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Available online http://ccforum.com/content/11/6/235 Review Clinical review: Beyond immediate survival from resuscitation – long-term outcome considerations after cardiac arrest Dilshan Arawwawala and Stephen J Brett Department of Anaesthesia and Intensive Care Medicine, Hammersmith Hospital, Du Cane Road, London W12 0HS, UK Corresponding author: Stephen J Brett, stephen.brett@imperial.ac.uk Published: 6 December 2007 This article is online at http://ccforum.com/content/11/6/235 © 2007 BioMed Central Ltd Critical Care 2007, 11:235 (doi:10.1186/cc6139) Abstract resuscitation intervention. A substantial body of literature concerning resuscitation from cardiac arrest now exists. However, not surprisingly, the greater part concerns the cardiac arrest event itself and optimising survival and outcome at relatively proximal time points. The aim of this review is to present the evidence base for interventions and therapeutic strategies that might be offered to patients surviving the immediate aftermath of a cardiac arrest, excluding components of resuscitation itself that may lead to benefits in long-term survival. In addition, this paper reviews the data on long-term impact, physical and neuropsychological, on patients and their families, revealing a burden that is often underestimated and underappreciated. As greater numbers of patients survive cardiac arrest, outcome measures more sophisticated than simple survival are required. Introduction Survival to a particular time after an ‘index’ cardiac arrest event, as recommended by the Utstein guidelines [1], is the most commonly reported outcome measure for resuscitation, with hospital discharge and 1-year survival often reported. Excessive mortality risk is greatest within the first year after arrest and, after 2 years, approaches that of an age- and gender-matched population [2]. A retrospective review of inhospital mortality identified neurological injury as the mode of early death in two thirds of out-of-hospital cardiac arrest (OOHCA) patients admitted to intensive care. Cardiovascular death and multi-organ failure death accounted for the remainder [3]. A number of studies have investigated survival rates at greater than 1 year and how survival following OOHCA has changed over time. Such studies suggest that longer-term survival figures are improving [4-7]. This may be due to changes in coronary artery disease patterns, practice, and/or subsequent medical With greater numbers of patients now surviving for longer periods, survival alone may be an inadequate assessment of resuscitation and post-resuscitation care. A more suitable tool may be assessment of quality of life (QOL) after hospital discharge. This requires an understanding of the psychosocial impact of cardiac arrest and its sequelae on the survivor and associated family members. The aim of this review is to present the evidence base for interventions and therapeutic strategies that might be offered to patients surviving the immediate aftermath of an OOHCA (excluding components of resuscitation itself) which may lead to benefits in long-term survival. In addition, this paper reviews the data on long-term impact, both physical and neuropsychological, on patients and their families. Methodology Search terms recommended by the American Heart Association [8] and International Liaison Committee on Resuscitation (ILCOR) were used. These were used by working parties evaluating evidence for the ILCOR 2005 Consensus statement [9]. An electronic search of the literature by means of PubMed was conducted using MeSH (Medical Subject Heading) main search terms ‘heart arrest’ or ‘cardiopulmonary resuscitation’. Additional terms recommended were ‘antiarrhythmia agent’, ‘glucose’, ‘hypothermia’ or ‘induced hypothermia’, ‘defibril- ACE = angiotensin-converting enzyme; ADL = activity of daily living; AVID = Antiarrhythmics Versus Implantable Defibrillators; CABG = coronary artery bypass grafting; CASH = Cardiac Arrest Study Hamburg; CIDS = Canadian Implantable Defibrillator Study; CPC = Cerebral Performance Category; DSM-IV = Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition; ECG = electrocardiogram; I-ADL = instrumental activity of daily living; ICD = implantable cardiac defibrillator; IES = Impact of Event Scale; ILCOR = International Liaison Committee on Resuscitation; LV = left ventricular; LVEF = left ventricular ejection fraction; MI = myocardial infarction; MMS = mini-mental state; MTH = moderate therapeutic hypothermia; MUSTT = Multicenter Unsustained Tachycardia Trial; OOHCA = out-of-hospital cardiac arrest; OPC = Overall Performance Category; P-ADL = personal activity of daily living; PTSD = post-traumatic stress disorder; QOL = quality of life; ROSC = return of spontaneous circulation; STEMI = ST segment elevation myocardial infarction; VF = ventricular fibrillation; VT = ventricular tachycardia. Page 1 of 17 (page number not for citation purposes) Critical Care Vol 11 No 6 Arawwawala and Brett lators, implantable’, ‘seizures’, ‘thrombolytic therapy’, ‘angioplasty’, ‘coronary artery bypass grafting’, and ‘ventricular dysfunction’. The primary search identified a total of 4,431 papers. The following search limits were then applied: human, adult, and English language. Application of search limits reduced the initial search to 1,038 articles. Studies were then reviewed for relevance. We excluded papers if they were reviews, case reports, or referred to interventions prior to the return of a spontaneous circulation; 58 papers were identified. Additional papers were obtained from the reference list used by the ILCOR working parties for the 2005 Consensus statement and from a manual search of reference lists from reviewed papers. A total of 73 papers were identified as relevant for inclusion. Using the search term ‘quality of life’ and the same primary search terms and limits, we identified 59 articles, of which 27 were relevant. A manual search of reference lists was also conducted, leading to the inclusion of another 13 articles. authors may reflect an enrolment bias as only patients with a confirmed initial rhythm of VF were included. In contrast, Engdahl and colleagues [14] have shown no improvement in survival in a Swedish cohort between 1981 and 1998. Notable differences, when compared with data from Scotland, include the proportion of those surviving to hospital discharge with an initial rhythm of VF and the number of patients receiving bystander resuscitation [5]. Pell and colleagues [5] found that almost all (greater than 94%) patients had an initial rhythm of VF or ventricular tachycardia (VT) compared with approximately 80% in the Swedish cohort. The number of patients receiving bystander resuscitation was consistently above 60% in the Scottish cohort compared with approximately 30% in the Swedish study. This lends support to current European Resuscitation Council recommendations on the need for early basic life support [15]. Interventions Overall, the literature retrieved was somewhat diverse and was not suitable for meta-analysis. Specifically, papers did not consistently report the patient populations in terms of cause of cardiac arrest or whether they occurred in-hospital or out-of-hospital and there was substantial heterogeneity. Thus, the evidence was synthesised into a narrative review. Overview of long-term mortality Survival studies performed during the period 1970 to 1985 found a 4-year survival of 40% to 61% [6,10-12]. Investigators (from several countries) examining long-term survival of patients discharged from the hospital following OOHCA have consistently shown an improvement. Pell and colleagues [5] showed that 5-year survival had improved in Scotland over a 10-year period (1991 to 2001) from 64.2% to 76%. This was due to a reduction in the risk of subsequent cardiac death. Part of this improvement was attributed to a higher percentage of patients less than 55 years of age and changes in clinical management after cardiac arrest. The subsequent use of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, antithrombotic agents, and revascularisation methods had increased over time. The authors also identified the increased use of implantable cardiac defibrillators (ICDs) and changes in smoking habits as reasons for the improvements observed [5]. Similar mortality results for OOHCA have been observed by Cobbe and colleagues [4], also in Scotland, for the period 1988 to 1994, with a 4-year survival rate of 68%. Rea and colleagues [13] found that long-term OOHCA survival in King County, WA, USA, had improved over a 26-year study period (1976 to 2001). Over each 5-year interval, cardiac mortality fell by 21% [13]. Again, the authors identified changes in clinical practice and lifestyle changes as being important. Data published from Olmstead County, MN, USA, from 1990 to 2001 of confirmed ventricular fibrillation (VF) cardiac arrests found a 5-year survival rate of 79% [7]. The higher figures obtained by these Page 2 of 17 (page number not for citation purposes) Changes in survival represent the culmination of several medical advances that have occurred over the previous two decades. Improvements in primary and secondary prevention of coronary artery disease and changes in resuscitation have all contributed. Interventions shown to improve outcome following return of spontaneous circulation (ROSC) include optimisation of ventricular function immediately after the event, revascularisation, arrhythmia management, and therapeutic hypothermia (Table 1). Revascularisation is integral to ventricular optimisation and arrhythmia management and will be discussed in conjunction with these interventions. The identification of the risk of ventricular arrhythmias after cardiac arrest by electrophysiological testing can predict long-term outcome. Thus, Wilber and colleagues [16] examined 166 survivors of OOHCA not associated with acute myocardial infarction (MI) and identified, over a mean follow-up of 21 months, a 33% (12/36) cardiac arrest recurrence rate in patients with inducible, but not suppressed, arrhythmias. This was compared with 12% (11/91) in whom inducible arrhythmias had been suppressed by surgery or antiarrhythmic agents [16]. Revascularisation Cardiac arrest survivors with significant coronary atherosclerotic disease have a 20% chance of VF recurrence at 1 year [17-19]. Of those admitted to hospital immediately after cardiac arrest, almost half have coronary artery occlusion. Furukawa and colleagues [20] showed, in postarrest patients with chronic coronary artery disease, ventricular arrhythmias unresponsive to therapy to be predictive of higher 2-year mortality. Patients surviving OOHCA often have a reversible ischaemic cause for their cardiac arrest. Ventricular arrhythmias as a cause of cardiac arrest often are associated with myocardial ischaemia. Bunch and colleagues [21] identified that 78% (66/79) of VF 1975 Kaiser et al. [23] 2000 Connolly et al. [44] 1997 2000 Kuck et al. [45] AVID [43] 2000 2003 Hennersdorf et al. [48] Connolly et al. [46] RCT. Subgroup of CIDS study 2004 Bokhari et al. [47] RCT RCT RCT Meta-analysis Prospective cohort Case-control Retrospective, observational Nagahara et al. [17] 2006 ICD or antiarrhythmic agents 1990 Kelly et al. [26] Retrospective, observational Retrospective, observational RCT 1992 1997 Bigger [28] AVID subgroup analysis Every et al. [24] 2002 Cook et al. [25] Prospective, observational Prospective cohort study 2003 Borger van der Burg et al. [27] Prospective, observational Study type Spaulding et al. [22] 1997 2004 Year Bendz et al. [18] Revascularisation Author(s) Interventions and their effect on outcome Table 1 Mixed arrest/non-arrest. VF/VT, symptomatic VT. LVEF <0.4 Cardiac arrest-VF/VT/ syncope Cardiac arrest Mixed arrest/non-arrest ventricular arrhythmias OOHCA survivors Sustained VF/VT or cardiac arrest OOHCA survivors OOHCA survivors Post-arrest OOHCA survivors OOHCA survivors IHD, LVEF <0.36, abnormal ECG Mixed arrest/non-arrest. VF/VT, symptomatic VT. LVEF <0.4 Cardiac arrest survivors Cardiac arrest with STEMI Population 1,016 659 288 1,866 204 120 58 11 50 285 84 900 281 142 40 Number ICD versus antiarrhythmic drug ICD versus antiarrhythmic drug ICD versus antiarrhythmic drug ICD versus antiarrhythmic drug ICD or antiarrhythmic agent Amiodarone or ICD ICD Surgical revascularisation Surgical revascularisation Surgical revascularisation PCI Surgical revascularisation versus surgical revascularisation + ICD Surgical revascularisation Surgical or PCI revascularisation PCI Intervention 2- and 3-year mortality and arrhythmia occurrence Mortality/arrhythmia recurrence Mortality/arrhythmia Mortality/arrhythmia Mortality over mean follow-up of 5 years Mortality over 11-year follow-up Incidence of malignant arrhythmias Mortality Arrhythmia reduction Recurrence of cardiac arrest and mortality In-hospital mortality Mortality 2-year mortality 4-year survival In-hospital and 2-year mortality Endpoint 1– 1– 1– 1– 2+ 1+ 2– 3 2– 2– 2+ 1+ 2++ 2++ 3 Continued overleaf Favours ICD Favours ICD Favours ICD Favours ICD Favours ICD Favours ICD Favours ICD Favours revascularisation Reduction in inducible VF only Favours revascularisation Favours PCI No advantage in ICD group Reduced mortality in revascularised group. Additive benefit to ICD Favours revascularisation Favours PCI Outcome Grade of evidence (Table 2) Available online http://ccforum.com/content/11/6/235 (page number not for citation purposes) Page 3 of 17 1997 1999 1996 1995 1993 1993 1993 1991 1990 1977 Haverkamp et al. [35] Buxton et al. [40] Moss et al. [41] Page 4 of 17 (page number not for citation purposes) Wever et al. [49] CASCADE [38] Powell et al. [50] Crandall et al. [51] Hallstrom et al. [34] Moosvi et al. [36] Myerburg et al. [37] 2005 2002 2002 Holzer et al. [81] HACA Group [79] Bernard et al. [69] RCT RCT Meta-analysis Case series Retrospective, observational Retrospective, observational Retrospective, observational Retrospective, observational RCT RCT RCT RCT Retrospective, observational Study type Post-OOH VF arrest Post-OOH VF cardiac arrest Post-cardiac arrest OOHCA survivors OOHCA survivors with CHD OOHCA survivors Cardiac arrest with no inducible arrhythmia Post-cardiac arrest due to ventricular arrhythmias OOHCA non-Q wave Post-cardiac arrest due to old MI Previous MI, LVEF <0.35, ventricular arrhythmia IHD and sustained inducible ventricular arrhythmias Inducible VF/VT and cardiac arrest survivors Population 77 275 385 12 209 941 194 336 228 66 196 754 396 Number Therapeutic hypothermia Therapeutic hypothermia Therapeutic hypothermia Quinidine or procainamide Quinidine or procainamide or no antiarrhythmic therapy Antiarrhythmic agents ICD ICD Amiodarone versus other antiarrhythmics ICD versus conventional TX ICD versus conventional TX Antiarrhythmic therapy versus conventional therapy Sotalol therapy Intervention Hospital mortality and neurological outcome 6-month mortality and neurological outcome Hospital and 6-month survival and neurological outcome 1-year mortality Incidence of sudden death 2-year mortality Mortality and sudden cardiac death Mortality and sudden cardiac death 2-year mortality Mortality, hospital days, interventions Mortality Cardiac arrest or death from arrhythmia 1- and 3-year mortality and cardiac arrest occurrence Endpoint 2– 2– 3 3 2+ 1– 1– 1– Continued overleaf Reduced mortality 1+ and better neurological outcome Reduced mortality 1+ and better neurological outcome Favours therapeutic hypothermia Favours antiarrhythmic 3 therapy Increased sudden 2– death in empiric antiarrhythmic therapy Increased mortality in patients given prophylactic antiarrhythmics Reduction in sudden cardiac death, no change in overall mortality Favours ICD Higher survival in amiodarone group Favours ICD Favours ICD Favours antiarrhythmic 1– therapy due to ICD May not be as effective as ICD Outcome Grade of evidence [151] Vol 11 No 6 Therapeutic hypothermia Year Author(s) Interventions and their effect on outcome Table 1 (continued) Critical Care Arawwawala and Brett AVID, antiarrhythmics Versus Implantable Defibrillators; CASCADE, Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation; CHD, coronary heart disease; CIDS, Canadian Implantable Defibrillator Study; ECG, electrocardiogram; HACA, Hypothermia After Cardiac Arrest; ICD, implantable cardiac defibrillator; IHD, ischaemic heart disease; LVEF, left ventricular ejection fraction; MI, myocardial infarction; OOH, out-of-hospital; OOHCA, out-of-hospital cardiac arrest; PCI, percutaneous coronary intervention; RCT, randomised controlled trial; STEMI, ST segment elevation myocardial infarction; TX, treatment; VF, ventricular fibrillation; VT, ventricular tachycardia. Improved survival and 2+ neurological outcome Hospital mortality and neurological outcome Therapeutic hypothermia 44 Prospective case-control 1997 Bernard et al. [78] OOHCA patients Hospital mortality and neurological outcome Therapeutic hypothermia Prospective case-control Yanagawa et al. [77] 1998 OOHCA patients 28 Improved survival and 2+ neurological outcome 2– Good neurological outcome Cerebral performance Therapeutic hypothermia 23 2000 Nagao et al. [71] Prospective cohort OOHCA patients Endpoint Study type Year Author(s) Interventions and their effect on outcome Table 1 (continued) Population Number Intervention Outcome Grade of evidence [151] Available online http://ccforum.com/content/11/6/235 OOHCA patients surviving to hospital discharge had ischaemic heart disease, with 47% of these presenting with an acute MI. Similar findings have been reported from Göteborg, Sweden, and Glasgow, Scotland [10,14]. Although there is a large body of evidence validating thrombolysis in patients with ST segment elevation myocardial infarction (STEMI), our search revealed no literature specific to a post-cardiac arrest subgroup in whom a spontaneous circulation has returned. Though relatively contraindicated in patients with prolonged cardiopulmonary resuscitation, thrombolysis would not be unreasonable to use in those patients with electrocardiogram (ECG) evidence of recent coronary artery occlusion. Clinical and ECG findings, however, may not predict arterial occlusion, and immediate angioplasty can improve survival to hospital discharge [22]. Angiography can identify the presence of thrombusassociated coronary artery occlusion that may be the cause of cardiac arrest. Revascularisation may improve survival through myocardial salvage. Bendz and colleagues [18] showed that OOHCA patients with ECG-confirmed STEMI receiving primary angioplasty had a survival rate comparable to a control non-cardiac arrest STEMI group 2 years after hospital discharge. However, the study included only patients with an arrest-toresuscitation time of less than 10 minutes and thus may have enrolled only those with a higher probability of survival. Unfortunately, no data on the incidence of arrhythmia postrevascularisation were given [18]. Retrospective case series have identified coronary artery bypass grafting (CABG) as a tool in reducing the incidence of recurrent arrest and prolonging survival after STEMI OOHCA [23,24]. Data extracted from the Antiarrhythmics Versus Implantable Defibrillators (AVID) study showed, in 281 patients (presenting with ventricular arrhythmias) who received CABG, an improvement in 5-year survival independent of ICD implantation [25]. A retrospective observational study of 50 post-cardiac arrest patients identified a reduction in inducible arrhythmias following CABG; VF was no longer inducible in all 11 patients who had inducible VF pre-operatively. In contrast, 80% of patients with inducible VT pre-operatively still had the arrhythmia following surgery [26]. Ventricular arrhythmia cardiac arrest survivors with coronary artery disease and non-inducible arrhythmias had a 100% survival rate (n = 18) over a 4-year follow-up (range, 1 to 48 months) compared with 87% (18/80) in patients not revascularised with inducible arrhythmias [27]. The CABG Patch trial, a prospective study of 900 patients with a left ventricular ejection fraction (LVEF) of less than 0.36 and ECG abnormalities scheduled for elective CABG who were randomly assigned to ICD or standard medical therapy, found that ICD use conferred no additional survival benefit to patients at high risk of arrhythmia formation [28]. In the control limb, the arrhythmia rate was low, implying that Page 5 of 17 (page number not for citation purposes) Critical Care Vol 11 No 6 Arawwawala and Brett Table 2 Scottish Intercollegiate Guideline Network: levels of evidence [151] Level of evidence Evidence required 1++ High-quality meta-analyses, systematic reviews of randomised controlled trials (RCTs), or RCTs with a very low risk of bias 1+ Well-conducted meta-analyses, systematic reviews of RCTs, or RCTs with a low risk of bias 1– Meta-analyses, systematic reviews of RCTs, or RCTs with a high risk of bias 2++ High-quality systematic reviews of case-control or cohort studies High-quality case-control or cohort studies with a very low risk of confounding, bias, or chance and a high probability that the relationship is causal 2+ Well-conducted case-control or cohort studies with a low risk of confounding, bias, or chance and a moderate probability that the relationship is causal 2– Case-control or cohort studies with a high risk of confounding, bias, or chance and a significant risk that the relationship is not causal 3 Non-analytic studies (for example, case reports and case series) 4 Expert opinion revascularisation reduces the incidence of arrhythmia formation and subsequent death. Revascularisation reduces the incidence of cardiac ischaemia that commonly precedes potentially fatal ventricular arrhythmias [29,30]. However, some patients following CABG may still have malignant arrhythmias. A case series of 23 cardiac arrest survivors discovered that 43% of patients received at least one ICD shock (range, 1 to 22 shocks) over a mean follow-up of 34 months. All patients had received CABG for ischaemia and were non-inducible with programmed stimulation [31]. percutaneous angioplasty, this may be purely historical and requires further assessment. Not all patients with potentially fatal arrhythmias have operable coronary artery disease. Therefore, revascularisation as a tool for arrhythmia management can be useful only in a specific cohort of patients. Though not specifically described in the post-cardiac arrest population, beta-blockers, aspirin, and statins have all been shown to prolong survival in patients with ischaemic heart disease. Thus, current guidelines produced by a task force representing the American Heart Association and American College of Cardiology state that patients with peri-MI ventricular arrhythmias in whom ischaemia is fully reversed do not require an ICD and that those with ischaemia not fully reversible should receive an ICD [32]. Pharmacological and electrical rhythm stabilisation Pharmacological and electrical methods often are employed to prevent the recurrence of arrhythmias, with amiodarone commonly used for arrhythmia prevention [33]. Retrospective studies of antiarrhythmic drug use after cardiac arrest have produced conflicting results [34-37]. The CASCADE (Cardiac Arrest in Seattle: Conventional Versus Amiodarone Drug Evaluation) study, a randomised multi-centre study of 228 patients post-VF confirmed cardiac arrest with electrophysiological evidence of an increased risk of further episodes, showed amiodarone to be superior to other antiarrhythmic agents at preventing VF arrests, sudden cardiac arrest, and ICD triggering episodes at 2, 5, and 6 years after the event [38]. However, the increasing use of ICDs may have a role in reducing long-term mortality, especially the high mortality rate seen in the first year after hospital discharge. Several observational studies have seen an increase in long-term survival and an increase in ICD use over the same time frames [10,13,14]. Pell and colleagues [5] estimated a 5-year mortality reduction if all patients fitting the criteria for ICDs had received them. Thus, revascularisation appears to improve survival through a reduction in malignant arrhythmias and, potentially, myocardial salvage. There is currently no evidence supporting the use of thrombolysis in patients post-arrest without electrographic evidence of acute MI. The literature suggests that there should be a greater use of early angiography and electrophysiological testing to identify the presence of reversible ischaemia and the need for revascularisation or the use of ICD or antiarrhythmic agents. Although there is more evidence supporting the use of CABG compared with The role of ICDs for ventricular arrhythmia management has been proven in randomised controlled trials. The Multicenter Unsustained Tachycardia Trial (MUSTT) prospectively randomly assigned 754 patients (with coronary artery disease, an LVEF of less than 40%, and spontaneous unsustained tachycardia or sustained tachycardia on electrophysiological manipulation) to either antiarrhythmic therapy (pharmacological or electrical) or conventional medical therapy (betablockers/ACE/diuretics/aspirin). The mean follow-up was 39 months. A 7% absolute risk reduction of death from arrhyth- Page 6 of 17 (page number not for citation purposes) Available online http://ccforum.com/content/11/6/235 mia or cardiac arrest was found in those randomly assigned to antiarrhythmic therapy. This was solely due to the use of ICDs and not pharmacological therapy [39]. Patients with ICDs not only had fewer cardiac arrests and arrhythmias, but also had improved survival every year for 5 years after enrolment compared with other study patients. Of those assigned to pharmacological agents, only 10% received amiodarone compared with more than 40% receiving class I antiarrhythmic agents. Whether this may have biased the result is uncertain [40]. The MADIT I (Multicenter Automatic Defibrillator Implantation I) study, a prospective randomised trial of 196 patients with inclusion criteria similar to those of the MUSTT study, identified a statistically significant positive outcome for those assigned to ICDs compared with pharmacological agents (54% 2-year reduction in all-cause mortality). The main antiarrhythmic agent in this study was amiodarone [41,42]. Specific to post-cardiac arrest patients, a meta-analysis of three randomised controlled trials (AVID, Canadian Implantable Defibrillator Study [CIDS], and Cardiac Arrest Study Hamburg [CASH]) investigated the role of ICDs versus amiodarone in ventricular arrhythmia reduction and mortality [43-47]. The meta-analysis concluded that there was a 27% reduction in the relative risk of dying (absolute reduction of 3.5% per year) and this was due almost entirely to a 50% reduction in arrhythmic death. The three studies enrolled patients with ventricular arrhythmias, the majority after cardiac arrest. The combined mean follow-up period was 2.3 (± 1.89 standard deviation) years. Patients with an LVEF of less than 35% benefited significantly more from an ICD than those with a greater ejection fraction. The prospective multi-centre CASH study of 288 patients post-cardiac arrest (secondary to sustained ventricular arrhythmias) randomly assigned patients to ICD or amiodarone or metoprolol. The minimum follow-up period was 2 years, with a mean of 57 ± 34 months. Overall mortality rates from all causes were 36.4% in the ICD arm and 44.4% in the antiarrhythmic arm (23% reduction). Although this was not statistically significant, there were fewer sudden deaths in the ICD group; 73% had evidence of coronary artery disease, raising the question of whether revascularisation would have altered the results. The AVID study was the only one to show a statistically significant difference. The AVID population consisted of patients with documented VF or symptomatic VT, whereas the CASH and CIDS studies were confined to cardiac arrest survivors. More than a third of the AVID study patients were not post-cardiac arrest. There were other significant differences in the inclusion criteria between the three studies. The AVID study, with more than 500 patients in each limb, identified a superior all-cause and arrhythmic death reduction (all-cause deaths 16.5% versus 10%, arrhythmic deaths 7.4% versus 3%, and 27% reduction in all-cause mortality at 2 years). The follow-up period was only 1.5 years as a statistically significant benefit of ICDs led to the early termination of the study. The longest follow-up period described has been 11 years. Patients reported were a subgroup of those enrolled from one centre into the CIDS study. Total mortality was 5.5% per year in the amiodarone group compared with 2.8% in the ICD group. Patients receiving amiodarone had not only a statistically higher mortality but also a greater recurrence of arrhythmias and drug side effects [47]. Similar results have been reported by Hennersdorf and colleagues [48] in Düsseldorf, Germany. This echoes a previous smaller study with a mean follow-up of 27 months [49]. A two-centre retrospective cohort study (Massachusetts/Los Angeles) of 331 OOHCA patients discharged from the hospital identified that 71% had coronary artery disease and reduced ventricular function, 97.6% had a ventricular arrhythmia as the cause of their arrest, and median follow-up was 35 months (range, 1 to 151 months). More deaths (34.3% versus 19.3%) and sudden cardiac deaths (14.4% versus 3.3%) occurred in patients without an ICD. Multivariate analysis identified predictors of cardiac mortality as an LVEF of less than 0.4, absence of ICD, and the presence of inducible VT before hospital discharge. Patients with ICDs had a lower mean follow-up period and less coronary disease, which may have influenced the overall outcome [50]. A retrospective study of 194 survivors of OOHCA with no significant inducible arrhythmias on electrophysiological testing identified that patients receiving an ICD had a lower incidence of sudden cardiac death. However, there was no change in overall mortality compared with those without an ICD. Patients with an ICD were younger and had significantly less coronary artery disease, which may have biased the results [51]. A prospective study of 204 patients post-cardiac arrest identified a significant reduction in mortality in patients (with inducible tachycardia) receiving ICD compared with those receiving antiarrhythmic agents. The mean follow-up period was 57 months [48]. ICDs in conjunction with additional antiarrhythmic agents have been compared with ICD therapy alone. A prospective multi-centre study randomly assigned patients with ICDs to amiodarone and beta-blocker, sotalol, or a beta-blocker (metoprolol, carvedilol, or bisoprolol) for 1 year. Patients had to have sustained VT, VF inducible VT or VF by programmed ventricular stimulation, or cardiac arrest (and an LVEF of less than 40%) as the reason for ICD insertion. The main outcome measure was ICD shock for any reason. Shocks occurred in 38.5% assigned to beta-blocker alone, 24.3% in the sotolol group, and 10.3% in the amiodarone and beta-blocker group. Given that ICD shocks are painful, this may help to improve patient acceptance of the devices [52]. Much of the evidence for arrhythmia management and its influence on long-term survival originated from patients with proven arrhythmias who were not specifically post-cardiac arrest. Although there is less evidence available for postcardiac arrest patients, the studies available are prospective, Page 7 of 17 (page number not for citation purposes) Critical Care Vol 11 No 6 Arawwawala and Brett randomised with large populations, and conclude that ICDs are superior to pharmacological agents alone at preventing further arrhythmias and prolonging survival. Although ICDs prevent sudden death, they add a considerable cost impact to patient care and produce painful shocks. Patient selection and, possibly, combined pharmacological therapy are important factors when looking to provide cost-effectiveness. Revascularisation remains an option for a specific subgroup of patients with reversible ischaemia. Cardiac dysfunction post-arrest Negovsky [53] described a multi-organ dysfunction syndrome that affects cardiovascular, neurological, pulmonary, and metabolic systems and that occurs after ROSC. Postresuscitation myocardial dysfunction is now recognised as a separate entity from myocardial stunning secondary to coronary artery occlusion and may lead to a worse prognosis [54]. Patients often require inotropic support following a cardiac arrest for depressed ventricular function; this often reverses within 24 to 48 hours [55-57]. In animal studies, global myocardial stunning has been linked to ischaemia duration, the number and type of defibrillation shocks, and the total dose of epinephrine used during resuscitation [58-63]. A prospective study of transthoracic echocardiography performed 6 hours after ROSC following OOHCA found, on multiple regression analysis, prolonged cardiopulmonary resuscitation, defibrillation, and high-dose epinephrine (greater than 5 mg) to be associated with poor left ventricular (LV) systolic function. Patients with an LVEF of less than 40% had a higher mortality over the course of 60 days after the event and significantly worse neurological outcomes (as assessed by Cerebral Performance Category [CPC] scores, see Table 3). Impaired LV diastolic function, assessed by isovolumetric relaxation times, was associated with nonVF/VT cardiac arrests and was an independent predictor of a poor outcome [64]. Attempts to correct the dysfunction mechanically and pharmacologically may lead to improved long-term outcomes. As yet, however, there is little robust evidence on which to base specific recommendations [65-68]. Therapeutic hypothermia after cardiac arrest Neurological injury accounts for a high proportion of early mortality in hospital and within the first year after discharge. Mechanisms described include reperfusion injury, production of free radicals and excitotoxic agents, the activation of degenerative enzymes, and reduced cerebral blood flow after arrest [69-73]. Animal studies have shown that mild therapeutic hypothermia (34°C to 36°C) can limit the degree of brain injury by minimising the above processes [74,75]. Some therapeutic benefit is lost if there is a delay (greater than 15 minutes after ROSC) in instituting hypothermia [76]. Human studies have shown that moderate therapeutic hypothermia (MTH) reduces hospital mortality and improves neurological outcome [69,77-80]. Bernard and colleagues [69] randomly assigned 77 post-OOH VF patients to Page 8 of 17 (page number not for citation purposes) normothermic or MTH (33°C) therapy. Survival to hospital discharge was improved in the MTH group (49% versus 33%) with higher Overall Performance Category (OPC) scores [69] (Table 3). The Hypothermia After Cardiac Arrest Study Group randomly assigned 275 witnessed VF/VT arrest patients to either maintenance of normothermia or MTH (32°C to 34°C) for 24 hours after arrest. Survival at 6 months was higher in the hypothermic group (59%) compared with the normothermic group (45%), with less neurological injury as assessed by CPC scores. Fifty-five percent of all patients in the treatment limb demonstrated a favourable neurological outcome (CPC 1 to 2) at 6 months compared with 39% in the control limb [79]. A subsequent meta-analysis of therapeutic hypothermia in post-VF arrest patients found that the number needed to treat to prevent one unfavourable neurological outcome was 6 (confidence interval, 4 to 13). Although the results are consistent, key differences between the studies used in the meta-analysis include: presenting rhythm, method of cooling, time taken to reach target temperature and duration of hypothermia [81]. To our knowledge, there have been no follow-up studies of long-term (greater than 1 year) neurological outcome of patients treated with post-arrest hypothermia. Despite the strict inclusion criteria, which may have led to enrolment bias, similar findings have been described in other studies [69,71,78,82]. Hypothermia has now been recommended by ILCOR and adopted into resuscitation guidelines as part of the ‘chain of survival’. Although the evidence to date has been primarily from VF OOHCA, ILCOR recommend that it be considered a treatment option for non-VF OOHCA [83]. Adopting therapeutic hypothermia as routine practice, however, has not occurred in some regions. Reasons given include technical difficulty and a perceived lack of evidence [84-87]. Although the evidence to date has been directed at improvements at 6 months to 1 year, it is reasonable to presume a long-term neurological benefit, but further follow-up studies are required to validate this statement. Glycaemic control Glycaemic control (80 to 110 mg/dL) in a critically ill population may provide short- and long-term survival benefits and is recommended in the management of patients with sepsis. Though an area of controversy, reducing the incidence of infection appears to account for much of the observed benefit [88,89]. Van den Berghe and colleagues [90] identified mortality benefit in critically ill medical patients managed with strict glycaemic control for a minimum of 3 days. The majority of OOHCA patients would fulfil both criteria and therefore may benefit [90]. Studies examining patients with brain ‘injuries’, however, are not conclusive. High mean glucose levels in patients with subarachnoid haemorrhage are associated with a poor neurological outcome and increased mortality. The Glucose Insulin in Stroke Trial, which used glucose/insulin/potassium infusions for 24 hours after admission to maintain serum glucose Available online http://ccforum.com/content/11/6/235 Table 3 Scoring system Scoring system Description EQ-5D Five questions on mobility, self-care, everyday activities, pain, and state of mind, each with three possible answers. Total score: 0 to 100. The higher the score, the better the quality of life. RAND 36 36 questions/statements on physical and emotional health with two to six choices for each question. 15D 15 dimensions with five levels that describe state of health. Patient chooses which best describes their state. Cerebral Performance Category (CPC) CPC 1: Conscious. Alert and able to work and lead a normal life. May have minor psychological or neurological deficits. CPC 2: Moderate cerebral disability. Conscious. Sufficient cerebral function for part-time work in sheltered environment or independent activities of daily life. May have hemiplegia, seizures, ataxia, dysarthria, or permanent memory or mental changes. CPC 3: Severe cerebral disability. Conscious. Dependent on others for daily support because of impaired brain function. CPC 4: Coma, vegetative state. CPC 5: Death. Certified brain dead or dead by traditional criteria. Overall Performance Category (OPC) OPC 1: Healthy, alert, capable of normal life. Good cerebral performance (CPC 1) plus no or only mild functional disability from non-cerebral organ system abnormalities. OPC 2: Moderate overall disability. Conscious. Moderate cerebral disability alone (CPC 2) or moderate disability from non-cerebral system dysfunction alone or both. Performs independent activities of daily life. May be able to work part-time in sheltered environment but disabled for competitive work. OPC 3: Severe overall disability. Conscious. Severe cerebral disability alone or severe disability from non-cerebral organ system dysfunction alone or both. Dependent on others for daily support. OPC 4: Same as CPC 4. OPC 5: Same as CPC 5. Activities of Daily Living (ADLs) Personal ADLs assess bathing, dressing, toilet visit, mobility, continence, and eating. Instrumental ADLs assess cleaning, shopping, cooking, and transportation. Functional Independence Measure (FIM™) An 18-point scale scoring from 1 to 7, with 7 being complete independence. Outcomes measured include self-care, sphincter control, transfers, locomotion, communication, and social cognition. Symptom Checklist 90 Revised score A 90-item self-report test designed to reflect psychological symptom patterns within the last 7 days. Impact of Event Scale A 15-point self-report questionnaire designed to assess current subjective stress for any specific life event. Post-traumatic Diagnostic Scale A 49-point self-report-style questionnaire aimed at assisting with the diagnosis of post-traumatic stress disorder. MMS A 30 point scale. Results in the range 0-23 indicate disturbance of cognition. Fields assessed are: Orientation, registration, attention and calculation, recall, language Hospital Anxiety and Depression Scale Seven questions for anxiety and seven questions for depression with a choice of four answers for each. Scores from 0 to 3 for each question, depending on answer given. The higher the total score, the more likely it is that affective symptoms are present. between 4 and 7 mmol/L, identified no mortality benefit. This study was underpowered due to slow recruitment [91-93]. The role of glucose control after OOHCA has been difficult to establish due to confounding factors (for example, time to ROSC) [94,95]. A prospective study of 145 patients admitted following ROSC from a witnessed VF arrest examined the association of glucose levels in neurological outcome. Patients receiving insulin or with a history of diabetes were excluded from the study. A significantly better neurological outcome (as assessed by CPC scores) at 6 months was identified in patients with lower median 24-hour glucose levels (146 ± 39 mg/dL interquartile range) compared with those with higher levels (184 ± 88 mg/dL) even after controlling for duration of arrest and lactate levels [96]. A retrospective observational study of 461 OOHCA patients identified, by multivariate analysis, that a glucose level of greater than 10.6 mmol/L within the first 24 hours after admission was associated with significantly higher hospital mortality [97]. A retrospective study of 98 patients identified mean blood glucose as being an independent predictor of survival at 6 months [98]. Whether glycaemic control confers longer survival and neurological benefits is unclear. High glucose levels may be a surrogate marker for the severity of brain injury incurred, reflecting the release of stress hormones (for example, cortisol, glucagon, and epinephrine). A study randomly assigning survivors of OOHCA to tight glycaemic control or no glucose control would, given the current levels of evidence for glycaemic control in critical care studies, be unethical. A sensible approach would be to prevent hyperglycaemia following OOHCA. Page 9 of 17 (page number not for citation purposes) Critical Care Vol 11 No 6 Arawwawala and Brett Anticonvulsant prophylaxis, thrombolysis, and neurological outcome Seizure activity after cardiac arrest is common, with observational studies identifying an incidence of up to 36% [99,100]. It is associated with a poor neurological outcome. However, the presence of seizure activity is likely to be the effect of significant cerebral injury. Small animal studies have described a reduction in the neuronal damage after cardiac arrest with lamotrogine and fosphenytoin [101,102]. There are, to date, no human studies examining whether anticonvulsant therapy affects patient outcome in this context. Small animal studies have demonstrated that peri-arrest thrombolysis can improve cerebral microcirculation flow and electroencephalogram readings immediately after ROSC [103,104]. To date, there are no human studies or case reports of thrombolysis being used after ROSC to improve neurological outcome. Given the level of available evidence, no recommendation can be made for the routine use of thrombolysis or prophylactic anticonvulsant drugs. Nishizawa and Kudoh [105] studied eight patients after OOHCA and discovered jugular bulb venous blood oxygen saturation altered in direct proportion to changes in mean arterial pressure. Impairment of cerebral autoregulation may be due to cerebral ischaemia accompanying cardiac arrest [105]. Similar results were obtained by Sundgreen and colleagues [106], identifying either a loss or right shift in cerebral autoregulation. Maintaining an appropriate mean arterial pressure may lead to less secondary brain injury. Although these are areas of considerable interest which may provide potential therapeutic avenues, recommendations cannot be made without further research. Neurocognitive and functional outcome: effects on survivors and families Gross neurological outcome When assessing how successful a resuscitation attempt has been, the initial Utstein recommendations focussed on survival at hospital discharge, with function assessed by CPC and OPC at discharge [107-109]. As up to 90% of hospital mortality following OOHCA is attributed to brain injury, this seems an appropriate outcome measure [110]. In Olmstead County, of patients who experienced a VF OOHCA, 145 (72%) patients were admitted alive, 79 (54%) survived to hospital discharge, 75 patients discharged had an OPC score of 1, and 5 patients discharged had a score of 2 (Table 3). Five patients were transferred to a nursing home with an OPC score of 3 to 4 [21]. Engdahl and colleagues [14] found that fewer patients were being discharged home with a CPC score of 1 or 2 over a 20-year period (1981 to 1991, 78%; 1991 to 1998, 63%) and more patients were being discharged to nursing homes and rehabilitation clinics. Such differences may reflect the study populations and community services available. A cause for the increase in Page 10 of 17 (page number not for citation purposes) patients requiring long-term care may be advances in periarrest management, with more patients surviving with what, historically, would have been unsurvivable brain injuries. Importantly, gross neurological outcome may improve with time. Among patients who had a CPC score of 2 at discharge, 77% improved to a CPC score of 1 one year later. Among patients with a CPC score of 3 at discharge, 25% improved to a CPC score of 2 and 4% to a CPC score of 1 one year later [111]. Mortality data give no indication of whether an individual returns to any degree of normal neurological function, and CPC/OPC, as somewhat gross measures, tend not to correlate with QOL as judged by questionnaires and structured interviews. Hsu and colleagues [112] studied 35 patients at an average of 7 months after arrest and found that CPC correlated poorly with QOL. A CPC score of 1 on discharge had a sensitivity of 78%, a specificity of 43%, a positive predictive value of 64%, and a negative predictive value of 60% for a QOL that was the same as or better than before the cardiac arrest [112]. Recent recommended guidelines (from participants of the Utstein Consensus Symposium) for research into in-hospital post-resuscitation care suggest the use of QOL markers as a measure of the effectiveness of care as well as outcome [113]. Three QOL scales are now recommended. These are the EQ-5D, the RAND 36, and the 15D [114-116] (Table 3). Functional outcome and quality of life Functional assessment is often made using activities of daily living (ADLs). Two different scales have been described: personal ADL (P-ADL) and instrumental ADL (I-ADL) (Table 3) [117,118]. Survivors of cardiac arrest frequently remain dependent on others for most activities. A prospective cohort study of patients after OOHCA examined ADLs 1 year after cardiac arrest, reporting that 5/26 patients remained dependent [119]. A small retrospective study with an average follow-up of 25 months found that P-ADL was a problem for 3/20 patients and that 7/20 patients were dependent for I-ADLs [120]. Grosvasser and colleagues [121], using a similar scoring system, found that 17/31 patients were dependent when followed up at least 3 years after the event. Lundgren-Nilsson and colleagues [110] assessed ADL using the Functional Independence Measure (FIM™) and the Instrumental Activity Measure (Table 3). They found that 61% were dependent for motor performance and 65% for social cognitive areas when assessed within 2 weeks of their cardiac arrest. The level of dependence fell at 45 days after the event to 43% (motor) and 56% (social cognitive) with no significant improvement between 45 days and 1 year [110]. Another marker of recovery often used is a return to prearrest social activities, including employment. The study of Pußwald and colleagues [122] of 12 survivors at a median period of 25 months after hospital discharge found that none