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Contents lists available at ScienceDirect

Resuscitationjou rn al hom epage : w ww.elsev ie r .com/ locate / resusc i ta t ion

uropean Resuscitation Council and European Society of Intensiveare Medicine Guidelines for Post-resuscitation Care 2015ection 5 of the European Resuscitation Council Guidelines foresuscitation 2015

erry P. Nolana,b,, Jasmeet Soarc, Alain Carioud, Tobias Cronberge,ronique R.M. Moulaert f, Charles D. Deaking, Bernd W. Bottigerh, Hans Friberg i,jetil Sundej, Claudio Sandronik

Department of Anaesthesia and Intensive Care Medicine, Royal United Hospital, Bath, UKSchool of Clinical Sciences, University of Bristol, UKAnaesthesia and Intensive Care Medicine, Southmead Hospital, Bristol, UKCochin University Hospital (APHP) and Paris Descartes University, Paris, FranceDepartment of Clinical Sciences, Division of Neurology, Lund University, Lund, SwedenAdelante, Centre of Expertise in Rehabilitation and Audiology, Hoensbroek, The Netherlands

Cardiac Anaesthesia and Cardiac Intensive Care and NIHR Southampton Respiratory Biomedical Research Unit, University Hospital, Southampton, UKDepartment of Anaesthesiology and Intensive Care Medicine, University Hospital of Cologne, Cologne, GermanyDepartment of Clinical Sciences, Division of Anesthesia and Intensive Care Medicine, Lund University, Lund, SwedenDepartment of Anaesthesiology, Division of Emergencies and Critical Care, Oslo University Hospital and Institute of Clinical Medicine, University of Oslo,slo, NorwayDepartment of Anaesthesiology and Intensive Care, Catholic University School of Medicine, Rome, Italy

ummary of changes since 2010 guidelines

In 2010, post-resuscitation care was incorporated into thedvanced Life Support section of the European Resuscitation Coun-il (ERC) Guidelines.1 The ERC and the European Society of Intensiveare Medicine (ESICM) have collaborated to produce these post-esuscitation care guidelines, which recognise the importance ofigh-quality post-resuscitation care as a vital link in the Chain ofurvival.2 These post-resuscitation care guidelines are being co-ublished in Resuscitation and Intensive Care Medicine.

The most important changes in post-resuscitation care since010 include:

There is a greater emphasis on the need for urgent coronarycatheterisation and percutaneous coronary intervention (PCI) fol-lowing out-of-hospital cardiac arrest of likely cardiac cause.Targeted temperature management remains important but there

is now an option to target a temperature of 36 C instead of thepreviously recommended 3234 C.

This article is being published simultaneously in Resuscitation and Intensiveare Medicine. Corresponding author.

E-mail address: [email protected] (J.P. Nolan).

ttp://dx.doi.org/10.1016/j.resuscitation.2015.07.018300-9572/ 2015 European Resuscitation Council. Published by Elsevier Ireland Ltd. All

Prognostication is now undertaken using a multimodal strategyand there is emphasis on allowing sufficient time for neurologicalrecovery and to enable sedatives to be cleared.

A novel section has been added which addresses rehabilitationafter survival from a cardiac arrest. Recommendations include thesystematic organisation of follow-up care, which should includescreening for potential cognitive and emotional impairments andprovision of information.

The international consensus on cardiopulmonaryresuscitation science and the guidelines process

The International Liaison Committee on Resuscitation (ILCOR,www.ilcor.org) includes representatives from the American HeartAssociation (AHA), the European Resuscitation Council (ERC), theHeart and Stroke Foundation of Canada (HSFC), the Australian andNew Zealand Committee on Resuscitation (ANZCOR), the Resusci-tation Council of Southern Africa (RCSA), the Inter-American HeartFoundation (IAHF), and the Resuscitation Council of Asia (RCA).Since 2000, researchers from the ILCOR member councils haveevaluated resuscitation science in 5-yearly cycles. The most recentInternational Consensus Conference was held in Dallas in February

2015 and the published conclusions and recommendations fromthis process form the basis of the ERC Guidelines 2015 and forthese ERC-ESICM post-resuscitation care guidelines. During thethree years leading up to this conference, 250 evidence reviewers

rights reserved.

dx.doi.org/10.1016/j.resuscitation.2015.07.018http://www.sciencedirect.com/science/journal/03009572http://www.elsevier.com/locate/resuscitationhttp://crossmark.crossref.org/dialog/?doi=10.1016/j.resuscitation.2015.07.018&domain=pdfmailto:[email protected]://www.ilcor.org/http://www.ilcor.org/http://www.ilcor.org/dx.doi.org/10.1016/j.resuscitation.2015.07.018

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rom 39 countries reviewed thousands of relevant, peer-reviewedublications to address 169 specific resuscitation questions, each

n the standard PICO (Population, Intervention, Comparison,utcome) format. To assess the quality of the evidence and the

trength of the recommendations, ILCOR adopted the GRADEGrading of Recommendations Assessment, Development andvaluation) methodology. Each PICO question was reviewed byt least two evidence reviewers who drafted a science statementased on their interpretation of all relevant data on the specificopic and the relevant ILCOR task force added consensus draftreatment recommendations. Final wording of science statementsnd treatment recommendations was completed after furthereview by ILCOR member organisations and by the editorialoard, and published in Resuscitation and Circulation as the 2015onsensus on Science and Treatment Recommendations (CoSTR).hese ERC-ESICM guidelines on post-resuscitation care are basedn the 2015 CoSTR document and represent consensus among theriting group, which included representatives of the ERC and the

SICM.

ntroduction

Successful return of spontaneous circulation (ROSC) is the firsttep towards the goal of complete recovery from cardiac arrest. Theomplex pathophysiological processes that occur following wholeody ischaemia during cardiac arrest and the subsequent reper-usion response during CPR and following successful resuscitationave been termed the post-cardiac arrest syndrome.3 Dependingn the cause of the arrest, and the severity of the post-cardiacrrest syndrome, many patients will require multiple organ sup-ort and the treatment they receive during this post-resuscitationeriod influences significantly the overall outcome and particularlyhe quality of neurological recovery.411 The post-resuscitationhase starts at the location where ROSC is achieved but, once sta-ilised, the patient is transferred to the most appropriate high-carerea (e.g., emergency room, cardiac catheterisation laboratory orntensive care unit (ICU)) for continued diagnosis, monitoring andreatment. The post-resuscitation care algorithm (Fig. 1) outlinesome of the key interventions required to optimise outcome forhese patients.

Some patients do awake rapidly following cardiac arrest inome reports it is as high as 1546% of the out-of hospital car-iac arrest patients admitted to hospital.1214 Response times,ates of bystander CPR, times to defibrillation and the durationf CPR impact on these numbers.14 Although we have no data,t is reasonable to recommend that if there is any doubt abouthe patients neurological function, the patients trachea shoulde intubated and treatment to optimise haemodynamic, respira-ory and metabolic variables, together with targeted temperature

anagement started, following the local standardised treatmentlan.

Of those comatose patients admitted to ICUs after cardiac arrest,s many as 4050% survive to be discharged from hospital depend-ng on the cause of arrest, system and quality of care.7,10,1320 Of theatients who survive to hospital discharge, the vast majority have

good neurological outcome although many with subtle cognitivempairment.2124

ost-cardiac arrest syndrome

The post-cardiac arrest syndrome comprises post-cardiac arrest

rain injury, post-cardiac arrest myocardial dysfunction, theystemic ischaemia/reperfusion response, and the persistent pre-ipitating pathology.3,25,26 The severity of this syndrome willary with the duration and cause of cardiac arrest. It may not

n 95 (2015) 202222 203

occur at all if the cardiac arrest is brief. Post-cardiac arrestbrain injury manifests as coma, seizures, myoclonus, varyingdegrees of neurocognitive dysfunction and brain death. Amongpatients surviving to ICU admission but subsequently dying in-hospital, brain injury is the cause of death in approximatelytwo thirds after out-of hospital cardiac arrest and approximately25% after in-hospital cardiac arrest.2730 Cardiovascular failureaccounts for most deaths in the first three days, while braininjury accounts for most of the later deaths.27,30,31 Withdrawalof life sustaining therapy (WLST) is the most frequent cause ofdeath (approximately 50%) in patients with a prognosticated badoutcome,14,30 emphasising the importance of the prognostica-tion plan (see below). Post-cardiac arrest brain injury may beexacerbated by microcirculatory failure, impaired autoregulation,hypotension, hypercarbia, hypoxaemia, hyperoxaemia, pyrexia,hypoglycaemia, hyperglycaemia and seizures. Significant myocar-dial dysfunction is common after cardiac arrest but typically startsto recover by 23 days, although full recovery may take sig-nificantly longer.3234 The whole body ischaemia/reperfusion ofcardiac arrest activates immune and coagulation pathways con-tributing to multiple organ failure and increasing the risk ofinfection.3541 Thus, the post-cardiac arrest syndrome has manyfeatures in common with sepsis, including intravascular volumedepletion, vasodilation, endothelial injury and abnormalities of themicrocirculation.4248

Airway and breathing

Control of oxygenation

Patients who have had a brief period of cardiac arrest respondingimmediately to appropriate treatment may achieve an immediatereturn of normal cerebral function. These patients do not requiretracheal intubation and ventilation but should be given with oxy-gen via a facemask if their arterial blood oxygen saturation is lessthan 94%. Hypoxaemia and hypercarbia both increase the likeli-hood of a further cardiac arrest and may contribute to secondarybrain injury. Several animal studies indicate that hyperoxaemiaearly after ROSC causes oxidative stress and harms post-ischaemicneurones.4953 One animal study showed that adjusting the frac-tional inspired concentration (FiO2) to produce an arterial oxygensaturation of 9496% in the first hour after ROSC (controlled reoxy-genation) achieved better neurological outcomes than achievedwith the delivery of 100% oxygen.54 One clinical registry studythat included more than 6000 patients supports the animal dataand shows post-resuscitation hyperoxaemia in the first 24 h isassociated with worse outcome, compared with both normox-aemia and hypoxaemia.55 A further analysis by the same groupshowed that the association between hyperoxia and outcome wasdose-dependent and that there was not a single threshold forharm.56 An observational study that included only those patientstreated with mild induced hypothermia also showed an associationbetween hyperoxia and poor outcome.57 In contrast, an observa-tional study of over 12,000 post-cardiac arrest patients showedthat after adjustment for the inspired oxygenation concentrationand other relevant covariates (including sickness severity), hyper-oxia was no longer associated with mortality.58 A meta-analysis of14 observational studies showed significant heterogeneity acrossstudies.59

The animal studies showing a relationship between hyperoxiaand worse neurological outcome after cardiac arrest have generally

evaluated the effect of hyperoxia in the first hour after ROSC. Thereare significant practical challenges with the titration of inspiredoxygen concentration immediately after ROSC, particularly inthe out-of hospital setting. The only prospective clinical study to

204 J.P. Nolan et al. / Resuscitation 95 (2015) 202222

Fig. 5.1. Post-resuscitation care algorithm. SBP: systolic blood pressure; PCI: percutaneous coronary intervention; CTPA: computed tomography pulmonary angiogram; ICU:intensive care unit; MAP: mean arterial pressure; ScvO2: central venous oxygenation; CO/CI: cardiac output/cardiac index; EEG: electroencephalography; ICD: implantedcardioverter defibrillator.

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ompare oxygen titrated to a target range (in this case 9094%xygen saturation) versus giving 100% oxygen after out of hos-ital cardiac arrest was stopped after enrolling just 19 patientsecause it proved very difficult to obtain reliable arterial bloodxygen saturation values using pulse oximetry.60 A recent studyf air versus supplemental oxygen in ST-elevation myocardialnfarction showed that supplemental oxygen therapy increased

yocardial injury, recurrent myocardial infarction and majorardiac arrhythmia and was associated with larger infarct size at

months.61

Given the evidence of harm after myocardial infarction and theossibility of increased neurological injury after cardiac arrest, asoon as arterial blood oxygen saturation can be monitored reliablyby blood gas analysis and/or pulse oximetry), titrate the inspiredxygen concentration to maintain the arterial blood oxygen sat-ration in the range of 9498%. Avoid hypoxaemia, which is alsoarmful ensure reliable measurement of arterial oxygen satura-ion before reducing the inspired oxygen concentration.

ontrol of ventilation

Consider tracheal intubation, sedation and controlled venti-ation in any patient with obtunded cerebral function. Ensurehe tracheal tube is positioned correctly, well above the carina.ypocarbia causes cerebral vasoconstriction and a decreased cere-ral blood flow.62 After cardiac arrest, hypocapnia induced byyperventilation causes cerebral ischaemia.6367 Observationaltudies using cardiac arrest registries document an associationetween hypocapnia and poor neurological outcome.68,69 Twobservation studies have documented an association with mildypercapnia and better neurological outcome among post-cardiacrrest patients in the ICU.69,70 Until prospective data are avail-ble, it is reasonable to adjust ventilation to achieve normocarbiand to monitor this using the end-tidal CO2 and arterial blood gasalues. Lowering the body temperature decreases the metabolismnd may increase the risk of hypocapnia during the temperaturentervention.71

Although protective lung ventilation strategies have not beentudied specifically in post-cardiac arrest patients, given that theseatients develop a marked inflammatory response, it seems ratio-al to apply protective lung ventilation: tidal volume 68 ml kg1

deal body weight and positive end expiratory pressure 48 cm2O.48,72

Insert a gastric tube to decompress the stomach; gastric dis-ension caused by mouth-to-mouth or bag-mask ventilation willplint the diaphragm and impair ventilation. Give adequate dosesf sedative, which will reduce oxygen consumption. A sedationrotocol is highly recommended. Bolus doses of a neuromuscularlocking drug may be required, particularly if using targeted tem-erature management (TTM) (see below). Limited evidence showshat short-term infusion (48 h) of short-acting neuromuscularlocking drugs given to reduce patient-ventilator dysynchrony andisk of barotrauma in ARDS patients is not associated with anncreased risk of ICU-acquired weakness and may improve outcomen these patients.73 There are some data suggesting that continu-us neuromuscular blockade is associated with decreased mortalityn post-cardiac arrest patients74; however, infusions of neuromus-ular blocking drugs interfere with clinical examination and mayask seizures. Continuous electroencephalography (EEG) is rec-

mmended to detect seizures in these patients, especially when

euromuscular blockade is used.75 Obtain a chest radiograph toheck the position of the tracheal tube, gastric tube and centralenous lines, assess for pulmonary oedema, and detect compli-ations from CPR such as a pneumothorax associated with ribractures.76,77

n 95 (2015) 202222 205

Circulation

Coronary reperfusion

Acute coronary syndrome (ACS) is a frequent cause of out-of-hospital cardiac arrest (OHCA): in a recent meta-analysis,the prevalence of an acute coronary artery lesion ranged from59% to 71% in OHCA patients without an obvious non-cardiacaetiology.78 Since the publication of a pioneering study in 1997,79

many observational studies have shown that emergent cardiaccatheterisation laboratory evaluation, including early percuta-neous coronary intervention (PCI), is feasible in patients with ROSCafter cardiac arrest.80,81 The invasive management (i.e., early coro-nary angiography followed by immediate PCI if deemed necessary)of these patients, particularly those having prolonged resuscita-tion and nonspecific ECG changes, has been controversial becauseof the lack of specific evidence and significant implications on useof resources (including transfer of patients to PCI centres).

Percutaneous coronary intervention following ROSC withST-elevation

In patients with ST segment elevation (STE) or left bundlebranch block (LBBB) on the post-ROSC electrocardiogram (ECG)more than 80% will have an acute coronary lesion.82 There areno randomised studies but given that many observational studiesreported increased survival and neurologically favourable out-come, it is highly probable that early invasive management isbeneficial in STE patients.83 Based on available data, emergent car-diac catheterisation laboratory evaluation (and immediate PCI ifrequired) should be performed in adult patients with ROSC afterOHCA of suspected cardiac origin with STE on the ECG. This rec-ommendation is based on low quality of evidence from selectedpopulations. Observational studies also indicate that optimal out-comes after OHCA are achieved with a combination of TTM and PCI,which can be included in a standardised post-cardiac arrest proto-col as part of an overall strategy to improve neurologically intactsurvival.81,84,85

Percutaneous coronary intervention following ROSC withoutST-elevation

In contrast to the usual presentation of ACS in non-cardiac arrestpatients, the standard tools to assess coronary ischaemia in cardiacarrest patients are less accurate. The sensitivity and specificity ofthe usual clinical data, ECG and biomarkers to predict an acutecoronary artery occlusion as the cause of OHCA are unclear.8689

Several large observational series showed that absence of STEmay also be associated with ACS in patients with ROSC followingOHCA.9093 In these non-STE patients, there are conflicting datafrom observational studies on the potential benefit of emergentcardiac catheterisation laboratory evaluation.92,94,95 A recentconsensus statement from the European Association for Percuta-neous Cardiovascular Interventions (EAPCI) has emphasised thatin OHCA patients, cardiac catheterisation should be performedimmediately in the presence of ST-elevation and considered assoon as possible (less than 2 h) in other patients in the absence ofan obvious non-coronary cause, particularly if they are haemody-namically unstable.96 Currently, this approach in patients withoutSTE remains controversial and is not accepted by all experts.However, it is reasonable to discuss and consider emergent cardiaccatheterisation laboratory evaluation after ROSC in patients with

the highest risk of a coronary cause for their cardiac arrest. Factorssuch as patient age, duration of CPR, haemodynamic instability,presenting cardiac rhythm, neurological status upon hospitalarrival, and perceived likelihood of cardiac aetiology can influence

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he decision to undertake the intervention in the acute phase or toelay it until later on in the hospital stay.

ndications and timing of computed tomography (CT) scanning

Cardiac causes of OHCA have been extensively studied in theast few decades; conversely, little is known on non-cardiac causes.arly identification of a respiratory or neurological cause wouldnable transfer of the patient to a specialised ICU for optimal care.mproved knowledge of prognosis also enables discussion about theppropriateness of specific therapies, including TTM. Early identi-cation of a respiratory or neurological cause can be achieved byerforming a brain and chest CT-scan at hospital admission, beforer after coronary angiography. In the absence of signs or symp-oms suggesting a neurological or respiratory cause (e.g., headache,eizures or neurological deficits for neurological causes, short-ess of breath or documented hypoxia in patients suffering from

known and worsening respiratory disease) or if there is clinicalr ECG evidence of myocardial ischaemia, coronary angiography isndertaken first, followed by CT scan in the absence of causative

esions. Several case series showed that this strategy enables diag-osis of non-cardiac causes of arrest in a substantial proportion ofatients.97,98 In those with cardiac arrest associated with traumar haemorrhage a whole body CT scan may be indicated.99,100

aemodynamic management

Post-resuscitation myocardial dysfunction causes haemody-amic instability, which manifests as hypotension, low cardiac

ndex and arrhythmias.32,101 Perform early echocardiography inll patients in order to detect and quantify the degree of myocar-ial dysfunction.33,102 Post-resuscitation myocardial dysfunctionften requires inotropic support, at least transiently. Based onxperimental data, dobutamine is the most established treatmentn this setting,103,104 but the systematic inflammatory responsehat occurs frequently in post-cardiac arrest patients may alsoause vasoplegia and severe vasodilation.32 Thus, noradrenaline,ith or without dobutamine, and fluid is usually the most effec-

ive treatment. Infusion of relatively large volumes of fluid isolerated remarkably well by patients with post-cardiac arrestyndrome.7,8,32 If treatment with fluid resuscitation, inotropesnd vasoactive drugs is insufficient to support the circulation,onsider insertion of a mechanical circulatory assistance devicee.g., IMPELLA, Abiomed, USA).7,105

Treatment may be guided by blood pressure, heart rate, urineutput, rate of plasma lactate clearance, and central venous oxygenaturation. Serial echocardiography may also be used, especiallyn haemodynamically unstable patients. In the ICU an arterial lineor continuous blood pressure monitoring is essential. Cardiac out-ut monitoring may help to guide treatment in haemodynamicallynstable patients but there is no evidence that its use affects out-ome. Some centres still advocate use of an intra aortic balloonump (IABP) in patients with cardiogenic shock, although the IABP-HOCK II Trial failed to show that use of the IABP improved 30-dayortality in patients with myocardial infarction and cardiogenic

hock.106,107

Similarly to the early goal-directed therapy that is recom-ended in the treatment of sepsis,108 although challenged by

everal recent studies,109111 a bundle of therapies, including apecific blood pressure target, has been proposed as a treatmenttrategy after cardiac arrest.8 However its influence on clini-al outcome is not firmly established and optimal targets for

ean arterial pressure and/or systolic arterial pressure remain

nknown.7,8,112114 One observational study of 151 post-cardiacrrest patients identified an association between a time-weightedverage mean arterial pressure (measured every 15 min) of greater

n 95 (2015) 202222

than 70 mmHg and good neurological outcome.113 A recent studyshowed an inverse relationship between mean arterial pressureand mortality.101 However, whether the use of vasoactive drugsto achieve such a blood pressure target achieves better neurologi-cal outcomes remains unknown. In the absence of definitive data,target the mean arterial blood pressure to achieve an adequateurine output (1 ml kg1 h1) and normal or decreasing plasma lac-tate values, taking into consideration the patients normal bloodpressure, the cause of the arrest and the severity of any myocar-dial dysfunction.3 These targets may vary depending on individualphysiology and co-morbid status. Importantly, hypothermia mayincrease urine output115 and impair lactate clearance.101

Tachycardia was associated with bad outcome in one retro-spective study.116 During mild induced hypothermia the normalphysiological response is bradycardia. In animal models this hasbeen shown to reduce the diastolic dysfunction that usually ispresent early after cardiac arrest.117 Bradycardia was previouslyconsidered to be a side effect, especially below a rate of 40 min1;however, recent retrospective studies have shown that bradycardiais associated with a good outcome.118,119 As long as blood pres-sure, lactate, SvO2 and urine output are sufficient, a bradycardiaof 40 min1 may be left untreated. Importantly, oxygen require-ments during mild induced hypothermia are reduced.

Relative adrenal insufficiency occurs frequently after successfulresuscitation from cardiac arrest and it appears to be associatedwith a poor prognosis when accompanied by post-resuscitationshock.120,121 Two randomised controlled trials involving 368patients with IHCA showed improved ROSC with the use of methyl-prednisolone and vasopressin in addition to adrenaline, comparedwith the use of placebo and adrenaline alone: combined RR 1.34(95% CI 1.211.43).122,123 No studies have assessed the effect ofadding steroids alone to standard treatment for IHCA. These studiescome from a single group of investigators and the population stud-ied had very rapid advanced life support, a high incidence of asys-tolic cardiac arrest, and low baseline survival compared with otherIHCA studies. Further confirmatory studies are awaited but, pend-ing further data, do not give steroids routinely after IHCA. There isno clinical evidence for the routine use of steroids after OHCA.

Immediately after a cardiac arrest there is typically a periodof hyperkalaemia. Subsequent endogenous catecholamine releaseand correction of metabolic and respiratory acidosis promotesintracellular transportation of potassium, causing hypokalaemia.Hypokalaemia may predispose to ventricular arrhythmias. Givepotassium to maintain the serum potassium concentrationbetween 4.0 and 4.5 mmol l1.

Implantable cardioverter defibrillators

Insertion of an implantable cardioverter defibrillator (ICD)should be considered in ischaemic patients with significant left ven-tricular dysfunction, who have been resuscitated from a ventriculararrhythmia that occurred later than 2448 h after a primary coro-nary event.124126 ICDs may also reduce mortality in cardiac arrestsurvivors at risk of sudden death from structural heart diseases orinherited cardiomyopathies.127,128 In all cases, a specialised elec-trophysiological evaluation should be performed before dischargefor placement of an ICD for secondary prevention of sudden cardiacdeath.

Disability (optimising neurological recovery)

Cerebral perfusion

Animal studies show that immediately after ROSC there is ashort period of multifocal cerebral no-reflow followed by transient

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lobal cerebral hyperaemia lasting 1530 min.129131 This is fol-owed by up to 24 h of cerebral hypoperfusion while the cerebral

etabolic rate of oxygen gradually recovers. After asphyxial car-iac arrest, brain oedema may occur transiently after ROSC but it

s rarely associated with clinically relevant increases in intracra-ial pressure.132,133 In many patients, autoregulation of cerebrallood flow is impaired (absent or right-shifted) for some time afterardiac arrest, which means that cerebral perfusion varies witherebral perfusion pressure instead of being linked to neuronalctivity.134,135 In a study that used near-infrared spectroscopy toeasure regional cerebral oxygenation, autoregulation was dis-

urbed in 35% of post-cardiac arrest patients and the majority ofhese had been hypertensive before their cardiac arrest136; thisends to support the recommendation made in the 2010 ERC Guide-ines: after ROSC, maintain mean arterial pressure near the patientsormal level.1 However, there is a significant gap in the knowledgebout how temperature impacts the optimal blood pressure.

edation

Although it has been common practice to sedate and ventilateatients for at least 24 h after ROSC, there are no high-level datao support a defined period of ventilation, sedation and neuro-

uscular blockade after cardiac arrest. Patients need to be sedateddequately during treatment with TTM, and the duration of seda-ion and ventilation is therefore influenced by this treatment. A

eta-analysis of drugs used for sedation during mild inducedypothermia showed considerable variability among 68 ICUs in aariety of countries.137 There are no data to indicate whether orot the choice of sedation influences outcome, but a combinationf opioids and hypnotics is usually used. Short-acting drugs (e.g.,ropofol, alfentanil, remifentanil) will enable more reliable and ear-

ier neurological assessment and prognostication (see Section 7).138

olatile anaesthetics have been used to sedate post cardiac arrestatients139 but although there are some animal data suggestingyocardial and neurological benefits,140 there are no clinical data

howing an advantage with this strategy. Adequate sedation willeduce oxygen consumption. During hypothermia, optimal seda-ion can reduce or prevent shivering, which enables the targetemperature to be achieved more rapidly. Use of published sedationcales for monitoring these patients (e.g., the Richmond or Ramsaycales) may be helpful.141,142

ontrol of seizures

Seizures are common after cardiac arrest and occur in approx-mately one-third of patients who remain comatose after ROSC.

yoclonus is most common and occurs in 1825%, the remainderaving focal or generalised tonicclonic seizures or a combinationf seizure types.31,143145 Clinical seizures, including myoclonusay or may not be of epileptic origin. Other motor manifesta-

ions could be mistaken for seizures146 and there are several typesf myoclonus147 the majority being non-epileptic. Use intermit-ent electroencephalography (EEG) to detect epileptic activity inatients with clinical seizure manifestations. Consider continuousEG to monitor patients with a diagnosed status epilepticus andffects of treatment.

In comatose cardiac arrest patients, EEG commonly detectspileptiform activity. Unequivocal seizure activity according totrict EEG-terminology148 is less common but post-anoxic status

pilepticus was detected in 2331% of patients using continuousEG-monitoring and more inclusive EEG-criteria.75,149,150 Patientsith electrographic status epilepticus may or may not have clin-

cally detectable seizure manifestations that may be masked by

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sedation. Whether systematic detection and treatment of electro-graphic epileptic activity improves patient outcome is not known.

Seizures may increase the cerebral metabolic rate151 and havethe potential to exacerbate brain injury caused by cardiac arrest:treat with sodium valproate, levetiracetam, phenytoin, benzodi-azepines, propofol, or a barbiturate. Myoclonus can be particularlydifficult to treat; phenytoin is often ineffective. Propofol is effec-tive to suppress post-anoxic myoclonus.152 Clonazepam, sodiumvalproate and levetiracetam are antimyoclonic drugs that maybe effective in post-anoxic myoclonus.147 After the first event,start maintenance therapy once potential precipitating causes (e.g.,intracranial haemorrhage, electrolyte imbalance) are excluded.

The use of prophylactic anticonvulsant drugs after cardiac arrestin adults has been insufficiently studied.153,154 Routine seizureprophylaxis in post-cardiac arrest patients is not recommendedbecause of the risk of adverse effects and the poor response to anti-epileptic agents among patients with clinical and electrographicseizures.

Myoclonus and electrographic seizure activity, including sta-tus epilepticus, are related to a poor prognosis but individualpatients may survive with good outcome (see Section 7).145,155 Pro-longed observation may be necessary after treatment of seizureswith sedatives, which will decrease the reliability of a clinicalexamination.156

Glucose control

There is a strong association between high blood glucoseafter resuscitation from cardiac arrest and poor neurologicaloutcome.13,15,20,157163 Although one randomised controlled trialin a cardiac surgical intensive care unit showed that tight con-trol of blood glucose (4.46.1 mmol l1 or 80110 mg dl1) usinginsulin reduced hospital mortality in critically ill adults,164 a sec-ond study by the same group in medical ICU patients showedno mortality benefit from tight glucose control.165 In one ran-domised trial of patients resuscitated from OHCA with ventricularfibrillation, strict glucose control (72108 mg dl1, 46 mmol l1)gave no survival benefit compared with moderate glucose control(108144 mg dl1, 68 mmol l1) and there were more episodesof hypoglycaemia in the strict glucose control group.166 Alarge randomised trial of intensive glucose control (81 mg dl1 108 mg dl1, 4.56.0 mmol l1) versus conventional glucose con-trol (180 mg dl1, 10 mmol l1 or less) in general ICU patientsreported increased 90-day mortality in patients treated with inten-sive glucose control.167,168 Severe hypoglycaemia is associatedwith increased mortality in critically ill patients,169 and comatosepatients are at particular risk from unrecognised hypoglycaemia.Irrespective of the target range, variability in glucose values isassociated with mortality.170 Compared with normothermia, mildinduced hypothermia is associated with higher blood glucosevalues, increased blood glucose variability and greater insulinrequirements.171 Increased blood glucose variability is associatedwith increased mortality and unfavourable neurological outcomeafter cardiac arrest.157,171

Based on the available data, following ROSC maintainthe blood glucose at 10 mmol l1 (180 mg dl1) and avoidhypoglycaemia.172 Do not implement strict glucose control in adultpatients with ROSC after cardiac arrest because it increases the riskof hypoglycaemia.

Temperature control

Treatment of hyperpyrexiaA period of hyperthermia (hyperpyrexia) is common in the

first 48 h after cardiac arrest.13,173176 Several studies documentan association between post-cardiac arrest pyrexia and poor

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utcomes.13,173,175178 The development of hyperthermia after period of mild induced hypothermia (rebound hyperthermia)s associated with increased mortality and worse neurologicalutcome.179182 There are no randomised controlled trials eval-ating the effect of treatment of pyrexia (defined as 37.6 C)ompared to no temperature control in patients after cardiac arrestnd the elevated temperature may only be an effect of a moreeverely injured brain. Although the effect of elevated temperaturen outcome is not proven, it seems reasonable to treat hyperther-ia occurring after cardiac arrest with antipyretics and to consider

ctive cooling in unconscious patients.

argeted temperature managementAnimal and human data indicate that mild induced hypother-

ia is neuroprotective and improves outcome after a period oflobal cerebral hypoxia-ischaemia.183,184 Cooling suppresses manyf the pathways leading to delayed cell death, including apopto-is (programmed cell death). Hypothermia decreases the cerebraletabolic rate for oxygen (CMRO2) by about 6% for each 1 C

eduction in core temperature and this may reduce the release ofxcitatory amino acids and free radicals.183,185 Hypothermia blockshe intracellular consequences of excitotoxin exposure (high cal-ium and glutamate concentrations) and reduces the inflammatoryesponse associated with the post-cardiac arrest syndrome. How-ver, in the temperature range 3336 C, there is no difference inhe inflammatory cytokine response in adult patients according to

recent study.186

All studies of post-cardiac arrest mild induced hypothermiaave included only patients in coma. One randomised trial and

pseudo-randomised trial demonstrated improved neurologicalutcome at hospital discharge or at 6 months in comatose patientsfter out-of-hospital VF cardiac arrest.187,188 Cooling was initiatedithin minutes to hours after ROSC and a temperature range of

234 C was maintained for 1224 h.Three cohort studies including a total of 1034 patients, have

ompared mild induced hypothermia (3234 C) to no temperatureanagement in OHCA and found no difference in neurolog-

cal outcome (adjusted pooled odds ratio (OR), 0.90 [95% CI.451.82].189191 One additional retrospective registry study of830 patients documented an increase in poor neurological out-ome among those with nonshockable OHCA treated with mildnduced hypothermia (adjusted OR 1.44 [95% CI 1.0392.006]).192

There are numerous before and after studies on the implemen-ation of temperature control after in hospital cardiac arrest buthese data are extremely difficult to interpret because of otherhanges in post cardiac arrest care that occurred simultaneously.ne retrospective cohort study of 8316 in-hospital cardiac arrest

IHCA) patients of any initial rhythm showed no difference in sur-ival to hospital discharge among those who were treated withild induced hypothermia compared with no active temperatureanagement (OR 0.9, 95% CI 0.651.23) but relatively few patientsere treated with mild induced hypothermia.193

In the Targeted Temperature Management (TTM) trial, 950ll-rhythm OHCA patients were randomised to 36 h of temperatureontrol (comprising 28 h at the target temperature followed bylow rewarm) at either 33 C or 36 C.31 Strict protocols were fol-owed for assessing prognosis and for withdrawal of life-sustainingreatment (WLST). There was no difference in the primary outcome

all cause mortality, and neurological outcome at 6 months waslso similar (hazard ratio (HR) for mortality at end of trial 1.06,5% CI 0.891.28; relative risk (RR) for death or poor neurological

utcome at 6 months 1.02, 95% CI 0.881.16). Detailed neurologicalutcome at 6 months was also similar.22,24 Importantly, patients inoth arms of this trial had their temperature well controlled so thatever was prevented in both groups. TTM at 33 C was associated

n 95 (2015) 202222

with decreased heart rate, elevated lactate, the need for increasedvasopressor support, and a higher extended cardiovascular SOFAscore compared with TTM at 36 C.101,194 Bradycardia during mildinduced hypothermia may be beneficial it is associated withgood neurological outcome among comatose survivors of OHCA,presumably because autonomic function is preserved.118,119

The optimal duration for mild induced hypothermia and TTMis unknown although it is currently most commonly used for24 h. Previous trials treated patients with 1228 h of targeted tem-perature management.31,187,188 Two observational trials found nodifference in mortality or poor neurological outcome with 24 hcompared with 72 h of hypothermia.195,196 The TTM trial providedstrict normothermia (

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hose who did not receive prehospital cooling. No individual trialound an effect on either poor neurological outcome or mortality.

Four RCTs provided low quality evidence for an increased riskf re-arrest among subjects who received prehospital inducedypothermia (RR, 1.22; 95% CI 1.011.46),204,205,207 although thisesult was driven by data from the largest trial.207 Three trialseported no pulmonary oedema in any group, two small pilot tri-ls found no difference in the incidence of pulmonary oedemaetween groups,204,208 and one trial showed an increase in pul-onary oedema in patients who received prehospital cooling (RR,

.34; 95% CI 1.151.57).207

Based on this evidence, prehospital cooling using a rapid infu-ion of large volumes of cold intravenous fluid immediately afterOSC is not recommended. It may still be reasonable to infuse cold

ntravenous fluid where patients are well monitored and a lowerarget temperature (e.g., 33 C) is the goal. Early cooling strategies,ther than rapid infusion of large volumes of cold intravenous fluid,nd cooling during cardiopulmonary resuscitation in the prehos-ital setting have not been studied adequately. Whether certainatient populations (e.g., patients for whom transport time to aospital is longer than average) might benefit from early coolingtrategies remains unknown.

ow to control temperature? The practical application of TTMs divided into three phases: induction, maintenance andewarming.210 External and/or internal cooling techniques can besed to initiate and maintain TTM. If a target temperature of 36 C

s chosen, for the many post cardiac arrest patients who arrive inospital with a temperature less than 36 C, a practical approach

s to let them rewarm spontaneously and to activate a TTM-devicehen they have reached 36 C. The maintenance phase at 36 C is

he same as for other target temperatures; shivering, for example,oes not differ between patients treated at 33 C and 36 C.31 Whensing a target of 36 C, the rewarming phase will be shorter.

If a lower target temperature, e.g., 33 C is chosen, an infusion of0 ml kg1 of 4 C saline or Hartmanns solution will decrease coreemperature by approximately 1.01.5 C.206,207,211 However, inne prehospital randomised controlled trial this intervention wasssociated with increased pulmonary oedema (diagnosed on thenitial chest radiograph) and an increased rate of re-arrest duringransport to hospital.207

Methods of inducing and/or maintaining TTM include:

Simple ice packs and/or wet towels are inexpensive; however,these methods may be more time consuming for nursing staff,may result in greater temperature fluctuations, and do not enablecontrolled rewarming.11,19,188,212219 Ice cold fluids alone cannotbe used to maintain hypothermia,220 but even the addition ofsimple ice packs may control the temperature adequately.218

Cooling blankets or pads.221227

Water or air circulating blankets.7,8,10,182,226,228234

Water circulating gel-coated pads.7,224,226,233,235238

Transnasal evaporative cooling209 this technique enables cool-ing before ROSC and is undergoing further investigation in a largemulticentre randomised controlled trial.239

Intravascular heat exchanger, placed usually in the femoral orsubclavian veins.7,8,215,216,226,228,232,240245

Extracorporeal circulation (e.g., cardiopulmonary bypass,ECMO).246,247

In most cases, it is easy to cool patients initially after ROSCecause the temperature normally decreases within this first

our.13,176 Admission temperature after OHCA is usually between5 C and 36 C and in a recent large trial the median tempera-ure was 35.3 C.31 If a target temperature of 36 C is chosen allow

slow passive rewarm to 36 C. If a target temperature of 33 C is

n 95 (2015) 202222 209

chosen, initial cooling is facilitated by neuromuscular blockade andsedation, which will prevent shivering.248 Magnesium sulphate, anaturally occurring NMDA receptor antagonist, that reduces theshivering threshold slightly, can also be given to reduce the shive-ring threshold.210,249

In the maintenance phase, a cooling method with effectivetemperature monitoring that avoids temperature fluctuations ispreferred. This is best achieved with external or internal cool-ing devices that include continuous temperature feedback toachieve a set target temperature.250 The temperature is typi-cally monitored from a thermistor placed in the bladder and/oroesophagus.210,251,252 As yet, there are no data indicating thatany specific cooling technique increases survival when com-pared with any other cooling technique; however, internal devicesenable more precise temperature control compared with externaltechniques.226,250

Plasma electrolyte concentrations, effective intravascular vol-ume and metabolic rate can change rapidly during rewarming,as they do during cooling. Rebound hyperthermia is associatedwith worse neurological outcome.179,180 Thus, rewarming shouldbe achieved slowly: the optimal rate is not known, but the con-sensus is currently about 0.250.5 C of rewarming per hour.228

Choosing a strategy of 36 C will reduce this risk.31

Physiological effects and side effects of hypothermia. The well-recognised physiological effects of hypothermia need to bemanaged carefully210:

Shivering will increase metabolic and heat production, thusreducing cooling rates strategies to reduce shivering are dis-cussed above. The occurrence of shivering in cardiac arrestsurvivors who undergo mild induced hypothermia is associatedwith a good neurological outcome253,254; it is a sign of a normalphysiological response. Occurrence of shivering was similar at atarget temperature of 33 C and 36 C.31 A sedation protocol isrequired.

Mild induced hypothermia increases systemic vascular resistanceand causes arrhythmias (usually bradycardia).241 Importantly,the bradycardia caused by mild induced hypothermia may bebeneficial (similar to the effect achieved by beta-blockers); itreduces diastolic dysfunction117 and its occurrence has beenassociated with good neurological outcome.118,119

Mild induced hypothermia causes a diuresis and electrolyteabnormalities such as hypophosphataemia, hypokalaemia, hypo-magnesaemia and hypocalcaemia.31,210,255

Hypothermia decreases insulin sensitivity and insulin secretion,and causes hyperglycaemia,188 which will need treatment withinsulin (see glucose control).

Mild induced hypothermia impairs coagulation and may increasebleeding, although this effect seems to be negligible256 and hasnot been confirmed in clinical studies.7,31,187 In one registrystudy, an increased rate of minor bleeding occurred with the com-bination of coronary angiography and mild induced hypothermia,but this combination of interventions was the also the best pre-dictor of good outcome.20

Hypothermia can impair the immune system and increase infec-tion rates.210,217,222 Mild induced hypothermia is associated withan increased incidence of pneumonia257,258; however, this seems

tional study, use of prophylactic antibiotics was associated witha reduced incidence of pneumonia.259 In another observationalstudy of 138 patients admitted to ICU after OHCA, early use ofantibiotics was associated with improved survival.260

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The serum amylase concentration is commonly increased duringhypothermia but the significance of this unclear.The clearance of sedative drugs and neuromuscular blockers isreduced by up to 30% at a core temperature of 34 C.261 Clear-ance of sedative and other drugs will be closer to normal at atemperature closer to 37.0 C.

ontraindications to targeted temperature management. Generallyecognised contraindications to TTM at 33 C, but which areot applied universally, include: severe systemic infection andre-existing medical coagulopathy (fibrinolytic therapy is not aontraindication to mild induced hypothermia). Two observationaltudies documented a positive inotropic effect from mild inducedypothermia in patients in cardiogenic shock,262,263 but in the TTMtudy there was no difference in mortality among patients withild shock on admission who were treated with a target temper-

ture of 33 C compared with 36 C.194 Animal data also indicatemproved contractile function with mild induced hypothermiarobably because of increased Ca2+ sensititvity.264

ther therapies

Neuroprotective drugs (Coenzyme Q10,223 thiopental,153

lucocorticoids,123,265 nimodipine,266,267 lidoflazine268 oriazepam154) used alone, or as an adjunct to mild inducedypothermia, have not been shown to increase neurologically

ntact survival when included in the post arrest treatment of cardiacrrest. The combination of xenon and mild induced hypothermiaas been studied in a feasibility trial and is undergoing furtherlinical evaluation.269

rognostication

This section has been adapted from the Advisory Statement on Neu-ological Prognostication in comatose survivors of cardiac arrest,270

ritten by members of the ERC ALS Working Group and of the Traumand Emergency Medicine (TEM) Section of the European Society ofntensive Care Medicine (ESICM), in anticipation of the 2015 Guide-ines.

Hypoxic-ischaemic brain injury is common after resuscitationrom cardiac arrest.271 Two thirds of those dying after admissiono ICU following out-of-hospital cardiac arrest die from neuro-ogical injury; this has been shown both before28 and after27,30,31

he implementation of target temperature management (TTM) forost-resuscitation care. Most of these deaths are due to activeithdrawal of life sustaining treatment (WLST) based on prog-ostication of a poor neurological outcome.27,30 For this reason,hen dealing with patients who are comatose after resuscitation

rom cardiac arrest minimising the risk of a falsely pessimistic pre-iction is essential. Ideally, when predicting a poor outcome thealse positive rate (FPR) should be zero with the narrowest possi-le confidence interval (CI). However, most prognostication studies

nclude so few patients that even if the FPR is 0%, the upper limitf the 95% CI is often high.272,273 Moreover, many studies are con-ounded by self-fulfilling prophecy, which is a bias occurring whenhe treating physicians are not blinded to the results of the outcomeredictor and use it to make a decision on WLST.272,274 Finally, bothTM itself and sedatives or neuromuscular blocking drugs used toaintain it may potentially interfere with prognostication indices,

specially those based on clinical examination.156

linical examination

Bilateral absence of pupillary light reflex at 72 h from ROSCredicts poor outcome with close to 0% FPR, both in TTM-reated and in non-TTM-treated patients (FPR 1 [03] and 0 [08],

n 95 (2015) 202222

respectively)156,275284 and a relatively low sensitivity (19% and18%, respectively). Similar performance has been documented forbilaterally absent corneal reflex.272,273

In non-TTM-treated patients276,285 an absent or extensor motorresponse to pain at 72 h from ROSC has a high (74 [6879]%)sensitivity for prediction of poor outcome, but the FPR is alsohigh (27 [1248]%). Similar results were observed in TTM-treatedpatients.156,277280,282284,286288 Nevertheless, the high sensitivityof this sign may enable it to be used to identify the population withpoor neurological status needing prognostication. Like the cornealreflex, the motor response can be suppressed by sedatives or neu-romuscular blocking drugs.156 When interference from residualsedation or paralysis is suspected, prolonging observation of theseclinical signs beyond 72 h from ROSC is recommended, in order tominimise the risk of obtaining false positive results.

Myoclonus is a clinical phenomenon consisting of sudden, brief,involuntary jerks caused by muscular contractions or inhibitions.A prolonged period of continuous and generalised myoclonic jerksis commonly described as status myoclonus. Although there is nodefinitive consensus on the duration or frequency of myoclonicjerks required to qualify as status myoclonus, in prognostica-tion studies in comatose survivors of cardiac arrest the minimumreported duration is 30 min. The names and definitions used forstatus myoclonus vary among those studies.

While the presence of myoclonic jerks in comatose survivorsof cardiac arrest is not consistently associated with poor outcome(FPR 9%),145,272 a status myoclonus starting within 48 h from ROSCwas consistently associated with a poor outcome (FPR 0 [05]%;sensitivity 8%) in prognostication studies made in non-TTM-treatedpatients,276,289,290 and is also highly predictive (FPR 0% [04]; sensi-tivity 16%) in TTM-treated patients.144,156,291 However, several casereports of good neurological recovery despite an early-onset, pro-longed and generalised myoclonus have been published. In some ofthese cases myoclonus persisted after awakening and evolved into achronic action myoclonus (LanceAdams syndrome).292297 In oth-ers it disappeared with recovery of consciousness.298,299 The exacttime when recovery of consciousness occurred in these cases mayhave been masked by the myoclonus itself and by ongoing sedation.Patients with post-arrest status myoclonus should be evaluated offsedation whenever possible; in those patients, EEG recording canbe useful to identify EEG signs of awareness and reactivity and toreveal a coexistent epileptiform activity.

While predictors of poor outcome based on clinical examinationare inexpensive and easy to use, they cannot be concealed from thetreating team and therefore their results may potentially influenceclinical management and cause a self-fulfilling prophecy. Clinicalstudies are needed to evaluate the reproducibility of clinical signsused to predict outcome in comatose post-arrest patients.

Electrophysiology

Short-latency somatosensory evoked potentials (SSEPs)In non-TTM-treated post-arrest comatose patients, bilateral

absence of the N20 SSEP wave predicts death or vegetative state(CPC 45) with 0 [03]% FPR as early as 24 h from ROSC,276,300,301

and it remains predictive during the following 48 h with a con-sistent sensitivity (4546%).276,300,302304 Among a total of 287patients with absent N20 SSEP wave at 72 h from ROSC, therewas only one false positive result (positive predictive value 99.7[98100]%).305

In TTM-treated patients, bilateral absence of the N20 SSEP

wave is also very accurate in predicting poor outcome both dur-ing mild induced hypothermia278,279,301,306 (FPR 2 [04]%) andafter rewarming277,278,286,288,304 (FPR 1 [03]%). The few cases offalse reports observed in large patient cohorts were due mainly

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o artefacts.279,284 SSEP recording requires appropriate skills andxperience, and utmost care should be taken to avoid electricalnterference from muscle artefacts or from the ICU environment.nterobserver agreement for SSEPs in anoxicischaemic coma is

oderate to good but is influenced by noise.307,308

In most prognostication studies bilateral absence of N20 SSEPas been used as a criterion for deciding on withdrawal of

ife-sustaining treatment (WLST), with a consequent risk of self-ulfilling prophecy.272 SSEP results are more likely to influencehysicians and families WLST decisions than those of clinicalxamination or EEG.309

lectroencephalographybsence of EEG reactivity. In TTM-treated patients, absence ofEG background reactivity predicts poor outcome with 2 [17]%PR288,310,311 during TH and with 0 [03]% FPR286,288,310 afterewarming at 4872 h from ROSC. However, in one prognosticationtudy in posthypoxic myoclonus three patients with no EEG reactiv-ty after TTM had a good outcome.144 Most of the prognosticationtudies on absent EEG reactivity after cardiac arrest are from theame group of investigators. Limitations of EEG reactivity includeack of standardisation as concerns the stimulation modality and

odest interrater agreement.312

tatus epilepticus. In TTM-treated patients, the presence of statuspilepticus (SE), i.e., a prolonged epileptiform activity, during THr immediately after rewarming150,291,313 is almost invariably ut not always followed by poor outcome (FPR from 0% to 6%),specially in presence of an unreactive150,314 or discontinuous EEGackground.75 All studies on SE included only a few patients. Defi-itions of SE were inconsistent among those studies.

urst-suppression. Burst-suppression has recently been defined asore than 50% of the EEG record consisting of periods of EEG

oltage

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ig. 5.2. Prognostication strategy algorithm. EEG: electroencephalography; NSE: neous circulation; FPR: false positive rate; CI: confidence interval.

All studies on prognostication after cardiac arrest using imag-ng have a small sample size with a consequent low precision, and

very low quality of evidence. Most of those studies are retrospec-ive, and brain CT or MRI had been requested at the discretion ofhe treating physician, which may have caused a selection bias andverestimated their performance.

uggested prognostication strategy

A careful clinical neurological examination remains the foun-ation for prognostication of the comatose patient after cardiacrrest.344 Perform a thorough clinical examination daily to detectigns of neurological recovery such as purposeful movements or todentify a clinical picture suggesting that brain death has occurred.

The process of brain recovery following global post-anoxicnjury is completed within 72 h from arrest in most patients.290,345

owever, in patients who have received sedatives 12 h beforehe 72 h post ROSC neurological assessment, the reliability oflinical examination may be reduced.156 Before decisive assess-ent is performed, major confounders must be excluded346,347;

part from sedation and neuromuscular blockade, these includeypothermia, severe hypotension, hypoglycaemia, and metabolicnd respiratory derangements. Suspend sedatives and neuromus-ular blocking drugs for long enough to avoid interference with

-specific enolase; SSEP: somatosensory evoked potentials; ROSC: return of sponta-

clinical examination. Short-acting drugs are preferred wheneverpossible. When residual sedation/paralysis is suspected, considerusing antidotes to reverse the effects of these drugs.

The prognostication strategy algorithm (Fig. 2) is applicable toall patients who remain comatose with an absent or extensor motorresponse to pain at 72 h from ROSC. Results of earlier prognostictests are also considered at this time point.

Evaluate the most robust predictors first. These predictorshave the highest specificity and precision (FPR

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hreshold is inconsistent in prognostication studies. These pre-ictors include the presence of early status myoclonus (within8 h from ROSC), high values of serum NSE at 4872 h after ROSC,n unreactive malignant EEG pattern (burst-suppression, statuspilepticus) after rewarming, the presence of a marked reductionf the GM/WM ratio or sulcal effacement on brain CT within 24 hfter ROSC or the presence of diffuse ischaemic changes on brainRI at 25 days after ROSC. Based on expert opinion, we suggestaiting at least 24 h after the first prognostication assessment

nd confirming unconsciousness with a Glasgow motor score of2 before using this second set of predictors. We also suggestombining at least two of these predictors for prognostication.

No specific NSE threshold for prediction of poor outcome with% FPR can be recommended at present. Ideally, every hospital lab-ratory assessing NSE should create its own normal values andut-off levels based on the test kit used. Sampling at multiple time-oints is recommended to detect trends in NSE levels and to reducehe risk of false positive results.335 Care should be taken to avoidaemolysis when sampling NSE.

Although the most robust predictors showed no false positivesn most studies, none of them singularly predicts poor outcome

ith absolute certainty when the relevant comprehensive evidences considered. Moreover, those predictors have often been used for

LST decisions, with the risk of a self-fulfilling prophecy. For thiseason, we recommend that prognostication should be multimodalhenever possible, even in presence of one of these predictors.part from increasing safety, limited evidence also suggests thatultimodal prognostication increases sensitivity.286,311,325,348

When prolonged sedation and/or paralysis is necessary, forxample, because of the need to treat severe respiratory insuffi-iency, we recommend postponing prognostication until a reliablelinical examination can be performed. Biomarkers, SSEP and imag-ng studies may play a role in this context, since they are insensitiveo drug interference.

When dealing with an uncertain outcome, clinicians shouldonsider prolonged observation. Absence of clinical improvementver time suggests a worse outcome. Although awakening haseen described as late as 25 days after arrest,291,298,349 most sur-ivors will recover consciousness within one week.31,329,350352

n a recent observational study,351 94% of patients awoke within.5 days from rewarming and the remaining 6% awoke within tenays. Even those awakening late, can still have a good neurologicalutcome.351

ehabilitation

Although neurological outcome is considered to be good for theajority of cardiac arrest survivors, cognitive and emotional prob-

ems and fatigue are common.23,24,279,353356 Long-term cognitivempairments are present in half of survivors.22,357,358 Memory is

ost frequently affected, followed by problems in attention andxecutive functioning (planning and organisation).23,359 The cog-itive impairments can be severe, but are mostly mild.22 In onetudy, of 796 OHCA survivors who had been employed before theirardiac arrest, 76.6% returned to work.360 Mild cognitive problemsre often not recognised by health care professionals and cannot beetected with standard outcome scales such as the Cerebral Per-ormance Categories (CPC) or the Mini-Mental State ExaminationMMSE).24,361 Emotional problems, including depression, anxietynd posttraumatic stress are also common.362,363 Depression isresent in 1445% of the survivors, anxiety in 1361% and symp-

oms of posttraumatic stress occur in 1927%.355 Fatigue is also

complaint that is often reported after cardiac arrest. Even sev-ral years after a cardiac arrest, 56% of the survivors suffer severeatigue.356

n 95 (2015) 202222 213

It is not only the patients who experience problems; theirpartners and caregivers can feel highly burdened and oftenhave emotional problems, including symptoms of posttraumaticstress.356,364 After hospital discharge both survivors and care-givers frequently experience a lack of information on importanttopics including physical and emotional challenges, implantablecardioverter defibrillators (ICD), regaining daily activities, partnerrelationships and dealing with health care providers.365 A system-atic review on coronary heart disease patients also showed theimportance of active information supply and patient education.366

Both cognitive and emotional problems have significant impactand can affect a patients daily functioning, return to work andquality of life.356,367,368 Therefore, follow-up care after hospitaldischarge is necessary. Although the evidence on the reha-bilitation phase appears scarce, three randomised controlledtrials have shown that the outcome after cardiac arrest canbe improved.369371 First, an eleven-session nursing interventionreduced cardiovascular mortality and depressive symptoms. Itdid so by focussing on physiological relaxation, self-management,coping strategies and health education.369 Another nursing inter-vention was found to improve physical symptoms, anxiety,self-confidence and disease knowledge.370,371 This interventionconsisted of eight telephone sessions, a 24/7 nurse pager sys-tem and an information booklet and was directed at improvingself-efficacy, outcome efficacy expectations and enhancing self-management behavioural skills.372 A third intervention calledStand still. . ., and move on, improved overall emotional state,anxiety and quality of life, and also resulted in a faster returnto work.373 This intervention aimed to screen early for cogni-tive and emotional problems, to provide information and support,to promote self-management and to refer to specialised care, ifneeded.374,375 It generally consisted of only one or two consul-tations with a specialised nurse and included supply of a specialinformation booklet.

The organisation of follow-up after cardiac arrest varies widelybetween hospitals and countries in Europe. Follow-up care shouldbe organised systematically and can be provided by a physician orspecialised nurse. It includes at least the following aspects:

Screening for cognitive impairments. There is currently no goldstandard on how to perform such screening. A good first stepwould be to ask the patient and a relative or caregiver about cog-nitive complaints (for example problems with memory, attention,planning). If feasible, administer a structured interview or check-list, such as the Checklist Cognition and Emotion,376 or a shortcognitive screening instrument, such as the Montreal CognitiveAssessment (MoCA) (freely available in many languages at http://www.mocatest.org). In cases where there are signs of cognitiveimpairments, refer to a neuropsychologist for neuropsychologi-cal assessment or to a specialist in rehabilitation medicine for arehabilitation programme.377

Screening for emotional problems. Ask whether the patient expe-riences any emotional problems, such as symptoms of depression,anxiety or posttraumatic stress. General measures that can be usedinclude the Hospital Anxiety and Depression Scale (HADS) andthe Impact of Event Scale.378,379 In case of emotional problemsrefer to a psychologist or psychiatrist for further examination andtreatment.355

Provision of information. Give active information on the potentialnon-cardiac consequences of a cardiac arrest including cogni-tive impairment, emotional problems and fatigue. Other topicsthat can be addressed include heart disease, ICDs, regaining dailyactivities, partner relationships and sexuality, dealing with healthcare providers and caregiver strain.365 It is best to combine writ-ten information with the possibility for personal consultation.

An example of an information booklet is available (in Dutch andEnglish).373,374

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rgan donation

Organ donation should be considered in those who havechieved ROSC and who fulfil criteria for death using neurologicalriteria.380 In those comatose patients in whom a decision is madeo withdraw life-sustaining therapy, organ donation should beonsidered after circulatory death occurs. Organ donation canlso be considered in individuals where CPR is not successful inchieving ROSC. All decisions concerning organ donation mustollow local legal and ethical requirements, as these vary inifferent settings.

Non-randomised studies have shown that graft survival atne year is similar from donors who have had CPR com-ared with donors who have not had CPR: adult hearts (3230rgans381387), adult lungs (1031 organs383,385,388), adult kidneys5000 organs381,383), adult livers (2911 organs381,383), and adultntestines (25 organs383).

Non-randomised studies have also shown that graft survival atne year was similar when organs recovered from donors withngoing CPR were compared to other types of donors for adultidneys (199 organs389391) or adult livers (60 organs390,392,393).

Solid organs have been successfully transplanted after cir-ulatory death. This group of patients offers an opportunity toncrease the organ donor pool. Organ retrieval from donationfter circulatory death (DCD) donors is classified as controlledr uncontrolled.394,395 Controlled donation occurs after plannedithdrawal of treatment following non-survivable injuries and ill-esses. Uncontrolled donation describes donation from patientsith unsuccessful CPR in whom a decision has been made that CPR

hould be stopped. Once death has been diagnosed, the assessmentf which includes a pre-defined period of observation to ensure apontaneous circulation does not return,396 organ preservation andetrieval takes place. Aspects or uncontrolled organ donation areomplex and controversial as some of the same techniques useduring CPR to attempt to achieve ROSC are also used for organreservation after death has been confirmed, e.g., mechanical chestompression and extracorporeal circulation. Locally agreed proto-ols must therefore be followed.

creening for inherited disorders

Many sudden death victims have silent structural heart disease,ost often coronary artery disease, but also primary arrhyth-ia syndromes, cardiomyopathies, familial hypercholesterolaemia

nd premature ischaemic heart disease. Screening for inher-ted disorders is crucial for primary prevention in relatives ast may enable preventive antiarrhythmic treatment and medicalollow-up.397399 This screening should be performed using clini-al examination, electrophysiology and cardiac imaging. In selectedases, genetic mutations associated with inherited cardiac diseaseshould also be searched.400

ardiac arrest centres

There is wide variability in survival among hospitals caringor patients after resuscitation from cardiac arrest.9,13,16,17,401403

any studies have reported an association between survival to hos-ital discharge and transport to a cardiac arrest centre but there

s inconsistency in the hospital factors that are most related toatient outcome.4,5,9,17,401,404416 There is also inconsistency in theervices that together define a cardiac arrest centre. Most experts

gree that such a centre must have a cardiac catheterisation labora-ory that is immediately accessible 24/7 and the facility to provideargeted temperature management. The availability of a neurol-gy service that can provide neuroelectrophysiological monitoring

n 95 (2015) 202222

(electroencephalography (EEG)) and investigations (e.g., EEG andsomatosensory evoked potentials (SSEPs)) is also essential.

There is some low-level evidence that ICUs admitting more than50 post-cardiac arrest patients per year produce better survivalrates than those admitting less than 20 cases per year17; how-ever, differences in case mix could account for these differences.An observational study showed that unadjusted survival to dis-charge was greater in hospitals that received 40 cardiac arrestpatients/year compared with those that received

citatio
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