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European Resuscitation Council and European Society of Intensive Care Medicine Guidelines for Post-resuscitation Care 2015

Section 5 of the European Resuscitation Council Guidelines for Resuscitation 2015

      Summary of changes since 2010 guidelines

      In 2010, post-resuscitation care was incorporated into the Advanced Life Support section of the European Resuscitation Council (ERC) Guidelines.
      • Deakin C.D.
      • Nolan J.P.
      • Soar J.
      • et al.
      European Resuscitation Council Guidelines for Resuscitation 2010. Section 4. Adult advanced life support.
      The ERC and the European Society of Intensive Care Medicine (ESICM) have collaborated to produce these post-resuscitation care guidelines, which recognise the importance of high-quality post-resuscitation care as a vital link in the Chain of Survival.
      • Nolan J.
      • Soar J.
      • Eikeland H.
      The chain of survival.
      These post-resuscitation care guidelines are being co-published in Resuscitation and Intensive Care Medicine.
      The most important changes in post-resuscitation care since 2010 include:
      • There is a greater emphasis on the need for urgent coronary catheterisation and percutaneous coronary intervention (PCI) following 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 the previously recommended 32–34 °C.
      • Prognostication is now undertaken using a multimodal strategy and there is emphasis on allowing sufficient time for neurological recovery and to enable sedatives to be cleared.
      • A novel section has been added which addresses rehabilitation after survival from a cardiac arrest. Recommendations include the systematic organisation of follow-up care, which should include screening for potential cognitive and emotional impairments and provision of information.

      The international consensus on cardiopulmonary resuscitation science and the guidelines process

      The International Liaison Committee on Resuscitation (ILCOR, www.ilcor.org) includes representatives from the American Heart Association (AHA), the European Resuscitation Council (ERC), the Heart and 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 Foundation (IAHF), and the Resuscitation Council of Asia (RCA). Since 2000, researchers from the ILCOR member councils have evaluated resuscitation science in 5-yearly cycles. The most recent International Consensus Conference was held in Dallas in February 2015 and the published conclusions and recommendations from this process form the basis of the ERC Guidelines 2015 and for these ERC-ESICM post-resuscitation care guidelines. During the three years leading up to this conference, 250 evidence reviewers from 39 countries reviewed thousands of relevant, peer-reviewed publications to address 169 specific resuscitation questions, each in the standard PICO (Population, Intervention, Comparison, Outcome) format. To assess the quality of the evidence and the strength of the recommendations, ILCOR adopted the GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology. Each PICO question was reviewed by at least two evidence reviewers who drafted a science statement based on their interpretation of all relevant data on the specific topic and the relevant ILCOR task force added consensus draft treatment recommendations. Final wording of science statements and treatment recommendations was completed after further review by ILCOR member organisations and by the editorial board, and published in Resuscitation and Circulation as the 2015 Consensus on Science and Treatment Recommendations (CoSTR). These ERC-ESICM guidelines on post-resuscitation care are based on the 2015 CoSTR document and represent consensus among the writing group, which included representatives of the ERC and the ESICM.

      Introduction

      Successful return of spontaneous circulation (ROSC) is the first step towards the goal of complete recovery from cardiac arrest. The complex pathophysiological processes that occur following whole body ischaemia during cardiac arrest and the subsequent reperfusion response during CPR and following successful resuscitation have been termed the post-cardiac arrest syndrome.
      • Nolan J.P.
      • Neumar R.W.
      • Adrie C.
      • et al.
      Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.
      Depending on the cause of the arrest, and the severity of the post-cardiac arrest syndrome, many patients will require multiple organ support and the treatment they receive during this post-resuscitation period influences significantly the overall outcome and particularly the quality of neurological recovery.
      • Spaite D.W.
      • Bobrow B.J.
      • Stolz U.
      • et al.
      Statewide regionalization of postarrest care for out-of-hospital cardiac arrest: association with survival and neurologic outcome.
      • Soholm H.
      • Wachtell K.
      • Nielsen S.L.
      • et al.
      Tertiary centres have improved survival compared to other hospitals in the Copenhagen area after out-of-hospital cardiac arrest.
      • Kirves H.
      • Skrifvars M.B.
      • Vahakuopus M.
      • Ekstrom K.
      • Martikainen M.
      • Castren M.
      Adherence to resuscitation guidelines during prehospital care of cardiac arrest patients.
      • Sunde K.
      • Pytte M.
      • Jacobsen D.
      • et al.
      Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest.
      • Gaieski D.F.
      • Band R.A.
      • Abella B.S.
      • et al.
      Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest.
      • Carr B.G.
      • Goyal M.
      • Band R.A.
      • et al.
      A national analysis of the relationship between hospital factors and post-cardiac arrest mortality.
      • Oddo M.
      • Schaller M.D.
      • Feihl F.
      • Ribordy V.
      • Liaudet L.
      From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest.
      • Knafelj R.
      • Radsel P.
      • Ploj T.
      • Noc M.
      Primary percutaneous coronary intervention and mild induced hypothermia in comatose survivors of ventricular fibrillation with ST-elevation acute myocardial infarction.
      The post-resuscitation phase starts at the location where ROSC is achieved but, once stabilised, the patient is transferred to the most appropriate high-care area (e.g., emergency room, cardiac catheterisation laboratory or intensive care unit (ICU)) for continued diagnosis, monitoring and treatment. The post-resuscitation care algorithm (Fig. 5.1) outlines some of the key interventions required to optimise outcome for these patients.
      Figure thumbnail gr1
      Fig. 5.1Post-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: implanted cardioverter defibrillator.
      Some patients do awake rapidly following cardiac arrest – in some reports it is as high as 15–46% of the out-of hospital cardiac arrest patients admitted to hospital.
      • Deakin C.D.
      • Fothergill R.
      • Moore F.
      • Watson L.
      • Whitbread M.
      Level of consciousness on admission to a Heart Attack Centre is a predictor of survival from out-of-hospital cardiac arrest.
      • Langhelle A.
      • Tyvold S.S.
      • Lexow K.
      • Hapnes S.A.
      • Sunde K.
      • Steen P.A.
      In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A comparison between four regions in Norway.
      • Tomte O.
      • Andersen G.O.
      • Jacobsen D.
      • Draegni T.
      • Auestad B.
      • Sunde K.
      Strong and weak aspects of an established post-resuscitation treatment protocol – a five-year observational study.
      Response times, rates of bystander CPR, times to defibrillation and the duration of CPR impact on these numbers.
      • Tomte O.
      • Andersen G.O.
      • Jacobsen D.
      • Draegni T.
      • Auestad B.
      • Sunde K.
      Strong and weak aspects of an established post-resuscitation treatment protocol – a five-year observational study.
      Although we have no data, it is reasonable to recommend that if there is any doubt about the patient's neurological function, the patient's trachea should be intubated and treatment to optimise haemodynamic, respiratory and metabolic variables, together with targeted temperature management started, following the local standardised treatment plan.
      Of those comatose patients admitted to ICUs after cardiac arrest, as many as 40–50% survive to be discharged from hospital depending on the cause of arrest, system and quality of care.
      • Sunde K.
      • Pytte M.
      • Jacobsen D.
      • et al.
      Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest.
      • Oddo M.
      • Schaller M.D.
      • Feihl F.
      • Ribordy V.
      • Liaudet L.
      From evidence to clinical practice: effective implementation of therapeutic hypothermia to improve patient outcome after cardiac arrest.
      • Langhelle A.
      • Tyvold S.S.
      • Lexow K.
      • Hapnes S.A.
      • Sunde K.
      • Steen P.A.
      In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A comparison between four regions in Norway.
      • Tomte O.
      • Andersen G.O.
      • Jacobsen D.
      • Draegni T.
      • Auestad B.
      • Sunde K.
      Strong and weak aspects of an established post-resuscitation treatment protocol – a five-year observational study.
      • Nolan J.P.
      • Laver S.R.
      • Welch C.A.
      • Harrison D.A.
      • Gupta V.
      • Rowan K.
      Outcome following admission to UK intensive care units after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database.
      • Keenan S.P.
      • Dodek P.
      • Martin C.
      • Priestap F.
      • Norena M.
      • Wong H.
      Variation in length of intensive care unit stay after cardiac arrest: where you are is as important as who you are.
      • Carr B.G.
      • Kahn J.M.
      • Merchant R.M.
      • Kramer A.A.
      • Neumar R.W.
      Inter-hospital variability in post-cardiac arrest mortality.
      • Niskanen M.
      • Reinikainen M.
      • Kurola J.
      Outcome from intensive care after cardiac arrest: comparison between two patient samples treated in 1986–87 and 1999–2001 in Finnish ICUs.
      • Hovdenes J.
      • Laake J.H.
      • Aaberge L.
      • Haugaa H.
      • Bugge J.F.
      Therapeutic hypothermia after out-of-hospital cardiac arrest: experiences with patients treated with percutaneous coronary intervention and cardiogenic shock.
      • Nielsen N.
      • Hovdenes J.
      • Nilsson F.
      • et al.
      Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest.
      Of the patients who survive to hospital discharge, the vast majority have a good neurological outcome although many with subtle cognitive impairment.
      • Sulzgruber P.
      • Kliegel A.
      • Wandaller C.
      • et al.
      Survivors of cardiac arrest with good neurological outcome show considerable impairments of memory functioning.
      • Lilja G.
      • Nielsen N.
      • Friberg H.
      • et al.
      cognitive function in survivors of out-of-hospital cardiac arrest after target temperature management at 33 degrees C versus 36 degrees C.
      • Moulaert V.R.M.P.
      • Verbunt J.A.
      • van Heugten C.M.
      • Wade D.T.
      Cognitive impairments in survivors of out-of-hospital cardiac arrest: a systematic review.
      • Cronberg T.
      • Lilja G.
      • Horn J.
      • et al.
      Neurologic function and health-related quality of life in patients following targeted temperature management at 33 degrees C vs 36 degrees C after out-of-hospital cardiac arrest: a randomized clinical trial.

      Post-cardiac arrest syndrome

      The post-cardiac arrest syndrome comprises post-cardiac arrest brain injury, post-cardiac arrest myocardial dysfunction, the systemic ischaemia/reperfusion response, and the persistent precipitating pathology.
      • Nolan J.P.
      • Neumar R.W.
      • Adrie C.
      • et al.
      Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.
      • Mongardon N.
      • Dumas F.
      • Ricome S.
      • et al.
      Postcardiac arrest syndrome: from immediate resuscitation to long-term outcome.
      • Stub D.
      • Bernard S.
      • Duffy S.J.
      • Kaye D.M.
      Post cardiac arrest syndrome: a review of therapeutic strategies.
      The severity of this syndrome will vary with the duration and cause of cardiac arrest. It may not occur at all if the cardiac arrest is brief. Post-cardiac arrest brain injury manifests as coma, seizures, myoclonus, varying degrees of neurocognitive dysfunction and brain death. Among patients surviving to ICU admission but subsequently dying in-hospital, brain injury is the cause of death in approximately two thirds after out-of hospital cardiac arrest and approximately 25% after in-hospital cardiac arrest.
      • Lemiale V.
      • Dumas F.
      • Mongardon N.
      • et al.
      Intensive care unit mortality after cardiac arrest: the relative contribution of shock and brain injury in a large cohort.
      • Laver S.
      • Farrow C.
      • Turner D.
      • Nolan J.
      Mode of death after admission to an intensive care unit following cardiac arrest.
      • Olasveengen T.M.
      • Sunde K.
      • Brunborg C.
      • Thowsen J.
      • Steen P.A.
      • Wik L.
      Intravenous drug administration during out-of-hospital cardiac arrest: a randomized trial.
      • Dragancea I.
      • Rundgren M.
      • Englund E.
      • Friberg H.
      • Cronberg T.
      The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest.
      Cardiovascular failure accounts for most deaths in the first three days, while brain injury accounts for most of the later deaths.
      • Lemiale V.
      • Dumas F.
      • Mongardon N.
      • et al.
      Intensive care unit mortality after cardiac arrest: the relative contribution of shock and brain injury in a large cohort.
      • Dragancea I.
      • Rundgren M.
      • Englund E.
      • Friberg H.
      • Cronberg T.
      The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest.
      • Nielsen N.
      • Wetterslev J.
      • Cronberg T.
      • et al.
      Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
      Withdrawal of life sustaining therapy (WLST) is the most frequent cause of death (approximately 50%) in patients with a prognosticated bad outcome,
      • Tomte O.
      • Andersen G.O.
      • Jacobsen D.
      • Draegni T.
      • Auestad B.
      • Sunde K.
      Strong and weak aspects of an established post-resuscitation treatment protocol – a five-year observational study.
      • Dragancea I.
      • Rundgren M.
      • Englund E.
      • Friberg H.
      • Cronberg T.
      The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest.
      emphasising the importance of the prognostication plan (see below). Post-cardiac arrest brain injury may be exacerbated by microcirculatory failure, impaired autoregulation, hypotension, hypercarbia, hypoxaemia, hyperoxaemia, pyrexia, hypoglycaemia, hyperglycaemia and seizures. Significant myocardial dysfunction is common after cardiac arrest but typically starts to recover by 2–3 days, although full recovery may take significantly longer.
      • Laurent I.
      • Monchi M.
      • Chiche J.D.
      • et al.
      Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest.
      • Ruiz-Bailen M.
      • Aguayo de Hoyos E.
      • Ruiz-Navarro S.
      • et al.
      Reversible myocardial dysfunction after cardiopulmonary resuscitation.
      • Chalkias A.
      • Xanthos T.
      Pathophysiology and pathogenesis of post-resuscitation myocardial stunning.
      The whole body ischaemia/reperfusion of cardiac arrest activates immune and coagulation pathways contributing to multiple organ failure and increasing the risk of infection.
      • Cerchiari E.L.
      • Safar P.
      • Klein E.
      • Diven W.
      Visceral, hematologic and bacteriologic changes and neurologic outcome after cardiac arrest in dogs. The visceral post-resuscitation syndrome.
      • Adrie C.
      • Monchi M.
      • Laurent I.
      • et al.
      Coagulopathy after successful cardiopulmonary resuscitation following cardiac arrest: implication of the protein C anticoagulant pathway.
      • Grimaldi D.
      • Guivarch E.
      • Neveux N.
      • et al.
      Markers of intestinal injury are associated with endotoxemia in successfully resuscitated patients.
      • Roberts B.W.
      • Kilgannon J.H.
      • Chansky M.E.
      • et al.
      Multiple organ dysfunction after return of spontaneous circulation in postcardiac arrest syndrome.
      • Bottiger B.W.
      • Bohrer H.
      • Boker T.
      • Motsch J.
      • Aulmann M.
      • Martin E.
      Platelet factor 4 release in patients undergoing cardiopulmonary resuscitation – can reperfusion be impaired by platelet activation?.
      • Bottiger B.W.
      • Motsch J.
      • Braun V.
      • Martin E.
      • Kirschfink M.
      Marked activation of complement and leukocytes and an increase in the concentrations of soluble endothelial adhesion molecules during cardiopulmonary resuscitation and early reperfusion after cardiac arrest in humans.
      • Bottiger B.W.
      • Motsch J.
      • Bohrer H.
      • et al.
      Activation of blood coagulation after cardiac arrest is not balanced adequately by activation of endogenous fibrinolysis.
      Thus, the post-cardiac arrest syndrome has many features in common with sepsis, including intravascular volume depletion, vasodilation, endothelial injury and abnormalities of the microcirculation.
      • Adrie C.
      • Adib-Conquy M.
      • Laurent I.
      • et al.
      Successful cardiopulmonary resuscitation after cardiac arrest as a “sepsis-like” syndrome.
      • Adrie C.
      • Laurent I.
      • Monchi M.
      • Cariou A.
      • Dhainaou J.F.
      • Spaulding C.
      Postresuscitation disease after cardiac arrest: a sepsis-like syndrome?.
      • Huet O.
      • Dupic L.
      • Batteux F.
      • et al.
      Postresuscitation syndrome: potential role of hydroxyl radical-induced endothelial cell damage.
      • Fink K.
      • Schwarz M.
      • Feldbrugge L.
      • et al.
      Severe endothelial injury and subsequent repair in patients after successful cardiopulmonary resuscitation.
      • van Genderen M.E.
      • Lima A.
      • Akkerhuis M.
      • Bakker J.
      • van Bommel J.
      Persistent peripheral and microcirculatory perfusion alterations after out-of-hospital cardiac arrest are associated with poor survival.
      • Bro-Jeppesen J.
      • Kjaergaard J.
      • Wanscher M.
      • et al.
      Systemic inflammatory response and potential prognostic implications after out-of-hospital cardiac arrest: a substudy of the target temperature management trial.
      • Sutherasan Y.
      • Penuelas O.
      • Muriel A.
      • et al.
      Management and outcome of mechanically ventilated patients after cardiac arrest.

      Airway and breathing

      Control of oxygenation

      Patients who have had a brief period of cardiac arrest responding immediately to appropriate treatment may achieve an immediate return of normal cerebral function. These patients do not require tracheal intubation and ventilation but should be given with oxygen via a facemask if their arterial blood oxygen saturation is less than 94%. Hypoxaemia and hypercarbia both increase the likelihood of a further cardiac arrest and may contribute to secondary brain injury. Several animal studies indicate that hyperoxaemia early after ROSC causes oxidative stress and harms post-ischaemic neurones.
      • Pilcher J.
      • Weatherall M.
      • Shirtcliffe P.
      • Bellomo R.
      • Young P.
      • Beasley R.
      The effect of hyperoxia following cardiac arrest – a systematic review and meta-analysis of animal trials.
      • Zwemer C.F.
      • Whitesall S.E.
      • D’Alecy L.G.
      Cardiopulmonary-cerebral resuscitation with 100% oxygen exacerbates neurological dysfunction following nine minutes of normothermic cardiac arrest in dogs.
      • Richards E.M.
      • Fiskum G.
      • Rosenthal R.E.
      • Hopkins I.
      • McKenna M.C.
      Hyperoxic reperfusion after global ischemia decreases hippocampal energy metabolism.
      • Vereczki V.
      • Martin E.
      • Rosenthal R.E.
      • Hof P.R.
      • Hoffman G.E.
      • Fiskum G.
      Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death.
      • Liu Y.
      • Rosenthal R.E.
      • Haywood Y.
      • Miljkovic-Lolic M.
      • Vanderhoek J.Y.
      • Fiskum G.
      Normoxic ventilation after cardiac arrest reduces oxidation of brain lipids and improves neurological outcome.
      One animal study showed that adjusting the fractional inspired concentration (FiO2) to produce an arterial oxygen saturation of 94–96% in the first hour after ROSC (controlled reoxygenation) achieved better neurological outcomes than achieved with the delivery of 100% oxygen.
      • Balan I.S.
      • Fiskum G.
      • Hazelton J.
      • Cotto-Cumba C.
      • Rosenthal R.E.
      Oximetry-guided reoxygenation improves neurological outcome after experimental cardiac arrest.
      One clinical registry study that included more than 6000 patients supports the animal data and shows post-resuscitation hyperoxaemia in the first 24 h is associated with worse outcome, compared with both normoxaemia and hypoxaemia.
      • Kilgannon J.H.
      • Jones A.E.
      • Shapiro N.I.
      • et al.
      Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality.
      A further analysis by the same group showed that the association between hyperoxia and outcome was dose-dependent and that there was not a single threshold for harm.
      • Kilgannon J.H.
      • Jones A.E.
      • Parrillo J.E.
      • et al.
      Relationship between supranormal oxygen tension and outcome after resuscitation from cardiac arrest.
      An observational study that included only those patients treated with mild induced hypothermia also showed an association between hyperoxia and poor outcome.
      • Janz D.R.
      • Hollenbeck R.D.
      • Pollock J.S.
      • McPherson J.A.
      • Rice T.W.
      Hyperoxia is associated with increased mortality in patients treated with mild therapeutic hypothermia after sudden cardiac arrest.
      In contrast, an observational study of over 12,000 post-cardiac arrest patients showed that after adjustment for the inspired oxygenation concentration and other relevant covariates (including sickness severity), hyperoxia was no longer associated with mortality.
      • Bellomo R.
      • Bailey M.
      • Eastwood G.M.
      • et al.
      Arterial hyperoxia and in-hospital mortality after resuscitation from cardiac arrest.
      A meta-analysis of 14 observational studies showed significant heterogeneity across studies.
      • Wang C.H.
      • Chang W.T.
      • Huang C.H.
      • et al.
      The effect of hyperoxia on survival following adult cardiac arrest: a systematic review and meta-analysis of observational studies.
      The animal studies showing a relationship between hyperoxia and worse neurological outcome after cardiac arrest have generally evaluated the effect of hyperoxia in the first hour after ROSC. There are significant practical challenges with the titration of inspired oxygen concentration immediately after ROSC, particularly in the out-of hospital setting. The only prospective clinical study to compare oxygen titrated to a target range (in this case 90–94% oxygen saturation) versus giving 100% oxygen after out of hospital cardiac arrest was stopped after enrolling just 19 patients because it proved very difficult to obtain reliable arterial blood oxygen saturation values using pulse oximetry.
      • Young P.
      • Bailey M.
      • Bellomo R.
      • et al.
      HyperOxic Therapy OR NormOxic Therapy after out-of-hospital cardiac arrest (HOT OR NOT): a randomised controlled feasibility trial.
      A recent study of air versus supplemental oxygen in ST-elevation myocardial infarction showed that supplemental oxygen therapy increased myocardial injury, recurrent myocardial infarction and major cardiac arrhythmia and was associated with larger infarct size at 6 months.
      • Stub D.
      • Smith K.
      • Bernard S.
      • et al.
      Air versus oxygen in ST-segment elevation myocardial infarction.
      Given the evidence of harm after myocardial infarction and the possibility of increased neurological injury after cardiac arrest, as soon as arterial blood oxygen saturation can be monitored reliably (by blood gas analysis and/or pulse oximetry), titrate the inspired oxygen concentration to maintain the arterial blood oxygen saturation in the range of 94–98%. Avoid hypoxaemia, which is also harmful – ensure reliable measurement of arterial oxygen saturation before reducing the inspired oxygen concentration.

      Control of ventilation

      Consider tracheal intubation, sedation and controlled ventilation in any patient with obtunded cerebral function. Ensure the tracheal tube is positioned correctly, well above the carina. Hypocarbia causes cerebral vasoconstriction and a decreased cerebral blood flow.
      • Menon D.K.
      • Coles J.P.
      • Gupta A.K.
      • et al.
      Diffusion limited oxygen delivery following head injury.
      After cardiac arrest, hypocapnia induced by hyperventilation causes cerebral ischaemia.
      • Bouzat P.
      • Suys T.
      • Sala N.
      • Oddo M.
      Effect of moderate hyperventilation and induced hypertension on cerebral tissue oxygenation after cardiac arrest and therapeutic hypothermia.
      • Buunk G.
      • van der Hoeven J.G.
      • Meinders A.E.
      Cerebrovascular reactivity in comatose patients resuscitated from a cardiac arrest.
      • Buunk G.
      • van der Hoeven J.G.
      • Meinders A.E.
      A comparison of near-infrared spectroscopy and jugular bulb oximetry in comatose patients resuscitated from a cardiac arrest.
      • Roine R.O.
      • Launes J.
      • Nikkinen P.
      • Lindroth L.
      • Kaste M.
      Regional cerebral blood flow after human cardiac arrest. A hexamethylpropyleneamine oxime single photon emission computed tomographic study.
      • Beckstead J.E.
      • Tweed W.A.
      • Lee J.
      • MacKeen W.L.
      Cerebral blood flow and metabolism in man following cardiac arrest.
      Observational studies using cardiac arrest registries document an association between hypocapnia and poor neurological outcome.
      • Roberts B.W.
      • Kilgannon J.H.
      • Chansky M.E.
      • Mittal N.
      • Wooden J.
      • Trzeciak S.
      Association between postresuscitation partial pressure of arterial carbon dioxide and neurological outcome in patients with post-cardiac arrest syndrome.
      • Schneider A.G.
      • Eastwood G.M.
      • Bellomo R.
      • et al.
      Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest.
      Two observation studies have documented an association with mild hypercapnia and better neurological outcome among post-cardiac arrest patients in the ICU.
      • Schneider A.G.
      • Eastwood G.M.
      • Bellomo R.
      • et al.
      Arterial carbon dioxide tension and outcome in patients admitted to the intensive care unit after cardiac arrest.
      • Vaahersalo J.
      • Bendel S.
      • Reinikainen M.
      • et al.
      Arterial blood gas tensions after resuscitation from out-of-hospital cardiac arrest: associations with long-term neurologic outcome.
      Until prospective data are available, it is reasonable to adjust ventilation to achieve normocarbia and to monitor this using the end-tidal CO2 and arterial blood gas values. Lowering the body temperature decreases the metabolism and may increase the risk of hypocapnia during the temperature intervention.
      • Falkenbach P.
      • Kamarainen A.
      • Makela A.
      • et al.
      Incidence of iatrogenic dyscarbia during mild therapeutic hypothermia after successful resuscitation from out-of-hospital cardiac arrest.
      Although protective lung ventilation strategies have not been studied specifically in post-cardiac arrest patients, given that these patients develop a marked inflammatory response, it seems rational to apply protective lung ventilation: tidal volume 6–8 ml kg−1 ideal body weight and positive end expiratory pressure 4–8 cm H2O.
      • Sutherasan Y.
      • Penuelas O.
      • Muriel A.
      • et al.
      Management and outcome of mechanically ventilated patients after cardiac arrest.
      • Slutsky A.S.
      • Ranieri V.M.
      Ventilator-induced lung injury.
      Insert a gastric tube to decompress the stomach; gastric distension caused by mouth-to-mouth or bag-mask ventilation will splint the diaphragm and impair ventilation. Give adequate doses of sedative, which will reduce oxygen consumption. A sedation protocol is highly recommended. Bolus doses of a neuromuscular blocking drug may be required, particularly if using targeted temperature management (TTM) (see below). Limited evidence shows that short-term infusion (≤48 h) of short-acting neuromuscular blocking drugs given to reduce patient-ventilator dysynchrony and risk of barotrauma in ARDS patients is not associated with an increased risk of ICU-acquired weakness and may improve outcome in these patients.
      • Alhazzani W.
      • Alshahrani M.
      • Jaeschke R.
      • et al.
      Neuromuscular blocking agents in acute respiratory distress syndrome: a systematic review and meta-analysis of randomized controlled trials.
      There are some data suggesting that continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients
      • Salciccioli J.D.
      • Cocchi M.N.
      • Rittenberger J.C.
      • et al.
      Continuous neuromuscular blockade is associated with decreased mortality in post-cardiac arrest patients.
      ; however, infusions of neuromuscular blocking drugs interfere with clinical examination and may mask seizures. Continuous electroencephalography (EEG) is recommended to detect seizures in these patients, especially when neuromuscular blockade is used.
      • Rundgren M.
      • Westhall E.
      • Cronberg T.
      • Rosen I.
      • Friberg H.
      Continuous amplitude-integrated electroencephalogram predicts outcome in hypothermia-treated cardiac arrest patients.
      Obtain a chest radiograph to check the position of the tracheal tube, gastric tube and central venous lines, assess for pulmonary oedema, and detect complications from CPR such as a pneumothorax associated with rib fractures.
      • Miller A.C.
      • Rosati S.F.
      • Suffredini A.F.
      • Schrump D.S.
      A systematic review and pooled analysis of CPR-associated cardiovascular and thoracic injuries.
      • Kashiwagi Y.
      • Sasakawa T.
      • Tampo A.
      • et al.
      Computed tomography findings of complications resulting from cardiopulmonary resuscitation.

      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 from 59% to 71% in OHCA patients without an obvious non-cardiac aetiology.
      • Larsen J.M.
      • Ravkilde J.
      Acute coronary angiography in patients resuscitated from out-of-hospital cardiac arrest – a systematic review and meta-analysis.
      Since the publication of a pioneering study in 1997,
      • Spaulding C.M.
      • Joly L.M.
      • Rosenberg A.
      • et al.
      Immediate coronary angiography in survivors of out-of-hospital cardiac arrest.
      many observational studies have shown that emergent cardiac catheterisation laboratory evaluation, including early percutaneous coronary intervention (PCI), is feasible in patients with ROSC after cardiac arrest.
      • Camuglia A.C.
      • Randhawa V.K.
      • Lavi S.
      • Walters D.L.
      Cardiac catheterization is associated with superior outcomes for survivors of out of hospital cardiac arrest: review and meta-analysis.
      • Grasner J.T.
      • Meybohm P.
      • Caliebe A.
      • et al.
      Postresuscitation care with mild therapeutic hypothermia and coronary intervention after out-of-hospital cardiopulmonary resuscitation: a prospective registry analysis.
      The invasive management (i.e., early coronary angiography followed by immediate PCI if deemed necessary) of these patients, particularly those having prolonged resuscitation and nonspecific ECG changes, has been controversial because of the lack of specific evidence and significant implications on use of resources (including transfer of patients to PCI centres).

      Percutaneous coronary intervention following ROSC with ST-elevation

      In patients with ST segment elevation (STE) or left bundle branch block (LBBB) on the post-ROSC electrocardiogram (ECG) more than 80% will have an acute coronary lesion.
      • Garcia-Tejada J.
      • Jurado-Roman A.
      • Rodriguez J.
      • et al.
      Post-resuscitation electrocardiograms, acute coronary findings and in-hospital prognosis of survivors of out-of-hospital cardiac arrest.
      There are no randomised studies but given that many observational studies reported increased survival and neurologically favourable outcome, it is highly probable that early invasive management is beneficial in STE patients.
      • Nikolaou N.I.
      • Arntz H.R.
      • Bellou A.
      • Beygui F.
      • Bossaert L.L.
      • Cariou A.
      European Resuscitation Council Guidelines for Resuscitation 2015. Section 8. Initial management of acute coronary syndromes resuscitation.
      Based on available data, emergent cardiac catheterisation laboratory evaluation (and immediate PCI if required) should be performed in adult patients with ROSC after OHCA of suspected cardiac origin with STE on the ECG. This recommendation is based on low quality of evidence from selected populations. Observational studies also indicate that optimal outcomes after OHCA are achieved with a combination of TTM and PCI, which can be included in a standardised post-cardiac arrest protocol as part of an overall strategy to improve neurologically intact survival.
      • Grasner J.T.
      • Meybohm P.
      • Caliebe A.
      • et al.
      Postresuscitation care with mild therapeutic hypothermia and coronary intervention after out-of-hospital cardiopulmonary resuscitation: a prospective registry analysis.
      • Callaway C.W.
      • Schmicker R.H.
      • Brown S.P.
      • et al.
      Early coronary angiography and induced hypothermia are associated with survival and functional recovery after out-of-hospital cardiac arrest.
      • Dumas F.
      • White L.
      • Stubbs B.A.
      • Cariou A.
      • Rea T.D.
      Long-term prognosis following resuscitation from out of hospital cardiac arrest: role of percutaneous coronary intervention and therapeutic hypothermia.

      Percutaneous coronary intervention following ROSC without ST-elevation

      In contrast to the usual presentation of ACS in non-cardiac arrest patients, the standard tools to assess coronary ischaemia in cardiac arrest patients are less accurate. The sensitivity and specificity of the usual clinical data, ECG and biomarkers to predict an acute coronary artery occlusion as the cause of OHCA are unclear.
      • Zanuttini D.
      • Armellini I.
      • Nucifora G.
      • et al.
      Predictive value of electrocardiogram in diagnosing acute coronary artery lesions among patients with out-of-hospital-cardiac-arrest.
      • Dumas F.
      • Manzo-Silberman S.
      • Fichet J.
      • et al.
      Can early cardiac troponin I measurement help to predict recent coronary occlusion in out-of-hospital cardiac arrest survivors?.
      • Sideris G.
      • Voicu S.
      • Dillinger J.G.
      • et al.
      Value of post-resuscitation electrocardiogram in the diagnosis of acute myocardial infarction in out-of-hospital cardiac arrest patients.
      • Muller D.
      • Schnitzer L.
      • Brandt J.
      • Arntz H.R.
      The accuracy of an out-of-hospital 12-lead ECG for the detection of ST-elevation myocardial infarction immediately after resuscitation.
      Several large observational series showed that absence of STE may also be associated with ACS in patients with ROSC following OHCA.
      • Dumas F.
      • Cariou A.
      • Manzo-Silberman S.
      • et al.
      Immediate percutaneous coronary intervention is associated with better survival after out-of-hospital cardiac arrest: insights from the PROCAT (Parisian Region Out of hospital Cardiac ArresT) registry.
      • Radsel P.
      • Knafelj R.
      • Kocjancic S.
      • Noc M.
      Angiographic characteristics of coronary disease and postresuscitation electrocardiograms in patients with aborted cardiac arrest outside a hospital.
      • Hollenbeck R.D.
      • McPherson J.A.
      • Mooney M.R.
      • et al.
      Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI.
      • Redfors B.
      • Ramunddal T.
      • Angeras O.
      • et al.
      Angiographic findings and survival in patients undergoing coronary angiography due to sudden cardiac arrest in Western Sweden.
      In these non-STE patients, there are conflicting data from observational studies on the potential benefit of emergent cardiac catheterisation laboratory evaluation.
      • Hollenbeck R.D.
      • McPherson J.A.
      • Mooney M.R.
      • et al.
      Early cardiac catheterization is associated with improved survival in comatose survivors of cardiac arrest without STEMI.
      • Bro-Jeppesen J.
      • Kjaergaard J.
      • Wanscher M.
      • et al.
      Emergency coronary angiography in comatose cardiac arrest patients: do real-life experiences support the guidelines?.
      • Dankiewicz J.
      • Nielsen N.
      • Annborn M.
      • et al.
      Survival in patients without acute ST elevation after cardiac arrest and association with early coronary angiography: a post hoc analysis from the TTM trial.
      A recent consensus statement from the European Association for Percutaneous Cardiovascular Interventions (EAPCI) has emphasised that in OHCA patients, cardiac catheterisation should be performed immediately in the presence of ST-elevation and considered as soon as possible (less than 2 h) in other patients in the absence of an obvious non-coronary cause, particularly if they are haemodynamically unstable.
      • Noc M.
      • Fajadet J.
      • Lassen J.F.
      • et al.
      Invasive coronary treatment strategies for out-of-hospital cardiac arrest: a consensus statement from the European association for percutaneous cardiovascular interventions (EAPCI)/stent for life (SFL) groups.
      Currently, this approach in patients without STE remains controversial and is not accepted by all experts. However, it is reasonable to discuss and consider emergent cardiac catheterisation laboratory evaluation after ROSC in patients with the highest risk of a coronary cause for their cardiac arrest. Factors such as patient age, duration of CPR, haemodynamic instability, presenting cardiac rhythm, neurological status upon hospital arrival, and perceived likelihood of cardiac aetiology can influence the decision to undertake the intervention in the acute phase or to delay it until later on in the hospital stay.

      Indications and timing of computed tomography (CT) scanning

      Cardiac causes of OHCA have been extensively studied in the last few decades; conversely, little is known on non-cardiac causes. Early identification of a respiratory or neurological cause would enable transfer of the patient to a specialised ICU for optimal care. Improved knowledge of prognosis also enables discussion about the appropriateness of specific therapies, including TTM. Early identification of a respiratory or neurological cause can be achieved by performing a brain and chest CT-scan at hospital admission, before or after coronary angiography. In the absence of signs or symptoms suggesting a neurological or respiratory cause (e.g., headache, seizures or neurological deficits for neurological causes, shortness of breath or documented hypoxia in patients suffering from a known and worsening respiratory disease) or if there is clinical or ECG evidence of myocardial ischaemia, coronary angiography is undertaken first, followed by CT scan in the absence of causative lesions. Several case series showed that this strategy enables diagnosis of non-cardiac causes of arrest in a substantial proportion of patients.
      • Chelly J.
      • Mongardon N.
      • Dumas F.
      • et al.
      Benefit of an early and systematic imaging procedure after cardiac arrest: insights from the PROCAT (Parisian Region Out of Hospital Cardiac Arrest) registry.
      • Arnaout M.
      • Mongardon N.
      • Deye N.
      • et al.
      Out-of-hospital cardiac arrest from brain cause: epidemiology, clinical features, and outcome in a multicenter cohort.
      In those with cardiac arrest associated with trauma or haemorrhage a whole body CT scan may be indicated.
      • Caputo N.D.
      • Stahmer C.
      • Lim G.
      • Shah K.
      Whole-body computed tomographic scanning leads to better survival as opposed to selective scanning in trauma patients: a systematic review and meta-analysis.
      • Truhlar A.
      • Deakin C.D.
      • Soar J.
      • et al.
      European Resuscitation Council Guidelines for Resuscitation 2015. Section 4. Cardiac arrest in special circumstances.

      Haemodynamic management

      Post-resuscitation myocardial dysfunction causes haemodynamic instability, which manifests as hypotension, low cardiac index and arrhythmias.
      • Laurent I.
      • Monchi M.
      • Chiche J.D.
      • et al.
      Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest.
      • Bro-Jeppesen J.
      • Annborn M.
      • Hassager C.
      • et al.
      Hemodynamics and vasopressor support during targeted temperature management at 33 degrees C versus 36 degrees C after out-of-hospital cardiac arrest: a post hoc study of the target temperature management trial.
      Perform early echocardiography in all patients in order to detect and quantify the degree of myocardial dysfunction.
      • Ruiz-Bailen M.
      • Aguayo de Hoyos E.
      • Ruiz-Navarro S.
      • et al.
      Reversible myocardial dysfunction after cardiopulmonary resuscitation.
      • Chang W.T.
      • Ma M.H.
      • Chien K.L.
      • et al.
      Postresuscitation myocardial dysfunction: correlated factors and prognostic implications.
      Post-resuscitation myocardial dysfunction often requires inotropic support, at least transiently. Based on experimental data, dobutamine is the most established treatment in this setting,
      • Kern K.B.
      • Hilwig R.W.
      • Berg R.A.
      • et al.
      Postresuscitation left ventricular systolic and diastolic dysfunction: treatment with dobutamine.
      • Vasquez A.
      • Kern K.B.
      • Hilwig R.W.
      • Heidenreich J.
      • Berg R.A.
      • Ewy G.A.
      Optimal dosing of dobutamine for treating post-resuscitation left ventricular dysfunction.
      but the systematic inflammatory response that occurs frequently in post-cardiac arrest patients may also cause vasoplegia and severe vasodilation.
      • Laurent I.
      • Monchi M.
      • Chiche J.D.
      • et al.
      Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest.
      Thus, noradrenaline, with or without dobutamine, and fluid is usually the most effective treatment. Infusion of relatively large volumes of fluid is tolerated remarkably well by patients with post-cardiac arrest syndrome.
      • Sunde K.
      • Pytte M.
      • Jacobsen D.
      • et al.
      Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest.
      • Gaieski D.F.
      • Band R.A.
      • Abella B.S.
      • et al.
      Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest.
      • Laurent I.
      • Monchi M.
      • Chiche J.D.
      • et al.
      Reversible myocardial dysfunction in survivors of out-of-hospital cardiac arrest.
      If treatment with fluid resuscitation, inotropes and vasoactive drugs is insufficient to support the circulation, consider insertion of a mechanical circulatory assistance device (e.g., IMPELLA, Abiomed, USA).
      • Sunde K.
      • Pytte M.
      • Jacobsen D.
      • et al.
      Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest.
      • Manzo-Silberman S.
      • Fichet J.
      • Mathonnet A.
      • et al.
      Percutaneous left ventricular assistance in post cardiac arrest shock: comparison of intra aortic blood pump and IMPELLA Recover LP2.5.
      Treatment may be guided by blood pressure, heart rate, urine output, rate of plasma lactate clearance, and central venous oxygen saturation. Serial echocardiography may also be used, especially in haemodynamically unstable patients. In the ICU an arterial line for continuous blood pressure monitoring is essential. Cardiac output monitoring may help to guide treatment in haemodynamically unstable patients but there is no evidence that its use affects outcome. Some centres still advocate use of an intra aortic balloon pump (IABP) in patients with cardiogenic shock, although the IABP-SHOCK II Trial failed to show that use of the IABP improved 30-day mortality in patients with myocardial infarction and cardiogenic shock.
      • Thiele H.
      • Zeymer U.
      • Neumann F.J.
      • et al.
      Intraaortic balloon support for myocardial infarction with cardiogenic shock.
      • Ahmad Y.
      • Sen S.
      • Shun-Shin M.J.
      • et al.
      Intra-aortic balloon pump therapy for acute myocardial infarction: a meta-analysis.
      Similarly to the early goal-directed therapy that is recommended in the treatment of sepsis,
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.
      although challenged by several recent studies,
      • Pro C.I.
      • Yealy D.M.
      • Kellum J.A.
      • et al.
      A randomized trial of protocol-based care for early septic shock.
      • ARISE Investigators
      • ANZICS Clinical Trials Group
      • Peake S.L.
      • Delaney A.
      • Beiley M.
      • et al.
      Goal-directed resuscitation for patients with early septic shock.
      • Mouncey P.R.
      • Osborn T.M.
      • Power G.S.
      • et al.
      Trial of early, goal-directed resuscitation for septic shock.
      a bundle of therapies, including a specific blood pressure target, has been proposed as a treatment strategy after cardiac arrest.
      • Gaieski D.F.
      • Band R.A.
      • Abella B.S.
      • et al.
      Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest.
      However its influence on clinical outcome is not firmly established and optimal targets for mean arterial pressure and/or systolic arterial pressure remain unknown.
      • Sunde K.
      • Pytte M.
      • Jacobsen D.
      • et al.
      Implementation of a standardised treatment protocol for post resuscitation care after out-of-hospital cardiac arrest.
      • Gaieski D.F.
      • Band R.A.
      • Abella B.S.
      • et al.
      Early goal-directed hemodynamic optimization combined with therapeutic hypothermia in comatose survivors of out-of-hospital cardiac arrest.
      • Beylin M.E.
      • Perman S.M.
      • Abella B.S.
      • et al.
      Higher mean arterial pressure with or without vasoactive agents is associated with increased survival and better neurological outcomes in comatose survivors of cardiac arrest.
      • Kilgannon J.H.
      • Roberts B.W.
      • Jones A.E.
      • et al.
      Arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest.
      • Walters E.L.
      • Morawski K.
      • Dorotta I.
      • et al.
      Implementation of a post-cardiac arrest care bundle including therapeutic hypothermia and hemodynamic optimization in comatose patients with return of spontaneous circulation after out-of-hospital cardiac arrest: a feasibility study.
      One observational study of 151 post-cardiac arrest patients identified an association between a time-weighted average mean arterial pressure (measured every 15 min) of greater than 70 mmHg and good neurological outcome.
      • Kilgannon J.H.
      • Roberts B.W.
      • Jones A.E.
      • et al.
      Arterial blood pressure and neurologic outcome after resuscitation from cardiac arrest.
      A recent study showed an inverse relationship between mean arterial pressure and mortality.
      • Bro-Jeppesen J.
      • Annborn M.
      • Hassager C.
      • et al.
      Hemodynamics and vasopressor support during targeted temperature management at 33 degrees C versus 36 degrees C after out-of-hospital cardiac arrest: a post hoc study of the target temperature management trial.
      However, whether the use of vasoactive drugs to achieve such a blood pressure target achieves better neurological outcomes remains unknown. In the absence of definitive data, target the mean arterial blood pressure to achieve an adequate urine output (1 ml kg−1 h−1) and normal or decreasing plasma lactate values, taking into consideration the patient's normal blood pressure, the cause of the arrest and the severity of any myocardial dysfunction.
      • Nolan J.P.
      • Neumar R.W.
      • Adrie C.
      • et al.
      Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke.
      These targets may vary depending on individual physiology and co-morbid status. Importantly, hypothermia may increase urine output
      • Zeiner A.
      • Sunder-Plassmann G.
      • Sterz F.
      • et al.
      The effect of mild therapeutic hypothermia on renal function after cardiopulmonary resuscitation in men.
      and impair lactate clearance.
      • Bro-Jeppesen J.
      • Annborn M.
      • Hassager C.
      • et al.
      Hemodynamics and vasopressor support during targeted temperature management at 33 degrees C versus 36 degrees C after out-of-hospital cardiac arrest: a post hoc study of the target temperature management trial.
      Tachycardia was associated with bad outcome in one retrospective study.
      • Torgersen C.
      • Meichtry J.
      • Schmittinger C.A.
      • et al.
      Haemodynamic variables and functional outcome in hypothermic patients following out-of-hospital cardiac arrest.
      During mild induced hypothermia the normal physiological response is bradycardia. In animal models this has been shown to reduce the diastolic dysfunction that usually is present early after cardiac arrest.
      • Post H.
      • Schmitto J.D.
      • Steendijk P.
      • et al.
      Cardiac function during mild hypothermia in pigs: increased inotropy at the expense of diastolic dysfunction.
      Bradycardia was previously considered to be a side effect, especially below a rate of 40 min−1; however, recent retrospective studies have shown that bradycardia is associated with a good outcome.
      • Staer-Jensen H.
      • Sunde K.
      • Olasveengen T.M.
      • et al.
      Bradycardia during therapeutic hypothermia is associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest.
      • Thomsen J.H.
      • Hassager C.
      • Bro-Jeppesen J.
      • et al.
      Sinus bradycardia during hypothermia in comatose survivors of out-of-hospital cardiac arrest – a new early marker of favorable outcome?.
      As long as blood pressure, lactate, SvO2 and urine output are sufficient, a bradycardia of ≤40 min−1 may be left untreated. Importantly, oxygen requirements during mild induced hypothermia are reduced.
      Relative adrenal insufficiency occurs frequently after successful resuscitation from cardiac arrest and it appears to be associated with a poor prognosis when accompanied by post-resuscitation shock.
      • Pene F.
      • Hyvernat H.
      • Mallet V.
      • et al.
      Prognostic value of relative adrenal insufficiency after out-of-hospital cardiac arrest.
      • Hekimian G.
      • Baugnon T.
      • Thuong M.
      • et al.
      Cortisol levels and adrenal reserve after successful cardiac arrest resuscitation.
      Two randomised controlled trials involving 368 patients with IHCA showed improved ROSC with the use of methylprednisolone and vasopressin in addition to adrenaline, compared with the use of placebo and adrenaline alone: combined RR 1.34 (95% CI 1.21–1.43).
      • Mentzelopoulos S.D.
      • Malachias S.
      • Chamos C.
      • et al.
      Vasopressin, steroids, and epinephrine and neurologically favorable survival after in-hospital cardiac arrest: a randomized clinical trial.
      • Mentzelopoulos S.D.
      • Zakynthinos S.G.
      • Tzoufi M.
      • et al.
      Vasopressin, epinephrine, and corticosteroids for in-hospital cardiac arrest.
      No studies have assessed the effect of adding steroids alone to standard treatment for IHCA. These studies come from a single group of investigators and the population studied had very rapid advanced life support, a high incidence of asystolic cardiac arrest, and low baseline survival compared with other IHCA studies. Further confirmatory studies are awaited but, pending further data, do not give steroids routinely after IHCA. There is no clinical evidence for the routine use of steroids after OHCA.
      Immediately after a cardiac arrest there is typically a period of hyperkalaemia. Subsequent endogenous catecholamine release and correction of metabolic and respiratory acidosis promotes intracellular transportation of potassium, causing hypokalaemia. Hypokalaemia may predispose to ventricular arrhythmias. Give potassium to maintain the serum potassium concentration between 4.0 and 4.5 mmol l−1.

      Implantable cardioverter defibrillators

      Insertion of an implantable cardioverter defibrillator (ICD) should be considered in ischaemic patients with significant left ventricular dysfunction, who have been resuscitated from a ventricular arrhythmia that occurred later than 24–48 h after a primary coronary event.
      • Lee D.S.
      • Green L.D.
      • Liu P.P.
      • et al.
      Effectiveness of implantable defibrillators for preventing arrhythmic events and death: a meta-analysis.
      • Vardas P.E.
      • Auricchio A.
      • Blanc J.J.
      • et al.
      Guidelines for cardiac pacing and cardiac resynchronization therapy: The Task Force for Cardiac Pacing and Cardiac Resynchronization Therapy of the European Society of Cardiology. Developed in collaboration with the European Heart Rhythm Association.
      • Steg P.G.
      • James S.K.
      • Atar D.
      • et al.
      ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation.
      ICDs may also reduce mortality in cardiac arrest survivors at risk of sudden death from structural heart diseases or inherited cardiomyopathies.
      • John R.M.
      • Tedrow U.B.
      • Koplan B.A.
      • et al.
      Ventricular arrhythmias and sudden cardiac death.
      • Soar J.
      • Callaway C.W.
      • Aibiki M.
      • et al.
      Part 4: advanced life support: 2015 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations.
      In all cases, a specialised electrophysiological evaluation should be performed before discharge for placement of an ICD for secondary prevention of sudden cardiac death.

      Disability (optimising neurological recovery)

      Cerebral perfusion

      Animal studies show that immediately after ROSC there is a short period of multifocal cerebral no-reflow followed by transient global cerebral hyperaemia lasting 15–30 min.
      • Buunk G.
      • van der Hoeven J.G.
      • Meinders A.E.
      Cerebral blood flow after cardiac arrest.
      • Angelos M.G.
      • Ward K.R.
      • Hobson J.
      • Beckley P.D.
      Organ blood flow following cardiac arrest in a swine low-flow cardiopulmonary bypass model.
      • Fischer M.
      • Bottiger B.W.
      • Popov-Cenic S.
      • Hossmann K.A.
      Thrombolysis using plasminogen activator and heparin reduces cerebral no-reflow after resuscitation from cardiac arrest: an experimental study in the cat.
      This is followed by up to 24 h of cerebral hypoperfusion while the cerebral metabolic rate of oxygen gradually recovers. After asphyxial cardiac arrest, brain oedema may occur transiently after ROSC but it is rarely associated with clinically relevant increases in intracranial pressure.
      • Sakabe T.
      • Tateishi A.
      • Miyauchi Y.
      • et al.
      Intracranial pressure following cardiopulmonary resuscitation.
      • Morimoto Y.
      • Kemmotsu O.
      • Kitami K.
      • Matsubara I.
      • Tedo I.
      Acute brain swelling after out-of-hospital cardiac arrest: pathogenesis and outcome.
      In many patients, autoregulation of cerebral blood flow is impaired (absent or right-shifted) for some time after cardiac arrest, which means that cerebral perfusion varies with cerebral perfusion pressure instead of being linked to neuronal activity.
      • Nishizawa H.
      • Kudoh I.
      Cerebral autoregulation is impaired in patients resuscitated after cardiac arrest.
      • Sundgreen C.
      • Larsen F.S.
      • Herzog T.M.
      • Knudsen G.M.
      • Boesgaard S.
      • Aldershvile J.
      Autoregulation of cerebral blood flow in patients resuscitated from cardiac arrest.
      In a study that used near-infrared spectroscopy to measure regional cerebral oxygenation, autoregulation was disturbed in 35% of post-cardiac arrest patients and the majority of these had been hypertensive before their cardiac arrest
      • Ameloot K.
      • Genbrugge C.
      • Meex I.
      • et al.
      An observational near-infrared spectroscopy study on cerebral autoregulation in post-cardiac arrest patients: time to drop ‘one-size-fits-all’ hemodynamic targets?.
      ; this tends to support the recommendation made in the 2010 ERC Guidelines: after ROSC, maintain mean arterial pressure near the patient's normal level.
      • Deakin C.D.
      • Nolan J.P.
      • Soar J.
      • et al.
      European Resuscitation Council Guidelines for Resuscitation 2010. Section 4. Adult advanced life support.
      However, there is a significant gap in the knowledge about how temperature impacts the optimal blood pressure.

      Sedation

      Although it has been common practice to sedate and ventilate patients for at least 24 h after ROSC, there are no high-level data to support a defined period of ventilation, sedation and neuromuscular blockade after cardiac arrest. Patients need to be sedated adequately during treatment with TTM, and the duration of sedation and ventilation is therefore influenced by this treatment. A meta-analysis of drugs used for sedation during mild induced hypothermia showed considerable variability among 68 ICUs in a variety of countries.
      • Chamorro C.
      • Borrallo J.M.
      • Romera M.A.
      • Silva J.A.
      • Balandin B.
      Anesthesia and analgesia protocol during therapeutic hypothermia after cardiac arrest: a systematic review.
      There are no data to indicate whether or not the choice of sedation influences outcome, but a combination of opioids and hypnotics is usually used. Short-acting drugs (e.g., propofol, alfentanil, remifentanil) will enable more reliable and earlier neurological assessment and prognostication (see Section 7).
      • Bjelland T.W.
      • Dale O.
      • Kaisen K.
      • et al.
      Propofol and remifentanil versus midazolam and fentanyl for sedation during therapeutic hypothermia after cardiac arrest: a randomised trial.
      Volatile anaesthetics have been used to sedate post cardiac arrest patients
      • Hellstrom J.
      • Owall A.
      • Martling C.R.
      • Sackey P.V.
      Inhaled isoflurane sedation during therapeutic hypothermia after cardiac arrest: a case series.
      but although there are some animal data suggesting myocardial and neurological benefits,
      • Knapp J.
      • Bergmann G.
      • Bruckner T.
      • Russ N.
      • Bottiger B.W.
      • Popp E.
      Pre- and postconditioning effect of Sevoflurane on myocardial dysfunction after cardiopulmonary resuscitation in rats.
      there are no clinical data showing an advantage with this strategy. Adequate sedation will reduce oxygen consumption. During hypothermia, optimal sedation can reduce or prevent shivering, which enables the target temperature to be achieved more rapidly. Use of published sedation scales for monitoring these patients (e.g., the Richmond or Ramsay Scales) may be helpful.
      • Ely E.W.
      • Truman B.
      • Shintani A.
      • et al.
      Monitoring sedation status over time in ICU patients: reliability and validity of the Richmond Agitation-Sedation Scale (RASS).
      • De Jonghe B.
      • Cook D.
      • Appere-De-Vecchi C.
      • Guyatt G.
      • Meade M.
      • Outin H.
      Using and understanding sedation scoring systems: a systematic review.

      Control of seizures

      Seizures are common after cardiac arrest and occur in approximately one-third of patients who remain comatose after ROSC. Myoclonus is most common and occurs in 18–25%, the remainder having focal or generalised tonic–clonic seizures or a combination of seizure types.
      • Nielsen N.
      • Wetterslev J.
      • Cronberg T.
      • et al.
      Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
      • Snyder B.D.
      • Hauser W.A.
      • Loewenson R.B.
      • Leppik I.E.
      • Ramirez-Lassepas M.
      • Gumnit R.J.
      Neurologic prognosis after cardiopulmonary arrest, III: seizure activity.
      • Bouwes A.
      • van Poppelen D.
      • Koelman J.H.
      • et al.
      Acute posthypoxic myoclonus after cardiopulmonary resuscitation.
      • Seder D.B.
      • Sunde K.
      • Rubertsson S.
      • et al.
      Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest.
      Clinical seizures, including myoclonus may or may not be of epileptic origin. Other motor manifestations could be mistaken for seizures
      • Benbadis S.R.
      • Chen S.
      • Melo M.
      What's shaking in the ICU? The differential diagnosis of seizures in the intensive care setting.
      and there are several types of myoclonus
      • Caviness J.N.
      • Brown P.
      Myoclonus: current concepts and recent advances.
      the majority being non-epileptic. Use intermittent electroencephalography (EEG) to detect epileptic activity in patients with clinical seizure manifestations. Consider continuous EEG to monitor patients with a diagnosed status epilepticus and effects of treatment.
      In comatose cardiac arrest patients, EEG commonly detects epileptiform activity. Unequivocal seizure activity according to strict EEG-terminology
      • Hirsch L.J.
      • LaRoche S.M.
      • Gaspard N.
      • et al.
      American Clinical Neurophysiology Society's standardized critical care EEG terminology: 2012 version.
      is less common but post-anoxic status epilepticus was detected in 23–31% of patients using continuous EEG-monitoring and more inclusive EEG-criteria.
      • Rundgren M.
      • Westhall E.
      • Cronberg T.
      • Rosen I.
      • Friberg H.
      Continuous amplitude-integrated electroencephalogram predicts outcome in hypothermia-treated cardiac arrest patients.
      • Mani R.
      • Schmitt S.E.
      • Mazer M.
      • Putt M.E.
      • Gaieski D.F.
      The frequency and timing of epileptiform activity on continuous electroencephalogram in comatose post-cardiac arrest syndrome patients treated with therapeutic hypothermia.
      • Legriel S.
      • Hilly-Ginoux J.
      • Resche-Rigon M.
      • et al.
      Prognostic value of electrographic postanoxic status epilepticus in comatose cardiac-arrest survivors in the therapeutic hypothermia era.
      Patients with electrographic status epilepticus may or may not have clinically detectable seizure manifestations that may be masked by sedation. Whether systematic detection and treatment of electrographic epileptic activity improves patient outcome is not known.
      Seizures may increase the cerebral metabolic rate
      • Ingvar M.
      Cerebral blood flow and metabolic rate during seizures. Relationship to epileptic brain damage.
      and have the potential to exacerbate brain injury caused by cardiac arrest: treat with sodium valproate, levetiracetam, phenytoin, benzodiazepines, propofol, or a barbiturate. Myoclonus can be particularly difficult to treat; phenytoin is often ineffective. Propofol is effective to suppress post-anoxic myoclonus.
      • Thomke F.
      • Weilemann S.L.
      Poor prognosis despite successful treatment of postanoxic generalized myoclonus.
      Clonazepam, sodium valproate and levetiracetam are antimyoclonic drugs that may be effective in post-anoxic myoclonus.
      • Caviness J.N.
      • Brown P.
      Myoclonus: current concepts and recent advances.
      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 arrest in adults has been insufficiently studied.
      • Randomized Clinical Study of Thiopental Loading in Comatose Survivors of Cardiac Arrest
      Brain Resuscitation Clinical Trial I Study Group.
      • Longstreth Jr., W.T.
      • Fahrenbruch C.E.
      • Olsufka M.
      • Walsh T.R.
      • Copass M.K.
      • Cobb L.A.
      Randomized clinical trial of magnesium, diazepam, or both after out-of-hospital cardiac arrest.
      Routine seizure prophylaxis in post-cardiac arrest patients is not recommended because of the risk of adverse effects and the poor response to anti-epileptic agents among patients with clinical and electrographic seizures.
      Myoclonus and electrographic seizure activity, including status epilepticus, are related to a poor prognosis but individual patients may survive with good outcome (see Section 7).
      • Seder D.B.
      • Sunde K.
      • Rubertsson S.
      • et al.
      Neurologic outcomes and postresuscitation care of patients with myoclonus following cardiac arrest.
      • Amorim E.
      • Rittenberger J.C.
      • Baldwin M.E.
      • Callaway C.W.
      • Popescu A.
      • Post Cardiac Arrest Service
      Malignant EEG patterns in cardiac arrest patients treated with targeted temperature management who survive to hospital discharge.
      Prolonged observation may be necessary after treatment of seizures with sedatives, which will decrease the reliability of a clinical examination.
      • Samaniego E.A.
      • Mlynash M.
      • Caulfield A.F.
      • Eyngorn I.
      • Wijman C.A.
      Sedation confounds outcome prediction in cardiac arrest survivors treated with hypothermia.

      Glucose control

      There is a strong association between high blood glucose after resuscitation from cardiac arrest and poor neurological outcome.
      • Langhelle A.
      • Tyvold S.S.
      • Lexow K.
      • Hapnes S.A.
      • Sunde K.
      • Steen P.A.
      In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A comparison between four regions in Norway.
      • Nolan J.P.
      • Laver S.R.
      • Welch C.A.
      • Harrison D.A.
      • Gupta V.
      • Rowan K.
      Outcome following admission to UK intensive care units after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database.
      • Nielsen N.
      • Hovdenes J.
      • Nilsson F.
      • et al.
      Outcome, timing and adverse events in therapeutic hypothermia after out-of-hospital cardiac arrest.
      • Daviaud F.
      • Dumas F.
      • Demars N.
      • et al.
      Blood glucose level and outcome after cardiac arrest: insights from a large registry in the hypothermia era.
      • Losert H.
      • Sterz F.
      • Roine R.O.
      • et al.
      Strict normoglycaemic blood glucose levels in the therapeutic management of patients within 12 h after cardiac arrest might not be necessary.
      • Skrifvars M.B.
      • Saarinen K.
      • Ikola K.
      • Kuisma M.
      Improved survival after in-hospital cardiac arrest outside critical care areas.
      • Mullner M.
      • Sterz F.
      • Binder M.
      • Schreiber W.
      • Deimel A.
      • Laggner A.N.
      Blood glucose concentration after cardiopulmonary resuscitation influences functional neurological recovery in human cardiac arrest survivors.
      • Calle P.A.
      • Buylaert W.A.
      • Vanhaute O.A.
      Glycemia in the post-resuscitation period. The Cerebral Resuscitation Study Group.
      • Longstreth Jr., W.T.
      • Diehr P.
      • Inui T.S.
      Prediction of awakening after out-of-hospital cardiac arrest.
      • Longstreth Jr., W.T.
      • Inui T.S.
      High blood glucose level on hospital admission and poor neurological recovery after cardiac arrest.
      Although one randomised controlled trial in a cardiac surgical intensive care unit showed that tight control of blood glucose (4.4–6.1 mmol l−1 or 80–110 mg dl−1) using insulin reduced hospital mortality in critically ill adults,
      • van den Berghe G.
      • Wouters P.
      • Weekers F.
      • et al.
      Intensive insulin therapy in the critically ill patients.
      a second study by the same group in medical ICU patients showed no mortality benefit from tight glucose control.
      • Van den Berghe G.
      • Wilmer A.
      • Hermans G.
      • et al.
      Intensive insulin therapy in the medical ICU.
      In one randomised trial of patients resuscitated from OHCA with ventricular fibrillation, strict glucose control (72–108 mg dl−1, 4–6 mmol l−1) gave no survival benefit compared with moderate glucose control (108–144 mg dl−1, 6–8 mmol l−1) and there were more episodes of hypoglycaemia in the strict glucose control group.
      • Oksanen T.
      • Skrifvars M.B.
      • Varpula T.
      • et al.
      Strict versus moderate glucose control after resuscitation from ventricular fibrillation.
      A large randomised trial of intensive glucose control (81 mg dl−1 – 108 mg dl−1, 4.5–6.0 mmol l−1) versus conventional glucose control (180 mg dl−1, 10 mmol l−1 or less) in general ICU patients reported increased 90-day mortality in patients treated with intensive glucose control.
      • Finfer S.
      • Chittock D.R.
      • Su S.Y.
      • et al.
      Intensive versus conventional glucose control in critically ill patients.
      • Investigators N.-S.S.
      • Finfer S.
      • Liu B.
      • et al.
      Hypoglycemia and risk of death in critically ill patients.
      Severe hypoglycaemia is associated with increased mortality in critically ill patients,
      • Krinsley J.S.
      • Grover A.
      Severe hypoglycemia in critically ill patients: risk factors and outcomes.
      and comatose patients are at particular risk from unrecognised hypoglycaemia. Irrespective of the target range, variability in glucose values is associated with mortality.
      • Meyfroidt G.
      • Keenan D.M.
      • Wang X.
      • Wouters P.J.
      • Veldhuis J.D.
      • Van den Berghe G.
      Dynamic characteristics of blood glucose time series during the course of critical illness: effects of intensive insulin therapy and relative association with mortality.
      Compared with normothermia, mild induced hypothermia is associated with higher blood glucose values, increased blood glucose variability and greater insulin requirements.
      • Cueni-Villoz N.
      • Devigili A.
      • Delodder F.
      • et al.
      Increased blood glucose variability during therapeutic hypothermia and outcome after cardiac arrest.
      Increased blood glucose variability is associated with increased mortality and unfavourable neurological outcome after cardiac arrest.
      • Daviaud F.
      • Dumas F.
      • Demars N.
      • et al.
      Blood glucose level and outcome after cardiac arrest: insights from a large registry in the hypothermia era.
      • Cueni-Villoz N.
      • Devigili A.
      • Delodder F.
      • et al.
      Increased blood glucose variability during therapeutic hypothermia and outcome after cardiac arrest.
      Based on the available data, following ROSC maintain the blood glucose at ≤10 mmol l−1 (180 mg dl−1) and avoid hypoglycaemia.
      • Padkin A.
      Glucose control after cardiac arrest.
      Do not implement strict glucose control in adult patients with ROSC after cardiac arrest because it increases the risk of hypoglycaemia.

      Temperature control

      Treatment of hyperpyrexia

      A period of hyperthermia (hyperpyrexia) is common in the first 48 h after cardiac arrest.
      • Langhelle A.
      • Tyvold S.S.
      • Lexow K.
      • Hapnes S.A.
      • Sunde K.
      • Steen P.A.
      In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A comparison between four regions in Norway.
      • Takino M.
      • Okada Y.
      Hyperthermia following cardiopulmonary resuscitation.
      • Hickey R.W.
      • Kochanek P.M.
      • Ferimer H.
      • Alexander H.L.
      • Garman R.H.
      • Graham S.H.
      Induced hyperthermia exacerbates neurologic neuronal histologic damage after asphyxial cardiac arrest in rats.
      • Takasu A.
      • Saitoh D.
      • Kaneko N.
      • Sakamoto T.
      • Okada Y.
      Hyperthermia: is it an ominous sign after cardiac arrest?.
      • Zeiner A.
      • Holzer M.
      • Sterz F.
      • et al.
      Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome.
      Several studies document an association between post-cardiac arrest pyrexia and poor outcomes.
      • Langhelle A.
      • Tyvold S.S.
      • Lexow K.
      • Hapnes S.A.
      • Sunde K.
      • Steen P.A.
      In-hospital factors associated with improved outcome after out-of-hospital cardiac arrest. A comparison between four regions in Norway.
      • Takino M.
      • Okada Y.
      Hyperthermia following cardiopulmonary resuscitation.
      • Takasu A.
      • Saitoh D.
      • Kaneko N.
      • Sakamoto T.
      • Okada Y.
      Hyperthermia: is it an ominous sign after cardiac arrest?.
      • Zeiner A.
      • Holzer M.
      • Sterz F.
      • et al.
      Hyperthermia after cardiac arrest is associated with an unfavorable neurologic outcome.
      • Hickey R.W.
      • Kochanek P.M.
      • Ferimer H.
      • Graham S.H.
      • Safar P.
      Hypothermia and hyperthermia in children after resuscitation from cardiac arrest.
      • Diringer M.N.
      • Reaven N.L.
      • Funk S.E.
      • Uman G.C.
      Elevated body temperature independently contributes to increased length of stay in neurologic intensive care unit patients.
      The development of hyperthermia after a period of mild induced hypothermia (rebound hyperthermia) is associated with increased mortality and worse neurological outcome.
      • Winters S.A.
      • Wolf K.H.
      • Kettinger S.A.
      • Seif E.K.
      • Jones J.S.
      • Bacon-Baguley T.
      Assessment of risk factors for post-rewarming “rebound hyperthermia” in cardiac arrest patients undergoing therapeutic hypothermia.
      • Bro-Jeppesen J.
      • Hassager C.
      • Wanscher M.
      • et al.
      Post-hypothermia fever is associated with increased mortality after out-of-hospital cardiac arrest.
      • Leary M.
      • Grossestreuer A.V.
      • Iannacone S.
      • et al.
      Pyrexia and neurologic outcomes after therapeutic hypothermia for cardiac arrest.
      • Bro-Jeppesen J.
      • Kjaergaard J.
      • Horsted T.I.
      • et al.
      The impact of therapeutic hypothermia on neurological function and quality of life after cardiac arrest.
      There are no randomised controlled trials evaluating the effect of treatment of pyrexia (defined as ≥37.6 °C) compared to no temperature control in patients after cardiac arrest and the elevated temperature may only be an effect of a more severely injured brain. Although the effect of elevated temperature on outcome is not proven, it seems reasonable to treat hyperthermia occurring after cardiac arrest with antipyretics and to consider active cooling in unconscious patients.

      Targeted temperature management

      Animal and human data indicate that mild induced hypothermia is neuroprotective and improves outcome after a period of global cerebral hypoxia-ischaemia.
      • Gunn A.J.
      • Thoresen M.
      Hypothermic neuroprotection.
      • Froehler M.T.
      • Geocadin R.G.
      Hypothermia for neuroprotection after cardiac arrest: mechanisms, clinical trials and patient care.
      Cooling suppresses many of the pathways leading to delayed cell death, including apoptosis (programmed cell death). Hypothermia decreases the cerebral metabolic rate for oxygen (CMRO2) by about 6% for each 1 °C reduction in core temperature and this may reduce the release of excitatory amino acids and free radicals.
      • Gunn A.J.
      • Thoresen M.
      Hypothermic neuroprotection.
      • McCullough J.N.
      • Zhang N.
      • Reich D.L.
      • et al.
      Cerebral metabolic suppression during hypothermic circulatory arrest in humans.
      Hypothermia blocks the intracellular consequences of excitotoxin exposure (high calcium and glutamate concentrations) and reduces the inflammatory response associated with the post-cardiac arrest syndrome. However, in the temperature range 33–36 °C, there is no difference in the inflammatory cytokine response in adult patients according to a recent study.
      • Bro-Jeppesen J.
      • Kjaergaard J.
      • Wanscher M.
      • et al.
      The inflammatory response after out-of-hospital cardiac arrest is not modified by targeted temperature management at 33 degrees C or 36 degrees C.
      All studies of post-cardiac arrest mild induced hypothermia have included only patients in coma. One randomised trial and a pseudo-randomised trial demonstrated improved neurological outcome at hospital discharge or at 6 months in comatose patients after out-of-hospital VF cardiac arrest.
      Hypothermia after Cardiac Arrest Study Group
      Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
      • Bernard S.A.
      • Gray T.W.
      • Buist M.D.
      • et al.
      Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
      Cooling was initiated within minutes to hours after ROSC and a temperature range of 32–34 °C was maintained for 12–24 h.
      Three cohort studies including a total of 1034 patients, have compared mild induced hypothermia (32–34 °C) to no temperature management in OHCA and found no difference in neurological outcome (adjusted pooled odds ratio (OR), 0.90 [95% CI 0.45–1.82].
      • Dumas F.
      • Grimaldi D.
      • Zuber B.
      • et al.
      Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry.
      • Testori C.
      • Sterz F.
      • Behringer W.
      • et al.
      Mild therapeutic hypothermia is associated with favourable outcome in patients after cardiac arrest with non-shockable rhythms.
      • Vaahersalo J.
      • Hiltunen P.
      • Tiainen M.
      • et al.
      Therapeutic hypothermia after out-of-hospital cardiac arrest in Finnish intensive care units: the FINNRESUSCI study.
      One additional retrospective registry study of 1830 patients documented an increase in poor neurological outcome among those with nonshockable OHCA treated with mild induced hypothermia (adjusted OR 1.44 [95% CI 1.039–2.006]).
      • Mader T.J.
      • Nathanson B.H.
      • Soares 3rd, W.E.
      • Coute R.A.
      • McNally B.F.
      Comparative effectiveness of therapeutic hypothermia after out-of-hospital cardiac arrest: insight from a large data registry.
      There are numerous before and after studies on the implementation of temperature control after in hospital cardiac arrest but these data are extremely difficult to interpret because of other changes in post cardiac arrest care that occurred simultaneously. One retrospective cohort study of 8316 in-hospital cardiac arrest (IHCA) patients of any initial rhythm showed no difference in survival to hospital discharge among those who were treated with mild induced hypothermia compared with no active temperature management (OR 0.9, 95% CI 0.65–1.23) but relatively few patients were treated with mild induced hypothermia.
      • Nichol G.
      • Huszti E.
      • Kim F.
      • et al.
      Does induction of hypothermia improve outcomes after in-hospital cardiac arrest?.
      In the Targeted Temperature Management (TTM) trial, 950 all-rhythm OHCA patients were randomised to 36 h of temperature control (comprising 28 h at the target temperature followed by slow rewarm) at either 33 °C or 36 °C.
      • Nielsen N.
      • Wetterslev J.
      • Cronberg T.
      • et al.
      Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
      Strict protocols were followed for assessing prognosis and for withdrawal of life-sustaining treatment (WLST). There was no difference in the primary outcome – all cause mortality, and neurological outcome at 6 months was also similar (hazard ratio (HR) for mortality at end of trial 1.06, 95% CI 0.89–1.28; relative risk (RR) for death or poor neurological outcome at 6 months 1.02, 95% CI 0.88–1.16). Detailed neurological outcome at 6 months was also similar.
      • Lilja G.
      • Nielsen N.
      • Friberg H.
      • et al.
      cognitive function in survivors of out-of-hospital cardiac arrest after target temperature management at 33 degrees C versus 36 degrees C.
      • Cronberg T.
      • Lilja G.
      • Horn J.
      • et al.
      Neurologic function and health-related quality of life in patients following targeted temperature management at 33 degrees C vs 36 degrees C after out-of-hospital cardiac arrest: a randomized clinical trial.
      Importantly, patients in both arms of this trial had their temperature well controlled so that fever was prevented in both groups. TTM at 33 °C was associated with decreased heart rate, elevated lactate, the need for increased vasopressor support, and a higher extended cardiovascular SOFA score compared with TTM at 36 °C.
      • Bro-Jeppesen J.
      • Annborn M.
      • Hassager C.
      • et al.
      Hemodynamics and vasopressor support during targeted temperature management at 33 degrees C versus 36 degrees C after out-of-hospital cardiac arrest: a post hoc study of the target temperature management trial.
      • Annborn M.
      • Bro-Jeppesen J.
      • Nielsen N.
      • et al.
      The association of targeted temperature management at 33 and 36 degrees C with outcome in patients with moderate shock on admission after out-of-hospital cardiac arrest: a post hoc analysis of the Target Temperature Management trial.
      Bradycardia during mild induced hypothermia may be beneficial – it is associated with good neurological outcome among comatose survivors of OHCA, presumably because autonomic function is preserved.
      • Staer-Jensen H.
      • Sunde K.
      • Olasveengen T.M.
      • et al.
      Bradycardia during therapeutic hypothermia is associated with good neurologic outcome in comatose survivors of out-of-hospital cardiac arrest.
      • Thomsen J.H.
      • Hassager C.
      • Bro-Jeppesen J.
      • et al.
      Sinus bradycardia during hypothermia in comatose survivors of out-of-hospital cardiac arrest – a new early marker of favorable outcome?.
      The optimal duration for mild induced hypothermia and TTM is unknown although it is currently most commonly used for 24 h. Previous trials treated patients with 12–28 h of targeted temperature management.
      • Nielsen N.
      • Wetterslev J.
      • Cronberg T.
      • et al.
      Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
      Hypothermia after Cardiac Arrest Study Group
      Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
      • Bernard S.A.
      • Gray T.W.
      • Buist M.D.
      • et al.
      Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia.
      Two observational trials found no difference in mortality or poor neurological outcome with 24 h compared with 72 h of hypothermia.
      • Yokoyama H.
      • Nagao K.
      • Hase M.
      • et al.
      Impact of therapeutic hypothermia in the treatment of patients with out-of-hospital cardiac arrest from the J-PULSE-HYPO study registry.
      • Lee B.K.
      • Lee S.J.
      • Jeung K.W.
      • Lee H.Y.
      • Heo T.
      • Min Y.I.
      Outcome and adverse events with 72-hour cooling at 32 degrees C as compared to 24-hour cooling at 33 degrees C in comatose asphyxial arrest survivors.
      The TTM trial provided strict normothermia (<37.5 °C) after hypothermia until 72 h after ROSC.
      • Nielsen N.
      • Wetterslev J.
      • Cronberg T.
      • et al.
      Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
      The term targeted temperature management or temperature control is now preferred over the previous term therapeutic hypothermia. The Advanced Life Support Task Force of the International Liaison Committee on Resuscitation made several treatment recommendations on targeted temperature management
      • Soar J.
      • Callaway C.W.
      • Aibiki M.
      • et al.
      Part 4: advanced life support: 2015 International consensus on cardiopulmonary resuscitation and emergency cardiovascular care science with treatment recommendations.
      and these are reflected in these ERC guidelines:
      • Maintain a constant, target temperature between 32 °C and 36 °C for those patients in whom temperature control is used (strong recommendation, moderate-quality evidence).
      • Whether certain subpopulations of cardiac arrest patients may benefit from lower (32–34 °C) or higher (36 °C) temperatures remains unknown, and further research may help elucidate this.
      • TTM is recommended for adults after OHCA with an initial shockable rhythm who remain unresponsive after ROSC (strong recommendation, low-quality evidence).
      • TTM is suggested for adults after OHCA with an initial nonshockable 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 (as undertaken in the two largest previous RCTs
        • Nielsen N.
        • Wetterslev J.
        • Cronberg T.
        • et al.
        Targeted temperature management at 33 degrees C versus 36 degrees C after cardiac arrest.
        Hypothermia after Cardiac Arrest Study Group
        Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest.
        ) (weak recommendation, very low-quality evidence).
      It is clear that the optimal target temperature after cardiac arrest is not known and that more high-quality large trials are needed.
      • Nielsen N.
      • Friberg H.
      Temperature management after cardiac arrest.

      When to control temperature?

      Whichever target temperature is selected, active temperature control is required to achieve and maintain the temperature in this range. Prior recommendations suggest that cooling should be initiated as soon as possible after ROSC, but this recommendation was based only on preclinical data and rational conjecture.
      • Nolan J.P.
      • Morley P.T.
      • Vanden Hoek T.L.
      • Hickey R.W.
      Therapeutic hypothermia after cardiac arrest. An advisory statement by the Advancement Life support Task Force of the International Liaison committee on Resuscitation.
      Animal data indicate that earlier cooling after ROSC produces better outcomes.
      • Kuboyama K.
      • Safar P.
      • Radovsky A.
      • et al.
      Delay in cooling negates the beneficial effect of mild resuscitative cerebral hypothermia after cardiac arrest in dogs: a prospective, randomized study.
      • Colbourne F.
      • Corbett D.
      Delayed postischemic hypothermia: a six month survival study using behavioral and histological assessments of neuroprotection.
      Observational studies are confounded by the fact that there is an association between patients who cool faster spontaneously and worse neurological outcome.
      • Haugk M.
      • Testori C.
      • Sterz F.
      • et al.
      Relationship between time to target temperature and outcome in patients treated with therapeutic hypothermia after cardiac arrest.
      • Benz-Woerner J.
      • Delodder F.
      • Benz R.
      • et al.
      Body temperature regulation and outcome after cardiac arrest and therapeutic hypothermia.
      • Perman S.M.
      • Ellenberg J.H.
      • Grossestreuer A.V.
      • et al.
      Shorter time to target temperature is associated with poor neurologic outcome in post-arrest patients treated with targeted temperature management.
      It is hypothesised that those with the most severe neurological injury are more prone to losing their ability to control body temperature.
      Five randomised controlled trials used cold intravenous fluids after ROSC to induce hypothermia,
      • Kim F.
      • Olsufka M.
      • Longstreth Jr., W.T.
      • et al.
      Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline.
      • Kamarainen A.
      • Virkkunen I.
      • Tenhunen J.
      • Yli-Hankala A.
      • Silfvast T.
      Prehospital therapeutic hypothermia for comatose survivors of cardiac arrest: a randomized controlled trial.
      • Bernard S.A.
      • Smith K.
      • Cameron P.
      • et al.
      Induction of therapeutic hypothermia by paramedics after resuscitation from out-of-hospital ventricular fibrillation cardiac arrest: a randomized controlled trial.
      • Kim F.
      • Nichol G.
      • Maynard C.
      • et al.
      Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial.
      one trial used cold intravenous fluid during resuscitation,
      • Debaty G.
      • Maignan M.
      • Savary D.
      • et al.
      Impact of intra-arrest therapeutic hypothermia in outcomes of prehospital cardiac arrest: a randomized controlled trial.
      and one trial used intra-arrest intranasal cooling.
      • Castren M.
      • Nordberg P.
      • Svensson L.
      • et al.
      Intra-arrest transnasal evaporative cooling: a randomized, prehospital, multicenter study (PRINCE: Pre-ROSC IntraNasal Cooling Effectiveness).
      The volume of cold fluid ranged from 20 to 30 ml kg−1 and up to 2 l, although some patients did not receive the full amount before arrival at hospital. All seven trials suffered from the unavoidable lack of blinding of the clinical team, and three also failed to blind the outcomes assessors. These trials showed no overall difference in mortality for patients treated with prehospital cooling (RR, 0.98; 95% CI 0.92–1.04) compared with those who did not receive prehospital cooling. No individual trial found an effect on either poor neurological outcome or mortality.
      Four RCTs provided low quality evidence for an increased risk of re-arrest among subjects who received prehospital induced hypothermia (RR, 1.22; 95% CI 1.01–1.46),
      • Kim F.
      • Olsufka M.
      • Longstreth Jr., W.T.
      • et al.
      Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline.
      • Kamarainen A.
      • Virkkunen I.
      • Tenhunen J.
      • Yli-Hankala A.
      • Silfvast T.
      Prehospital therapeutic hypothermia for comatose survivors of cardiac arrest: a randomized controlled trial.
      • Kim F.
      • Nichol G.
      • Maynard C.
      • et al.
      Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial.
      although this result was driven by data from the largest trial.
      • Kim F.
      • Nichol G.
      • Maynard C.
      • et al.
      Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial.
      Three trials reported no pulmonary oedema in any group, two small pilot trials found no difference in the incidence of pulmonary oedema between groups,
      • Kim F.
      • Olsufka M.
      • Longstreth Jr., W.T.
      • et al.
      Pilot randomized clinical trial of prehospital induction of mild hypothermia in out-of-hospital cardiac arrest patients with a rapid infusion of 4 degrees C normal saline.
      • Debaty G.
      • Maignan M.
      • Savary D.
      • et al.
      Impact of intra-arrest therapeutic hypothermia in outcomes of prehospital cardiac arrest: a randomized controlled trial.
      and one trial showed an increase in pulmonary oedema in patients who received prehospital cooling (RR, 1.34; 95% CI 1.15–1.57).
      • Kim F.
      • Nichol G.
      • Maynard C.
      • et al.
      Effect of prehospital induction of mild hypothermia on survival and neurological status among adults with cardiac arrest: a randomized clinical trial.