post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication: a...

International Emergency Nursing (2010) 18, 8–28

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Post-cardiac arrest syndrome: Epidemiology,pathophysiology, treatment, and prognostication:A Scientific Statement from the International LiaisonCommittee on Resuscitation; the American HeartAssociation Emergency Cardiovascular CareCommittee; the Council on Cardiovascular Surgeryand Anesthesia; the Council on Cardiopulmonary,Perioperative, and Critical Care; the Councilon Clinical Cardiology; the Councilon Stroke (Part II) q,qq,qqq

Jerry P. Nolan *, Robert W. Neumar, Christophe Adrie, Mayuki Aibiki,Robert A. Berg, Bernd W. Bbttiger, Clifton Callaway, Robert S.B. Clark,Romergryko G. Geocadin, Edward C. Jauch, Karl B. Kern, Ivan Laurent,W.T. Longstreth, Raina M. Merchant, Peter Morley, Laurie J. Morrison,Vinay Nadkarni, Mary Ann Peberdy, Emanuel P. Rivers,Antonio Rodriguez-Nunez, Frank W. Sellke, Christian Spaulding,Kjetil Sunde, Terry Vanden Hoek

Consultant in Anaesthesia and Intensive Care Medicine, Royal United Hospital, Bath, United Kingdom

1755-599X/$ - see front matter ª 2009 Published by Elsevier Ltd.doi:10.1016/j.ienj.2009.07.001

q A Spanish translated version of the summary of this article appears as Appendix in the online version at doi:10.1016/j.resuscita-tion.2008.09.17.qq Endorsed by the American College of Emergency Physicians, Society for Academic Emergency Medicine, Society of Critical Care Medicine,and Neurocritical Care Society.qqq This article was originally co-published in Resuscitation and Circulation. This article is republished with permission from Circulation.2008; 118:2452–2483 ª 2008, American Heart Association, Inc. and Resuscitation. 79/3: 350–379 ª 2008 Elsevier Ireland Ltd.* Corresponding author. Tel.: +44 122 582 5010; fax: +44 122 582 5061.E-mail address: [email protected] (J.P. Nolan).

http://dx.doi.org/10.1016/j.ienj.2009.07.001

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KEYWORDSPost-cardiac arrestsyndrome;Therapeutic hypothermia

Abstract

Aim of the review:To review the epidemiology, pathophysiology, treatment and prognostication in relation to thepost-cardiac arrest syndrome.Methods:Relevant articles were identified using PubMed, EMBASE and an American Heart AssociationEndNote master resuscitation reference library, supplemented by hand searches of key papers.Writing groups comprising international experts were assigned to each section. Drafts of thedocument were circulated to all authors for comment and amendment.Results:The 4 key components of post-cardiac arrest syndrome were identified as (1) post-cardiacarrest 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 arrestsyndrome are potentially treatable.ª 2009 Published by Elsevier Ltd.

Therapeutic hypothermia

Post-cardiac arrest syndrome 9

Therapeutic hypothermia should be part of a standardisedtreatment 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-analysisshowed improved outcome in adults who remained comatoseafter initial resuscitation from out-of-hospital ventricularfibrillation (VF) cardiac arrest and who were cooled withinminutes to hours after ROSC (HCAG, 2002; Bernard et al.,2002; Holzer et al., 2005). Patients in these studies werecooled to 33 �C or the range of 32–34 �C for 12–24 h. TheHypothermia After Cardiac Arrest (HACA) study included asmall subsetofpatientswith in-hospital cardiacarrest (HCAG,2002). Four studies with historical control groups reportedbenefit after therapeutic hypothermia in comatose survivorsof out-of-hospital non-VF arrest (Bernard et al., 1997) andall rhythmarrests (Oddoetal., 2006; Sundeetal., 2007;Buschet al., 2006) Other observational studies provide evidencepossiblebenefitaftercardiacarrest fromother initial rhythmsand in other settings (Arrich, 2007; Holzer et al., 2006). Mildhypothermia is theonly therapyapplied in thepost-cardiacar-rest setting that has been shown to increase survival rates.The patients who may benefit from this treatment have notbeen fully elucidated, and the ideal induction technique(alone or in combination), target temperature, duration,and rewarming rate have yet to be established.

Animal studies demonstrate a benefit of very early coolingeither during CPR or within 15 min of ROSC when cooling ismaintained for only a short duration (1–2 h) Kuboyamaet al., 1993; Abella et al., 2004. When prolonged cooling isused (>24 h), however, less is known about the therapeuticwindow. Equivalent neuroprotection was produced in a ratmodel of cardiac arrest when a 24 h period of cooling was ini-tiated either at the time of ROSC or delayed by 1 h (Hickset al., 2000). In a gerbil forebrain ischaemiamodel, sustainedneuroprotection was achieved when hypothermia was initi-ated at 1, 6, or 12 h after reperfusion and maintained for48 h (Colbourne et al., 1999); however, neuroprotection diddecrease when the start of therapy was delayed. The median

time to achieve target temperature in the HACA trial was 8 h(IQR 6–26) HCAG, 2002, whereas in the Bernard study, aver-age core temperaturewas reported to be 33.5 �Cwithin 2 h ofROSC (Bernard et al., 2002). Clearly, additional clinical stud-ies are needed to optimize this therapeutic strated.

The practical approach of therapeutic hypothermia can bedivided into 3 phases: induction, maintenance, and rewarm-ing. Induction can be instituted easily and inexpensively withintravenous ice-cold fluids (30 mL/kg of saline 0.9% orRinger’s lactate) (Kliegel et al., 2005; Bernard et al., 2003;Virkkunen et al., 2004; Kim et al., 2007; Polderman et al.,2005) or traditional ice packs placed on the groin and armpitsand around the neck and head. In most cases it is easy to coolpatients initially after ROSC because their temperature nor-mally decreases within the first hour (Langhelle et al.,2003; Zeiner et al., 2001). Initial cooling is facilitated by con-comitant neuromuscular blockade with sedation to preventshivering. Patients can be transferred to the angiography lab-oratory with ongoing cooling using these easily applied meth-ods (Sunde et al., 2007; Knafelj et al., 2007). Surface orinternal cooling devices (as described below) can also be usedeither alone or in combination with the above measures tofacilitate induction (Holzer et al., 2006; Haugk et al., 2007).

In the maintenance phase, effective temperature moni-toring is needed to avoid significant temperature fluctua-tions. This is best achieved with external or internalcooling devices that include continuous temperature feed-back to achieve a target temperature. External devices in-clude cooling blankets or pads with water-filled circulatingsystems or more advanced systems in which cold air is circu-lated through a tent. Intravascular cooling catheters areinternal cooling devices which are usually inserted into afemoral or subclavian vein. Less sophisticated methods,such as cold wet blankets placed on the torso and aroundthe extremities, or ice packs combined with ice-cold fluids,can also be effective; but these methods may be more timeconsuming for nursing staff, result in greater temperaturefluctuations, and do not enable controlled rewarming(Merchant et al., 2006a). Ice-cold fluids alone cannot beused to maintain hypothermia (Kliegel et al., 2007).

The rewarming phase can be regulated using the externalor internal devices used for cooling or by other heating sys-tems. The optimal rate of rewarming is not known, but cur-rent consensus is to rewarm at about 0.25–0.5 �C/h (Arrich,2007). Particular care should be taken during the coolingand rewarming phases because metabolic rate, plasma elec-trolyte concentrations, and haemodynamic conditions maychange rapidly.

Therapeutic hypothermia is associated with several com-plications (Polderman, 2004). Shivering is common, particu-larly during the induction phase (Mahmood and Zweifler,2007). Mild hypothermia increases systemic vascular resis-tance, which reduces cardiac output. A variety of arrhyth-mias may be induced by hypothermia, but bradycardia isthemost common (Holzer et al., 2006). Hypothermia inducesa diuresis and coexisting hypovolaemia will compound hae-modynamic instability. Diuresis may produce electrolyteabnormalities including hypophosphatemia, hypokalaemia,hypomagnesemia and hypocalcemia and these, in turn,may cause dysrhythmias (Polderman, 2004; Poldermanet al., 2001). The plasma concentrations of these electro-lytes should be measured frequently and electrolytes shouldbe replaced to maintain normal values. Hypothermia de-creases insulin sensitivity and insulin secretion, which resultsin hyperglycaemia (Bernard et al., 2002). This should be trea-ted with insulin (see Section ‘Glucose control’). Effects onplatelet and clotting function account for impaired coagula-tion and increased bleeding. Hypothermia can impair the im-mune system and increase infection rates (Sessler, 2001). Inthe HACA study, pneumonia was more common in the cooledgroup but this did not reach statistical significance (HCAG,2002). The serum amylase may increase during hypothermiabut its significance is unclear. The clearance of sedativedrugs and neuromuscular blockers is reduced by up to 30%at a temperature of 34 �C (Tortorici et al., 2007).

Magnesium sulphate, a naturally occurring NMDA recep-tor antagonist, reduces shivering thresholds and can be gi-ven to reduce shivering during cooling (Wadhwa et al.,2005). Magnesium is also a vasodilator, and therefore in-creases cooling rates (Zweifler et al., 2004). It has anti-arrhythmic properties, and there are some animal data indi-cating that magnesium provides added neuroprotection incombination with hypothermia (Zhu et al., 2004). Magne-sium sulphate 5 g can be infused over 5 h, which coversthe period of hypothermia induction. The shivering thresh-old can also be reduced by warming the skin - the shiveringthreshold is reduced by 1 �C for every 4 �C increase in skintemperature (Cheng et al., 1995). Application of a forcedair warming blanket reduces shivering during intravascularcooling (Guluma et al., 2006).

If therapeutic hypothermia is not feasible or contraindi-cated, then, at a minimum, pyrexia must be prevented. Pyr-exia is common in the first 48 h after cardiac arrest (Takasuet al., 2001; Takino and Okada, 1991; Hickey et al., 2003).The risk of a poor neurological outcome increases for each de-gree of body temperature >37 �C (Zeiner et al., 2001).

In summary, both preclinical and clinical evidencestrongly support mild therapeutic hypothermia as an effec-tive therapy for the post-cardiac arrest syndrome. Uncon-scious adult patients with spontaneous circulation afterout-of-hospital VF cardiac arrest should be cooled to 32–34 �C for at least 12–24 h (Nolan et al., 2003). Most experts

currently recommend cooling for at least 24 h. Althoughdata support cooling to 32–34 �C, the optimal temperaturehas not been determined. Induced hypothermia might alsobenefit unconscious adult patients with spontaneous circu-lation after out-of-hospital cardiac arrest from a nonshock-able rhythm or in-hospital cardiac arrest (Nolan et al.,2003). Although the optimal timing of initiation has notbeen clinically defined, current concensus is to initiate cool-ing as soon as possible. The therapeutic window, or timeafter ROSC at which Therapeutic hypothermia is no longerbeneficial, is also not defined. Rapid intravenous infusionof ice-cold 0.9% saline or Ringer’s lactate (30 mL kg�1) is asimple, effective method for initiating cooling. Shiveringshould be treated by ensuring adequate sedation or neuro-muscular blockade with sedation. Bolus doses of neuromus-cular blocking drugs are usually adequate, but infusions areoccasionally necessary. Slow rewarming is recommended(0.25–0.5 �C/h), although the optimum rate for rewarminghas not been clinically defined. If therapeutic hypothermiais not undertaken, pyrexia during the first 72 h after cardiacarrest should be treated aggressively with antipyretics oractive cooling.

Sedation and neuromuscular blockade

If patients do not show adequate signs of awakening withinthe first 5–10 min after ROSC, tracheal intubation (if not al-ready achieved),mechanical ventilation, and sedationwill berequired. Adequate sedation will reduce oxygen consump-tion, which is further reducedwith therapeutic hypothermia.Use of published sedation scales for monitoring these pa-tients (e.g., the Richmond or Ramsay Scales) may be helpful(Ely et al., 2003; De Jonghe et al., 2000). Both opioids (anal-gesia) and hypnotics (e.g., propofol or benzodiazepines)should be used. During therapeutic hypothermia, optimalsedation can prevent shivering, and achieve target tempera-ture earlier. If shivering occurs despite deep sedation, neuro-muscular blocking drugs (as an intravenous bolus or infusion)should be used with close monitoring of sedation and neuro-logical signs such as seizures. Because of the relatively highincidence of seizures after cardiac arrest, continuous elec-troencephalographic (EEG) monitoring for patients duringsustained neuromuscular blockade is advised (Rundgrenet al., 2006). The duration of action of neuromuscular block-ers is prolonged during hypothermia (Tortorici et al., 2007).

Although it has been common practice to sedate and ven-tilate patients for at least 24 h after ROSC, there are no se-cure data to support routines of ventilation, sedation, orneuromuscular blockade after cardiac arrest. The durationof sedation and ventilation may be influenced by the useof therapeutic hypothermia.

In summary, critically ill post-cardiac arrest patients willrequire sedation for mechanical ventilation and therapeutichypothermia. Use of sedation scales for monitoring may behelpful. Adequate sedation is particularly important for pre-vention of shivering during induction of therapeutic hypo-thermia, maintenance, and rewarming. Neuromuscularblockade may facilitate induction of therapeutic hypother-mia, but if continuous infusions of neuromuscular blockingdrugs become necessary, continuous EEG monitoring shouldbe considered.

10 J.P. Nolan et al.

Seizure sincre and prevention

Seizures or myoclonus or both occur in 5–15% of adult pa-tients who achieve ROSC and 10–40% of those who remaincomatose (Krumholz et al., 1988; Levy et al., 1985; Snyderet al., 1980; Zandbergen et al., 2006a). Seizures increasecerebralmetabolismbyup to 3-fold (Ingvar, 1986). No studiesdirectly address the use of prophylactic anticonvulsant drugsafter cardiac arrest in adults. Anticonvulsants such as thio-pental, and especially phenytoin, are neuroprotective in ani-malmodels (Ebmeyer et al., 2000; Imaizumi et al., 1995; Taftet al., 1989), but a clinical trial of thiopental after cardiac ar-rest showed no benefit (Brain Resuscitation Clinical Trial I,1986). Myoclonus can be particularly difficult to treat; phe-nytoin is often ineffective. Clonazepam is the most effectiveantimyoclonic drug, but sodium valproate and levetiracetammay also be effective (Caviness and Brown, 2004). Effectivetreatment of myoclonus with propofol has been described(Wijdicks, 2002).With therapeutic hypothermia, good neuro-logical outcomes have been reported in patients initially dis-playing severe post-arrest status epilepticus (Sunde et al.,2006; Hovland et al., 2006).

In summary, prolonged seizures may cause cerebral in-jury and should be treated promptly and effectively withbenzodiazepines, phenytoin, sodium valproate, propofol,or a barbiturate. Each of these drugs can cause hypotension,and this must be treated appropriately. Clonazepam is thedrug of choice for the treatment of myoclonus. Maintenancetherapy should be started after the first event once poten-tial precipitating causes (e.g., intracranial haemorrhage,electrolyte imbalance) are excluded. Prospective studiesare needed to determine the benefit of continuous EEGmonitoring.

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 ratesin critically ill adults in a surgical ICU (van den Bergheet al., 2001) and appeared to protect the central and periph-eral nervous system (Van den Berghe et al., 2005). When thesame group repeated this study in a medical ICU, the overallmortality rate was similar in the intensive insulin and controlgroups (Van den Berghe et al., 2006). Among the patientswith an ICU stay of >3 days, intensive insulin therapy reducedthe mortality rate from 52.5% (control group) to 43%(P = 0.009). Of the 1200 patients in the medical ICU study,61 had neurological disease; the mortality rate among thesepatients was the same in the control and treatment groups(29% versus 30%) (Van den Berghe et al., 2006). Two studiesindicate that the median length of ICU stay for ICU survivorsafter admission following cardiac arrest is approximately3.4 days (Nolan et al., 2007; Sunde et al., 2007).

Hyperglycaemia is common after cardiac arrest. Bloodglucose concentrations must be monitored frequently inthese patients and hyperglycaemia treated with an insulininfusion. Recent studies indicate that post-cardiac arrest pa-tients may be treated optimally with a target range for bloodglucose concentration of up to 8 mmol L�1 (144 mg dL�1)Sunde et al., 2007; Oksanen et al., 2007; Losert et al.,2008. In a recent study, 90 unconscious survivors of out-of-

hospital VF cardiac arrest were cooled and randomized into2 treatment groups: a strict glucose control (SGC) group,with a blood glucose target of 4–6 mmol L�1 (72–108 mg dL�1), and a moderate glucose control (MGC) group,with a blood glucose target of 6–8 mmol L�1 (108–144 mg dL�1) Oksanen et al., 2007. Episodes of moderatehypoglycaemia (<3.0 mmol L�1 or 54 mg dL�1) occurred in18% of the SGC group and 2% of the MGC group (P = 0.008);however, there were no episodes of severe hypoglycaemia(<2.2 mmol L�1 or 40 mg dL�1). There was no difference inmortality. A target glucose range with an upper value of8.0 mmol L�1 (144 mg dL�1) has been suggested by others(Sunde et al., 2007; Losert et al., 2008; Finney et al.,2003). The lower value of 6.1 mmol L�1 may not reduce mor-tality any further but instead may expose patients to thepotentially harmful effects of hypoglycaemia (Oksanenet al., 2007). The incidence of hypoglycaemia in another re-cent study of intensive insulin therapy exceeded 18%(Brunkhorst et al., 2006), and some have cautioned againstits routine use in the critically ill (Marik and Varon, 2007;Watkinson et al., 2006). Regardless of the chosen glucosetarget range, blood glucose must be measured frequently(Sunde et al., 2007; Oksanen et al., 2007), especially wheninsulin is started and during cooling and rewarming periods.

Neuroprotective pharmacology

Over the past 3 decades investigators have used animalmodels of global cerebral ischaemia to study numerous neu-roprotective modalities, including anesthetics, anticonvul-sants, calcium and sodium channel antagonists, N-methylD-aspartate (NMDA)-receptor antagonists, immunosuppres-sants, growth factors, protease inhibitors, magnesium, and7-aminobutyric acid (GABA) agonists. Many of these tar-geted pharmacological neuroprotective strategies that fo-cus on specific injury mechanisms have shown benefit inpreclinical studies. Yet, none of the interventions testedthus far in prospective clinical trials have improved out-comes after out-of-hospital cardiac arrest (BrainResuscitation Clinical Trial I, 1986; Brain ResuscitationClinical Trial II, 1991; Roine et al., 1990).

There are many negative or neutral studies of targetedneuroprotective trials in humans with acute ischaemicstroke. Over the past 10 years the Stroke Therapy AcademicIndustry Roundtable (STAIR) has made recommendations forpreclinical evidence of drug efficacy and enhancing acutestroke trial design and performance in studies of neuropro-tective therapies in acute stroke (Fisher et al., 2007).Despite improved trial design and relatively large humanclinical trials, results from neuroprotective studies remaindisappointing (Lees et al., 2006; Warach et al., 2006; Clarket al., 1999).

In summary, there is inadequate evidence to recommendany pharmacological neuroprotective strategies to reducebrain injury in post-cardiac arrest patients.

Adrenal dysfunction

Relative adrenal insufficiency occurs frequently after suc-cessful resuscitation of out-of-hospital cardiac arrest andis associated with increased mortality (see Section ‘Epide-


miology of the post-cardiac arrest syndrome’) (Hekimianet al., 2004; Pene et al., 2005). One small study has demon-strated increased ROSC when patients with out-of-hospitalcardiac arrest were treated with hydrocortisone (Tsaiet al., 2007), but the use of steroids has not been studiedin the post-cardiac arrest phase. The use of low-dose ste-roids, even in septic shock, for which they are commonly gi-ven, remains controversial (Meyer and Hall, 2006). Althoughrelative adrenal insufficiency may exist after ROSC, there isno evidence that treatment with steroids improves long-term outcomes. Therefore, routine use of steroids after car-diac arrest is not recommended.

Renal failure

Renal failure is common in any cohort of critically ill pa-tients. 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 oftherapeutic hypothermia (Knafelj et al., 2007). In anotherstudy, renal function was impaired transiently in out-of-hos-pital post-cardiac arrest patients treated with therapeutichypothermia, required no interventions, and returned tonormal by 28 days (Zeiner et al., 2004). The indicationsfor starting renal replacement therapy in comatose cardiacarrest survivors are the same as those used for critically illpatients in general (Lameire et al., 2005).

Infection

Complications inevitably occur during the treatment ofpost-cardiac arrest patients as they do during the treatmentof any critically ill patients. Although several studies haveshown no statistical difference in complication rates be-tween patients with out-of-hospital cardiac arrest who aretreated with hypothermia and those who remain normother-mic, these studies are generally underpowered to show thisconclusively (Oddo et al., 2006; Busch et al., 2006). Pneu-monia caused by aspiration or mechanical ventilation isprobably the most important complication in comatosepost-cardiac arrest patients, occurring in up to 50% ofpatients after out-of-hospital cardiac arrest (HCAG, 2002;Sunde et al., 2007). In comparison with other intubatedcritically ill patients, post-cardiac arrest patients are at par-ticularly high risk of developing pneumonia within the first48 h of intubation (Rello et al., 1999).

Placement of implantable cardioverter-defibrillators

In survivors with good neurological recovery, insertion of anICD is indicated if subsequent cardiac arrests cannot be reli-ably prevented by other treatments (such as a pacemakerfor atrioventricular block, transcatheter ablation of a singleectopic pathway, or valve replacement for critical aorticstenosis) (AVID, 1997; Connolly et al., 2000a,b; Kucket al., 2000; Moss et al., 2002; Zipes et al., 2006; Bardyet al., 2005; Ezekowitz et al., 2003; Goldberger andLampert, 2006). For patients with underlying coronary dis-

ease, an ICD is strongly recommended if myocardial ischae-mia was not identified as the single trigger of sudden cardiacdeath or if it cannot be treated by coronary revasculariza-tion. Systematic implementation of ICD therapy should beconsidered for survivors of sudden cardiac death with per-sistent low (<30%) left ventricular ejection fraction. Detec-tion of asynchrony is important because stimulation atmultiple sites may further improve prognosis when com-bined with medical treatment (diuretics, (3-blockers,angiotensin-converting enzyme [ACE] inhibitors) in patientswith low left ventricular ejection fraction (Goldberger andLampert, 2006).

Long-term management

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

Post-cardiac arrest prognostication

With the brain’s heightened susceptibility to globalischaemia, the majority of cardiac arrest patients whoare successfully resuscitated have impaired consciousness,and some remain in a vegetative state. The need for pro-tracted high-intensity care of neurologically devastatedsurvivors presents an immense burden to healthcare sys-tems, patients’ families, and society in general (Grayet al., 1991; Hamel et al., 2002). To limit this burden,clinical factors and diagnostic tests are used to prognosti-cate functional outcome. With the limitation of care orwithdrawal of life-sustaining therapies as a likely outcomeof prognostication, studies have focused on poor long-term prognosis (vegetative state or death) based on clin-ical or test findings that indicate irreversible brain injury.A recent study showed that prognostication based on neu-rological examination and diagnostic modalities influencedthe decision of physicians and families on the timing ofwithdrawal of life-sustaining therapies (Geocadin et al.,2006).

Recently several systematic reviews evaluated predictorsof poor outcome, including clinical circumstances of cardiacarrest and resuscitation, patient characteristics, neurologi-cal examination, electrophysiological studies, biochemicalmarkers, and neuroimaging (Wijdicks et al., 2006; Boothet al., 2004; Zandbergen et al., 1998). Despite a large bodyof research in this area, the timing and optimal approach toprognostication of futility is controversial. Most impor-tantly, the impact of therapeutic hypothermia on the over-all accuracy of clinical prognostication has undergone onlylimited prospective evaluation.

This section approaches important prognostic factors asa manifestation of specific neurological injury in the contextof the overall neurological presentation. Having been themost studied factor with widest applicability even in institu-tions with limited technologies and expertise, the primaryfocus is on neurological examination, with the use ofadjunctive prognostic factors to enhance the accuracy ofpredicting poor outcome. We will present classical factorsin patients not treated with hypothermia followed by recent


studies on the impact of therapeutic hypothermia on prog-nostic factors and clinical outcome.

Prognostication in patients not treated withhypothermia

Pre-cardiac arrest factors

Many studies have identified factors associated with poorfunctional outcome after resuscitation, but no studies haveshown a reliable predictor of outcome. Advanced age isassociated with decreased survival after resuscitation(Sandroni et al., 2007; Skogvoll et al., 1999; Skrifvarset al., 2007), but at least one study suggested that advancedage 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 poor pre-cardiac arresthealth, including conditions such as diabetes (Skrifvarset al., 2007; De Groote et al., 2004), sepsis (Ballew et al.,1994), metastatic cancer (Ebell, 1992), renal failure (deVos et al., 1999), homebound lifestyle (Ebell, 1992), andstroke (de Vos et al., 1999) were associated with outcomebut not enough to be reliable predictors of function. Theprearrest Acute Physiology and Chronic Health Evaluation(APACHE) II and III scores also were not reliable predictors(Ebell, 1992; Ebell and Preston, 1993).

Intra-cardiac arrest factors

Many factors during the resuscitation process have beenassociated with functional outcome, but no single factorhas been identified as a reliable predictor. Some associationwith poor functional outcome has been made between along interval between collapse and the start of CPR and in-creased duration of CPR to ROSC (Rogove et al., 1995; Bereket al., 1997), but high false-positive rates make these unre-liable for predicting poor outcome (Wijdicks et al., 2006).Furthermore, the quality of CPR is likely to influence out-come. Lack of adherence to established CPR guidelines(Abella et al., 2005a; Ko et al., 2004; Wik et al., 2005),including failure to deliver a shock or achieve ROSC beforetransport (Morrison et al., 2006), and long preshock pauseswith extended interruption to assess rhythms and provideventilation have been associated with poor outcome (Abellaet al., 2005a; Wik et al., 2005). A maximum end-tidal carbondioxide (ETCO2) of <10 mm Hg (as a marker of cardiac out-put during CPR) is associated with worse outcomes (Ahrenset al., 2001; Cantineau et al., 1996; Grmec and Klemen,2001; Grmec and Kupnik, 2003; Levine et al., 1997; Wayneet al., 1995). Other arrest-related factors associated withpoor outcome that are unreliable as predictors are asystoleas the initial cardiac rhythm (Pepe et al., 1993; Wrightet al., 1990) and noncardiac causes of arrest (Rogoveet al., 1995; Van Hoeyweghen et al., 1989).

Post-cardiac arrest factors

The bedside neurological examination remains one of themost reliable and widely validated predictors of functional

outcome after cardiac arrest (Levy et al., 1985; Wijdickset al., 2006; Booth et al., 2004; Zandbergen et al., 1998).With sudden interruption of blood flow to the brain, highercortical functions, such as consciousness, are lost first,whereas lower brain-stem functions, such as spontaneousbreathing activity, are lost last (Jorgensen, 1997). Not sur-prisingly, retention of any neurological function during orimmediately after CPR portends a good neurological out-come. The absence of neurological function immediatelyafter ROSC, however, is not a reliable predictor of poor neu-rological outcome. The reliability and validity of neurologi-cal examination as a predictor of poor outcome depends onthe presence of neurological deficits at specific time pointsafter ROSC (Booth et al., 2004; Zandbergen et al., 1998).Findings of prognostic value include the absence of pupillarylight reflex, corneal reflex, facial movements, eye move-ments, gag, cough, and motor response to painful stimuli.Of these, the absence of pupillary light response, cornealreflex, or motor response to painful stimuli at day 3 providethe most reliable predictor of poor outcome (vegetativestate or death) (Zandbergen et al., 2006a, 1998; Wijdickset al., 2006). On the basis of a systematic review of the lit-erature, it was reported that absent brainstem reflexes or aGlasgow Coma Scale (GCS) motor score of <2 at 72 h had afalse-positive rate (FPR) of 0% (95% Cl 0–3%) for predictingpoor outcome (Wijdicks et al., 2006). In a recent prospec-tive trial it was reported that absent pupillary or corneal re-flexes at 72 h had a 0% FPR (95% Cl 0–9%), whereas absentmotor response at 72 h had a 5% FPR (95% Cl 2–9%) for pooroutcome (Zandbergen et al., 2006a). Poor neurological out-come is expected with these findings because of the exten-sive brain injury involving the upper brainstem (midbrain),which is the location of the ascending reticular formation(responsible for arousal) and where the pupillary light re-sponse and motor response to pain is facilitated (Auer andSutherland, 2002). When the neurological examination isused as the basis for prognostication, it is important to con-sider that physiological and pathological factors (hypoten-sion, shock, and severe metabolic abnormalities) andinterventions (paralytics, sedatives, and hypothermia) mayinfluence the findings and lead to errors in interpretation(Wijdicks et al., 2006). Therefore, adequate efforts mustbe undertaken to stabilize the patient medically beforeprognosis is determined. Use of the bedside neurologicalexamination can also be compromised by complicationssuch as seizures and myoclonus, which, if prolonged andrepetitive, may carry their own grave prognosis (Wijdickset al., 1990). Although status myoclonus has been regardedas a reliable predictor of poor outcome (FPR 0% [95%Cl0–8.8%]) (Wijdicks et al., 2006), it may be misdiagnosed bynon-neurologists.

Combinations of neurological findings have been studiedin an attempt to find a simple summary scale such as theGCS (Teasdale and Jennett, 1974), which is based on the pa-tient’s best verbal, eye, and motor responses. The GCSscore – especially a low motor component score – is asso-ciated with poor outcome (Sacco et al., 1990; Urban andCereda, 1985; Mullie et al., 1988). The importance of brain-stem reflexes in the assessment of brain injury has beenincorporated into a GCS-style scale called the Full Outlineof UnResponsiveness (FOUR) scale; the FOUR score includesthe 4 components of eye, motor, and cranial nerve reflexes


(i.e., pupillary light response) and respiration (Wijdickset al., 2005). Some of the best predictors of neurologicaloutcome are cranial nerve findings and motor response topain. A measure that combines these findings, such as theFOUR score, may have better utility. Unfortunately, nostudies have been undertaken to assess the utility of theFOUR score in cardiac arrest survivors.

Neurophysiological tests

The recording of somatosensory-evoked potentials (SSEP) isa neurophysiological test of the integrity of the neuronalpathways from a peripheral nerve, spinal cord, or brainstemto the cerebral cortex (Young, 2000; Rothstein, 2000). TheSSEP is probably the best and most reliable prognostic testbecause it is influenced less by common drugs and metabolicderangements. The N20 component (representing the pri-mary cortical response) of the SSEP with median nerve stim-ulation is the best studied evoked-potential waveform inprognostication (Zandbergen et al., 2006a, 1998, 2001;Bassetti et al., 1996; Rothstein et al.,1991). In an unrespon-sive cardiac arrest survivor, the absence of the bilateral N20component of the SSEP with median nerve stimulation from24 h to one week after ROSC very reliably predicts poor out-come (FPR for poor outcome = 0.7%, 95% Cl 0.1–3.7)(Wijdicks et al., 2006; Booth et al., 2004; Zandbergenet al., 1998). The presence of the N20 waveform in coma-tose survivors, however, did not reliably predict a good out-come (Zandbergen et al., 2006b). It also has been suggestedthat the absence of the N20 waveform is better than thebedside neurological examination as a predictor of poor out-come (Zandbergen et al., 2006a). Widespread implementa-tion of the SSEP in postresuscitation care requires advancedneurological training; this investigation can be completedand interpreted only in specialized centres. Other evokedpotentials such as brainstem auditory and visual and long-la-tency evoked-potential tests have not been thoroughlytested or widely replicated for their prognosticvalue in brain injury after cardiac arrest (Zandbergenet al., 2006b; Sohmer et al., 1986; Fischer et al., 2006; Madlet al., 2000).

Electroencephalography has been extensively studied asa tool for evaluating the depth of coma and extent of dam-age after cardiac arrest. Many malignant EEG patterns havebeen associated with poor functional outcome, the mostreliable of which appear to be generalized suppression to<20 lV, burst-suppression pattern with generalized epilepti-form activity, and generalized periodic complexes on a flatbackground (Wijdicks et al., 2006). However, the predictivevalue of individual patterns is poorly understood becausemost studies categorize a panel of patterns as malignant.A meta-analysis of studies reporting malignant EEG patternswithin the first 3 days after ROSC calculated an FPR of 3%(95% Cl 0.9–11%) Wijdicks et al., 2006. The authors con-cluded that the EEG alone was insufficient to prognosticatefutility. Electroencephalography is non-invasive and easy torecord even in unstable patients, but its widespread appli-cation is hampered by the lack of a unified classificationsystem, lack of consistent study design, the need for EEGexpertise, and its susceptibility to numerous drugs andmetabolic disorders (Young, 2000; Bassetti et al., 1996;

Rothstein et al., 1991; Chen et al., 1996; Scollo-Lavizzariand Bassetti, 1987; Synek, 1990; Edgren et al., 1987). Re-cent advances in the analysis of electroencephalographyand continuous bedside recording have addressed many ofthese limitations. Quantitative EEG (QEEG) analysis will en-able non-neurologists to use this technology at the bedside(Scollo-Lavizzari and Bassetti, 1987; Synek, 1990; Koeniget al., 2006). Given the capability of the EEG to monitorbrain activity continuously, future research can focus ondeveloping better methods to prognosticate early, trackthe brain’s real-time response to therapies, help understandthe impact of neurological injury caused by seizures, anddevelop novel treatment strategies (Rundgren et al., 2006).

Neuroimaging and monitoring modalities

Neuroimaging is performed to define structural brain injuryrelated to cardiac arrest. The absence of a well-designedstudy has limited the use of neuroimaging in the predictionof outcome after cardiac arrest. The most common type ofneuroimaging studied has been cranial CT. Cranial CT stud-ies can show widespread injury to the brain with changes inoedema characteristics (Torbey et al., 2000, 2004). Acquir-ing MRI studies is challenging in critically ill patients be-cause of restrictions on the type of equipment that can beplaced in the room; however, this is becoming less problem-atic, and MRI studies in the critically ill are increasinglybeing undertaken. Some limited studies have shown thatdiffuse cortical abnormalities in diffusion-weighted imaging(DWI) or fluid-attenuated inversion recovery (FLAIR) areassociated with poor outcome (Wijdicks et al., 2001). Func-tional neuroimaging with magnetic resonance spectroscopy(Martin et al., 1991) and positron emission tomography(PET) showing metabolic abnormality (i.e., increasing lac-tate) in the brain are associated with poor outcome (Kanoet al., 2006). Other neurological factors that define neuro-logical injury but were not reliable predictors of outcomeare ICP/CPP (Gueugniaud et al., 1991), brain energy metab-olism (Ducasse et al., 1984), CBF by xenon CT (Inoue et al.,2007), and jugular bulb venous oxygen concentrations(Buunk et al., 1999).

At this time the practical utility of neuroimaging, espe-cially CT scans, is limited to excluding intracranial patholo-gies such as haemorrhage or stroke. The limited studiesavailable hinder the effective use of neuroimaging for prog-nostication. Nonetheless, neuroimaging continues to be use-ful for understanding the brain’s response to cardiac arrest.Well-designed prospective studies are needed to fullyunderstand the utility of neuroimaging techniques at keytimes after resuscitation. Functional neuroimaging has beenused successfully to characterise injury in other areas of thebrain. The development of portable imaging devices and im-proved functional neuroimaging studies may provide a wayto study the utility of neuroimaging during the acute period,not only as a prognostic tool but also to guide treatment.

Biochemical markers

Biochemical markers derived initially from cerebrospinalfluid (CSF) (creatine phosphokinase [CPK]-BB) (Tirschwellet al., 1997; Longstreth et al., 1981) or peripheral blood


(neuron-specific enolase [NSE] and S100b) have been used toprognosticate functional outcome after cardiac arrest. Theease of obtaining samples has favored blood-based bio-chemical markers over those in CSF. NSE is a cytoplasmicglycolytic enzyme found in neurons, cells, and tumors ofneuroendocrine origin; concentrations increase in serum afew hours after injury. One study showed that an NSE cutoffof >71.0 lgL�1 drawn between 24 and 48 h after ROSC wasrequired to achieve an FPR of 0% (95% Cl 0–43%) for predict-ing poor outcome with a sensitivity of 14% (Grubb et al.,2007). Another study showed that serum NSE concentrations>33 lg L�1 drawn between 24 and 72 h after ROSC predictedpoor outcome after one month with an FPR of 0% (95% Cl 0–3%) Zandbergen et al., 2006a. Numerous other studies showvarying thresholds from 30 to 65 lg L�1 for poor outcomeand mortality (Usui et al., 1994; Tiainen et al., 2003; Roineet al., 1989; Prohl et al., 2007; Martens et al., 1998;Martens, 1996; Karkela et al., 1993).

The biochemical marker S100b is a calcium-binding pro-tein from astroglial and Schwann cells. In cardiac arrest sur-vivors, one study showed that an S100b cutoff of >1.2 lg L�1

drawn between 24 and 48 h after ROSC was required toachieve an FPR of 0% (95% Cl 0–14%), with a sensitivity of45% (Grubb et al., 2007). Other less robust studies show sim-ilar high specificity with low sensitivity (Prohl et al., 2007;Martens et al., 1998; Hachimi-ldrissi et al., 2002; Mussacket al., 2002; Pfeifer et al., 2005; Piazza et al., 2005).

Although a recommendation has been made on the use ofbiochemical markers, specifically NSE > 33 lg L�1 as a pre-dictor of poor outcome (Wijdicks et al., 2006), care must ta-ken. This caution is based on problems such as lack ofstandardisation in study design and patient treatment, widevariability of threshold values to predict poor outcome, anddiffering measurement techniques. These limitations makeit difficult to analyze these studies in aggregate. A well-de-signed study to standardise these tests at strategic timesafter cardiac arrest is necessary to determine their benefit.

Multimodality prediction of neurologicaloutcome

More accurate prognostication can potentially be achieved byusing several methods to investigate neurological injury.Some studies have suggested that combining neurologicalexaminationwith other adjunctive tests enhances the overallaccuracy 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 multi-modal prognostication protocol has been prospectively vali-dated, however.

Prognostication in hypothermia-treatedpatients

Therapeutic hypothermia improved survival and functionaloutcome for one in every 6 comatose cardiac arrest survi-vors treated (Holzer et al., 2005). As a neuroprotectiveintervention, hypothermia alters the progression of neuro-logical injury; hypothermia alters the evolution of recoverywhen patients who received therapeutic hypothermia are

compared with those who did not. Therefore, prognostica-tion strategies established in patients who were not treatedwith hypothermia might not accurately predict the outcomeof those treated with hypothermia. Hypothermia may maskneurological examination or delay the clearance of medica-tion, such as sedative or neuromuscular blocking drugs thatmay mask neurological function (Tortorici et al., 2007;Wijdicks et al., 2006; Fukuoka et al., 2004). Although theincidence of seizures in the HACA study was similar in thehypothermia and placebo groups, (HCAG, 2002) there issome concern that seizures may be masked when a neuro-muscular blocking drug is used (Hovland et al., 2006).

There are no studies detailing the prognostic accuracy ofthe neurological examination in cooled post-cardiac arrestpatients. SSEPs andbiochemicalmarkers have undergone lim-ited investigation in this patient population. One study foundbilateral absence of cortical N20 responses at 24–28 h aftercardiac arrest in 3 of 4 hypothermia-treated patients withpermanent coma [FPR 0% (95% Cl 0–100%); sensitivity 75%(95% Cl 30–95%)] Tiainen et al., 2005. An earlier study fromthe same group found that the 48 hNSE and S100 values whichachieved a 0% FPR for poor outcomewere 2–3 times higher inpatients treated with hypothermia compared with the nor-mothermic control group [NSE >25 versus 8.8 lg L�1; S100b0.23 versus 0.12 lg L�1] (Tiainen et al., 2003).

In summary, there are both theoretical and evidence-based concerns suggesting that the approach to earlyprognostication might need to be modified when post-car-diac arrest patients are treated with therapeutic hypother-mia. The relative impact of hypothermia on prognosticaccuracy appears to vary among individual strategies, andis inadequately studied. The recovery period after hypother-mia therapy has not been clearly defined, and early with-drawal of life-sustaining therapies may not be in the bestinterest of patients and their families. Until more is knownabout the impact of therapeutic hypothermia, prognostica-tion should probably be delayed, but the optimal time hasyet to be determined. Ideally bedside monitoring systemsneed to be developed to enable tracking of evolving brain in-jury and the brain’s response to therapy (e.g., hypothermia).

Paediatrics: special considerations

In children, cardiac arrests are caused typically by respira-tory failure, circulatory shock or both. In contrast to adults,children rarely develop sudden arrhythmogenic VF arrestsfrom coronary artery disease. Arrhythmogenic VF/ventricu-lar tachycardia (VT) arrests occur in 5–20% of out-of-hospi-tal paediatric cardiac arrests and approximately 10% of in-hospital paediatric arrests (Young et al., 2004; Samsonet al., 2006; Herlitz et al., 2005; Tibballs and Kinney, 2006).

Although clinical data are limited, differences in bothcardiac arrest aetiology and developmental status are likelyto contribute to differences between adult and paediatricpost-cardiac arrest syndrome (Laurent et al., 2002; Samsonet al., 2006; Morris and Nadkarni, 2003; Hickey and Painter,2006; Rodriguez-Nunez et al., 2006). For example, theseverity and duration post-cardiac arrest myocardialstunning in paediatric animal models is substantially lessthan in adult animals (Kern et al., 1996; Berg et al., 2005;Killingsworth et al., 2002; Berg et al., 2004).


In terms of treatment, there is a critical knowledge gapfor postarrest interventions in children (Gazmuri et al.,2007). Therefore, management strategies are based primar-ily on general principles of intensive care or extrapolation ofevidence obtained from adults, newborns, and animal stud-ies (HCAG, 2002; Bernard et al., 2002; Oddo et al., 2006;Sunde et al., 2007; Polderman, 2004; Morris and Nadkarni,2003; Hickey and Painter, 2006; Azzopardi et al., 2000;Gluckman et al., 2005; Wyatt et al., 2007; Wiklund et al.,2005; Gunn et al., 1998; Fink et al., 2005; Nozari et al.,2004). Based upon this extrapolation, close attention totemperature management (avoidance of hyperthermia andconsideration of induction of hypothermia), glucose man-agement (control of hyperglycaemia and avoidance of hypo-glycaemia (Srinivasan et al., 2004; Wintergerst et al., 2006;Faustino and Apkon, 2005), blood pressure (avoidance ofage-adjusted hypotension), ventilation (avoidance of hyper-or hypocarbia and avoidance of over ventilation), and hae-mo-dynamic support (maintenance of adequate cardiac out-put to meet metabolic demand) are recommended byconsensus for children post-cardiac arrest, but are not sup-ported by specific interventional studies in the post-arrestsetting.

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 isa well-established treatment in adult survivors of cardiacarrest (Oddo et al., 2006; Sunde et al., 2007). Studies ofhypoxic-ischaemic encephalopathy in newborns indicatethat mild hypothermia is safe and feasible and may be neu-roprotective (Azzopardi et al., 2000; Gluckman et al., 2005;Wyatt et al., 2007; Gunn et al., 1998; Simbruner et al.,1999; Compagnoni et al., 2002; Battin et al., 2003; Eicheret al., 2005; Lin et al., 2006), although the pathophysiologyof newborn hypoxic-ischaemic encephalopathy differs fromcardiac arrest and the post-cardiac arrest syndrome. Fur-thermore, pyrexia is common after cardiac arrest in chil-dren and is associated with poor neurological outcome(Hickey et al., 2000). Therefore post-cardiac arrest pyrexiashould be actively prevented and treated. Although post-cardiac arrest-induced hypothermia is a rational therapeu-tic approach, it has not been adequately evaluated in chil-dren. Despite this, several centres treat children aftercardiac arrest with therapeutic hypothermia based onextrapolation of the adult data (Haque et al., 2006). Thereare several physical and pharmacological methods for tem-perature control, all feasible in the paediatric intensivecare environment, with specific advantages and disadvan-tages (Kliegel et al., 2005; Virkkunen et al., 2004; Al-Senaniet al., 2004; De Georgia et al., 2004; Wang et al., 2004).

Extracorporeal membrane oxygenation

Perhaps the ultimate technology to control postresuscita-tion temperature and haemodynamic parameters is ECMO.Several studies have shown that placing children on ECMOduring 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 ofCPR 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 flow and excel-lent CPR during the low-flow period, as well as excellenthaemodynamic support and temperature control duringthe postresuscitation phase. According to the Extracorpo-real Life Support registry, E-CPR has become one of themost common indications for ECMO therapy over the pastfew years.

Paediatric cardiac arrest carerequires

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

Paediatric post-cardiac arrest care requires specificallyadapted equipment and training to deliver critical interven-tions rapidly and safely to avoid latent errors and prevent-able morbidity and mortality. Survival of children after in-hospital arrest is greater when they are treated in hospitalsthat employ specialized paediatric staff (Donoghue et al.,2006). These data suggest that development of regionalizedpaediatric cardiac arrest centres may improve outcomesafter paediatric cardiac arrests, similar to improvementswith trauma centres and regionalized neonatal intensivecare. For now, stabilization and transfer of paediatric

Table 1 Barriers to implementation.

Structural barriersResources – human and financial – often perceived as amajor problem but, in reality, it is more frequently alogistical issueOrganizationalLeadershipScientific – a low level of evidence may makeimplementation more difficultPersonal barriersIntellectual – lack of awareness that a guidelines existsPoor attitude – inherent resistance to changeMotivation – change requires effortEnvironmental barriersPolitical – a recommendation by one organization may notbe adopted by anotherEconomicalCultural – these may impact the extent of treatment deededappropriate in the postresuscitation phase hospital

Table 2 Implementation strategies.

Select a local champion – an influential and enthusiasticperson should lead local implementation of guidelinesDevelop a simple, pragmatic protocol – a simple localtreatment protocol should be developed withcontributions from all relevant disciplinesIdentify weak links in the local systemPrioritize interventionsDevelop educational materialsPilot phase


postarrest patients to optimally equipped and staffed spe-cialized paediatric facilities should be encouraged (Crayand Heard, 1995; Goh and Mok, 2001).

Challenges to implementation

Publication of clinical guidelines alone is frequently inade-quate to change practice. There are often several barriersto changing clinical practice, and these will need to be iden-tified and overcome before changes can be implemented.

The purpose of the following section is to provide insightinto the challenges and barriers to implementing optimizedpost-cardiac arrest care.

Existing studies showing poor implementation

In 2003 the advanced life support task force of the Interna-tional Liaison Committee on Resuscitation (ILCOR) publishedan advisory statement on the use of therapeutic hypother-mia (Nolan et al., 2003). This statement recommended that

Table 3 Critical knowledge gaps related to post-cardiac arrest syndrome.

EpidemiologyWhat epidemiological mechanism can be developed to monitor trends in post-cardiac arrest outcomes?PathophysiologyWhat is the mechanism(s) and time course of post-cardiac arrest coma?What is the mechanism(s) and time course of post-cardiac arrest delayed neurodegeneration?What is the mechanism(s) and time course of post-cardiac arrest myocardial dysfunction?What is the mechanism(s) and time course of impaired oxygen delivery and utilisation after cardiac arrest?What is the role of intravascular coagulation in post-cardiac arrest organ dysfunction and failure?What is the mechanism(s), time course, and significance of post-cardiac arrest adrenal insufficiency?Therapy1. What is the optimal application of therapeutic hypothermia in the post-cardiac arrest patient?a. Which patients benefit?b. What is the optimal target temperature, onset, duration, and rewarming rate?c. What is the most effective cooling technique - external versus internal?d. What are the indications for neuromuscular blockade?

2. Which patients should have early PCI?3. What is the optimal therapy for post-cardiac arrest myocardial dysfunction?a. Pharmacologicalb. Mechanical

4. What is the clinical benefit of controlled reoxygenation?5. What is the clinical benefit of early haemodynamic optimization according to protocol?6. What are the optimal goals (parameters and target ranges) for early haemodynamic optimization?a. MAP?b. CVP?c. Central or mixed venous oxygen saturation?d. Haemoglobin concentration and transfusion threshold?e. Lactate level or lactate clearance rate?f. Urine outputg. Oxygen delivery?h. Other?

7. What is the clinical benefit of glucose control and what is the optimal target glucose range?8. What is the clinical benefit of high-volume haemofiltration?9. What is the clinical benefit of early glucocorticoid therapy?10. What is the clinical benefit of prophylactic anticonvulsants?11. What is the clinical benefit of a defined period of sedation and ventilation?12. What is the clinical benefit of neuroprotective agents?PrognosisWhat is the optimal decision rule for prognostication of futility?What is the impact of therapeutic hypothermia on the reliability of prognostication of futility?PaediatricsWhat is the evidence specific to children for the knowledge gaps listed above?What is the role of ECMO in paediatric cardiac arrest and postarrest support?BarriersWhat is the most effective approach to implement therapeutic hypothermia and optimized post-cardiac arrest care?What is the value of regionalization of post-cardiac arrest care to specialized centres?

PCI indicates percutaneous coronary intevention; MAP, mean arterial pressure; CVP, central venous pressure; and EMCO, extracorporeamembrane oxygenation.


comatose survivors of out-of-hospital VF cardiac arrestshould be cooled to 32–34 �C for 12–24 h. Despite this rec-ommendation, which was based on the results of 2 random-ized controlled trials, implementation of therapeutichypothermia has been slow. A survey of all ICUs in the Uni-ted Kingdom showed that by 2006 only 27% of units had everused mild hypothermia to treat post-cardiac arrest patients(Laver et al., 2006). Similar findings were reported in sur-veys in the United States (Abella et al., 2005b; Merchantet al., 2006b) and Germany (Wolfrum et al., 2007). Success-ful implementation has been described by several centres,however (Oddo et al., 2006; Sunde et al., 2007; Knafeljet al., 2007; Busch et al., 2006; Hovdenes et al., 2007; Scottet al., 2006).

Barriers to implementation

The numerous barriers to implementation of guidelineshave been recently described and may be classified as struc-tural, personal, or environmental (Table 1) (Bosse et al.,2006).

Implementation strategies

Clinical guidelines that are evidence-based and stronglysupported by well recognised and respected professionalorganizations are more likely to be adopted by practicingclinicians. Many strategies to improve implementation havebeen described (Table 2) (Bosse et al., 2006; Grol andGrimshaw, 2003).

Monitoring of implementation

All clinical practices should be audited, especially whenchange is implemented. By measuring current performanceagainst defined standards (e.g., time to achieve targettemperature when using therapeutic hypothermia), it is pos-sible to identify which local protocols and practices needmodification. Process as well as clinical factors should bemonitored as part of the quality program. The iterative pro-cess of reaudit and further change as necessary should en-able optimal performance. Ideally the standards againstwhich local practice is audited are established at the na-tional or international level. This type of benchmarkingexercise is now common practice throughout many health-care systems.

Resource issues

Many of the interventions applied in the postresuscitationperiod do not require expensive equipment. The moreexpensive cooling systems have some advantages but areby no means essential. Maintenance of an adequate meanarterial blood pressure and control of blood glucose are alsorelatively inexpensive interventions. In some healthcaresystems the lack of 24 h interventional cardiology systemsmakes it difficult to implement timely PCI, but in most casesit should still be possible to achieve reperfusion with throm-bolytic therapy.

Practical problems

Postresuscitation care is delivered by many different groupsof healthcare providers in multiple locations. Pre-hospitaltreatment by EMS may involve both paramedics and physi-cians, and continuation of treatment in-hospital will involveemergency physicians and nurses, cardiologists, neurolo-gists, critical care physicians and nurses, and cardiac cath-eter laboratory staff. Treatment guidelines will have to bedisseminated across all these specialty groups. Implementa-tion in all these environments may also be challenging; e.g.,maintenance of hypothermia during cardiac catheterizationmay be problematic.

Therapies such as primary PCI and therapeutic hypo-thermia may not be available 24 h in many hospitalsadmitting comatose post-cardiac arrest patients. For thisreason, the concept of ‘regional cardiac arrest centres’(similar in concept to level one trauma centres) has beenproposed (Lurie et al., 2005). The concentration of post-cardiac arrest patients in regional centres may improveoutcome (this is not yet proven) and should help to facil-itate research.

Critical knowledge gaps

In addition to summarizing what is known about the path-ophysiology and management of post-cardiac arrest syn-drome, a goal of this statement is to highlight what isnot known. Table 3 outlines the critical knowledge gapsidentified by the writing group. The purpose of this listis to stimulate preclinical and clinical research that willlead to evidence-based optimization of post-cardiac arrestcare.

Acknowledgments

This paper was originally co-published in Resuscitation andCirculation. This article is republished with permission fromCirculation. 2008; 118:2452–2483 ª 2008, American HeartAssociation, Inc. and Resuscitation. 79/3:350–379 ª 2008Elsevier Ireland Ltd. With the permission of the authorsthe paper has been divided into two parts. The first partwas published in issue 17/4. The reference section is pub-lished in full in both parts.

Appendix A. Disclosures

Writing group and reviewer disclosures can be found atdoi:10.1016/j. resuscitation. 2008.09.017.

References

Abella, B.S., Zhao, D., Alvarado, J., Hamann, K., Vanden Hoek,T.L., Becker, L.B., 2004. Intra-arrest cooling improves outcomesin a murine cardiac arrest model. Circulation 109, 2786–2791.

Abella, B.S., Alvarado, J.P., Myklebust, H., et al, 2005a. Quality ofcardiopulmonary resuscitation during in-hospital cardiac arrest.JAMA 293, 305–310.


Abella, B.S., Rhee, J.W., Huang, K.N., Vanden Hoek, T.L., Becker,L.B., 2005b. Induced hypothermia is underused after resuscita-tion from cardiac arrest: a current practice survey. Resuscita-tion 64, 181–186.

Ahrens, T., Schallom, L., Bettorf, K., et al, 2001. End-tidal carbondioxide measurements as a prognostic indicator of outcome incardiac arrest. Am. J. Crit. Care 10, 391–398.

Al-Senani, F.M., Graffagnino, C., Grotta, J.C., et al, 2004. Aprospective, multicenter pilot study to evaluate the feasibilityand safety of using the CoolGard System and Icy catheterfollowing cardiac arrest. Resuscitation 62, 143–150.

Arrich, J., 2007. Clinical application of mild therapeutic hypother-mia after cardiac arrest. Crit. Care Med. 35, 1041–1107.

Auer, R., Sutherland, G., 2002. Hypoxia and related conditions. In:Graham, D., Lantos, P. (Eds.), Greenfield’s Neuropathology. TheCerebral Resuscitation Study Group, London, England.

A comparison of antiarrhythmic-drug therapy with implantabledefibrillators in patients resuscitated from near-fatal ventriculararrhythmias, 1997. The Antiarrhythmics versus ImplantableDefib-rillators (AVID) Investigators. N. Engl. J. Med. 337,1576–1583.

Azzopardi, D., Robertson, N.J., Cowan, F.M., Rutherford, M.A.,Ram-pling, M., Edwards, A.D., 2000. Pilot study of treatmentwith whole body hypothermia for neonatal encephalopathy.Pediatrics 106, 684–694.

Ballew, K.A., Philbrick, J.T., Caven, D.E., Schorling, J.B., 1994.Predictors of survival following in-hospital cardiopulmonaryresuscitation. A moving target. Arch. Intern. Med. 154, 2426–2432.

Bardy, G.H., Lee, K.L., Mark, D.B., et al, 2005. Amiodarone or animplantable cardioverter–defibrillator for congestive heartfailure. N. Engl. J. Med. 352, 225–237.

Bassetti, C., Bomio, F., Mathis, J., Hess, C.W., 1996. Early prognosisin coma after cardiac arrest: a prospective clinical, electro-physiological, and biochemical study of 60 patients. J. Neurol.Neurosurg. Psychiat. 61, 610–615.

Battin, M.R., Penrice, J., Gunn, T.R., Gunn, A.J., 2003. Treatmentof term infants with head cooling and mild systemic hypothermia(350 �C and 34.5 �C) after perinatal asphyxia. Pediatrics 111,244–251.

Becker, L.B., Han, B.H., Meyer, P.M., et al, 1993. Racial differ-ences in the incidence of cardiac arrest and subsequent survival.The CPR Chicago project. N. Engl. J. Med. 329, 600–606.

Berek, K., Jeschow, M., Aichner, F., 1997. The prognostication ofcerebral hypoxia after out-of-hospital cardiac arrest in adults.Eur. Neurol. 37, 135–145.

Berg, R.A., Chapman, F.W., Berg, M.D., et al, 2004. Attenuatedadult biphasic shocks compared with weight-based monophasicshocks in a swine model of prolonged pediatric ventricularfibrillation. Resuscitation 61, 189–197.

Berg, R.A., Samson, R.A., Berg, M.D., et al, 2005. Better outcomeafter pediatric defibrillation dosage than adult dosage in a swinemodel of pediatric ventricular fibrillation. J. Am. Coll. Cardiol.45, 786–789.

Bernard, S.A., Buist, M., 2003. Induced hypothermia in critical caremedicine: a review. Crit. Care Med. 31, 2041–2051.

Bernard, S.A., Jones, B.M., Home, M.K., 1997. Clinical trial ofinduced hypothermia in comatose survivors of out-of-hospitalcardiac arrest. Ann. Emerg. Med. 30, 146–153.

Bernard, S.A., Gray, T.W., Buist, M.D., et al, 2002. Treatment ofcomatose survivors of out-of-hospital cardiac arrest withinduced hypothermia. N. Engl. J. Med. 346, 557–563.

Bernard, S., Buist, M., Monteiro, O., Smith, K., 2003. Inducedhypothermia using large volume, ice-cold intravenous fluid incomatose survivors of out-of-hospital cardiac arrest: a pre-liminary report. Resuscitation 56, 9–13.

Booth, C.M., Boone, R.H., Tomlinson, G., Detsky, A.S., 2004. Is thispatient dead, vegetative, or severely neurologically impaired?

Assessing outcome for comatose survivors of cardiac arrest.JAMA 291, 870–879.

Bosse, G., Breuer, J.P., Spies, C., 2006. The resistance to changingguidelines – what are the challenges and how to meet them.Best Pract. Res. Clin. Anaesthesiol. 20, 379–395.

Randomized clinical study of thiopental loading in comatosesurvivors of cardiac arrest, 1986. Brain Resuscitation ClinicalTrial I Study Group. N. Engl. J. Med. 314, 397–403.

Brain Resuscitation Clinical Trial II Stuudy Group, 1991. A random-ized clinical study of a calcium-entry blocker (lidoflazine) in thetreatment of comatose survivors of cardiac arrest. N. Engl. J.Med. 324, 1225–1231.

Brunkhorst, F.M., Engel, C., Bloos, F., et al, 2006. Intensive insulintherapy and pentastarch resuscitation in severe sepsis. N. Engl.J. Med. 332, 865–866.

Busch, M., Soreide, E., Lossius, H.M., Lexow, K., Dickstein, K.,2006. Rapid implementation of therapeutic hypothermia incomatose out-of-hospital cardiac arrest survivors. Acta Anaes-thesiol. Scand. 50, 1277–1283.

Buunk, G., van der Hoeven, J.G., Meinders, A.E., 1999. Prognosticsignificance of the difference between mixed venous and jugularbulb oxygen saturation in comatose patients resuscitated from acardiac arrest. Resuscitation 41, 257–262.

Cantineau, J.P., Lambert, Y., Merckx, P., et al, 1996. End-tidalcarbon dioxide during cardiopulmonary resuscitation in humanspresenting mostly with asystole: a predictor of outcome. Crit.Care Med. 24, 791–796.

Caviness, J.N., Brown, P., 2004. Myoclonus: current concepts andrecent advances. Lancet Neurol. 3, 598–607.

Chen, R., Bolton, C.F., Young, B., 1996. Prediction of outcome inpatients with anoxic coma: a clinical and electrophysiologicstudy. Crit. Care Med. 24, 672–678.

Cheng, C., Matsukawa, T., Sessler, Dl, et al, 1995. Increasing meanskin temperature linearly reduces the core-temperature thresh-olds for vasoconstriction and shivering in humans. Anesthesiol-ogy 82, 1160–1168.

Chu, K., Swor, R., Jackson, R., et al, 1998. Race and survival afterout-of-hospital cardiac arrest in a suburban community. Ann.Emerg. Med. 31, 478–482.

Clark, W.M., Williams, B.J., Selzer, K.A., Zweifler, R.M., Sabounj-ian, L.A., Gammans, R.E., 1999. A randomized efficacy trial ofciticoline in patients with acute ischemic stroke. Stroke 30,2592–2597.

Colbourne, F., Sutherland, G.R., Auer, R.N., 1999. Electron micro-scopic evidence against apoptosis as the mechanismof neuronal death in global ischemia. J. Neurosci. 19, 4200–4210.

Compagnoni, G., Pogliani, L., Lista, G., Castoldi, F., Fontana,P., Mosca, F., 2002. Hypothermia reduces neurological dam-age in asphyxiated newborn infants. Biol. Neonate. 82, 222–227.

Connolly, S.J., Gent, M., Roberts, R.S., et al, 2000a. Canadianimplantable defibrillator study (CIDS): a randomized trial of theimplantable cardioverter defibrillator against amiodarone. Cir-culation 101, 1297–1302.

Connolly, S.J., Hallstrom, A.P., Cappato, R., et al, 2000b. Meta-analysis of the implantable cardioverter defibrillator secondaryprevention trials. AVID, CASH and CIDS studies. Antiarrhythmicsvs. Implantable Defibrillator study. Cardiac Arrest Study Ham-burg. Canadian Implantable Defibrillator Study. Eur. Heart J. 21,2071–2078.

Cray, S.H., Heard, C.M., 1995. Transport for paediatric intensivecare. Measuring the performance of a specialist transportservice. Paediatr. Anaesth. 5, 287–292.

De Georgia, M.A., Krieger, D.W., Abou-Chebl, A., et al, 2004.Cooling for Acute Ischemic Brain Damage (COOL AID): afeasibility trial of endovascular cooling. Neurology 63,312–317.


De Groote, P., Lamblin, N., Mouquet, F., et al, 2004. Impact ofdiabetes mellitus on long-term survival in patients with conges-tive heart failure. Eur. Heart J. 25, 656–662.

De Jonghe, B., Cook, D., Appere-De-Vecchi, C., Guyatt, G., Meade,M., Outin, H., 2000. Using and understanding sedation scoringsystems: a systematic review. Intensive Care Med. 26, 275–285.

de Vos, R., Koster, R.W., De Haan, R.J., Oosting, H., van der Wouw,P.A., Lampe-Schoenmaeckers, A.J., 1999. In-hospital cardiopul-monary resuscitation: prearrest morbidity and outcome. Arch.Intern. Med. 159, 845–850.

Donoghue, A.J., Nadkarni, V.M., Elliott, M., Durbin, D., 2006. Effectof hospital characteristics on outcomes from pediatric cardio-pulmonary resuscitation: a report from the national registry ofcardiopulmonary resuscitation. Pediatrics 118, 995–1001.

Ducasse, J.L., Marc-Vergnes, J.P., Cathala, B., Genestal, M.,Lareng, L., 1984. Early cerebral prognosis of anoxic encepha-lopathy using brain energy metabolism. Crit. Care Med. 12, 897–900.

Ebell, M.H., 1992. Prearrest predictors of survival following in-hospital cardiopulmonary resuscitation: a meta-analysis. J. Fam.Pract. 34, 551–558.

Ebell, M.H., Preston, P.S., 1993. The effect of the APACHE II scoreand selected clinical variables on survival following cardiopul-monary resuscitation. Fam. Med. 25, 191–196.

Ebell, M.H., Smith, M., Kruse, J.A., Drader-Wilcox, J., Novak, J.,1995. Effect of race on survival following in-hospital cardiopul-monary resuscitation. J. Fam. Pract. 40, 571–577.

Ebmeyer, U., Safar, P., Radovsky, A., et al, 2000. Thiopentalcombination treatments for cerebral resuscitation after pro-longed cardiac arrest in dogs. Exploratory outcome study.Resuscitation 45, 119–131.

Edgren, E., Hedstrand, U., Nordin, M., Rydin, E., Ronquist, G.,1987. Prediction of outcome after cardiac arrest. Crit. CareMed. 15, 820–825.

Eicher, D.J., Wagner, C.L., Katikaneni, L.P., et al, 2005. Moderatehypothermia in neonatal encephalopathy: safety outcomes.Pediatr. Neurol. 32, 18–24.

Ely, E.W., Truman, B., Shintani, A., et al, 2003. Monitoringsedation status over time in ICU patients: reliability and validityof the Richmond Agitation-Sedation Scale (RASS). JAMA 289,2983–2991.

Ezekowitz, J.A., Armstrong, P.W., McAlister, F.A., 2003. Implant-able cardioverter defibrillators in primary and secondary pre-vention: a systematic review of randomized, controlled trials.Ann. Intern. Med. 138, 445–452.

Faustino, E.V., Apkon, M., 2005. Persistent hyperglycemia incritically ill children. J. Pediatr. 146, 30–34.

Fink, E.L., Marco, C.D., Donovan, H.A., et al, 2005. Brief inducedhypothermia improves outcome after asphyxial cardiopulmonaryarrest in juvenile rats. Dev. Neurosci. 27, 191–199.

Finney, S.J., Zekveld, C., Elia, A., Evans, T.W., 2003. Glucosecontrol and mortality in critically ill patients. JAMA 290, 2041–2047.

Fischer, C., Luaute, J., Nemoz, C., Morlet, D., Kirkorian, G.,Mauguiere, F., 2006. Improved prediction of awakening ornonawakening from severe anoxic coma using tree-based clas-sification analysis. Crit. Care Med. 34, 1520–1524.

Fisher, M., Hanley, D.F., Howard, G., Jauch, E.C., Warach, S.,2007. Recommendations from the STAIR V meeting on acutestroke trials, technology and outcomes. Stroke 38, 245–248.

Fukuoka, N., Aibiki, M., Tsukamoto, T., Seki, K., Morita, S., 2004.Biphasic concentration change during continuous midazolamadministration in brain-injured patients undergoing therapeuticmoderate hypothermia. Resuscitation 60, 225–230.

Gazmuri, R.J., Nolan, J.P., Nadkarni, V.M., et al, 2007. Scien-tific knowledge gaps and clinical research priorities forcardiopulmonary resuscitation and emergency cardiovascularcare identified during the 2005 international consensus

conference on ECC and CPR science with treatment recom-mendations. A consensus statement from the internationalliaison committee on resuscitation; the American heartassociation emergency cardiovascular care committee; thestroke council; and the cardiovascular nursing council.Resuscitation 75, 400–411.

Geocadin, R.G., Buitrago, M.M., Torbey, M.T., Chandra-Strobos, N.,Williams, M.A., Kaplan, P.W., 2006. Neurologic prognosis andwithdrawal of life support after resuscitation from cardiacarrest. Neurology 67, 203–210.

Gluckman, P.D., Wyatt, J.S., Azzopardi, D., et al, 2005. Selectivehead cooling with mild systemic hypothermia after neonatalencephalopathy: multicentre randomised trial. Lancet 365,663–670.

Goh, A.Y., Mok, Q., 2001. Centralization of paediatric intensivecare: are critically ill children appropriately referred to aregional centre? Intensive Care Med. 27, 730–735.

Goldberger, Z., Lampert, R., 2006. Implantable cardioverter-defibrillators: expanding indications and technologies. Dis 21,106–111.

Gray, W.A., Capone, R.J., Most, A.S., 1991. Unsuccessful emer-gency medical resuscitation – are continued efforts in theemergency department justified? N. Engl. J. Med. 325, 1393–1398.

Grmec, S., Klemen, P., 2001. Does the end-tidal carbon dioxide(EtCO2) concentration have prognostic value during out-of-hospital cardiac arrest? Eur. J. Emerg. Med. 8, 263–269.

Grmec, S., Kupnik, D., 2003. Does the Mainz Emergency EvaluationScoring (MEES) in combination with capnometry (MEESc) help inthe prognosis of outcome from cardiopulmonary resuscitation ina prehospital setting? Resuscitation 58, 89–96.

Grol, R., Grimshaw, J., 2003. From best evidence to best practice:effective implementation of change in patients’ care. Lancet362, 1225–1230.

Grubb, N.R., Simpson, C., Sherwood, R., et al, 2007. Prediction ofcognitive dysfunction after resuscitation from out-of-hospitalcardiac arrest using serum neuron-specific enolase and proteinS-100. Heart.

Gueugniaud, P.Y., Garcia-Darennes, F., Gaussorgues, P., Ban-calari, G., Petit, P., Robert, D., 1991. Prognostic signifi-cance of early intracranial and cerebral perfusion pressuresin post-cardiac arrest anoxic coma. Intensive Care Med. 17,392–398.

Guluma, K.Z., Hemmen, T.M., Olsen, S.E., Rapp, K.S., Lyden, P.D.,2006. A trial of therapeutic hypothermia via endovascularapproach in awake patients with acute ischemic stroke: meth-odology. Acad Emerg. Med. 13, 820–827.

Gunn, A.J., Gluckman, P.D., Gunn, T.R., 1998. Selective headcooling in newborn infants after perinatal asphyxia: a safetystudy. Pediatrics 102, 885–892.

Hachimi-ldrissi, S., Van der Auwera, M., Schiettecatte, J., Ebinger,G., Michotte, Y., Huyghens, L., 2002. S-100 protein as earlypredictor of regaining consciousness after out of hospital cardiacarrest. Resuscitation 53, 251–257.

Hamel, M.B., Phillips, R., Teno, J., et al, 2002. Cost effectivenessof aggressive care for patients with nontraumatic coma. Crit.Care Med. 30, 1191–1196.

Haque, I.U., Latour, M.C., Zaritsky, A.L., 2006. Pediatric criticalcare community survey of knowledge and attitudes towardtherapeutic hypothermia in comatose children after cardiacarrest. Pediatr. Crit. Care Med. 7, 7–14.

Haugk, M., Sterz, F., Grassberger, M., et al, 2007. Feasibility andefficacy of a new non-invasive surface cooling device inpost-resuscitation intensive care medicine. Resuscitation 75,76–81.

Hypothermia after Cardiac Arrest Study Group, 2002. Mild thera-peutic hypothermia to improve the neurologic outcome aftercardiac arrest. N. Engl. J. Med. 346, 549–556.


Hekimian, G., Baugnon, T., Thuong, M., et al, 2004. Cortisol levelsand adrenal reserve after successful cardiac arrest resuscitation.Shock 22, 116–119.

Herlitz, J., Engdahl, J., Svensson, L., Young, M., Angquist, K.A.,Holm-berg, S., 2005. Characteristics and outcome among chil-dren suffering from out of hospital cardiac arrest in Sweden.Resuscitation 64, 37–40.

Hickey, R.W., Painter, M.J., 2006. Brain injury from cardiac arrestin children. Neurol. Clin. 24, 147–158, viii.

Hickey, R.W., Kochanek, P.M., Ferimer, H., Graham, S.H., Safar,P., 2000. Hypothermia and hyperthermia in children afterresuscitation from cardiac arrest. Pediatrics 106 (pt 1), 118–122.

Hickey, R.W., Kochanek, P.M., Ferimer, H., Alexander, H.L.,Garman, R.H., Graham, S.H., 2003. Induced hyperthermiaexacerbates neurologic neuronal histologic damage afterasphyxial cardiac arrest in rats. Crit. Care Med. 31, 531–535.

Hicks, S.D., DeFranco, D.B., Callaway, C.W., 2000. Hypothermiaduring reperfusion after asphyxial cardiac arrest improvesfunctional recovery and selectively alters stress-induced proteinexpression. J. Cereb. Blood Flow Metab. 20, 520–530.

Holzer, M., Bernard, S.A., Hachimi-ldrissi, S., Roine, R.O., Sterz, F.,Mull-ner, M., 2005. Hypothermia for neuroprotection aftercardiac arrest: systematic review and individual patient datameta-analysis. Crit. Care Med. 33, 414–418.

Holzer, M., Mullner, M., Sterz, F., et al, 2006. Efficacy and safetyof endovascular cooling after cardiac arrest: cohort study andBayesian approach. Stroke 37, 1792–1797.

Hovdenes, J., Laake, J.H., Aaberge, L., Haugaa, H., Bugge, J.F.,2007. Therapeutic hypothermia after out-of-hospital cardiacarrest: experiences with patients treated with percutaneouscoronary intervention and cardiogenic shock. Acta Anaesthesiol.Scand. 51, 137–142.

Hovland, A., Nielsen, E.W., Kluver, J., Salvesen, R., 2006. EEGshould be performed during induced hypothermia. Resuscitation68, 143–146.

Imaizumi, S., Kurosawa, K., Kinouchi, H., Yoshimoto, T., 1995.Effect of phenytoin on cortical Na(+)–K(+)-ATPaseactivity in global ischemic rat brain. J. Neurotrauma. 12, 231–234.

Ingvar, M., 1986. Cerebral blood flow and metabolic rate duringseizures. Relationship to epileptic brain damage. Ann. N Y Acad.Sci. 462, 194–206.

Inoue, Y., Shiozaki, T., Irisawa, T., et al, 2007. Acute cerebralblood flow variations after human cardiac arrest assessed bystable xenon enhanced computed tomography. Curr. Neurovasc.Res. 4, 49–54.

Jorgensen, E.O., 1997. Course of neurological recovery and cerebralprognostic signs during cardio-pulmonary resuscitation. Resus-citation 35, 9–16.

Kano, H., Houkin, K., Harada, K., et al, 2006. Neuronal cell injuryin patients after cardiopulmonary resuscitation: evaluation bydiffusion-weighted imaging and magnetic resonance spectros-copy. Neurosurg. Rev. 29, 88–92.

Karkela, J., Bock, E., Kaukinen, S., 1993. CSF and serum brain-specific creatine kinase isoenzyme (CK-BB), neuron-specificenolase (NSE) and neural cell adhesion molecule (NCAM) asprognostic markers for hypoxic brain injury after cardiac arrestin man. J. Neurol. Sci. 116, 100–109.

Kern, K.B., Hilwig, R.W., Rhee, K.H., Berg, R.A., 1996. Myocardialdysfunction after resuscitation from cardiac arrest: an exampleof global myocardial stunning. J. Am. Coll. Cardiol. 28, 232–240.

Killingsworth, C.R., Melnick, S.B., Chapman, F.W., et al, 2002.Defibrillation threshold and cardiac responses using an externalbiphasic defibrillator with pediatric and adult adhesive patchesin pediatric-sized piglets. Resuscitation 55, 177–185.

Kim, F., Olsufka, M., Longstreth Jr., W.T., et al, 2007. Pilotrandomized clinical trial of prehospital induction of mild

hypothermia in out-of-hospital cardiac arrest patients with arapid infusion of 4 �C normal saline. Circulation 115, 3064–3070.

Kliegel, A., Losert, H., Sterz, F., et al, 2005. Cold simple intrave-nous infusions preceding special endovascular cooling for fasterinduction of mild hypothermia after cardiac arrest – a feasibilitystudy. Resuscitation 64, 347–351.

Kliegel, A., Janata, A., Wandaller, C., et al, 2007. Cold infusionsalone are effective for induction of therapeutic hypothermia butdo not keep patients cool after cardiac arrest. Resuscitation 73,46–53.

Knafelj, R., Radsel, P., Ploj, T., Noc, M., 2007. Primary percuta-neous coronary intervention and mild induced hypothermia incomatose survivors of ventricular fibrillation with ST-elevationacute myocardial infarction. Resuscitation 74, 227–234.

Ko, P.C., Ma, M.H., Yen, Z.S., Shih, C.L., Chen, W.J., Lin, F.Y.,2004. Impact of community-wide deployment of biphasic wave-form automated external defibrillators on out-of-hospital car-diac arrest in Taipei. Resuscitation 63, 167–174.

Koenig, M.A., Kaplan, P.W., Thakor, N.V., 2006. Clinical neuro-physiologic monitoring and brain injury from cardiac arrest.Neurol. Clin. 24, 89–106.

Krumholz, A., Stern, B.J., Weiss, H.D., 1988. Outcome from comaafter cardiopulmonary resuscitation: relation to seizures andmyoclonus. Neurology 38, 401–405.

Kuboyama, K., Safar, P., Radovsky, A., Tisherman, S.A., Stezoski,S.W., Alexander, H., 1993. Delay in cooling negates thebeneficial effect of mild resuscitative cerebral hypothermiaafter cardiac arrest in dogs: a prospective, randomized study.Crit. Care Med. 21, 1348–1358.

Kuck, K.H., Cappato, R., Siebels, J., Ruppel, R., 2000. Randomizedcomparison of antiarrhythmic drug therapy with implantabledefibrillators in patients resuscitated from cardiac arrest: theCardiac Arrest Study Hamburg (CASH). Circulation 102, 748–754.

Lameire, N., Van Biesen, W., Vanholder, R., 2005. Acute renalfailure. Lancet 365, 417–430.

Langhelle, A., Tyvold, S.S., Lexow, K., Hapnes, S.A., Sunde, K.,Steen, P.A., 2003. In-hospital factors associated with improvedoutcome after out-of-hospital cardiac arrest. A comparisonbetween four regions in Norway. Resuscitation 56, 247–263.

Laurent, I., Monchi, M., Chiche, J.D., et al, 2002. Reversiblemyocardial dysfunction in survivors of out-of-hospital cardiacarrest. J. Am. Coll. Cardiol. 40, 2110–2116.

Laver, S.R., Padkin, A., Atalla, A., Nolan, J.P., 2006. Therapeutichypothermia after cardiac arrest. A survey of practice in intensivecare units in the United Kingdom. Anaesthesia 61, 873–877.

Lees, K.R., Zivin, J.A., Ashwood, T., et al, 2006. NXY-059 for acuteischemic stroke. N. Engl. J. Med. 354, 588–600.

Levine, R.L., Wayne, M.A., Miller, C.C., 1997. End-tidal carbondioxide and outcome of out-of-hospital cardiac arrest. N. Engl.J. Med. 337, 301–306.

Levy, D.E., Caronna, J.J., Singer, B.H., Lapinski, R.H., Frydman,H., Plum, F., 1985. Predicting outcome from hypoxic-ischemiccoma. JAMA 253, 1420–1426.

Lin, Z.L., Yu, H.M., Lin, J., Chen, S.Q., Liang, Z.Q., Zhang, Z.Y.,2006. Mild hypothermia via selective head cooling as neuropro-tective therapy in term neonates with perinatal asphyxia: anexperience from a single neonatal intensive care unit. J.Perinatol. 26, 180–184.

Longstreth Jr., W.T., Clayson, K.J., Sumi, S.M., 1981. Cerebrospinalfluid and serum creatine kinase BB activity after out-of-hospitalcardiac arrest. Neurology 31, 455–458.

Losert, H., Sterz, F., Roine, R.O., et al, 2008. Strict normoglycae-mic blood glucose levels in the therapeutic management ofpatients within 12 h after cardiac arrest might not be necessary.Resuscitation 76, 214–220.

Lurie, K.G., Idris, A., Holcomb, J.B., 2005. Level 1 cardiac arrestcenters: learning from the trauma surgeons. Acad. Emerg. Med.12, 79–80.


Madl, C., Kramer, L., Domanovits, H., et al, 2000. Improvedoutcome prediction in unconscious cardiac arrest survivors withsensory evoked potentials compared with clinical assessment.Crit. Care Med. 28, 721–726.

Mahmood, M.A., Zweifler, R.M., 2007. Progress in shivering control.J. Neurol. Sci. 261, 47–54.

Marik, P.E., Varon, J., 2007. Intensive insulin therapy in the ICU: isit now time to jump off the bandwagon? Resuscitation 74, 191–193.

Martens, P., 1996. Serum neuron-specific enolase as a prognosticmarker for irreversible brain damage in comatose cardiac arrestsurvivors. Acad. Emerg. Med. 3, 126–131.

Martens, P., Raabe, A., Johnsson, P., 1998. Serum S-100 andneuron-specific enolase for prediction of regaining conscious-ness after global cerebral ischemia. Stroke 29, 2363–2366.

Martin, G.B., Paradis, N.A., Helpern, J.A., Nowak, R.M., Welch,K.M., 1991. Nuclear magnetic resonance spectroscopy study ofhuman brain after cardiac resuscitation. Stroke 22, 462–468.

Merchant, R.M., Abella, B.S., Peberdy, M.A., et al, 2006a. Thera-peutic hypothermia after cardiac arrest: unintentional overco-oling is common using ice packs and conventional coolingblankets. Crit. Care Med. 34, S490–S494.

Merchant, R.M., Soar, J., Skrifvars, M.B., et al, 2006b. Therapeutichypothermia utilization among physicians after resuscitationfrom cardiac arrest. Crit. Care Med. 34, 1935–1940.

Meyer, N.J., Hall, J.B., 2006. Relative adrenal insufficiency in theICU: can we at least make the diagnosis? Am. J. Respir. Crit.Care Med. 174, 1282–1284.

Morris, M.C., Nadkarni, V.M., 2003. Pediatric cardiopulmonary-cerebral resuscitation: an overview and future directions. Crit.Care Clin. 19, 337–364.

Morris, M.C., Wernovsky, G., Nadkarni, V.M., 2004. Survivaloutcomes after extracorporeal cardiopulmonary resuscitationinstituted during active chest compressions following refractoryin-hospital pediatric cardiac arrest. Pediatr. Crit. Care Med. 5,440–446.

Morrison, L.J., Visentin, L.M., Kiss, A., et al, 2006. Validation of arule for termination of resuscitation in out-of-hospital cardiacarrest. N. Engl. J. Med. 355, 478–487.

Moss, A.J., Zareba, W., Hall, W.J., et al, 2002. Prophylacticimplantation of a defibrillator in patients with myocardialinfarction and reduced ejection fraction. N. Engl. J. Med. 346,877–883.

Mullie, A., Verstringe, P., Buylaert, W., et al, 1988. Predictivevalue of Glasgow coma score for awakening after out-of-hospitalcardiac arrest. Cerebral resuscitation study group of the belgiansociety for intensive care. Lancet 1, 137–140.

Mussack, T., Biberthaler, P., Kanz, K.G., et al, 2002. Serum S-100Band interleukin-8 as predictive markers for comparative neuro-logic outcome analysis of patients after cardiac arrest andsevere traumatic brain injury. Crit. Care Med. 30, 2669–2674.

Nadkarni, V.M., Larkin, G.L., Peberdy, M.A., et al, 2006. Firstdocumented rhythm and clinical outcome from in-hospitalcardiac arrest among children and adults. JAMA 295, 50–57.

Nolan, J.P., Morley, P.T., Vanden Hoek, T.L., Hickey, R.W., 2003.Therapeutic hypothermia after cardiac arrest. An advisorystatement by the Advancement Life support Task Force of theInternational Liaison committee on Resuscitation. Resuscitation57, 231–235.

Nolan, J.P., Laver, S.R., Welch, C.A., Harrison, D.A., Gupta, V.,Rowan, K., 2007. Outcome following admission to UK intensivecare units after cardiac arrest: a secondary analysis of theICNARC Case Mix Programme Database. Anaesthesia 62, 1207–1216.

Nozari, A., Safar, P., Stezoski, S.W., et al, 2004. Mild hypothermiaduring prolonged cardiopulmonary cerebral resuscitationincreases conscious survival in dogs. Crit. Care Med. 32, 2110–2116.

Oddo, M., Schaller, M.D., Feihl, F., Ribordy, V., Liaudet, L., 2006.From evidence to clinical practice: effective implementation oftherapeutic hypothermia to improve patient outcome aftercardiac arrest. Crit. Care Med. 34, 1865–1873.

Oksanen, T., Skrifvars, M.B., Varpula, T., et al, 2007. Strict versusmoderate glucose control after resuscitation from ventricularfibrillation. Intensive Care Med..

Pene, F., Hyvernat, H., Mallet, V., et al, 2005. Prognostic value ofrelative adrenal insufficiency after out-of-hospital cardiacarrest. Intensive Care Med. 31, 627–633.

Pepe, P.E., Levine, R.L., Fromm Jr., R.E., Curka, P.A., Clark, P.S.,Zachariah, B.S., 1993. Cardiac arrest presenting with rhythmsother than ventricular fibrillation: contribution of resuscitativeefforts toward total survivorship. Crit. Care Med. 21, 1838–1843.

Pfeifer, R., Borner, A., Krack, A., Sigusch, H.H., Surber, R., Figulla,H.R., 2005. Outcome after cardiac arrest: predictive values andlimitations of the neuroproteins neuron-specific enolase andprotein S-100 and the Glasgow Coma Scale. Resuscitation 65,49–55.

Piazza, O., Cotena, S., Esposito, G., De Robertis, E., Tufano, R.,2005. S100B is a sensitive but not specific prognostic index incomatose patients after cardiac arrest. Minerva Chir. 60, 477–480.

Polderman, K.H., 2004. Application of therapeutic hypothermia inthe intensive care unit. Opportunities and pitfalls of a promisingtreatment modality – Part 2: practical aspects and side effects.Intensive Care Med. 30, 757–769.

Polderman, K.H., Peerdeman, S.M., Girbes, A.R., 2001. Hypo-phosphatemia and hypomagnesemia induced by cooling inpatients with severe head injury. J. Neurosurg. 94, 697–705.

Polderman, K.H., Rijnsburger, E.R., Peerdeman, S.M., Girbes, A.R.,2005. Induction of hypothermia in patients with various types ofneurologic injury with use of large volumes of ice-cold intrave-nous fluid. Crit. Care Med. 33, 2744–2751.

Prohl, J., Rother, J., Kluge, S., et al, 2007. Prediction of short-term and long-term outcomes after cardiac arrest: a prospectivemultivariate approach combining biochemical, clinical, elec-trophysiological, and neuropsychological investigations. Crit.Care Med. 35, 1230–1237.

Rello, J., Diaz, E., Roque, M., Valles, J., 1999. Risk factors fordeveloping pneumonia within 48 hours of intubation. Am. J.Respir. Crit. Care Med. 159, 1742–1746.

Rodriguez-Nunez, A., Lopez-Herce, J., Garcia, C., Dominguez, P.,Carrillo, A., Bellon, J.M., 2006. Pediatric defibrillation aftercardiac arrest: initial response and outcome. Crit. Care 10,R113.

Rogove, H.J., Safar, P., Sutton-Tyrrell, K., Abramson, N.S., 1995.Old age does not negate good cerebral outcome after cardio-pulmonary resuscitation: analyses from the brain resuscitationclinical trials. The brain resuscitation clinical trial I and II studygroups. Crit. Care Med. 23, 18–25.

Roine, R.O., Somer, H., Kaste, M., Viinikka, L., Karonen, S.L., 1989.Neurological outcome after out-of-hospital cardiac arrest. Pre-diction by cerebrospinal fluid enzyme analysis. Arch. Neurol. 46,753–756.

Roine, R.O., Kaste, M., Kinnunen, A., Nikki, P., Sarna, S., Kajaste,S., 1990. Nimodipine after resuscitation from out-of-hospitalventricular fibrillation. A placebo-controlled, double-blind, ran-domized trial. JAMA 264, 3171–3177.

Rothstein, T.L., 2000. The role of evoked potentials in anoxic-ischemic coma and severe brain trauma. J. Clin. Neurophysiol.17, 486–497.

Rothstein, T.L., Thomas, E.M., Sumi, S.M., 1991. Predictingoutcome in hypoxic-ischemic coma. A prospective clinical andelectrophysiologic study. Electroencephalogr. Clin. Neurophys-iol. 79, 101–107.


Rundgren, M., Rosen, I., Friberg, H., 2006. Amplitude-integratedEEG (aEEG) predicts outcome after cardiac arrest and inducedhypothermia. Intensive Care Med. 32, 836–842.

Sacco, R.L., VanGool, R., Mohr, J.P., Hauser, W.A., 1990. Non-traumatic coma, Glasgow coma score and coma etiology aspredictors of 2-week outcome. Arch. Neurol. 47, 1181–1184.

Samson, R.A., Nadkarni, V.M., Meaney, P.A., Carey, S.M., Berg,M.D., Berg, R.A., 2006. Outcomes of in-hospital ventricularfibrillation in children. N. Engl. J. Med. 354, 2328–2339.

Sandroni, C., Nolan, J., Cavallaro, F., Antonelli, M., 2007. In-hospital cardiac arrest: incidence, prognosis and possible mea-sures to improve survival. Intensive Care Med. 33, 237–245.

Scollo-Lavizzari, G., Bassetti, C., 1987. Prognostic value of EEG inpostanoxic coma after cardiac arrest. Eur. Neurol. 26, 161–170.

Scott, B.D., Hogue, T., Fixley, M.S., Adamson, P.B., 2006. Inducedhypothermia following out-of-hospital cardiac arrest; initialexperience in a community hospital. Clin. Cardiol. 29, 525–529.

Sessler, Dl, 2001. Complications and treatment of mild hypother-mia. Anesthesiology 95, 531–543.

Simbruner, G., Haberl, C., Harrison, V., Linley, L., Willeitner, A.E.,1999. Induced brain hypothermia in asphyxiated human newborninfants: a retrospective chart analysis of physiological andadverse effects. Intensive Care Med. 25, 1111–1117.

Skogvoll, E., Isern, E., Sangolt, G.K., Gisvold, S.E., 1999. In-hospitalcardiopulmonary resuscitation. Five years’ incidence and sur-vival according to the Utstein template. Acta Anaesthesiol.Scand. 43, 177–184.

Skrifvars, M.B., Castren, M., Aune, S., Thoren, A.B., Nurmi, J.,Herlitz, J., 2007. Variability in survival after in-hospital cardiacarrest depending on the hospital level of care. Resuscitation 73,73–81.

Snyder, B.D., Hauser, W.A., Loewenson, R.B., Leppik, I.E.,Ramirez-Lassepas, M., Gumnit, R.J., 1980. Neurologic prognosisafter cardiopulmonary arrest: III. Seizure activity. Neurology 30,1292–1297.

Soar, J., Nolan, J.P., 2007. Mild hypothermia for post cardiac arrestsyndrome. BMJ 335, 459–460.

Sohmer, H., Freeman, S., Gafni, M., Goitein, K., 1986. Thedepression of the auditory nerve-brain-stem evoked responsein hypoxaemia – mechanism and site of effect. Electroencep-halogr Clin. Neurophysiol. 64, 334–338.

Srinivasan, V., Spinella, P.C., Drott, H.R., Roth, C.L., Helfaer, M.A.,Nadkarni, V., 2004. Association of timing, duration, and inten-sity of hyperglycemia with intensive care unit mortality incritically ill children. Pediatr. Crit. Care Med. 5, 329–336.

Sunde, K., Dunlop, O., Rostrup, M., Sandberg, M., Sjoholm, H.,Jacob-sen, D., 2006. Determination of prognosis after cardiacarrest may be more difficult after introduction of therapeutichypothermia. Resuscitation 69, 29–32.

Sunde, K., PytteM, Jacobsen, D., et al, 2007. Implementation of astandardised treatment protocol for post resuscitation careafter out-of-hospital cardiac arrest. Resuscitation 73, 29–39.

Synek, V.M., 1990. Value of a revised EEG coma scale for prognosisafter cerebral anoxia and diffuse head injury. Clin. Electroen-cephalogr. 21, 25–30.

Taft, W.C., Clifton, G.L., Blair, R.E., DeLorenzo, R.J., 1989.Phenytoin protects against ischemia-produced neuronal celldeath. Brain Res. 483, 143–148.

Takasu, A., Saitoh, D., Kaneko, N., Sakamoto, T., Okada, Y., 2001.Hyperthermia: is it an ominous sign after cardiac arrest?Resuscitation 49, 273–277.

Takino, M., Okada, Y., 1991. Hyperthermia following cardiopulmo-nary resuscitation. Intensive Care Med. 17, 419–420.

Teasdale, G., Jennett, B., 1974. Assessment of coma and impairedconsciousness. A practical scale. Lancet 2, 81–84.

Tiainen, M., Roine, R.O., Pettila, V., Takkunen, 0, 2003. Serumneuron-specific enolase and S-100B protein in cardiac arrestpatients treated with hypothermia. Stroke 34, 2881–2886.

Tiainen, M., Kovala, T.T., Takkunen, O.S., Roine, R.O., 2005.Somatosen-sory and brainstem auditory evoked potentials incardiac arrest patients treated with hypothermia. Crit. CareMed. 33, 1736–1740.

Tibballs, J., Kinney, S., 2006. A prospective study of outcome of in-patient paediatric cardiopulmonary arrest. Resuscitation 71,310–318.

Tirschwell, D.L., Longstreth Jr., W.T., Rauch-Matthews, M.E.,et al, 1997. Cerebrospinal fluid creatine kinase BB isoenzymeactivity and neurologic prognosis after cardiac arrest. Neurology48, 352–357.

Torbey, M.T., Selim, M., Knorr, J., Bigelow, C., Recht, L., 2000.Quantitative analysis of the loss of distinction between gray andwhite matter in comatose patients after cardiac arrest. Stroke31, 2163–2167.

Torbey, M.T., Geocadin, R., Bhardwaj, A., 2004. Brain arrestneurological outcome scale (BrANOS): predicting mortality andsevere disability following cardiac arrest. Resuscitation 63, 55–63.

Tortorici, M.A., Kochanek, P.M., Poloyac, S.M., 2007. Effects ofhypothermia on drug disposition, metabolism, and response: afocus of hypothermia-mediated alterations on the cytochromeP450 enzyme system. Crit. Care Med. 35, 2196–2204.

Tsai, M.S., Huang, C.H., Chang, W.T., et al, 2007. The effect ofhydrocortisone on the outcome of out-of-hospital cardiac arrestpatients: a pilot study. Am. J. Emerg. Med. 25, 318–325.

Urban, P., Cereda, J.M., 1985. Glasgow coma score 1 h aftercardiac arrest. Lancet 2, 1012.

Usui, A., Kato, K., Murase, M., et al, 1994. Neural tissue-relatedproteins (NSE, GO alpha, 28-kDa calbindin-D. S100b and CK-BB)in serum and cerebrospinal fluid after cardiac arrest. J. Neurol.Sci. 123, 134–139.

van den Berghe, G., Wouters, P., Weekers, F., et al, 2001.Intensive insulin therapy in the critically ill patients. N. Engl.J. Med. 345, 1359–1367.

Van den Berghe, G., Schoonheydt, K., Becx, P., Bruyninckx, F.,Wouters, P.J., 2005. Insulin therapy protects the central andperipheral nervous system of intensive care patients. Neurology64, 1348–1353.

Van den Berghe, G., Wilmer, A., Hermans, G., et al, 2006. Intensiveinsulin therapy in the medical ICU. N. Engl. J. Med. 354, 449–461.

Van Hoeyweghen, R., Mullie, A., Bossaert, L., 1989. Decisionmaking to cease or to continue cardiopulmonary resuscitation(CPR). The cerebral resuscitation study group. Resuscitation 17(Suppl.), S137–S1347, discussion S99–206.

Virkkunen, I., Yli-Hankala, A., Silfvast, T., 2004. Induction oftherapeutic hypothermia after cardiac arrest in prehospitalpatients using ice-cold Ringer’s solution: a pilot study. Resus-citation 62, 299–302.

Wadhwa, A., Sengupta, P., Durrani, J., et al, 2005. Magnesiumsulphate only slightly reduces the shivering threshold in humans.Br. J. Anaesth. 94, 756–762.

Wang, H., Olivero, W., Lanzino, G., et al, 2004. Rapid and selectivecerebral hypothermia achieved using a cooling helmet. J.Neurosurg. 100, 272–277.

Warach, S., Kaufman, D., Chiu, D., et al, 2006. Effect of theGlycine Antagonist Gavestinel on cerebral infarcts in acutestroke patients, a randomized placebo-controlled trial: the GAINMRI Substudy. Cerebrovasc Dis. 21, 106–111.

Watkinson, P., Barber, V.S., Young, J.D., 2006. Strict glucosecontrol in the critically ill. BMJ 332, 865–866.

Wayne, M.A., Levine, R.L., Miller, C.C., 1995. Use of end-tidalcarbon dioxide to predict outcome in prehospital cardiac arrest.Ann. Emerg. Med. 25, 762–767.

Wijdicks, E.F., 2002. Propofol in myoclonus status epilepticus incomatose patients following cardiac resuscitation. J. Neurol.Neurosurg. Psychiatry 73, 94–95.


Wijdicks, E.F., Parisi, J.E., Sharbrough, F.W., 1990. Prognosticvalue of myoclonus status in comatose survivors of cardiacarrest. Ann. Neurol. 47, 1181–1184.

Wijdicks, E.F., Campeau, N.G., Miller, G.M., 2001. MR imaging incomatose survivors of cardiac resuscitation. AJNR Am. J.Neuroradiol. 22, 1561–1565.

Wijdicks, E.F., Bamlet, W.R., Maramattom, B.V., Manno, E.M.,McClelland, R.L., 2005. Validation of a new coma scale: theFOUR score. Ann. Neurol. 58, 585–593.

Wijdicks, E.F., Hijdra, A., Young, G.B., Bassetti, C.L., Wiebe, S.,2006. Practice parameter: prediction of outcome in comatosesurvivors after cardiopulmonary resuscitation (an evidence-based review): report of the Quality Standards Subcommitteeof the American Academy of Neurology. Neurology 67, 203–210.

Wik, L., Kramer-Johansen, J., Myklebust, H., et al, 2005. Quality ofcardiopulmonary resuscitation during out-of-hospital cardiacarrest. JAMA 293, 299–304.

Wiklund, L., Sharma, H.S., Basu, S., 2005. Circulatory arrest as amodel for studies of global ischemic injury and neuroprotection.Ann. NY Acad. Sci. 1053, 205–219.

Wintergerst, K.A., Buckingham, B., Gandrud, L., Wong, B.J., Kache,S., Wilson, D.M., 2006. Association of hypoglycemia, hypergly-cemia, and glucose variability with morbidity anddeath in the pediatric intensive care unit. Pediatrics 118, 173–179.

Wolfrum, S., Radke, P.W., Pischon, T., Willich, S.N., Schunkert, H.,Kurowski, V., 2007. Mild therapeutic hypothermia after cardiacarrest – a nationwide survey on the implementation of theILCOR guidelines in German intensive care units. Resuscitation72, 207–213.

Wright, D., Bannister, J., Ryder, M., Mackintosh, A.F., 1990.Resuscitation of patients with cardiac arrest by ambulance staffwith extended training in West Yorkshire. BMJ 301, 600–602.

Wyatt, J.S., Gluckman, P.D., Liu, P.Y., et al, 2007. Determinantsof outcomes after head cooling for neonatal encephalopathy.Pediatrics 119, 912–921.

Young, G.B., 2000. The EEG in coma. J. Clin. Neurophysiol. 17,473–485.

Young, K.D., Gausche-Hill, M., McClung, C.D., Lewis, R.J., 2004. Aprospective, population-based study of the epidemiology andoutcome of out-of-hospital pediatric cardiopulmonary arrest.Pediatrics 114, 157–164.

Zandbergen, E.G., de Haan, R.J., Stoutenbeek, C.P., Koelman,J.H., Hijdra, A., 1998. Systematic review of early prediction ofpoor outcome in anoxic-ischaemic coma. Lancet 352, 1808–1812.

Zandbergen, E.G., de Haan, R.J., Hijdra, A., 2001. Systematicreview of prediction of poor outcome in anoxicischaemic comawith biochemical markers of brain damage. Intensive Care Med.27, 1661–1667.

Zandbergen, E.G., Hijdra, A., Koelman, J.H., et al, 2006a. Predic-tion of poor outcome within the first 3 days of postanoxic coma.Neurology 66, 62–68.

Zandbergen, E.G., Koelman, J.H., de Haan, R.J., Hijdra, A., 2006b.SSEPs and prognosis in postanoxic coma: only short or also longlatency responses? Neurology 67, 583–586.

Zandbergen, E.G., Hijdra, A., de Haan, R.J., et al, 2006c. Inter-observer variation in the interpretation of SSEPs in anoxic-ischaemic coma. Clin. Neurophysiol. 117, 1529–1535.

Zeiner, A., Holzer, M., Sterz, F., et al, 2001. Hyperthermia aftercardiac arrest is associated with an unfavorable neurologicoutcome. Arch. Intern. Med. 161, 2007–2012.

Zeiner, A., Sunder-Plassmann, G., Sterz, F., et al, 2004. The effectof mild therapeutic hypothermia on renal function after cardio-pulmonary resuscitation in men. Resuscitation 60, 253–261.

Zhu, H., Meloni, B.P., Moore, S.R., Majda, B.T., Knuckey, N.W.,2004. Intravenous administration of magnesium is only neuro-

protective following transient global ischemia when presentwith post-ischemic mild hypothermia. Brain Res. 1014, 53–60.

Zipes, D.P., Camm, A.J., Borggrefe, M., et al, 2006. ACC/AHA/ESC2006 Guidelines for Management of Patients With Ventricu-larArrhythmias and the Prevention of Sudden Cardiac Death).Report of the American College of Cardiology/American HeartAssociation Task Force and the European Society of CardiologyCommittee for Practice Guidelines (Writing Committee toDevelop Guidelines for Management of Patients With VentricularArrhythmias and the Prevention of Sudden Cardiac Death). J.Am. Coll. Cardiol. 48, e247–e346.

Zweifler, R.M., Voorhees, M.E., Mahmood, M.A., Parnell, M., 2004.Magnesium sulfate increases the rate of hypothermia via surfacecooling and improves comfort. Stroke 35, 2331–2334.

Further reading

Adams, J.A., 2006. Endothelium and cardiopulmonary resuscitation.Crit. Care Med. 34, S458–S465.

Adrie, C., Adib-Conquy, M., Laurent, I., et al, 2002. Successfulcardiopulmonary resuscitation after cardiac arrest as a ‘‘sepsis-like’’ syndrome. Circulation 106, 562–568.

Adrie, C., Laurent, I., Monchi, M., Cariou, A., Dhainaou, J.F.,Spaulding, C., 2004. Postresuscitation disease after cardiacarrest: a sepsis-like syndrome? Curr. Opin. Crit. Care 10, 208–212.

Adrie, C., Monchi, M., Laurent, I., et al, 2005. Coagulopathy aftersuccessful cardiopulmonary resuscitation following cardiacarrest: implication of the protein C anticoagulant pathway. J.Am. Coll. Cardiol. 46, 21–28.

Adrie, C., Haouache, H., Saleh, M., et al, 2008. An underrecognizedsource of organ donors: patients with brain death aftersuccessfully resuscitated cardiac arrest. Intensive Care Med.34, 132–137.

Ali, A.A., Lim, E., Thanikachalam, M., et al, 2007. Cardiac arrest inthe organ donor does not negatively influence recipient survivalafter heart transplantation. Eur. J. Cardiothorac. Surg. 31, 929–933.

Ames III., A., Wright, R.L., Kowada, M., Thurston, J.M., Majno, G.,1968. Cerebral ischemia. II. The no-reflow phenomenon. Am. J.Pathol. 52, 437–453.

Antman, E.M., Anbe, D.T., Armstrong, P.W., et al, 2004. ACC/AHAguidelines for the management of patients with ST-elevationmyocardial infarction – executive summary. A report of theAmerican College of Cardiology/American Heart AssociationTask Force on Practice Guidelines (Writing Committee to revisethe 1999 guidelines for the management of patients with acutemyocardial infarction). J. Am. Coll. Cardiol. 44, 671–719.

Auer, R.N., 1998. Insulin, blood glucose levels, and ischemic braindamage. Neurology 51, S39–S43.

Aufderheide, T.P., Lurie, K.G., 2004. Death by hyperventilation: acommon and life-threatening problem during cardiopulmonaryresuscitation. Crit. Care Med. 32, S345–S3451.

Aufderheide, T.P., Sigurdsson, G., Pirrallo, R.G., et al, 2004.Hyperventilation-induced hypotension during cardiopulmonaryresuscitation. Circulation 109, 1960–1965.

Balan, I.S., Fiskum, G., Hazelton, J., Cotto-Cumba, C., Rosen-thai,R.E., 2006. Oximetry-guided reoxygenation improves neurolog-ical outcome after experimental cardiac arrest. Stroke 37,3008–3013.

Bano, D., Nicotera, P., 2007. Ca2+ signals and neuronal death inbrain ischemia. Stroke 38, 674–676.

Bass, E., 1985. Cardiopulmonary arrest. Pathophysiology andneurologic complications. Ann. Intern. Med. 103, 920–927.

Beckstead, J.E., Tweed, W.A., Lee, J., MacKeen, W.L., 1978.Cerebral blood flow and metabolism in man following cardiacarrest. Stroke 9, 569–573.


Bendz, B., Eritsland, J., Nakstad, A.R., et al, 2004. Long-termprognosis after out-of-hospital cardiac arrest and primarypercutaneous coronary intervention. Resuscitation 63, 49–53.

Blomgren, K., Zhu, C., Hallin, U., Hagberg, H., 2003. Mitochondriaand ischemic reperfusion damage in the adult and in thedeveloping brain. Biochem. Biophys. Res. Commun. 304, 551–559.

Blomqvist, P., Wieloch, T., 1985. Ischemic brain damage in ratsfollowing cardiac arrest using a long-term recovery model. J.Cereb. Blood Flow Metab. 5, 420–431.

Bottiger, B.W., Motsch, J., Bohrer, H., et al, 1995. Activation ofblood coagulation after cardiac arrest is not balanced ade-quately by activation of endogenous fibrinolysis. Circulation 92,2572–2578.

Bottiger, B.W., Krumnikl, J.J., Gass, P., Schmitz, B., Motsch, J.,Martin, E., 1997. The cerebral ‘no-reflow’ phenomenon aftercardiac arrest in rats––influence of low-flow reperfusion.Resuscitation 34, 79–87.

Breil, M., Krep, H., Sinn, D., et al, 2003. Hypertonic salineimproves myocardial blood flow during CPR, but is not enhancedfurther by the addition of hydroxy ethyl starch. Resuscitation 56,307–317.

Bricolo, A., Turazzi, S., Feriotti, G., 1980. Prolonged posttraumaticunconsciousness: therapeutic assets and liabilities. J. Neuro-surg. 52, 625–634.

Brierley, J.B., Meldrum, B.S., Brown, A.W., 1973. The threshold andneuropathology of cerebral ‘‘anoxic-ischemic’’ cell change.Arch. Neurol. 29, 367–374.

Bulut, S., Aengevaeren, W.R., Luijten, H.J., Verheugt, F.W., 2000.Successful out-of-hospital cardiopulmonary resuscitation: whatis the optimal in-hospital treatment strategy? Resuscitation 47,155–161.

Buunk, G., van der Hoeven, J.G., Frolich, M., Meinders, A.E., 1996.Cerebral vasoconstriction in comatose patients resuscitatedfrom a cardiac arrest? Intensive Care Med. 22, 1191–1196.

Buunk, G., van der Hoeven, J.G., Meinders, A.E., 1997. Cerebro-vascular reactivity in comatose patients resuscitated from acardiac arrest. Stroke 28, 1569–1573.

Calle, P.A., Buylaert, W.A., Vanhaute, O.A., 1989. Glycemia in thepost-resuscitation period. The Cerebral Resuscitation StudyGroup. Resuscitation 17 (Suppl), S181–S188, discussion S99-206.

Cavaillon, J.M., Adrie, C., Fitting, C., Adib-Conquy, M., 2003.Endotoxin tolerance: is there a clinical relevance? J. EndotoxinRes. 9, 101–107.

Cerchiari, E.L., Safar, P., Klein, E., Cantadore, R., Pinsky, M., 1993.Cardiovascular function and neurologic outcome after cardiacarrest in dogs. The cardiovascular post-resuscitation syndrome.Resuscitation 25, 9–33.

Cerchiari, E.L., Safar, P., Klein, E., Diven, W., 1993. Visceral,hematologic and bacteriologic changes and neurologic outcomeafter cardiac arrest in dogs. The visceral post-resuscitationsyndrome. Resuscitation 25, 119–136.

Coles, J.P., Fryer, T.D., Coleman, M.R., et al, 2007. Hyperventi-lation following head injury: effect on ischemic burden andcerebral oxidative metabolism. Crit. Care Med. 35, 568–578.

Courtney, D.M., Kline, J.A., 2005. Prospective use of a clinicaldecision rule to identify pulmonary embolism as likely cause ofoutpatient cardiac arrest. Resuscitation 65, 57–64.

Davies, M.J., Thomas, A., 1984. Thrombosis and acute coronary-artery lesions in sudden cardiac ischemic death. N. Engl. J. Med.310, 1137–1140.

de Vos, R., de Haes, H.C., Koster, R.W., de Haan, R.J., 1999.Quality of survival after cardiopulmonary resuscitation. Arch.Intern. Med. 159, 249–254.

Dellinger, R.P., Levy, M.M., Carlet, J.M., et al, 2008. Survivingsepsis campaign: international guidelines for management ofsevere sepsis and septic shock: 2008. Crit. Care Med. 36, 296–327.

Donnino, M.W., Miller, J., Goyal, N., et al, 2007. Effective lactateclearance is associated with improved outcome in post-cardiacarrest patients. Resuscitation 75, 229–234.

Donoghue, A.J., Nadkarni, V., Berg, R.A., et al, 2005. Out-of-hospital pediatric cardiac arrest: an epidemiologic review andassessment of current knowledge. Ann. Emerg. Med. 46, 512–522.

Engdahl, J., Abrahamsson, P., Bang, A., Lindqvist, J., Karlsson, T.,Herlitz, J., 2000. Is hospital care of major importance foroutcome after out-of-hospital cardiac arrest? Experienceacquired from patients with out-of-hospital cardiac arrestresuscitated by the same Emergency Medical Service andadmitted to one of two hospitals over a 16-year period in themunicipality of Goteborg. Resuscitation 43, 201–211.

Esmon, C.T., 2003. Coagulation and inflammation. J. EndotoxinRes. 9, 192–198.

Fertl, E., Vass, K., Sterz, F., Gabriel, H., Auff, E., 2000. Neurolog-ical rehabilitation of severely disabled cardiac arrest survivors.Part I. Course of post-acute inpatient treatment. Resuscitation17, 438–452.

Fischer, M., Bottiger, B.W., Popov-Cenic, S., Hossmann, K.A., 1996.Thrombolysis using plasminogen activator and heparin reducescerebral no-reflow after resuscitation from cardiac arrest: anexperimental study in the cat. Intensive Care Med. 22, 1214–1223.

Forsman, M., Aarseth, H.P., Nordby, H.K., Skulberg, A., Steen,P.A., 1989. Effects of nimodipine on cerebral blood flow andcerebrospinal fluid pressure after cardiac arrest: correlationwith neurologic outcome. Anesth. Analg. 68, 436–443.

Gando, S., Nanzaki, S., Morimoto, Y., Kobayashi, S., Kemmotsu, O.,2000. Out-of-hospital cardiac arrest increases soluble vascularendothelial adhesion molecules and neutrophil elastase associ-ated with endothelial injury. Intensive Care Med. 26, 38–44.

Garot, P., Lefevre, T., Eltchaninoff, H., et al, 2007. Six-monthoutcome of emergency percutaneous coronary intervention inresuscitated patients after cardiac arrest complicating ST-elevation myocardial infarction. Circulation 115, 1354–1362.

Gazmuri, R.J., Weil, M.H., Bisera, J., Tang, W., Fukui, M., McKee,D., 1996. Myocardial dysfunction after successful resuscitationfrom cardiac arrest. Crit. Care Med. 24, 992–1000.

Geppert, A., Zorn, G., Karth, G.D., et al, 2000. Soluble selectinsand the systemic inflammatory response syndrome after suc-cessful cardiopulmonary resuscitation. Crit. Care Med. 28,2360–2365.

Giacino, J.T., Ashwal, S., Childs, N., et al, 2002. The minimallyconscious state: definition and diagnostic criteria. Neurology 58,349–353.

Gorjup, V., Radsel, P., Kocjancic, S.T., Erzen, D., Noc, M., 2007.Acute ST-elevation myocardial infarction after successful car-diopulmonary resuscitation. Resuscitation 72, 379–385.

Groswasser, Z., Cohen, M., Costeff, H., 1989. Rehabilitationoutcome after anoxic brain damage. Arch. Phys. Med. Rehabil.70, 186–188.

Herlitz, J., Ekstrom, L., Wennerblom, B., Axelsson, A., Bang, A.,Holm-berg, S., 1995. Hospital mortality after out-of-hospitalcardiac arrest among patients found in ventricular fibrillation.Resuscitation 29, 11–21.

Herlitz, J., Engdahl, J., Svensson, L., Angquist, K.A., Silfverstolpe,J., Holmberg, S., 2006. Major differences in 1-month survivalbetween hospitals in Sweden among initial survivors of out-of-hospital cardiac arrest. Resuscitation 70, 404–409.

Hossmann, K.A., Oschlies, U., Schwindt, W., Krep, H., 2001.Electron microscopic investigation of rat brain after briefcardiac arrest. Acta Neuropathol. (Berl) 101, 101–113.

Huang, L., Weil, M.H., Tang, W., Sun, S., Wang, J., 2005.Comparison between dobutamine and levosimendan for man-agement of postresuscitation myocardial dysfunction. Crit. CareMed. 33, 487–491.


Huikuri, H.V., Castellanos, A., Myerburg, R.J., 2001. Sudden deathdue to cardiac arrhythmias. N. Engl. J. Med. 345, 1473–1482.

Jacobs, I., Nadkarni, V., Bahr, J., et al, 2004. Cardiac arrest andcardiopulmonary resuscitation outcome reports: update andsimplification of the Utstein templates for resuscitation regis-tries. A statement for healthcare professionals from a task forceof the International Liaison Committee on Resuscitation (Amer-ican Heart Association, European Resuscitation Council, Austra-lian Resuscitation Council, New Zealand ResuscitationCouncil,Heart and Stroke Foundation of Canada, InterAmerican HeartFoundation, Resuscitation Council of Southern Africa). Resusci-tation 63, 233–249.

1966. Cardiopulmonary resuscitation. JAMA 198, 372–379.Karimova, A., Pinsky, D.J., 2001. The endothelial response to

oxygen deprivation: biology and clinical implications. IntensiveCare Med. 27, 19–31.

Katz, L.M., Wang, Y., Ebmeyer, U., Radovsky, A., Safar, P., 1998.Glucose plus insulin infusion improves cerebral outcome afterasphyxial cardiac arrest. Neuroreport 9, 3363–3367.

Keelan, P.C., Bunch, T.J., White, R.D., Packer, D.L., Holmes Jr.,D.R., 2003. Early direct coronary angioplasty in survivors of out-of-hospital cardiac arrest. Am. J. Cardiol. 91, 1461–1463. A6.

Keenan, S.P., Dodek, P., Martin, C., Priestap, F., Norena, M., Wong,H., 2007. Variation in length of intensive care unit stay aftercardiac arrest: where you are is as important as who you are.Crit. Care Med. 35, 836–841.

Kern, K.B., Hilwig, R.W., Berg, R.A., et al, 1997. Postresuscitationleft ventricular systolic and diastolic dysfunction. Treatmentwith dobutamine. Circulation 95, 2610–2613.

Khot, S., Tirschwell, D.L., 2006. Long-term neurological complica-tions after hypoxic-ischemic encephalopathy. Semin. Neurol. 26,422–431.

Kliegel, A., Losert, H., Sterz, F., et al, 2004. Serial lactatedeterminations for prediction of outcome after cardiac arrest.Medicine (Baltimore) 83, 274–279.

Krep, H., Breil, M., Sinn, D., Hagendorff, A., Hoeft, A., Fischer, M.,2000. Effects of hypertonic versus isotonic infusion therapy onregional cerebral blood flow after experimental cardiac arrestcardiopulmonary resuscitation in pigs. Resuscitation 47, 155–161, 139.

Kuisma, M., Alaspaa, A., 1997. Out-of-hospital cardiac arrests ofnon-cardiac origin. Epidemiology and outcome. Eur. Heart J. 18,1122–1128.

Kurkciyan, I., Meron, G., Sterz, F., et al, 2000. Pulmonary embo-lism as a cause of cardiac arrest: presentation and outcome.Arch. Intern. Med. 160, 1529–1535.

Kurkciyan, I., Meron, G., Sterz, F., et al, 2003. Major bleedingcomplications after cardiopulmonary resuscitation: impact ofthrombolytic treatment. J. Intern. Med. 253, 128–135.

Kurusz, M., Zwischenberger, J.B., 2002. Percutaneous cardiopul-monary bypass for cardiac emergencies. Perfusion 17, 269–277.

Lai, C.S., Hostler, D., D’Cruz, B.J., Callaway, C.W., 2004. Preva-lence of troponin-T elevation during out-of-hospital cardiacarrest. Am. J. Cardiol. 93, 754–756.

Langhelle, A., Nolan, J., Herlitz, J., et al, 2005. Recommendedguidelines for reviewing, reporting, and conducting research onpost-resuscitation care: the Utstein style. Resuscitation 66,271–283.

Laurent, I., Adrie, C., Vinsonneau, C., et al, 2005. High-volumehemofil-tration after out-of-hospital cardiac arrest: a random-ized study. J. Am. Coll. Cardiol. 46, 432–437.

Laver, S., Farrow, C., Turner, D., Nolan, J., 2004. Mode of deathafter admission to an intensive care unit following cardiacarrest. Intensive Care Med. 30, 2126–2128.

Leonov, Y., Sterz, F., Safar, P., Johnson, D.W., Tisherman, S.A.,Oku, K., 1992. Hypertension with hemodilution prevents multi-focal cerebral hypoperfusion after cardiac arrest in dogs. Stroke23, 45–53.

Levy, D.E., Knill-Jones, R.P., Plum, F., 1978. The vegetative stateand its prognosis following nontraumatic coma. Ann. NY Acad.Sci. 315, 293–306.

lida, K., Satoh, H., Arita, K., Nakahara, T., Kurisu, K., Ohtani, M.,1997. Delayed hyperemia causing intracranial hypertension aftercardiopulmonary resuscitation. Crit. Care Med. 25, 971–976.

Lipton, P., 1999. Ischemic cell death in brain neurons. Physiol. Rev.79, 1431–1568.

Liu, Y., Rosenthal, R.E., Haywood, Y., Miljkovic-Lolic, M., Vander-hoek, J.Y., Fiskum, G., 1998. Normoxic ventilation after cardiacarrest reduces oxidation of brain lipids and improves neurolog-ical outcome. Stroke 29, 1679–1686.

Longstreth Jr., W.T., Inui, T.S., 1984. High blood glucose level onhospital admission and poor neurological recovery after cardiacarrest. Ann. Neurol. 15, 59–63.

Longstreth Jr., W.T., Diehr, P., Inui, T.S., 1983. Prediction ofawakening after out-of-hospital cardiac arrest. N. Engl. J. Med.308, 1378–1382.

Longstreth Jr., W.T., Copass, M.K., Dennis, L.K., Rauch-Matthews,M.E., Stark, M.S., Cobb, L.A., 1993. Intravenous glucose afterout-of-hospital cardiopulmonary arrest: a community-basedrandomized trial. Neurology 43, 2534–2541.

Longstreth Jr., W.T., Fahrenbruch, C.E., Olsufka, M., Walsh, T.R.,Copass, M.K., Cobb, L.A., 2002. Randomized clinical trial ofmagnesium, diazepam, or both after out-of-hospital cardiacarrest. Neurology 59, 506–514.

Martin, L.J., Al-Abdulla, N.A., Brambrink, A.M., Kirsch, J.R.,Sieber, F.E., Portera-Cailliau, C., 1998. Neurodegeneration inexcitotoxicity, global cerebral ischemia, and target deprivation:a perspective on the contributions of apoptosis and necrosis.Brain Res. Bull. 46, 281–309.

Mashiko, K., Otsuka, T., Shimazaki, S., et al, 2002. An out-come study of out-of-hospital cardiac arrest using theUtstein template – a Japanese experience. Resuscitation 55,241–246.

Massetti, M., Tasle, M., Le Page, 0, et al, 2005. Back fromirreversibility: extracorporeal life support for prolonged cardiacarrest. Ann. Thorac. Surg. 79, 178–183, discussion 83-4.

Mclntyre, L.A., Fergusson, D.A., Hutchison, J.S., et al, 2006. Effectof a liberal versus restrictive transfusion strategy on mortality inpatients with moderate to severe head injury. Neurocrit. Care 5,4–9.

Michenfelder, J.D., Milde, J.H., 1990. Postischemic canine cerebralblood flow appears to be determined bycerebral metabolic needs. J. Cereb. Blood Flow Metab. 10,71–76.

Moers, C., Leuvenink, H.G., Ploeg, R.J., 2007. Non-heart beatingorgan donation: overview and future perspectives. Transpl. Int.20, 567–575.

Morimoto, Y., Kemmotsu, O., Kitami, K., Matsubara, I., Tedo, I.,1993. Acute brain swelling after out-of-hospital cardiac arrest:pathogenesis and outcome. Crit. Care Med. 21, 104–110.

Moruzzi, G., Magoun, H.W., 1995. Brain stem reticular formationand activation of the EEG. 1949. J. Neuropsychi. Clin. Neurosci.7, 251–267.

Muizelaar, J.P., Marmarou, A., Ward, J.D., et al, 1991. Adverseeffects of prolonged hyperventilation in patients with severehead injury: a randomized clinical trial. J. Neurosurg. 75, 731–739.

Mullner, M., Hirschl, M.M., Herkner, H., et al, 1996. Creatinekinase-mb fraction and cardiac troponin T to diagnose acutemyocardial infarction after cardiopulmonary resuscitation. J.Am. Coll. Cardiol. 28, 1220–1225.

Mullner, M., Sterz, F., Binder, M., et al, 1996. Arterial bloodpressure after human cardiac arrest and neurological recovery.Stroke 27, 59–62.

Mullner, M., Sterz, F., Binder, M., Schreiber, W., Deimel, A., Lag-gner, A.N., 1997. Blood glucose concentration after cardiopul-


monary resuscitation influences functional neurological recoveryin human cardiac arrest survivors. J. Cereb. Blood Flow Metab.17, 430–436.

Nagao, K., Hayashi, N., Kanmatsuse, K., et al, 2000. Cardiopulmo-nary cerebral resuscitation using emergency cardiopulmonarybypass, coronary reperfusion therapy and mild hypothermia inpatients with cardiac arrest outside the hospital. J. Am. Coll.Cardiol. 36, 776–783.

Negovsky, V.A., 1972. The second step in resuscitation – thetreatment of the ‘post-resuscitation disease’. Resuscitation 1,1–7.

Negovsky, V.A., 1988. Postresuscitation disease. Crit. Care Med. 16,942–946.

Negovsky, V.A., Gurvitch, A.M., 1995. Post-resuscitation disease –a new nosological entity. Its reality and significance. Resuscita-tion 30, 23–27.

Neumar, R.W., 2000. Molecular mechanisms of ischemic neuronalinjury. Ann. Emerg. Med. 36, 483–506.

Nichol, G., Karmy-Jones, R., Salerno, C., Cantore, L., Becker, L.,2006. Systematic review of percutaneous cardiopulmonarybypass for cardiac arrest or cardiogenic shock states. Resusci-tation 70, 381–394.

Nishizawa, H., Kudoh, I., 1996. Cerebral autoregulation is impairedin patients resuscitated after cardiac arrest. Acta Anaesthesiol.Scand. 40, 1149–1153.

Medical aspects of the persistent vegetative state (1) 1994. Themulti-society task force on PVS. N. Engl. J. Med. 330, 1499–1508.

Oku, K., Kuboyama, K., Safar, P., et al, 1994. Cerebral andsystemic arteriovenous oxygen monitoring after cardiac arrest.Inadequate cerebral oxygen delivery. Resuscitation 27, 141–152.

Opie, L.H., 1989. Reperfusion injury and its pharmacologic modi-fication. Circulation 80, 1049–1062.

Ornato, J.P., Ryschon, T.W., Gonzalez, E.R., Bredthauer, J.L.,1985. Rapid change in pulmonary vascular hemodynamics withpulmonary edema during cardiopulmonary resuscitation. Am. J.Emerg. Med. 3, 137–142.

Parvizi, J., Damasio, A.R., 2003. Neuroanatomical correlates ofbrain-stem coma. Brain 126, 1524–1536.

Pearse, R., Dawson, D., Fawcett, J., Rhodes, A., Grounds, R.M.,Bennett, E.D., 2005. Early goal-directed therapy after majorsurgery reduces complications and duration of hospital stay. Arandomised, controlled trial [ISRCTN38797445]. Crit. Care 9,R687–R693.

Peberdy, M.A., Kaye, W., Ornato, J.P., et al, 2003. Cardiopulmo-nary resuscitation of adults in the hospital: a report of 14720cardiac arrests from the National Registry of CardiopulmonaryResuscitation. Resuscitation 58, 297–308.

Pell, J.P., Sirel, J.M., Marsden, A.K., Ford, I., Walker, N.L., Cobbe,S.M., 2003. Presentation, management, and outcome of out ofhospital cardiopulmonary arrest: comparison by underlyingaetiology. Heart 89, 839–842.

Plotz, F.B., Slutsky, A.S., van Vught, A.J., Heijnen, C.J., 2004.Ventilator-induced lung injury and multiple system organfailure: a critical review of facts and hypotheses. Intensive CareMed. 30, 1865–1872.

Plum, F., Posner, J., 1980. The Diagnosis of Coma and Stupor.Davis, PA, Philadelphia.

Polonen, P., Ruokonen, E., Hippelainen, M., Poyhonen, M., Takala,J., 2000. A prospective, randomized study of goal-orientedhemodynamic therapy in cardiac surgical patients. Anesth.Analg. 90, 1052–1059.

Prengel, A.W., Lindner, K.H., Ensinger, H., Grunert, A., 1992.Plasma catecholamine concentrations after successful resusci-tation in patients. Crit. Care Med. 20, 609–614.

Pulsinelli, W.A., 1985. Selective neuronal vulnerability: morpho-logical and molecular characteristics. Prog. Brain Res. 63, 29–37.

Pulsinelli, W.A., Waldman, S., Rawlinson, D., Plum, F., 1982.Moderate hyperglycemia augments ischemic brain damage: aneuropathologic study in the rat. Neurology 32, 1239–1246.

Pusswald, G., Fertl, E., Faltl, M., Auff, E., 2000. Neurologicalrehabilitation of severely disabled cardiac arrest survivors. PartII. Life situation of patients and families after treatment.Resuscitation 47, 241–248.

Quintero-Moran, B., Moreno, R., Villarreal, S., et al, 2006. Percu-taneous coronary intervention for cardiac arrest secondary toST-elevation acute myocardial infarction. Influence of immedi-ate paramedical/medical assistance on clinical outcome. J.Invasive Cardiol. 18, 269–272.

Richards, E.M., Fiskum, G., Rosenthal, R.E., Hopkins, I., McKenna,M.C., 2007. Hyperoxic reperfusion after global ischemiadecreases hippocampal energy metabolism. Stroke 38, 1578–1584.

Richling, N., Herkner, H., Holzer, M., Riedmueller, E., Sterz, F.,Schreiber, W., 2007. Thrombolytic therapy vs. primary percuta-neous intervention after ventricular fibrillation cardiac arrestdue to acute ST-segment elevation myocardial infarction anditseffect on outcome. Am. J. Emerg. Med. 25, 545–550.

Rivers, E.P., Martin, G.B., Smithline, H., et al, 1992. The clinicalimplications of continuous central venous oxygen saturationduring human CPR. Ann. Emerg. Med. 21, 1094–1101.

Rivers, E.P., Rady, M.Y., Martin, G.B., et al, 1992. Venoushyperoxia after cardiac arrest. Characterization of a defect insystemic oxygen utilization. Chest 102, 1787–1793.

Rivers, E.P., Wortsman, J., Rady, M.Y., Blake, H.C., McGeorge,F.T., Buderer, N.M., 1994. The effect of the total cumulativeepinephrine dose administered during human CPR on hemody-namic, oxygen transport, and utilization variables in thepostresuscitation period. Chest 106, 1499–1507.

Rivers, E., Nguyen, B., Havstad, S., et al, 2001. Early goal-directedtherapy in the treatment of severe sepsis and septic shock. N.Engl. J. Med. 345, 1368–1377.

Roine, R.O., Launes, J., Nikkinen, P., Lindroth, L., Kaste, M., 1991.Regional cerebral blood flow after human cardiac arrest. Ahexamethylpropyleneamine oxime single photon emission com-puted tomographic study. Arch. Neurol. 48, 625–629.

Roine, R.O., Kajaste, S., Kaste, M., 1993. Neuropsychologicalsequelae of cardiac arrest. JAMA 269, 237–242.

Ruiz-Bailen, M., Aguayo de Hoyos, E., Ruiz-Navarro, S., et al, 2005.Reversible myocardial dysfunction after cardiopulmonary resus-citation. Resuscitation 66, 175–181.

Sakabe, T., Tateishi, A., Miyauchi, Y., et al, 1987. Intracranialpressure following cardiopulmonary resuscitation. IntensiveCare Med. 13, 256–259.

Sanchez-Fructuoso, Al, Marques, M., Prats, D., et al, 2006. Victimsof cardiac arrest occurring outside the hospital: a source oftransplantable kidneys. Ann. Intern. Med. 145, 157–164.

Sandier, D.A., Martin, J.F., 1989. Autopsy proven pulmonaryembolism in hospital patients: are we detecting enough deepvein thrombosis? J. R Soc. Med. 82, 203–205.

Schaafsma, A., de Jong, B.M., Bams, J.L., Haaxma-Reiche, H.,Pruim, J., Zijlstra, J.G., 2003. Cerebral perfusion and metab-olism in resuscitated patients with severe post-hypoxic enceph-alopathy. J. Neurol. Sci. 210, 23–30.

Schiff, N.D., Plum, F., 2000. The role of arousal and ‘‘gating’’systems in the neurology of impaired consciousness. J. Clin.Neurophysiol. 17, 438–452.

Schreiber, W., Gabriel, D., Sterz, F., et al, 2002. Thrombolytictherapy after cardiac arrest and its effect on neurologicaloutcome. Resuscitation 52, 63–69.

Schultz, C.H., Rivers, E.P., Feldkamp, C.S., et al, 1993. A charac-terization of hypothalamic-pituitary-adrenal axis function duringand after human cardiac arrest. Crit. Care Med. 21, 1339–1347.

Shaffner, D.H., Eleff, S.M., Brambrink, A.M., et al, 1999. Effect ofarrest time and cerebral perfusion pressure during cardiopul-


monary resuscitation on cerebral blood flow, metabolism,adenosine triphosphate recovery, and pH in dogs. Crit. CareMed. 27, 1335–1342.

Shoemaker, W.C., Appel, P.L., Kram, H.B., 1988. Tissue oxygendebt as a determinant of lethal and nonlethal postoperativeorgan failure. Crit. Care Med. 16, 1117–1120.

Shoemaker, W.C., Appel, P.L., Kram, H.B., 1992. Role of oxygendebt in the development of organ failure sepsis, and death inhigh-risk surgical patients. Chest 102, 208–215.

Skrifvars, M.B., Pettila, V., Rosenberg, P.H., Castren, M., 2003. Amultiple logistic regression analysis of in-hospital factors relatedto survival at six months in patients resuscitatedfrom out-of-hospital ventricular fibrillation. Resuscitation 59, 319–328.

Spaulding, C.M., Joly, L.M., Rosenberg, A., et al, 1997. Immediatecoronary angiography in survivors of out-of-hospital cardiacarrest. N. Engl. J. Med. 336, 1629–1633.

Steiner, L.A., Balestreri, M., Johnston, A.J., et al, 2004. Sustainedmoderate reductions in arterial CO2 after brain trauma time-course of cerebral blood flow velocity and intracranial pressure.Intensive Care Med. 30, 2180–2187.

Stephenson Jr., H.E., Reid, L.C., Hinton, J.W., 1953. Some commondenominators in 1200 cases of cardiac arrest. Ann. Surg. 137,731–744.

Sterz, F., Leonov, Y., Safar, P., et al, 1992. Multifocal cerebralblood flow by Xe-CT and global cerebral metabolism afterprolonged cardiac arrest in dogs. Reperfusion with open-chestCPR or cardiopulmonary bypass. Resuscitation 24, 27–47.

Stevens, R.D., Bhardwaj, A., 2006. Approach to the comatosepatient. Crit. Care Med. 34, 31–41.

Stiell, I.G., Wells, G.A., Field, B., et al, 2004. Advanced cardiaclife support in out-of-hospital cardiac arrest. N. Engl. J. Med.351, 647–656.

Sundgreen, C., Larsen, F.S., Herzog, T.M., Knudsen, G.M., Boesg-aard, S., Aldershvile, J., 2001. Autoregulation of cerebral bloodflow in patients resuscitated from cardiac arrest. Stroke 32,128–132.

Sung, K., Lee, Y.T., Park, P.W., et al, 2006. Improved survival aftercardiac arrest using emergent autopriming percutaneous car-diopulmonary support. Ann. Thorac. Surg. 82, 651–656.

Taraszewska, A., Zelman, I.B., Ogonowska, W., Chrzanowska, H.,2002. The pattern of irreversible brain changes after cardiacarrest in humans. Folia Neuropathol. 40, 133–141.

The Acute Respiratory Distress Syndrome Network, 2000. Ventila-tion with lower tidal volumes as compared with traditional tidalvolumes for acute lung injury and the acute respiratory distresssyndrome. N. Engl. J. Med. 342, 1301–1308.

Vaagenes, P., Safar, P., Moossy, J., et al, 1997. Asphyxiation versusventricular fibrillation cardiac arrest in dogs. Differences incerebral resuscitation effects – a preliminary study. Resuscita-tion 35, 41–52.

van Alem, A.P., de Vos, R., Schmand, B., Koster, R.W., 2004.Cognitive impairment in survivors of out-of-hospital cardiacarrest. Am. Heart J. 148, 416–421.

Vasquez, A., Kern, K.B., Hilwig, R.W., Heidenreich, J., Berg, R.A.,Ewy, G.A., 2004. Optimal dosing of dobutamine for treatingpost-resuscitation left ventricular dysfunction. Resuscitation 61,199–207.

Vereczki, V., Martin, E., Rosenthal, R.E., Hof, P.R., Hoffman, G.E.,Fiskum, G., 2006. Normoxic resuscitation after cardiac arrestprotects against hippocampal oxidative stress, metabolic dys-function, and neuronal death. J. Cereb. Blood Flow Metab. 26,821–835.

Wass, C.T., Scheithauer, B.W., Bronk, J.T., Wilson, R.M., Lanier,W.L., 1996. Insulin treatment of corticosteroid-associatedhyperglycemia and its effect on outcome after forebrainischemia in rats. Anesthesiology 84, 644–651.

White, B.C., Grossman, L.I., Krause, G.S., 1993. Brain injuryby global ischemia and reperfusion: a theoretical perspec-tive on membrane damage and repair. Neurology 43, 1656–1665.

Wilson, D.J., Fisher, A., Das, K., et al, 2003. Donors with cardiacarrest: improved organ recovery but no preconditioning benefitin liver allografts. Transplantation 75, 1683–1687.

Wolfson Jr., S.K., Safar, P., Reich, H., et al, 1992. Dynamicheterogeneity of cerebral hypoperfusion after prolonged cardiacarrest in dogs measured by the stable xenon/CT technique: apreliminary study. Resuscitation 23, 1–20.

Young, G.B., Pigott, S.E., 1999. Neurobiological basis of conscious-ness. Arch. Neurol. 56, 153–157.

Zhang, C., Siman, R., Xu, Y.A., Mills, A.M., Frederick, J.R., Neumar,R.W., 2002. Comparison of calpain and caspase activities in theadult rat brain after transient forebrain ischemia. Neurobiol.Dis. 10, 289–295.

Zheng, Z.J., Croft, J.B., Giles, W.H., Mensah, G.A., 2001. Suddencardiac death in the United States 1989 to 1998. Circulation 104,2158–2163.

Zipes, D.P., Wellens, H.J., 1998. Sudden cardiac death. Circulation98, 2334–2351.

Zwemer, C.F., Whitesall, S.E., D’Alecy, L.G., 1994. Cardiopulmo-nary-cerebral resuscitation with 100% oxygen exacerbates neu-rological dysfunction following nine minutes of normothermiccardiac arrest in dogs. Resuscitation 27, 159–170.


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