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 (Part II),☆☆,⋆

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Abstract

Aim of the review

To review the epidemiology, pathophysiology, treatment and prognostication in relation to the post-cardiac arrest syndrome.

Methods

Relevant articles were identified using PubMed, EMBASE and an American Heart Association EndNote master resuscitation reference library, supplemented by hand searches of key papers. Writing groups comprising international experts were assigned to each section. Drafts of the document were circulated to all authors for comment and amendment.

Results

The 4 key components of post-cardiac arrest syndrome were identified as (1) post-cardiac arrest brain injury, (2) post-cardiac arrest myocardial dysfunction, (3) systemic ischaemia/reperfusion response, and (4) persistent precipitating pathology.

Conclusions

A growing body of knowledge suggests that the individual components of the postcardiac arrest syndrome are potentially treatable.

Section snippets

Therapeutic hypothermia

Therapeutic hypothermia should be part of a standardised treatment strategy for comatose survivors of cardiac arrest (Sunde et al., 2007, Nolan et al., 2003, Soar and Nolan, 2007). Two randomized clinical trials and a meta-analysis showed improved outcome in adults who remained comatose after initial resuscitation from out-of-hospital ventricular fibrillation (VF) cardiac arrest and who were cooled within minutes to hours after ROSC (HCAG, 2002, Bernard et al., 2002, Holzer et al., 2005).

Sedation and neuromuscular blockade

If patients do not show adequate signs of awakening within the first 5–10 min after ROSC, tracheal intubation (if not already achieved), mechanical ventilation, and sedation will be required. Adequate sedation will reduce oxygen consumption, which is further reduced with therapeutic hypothermia. Use of published sedation scales for monitoring these patients (e.g., the Richmond or Ramsay Scales) may be helpful (Ely et al., 2003, De Jonghe et al., 2000). Both opioids (analgesia) and hypnotics

Seizure sincre and prevention

Seizures or myoclonus or both occur in 5–15% of adult patients who achieve ROSC and 10–40% of those who remain comatose (Krumholz et al., 1988, Levy et al., 1985, Snyder et al., 1980, Zandbergen et al., 2006a). Seizures increase cerebral metabolism by up to 3-fold (Ingvar, 1986). No studies directly address the use of prophylactic anticonvulsant drugs after cardiac arrest in adults. Anticonvulsants such as thiopental, and especially phenytoin, are neuroprotective in animal models (Ebmeyer et

Glucose control

Tight control of blood glucose (4.4–6.1 mmol L−1 or 80–110 mg dL−1) with insulin reduced hospital mortality rates in critically ill adults in a surgical ICU (van den Berghe et al., 2001) and appeared to protect the central and peripheral nervous system (Van den Berghe et al., 2005). When the same group repeated this study in a medical ICU, the overall mortality rate was similar in the intensive insulin and control groups (Van den Berghe et al., 2006). Among the patients with an ICU stay of >3 days,

Neuroprotective pharmacology

Over the past 3 decades investigators have used animal models of global cerebral ischaemia to study numerous neuroprotective modalities, including anesthetics, anticonvulsants, calcium and sodium channel antagonists, N-methyl D-aspartate (NMDA)-receptor antagonists, immunosuppressants, growth factors, protease inhibitors, magnesium, and 7-aminobutyric acid (GABA) agonists. Many of these targeted pharmacological neuroprotective strategies that focus on specific injury mechanisms have shown

Adrenal dysfunction

Relative adrenal insufficiency occurs frequently after successful resuscitation of out-of-hospital cardiac arrest and is associated with increased mortality (see Section ‘Epidemiology of the post-cardiac arrest syndrome’) (Hekimian et al., 2004, Pene et al., 2005). One small study has demonstrated increased ROSC when patients with out-of-hospital cardiac arrest were treated with hydrocortisone (Tsai et al., 2007), but the use of steroids has not been studied in the post-cardiac arrest phase.

Renal failure

Renal failure is common in any cohort of critically ill patients. In a recent study of comatose survivors of out-of-hospital cardiac arrest, 5 of 72 (7%) received haemodialysis, and the incidence was the same with or without the use of therapeutic hypothermia (Knafelj et al., 2007). In another study, renal function was impaired transiently in out-of-hospital post-cardiac arrest patients treated with therapeutic hypothermia, required no interventions, and returned to normal by 28 days (Zeiner et

Infection

Complications inevitably occur during the treatment of post-cardiac arrest patients as they do during the treatment of any critically ill patients. Although several studies have shown no statistical difference in complication rates between patients with out-of-hospital cardiac arrest who are treated with hypothermia and those who remain normothermic, these studies are generally underpowered to show this conclusively (Oddo et al., 2006, Busch et al., 2006). Pneumonia caused by aspiration or

Placement of implantable cardioverter-defibrillators

In survivors with good neurological recovery, insertion of an ICD is indicated if subsequent cardiac arrests cannot be reliably prevented by other treatments (such as a pacemaker for atrioventricular block, transcatheter ablation of a single ectopic pathway, or valve replacement for critical aortic stenosis) (AVID, 1997, Connolly et al., 2000a, Connolly et al., 2000b, Kuck et al., 2000, Moss et al., 2002, Zipes et al., 2006, Bardy et al., 2005, Ezekowitz et al., 2003, Goldberger and Lampert,

Long-term management

Issues related to long-term management are beyond the scope of this scientific statement but include cardiac and neurological rehabilitation and psychiatric disorders.

Post-cardiac arrest prognostication

With the brain’s heightened susceptibility to global ischaemia, the majority of cardiac arrest patients who are successfully resuscitated have impaired consciousness, and some remain in a vegetative state. The need for protracted high-intensity care of neurologically devastated survivors presents an immense burden to healthcare systems, patients’ families, and society in general (Gray et al., 1991, Hamel et al., 2002). To limit this burden, clinical factors and diagnostic tests are used to

Pre-cardiac arrest factors

Many studies have identified factors associated with poor functional outcome after resuscitation, but no studies have shown a reliable predictor of outcome. Advanced age is associated with decreased survival after resuscitation (Sandroni et al., 2007, Skogvoll et al., 1999, Skrifvars et al., 2007), but at least one study suggested that advanced age did not predict poor neurological outcome in survivors (Rogove et al., 1995). Race (Chu et al., 1998, Ebell et al., 1995, Becker et al., 1993) and

Intra-cardiac arrest factors

Many factors during the resuscitation process have been associated with functional outcome, but no single factor has been identified as a reliable predictor. Some association with poor functional outcome has been made between a long interval between collapse and the start of CPR and increased duration of CPR to ROSC (Rogove et al., 1995, Berek et al., 1997), but high false-positive rates make these unreliable for predicting poor outcome (Wijdicks et al., 2006). Furthermore, the quality of CPR

Post-cardiac arrest factors

The bedside neurological examination remains one of the most reliable and widely validated predictors of functional outcome after cardiac arrest (Levy et al., 1985, Wijdicks et al., 2006, Booth et al., 2004, Zandbergen et al., 1998). With sudden interruption of blood flow to the brain, higher cortical functions, such as consciousness, are lost first, whereas lower brain-stem functions, such as spontaneous breathing activity, are lost last (Jorgensen, 1997). Not surprisingly, retention of any

Neurophysiological tests

The recording of somatosensory-evoked potentials (SSEP) is a neurophysiological test of the integrity of the neuronal pathways from a peripheral nerve, spinal cord, or brainstem to the cerebral cortex (Young, 2000, Rothstein, 2000). The SSEP is probably the best and most reliable prognostic test because it is influenced less by common drugs and metabolic derangements. The N20 component (representing the primary cortical response) of the SSEP with median nerve stimulation is the best studied

Neuroimaging and monitoring modalities

Neuroimaging is performed to define structural brain injury related to cardiac arrest. The absence of a well-designed study has limited the use of neuroimaging in the prediction of outcome after cardiac arrest. The most common type of neuroimaging studied has been cranial CT. Cranial CT studies can show widespread injury to the brain with changes in oedema characteristics (Torbey et al., 2000, Torbey et al., 2004). Acquiring MRI studies is challenging in critically ill patients because of

Biochemical markers

Biochemical markers derived initially from cerebrospinal fluid (CSF) (creatine phosphokinase [CPK]-BB) (Tirschwell et al., 1997, Longstreth et al., 1981) or peripheral blood (neuron-specific enolase [NSE] and S100β) have been used to prognosticate functional outcome after cardiac arrest. The ease of obtaining samples has favored blood-based biochemical markers over those in CSF. NSE is a cytoplasmic glycolytic enzyme found in neurons, cells, and tumors of neuroendocrine origin; concentrations

Multimodality prediction of neurological outcome

More accurate prognostication can potentially be achieved by using several methods to investigate neurological injury. Some studies have suggested that combining neurological examination with other adjunctive tests enhances the overall accuracy and efficiency of prognosticating poor outcome (Booth et al., 2004, Bassetti et al., 1996, Madl et al., 2000, Zandbergen et al., 2006c). No clinical decision rule or multimodal prognostication protocol has been prospectively validated, however.

Prognostication in hypothermia-treated patients

Therapeutic hypothermia improved survival and functional outcome for one in every 6 comatose cardiac arrest survivors treated (Holzer et al., 2005). As a neuroprotective intervention, hypothermia alters the progression of neurological injury; hypothermia alters the evolution of recovery when patients who received therapeutic hypothermia are compared with those who did not. Therefore, prognostication strategies established in patients who were not treated with hypothermia might not accurately

Paediatrics: special considerations

In children, cardiac arrests are caused typically by respiratory failure, circulatory shock or both. In contrast to adults, children rarely develop sudden arrhythmogenic VF arrests from coronary artery disease. Arrhythmogenic VF/ventricular tachycardia (VT) arrests occur in 5–20% of out-of-hospital paediatric cardiac arrests and approximately 10% of in-hospital paediatric arrests (Nadkarni et al., 2006, Young et al., 2004, Samson et al., 2006, Herlitz et al., 2005, Tibballs and Kinney, 2006).

Temperature management

Mild hypothermia is a promising neuroprotective and cardio-protective treatment in the postarrest phase (Nolan et al., 2003, Holzer et al., 2005, Bernard and Buist, 2003) and is a well-established treatment in adult survivors of cardiac arrest (Oddo et al., 2006, Sunde et al., 2007). Studies of hypoxic-ischaemic encephalopathy in newborns indicate that mild hypothermia is safe and feasible and may be neuroprotective (Azzopardi et al., 2000, Gluckman et al., 2005, Wyatt et al., 2007, Gunn et

Extracorporeal membrane oxygenation

Perhaps the ultimate technology to control postresuscitation temperature and haemodynamic parameters is ECMO. Several studies have shown that placing children on ECMO during prolonged CPR (E-CPR) can result in good outcomes. In one report, 66 children were placed on ECMO during CPR over 7 years (Morris et al., 2004). The median duration of CPR before establishment of ECMO was 50 min, and 35% (23 of 66) of these children survived to hospital discharge. These children had only brief periods of no

Paediatric cardiac arrest carerequires

High-quality multimodal postarrest care improves survival and neurological outcome in adults (Sunde et al., 2007).

Paediatric post-cardiac arrest care requires specifically adapted equipment and training to deliver critical interventions rapidly and safely to avoid latent errors and preventable morbidity and mortality. Survival of children after in-hospital arrest is greater when they are treated in hospitals that employ specialized paediatric staff (Donoghue et al., 2006). These data suggest

Challenges to implementation

Publication of clinical guidelines alone is frequently inadequate to change practice. There are often several barriers to changing clinical practice, and these will need to be identified and overcome before changes can be implemented. The purpose of the following section is to provide insight into the challenges and barriers to implementing optimized post-cardiac arrest care.

Existing studies showing poor implementation

In 2003 the advanced life support task force of the International Liaison Committee on Resuscitation (ILCOR) published an advisory statement on the use of therapeutic hypothermia (Nolan et al., 2003). This statement recommended that comatose survivors of out-of-hospital VF cardiac arrest should be cooled to 32–34 °C for 12–24 h. Despite this recommendation, which was based on the results of 2 randomized controlled trials, implementation of therapeutic hypothermia has been slow. A survey of all

Barriers to implementation

The numerous barriers to implementation of guidelines have been recently described and may be classified as structural, personal, or environmental (Table 1) (Bosse et al., 2006).

Implementation strategies

Clinical guidelines that are evidence-based and strongly supported by well recognised and respected professional organizations are more likely to be adopted by practicing clinicians. Many strategies to improve implementation have been described (Table 2) (Bosse et al., 2006, Grol and Grimshaw, 2003).

Monitoring of implementation

All clinical practices should be audited, especially when change is implemented. By measuring current performance against defined standards (e.g., time to achieve target temperature when using therapeutic hypothermia), it is possible to identify which local protocols and practices need modification. Process as well as clinical factors should be monitored as part of the quality program. The iterative process of reaudit and further change as necessary should enable optimal performance. Ideally

Resource issues

Many of the interventions applied in the postresuscitation period do not require expensive equipment. The more expensive cooling systems have some advantages but are by no means essential. Maintenance of an adequate mean arterial blood pressure and control of blood glucose are also relatively inexpensive interventions. In some healthcare systems the lack of 24 h interventional cardiology systems makes it difficult to implement timely PCI, but in most cases it should still be possible to achieve

Practical problems

Postresuscitation care is delivered by many different groups of healthcare providers in multiple locations. Pre-hospital treatment by EMS may involve both paramedics and physicians, and continuation of treatment in-hospital will involve emergency physicians and nurses, cardiologists, neurologists, critical care physicians and nurses, and cardiac catheter laboratory staff. Treatment guidelines will have to be disseminated across all these specialty groups. Implementation in all these

Critical knowledge gaps

In addition to summarizing what is known about the pathophysiology and management of post-cardiac arrest syndrome, a goal of this statement is to highlight what is not known. Table 3 outlines the critical knowledge gaps identified by the writing group. The purpose of this list is to stimulate preclinical and clinical research that will lead to evidence-based optimization of post-cardiac arrest care.

Acknowledgments

This paper was originally co-published in Resuscitation and Circulation. This article is republished with permission from Circulation. 2008; 118:2452–2483 © 2008, American Heart Association, Inc. and Resuscitation. 79/3:350–379 © 2008 Elsevier Ireland Ltd. With the permission of the authors the paper has been divided into two parts. The first part was published in issue 17/4. The reference section is published in full in both parts.

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    A Spanish translated version of the summary of this article appears as Appendix in the online version at doi:10.1016/j.resuscitation.2008.09.17.

    ☆☆

    Endorsed by the American College of Emergency Physicians, Society for Academic Emergency Medicine, Society of Critical Care Medicine, and Neurocritical Care Society.

    ⋆

    This article was originally co-published in Resuscitation and Circulation. This article is republished with permission from Circulation. 2008; 118:2452–2483 © 2008, American Heart Association, Inc. and Resuscitation. 79/3: 350–379 © 2008 Elsevier Ireland Ltd.

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