haemodynamically stable patients without ST-segment elevation
lesion has been used for more than 20 years. This strategy is supported successfully resuscitated after an out-of-hospital cardiac arrest’.11
by many observational studies that reported a significant association Ideally, coronary interventions would be undertaken only in those
between early PCI with survival and favourable neurological outcome patients without permanent severe neurological injury. Patients with
after OHCA. Whilst the benefit of early PCI in OHCA caused by a recent irreversible hypoxic-ischaemic brain injury are unlikely to benefit from
coronary occlusion is universally acknowledged, the main challenge is PCI, even if a culprit coronary lesion is successfully treated.117
to identify the best candidates for coronary angiography (CAG) among However, the absence of a universally acceptable prognostic tool in
all resuscitated patients. In patients with ST segment elevation (STE) or the first hours after ROSC makes it impossible to identify such patients
left bundle branch block (LBBB) on the post-ROSC electrocardiogram with high sensitivity and specificity at the time of hospital admission.
(ECG) more than 80% will have an acute coronary lesion.111 A
systematic review completed for the 2015 ILCOR CoSTR identified [7_TD$IF]Haemodynamic monitoring and management
15 observational studies enrolling 3800 patients showing a mortality
benefit for emergent versus delayed or no cardiac catheterisation Haemodynamic monitoring
among patients with ROSC after cardiac arrest with evidence of STE on [8_TD$IF]Post-resuscitation myocardial dysfunction and low cardiac index may
their ECG.112 The treatment recommendation from 2015 was to occur in up to 60% of post-cardiac arrest patients30,118 and may be
234 RESUSCITATION 161 (2021) 220 269
even more common in patients with an acute myocardial infarction outcome, we do not have high certainty evidence to guide an optimal
(AMI) as the cause of the arrest.119 Early echocardiography can MAP target.
identify underlying cardiac pathology, quantify the degree of Mean arterial pressure (MAP) is one of the main determinants of
myocardial dysfunction and help guide haemodynamic management. cerebral blood flow (CBF).143 Although a high MAP is generally
Serial echocardiography or invasive monitoring with a pulmonary required in non-anoxic brain injured patients because of cerebral
artery catheter quantifies myocardial dysfunction and indicates swelling and increased intracranial pressure (ICP),144 few data on ICP
trends.28,29,120 Impaired cardiac function is most common during values are available in cardiac arrest survivors. In many post-cardiac
the first 24 48 h after which it gradually resolves.30,118 Whether low arrest patients, CBF autoregulation is impaired or the lower limit is
cardiac output (or index) is associated with poor outcome is currently right-shifted.133,145 This means that at lower MAP values, in some
unclear. A sub-study of the TTM trial showed that low cardiac index patients CBF may be MAP-dependent with an increased risk of
may not be associated with outcome if lactate clearance is cerebral hypoperfusion (i.e. hypotension) or hyperaemia and
maintained.121 These findings were independent of target tempera- intracranial hypertension (i.e. hypertension).
ture. Both non-invasive and invasive monitoring with echocardiogra- The use of cerebral oxygen saturation or ICP monitoring to
phy, arterial lines and measurement of cardiac output are commonly determine the presence of autoregulation and to determine an optimal
used in intensive care and it is reasonable to use these to guide MAP may enable a more individualised approach.146 In a retrospec-
treatment in cardiac arrest patients (best practice statement). tive study, the estimated optimal MAP (i.e. MAP target at which the
autoregulation is more effective) was 85 mmHg in post-cardiac arrest
[9_TD$IF]Haemodynamic management patients with preserved autoregulation and 100 mmHg when the
autoregulation was impaired.133 Another small observational study
[10_TD$IF]Mean arterial pressure and cerebral perfusion calculated a median optimal MAP of 89 mmHg in the same setting.147
[1_TD$IF]A systematic review completed for the 2015 ILCOR CoSTR searched However, there are no prospective studies evaluating whether an
for studies that compared titration of therapy to achieve a specific autoregulation-driven MAP target may influence neurological injury
haemodynamic goal with no haemodynamic goal.122 At that time, only and/or outcome. A more recent study has shown that after cardiac
observational studies were identified.123 127 That systematic review arrest, in particular in cases of non-cardiac origin, episodes of
also identified observational studies that compared a bundle of elevated ICP and/or brain hypoxia are frequent and a higher MAP is
therapies with a specific blood pressure target with no bundle.128 130 necessary to improve brain oxygenation.147 Preliminary evidence
The 2015 CoSTR treatment recommendations were: based on measurement of brain tissue oxygenation (PbtO2) has
We suggest haemodynamic goals (e.g., MAP, systolic blood shown that in resuscitated comatose patients impairment of oxygen
pressure) be considered during post-resuscitation care and as diffusion to the brain may cause persisting brain hypoxia despite
part of any bundle of post-resuscitation interventions (weak optimisation of oxygen delivery to the brain.148 The implementation
recommendation, low-quality evidence). and the safety of these invasive monitoring tools in cardiac arrest
There is insufficient evidence to recommend specific haemody- patients need to be further evaluated. While these are all
namic goals; such goals should be considered on an individual observational findings, they indicate optimal MAP targets may need
patient basis and are likely to be influenced by post-cardiac arrest to be individualised and support further research into identification of
status and pre-existing comorbidities (weak recommendation, optimal MAP targets for individual cardiac arrest survivors receiving
low-quality evidence). intensive care. In the post cardiac arrest patient, transcranial Doppler
(TCD) can give information about cerebral haemodynamics and, in the
An evidence update for this topic was included in the 2020 ILCOR future, may have a role in optimising haemodynamics in these
CoSTR and included two RCTs9,131,132 and 11 observational patients.149 Changes in cerebral blood flow can be seen using TCD
studies121,133 142 published since the 2015 systematic review.122 and this may be a target to for treatment.150 152 However, the
Two RCTs (including 232 patients) compared a blood pressure target technique and interpretations of the images is operator dependent and
of 65 75 mmHg to 80 100 mmHg with131 and without132 goal- requires an acoustic window in the patient. Moreover, cerebral
directed optimisation of cardiac function. These studies were not haemodynamics are continuously changing and serial measurements
powered for clinical outcomes but used surrogate markers of are possible only intermittently and the monitoring is labour-intensive.
neurological injury such as MRI131 and NSE.132 Whilst these studies Based on the evidence summarised by ILCOR9 we suggest avoiding
showed that higher MAP targets with vasopressors are safe, and do hypotension (MAP < 65 mmHg) and targeting MAP to achieve
not, for example, lead to cardiac arrhythmias, they failed to show any adequate urine output (>0.5 mL 1 kg h 1) and normal or decreasing
clear improvement in surrogate markers of brain injury with a higher lactate values (best practice statement).
MAP target.
Nine observational studies found hypotension was associated with [12_TD$IF]Heart rate
poor outcome.134 139,141,142 One study found time spent below Tachycardia was associated with poor outcome in one retrospective
optimal MAP (assessed by correlation between near-infrared study.153 During mild induced hypothermia the normal physiological
spectroscopy and blood pressure) was associated with poor response is bradycardia. In animal models this has been shown to
outcome;133 one study did not find low cardiac output to be associated reduce the diastolic dysfunction that is usually present early after
with poor outcome,121 while the last study documented better cardiac arrest.154 Bradycardia was previously considered to be a side
outcomes among patients given fluids compared with vasopressors effect, especially below a rate of 40 min 1; however, bradycardia has
to increase MAP.140 These observations are similar to the five been shown to be associated with a good outcome.155,156 Similar
observational studies included in the 2015 ILCOR Guidelines.122 association between bradycardia and improved long-term outcome
While hypotension (<65 mmHg) is consistently associated with poor has been shown in patients not treated with TTM.157
RESUSCITATION 161 (2021) 220 269 235
Sedation, controlled ventilation and a temperature between 32 arrest, and hydrocortisone in those with post-ROSC shock compared
36 C lowers oxygen consumption in cardiac arrest patients. with only adrenaline and placebo (18/130 [13.9%] versus 7/138
Although bradycardia generally reduces cardiac output, this is well [5.1%]; RR, 2.94; 95% CI, 1.16 6.50) 163 Only the third RCT confined
tolerated in this post-arrest setting. We suggest bradycardia (heart the use of steroids to the post-resuscitation phase; it did not show any
rate < 30 40 min 1) be left untreated as long as there are no signs of benefit for steroid post-ROSC but included only 50 patients.166
hypoperfusion (i.e. increasing lactate, reduced urinary output etc.) One trial has recently been completed but is not yet published
(best practice statement). (NCT02790788). ILCOR recommended a systematic review be
undertaken once the recently completed trial is published, and
[13_TD$IF]Fluid resuscitation, vasoactive and inotropic drugs therefore left the treatment recommendation unchanged from
[14_TD$IF]There is limited evidence to guide optimal fluid therapy for post- 2010:167
cardiac arrest patients. One study during which invasive monitoring There is insufficient evidence to support or refute the use of
and filling pressures were used observed that up to 5 7 L of fluid were corticosteroids for patients with ROSC following cardiac arrest.
given during the first 24 h.30 One retrospective study indicated that
with a treatment algorithm involving the pulse contour continuous Until there is higher-certainty evidence supportive of their use, we
cardiac output (PiCCO) system larger fluid volumes (range 4 5 L suggest that steroids are not given routinely to post-cardiac arrest
during the first 24 h) were associated with a lower incidence of acute patients (weak recommendation, low-certainty evidence).
kidney injury.158
There is little direct evidence comparing various vasoactive drugs [16_TD$IF]Potassium
for post-cardiac arrest patients, therefore this recommendation is Hyperkalaemia is common immediately after cardiac arrest. Subse-
based on indirect evidence from critically ill patients in general. The quent endogenous catecholamine release and correction of metabolic
most recent Cochrane review on vasopressors for hypotensive shock and respiratory acidosis promotes intracellular transportation of
included 28 RCTs (n = 3497 patients) and did not find any mortality potassium, causing hypokalaemia. Hyperkalaemia in the post-cardiac
benefit from any of the six vasopressors assessed. Acknowledging arrest period is associated with worse outcome.168 Hypokalaemia, on
noradrenaline as the most commonly used vasopressor, their the other hand may predispose to ventricular arrhythmias. Based on
suggestion was that major changes in clinical practice were not these observational studies we suggest that potassium be given to
needed.159 As noradrenaline is the most widely used vasoactive agent maintain the serum potassium concentration between 4.0 and
for post-cardiac arrest patients, we suggest using noradrenaline as 4.5 mmol L 1 (best practice statement).
the first-line vasoactive agent in hypotensive post-cardiac arrest
patients. A recent RCT comparing noradrenaline with adrenaline in [17_TD$IF]Mechanical circulatory support
57 patients with acute myocardial infarction and cardiogenic shock [18_TD$IF]If treatment with fluid resuscitation, inotropes and vasoactive drugs is
was terminated early because of significantly more refractory shock in insufficient to support the circulation, consider insertion of a
patients treated with adrenaline.160 The COMACARE and NEURO- mechanical circulatory assistance device (e.g. IMPELLA, Abiomed,
PROTECT pilot trials also used noradrenaline as the drug of choice to USA).126,169,170 One study indicated that 10 15% of patients with
achieve higher MAP targets.131,132 None of the studies showed any OHCA and ongoing cardiogenic shock eventually require mechanical
evidence of relevant tachycardia, arrhythmias or recurrent shock in circulatory support.171 In patients with cardiogenic shock without
the higher MAP group, despite the use of significantly higher doses of cardiac arrest some centres still advocate use of an intra-aortic
noradrenaline compared with the lower MAP group. This suggests balloon pump (IABP), although the IABP-SHOCK II Trial failed to show
that noradrenaline is well tolerated in post-cardiac arrest patients.131 that use of the IABP improved 30-day mortality in patients with
Post-resuscitation myocardial dysfunction often requires inotropic myocardial infarction and cardiogenic shock.172,173 One recent small
support. Based on experimental data, dobutamine is the most RCT found no difference in outcome in patients with acute myocardial
established treatment in this setting,161,162 but the systemic infarction and cardiogenic shock treated with an IMPELLA device
inflammatory response that occurs frequently in post-cardiac arrest compared with an IABP.174 Another retrospective study including only
patients also causes vasoplegia and severe vasodilation.30 The post-cardiac arrest patients found no difference in clinical outcome but
NEUROPROTECT trial used dobutamine to increase cardiac index in higher incidence of bleeding with the use of IMPELLA compared with
the higher MAP group. Although this did not decrease neurological IABP.169 Thus far, the evidence about which type of mechanical
injury it also did not increase myocardial injury.131 device is superior appears inconclusive and thus their use should be
decided on a case-by-case basis.
[15_TD$IF]Steroids The 2015 ESC Guidelines for the management of patients with
ILCOR performed an evidence update on use of steroids for post- ventricular arrhythmias and the prevention of sudden cardiac death
cardiac arrest patients for the 2020 guidelines.9 Three small RCTs and include the following recommendation for the use of mechanical
a large observational study have addressed the use of steroids in post- circulatory support: left-ventricular assist devices or arterio-venous
cardiac arrest patients.163 166 Two of the RCTs used steroids both extra corporal membrane oxygenation should also be considered in
during CPR for IHCA and after ROSC.163,164 The first of these RCTs haemodynamically unstable patients with acute coronary syndromes
showed improved survival to discharge with a combination of (ACS) and recurrent ventricular tachycardia (VT) or ventricular
methylprednisolone, vasopressin, and adrenaline during cardiac fibrillation (VF) despite optimal therapy.175
arrest and hydrocortisone after ROSC for those with shock, compared
with the use of only adrenaline and placebo (9/48 [19%] versus 2/52 [19_TD$IF]Implantable cardioverter defibrillators
[4%];RR, 4.87; 95% CI, 1.17 13.79).164 The second RCT showed An implantable cardioverter defibrillator (ICD) is a device used for
improved survival to discharge with favourable neurological outcome the treatment of certain life-threatening arrhythmias. The Europe-
with methylprednisolone, vasopressin, and adrenaline during cardiac an Society of Cardiology has published guidelines on the
236 RESUSCITATION 161 (2021) 220 269
indications for ICD therapy.175 An ICD may be implanted for that may or may not be defined as electrographic ‘seizures’ or, if
primary or secondary prevention. The former applies to those who prolonged as ‘status epilepticus’, and depend on the local EEG-
have not experienced a dangerous arrhythmia but who are interpreter.
considered at high risk of one. This group includes patients with Sedative drugs have potent seizure-suppressing effects and
cardiomyopathies, inherited primary arrhythmic syndromes, con- are recommended as third-line treatment of status epilepticus.
genital heart disease but also individuals with primary arrhythmias Propofol and benzodiazepines are used routinely during the first
in structurally normal hearts.176,177 Secondary prevention refers to days after cardiac arrest while the patient is mechanically
patients who have already survived a dangerous arrhythmic event ventilated and treated with TTM. Depending on the dosing, these
and are still considered at risk of further events. Careful selection drugs will suppress clinical myoclonus and epileptiform activity in
of patients is needed to identify those who may benefit from ICD the EEG.188,189 The seizures may be unmasked during sedation
implantation and whose lives can be prolonged by preventing holds. There is limited evidence that conventional antiepileptic
arrhythmic SCD. drugs (mainly valproate and levetiracetam) suppress epileptic
activity on the EEG of post cardiac arrest patients.190 These drugs
Disability (optimising neurological recovery) are known to supress myoclonus of other origins.191 Phenytoin
and the pro-drug fosphenytoin are still used widely for the
Control of seizures treatment of status epilepticus. In post-cardiac arrest patients
Seizures are reported in 20 30% of cardiac arrest patients in the however, their negative inotropic and vasodilating effects makes
ICU and are usually a sign of a severe hypoxic-ischaemic brain them less suitable.192 In a recently reported trial, valproate,
injury. Seizures may be observed as clinical convulsions (clinical levetiracetam and fosphenytoin were equally effective in terminat-
seizure) and/or as typical activity in the EEG (electrographic ing convulsive status epilepticus but fosphenytoin caused more
seizure). episodes of hypotension.12
Myoclonus are sudden, brief, shock-like involuntary muscle There is currently no evidence supporting prophylactic treat-
contractions and by far the most common type of clinical seizure in ment with antiepileptic drugs in the post-arrest setting. Previous
post-arrest patients.178,179 It is often generalised but may be focal studies on the effects of bolus-doses of thiopental193 and
(periodic eye-opening, swallowing, diaphragmic contractions etc.) or diazepam/magnesium194 after resuscitation showed no benefit in
multi-focal.180 It typically develops during the first 1 2 days after the terms of survival or neurologic function but these studies were
arrest and is often transient during the first days-week. It is associated designed to investigate neuroprotection, not seizure suppression.
with a poor prognosis but some patients survive with a good Whether treatment of detected clinical and electrographic seizures
outcome.181,182 Most post-hypoxic myoclonus has a cortical origin183 alters patient outcome has not previously been studied in a
and the EEG shows synchronous time-locked discharges or burst- randomised fashion but a multicentre trial of aggressive treatment
suppression in a substantial proportion of patients.181 of post-anoxic status epilepticus is currently ongoing.195 In case
Focal and generalised tonic-clonic seizures also occur after series, 4 44% of patients with post-anoxic status epilepticus had a
cardiac arrest, and it is not uncommon that an individual patient has good outcome.196 199 These patients were usually treated with
several seizure sub-types.178 multiple anti-epileptic drugs and had a delayed awakening, often
Lance-Adams syndrome is a less frequent form of myoclonus beyond two weeks.
usually developing in a patient who has regained conscious- The EEG is an important tool to detect corresponding electro-
ness.184,185 It is more common after hypoxic cardiac arrest and graphic seizure activity in a patient with observed clinical convulsions
mainly affects the limbs where it is induced by purposeful actions or and to monitor treatment effects. Shivering is a common seizure mimic
sensory stimulation. It may be disabling and often becomes during TTM. Active treatment of status epilepticus usually neces-
chronic.182 sitates repeated routine EEGs or continuous EEG-monitoring. The
Some of the evidence informing this guideline is set out in a relative benefit of continuous EEG compared with routine EEG has not
systematic review that informed the ILCOR 2015 CoSTR122 and been shown. Continuous EEG monitoring is labour intensive and likely
updated in 2020.9 The 2020 updated treatment recommendations are: to add significant cost to patient care. The net cost-effectiveness of this
We suggest against seizure prophylaxis in adult post-cardiac approach is controversial and may depend substantially on the
arrest survivors (weak recommendation, very low certainty setting.200,201
evidence). Since post-anoxic seizures and status epilepticus are manifes-
We suggest treatment of seizures in adult post-cardiac arrest tations of hypoxic-ischaemic brain injury, an assessment of the
survivors (weak recommendation, very low certainty evidence). prognosis and potential for an eventual good outcome are central
components of a treatment strategy. The EEG-background pattern is
Studies using continuous EEG-monitoring reveal that electro- important but may sometimes be difficult to assess if there are
graphic epileptiform activity and clinical convulsions are equally concomitant abundant discharges. A continuous, normal voltage and
common and that there is a substantial overlap.186 The evaluation reactive EEG background are benign features whereas a burst-
of electrographic seizures is often confounded by the concomitant suppression pattern or a suppressed background without reactivity
effects of brain injury, metabolic factors and sedation, making are features related to worse prognosis.181,199 Early onset (<24 h) of
possible clinical correlates and effects of treatment harder to electrographic seizures, before the recovery of a continuous
evaluate. New definitions of electrographic status epilepticus background is associated with worse prognosis.197,202,203 In these
have been published recently by the American Clinical Neuro- patients, the EEG is often affected by the ongoing treatment. It is
physiology Society (ACNS).187 The ACNS uses strict and therefore suggested that additional information is obtained on the
conservative criteria which are typically not fulfilled by post-arrest severity of brain injury from methods not significantly affected by
patients.186 Instead, most of these patients have EEG-patterns sedative and anti-epileptic drugs such as somatosensory evoked
RESUSCITATION 161 (2021) 220 269 237
potentials, serum NSE and neuroradiological investigations (prefera- reasonable definition of fever is therefore body temperature above
bly MRI). 37.7 C, as recently used in a large randomised cardiac arrest
Seizures may increase the cerebral metabolic rate and have the trial.14 However, this definition in critically ill patients usually relies
potential to exacerbate brain injury caused by cardiac arrest: treat on measurement of ‘core’ temperature (i.e. blood, bladder,
seizures with levetiracetam and/or sodium valproate. Consider oesophagus) and is only an estimation of brain temperature, which
possible drug interactions. After the first event, start maintenance could exceed it by 0.4 C to 2.0 C.209
therapy. Additional treatment options include perampanel, zonisa- Fever is common during the first 2 3 days after cardiac arrest and
mide or topiramate. Consider increased dose of propofol or is associated with worse outcomes in observational studies.210 Fever
benzodiazepines to suppress myoclonus and electrographic seiz- following TTM (i.e. induction of hypothermia at 32 36 C) is also
ures. Thiopental or phenobarbital may be considered in selected called rebound hyperthermia and is associated with worse outcomes,
patients. in particular with high temperatures.211,212 Whether fever contributes
Treatment with sedatives and conventional antiepileptic drugs in to poor neurological outcome or is just a marker of severe brain injury
high doses may delay awakening, prolong the need for mechanical remains unknown. To date, no randomised trial has compared
ventilation, and increase critical care length of stay.204 Consider that controlled normothermia (i.e. keeping target temperature below
generalised myoclonus in combination with epileptiform discharges 37.8 C) with no fever control.
may be early signs of Lance-Adams syndrome which is compatible
with awakening and a good outcome.181,184 In such cases, aggressive [21_TD$IF]Targeted temperature management
treatment may confound the clinical examination and lead to overly
pessimistic prognostication. [10_TD$IF]Cooling versus normothermia
[1_TD$IF]A meta-analysis shows that mild induced hypothermia is neuro-
Temperature control protective and improves outcomes in animal models of cardiac
A comprehensive systematic review of TTM was conducted for the arrest.213 The authors conclude that there may be translational gaps
2015 COSTR.122,205 207 Following an evidence review for the because research on large (gyrencephalic) and comorbid animals is
2020 CoSTR, these ILCOR treatment recommendations remained uncommon. The theoretical background that lowering core tempera-
unchanged from 2015.9 ture suppresses several detrimental pathways leading to neuronal
We recommend selecting and maintaining a constant target death is well established, but the specific mechanisms of hypothermic
temperature between 32 C and 36 C for those patients in whom neuroprotection remain unclear.214 Hypothermia decreases the
temperature control is used (strong recommendation, moderate- cerebral metabolic rate for oxygen (CMRO2) by about 6% for each
quality evidence). Whether certain subpopulations of cardiac 1 C reduction in core temperature and this reduces the release of
arrest patients may benefit from lower (32 34 C) or higher excitatory amino acids and the production of free radicals.215,216 In the
(36 C) temperatures remains unknown, and further research may temperature range of 33 C to 36 C, however, there is no difference in
help elucidate this. the inflammatory cytokine response in adult patients.217
We recommend targeted temperature management as opposed All studies evaluating post-cardiac arrest patients and mild
to no targeted temperature management for adults with OHCA induced hypothermia included only patients with altered conscious-
with an initial shockable rhythm who remain unresponsive after ness (i.e. Glasgow Coma Scale < 9). One randomised trial and a
ROSC (strong recommendation, low-quality evidence). quasi-randomised trial demonstrated improved neurological outcome
We suggest targeted temperature management as opposed to no at hospital discharge or at 6 months in comatose patients after out-of-
targeted temperature management for adults with OHCA with an hospital witnessed cardiac arrest with an initial shockable
initial non-shockable rhythm who remain unresponsive after rhythm.218,219 Cooling was initiated within minutes to hours after
ROSC (weak recommendation, very low-quality evidence). ROSC and a target temperature of 32 34 C was maintained for 12
We suggest targeted temperature management as opposed to no 24 h. These two trials represented the beginning of modern post-
targeted temperature management for adults with IHCA with any cardiac arrest care. More recently, a French multicentre trial
initial rhythm who remain unresponsive after ROSC (weak randomised 581 adult patients who were comatose after resuscitation
recommendation, very low-quality evidence). of either an IHCA or OHCA with an initial non-shockable rhythm (i.e.
We suggest that if TTM is used, duration should be at least 24 h asystole or pulseless electrical activity) to either TTM with a target
(weak recommendation, very-low-quality evidence). temperature of 33 C or a target temperature of 37 C, for 24 h.13 The
We recommend against routine use of prehospital cooling with use of TTM at 33 C led to a higher percentage of patients who
rapid infusion of large volumes of cold IV fluid immediately after survived with a favourable neurological outcome at day 90, assessed
ROSC (strong recommendation, moderate-quality evidence). as a cerebral performance category score (CPC) of 1 2, (10.2%
We suggest prevention and treatment of fever in persistently versus 5.7%, difference 4.5%; 95% CI 0.1 8.9; P = 0.04), while
comatose adults after completion of TTM between 32 C and 36 C mortality did not differ (81.3% versus 83.2%, difference 1.9; 95% CI
(weak recommendation, very-low-quality evidence). 8.0 4.3). The benefit of a lower target temperature was more
evident in patients with shorter time to ROSC (<15 min) and among in-
Treatment of fever hospital cardiac arrest patients. These results differ from a previous
[20_TD$IF]The definition of fever varies in different studies and no specific retrospective registry study of 1830 patients with non-shockable
evaluation of the cause (i.e. ischaemia-reperfusion, neurogenic OHCA where poor neurological outcome was more common among
fever, infection) is generally reported. A large observational study those receiving mild induced hypothermia (adjusted OR 1.44 [95% CI,
investigating serial measurements in more than 35,000 individuals 1.04 2.01].220 The ongoing targeted hypothermia versus targeted
concluded that mean body temperature measured in the oral cavity normothermia after OHCA (TTM2) trial will compare a target
was 36.6 C (99% ranges: 35.3 37.7 C) in healthy adults.208 A temperature of 33 C with strict normothermia (<37.8 C) during a
238 RESUSCITATION 161 (2021) 220 269
40-h intervention period in 1900 patients and will address the occurred after publication of the TTM-trial, with a rising average lowest
effectiveness of cooling procedures in cardiac arrest patients in temperature in the ICU and reduced use of TTM. Furthermore,
comparison with fever management.14 survival decreased, but was not statistically associated with a
decreased use of TTM.238 In this setting, the optimal temperature
[2_TD$IF]Timing to initiate hypothermia during mild induced hypothermia is therefore unknown and more high-
[23_TD$IF]Animal data suggest that TTM should be initiated as soon as quality large trials are needed.240
possible,221 although delays of several hours seem to be neuro-
protective in several species.213 Early cooling, i.e. initiated in the pre- [25_TD$IF]Duration of hypothermia
hospital field after ROSC, has been tested in some RCTs222,223; [20_TD$IF]The optimal duration for mild induced hypothermia and TTM is
although target temperature could be achieved faster than with unknown although the period of hypothermia is most commonly 24 h.
standard in-hospital cooling, no significant effect on patient outcomes Previous trials treated patients with 12 to 28 h of TTM.27,218,219 Two
was reported. Moreover, in one study pre-hospital use of cold fluids to observational trials found no difference in outcomes with 24 h
induce early hypothermia was associated with more re-arrests in the compared with 72 h of TTM.241,242 A recent randomised trial
field and more frequent pulmonary oedema on admission than the (n = 351) investigated TTM at 33 C during 48 h or 24 h in unconscious
control group.224 patients after OHCA.243 There was no significant difference in poor
Intra-arrest hypothermia (i.e. initiated during CPR) has been neurological outcome between groups (absolute difference 4.9%;
proposed as an effective method to provide TTM; however, use of cold relative risk (RR) for a cerebral performance category 1 2 at 6 months
fluids during CPR in a large RCT including OHCA patients showed no 1.08, 95% CI 0.93 1.25). Adverse events were more common in the
improvement in outcome from this strategy and even a decreased prolonged cooling group (RR 1.06, 95% CI 1.01 1.12).
ROSC rate in patients with an initial shockable rhythm.224 One small
feasibility trial225 and one RCT226 have tested the use of trans-nasal [26_TD$IF]Contraindications to targeted temperature management
evaporative cooling, which could induce rapid cooling in OHCA [ ithin the recommended TTM range of 32 36 C there are few, if any,
27_TD$IF]W
patients. Both trials reported no significant benefits on patient recognised contraindications. Results from a post hoc analysis of the
outcomes, although in the latter trial a post hoc analysis of the TTM-trial suggest that if there is severe cardiovascular impairment at
subgroup of patients with an initial shockable rhythm and in whom 33 C a higher temperature might be targeted.232
cooling was initiated < 20 min from collapse showed improved
neurological outcome at 90 days.226,227 [28_TD$IF]Other therapies to improve neurological outcome
In contrast to a number of positive results from studies in experimental
[24_TD$IF]Optimal target temperature during hypothermia settings,18 several neuroprotective drugs failed to demonstrate a
[20_TD$IF]The Targeted Temperature Management after Cardiac Arrest trial positive clinical effect.164,193,194,244 247 More recently, erythropoie-
(TTM-trial) randomised 950 OHCA patients with both initial shockable tin,248 cyclosporine,249 and exenatide,250 used alone, or as an adjunct
and non-shockable rhythms to a strategy including 36 h of tempera- to mild induced hypothermia, have also not been shown to increase
ture control (i.e. 28 h at target temperature followed by slow neurologically intact survival when included in the post arrest
rewarming) and fever control up to 72 h after randomisation; the treatment of cardiac arrest patients. The combination of xenon and
two target temperatures during the intervention phase were 33 C or mild induced hypothermia, which is beneficial and superior to mild
36 C.27 Strict protocols were followed for assessing prognosis and for induced hypothermia alone in experimental settings,18,251 has been
withdrawal of life-sustaining treatment (WLST). There was no studied in several trials with no convincing effects252 254 and is
difference in the primary outcome (i.e. all-cause mortality; hazard undergoing further clinical evaluation (XePOHCAS, EudraCT Number
ratio 1.06 [95% CI 0.89 1.28]) or in neurological outcome at 6 months 2017-00251432). Moreover, volatile anaesthetic drugs have demon-
(relative risk 1.02 [0.88 1.16]). Neurological outcome and cognitive strated positive effects on cardiac and cerebral recovery in
function were also similar,228,229 as were brain injury biomarker experimental settings,255 and clinical feasibility studies,256 258 but
values.230,231 TTM at 33 C was associated with decreased heart rate, outcome data are lacking. Most recently, it has been shown that pig
elevated lactate, the need for increased vasopressor support, and a brain cells can survive and show electrical activity for more than 4 6 h
higher extended cardiovascular SOFA score compared with TTM at after decapitation, when reperfusion of the brain was performed in
36 C.136,232 A small three-armed randomised trial compared 32 C highly artificial experimental settings.259 Very specific extracorporeal
with 33 C and 34 C and found no difference in good neurological life support concepts (i.e. controlled reperfusion of the whole body)
outcome, assessed as a modified Rankin Score (mRS) of 0 3 at day have also demonstrated good neurological survival following 15
90 (62.3% (95% CI 48.3 76.6) vs. 68.2% 95% CI 52.4 81.4) vs. 20 min of experimental cardiac arrest and in humans.260,261 These
65.1% (95% CI 49.0 79.0)).233 concepts are currently also undergoing further clinical evaluation.262
Since the publication of previous guidelines, many sites have
changed to a target temperature of 36 C in routine practice.234,235 General intensive care management
There have been reports that a change to 36 C has led to worse
temperature control and more early fever,236 but there are other There has been a recent systematic review and an ILCOR CoSTR on
reports showing good compliance with a 36 C-protocol and a possible the subject of prophylactic antibiotics.9,263 The ILCOR recommenda-
clinical advantage, such as earlier awakening and less sedative tion states:
use.237 Results from two large registry analyses, one from the cardiac We suggest against the use of prophylactic antibiotics in patients
arrest registry to enhance survival (CARES) surveillance group in the following ROSC (weak recommendation, low certainty of evidence).
US238 and one from the Australian and New Zealand Intensive Care
Society Centre for Outcome and Resource Evaluation (ANZICS- The remaining guidelines for the general ICU management of post-
CORE)239 indicate that a widespread change in TTM-use has cardiac arrest patients are based on expert opinion. Most aspects of
RESUSCITATION 161 (2021) 220 269 239
post cardiac arrest care follow general ICU practices. Some differences These appear more common in those treated with an invasive TTM
and nuances are inherent. Few aspects of general intensive care have device, likely related to catheter placement in the femoral vein.281 No
been studied separately in the cardiac arrest population, but cardiac specific evidence exists on DVT prophylaxis in cardiac arrest patients.
arrest patients have been included in trials on general intensive care Thus, treatment should be individualised and be based on general ICU
practices. Specific features of the post cardiac arrest patients include recommendations.277
the risk of brain injury and need to apply neurointensive care principles, Hyperglycaemia is common after OHCA.168 Hyperglycaemia is
the high occurrence of myocardial dysfunction, the use of anti- best managed with continuous infusion of insulin. The 2019 Guidelines
coagulants and anti-platelet drugs and the high risk of aspiration of the American Diabetes Association recommend a target glucose
pneumonitis among others. The typical length of stay in cardiac arrest range of 7.8 10.0 mmol L 1 (140 180 mg dL 1) for the majority of
patients will vary from three days to several weeks because of critically ill patients.282 Tight glucose control does not appear to
differences in time to awakening. This will influence certain aspects of convey benefit and may be associated with hypoglycaemia (<4.0
care such as the initiation of and management of nutrition. mmol L 1 (<70 mg dL 1),283 which is harmful in critically ill patients.284
Many post cardiac arrest patients will require appropriate sedation In general, glucose containing solutions are not recommended in
and pain management, particularly those who are treated with TTM. patients with brain injury,285 but they may be needed to treat
During TTM, shivering is common this can be managed with opioids hypoglycaemia.284
and sedation. TTM influences the metabolism of several drugs and
effects are in general prolonged. One RCT has compared the use of Prognostication
propofol and fentanyl with midazolam and fentanyl.264 In a trial of
59 patients, the use of propofol and remifentanil resulted in shorter About two-thirds of in-hospital deaths in patients who are admitted
time to awakening but was associated with more frequent need of to an intensive care unit in a coma following resuscitation from
noradrenaline.264 Similar findings have been shown in observational OHCA are caused by hypoxic-ischaemic brain injury.23,24 In a
studies.265 Sedation breaks are best initiated after TTM and minority of cases these deaths occur as a direct consequence of
rewarming has been completed. hypoxic-ischaemic brain injury which results in an irreversible loss of
Routine use of neuromuscular blocking drugs has been shown to all brain function, i.e., brain death.286 However, most of these
be beneficial in observational studies,266,267 but one small random- neurological deaths result from active withdrawal of life-sustaining
ised pilot trial failed to show any such benefit.268 In patients with ARDS treatment (WLST) in patients where the severity of hypoxic-
and critical hypoxaemia, a meta-analysis has shown beneficial effects ischaemic brain injury indicates that survival with a poor neurologi-
on outcome with the use of neuromuscular blockers.269 Thus, in cal outcome is very likely.26,287 Accurate prognostication is
patients with critical hypoxaemia and ARDS following cardiac arrest, therefore essential in order to avoid an inappropriate WLST in
the use of a neuromuscular blocker may be considered, given the patients who still have a chance of a neurologically meaningful
evidence for their use in ARDS. Patients should be nursed 30 head- recovery and to avoid futile treatment in patients with a severe and
up. This may decrease intracranial pressure (ICP) and decrease the irreversible neurological injury.
risk of aspiration pneumonia. Many patients are at high risk of
developing aspiration and ventilator-associated pneumonia.270 A Outcome measures in neuroprognostication studies
recent RCT examined the prophylactic use of antibiotics in OHCA Neurological outcome after cardiac arrest is most commonly reported
patients.271 Whilst the study showed a decrease in ventilator using Cerebral Performance Categories (CPC).288 The CPC is
associated pneumonia it did not find any other differences in other expressed as a five-point scale: CPC 1 (no or minimal neurological
clinical outcomes; therefore, prophylactic antibiotics are not recom- disability); CPC 2 (minor neurological disability); CPC 3 (severe
mended. However, antibiotics can be considered in cases with clear neurological disability); CPC 4 (persistent vegetative state); and CPC
suspicious infiltrates on the chest X-rays. 5 (death). Another commonly used outcome measure is the modified
Patients require a nasogastric tube to decompress any abdominal Rankin Score (mRS),289 which includes 7 scores, from 0 (no
distension. One small observational study has indicated that low-dose symptoms) to 6 (dead). In 2018, a statement from ILCOR290
enteral feeding is tolerated during TTM after OHCA.272 Gastric feeding suggested using mRS rather than CPC for measuring functional
may be initiated at low rates (trophic feeding) during TTM and increased recovery after cardiac arrest, because mRS is more suitable than CPC
after rewarming if indicated. If TTM of 36 C is used as the target for discriminating between mild and moderate disability291,292 and has
temperature, gastric feeding rates may be increased early during TTM. a substantial interrater reliability.293 However, most studies on
Routine use of ulcer prophylaxis in intensive care patients does not neurological prognosis after cardiac arrest still use CPC.
decrease mortality.273,274 However, a recent meta-analysis showed For both clarity and statistical purposes in studies on neuro-
that in high-risk patients, the use of ulcer prophylaxis decreased prognostication after cardiac arrest the outcome is dichotomised as
gastrointestinal bleeding.275 Post-cardiac arrest patients are likely to ‘good’ or ‘poor’. However, there is no universal consensus on what
be at higher risk than general ICU patients given the use of represents a poor neurological outcome. Up to 2006, most
anticoagulant and antiplatelet agents both pre and post arrest.276 neuroprognostication studies reported CPC 4 or 5 (vegetative state
Therefore, it appears reasonable to administer stress ulcer prophy- or death) as a poor outcome, and CPC from 1 to 3 (from absent to
laxis in post-cardiac arrest patients, especially in those with severe neurological disability) as a good outcome, while after that
coagulopathy.35 date an increasing number of studies included CPC 3 (severe
Unless patients receive anticoagulation because of a myocardial neurological disability) among poor neurological outcomes.294 In a
infarction or ischaemia, deep venous thrombosis prophylaxis is recent systematic review,15 among 94 total studies on neurological
recommended in critically ill patients.277,278 The use of antiplatelet prognostication after cardiac arrest, 90 (96%) defined poor
drugs do not prevent DVTs.279 Out-of-hospital cardiac arrest patients neurological outcome as CPC 3 5 and only four defined poor
are at risk for developing DVTs especially if treated with TTM.280 outcome as CPC 4 5.
240 RESUSCITATION 161 (2021) 220 269
In prognostic accuracy studies, a predictor (index test) is assessed This has been described in some studies conducted in countries or
for its ability to predict an outcome. This design is like that of diagnostic communities where treatment limitations are not accepted due to
accuracy studies. However, while in diagnostic accuracy studies the cultural, legal or religious reasons.300,301
index test is evaluated against another test which represents the Other strategies to reduce the risk of falsely pessimistic predictions
reference standard, or gold standard, prognostic accuracy studies include avoiding confounding from treatments (e.g., sedatives or other
evaluate the index test against the occurrence of the predicted event drugs) affecting the results of some predictors, such as clinical
(target condition) after test recording.295 When test results are examination or EEG; avoiding basing decisions on life-sustaining
expressed in binary format (i.e., positive vs. negative) the accuracy is treatments on the results of a single index test, but rather using a
expressed using sensitivity and specificity, which measure the ability multimodal approach (Fig. 5); and always interpreting the results of the
of the test to identify those who will develop or not develop the target index tests within the clinical context.
condition, respectively. Since most neuroprognostic tests predict poor A specific source of bias in neuroprognostic studies after cardiac
neurological outcome, having a high specificity (i.e., a very low rate of arrest is the presence of a time lag between the recording of the index
falsely pessimistic predictions potentially leading to an inappropriate test, which is usually done very early after the arrest, and the
WLST) is desirable. Ideally, an index test should be 100% specific, i.e., assessment of the target condition, i.e., neurological outcome. Since
its false positive rate (FPR) should be zero, but this is difficult to recovery from hypoxic-ischaemic brain injury following cardiac arrest
achieve in practice. There is no universal consensus on how specific requires time, the minimum recommended timing for its assessment is
an index test should be for neuroprognostication after cardiac arrest. 30 days or later from the event or neurological discharge.290 However,
In a recent survey of 640 healthcare providers, the majority (56%) felt further neurological recovery can occur later. Consequently, an early
an acceptable FPR for WLST from patients who might otherwise have prediction of outcome which is confirmed by CPC or mRS measured at
recovered was 0.1%.296 Along with the absolute value of specificity, hospital discharge may occasionally prove false when the outcome is
precision of its estimate is important. A very specific test predicting reassessed later.302 For that reason, guidelines suggest reassessing
poor outcome is of little clinical use when its precision is low, (i.e., when neurological outcome at three or six months after the event.295 The
the confidence intervals [CIs] around the point estimate of its majority of studies included in the systematic review informing the
specificity are wide), because this indicates a high degree of present guidelines reports neurological outcome at least six months
uncertainty around the estimated specificity. In the 2014 ERC-ESICM after cardiac arrest.15
Advisory Statement on neuroprognostication after cardiac arrest,297 Another bias which is partly related to the time delay between index
the most robust predictors were identified as those in which the upper test assessment and outcome is the interference from extracerebral
boundary of the 95% CI of the FPR was below 5%. causes of death after cardiac arrest. These include cardiovascular
For some neuroprognostic tests used after cardiac arrest, such as instability, which is the second most common cause of in-hospital
the blood values of biomarkers of neurological injury or the grey matter death after cardiac arrest,23 and multiple organ failure due to global
to white matter density ratio on brain CT, the results are expressed as ischaemia-reperfusion injury.303,304 Although the incidence of these
a continuous variable. In this case, sensitivity and specificity will complications is maximal early after arrest, death from extracerebral
depend on the value of the variable that is chosen as a threshold to organ failure may occur after neurological recovery.305 The preva-
separate positive from negative test results, and the values of lence of death after awakening was 16% in ICU in a single-centre
sensitivity and specificity that are obtained by varying the positivity study,306 and 4.2% during hospital stay in a recent multicentre
threshold across all its possible values are expressed by a receiver European study including 4646 patients.307 In that study, death
operating characteristic (ROC) curve. The problem with dichotomising occurred at a median time of 9 (3 18) days after awakening, and it
continuous predictive variables to obtain a binary test result is that was more common after IHCA than after OHCA.
finding a consistent threshold for 100% specificity is difficult. Very high
values of test results can be caused by outliers, which cause distortion Clinical examination
and reduce test sensitivity. These guidelines are supported by evidence derived from a
systematic review on prognostication and 2020 ILCOR CoSTRs.9,15
Main sources of bias in neuroprognostication The relevant treatment recommendations in the 2020 ILCOR CoSTR
One of the major biases in neuroprognostication after cardiac arrest is are:
self-fulfilling prophecy. This occurs when the treating team is aware of We suggest using pupillary light reflex at 72 h or later after ROSC
the result of the prognostic test and uses it for decisions that affect for predicting neurological outcome of adults who are comatose
patient's outcome, e.g., WLST. This leads to an overestimation of the after cardiac arrest (weak recommendation, very-low-certainty
test performance, and - potentially - to an inappropriate WLST. In a evidence).
systematic review on neuroprognostication after cardiac arrest We suggest using quantitative pupillometry at 72 h or later after
published in 2013,298,299 64/73 (88%) studies were at risk of self- ROSC for predicting neurological outcome of adults who are
fulfilling prophecy bias. comatose after cardiac arrest (weak recommendation, low-
Ideally, to avoid self-fulfilling prophecy bias, the index tests should certainty evidence).
be investigated blindly. However, this is difficult to achieve in practice. We suggest using bilateral absence of corneal reflex at 72 h or
Concealing results of clinical examination from the treating team is later after ROSC for predicting poor neurological outcome in adults
almost impossible, while concealing results of EEG or brain imaging who are comatose after cardiac arrest (weak recommendation,
would be unethical, since they may reveal the presence of potentially very low-certainty evidence).
treatable complications (e.g., seizures or intracranial hypertension, We suggest using presence of myoclonus or status myoclonus
respectively). Nevertheless, some predictors such as biomarkers within 96 h after ROSC, in combination with other tests, for
have been evaluated blindly.230 A special condition limiting the risk of predicting poor neurological outcome in adults who are comatose
self-fulfilling prophecy bias is the absence of an active WLST policy. after cardiac arrest (weak recommendation, very low-certainty
RESUSCITATION 161 (2021) 220 269 241
evidence). We also suggest recording EEG in presence of [30_TD$IF]Myoclonus and status myoclonus
myoclonic jerks in order to characterise the phenotype of the [31_TD$IF]Myoclonus consists of sudden, brief, involuntary jerks caused by
myoclonus. muscular contractions or inhibitions. Their distribution can be focal,
multifocal, or generalised.314 Presence of myoclonus within 96 h
Ocular reflexes. Ocular reflexes currently used for neurological from ROSC in patients who are comatose after cardiac arrest is
prognostication after cardiac arrest include pupillary reflex and associated with poor neurological outcome in most cases.15
corneal reflex. The pupillary light reflex (PLR) comprises a However, a false positive rate of up to 22% has been described.315
temporary reduction of pupil size induced by a light stimulus. Most prognostication studies did not provide a definition or
Standard PLR (s-PLR) is evaluated visually and elicited generally description of myoclonus. In some patients with favourable
using a penlight. In recent years, a quantitative evaluation of PLR outcome, myoclonus may persist after recovery of consciousness
using portable pupillometers has become available in the ICU. A in a chronic form of action myoclonus (i.e., triggered by spontaneous
bilaterally absent s-PLR has low specificity for predicting poor movements) known as Lance-Adams syndrome.182,316
outcome in the first hours after ROSC, but its accuracy Clinical myoclonus can inconsistently be associated with electrical
progressively increases, and it achieves 100% specificity after seizures, therefore recording an EEG can be useful. Some studies
96 h from ROSC with 20 25% sensitivity.15 This is presumably have identified specific EEG features associated with benign
due to the process of brain recovery after anoxic-ischaemic injury, myoclonus, such as a reactive179,184 and/or continuous EEG
but it may be due partly to interference from sedatives used in the background.179,181 The presence of diffuse and continuous myoclonic
early post-resuscitation phase to maintain TTM. Standard PLR is jerks is usually described as status myoclonus. However, a consensus
inexpensive and easy to use, but it is subjective and prone to definition of status myoclonus is lacking. The 2014 ERC-ESICM
interrater variability.308 Advisory Statement on neurologic prognostication after cardiac arrest
Quantitative evaluation of PLR (automated pupillometry) provides suggested that in comatose survivors of cardiac arrest status
an objective and quantifiable measurement of the pupillary response. myoclonus should be defined as a continuous and generalised
The most common pupillometry measures are the percentage myoclonus persisting for 30 min or more.297 Evidence from two
reduction of pupillary size, generally indicated as qPLR309 and the studies that did not distinguish electrographic features of status
neurological pupil index (NPi).310 NPi is calculated from several myoclonus15 showed that status myoclonus within 24 h317 or within
dynamic parameters of the pupillary response (including constriction seven days from ROSC178,317 is almost invariably associated with
and dilation velocity, size, and percentage size reduction after poor neurological outcome (specificity 99 100%).
stimulation) using a proprietary algorithm. A NPi value 3 is considered The advantages of predictors based on clinical examination include
normal. Limited evidence showed that, unlike s-PLR, NPi can predict minimal equipment and costs (except pupillometry) and availability at
unfavourable outcome with no false positive results from 24 h or less to the bedside. Their major limitations include interference from sedatives,
72 h from ROSC.15 In one study this was because of the ability of opioids, and except for the PLR from muscle relaxants. In addition,
pupillometer to detect a response even when the pupil size was very their assessment is prone to subjectivity. Use of automated assess-
small, presumably from sedation.310 Results of pupillometry are ment, like pupillometry for PLR, may at least address these limitations.
expressed as a continuous measure, and threshold for 100% specificity Finally, results of clinical examination cannot be concealed from the
varied among studies. In three studies included in a recent review this treating team, potentially causing a self-fulfilling prophecy bias.
threshold for NPi was <2.4 before 24 h and 2.0 at 24 72 h.15 Another
limitation of automated pupillometry is its additional cost. [32_TD$IF]Neurophysiology
The corneal reflex (CR) is elicited by touching the outer margin These guidelines are supported by evidence derived from a
(limbus) of the cornea with a cotton wisp. Alternatively, in order to systematic review on prognostication and 2020 ILCOR CoSTRs.9,15
minimise the risk of corneal abrasion, an air or water squirt can be The relevant treatment recommendations in the 2020 ILCOR CoSTR
used.311 The corresponding response is represented by an eye blink. are:
In patients who are comatose after cardiac arrest, an absent CR We recommend that neuroprognostication always be undertaken
predicts poor neurological outcome after 72 h from ROSC with 100% using a multi-modal approach because no single test has sufficient
specificity and 25- 40% sensitivity.15 Like PLR, CR is prone to specificity to eliminate false positives (strong recommendation,
interference from sedation. In addition, it may be affected by muscle very-low-certainty evidence).
relaxants. A recent survey showed that the modalities with which CR is We suggest using a bilaterally absent N20 wave of somatosensory
assessed in comatose patients are inconsistent.312 evoked potential (SSEP) at 24 h from ROSC in combination with
other indices to predict poor outcome in adult patients who are
Motor response comatose after cardiac arrest (weak recommendation, very low-
[29_TD$IF]An absent or extensor motor response to pain (motor component [M] certainty evidence).
1 or 2 of the Glasgow Coma Score) is associated with poor We suggest against using the absence of EEG background
neurological outcome after cardiac arrest.15 However, its specificity reactivity alone to predict poor outcome in adult patients who are
is low, almost never achieving 100%, even when it is assessed after comatose after cardiac arrest (weak recommendation, very low-
96 h from ROSC. Like CR, motor response is based on striate muscle certainty evidence).
contraction and, as such, it can be affected by muscle relaxants. We suggest using the presence of seizure activity on EEG in
Because of its high sensitivity (>60% at 72 h or later from ROSC) a combination with other indices to predict poor outcome in adult
M = 1 2 can be used as a criterion for identifying patients needing patients who are comatose after cardiac arrest (weak recommen-
prognostication after cardiac arrest. However, recent evidence dation, very low-certainty evidence).
showed that using M 3 as an entry point increases the sensitivity We suggest using burst-suppression on EEG at 24 h from ROSC
for prediction of poor outcome without reducing specificity.313 in combination with other indices to predict poor outcome in adult
242 RESUSCITATION 161 (2021) 220 269
patients who are comatose and who are off sedation after cardiac [37_TD$IF]Reactivity
arrest (weak recommendation, very low-certainty evidence). EEG-reactivity is a measurable change in amplitude or frequency
upon external stimulation (auditory and pain). There is no generally
Electroencephalography (EEG) acknowledged standard for reactivity testing and the prognostic
[3_TD$IF]Electroencephalography (EEG) is one of the most widely used and performance of this feature varied substantially between studies.15,339
studied methods to assess brain function and prognosis after Absence of EEG-reactivity during the first 24 h after cardiac arrest is
cardiac arrest.318 EEG is also important for diagnosing and treating an indicator of a poor outcome with high sensitivity but low
seizures. specificity (41.7 87.5%).336,340 342 After 24 h, the sensitivity of
The main aspects when assessing EEG are the background absent reactivity remains high but the specificity varied from 50 to
activity, superimposed discharges and reactivity. The EEG back- 100%.326,328,334,336,341 345 Interrater agreement for the assessment
ground continuity is most important for the prognosis and is commonly of EEG-reactivity varied from slight-almost perfect.328,346 Stimulus-
categorised as continuous, discontinuous, burst suppression (50 evoked rhythmic, periodic or ictal discharges (SIRPIDS) are not a
99% suppression periods) or suppression (>99% activity <10 mV manifestation of normal background reactivity their prognostic
amplitude).319 A standardised terminology for critical care EEG has significance is still undefined.203,347
been proposed by the ACNS.187
Immediately after a cardiac arrest, the EEG is suppressed in many [38_TD$IF]Superimposed patterns
patients, but it returns to a continuous normal voltage EEG within the
first 24 h in most patients who ultimately achieve a good out- [39_TD$IF]Periodic discharges
come.320,321 The time for this restitution is correlated with A ‘periodic’ pattern is a waveform that occurs repeatedly, with a
outcome.319,322 The EEG-background is often discontinuous and of quantifiable interval between discharges. If no such interval exists,
low frequency on its first appearance.320,323 Sedative drugs affect the pattern is termed ‘rhythmic’.187 Periodic discharges (PDs) may
background continuity and have the potential to induce discontinuous be superimposed on various backgrounds and are related to a
or burst-suppression background in a dose-dependent manner.324,325 worse prognosis. Generalised periodic discharges (GPDs) are a
sign of a poor prognosis with limited specificity.326,327,330,334 In
[34_TD$IF]Background patterns general, the background on which PDs appear is more related to the
neurological outcome.319 PDs on a continuous and reactive EEG-
Suppression background should not be considered as an indicator of a poor
A suppressed (<10 mV) or low-voltage (<20 mV) background is outcome.181
relatively common during the first day after a cardiac arrest in patients
who later recover.300,320,321 However, 24 h after ROSC, a suppressed [40_TD$IF]Sporadic epileptiform discharges
EEG-background <10 mV is a reliable sign of a poor prognosis,326 331 [41_TD$IF]‘Sporadic epileptiform discharges’ describes sharp waves or spikes
although two false positive predictions by this pattern 48 72 h after resembling those seen in patients with epilepsy, but without the
cardiac arrest were reported in one study.328 There was moderate regularity of a periodic pattern. The frequency by which they appear
interrater agreement for suppressed background among senior may vary extensively from ‘rare’ (<1 h 1) to ‘abundant’ (1/10 s),
neurophysiologists.328,332 bordering on periodic discharges. While their appearance is related to
a worse outcome, their specificity to predict poor outcome ranges from
[35_TD$IF]Burst suppression 66.7 to 100%15 and reports on the potentially important frequency or
According to the ACNS-terminology, burst suppression (BS) is number of discharges was lacking in studies.300,328,330,331 Presence
defined as 50 99% of the recording consisting of suppression of sporadic epileptiform discharges is NOT a reliable indicator of a
alternating with bursts. The terminology does not have any poor neurological prognosis.
amplitude criteria for the bursts but these may be defined further
as ‘highly epileptiform bursts’, based on appearance 187 ‘Presence [42_TD$IF]Electrographic seizures and electrographic status epilepticus
of ‘identical bursts’ (either the first 0.5 s of each burst or each [20_TD$IF]The ACNS defines ‘unequivocal seizures’ as generalised rhythmic
stereotyped cluster of 2 bursts appears visually similar in >90% spike-and-wave discharges with a frequency 3 Hz or clearly evolving
of bursts in each channel) portend a poor prognosis in post-anoxic discharges of any type >4 Hz.187 This definition was inconsistently
coma.333 One research group also proposed a separation of BS- used in studies. Seizures had a low sensitivity but high specificity for a
patterns into ‘synchronous’ (with highly epileptiform or identical poor outcome regardless of timing.326,328,330,334,348
bursts) and ‘heterogenous’ (not ‘synchronous’).331 The criteria The term ‘electrographic status epilepticus’ (ESE) is defined as an
used for burst amplitude and appearance varies considerably electrographic seizure for 10 continuous minutes or for a total
between studies. A substantial portion of patients with BS during duration of 20% of any 60-min period of recording. This definition has
the first 24 h and occasional patients with BS-pattern after 24 h still been included for the first time in the 2021 update of the ACNS
have a good outcome, which is possibly related to sedation terminology and none of the currently available prognostic studies has
use.302,320,326 328,334 336 There was substantial interrater agree- incorporated it yet. Some studies based their definition of ESE on the
ment among experienced neurophysiologists for BS.328 ACNS classification of unequivocal seizures extending 30 min but
also included epileptiform discharges 1 Hz,197,322 and in one study
[36_TD$IF]Discontinuous 0.5 Hz as ESE.349 Other studies had an unclear definition of
A discontinuous background with suppression periods >10% of ESE.302,334,335,341 The proportion of patients classified with ESE
the recording has low prognostic performance during the first varied considerably between studies, possibly reflecting differences in
24 h after cardiac arrest337,338 and an inconsistent performance definitions. One study showed that ESE evolves from high frequency
after 24 h.326 328,338 discharges early after onset to progressively slower frequencies
RESUSCITATION 161 (2021) 220 269 243
during the following days and weeks.186 Regardless of the We recommend that neuroprognostication always be undertaken
classification used, ESE is associated with a worse prognosis after using a multi-modal approach because no single test has sufficient
cardiac arrest, but some patients have a good outcome.196,197,199 As specificity to eliminate false positives (strong recommendation,
with periodic discharges, it is important to consider if the EEG- very-low-certainty evidence).
background is continuous and reactivity is present, which are both We suggest using neuron specific enolase (NSE) within 72 h after
favourable features.197,199 Because of the lack of a standardised ROSC, in combination with other tests, for predicting neurological
classification, we recommend avoiding the term ‘status epilepticus’ for outcome of adults who are comatose after cardiac arrest (weak
assessments of prognosis but instead to classify the EEG-background recommendation, very-low-certainty evidence). There is no
and superimposed discharges and unequivocal seizures according to consensus on a threshold value.
the standardised ACNS terminology.187 We suggest against using S-100B protein for predicting
neurological outcome of adults who are comatose after cardiac
[43_TD$IF]Categories of patterns arrest (weak recommendation, low-certainty evidence).
[6_TD$IF]In several studies, the most unfavourable patterns were grouped as We suggest against using serum levels of glial fibrillary acidic
‘malignant’ or ‘highly malignant’. The most common grouping included protein (GFAP), serum tau protein, or neurofilament light chain
suppressed background with or without periodic discharges and burst- (Nfl) for predicting poor neurological outcome of adults who are
suppression as ‘highly malignant patterns’.326 There was substantial comatose after cardiac arrest (weak recommendation, very low-
interrater agreement for these ‘highly malignant patterns’,346 and the certainty evidence).
specificity for poor outcome was 90.6 100%.326,327,329,336,338,340,350
An alternative categorisation of ‘unfavourable patterns’ using a stricter Protein biomarkers that are released following injury to neurons and
definition of burst-suppression has been suggested.331 glial cells may be measured in blood and are likely to correlate with the
extent of brain injury and with neurological outcome. Neuron-specific
[4_TD$IF]Quantitative EEG-indices biomarkers include NSE, Nfl and tau protein, while S100B and GFAP
[45_TD$IF]Automated assessment of quantitative EEG-features such as the burst- originate from astrocytes. Neuron specific enolase has been recom-
suppression amplitude ratio and reactivity has been tested in individual mended for assessment of brain injury and to help prognosticate
studies.351,352 Combinations of quantitative EEG-features include the outcome after cardiac arrest since the last revision in 2015.2 Their actual
Bi-spectral index (BIS) and the Cerebral Recovery Index.353 The use in clinical practice, however, is not known. Several reports on novel
threshold value and specificity for BIS to predict poor outcome varied biomarker candidates have been published since 2015.231,370 372
widely between studies.354 356 Automated assessments may decrease Importantly, a multimodal approach should be used for assess-
subjectivity in EEG assessments. Prospective multi-centre studies are ment of comatose survivors after cardiac arrest. Advantages of
needed to assess the prognostic performance after cardiac arrest. biomarkers include quantitative results, the relative ease of sampling
and interpretation and their independence from the effects of
[46_TD$IF]Evoked potentials sedatives. Limitations include availability, lack of robust laboratory
references, insufficiently large study populations, and lack of external
Somatosensory evoked potentials (SSEPs) validation for some. Most of the available evidence is limited to a time
When performing SSEPs the median nerve is electrically stimulated and span of up to 72 h after cardiac arrest which is relevant for most
the ascending signals are recorded from the peripheral plexus brachialis, patients. However, it necessitates a strategy for prospective sampling
cervical level, subcortical level and the sensory cortex (N20-potential). before the assessment of prognosis >72 h post-arrest. Very limited
SSEPs may be depressed by barbiturate coma but are preserved with evidence supports the use of biomarkers after 72 h in patients who fail
other sedative drugs such as propofol and midazolam.357 A bilateral to awaken. Large studies investigating and validating promising novel
absence of the short-latency N20-potentials over the sensory cortex is a biomarkers are needed to confirm their predictive value, to assess
reliable sign of a poor prognosis after cardiac arrest with high specificity their reproducibility, and to identify consistent thresholds for a
and limited sensitivity both early and late after cardiac ar- specificity that should be close to 100%. The rationale for accepting
rest.201,202,302,310,331,335,337,338,340,342,343,350,352,358 366 Occasional false a specificity of less than 100% would be that using blood biomarkers,
positive predictions were reported.367 The interrater reliability for there will always be outliers that must be taken into consideration, e.g.
interpretation of SSEPs was moderate to good.368,369 The quality of due to poor calibration or issues with laboratory standards,
the recording is very important and noise from muscle activity is an haemolysis or due to poor technique in handling of samples.
important limiting factor which may be eliminated by neuromuscular Demanding 100% specificity from a blood biomarker will lower the
blocking drugs.357,368 sensitivity to levels where their clinical use can be questioned, while
allowing an FPR of 1% or 2% will increase their clinical relevance. With
[48_TD$IF]Visual evoked potentials (VEP) and auditory evoked potentials a multimodal approach, every prognostic method used for assess-
(AEP) ment of an individual patient must point in the same direction in order to
[14_TD$IF]There are few data supporting the use of visual evoked potentials be trusted. This may be particularly true for biomarkers because of
(VEPs)358 and auditory evoked potentials (AEPs)361,364 to prognosti- their continuous nature; normal or mildly elevated levels (at correct
cate outcome after cardiac arrest. These results need validation sampling time) should always alert the clinician of potential error in
before VEPs or AEPs can be recommended in this context. other methods indicating poor prognosis.
[49_TD$IF]Biomarkers Neuron-specific enolase (NSE)

These guidelines are supported by evidence derived from a systematic [50_TD$IF]Neuron specific enolase has been studied extensively; since the last
review on prognostication and 2020 ILCOR CoSTRs.9,15 The relevant systematic reviews,298,299 at least 13 observational studies have been
treatment recommendations in the 2020 ILCOR CoSTR are: published with threshold values ranging from 33 120 mg L 1 within 72 h
244 RESUSCITATION 161 (2021) 220 269
predicting poor neurological outcome from hospital discharge to 6 months with 100% specificity and a sensitivity of 4% to 42% (very low certainty
with specificity ranging from 75 100% and sensitivity ranging from 7.8% of evidence).371 An ultra-sensitive single molecule assay (SIMoA) was
to 83.6%. In the largest study to date, outliers were described.373 Patients used, with a detection limit at the single molecular level.383
with high NSE (>90 mg L 1) and good outcome had confounders for NSE
elevation and most patients with low NSE (<17 mg L 1) who died had a [54_TD$IF]Serum neurofilament light chain (Nfl)
cause of death other than hypoxic/ischaemic encephalopathy. The study [6_TD$IF]In one large study, serum Nfl with a threshold value ranging from 1539
was excluded from the recent systematic review because the primary to 12,317 pg mL 1 at 24 72 h predicted poor neurological outcome
outcome was CPC at ICU discharge.15 A large substudy of the TTM-trial (CPC 3 5) at 6 months with 100% specificity and sensitivity ranging
identified a threshold of 48 mg L 1 at 48 h and a threshold of 38 mg L 1 at from 53.1% to 65% (moderate certainty of evidence).231 The same
72 h with a specificity of 98% (FPR 2%) for poor neurological outcome at 6 ultra-sensitive SIMoA technique was used for detection of Nfl as was
months.230 In another study, NSE with a threshold of 50.2 mg L 1 at day used for tau protein (see above). In a post hoc analysis of the
4 predicted poor neurological outcome at one month with 100% specificity COMACARE trial, which used the same SIMoA technique for analysis,
and 42.1% sensitivity.374 thresholds for serum Nfl that achieved 99% specificity for a poor
NSE decreases after 24 h in patients with good outcome and typically outcome were 127, 262, and 344 pg mL 1 at 24 h, 48 h and 72 h
increases in patients with a poor outcome to peak at 48 96 h. NSE respectively; sensitivities ranged from 78% to 85%.384 In another
performs poorly at 24 h and best at 48 or 72 h. High NSE at 48 or 72 h after study that did not use the SIMoA technique, serum Nfl with a threshold
cardiac arrest is a robust predictor of a poor outcome.230,365,373 378 value ranging from 252 to 405 pg mL 1 from day 1 to day 7 predicted
Increasing NSE from 24 48 or 48 72 h is a reliable indicator of a poor poor neurological outcome (CPC 4 5) at 6 months with 100%
prognosis with similar performance as the absolute value.379 One small specificity and sensitivity ranging from 55.6% to 94.4%.372
study found that a 48:24 h NSE ratio 1.7 had a 100% specificity for poor
outcome.375 In a recent study, the prognostic performance of NSE was [5_TD$IF]Imaging
clearly dependent on age and severity of the insult (time to ROSC).380 It These guidelines are supported by evidence derived from a
performed best in the youngest quartile and in patients with longer time to systematic review on prognostication and 2020 ILCOR CoSTRs.9,15
ROSC. Several different analytical assays were used in the included The relevant treatment recommendations in the 2020 ILCOR CoSTR
studies but the methodology for routine clinical use provided by Roche are:
and Brahms were most frequent. NSE has been used as a surrogate We suggest using brain imaging studies for prognostication only in
marker for brain injury in two recent trials.75,96 centres where specific experience is available (weak recommen-
Thresholds for high NSE values must be established in dation, very-low-quality evidence).
collaboration with the local laboratory considering the analytical We suggest using the presence of a marked reduction of the grey
method. Red blood cells contain NSE so haemolysis (free haemo- matter/white matter (GM/WM) ratio on brain CT within 72 h after
globin) must be measured and samples discarded if the haemolysis ROSC or the presence of extensive diffusion restriction on brain
index threshold is exceeded because this may generate a falsely high MRI at 2 to 7 days after ROSC in combination with other predictors
NSE value.381 The half-life of free haemoglobin is approximately 2 for prognosticating a poor neurologic outcome in patients who are
4 h compared with the 30-h half-life of NSE. Thus, the NSE value comatose after cardiac arrest and who are treated with TTM (weak
may be inappropriately increased (by NSE from red blood cells) at a recommendation, very-low-quality evidence).
time when free haemoglobin is no longer detectable, which is a
concern when using NSE for prognostication after cardiac arrest.381 Computed tomography (CT) of the brain
[56_TD$IF]Following cardiac arrest, hypoxic-ischaemic brain injury causes
[51_TD$IF]S100B cytotoxic oedema, which appears as an attenuation of the GM/WM
Three observational studies have been published since interface, and vasogenic oedema leading to brain swelling, visible as
2013,376,377,382 two of them investigated S100B immediately after an effacement of cortical sulci.385 Measurement of the ratio between
ROSC and identified threshold values ranging from 3.56 to 16.6 with the GM and the WM densities (GWR), expressed in Hounsfield units is
100% specificity of poor outcome but with low sensitivities of 2.8% to a method to quantify the degree of oedema. The density of the GM is
26.9%. In the largest study, S100B discriminated best at 24 h with a higher than that of the WM, so that GWR is normally higher than 1. The
threshold value of 2.59 mg L 1 for 100% specificity but with a low lower the GWR, the greater the severity of brain oedema.
sensitivity of 10%, the corresponding sensitivity for 98% specificity GWR reduction occurs early in patients with severe hypoxic-
(2% FPR) was 32% (threshold value 0.36 mg L 1).382 The authors ischaemic brain injury. In a recent systematic review most studies on
concluded that S100B did not add any real value to present reduced GWR showed that this sign was 100% specific for poor
prognostication models with or without NSE. S100B is also very neurological outcome as early as 1 h after ROSC.15 However, in
rarely used in clinical practice and for these reasons is not included in other studies,301,386 388 a reduced GWR was 100% specific for poor
our recommendations. neurological outcome up to 72 h after ROSC. The methods for GWR
measurement varied across studies. In most of them, GWR was
[52_TD$IF]Glial fibrillary acidic protein (GFAP) calculated between GM and WM areas within the basal ganglia. In
[6_TD$IF]In one observational study with 100 patients, GFAP with a threshold others, measurements within the cerebrum (centrum semiovale and
value of 0.08 mg L 1 at 48 h 12 h predicted poor neurological high convexity area) were performed.389 391 In almost all studies, a
outcome at one month with 100% specificity and 21.3% sensitivity.370 GWR threshold for 100% specificity was identified. However, its
value varied across studies. For instance, the threshold for 100%
[53_TD$IF]Serum Tau specificity of the average GWR measured at the basal ganglia and
In one study, serum tau protein with a threshold value ranging from the cerebrum ranged from 1.1 and 1.23 within 2 h from ROSC.15
72.7 to 875.6 ng L 1 predicted poor neurological outcome at 6 months GWR sensitivity also varied widely across studies, probably
RESUSCITATION 161 (2021) 220 269 245
reflecting differences between scanners and software,392 in the Among the remaining 330 patients in whom no major predictor or
methods of calculation, or in the aetiology of the arrest.390,393 In one combination of predictors suggesting poor outcome were detected,
substudy of the TTM trial, oedema on brain CT was assessed two thirds had good neurological outcome at three months. Finally, in a
visually without formal GWR measurement.394 In that study, retrospective multicentre cohort of 585 patients from the TTM trial, the
specificity for poor neurological outcome was 98.4 [94.3 99.6]% ERC-ESICM algorithm had 0% (95% CI 0 1.2%) FPR for predicting
with 33.6 [28.1 39.5]% sensitivity. Most studies on brain CT were poor neurological outcome at six months.313
single centre with retrospective design. The 2015 ERC-ESICM prognostication algorithm was based on a
combination of predictors including results of clinical examination
[57_TD$IF]Magnetic resonance imaging (MRI) of the brain (absent or extensor motor response, absent pupillary and corneal
[58_TD$IF]Along with CT, magnetic resonance imaging (MRI) of the brain is the reflexes, status myoclonus), biomarkers (high blood values of NSE),
most investigated imaging-based predictive index in patients who are electrophysiology (unreactive burst-suppression or status epilepticus
comatose after cardiac arrest.15 Brain MRI is more challenging to on EEG, bilaterally absent N20 SSEP wave) and imaging (signs of
perform in ventilated ICU-patients and MRI was generally performed diffuse anoxic brain injury on CT or MRI). The evidence supporting
later than brain CT, usually at 48 h or later from ROSC. On brain MRI, these predictors had been assessed in two reviews published in
cytotoxic oedema from hypoxic-ischaemic brain injury appears as a 2013.298,299 To facilitate an update for the present guidelines, a new
hyperintensity on diffusion-weighted imaging (DWI) sequences.395 In review has been conducted and its results are reported in the previous
several studies, presence of DWI lesions is associated with poor paragraphs of the present guidelines focusing on individual
neurological outcome after cardiac arrest.389,396 399 However, the prognostication modalities.15 The 2020 review largely confirmed
assessment was done qualitatively, and specificity was inconsistent the results of the 2013 reviews and the reliability of the predictors
(range 55.7 100%). Apparent diffusion coefficient (ADC) enables a suggested in the 2015 algorithm. However, some important differ-
semiquantitative assessment of DWI changes, therefore limiting ences were noted:
subjectivity. However, the ADC metrics in prognostication studies Absent pupillary and corneal reflexes achieved 0% FPR
varied.15 These include lowest minimum or mean ADC,400 mean consistently only after day 4, rather than after day 3 as in the
ADC,401 the proportion of brain volume below a given ADC previous review.
threshold,401,402 and the maximum size of the MRI clusters with Automated measurement of absent pupillary reflex using
minimum ADC.400 Most of these studies assessed global ADC, while pupillometry may enable a more accurate prediction than standard
one of them assessed regional ADC.400 In all these studies, an ADC (manual) assessment of pupillary reflex (s-PLR), and it is more
threshold for 100% specificity was identified, often with sensitivities reproducible.
above 50%. All studies on ADC MRI had a small sample size, which The accuracy of NSE was higher at 48 72 h than at 24 h from
limited their precision. In many studies, imaging was performed at the ROSC.
discretion of the treating physician, which may have introduced a The low FPR of unreactive EEG background documented in a few
selection bias. of the studies on TTM-treated patients in the 2013 review was not
Unlike clinical examination and EEG, imaging studies are not confirmed in the 2020 review.
prone to interference from sedative drugs. In addition, they can be No consistent definition was found for status epilepticus, a
assessed blindly. Their major limitation is the lack of standardisation predictor suggested in the 2015 guidelines.
of measurement techniques. Despite the available studies showed a Presence of a suppressed EEG background or burst-suppression
high accuracy both for brain CT and MRI, the number of studies was predicted poor outcome with very low FPR, especially when
limited with a wide variability in the adopted measurement recorded after 24 72 h from ROSC; in the previous reviews,
techniques which greatly limits the reproducibility of their results. evidence supporting suppression was negligible, and definitions
For this reason, it is reasonable to reserve the use of imaging of burst-suppression were heterogeneous.
studies for prognostication only in centres where specific experi- Several prognostication studies classified EEG according to the
ence is available. Since there is currently no standard for CT-GWR Standardised Critical Care EEG Terminology (2012 version) of the
or MR-ADC measurements these techniques can be recommended American Clinical Neurophysiology Society (ACNS).404
to confirm the presence of generalised and extensive ischaemic
injury apparent from conventional visual analysis by an experienced The risk of bias for most of the available studies was high. As in
neuroradiologist. Finally, imaging studies cannot be performed at previous reviews, a major limitation in most studies was lack of
the bedside and MRI may not be feasible in the most unstable blinding; furthermore, several predictors of poor neurological outcome
patients, which limits its applicability especially in the early post- were used as criteria for WLST. In both cases, this may have resulted
resuscitation period. in a self-fulfilling prophecy. However, the 2020 review included studies
where no WLST was performed, therefore limiting the risk of self-
[32_TD$IF]Multimodal prognostication fulfilling prophecy.300,358,387,393,398 Predictors assessed in these
In 2015, the ERC-ESICM Guidelines on Post-Resuscitation Care studies included EEG, SSEPs, and brain CT. Based on results of
included an algorithm for the prediction of poor neurological outcome the 2020 review, most of the recommendations included in the
in patients who are comatose after cardiac arrest.1 This algorithm has 2015 prognostication algorithm remain valid.
been validated in recent retrospective studies. One study in 226
patients showed that the 2015 ERC-ESICM prognostication guide- Suggested prognostication strategy
lines had a 0% FPR for predicting poor outcome (CPC from 3 to 5) both Prognostic assessment should start with an accurate clinical
at hospital discharge and at six months.302 Similarly, in a larger single- examination.405 Its main scope is to confirm that the patient is
centre cohort including 485 comatose resuscitated patients the ERC- comatose because of hypoxic-ischaemic brain injury. Clinical
ESICM algorithm predicted CPC 3 5 with 0% FPR in 155 patients.403 examination should be performed daily to detect signs of neurological
246 RESUSCITATION 161 (2021) 220 269
recovery such as purposeful movements or to identify a clinical picture indeterminate in another validation study, the majority had low and
suggesting impending brain death. The latter may include fixed, decreasing NSE values and all but one had ventricular fibrillation on
dilated pupils, diabetes insipidus, and cardiovascular changes the initial ECG.313 Other potentially useful indices of good neurological
suggesting herniation, such as bradycardia associated with hyper- outcome include absence of diffusion changes on brain MRI and low
tension or an otherwise unexplained haemodynamic instability. Brain blood values of neurofilament light chain within 72 h from
death occurs in 5 10% of patients who die after cardiac arrest ROSC.231,389,397,398 Recent evidence showed that a benign EEG is
resuscitated with conventional CPR and in about 25% of patients who not associated with the presence of other predictors of poor
die after resuscitation with extracorporeal CPR.286 In most cases, neurological outcome, especially a bilaterally absent N20 SSEP
brain death occurs during the first 3 4 days after ROSC. A suggested wave.408 410 Therefore, when predictors suggesting a potential for
algorithm for brain death screening after cardiac arrest is shown in recovery coexist with others suggesting a poor outcome, there is a
Fig. 7. The World Brain Death Project (WBDP) consensus group has chance that the latter signal is a false positive. We suggest that in this
published detailed guidance on the determination of brain death after case the results of predictive indices are reassessed, and index tests
treatment with targeted temperature management (TTM).406 be repeated if possible.
In most patients, awakening from coma following cardiac arrest In a comatose patient with M 3 at 72 h from ROSC, in absence
occurs within 3 4 days from ROSC.202,305 However, patients who are of confounders, poor outcome is likely when two or more of the
initially unconscious following cardiac arrest are usually treated with following predictors are present: no pupillary and corneal reflexes at
sedatives and neuromuscular blocking drugs to enable targeted 72 h, bilaterally absent N20 SSEP wave at 24 h, highly malignant
temperature management (TTM), and to facilitate mechanical EEG at >24 h, NSE >60 mg/L at 48 h and/or 72 h, status myoclonus
ventilation and other life support measures. Therefore, to enable a 72 h, or a diffuse and extensive anoxic injury on brain CT/MRI. Most
reliable clinical examination, these drugs should be stopped for of these signs can be recorded before 72 h from ROSC, however their
sufficient time to avoid interference from their effects. The WBDP results will be evaluated only at the time of clinical prognostic
consensus group recommends that clinical examination be delayed assessment. A recent study has shown that a strategy of using
until at least 5 elimination half-lives of the drug administered with the 2 predictors had 0 [0 8]% FPR compared with 7 [1 18]% of the
longest half-life.406 Although this recommendation has been made in 2015 ERC-ESICM stepwise strategy (due to false positives for
the context of diagnosing brain death, it is equally relevant to pupillary light reflexes).411
prognostic assessment if this is being used to make a WLST decision. Evidence from both the 2013 and the 2020 reviews showed that a
Short-acting drugs are preferred whenever possible but even a short- bilaterally absent N20 SSEP wave is the most widely documented
acting drug such as propofol has a half-life of 2.3 4.7 h, which implies predictor of poor outcome and the one most consistently associated
the need to stop sedatives for at least 24 h in most cases. This will be with 100% specificity. However, false positive predictions have
much longer if there is renal and/or hepatic impairment or if longer- occasionally been reported. In some of these cases, the cause of a
acting drugs have been given. When residual sedation or paralysis is false positive result was an incorrect reading of the SSEP record
suspected, consider using antidotes to reverse the effects of these because of artefacts.412 Neuromuscular blockade improves readabil-
drugs. Use caution when administering flumazenil to reverse the effect ity of SSEPs and it should be considered whenever possible.413
of benzodiazepines because this may precipitate seizures. Apart from Pupillary light reflex and corneal reflex are also very specific for poor
sedation and neuromuscular blockade, other major confounders outcome when bilaterally absent at 72 h or more after ROSC. Based on
include hypothermia, severe hypotension, sepsis, and metabolic or expert opinion, we suggest that both reflexes should be absent at the
respiratory derangements. time of prognostic assessment for them to reliably predict poor
A poor motor response has a relatively low specificity, but a high outcome. Unlike SSEPs, ocular reflexes are prone to interference from
sensitivity for prediction of poor neurological outcome after cardiac sedation. Corneal reflexes may also be affected by neuromuscular
arrest. Therefore, it can be used to identify patients needing blocking drugs. These confounders should be excluded before ocular
prognostication. An absent or extensor motor response (M 2) of reflexes are assessed. Visual evaluation of PLR may be hampered
the Glasgow Coma Scale was the entry point of the 2015 prognosti- when the pupil size is less than 6 mm.308 Limited evidence shows that in
cation algorithm. However, recent evidence showed that using resuscitated comatose patients automated pupillometry is more
M 3 as an entry point increases the sensitivity for prediction of sensitive than s-PLR in detecting pupil response to light when pupil
poor outcome without reducing specificity.313,407 The prognostication size is small, which reduces the risk of false positive results.310 Unlike s-
strategy described below applies to patients who are comatose with a PLR, automated pupillometry delivers a stimulating light source with
motor response (M) equal to or below 3 (abnormal flexion, extension, standard characteristics (intensity, duration, and distance from the eye)
or nil) at 72 h after ROSC. Results of earlier prognostic tests are also and measures pupillary response quantitatively, which ensures
considered at this time. reproducibility. For this reason, we suggest detecting the absence of
Signs suggesting the potential for recovery should be actively PLR with a pupillometer, if available.
sought. These are often identified early in the clinical course after Status myoclonus is a prolonged period of myoclonic jerks.
resuscitation. In a study on 357 comatose survivors of cardiac arrest, a Although there is no universal definition for status myoclonus, based
benign EEG (continuous, reactive, non-suppressed background on our previous definition1 we suggest that, in comatose survivors of
without epileptiform discharges) recorded within 24 h from ROSC cardiac arrest, status myoclonus should be defined as a continuous
predicted good neurological outcome with 76 [69 82]% sensitivity and generalised myoclonus persisting for 30 min or more. In the
and 88 [82 92]% specificity.338 In 250 patients with indeterminate 2020 review informing the present guidelines, status myoclonus was
outcome on day 3 according to the 2015 ERC-ESICM prognostication documented in two studies, one of which used a definition comparable
algorithm presence of a benign EEG was associated with good to that given above. In total, among 113 patients showing this sign,
neurological outcome in 184 cases (positive predictive value 74%).403 there was only one false positive result. Aside from duration and
Among 14 patients who recovered after their outcome was defined as continuity, other clinical features of myoclonus suggest poor outcome.
RESUSCITATION 161 (2021) 220 269 247
These include a generalised (vs. focal), axial (vs. distal), or WM) interface due to cytotoxic oedema. In the review informing these
stereotyped (vs. variable) distribution. Conversely, some EEG guidelines, the first sign was evaluated qualitatively in one study,394
features, such as a continuous or reactive background or presence based on visual inspection from a neuroradiologist, while most studies
of spike-wave discharges synchronised with the myoclonic jerks assessed the reduced GM/WM interface as the ratio of the densities of
indicate a potential for good outcome.181 We suggest recording an the grey matter and the white matter (GWR) measured in Hounsfield
EEG in patients with post-arrest status myoclonus, in order both to units. This was generally done within 2 h from ROSC, but some studies
identify an associated epileptiform activity and to detect signs assessed GWR within 24 h,301,386 and one within 72 h.388 As for other
associated with potential recovery. predictors based on continuous variables, the GWR thresholds for 0%
Among unfavourable EEG patterns, those more consistently FPR varied across studies, presumably because of variations in the
associated with poor neurological outcome are suppression and burst methods for GWR calculation, or in the software or scanner’
suppression. According to the ACNS, a suppressed EEG background characteristics.15
is defined as >99% of activity having a voltage less than 10 mV, while Hypoxic-ischaemic brain injury reduces water diffusivity, which
burst-suppression is defined as 50 99% of the record consisting of appears on magnetic resonance imaging (MRI) as a hyperintensity on
suppression, alternated with bursts. In the 2013 reviews, definitions of diffusion weighted imaging (DWI) with corresponding low apparent
these patterns were inconsistent. We suggest using the ACNS diffusion coefficient (ADC) values. In severe hypoxic-ischaemic brain
terminology when assessing these patterns for prognostication, in injury, hyperintensity on DWI involves the cerebral cortex extensively
order to ensure an unequivocal identification.187 During the first 12 and the basal ganglia. Measurement of ADC enables a quantitative
24 h after ROSC, both these patterns have a greater prevalence, assessment of the severity of diffusion changes. In studies on
but also a higher risk of false positive prediction. Confounding from prognostication after cardiac arrest, three methods for ADC
sedatives used to facilitate TTM may contribute to this. We suggest measurement were described: the mean global or regional ADC
using these EEG patterns for prognostication only after 24 h from value of the brain,401 the proportion of voxels with low ADC,402 and the
ROSC. Absence of EEG background reactivity has an inconsistent maximum size of the MRI clusters with minimum ADC.400 All these
specificity for poor neurological outcome and we no longer studies identified ADC thresholds for 0% FPR, often with a
recommend using it for this purpose. corresponding high sensitivity. However, these thresholds were
High blood NSE values are a sign of neuronal cell damage and inconsistent across different areas of the brain within the same study
have long been recommended as a predictor of poor neurological and the same technique.
outcome after cardiac arrest.414 However, there is still uncertainty Because of the lack of standardisation in measurement methods
about what are the optimal timings and thresholds. Evidence from our and the lack of multicentre validation studies using comparable
review showed that, while prediction with 0% FPR can be achieved measurement techniques, we suggest that predictive indices based
anytime from 24 h to 7 days after ROSC, the sensitivity of an individual on neuroimaging are used only in places where specific experience is
NSE measurement for prediction of poor neurological outcome with available. We also suggest that centres using neuroimaging for
0% FPR is highest at 48 72 h after ROSC.15 However, our review prognostication after cardiac arrest create their own normal values
confirmed that the NSE threshold value for 0% FPR is inconsistent and threshold values based on the technique used.
because of a few patients with good neurological outcome despite When none of the criteria for poor outcome described above are
very high NSE values. The presence of these outliers can be partly present, neurological outcome remains indeterminate (Fig. 5). We
explained with a release of NSE from extracerebral sources, such as therefore suggest observation and repeated re-evaluation of patients with
red blood cells or neuroendocrine tumours. Repeated blood sampling indeterminate outcome to detect signs of awakening. In three studies
and careful exclusion of extracerebral sources is recommended when conducted in resuscitated comatose patients treated with TTM for 24 h,
using NSE for neuroprognostication. Another cause of variability for the prevalence of late awakening, defined as a recovery of consciousness
the NSE thresholds is represented by the different measurement at 48 h from suspension of sedation was 20/89 (22%),415 56/194
techniques used.381 In our 2020 review, the highest recorded NSE (29%),305 and 78/228 (34%).204 Last awakening occurred on day 11, day
thresholds for 0% FPR at 48 and 72 h from ROSC were 120 mg L 1 12, and day 23 from suspension of sedation, respectively. In two other
and 79 mg L 1, respectively. However, these data refer to outliers, and studies, the last patient awoke on day 22 and day 29.403,416 Organ
in most studies the 0% FPR threshold was 60 mg L 1 and 50 mg L 1, dysfunction, such as post-resuscitation shock or renal failure204,305 and
respectively. Based on these data, we presume that the risk of a false use of midazolam instead of propofol for sedation204,265 were associated
positive prediction associated with an NSE value of 60 mg L 1 is with a higher likelihood of late awakening, which suggests that at least
minimal, especially because the NSE signal should be confirmed by at some of these cases may have been due to a reduced clearance of
least another predictor. Nevertheless, we suggest that hospital sedation. In a before-and-after study comparing two sedative regimens
laboratories using NSE create their own normal values and cut-off (propofol-remifentanil versus midazolam-fentanyl) in 460 comatose
levels based on the test kit used. Increasing NSE values between 24 h resuscitated patients undergoing TTM, use of propofol-remifentanil was
and 48 h or between 24/48 h and 72 h also suggests a poor outcome associated with significantly lower odds of delayed awakening after
even if the incremental prognostic value of adding NSE trends to a adjustment (OR 0.08 [0.03 0.2]),305 confirming indirect evidence from a
single NSE value is uncertain.15,375,379 We suggest performing serial previous smaller study.264
NSE samples at 24, 48, and 72 h after ROSC so that NSE trends can Late awakening does not preclude full neurological recovery.
be detected and confounding from occasional haemolysis can be However, the likelihood of awakening in resuscitated patients who
minimised. remain comatose decreases progressively with time and the rates of
Signs of diffuse and extensive hypoxic-ischaemic brain injury on good neurological outcome are generally lower in late vs. early
brain CT include an effacement of cortical sulci and reduced ventricle awakeners.204,305,416
size (mainly from vasogenic oedema) and a reduced density of the The present guidelines apply only to neurological prognostication.
grey matter with reduction or loss of the grey matter/white matter (GM/ Besides hypoxic-ischaemic brain injury, other, albeit less common,
248 RESUSCITATION 161 (2021) 220 269
causes of death in resuscitated comatose patients include cardiovas- uncertainty may also be important, leading to overly pessimistic
cular instability,23 and multiple organ failure.303,304 These factors may perceptions of the prognosis.427
result in treatment limitations independently from the patient's Although some tests show high specificity for predicting a poor
neurological status or cause non-neurological death even after outcome before 72 h, we recommend that, in general, conclusions
neurological recovery has occurred.295,307,417 In clinical practice, a about the neurological prognosis are postponed until at least 72 h after
comprehensive prognostic approach in resuscitated comatose the cardiac arrest and the influence of sedative and metabolic factors
patients should inevitably consider the role of extracerebral factors have been ruled out. This will enable most patients with good outcome
as well as patient characteristics such as age, comorbidities, and to awaken before the prognostic assessment, decreasing the risk of
functional status. false predictions.265 We encourage local protocols on how to collect
information about the extent of brain injury during the first days. Use all
Withdrawal of life-sustaining therapy available resources to inform a multimodal assessment.9,15 Relatives
will require regular clear and structured information and an
While a minority of the resuscitated patients treated in an ICU die understanding of their role in decision-making. Early indicators of
during the first few days due to cardiovascular collapse or massive poor prognosis may be conveyed in a balanced fashion to inform
brain swelling causing brain death, most deaths will be secondary to a relatives that the situation is grave and enable time for adjustment
decision to withdraw life-sustaining therapy (WLST).22,23,26,303 before critical decisions are made. The bedside nurses are confronted
Generally, a presumption that the final neurological outcome of the by grieving caregivers, which may be very stressful.426 Allocate
patient will be poor is central to this decision.26 Pre-existing co- sufficient time for communication around the prognosis within the
morbidities may also contribute to a WLST decision.22 The clinical team and with the relatives.428
team discussing the prognosis of an individual patient needs to While the assessment of post-cardiac arrest neurological
consider that inaccurately pessimistic prognostication could lead to prognosis and discussions about WLST are most often linked, try
WLST in patients who might otherwise achieve a good functional to separate these processes in discussions and documentation.
outcome but also that overly conservative prognostication could leave Decisions about WLST need to consider several aspects other than
patients in a severely disabled state undesired by themselves and the perceived brain injury; for example, age, co-morbidities and the
their relatives.418 Patients may not receive specific treatments prognosis for general organ function.22 Consequently, for ethical
because they are not available, or because there is an active decision reasons, WLST may be considered for patients in whom the
to withhold them. The main reasons for withholding treatments are that neurological prognosis is uncertain or even favourable. Conversely,
they will not benefit the patient or, if known, the patient's wishes not to intensive care may be prolonged despite dismal neurological
have a specific treatment.418,419 There are few specific data on prognosis because absolute certainty is unobtainable for an individual
withholding life sustaining therapies in post-cardiac arrest patients patient.429 The patient's preferences are central. Since the patient
specifically. cannot be asked and advance directives are rare among cardiac
The practice of WLST varies widely across Europe and impacts the arrest victims, the relatives are usually the primary source of
proportion of CA-patients surviving with severe brain injury (CPC 3 information about the patient's likely wishes.
4). Lacking high-quality data, this fraction appears to vary widely
from approximately 10 50%.243,300,417 The most apparent effects are Long-term outcome after cardiac arrest
seen for patients who remain in an unresponsive wakefulness/
vegetative state (CPC 4). As an example, 1/243 (0.4%) survivors in a Long-term outcome
northern European study243 compared with 61/195 (31%) in an Italian In countries where WLST is not practiced widely, poor outcome
multi-centre study300 were in CPC 4 at 6 months. Evidence for because of hypoxic-ischaemic brain injury is common.387,430 The
variation in WLST practice across Europe was also found in the prognosis of patients who are still comatose or in an unresponsive
Ethicus Study: physicians from southern Europe were less prone to wakefulness state one month after the cardiac arrest is poor and they
withdraw treatment compared with those from northern Europe, and rarely recover.430,431 In contrast, in countries practising WLST, the
there was also an effect of religion.420 The Ethicus-2 Study has shown majority of survivors are defined as having a ‘good’ neurological
that the frequency of WLST and withholding decisions among general outcome based on global outcome measures such as Cerebral
ICU patients has increased over the last 15 20 years.421 Performance Categories (CPC), modified Rankin Scale (mRS) or the
Recent studies, based on propensity score matching, indicate that Glasgow Outcome Scale/Extended (GOS/E).290,412,432 434 However,
premature (<72 h) WLST for neurological reasons are common and these measures are not sufficiently sensitive to capture the problems
may be the cause of death for a substantial proportion of patients who that many of the survivors experience, including cognitive, emotional
might have recovered to a good outcome if their intensive care and physical problems and fatigue.435 437 In fact, approximately 40
treatment had been prolonged.422,423 The brain stem is more resistant 50% of the survivors have long-term cognitive impairments.229,438,439
to hypoxic-ischaemic injury than the cerebrum and the recovery of Impairments are mostly mild to moderate and, although all cognitive
functions such as spontaneous breathing and sleep-wake cycle is part domains can be affected, most problems are seen in memory, attention,
of the trajectory towards an unresponsive wakefulness/vegetative processing speed and executive functioning (e.g. planning, organisa-
syndrome. The period when the patient is still dependent on intensive tion, initiation, flexibility).229,435,438 440 In general, most cognitive
care is sometimes referred to as the ‘window of opportunity for recovery occurs during the first three months after the cardiac
death’.424 This perception may cause a sense of urgency for the arrest.441 443
relatives and treating team indirectly impacting decisions on Emotional problems are also common. Three to six months after
premature WLST.425,426 One qualitative study identified limitations the cardiac arrest anxiety is present in 15 30% of the survivors and
in family-team communication as an important factor for premature remains in 15 23% at 12 months.444 446 Depressive symptoms
WLST after cardiac arrest.426 Caregivers’ inappropriate avoidance of range from 13 32% at 3 6 months and decrease to 5 15% at
RESUSCITATION 161 (2021) 220 269 249
12 months.444 447 Symptoms of post-traumatic stress remain in provided before discharge from the ICU and the hospital, based
about a quarter of the survivors.436,444,447,448 Furthermore, some on functional assessments of physical and non-physical (e.g.
survivors show behavioural problems, such as aggressive/ cognitive and emotional) impairments.471 However, a recent AHA
uninhibited behaviour or emotional lability.439 Scientific Statement focusing on survivorship highlights that
Fatigue is also frequently reported and is present in approximately discharge planning and organisation of further rehabilitation needs
70% of the survivors at six months and remains in half of the survivors after cardiac arrest is often lacking.437
one year after the event.444,449,450 Physical problems, including rib We therefore recommend providing information and performing
fractures, muscle weakness and ambulation difficulties, have also functional assessments of physical and non-physical impairments
been reported.437,444,451,452 However, the impact of survival on before discharge from the hospital to identify potential rehabilitation
physical function has received little attention; when compared with needs and arrange referral for rehabilitation if indicated (Fig. 6).
age and gender-matched populations, reduced physical functioning
has been reported in survivors at 3-months,453 6-months,452 12- [59_TD$IF]Follow-up and screening after hospital discharge
months,434 and three years.451 Almost half of survivors report [60_TD$IF]Although cognitive impairments, emotional problems and fatigue are
limitations because of physical difficulties at 6-months,452 with up common after cardiac arrest, these ‘invisible problems’ are not always
to 40% describing mobility problems434,439,444,454 and limitations in recognised by healthcare professionals.442,450,453,457,464 Since these
usual activities at 12-months.434,444,454 problems have a significant impact on long-term outcome and quality
After discharge, most survivors are able to return home and only a of life, follow-up should be organised in such a way that these
small percentage (1 10%) need to be admitted to a long-term care problems are detected early enabling appropriate care or rehabilita-
facility.444,454,455 The large majority (82 91%) are independent in tion to be arranged.472 474
their basic activities of daily living (ADL).228,438,451,454 Although most Evidence on this subject is scarce but results from one RCT
survivors are able to resume their pre-arrest activities, they showed that an early intervention service for cardiac arrest survivors
experience more restrictions in societal participation compared with and their caregivers improved emotional well-being and quality of life,
myocardial infarction patients.444,450 Cognitive impairments, depres- resulted in a faster return to work and was cost-effective.475,476 This
sion, fatigue and restricted mobility are negative predictors for future individualised programme is provided by a specialised nurse, starts
participation.450 soon after discharge from the hospital and comprises one to six
Of those who were previously working, 63 85% are able to return consultations during the first three months. The intervention consists
to work, although some need to adapt their working hours or of screening for cognitive and emotional problems, provision of
activities.434,444,450,451,454,456 458 Decreased likelihood of return to information and support, and referral to further specialised care if
work is associated with cognitive problems and fatigue, unwitnessed indicated.477,478 There are several other examples of how follow-up
OHCA, absence of bystander CPR, female gender, higher age and after cardiac arrest can be organised.474,479,480 UK NICE guidelines
lower socio-economic status.450,453,456 458 for rehabilitation after critical illness likewise recommend a follow-up
Cognitive impairments, emotional problems and female gender and reassessment for physical and non-physical problems 2
are associated with a lower quality of life.434,442,452,453,459 464 3 months after discharge to enable identification of remaining
However, general health related quality of life is, on average, reported problems and to provide further support as needed.471 For cardiac
as good with overall scores approaching normal population values, as arrest survivors, reassessments have also been suggested at 3, 6 and
was shown in two systematic reviews and confirmed in several more 12 months.437
recent studies.228,434,454,465,466 Such generic assessments lack We therefore suggest the systematic follow-up of all cardiac arrest
sufficient granularity to comprehensively capture the breadth of survivors within three months following hospital discharge which
problems experienced by survivors, with the result that the impact of should, at least, include cognitive screening, screening for emotional
cardiac arrest survival may be incompletely captured.290 Supple- problems and fatigue, and the provision of information and support for
menting such generic assessment with condition or problem-specific patients and their family (Fig. 6).
assessment is recommended.290
More detailed information on recovery and long-term outcome [61_TD$IF]Screening for cognitive problems
after cardiac arrest, as well as a description of the current rehabilitation [62_TD$IF]To screen for cognition, the patient can be asked about common
practices in Europe can be found in the epidemiology section of the cognitive complaints, such as memory problems, attention difficulties,
2021 European Resuscitation Council Guidelines.467 distractibility, slowness in thinking, irritability and problems in initiation,
planning, multi-tasking or flexibility. Family members can also provide
In-hospital assessment and follow-up after hospital useful insight into changes in cognition and behaviour. A structured
discharge questionnaire, such as the Informant Questionnaire of Cognitive
decline in the Elderly Cardiac Arrest version (IQCODE-CA) or the
Early rehabilitation and assessment during hospital phase Checklist Cognition and Emotion (CLCE-24), may be used.481,482
[14_TD$IF]There are no studies of early rehabilitation interventions for cardiac Formal cognitive screening is recommended because patients are not
arrest survivors specifically but there is substantial overlap with the always aware of their cognitive impairments.443,472,483 We suggest
post-intensive care syndrome (PICS). For other ICU patients, use of the Montreal Cognitive Assessment (MoCA) tool, which takes
interventions of early mobilisation and prevention of delirium are approximately 10 min to administer, is easy to use and available in
described, and similar interventions are thought to be useful for many languages (see www.mocatest.org).480,483 485 If there are
cardiac arrest patients as well.437,468 470 Recommendations in the signs of cognitive impairment, consider referral to a neuropsychologist
UK National Institute for Health and Care Excellence (NICE) for more extensive neuropsychological assessment or another
guidelines for rehabilitation after critical illness suggest that specialist in cognitive rehabilitation, such as an occupational therapist,
individualised rehabilitation plans and information should be should be considered.486
250 RESUSCITATION 161 (2021) 220 269
[63_TD$IF]Screening for emotional problems and fatigue frequently offered as a centre-based out-patient service, but can also
[62_TD$IF]To screen for emotional problems, the presence of emotional be organised in a home-based setting in combination with tele-
symptoms, including symptoms of anxiety, depression and posttrau- monitoring.508 In specific cases it can be provided as an inpatient
matic stress, can be explored. Questionnaires, such as the Hospital programme.505 Not all cardiac arrest survivors are eligible for or have
Anxiety and Depression Scale (HADS), may be useful.437,473,480,487 If access to cardiac rehabilitation, either because of the cause of the
severe emotional problems are detected we suggest referral to a cardiac arrest or because of variation in national or insurance
psychologist or psychiatrist for further evaluation and treatment. We policies.509
also suggest assessing the presence of fatigue; however, assessment Within cardiac rehabilitation programmes little attention is paid to
guidance in this population is currently lacking. In case of severe potential cognitive problems. Among cardiac patients in general,
fatigue consider referral to a specialist in rehabilitation medicine for cognitive and emotional problems have not been addressed well in
advice on appropriate care. cardiac rehabilitation programmes.510 512 For cardiac arrest survi-
vors, there are some examples in which cardiac and cognitive
[64_TD$IF]Provision of information and support for survivor and family rehabilitation have been integrated, although evidence of effects is still
members lacking.474,480
[65_TD$IF]Exploring the need for and subsequent provision of appropriate
information to patients and their family, preferably both in oral and Cognitive rehabilitation, fatigue management and
written form, is recommended.488 The active engagement of survivors psychosocial interventions
and their family members to better understand their needs and how The goal of cognitive rehabilitation is to reduce the impact of cognitive
they would like to receive such information, is recommended as part of impairments and to improve overall well-being and daily function-
this process.437 Information should cover not only medical subjects ing.513 It can include additional neuropsychological assessment to get
such as cardiac disease, risk factors, medication and ICD, but can also more insight into the nature and severity of the cognitive impairments
address other topics such as potential physical, cognitive and and other influencing factors. Extensive patient education is essential
emotional changes and fatigue, resuming daily activities, driving to give the patient and their family more insight into what has changed
and work, relationship and sexuality.477,488 491 in their cognition and behaviour. Compensation strategies, such as
It is also important to monitor the well-being of family members memory strategy training and metacognitive strategy training (e.g.
because the impact and burden can be substantial.490,492 Partners self-monitoring, self-regulation and planning ahead) and the use of
often have emotional problems, including symptoms of anxiety and external (memory) aids may be helpful.486 Although there are no
posttraumatic stress, especially in women and those who witnessed specific studies on the effects of cognitive rehabilitation in patients with
the resuscitation.493,494 Consider referral to a social worker, brain injury caused by cardiac arrest, a recent evidence-based review
psychologist or psychiatrist when indicated. on cognitive rehabilitation after stroke and traumatic brain injury, can
serve as a guideline.486
[6_TD$IF]1Rehabilitation after cardiac arrest Fatigue management can be included in cognitive rehabilitation or
provided alone.514,515 There is weak evidence that a 4-week
In-patient neurological rehabilitation telephone intervention, based on energy conservation and prob-
In the presence of significant hypoxic-ischaemic brain injury, patients lem-solving therapy, can be of benefit for cardiac arrest survivors with
may require inpatient neurological rehabilitation and, although the moderate to severe fatigue.516,517
evidence is limited, several small retrospective studies have shown There is also evidence that psychosocial interventions specifically
that functional improvements can be achieved, reducing the burden of designed for cardiac arrest survivors can be valuable. Two RCTs
care on the family and society.495 497 showed benefit from nurse-led psychosocial interventions, either by
Although specific guidelines and evidence for neurological telephone or face-to-face.518,519 These interventions addressed self-
rehabilitation after cardiac arrest is lacking, there is more evidence management, coping strategies, relaxation, information and health
and multiple clinical practice guidelines for other types of acquired education.519,520
brain injury such as traumatic brain injury and stroke which can guide There are currently no studies on the effectiveness of social
the treatment of patients with hypoxic-ischaemic brain injury due to support networks or virtual/online forums, but these may have
cardiac arrest.498 500 These guidelines provide practical recommen- additional value as a new and easily accessible form of psychosocial
dations on topics such as motor function, physical rehabilitation, support and information after cardiac arrest.437
cognition, communication, activities of daily living and psychosocial
issues. Guidelines on rehabilitation after critical illness/post-intensive Organ donation
care syndrome (PICS) can also be useful.471,501 503
Comatose post cardiac arrest patients who do not survive have the
Cardiac rehabilitation potential to become organ donors. This is important as demand for
Many cardiac arrest survivors are eligible to enrol in a cardiac organs exceeds supply.521 Post cardiac arrest patients are an
rehabilitation programme.504 There is evidence that cardiac rehabili- increasing source of solid organ donors.522 This guideline supports
tation reduces cardiovascular mortality and hospital admissions, giving the opportunity for organ donation to patients and families when
improves quality of life, and is cost-effective.504 507 Cardiac brain death occurs or there is a decision to withdraw life sustaining
rehabilitation programmes are mostly generic programmes, in which treatment.
patients with different cardiac diseases, e.g. post-acute coronary This guideline specifically addresses the organ donation pathways
syndrome, heart failure or post cardiac surgery, can participate. It following neurological (brain) death or controlled donation after
involves exercise training, risk factor management, lifestyle advice, circulatory death (Maastricht category III donors) in patients that
education and psychological support.505 Cardiac rehabilitation is achieve ROSC or are treated with E-CPR (Fig. 7).523 Uncontrolled
RESUSCITATION 161 (2021) 220 269 251
donation after circulatory death uDCD (Maastricht category I/II Care (ACVA), and many other European organisations including the
donors) is addressed in the Advanced Life Support section of the ERC and ESICM, states that the minimum requirements for a cardiac
guidelines.523 arrest centre are 24/7 availability of an on-site coronary angiography
A previous 2015 ILCOR CoSTR and an ILCOR Scientific laboratory, an emergency department, an intensive care unit (ICU),
Statement on organ donation following CPR underpin this guide- imaging facilities, such as echocardiography, computed tomography,
line.122 Recent CPR should not prevent organ donation. Observa- and magnetic resonance imaging.16
tional studies show that organs (heart, lung, kidney, liver, pancreas, ILCOR suggests that wherever possible, adult patients with non-
intestine) from donors who have had CPR have similar graft survival traumatic OHCA cardiac arrest should be cared for in cardiac arrest
rates compared with donors who have not had CPR.524,525 centres.17 This weak recommendation is based on very low certainty
A systematic review identified 26 studies that showed the evidence from a systematic review that included 21 observational
prevalence of brain death in comatose ventilated patients with studies.535 555 and 1 pilot randomised trial.556 Seventeen of these
hypoxic ischaemic brain injury who died following CPR was 12.6% studies were included in a meta-analysis that found that patients cared
(95% CI 10.2 15.2%) with a higher prevalence following eCPR for at cardiac arrest centres had improved survival to hospital
(27.9% [19.7 36.6%] vs. 8.3% [6.5 10.4%]) and that approximately discharge with favourable neurological outcome, but this was non-
40% of these proceeded to organ donation.286 The median time to significant at 30 days.535 541,545 552,554,555
diagnose brain death was 3.2 days. This systematic review concluded One observational study reported higher adjusted patient survival
that patients who are unconscious after resuscitation from cardiac associated with direct transfer to a cardiac arrest centre compared
arrest, especially when resuscitated using e-CPR, should be with secondary interfacility transfer,552 but two other studies making
assessed for signs of brain death. the same comparisons report no difference in adjusted survival.536,541
Furthermore, in those who do not fulfil criteria for neurological One observational study reported higher adjusted survival in patients
death, WLST because of a poor neurological prognosis is a common who underwent secondary transfer to a cardiac arrest centre
cause of death. After OHCA, approximately two thirds of deaths will be compared with remaining at the initial non-cardiac arrest centre.550
following WLST because of a poor neurological prognosis.22,23 This
group of patients provides an increasing source of donors following
controlled donation after circulatory death.526 Conflict of interest statement
There is variation between countries regarding organ donation
practices and clinicians must follow local legal and ethical Jerry P. Nolan, Editor in Chief Resuscitation; Claudio Sandroni,
requirements. Associate Editor, Intensive Care Medicine; Bernd W. Böttiger,
Treasurer of the European Resuscitation Council (ERC); Chairman
Investigating sudden unexplained cardiac arrest of the German Resuscitation Council (GRC); Member of the Advanced
Life Support (ALS) Task Force of the International Liaison Committee
Many sudden cardiac death victims have silent structural heart on Resuscitation (ILCOR); Member of the Executive Committee of the
disease, most often coronary artery disease, but also primary German Interdisciplinary Association for Intensive Care and Emergen-
arrhythmia syndromes, cardiomyopathies, familial hypercholester- cy Medicine (DIVI), Founder of the Deutsche Stiftung Wiederbelebung;
olaemia and premature ischaemic heart disease. In the course of an Associate Editor of the European Journal of Anaesthesiology (EJA),
autopsy of victims of sudden unexplained death (SUD), blood or Co-Editor of Resuscitation; Editor of Notfall + Rettungsmedizin, Co-
tissue samples should be taken and stored for future genetic Editor of the Brazilian Journal of Anesthesiology. Received fees for
analysis.527 Screening for genetic disorders is crucial for primary lectures from the following companies: Forum für medizinische
prevention in relatives as it may enable preventive antiarrhythmic Fortbildung (FomF), Baxalta Deutschland GmbH, ZOLL Medical
treatment and medical follow-up.528 530 A multidisciplinary cardi- Deutschland GmbH, C.R. Bard GmbH, GS Elektromedizinische Geräte
ogenetic team should perform the family investigation. Initial G. Stemple GmbH, Novartis Pharma GmbH, Philips GmbH Market
evaluation may include clinical examination, electrophysiology DACH, Bioscience Valuation BSV GmbH. Alain Cariou, Speaker's Fee
and cardiac imaging. A genetic test should be considered according from Bard Medical; Tobias Cronberg; Hans Friberg; Cornelia
to the combination the results of cardiac family screening and Genbrugge; Gisela Lilja; Véronique RM Moulaert; Nikolaos Nikolaou;
pathology findings. The genetic test should be performed initially on Theresa Mariero Olasveengen no conflicts of interest. Markus B.
the DNA of the deceased and testing of relatives should then be Skrifvars, Speaker's Fee from Bard Medical (Ireland); Fabio Silvio
offered if a pathogenic or likely pathogenic variant is identi- Taccone, Speaker's Fees from BD and Zoll; Jasmeet Soar, Editor,
fied.527,531 Given the implications for relatives, there may be local Resuscitation.
ethical guidelines for genetic testing.
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