Annales Franc¸aises d’Anesthe´sie et de Re´animation 33 (2014) 98–101
Anarlf meeting
Neurological consequences of cardiac arrest: Where do we stand?§,§§ Conse´quences neurologiques post-arreˆt cardiaque : ou` en sommes-nous ? G. Geri a,d,f, N. Mongardon c,e, F. Daviaud a,d, J.-P. Empana d,f, F. Dumas b,d,f, A. Cariou a,*,d,f a
Medical Intensive Care Unit, Cochin Hospital, Assistance publique des Hoˆpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France Emergency Department, Cochin Hospital, Assistance publique des Hoˆpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France Department of Anesthesiology and Surgical Intensive Care, Henri-Mondor Hospital, Assistance publique des Hoˆpitaux de Paris, 51, avenue du Mare´chal-de-Lattre-de-Tassigny, 94000 Cre´teil, France d Faculte´ de me´decine, universite´ Paris Descartes & Sorbonne Paris Cite´, 15, rue de l’E´cole-de-Me´decine, 75006 Paris, France e Faculte´ de me´decine, universite´ Paris Est, 8, avenue du Ge´ne´ral-Sarrail, 94000 Cre´teil, France f Paris Cardiovascular Research Center, European Georges-Pompidou Hospital, INSERM U970, 56, rue Leblanc, 75015 Paris, France b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Cardiac arrest Prognostication Therapeutic hypothermia Cardio-pulmonary resuscitation
With increasing public education in basic life support and with the widespread use of automated defibrillators, post-cardiac arrest comatose patients represent a growing part of ICU admissions. However the prognosis remains very poor and only a very low proportion of these resuscitated patients will recover and will leave the hospital without major neurological impairments. Neurological dysfunction predominantly includes disorders of consciousness, and may also include other manifestations such as seizures, myoclonus status epilepticus and other forms of movement disorders including post-anoxic myoclonus. In the most severe cases, coma may be irreversible or evolve towards a minimally conscious state, a vegetative state or even brain death. These severe conditions represent by far the leading cause of mortality and disability in such patients. Currently, early use of mild therapeutic hypothermia is the only treatment that demonstrated its ability to decrease neurological consequences and to improve the prognosis. Prognostication outcome is still mainly based on a rigorous clinical evaluation coupled with neuro-physiological investigations, but brain functional imaging could become a valuable tool in the near future. Clinical research focusing on survivors should be strongly encouraged in order to assess the mid- and long-terms outcome of survivors and to evaluate the impact of new treatments or strategies. ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved. R E´ S U M E´
Mots cle´s : Arreˆt cardiaque E´valuation pronostique Hypothermie the´rapeutique Re´animation cardiopulmonaire
La prise en charge de patients re´anime´s avec succe`s d’un arreˆt cardiaque extrahospitalier repre´sente une part d’activite´ de plus en plus importante en re´animation, graˆce notamment aux progre`s re´alise´s en matie`re d’e´ducation du grand publique pour la re´animation cardiopulmonaire et la diffusion des de´fibrillateurs semi-automatiques. Cependant, le pronostic reste sombre et seulement une faible proportion de ces patients re´anime´s avec succe`s sortiront de l’hoˆpital sans se´quelle neurologique majeure et retrouveront leur e´tat neurologique ante´rieur. Les se´quelles neurologiques sont domine´es par les troubles de la conscience, mais peuvent e´galement se pre´senter sous la forme de crises convulsives, d’e´tat de mal e´pileptique et d’autres formes de mouvements anormaux comme les myoclonies postanoxiques. Dans les cas les plus se´ve`res, le coma est irre´versible ou e´volue vers un e´tat pauci-relationnel, un e´tat ve´ge´tatif ou la mort ence´phalique. Ces se´quelles lourdes repre´sentent la principale cause de mortalite´ et de handicap chez ces patients. Actuellement, l’hypothermie the´rapeutique est le seul traitement ayant de´montre´ son efficacite´ pour la diminution des se´quelles neurologiques et l’ame´lioration du pronostic. Pre´dire l’e´volution neurologique est toujours actuellement base´e sur une e´valuation neurologique clinique rigoureuse, associe´e aux explorations neurophysiologiques, mais
French NeuroAnesthesia and Intensive Care society Meeting, Paris, November 2013, 21st and 22nd: ‘‘The acutely brain-injured patient: consciousness and neuroethic’’. This article is published under the responsibility of the Scientific Committee of the ‘‘35e Journe´e de l’Association des neuro-anesthe´sistes re´animateurs de langue franc¸aises’’ de la SFAR. The editorial board of the Annales franc¸aises d’anesthe´sie et de re´animation was not involved in the conception and validation of its content. * Corresponding author. E-mail address: [email protected] (A. Cariou). §
§§
0750-7658/$ – see front matter ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.annfar.2013.11.003
G. Geri et al. / Annales Franc¸aises d’Anesthe´sie et de Re´animation 33 (2014) 98–101
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l’imagerie fonctionnelle ce´re´brale pourrait devenir un outil pertinent a` l’avenir. Les e´tudes s’inte´ressant particulie`rement aux survivants doivent eˆtre soutenues afin d’e´valuer le devenir a` moyen et long termes de ces patients et l’impact des nouvelles strate´gies the´rapeutiques. ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Publie´ par Elsevier Masson SAS. Tous droits re´serve´s.
1. Scope of the problem Sudden cardiac death remains a major public health issue, as highlighted by epidemiological data showing that nearly 40,000 people are supported for out-of-hospital cardiac arrest (CA) in France each year. Even more problematic, only a very low proportion of resuscitated patients will recover and will leave the hospital without major neurological impairments [1–6]. Across the different studies focusing on early prognostic factors, a common finding is that the frequency and intensity of post-CA complications depend mainly on the quality and duration of cardio-pulmonary resuscitation (CPR). Nevertheless, with increasing public education in basic life support and with the widespread use of automated defibrillators, post-CA comatose patients have now become more and more frequent among ICU population. After traumatic brain injury and drug overdose, CA is considered to be the third cause of coma in Western countries, a fact that is associated with a multitude of medical, ethical, and economic questions. In parallel, experimental and clinical research has focused on a better comprehension of the mechanisms responsible for post-CA brain damages, as well as on the development of several neuroprotective strategies able to improve outcome of these patients. 2. Pathophysiology of brain damages Contrary to traumatic or focal ischemic causes of coma, CA provokes a global ischemic insult to the brain. The extent of cerebral damage is largely influenced by the duration of interrupted cerebral blood flow. Accordingly, minimizing both the arrest time (‘‘noflow’’) and CPR time (‘‘low-flow’’) are key issues. Schematically, cerebral oxygen stores and consciousness are lost within 20 seconds of the onset of CA, while glucose and adenosine triphosphate (ATP) stores are lost within 5 minutes. Cerebral ischemia then triggers a complex cascade of pathways, which lead to neuronal death and clinically translates in post-CA coma [7]. Of importance, it is now well demonstrated that brain injury continues even after restoration of cerebral perfusion and oxygenation, in a process known as ‘‘reperfusion injury’’. The injurious mechanisms involved in this process are partially modulated by brain temperature, as hyperthermia may worsen the anoxic insult [8]. Finally, even after the restoration of adequate blood supply and cellular energy stores, a global hypoperfusion state is commonly observed, called the ‘‘no reflow phenomenon’’, which results from the combination of increased blood viscosity, microvascular alterations and altered cerebral flow regulation [9]. This hypoperfusion, potentially associated with other secondary injuries, such as alterations in blood glucose concentrations, abnormal carbon dioxide levels, seizures and hyperthermia, may further lead to secondary brain injury and may worsen initial brain damages. 3. Clinical consequences of post-CA brain damages CA and subsequent brain damages may result in heterogeneous neurological signs and symptoms, reflecting the different susceptibility of cerebral areas to anoxia. These differences could be related either to the poor circulation, to the higher energy requirement and glutamate release of cerebral cells or to the
lower expression of some proteins, such as heat-shock proteins, which confer a relative tolerance to ischemia, in certain vulnerable brain regions [10,11]. Nevertheless, neurological dysfunction in post-CA patients predominantly includes disorders of consciousness, which ranges from mild confusion (difficult concentrating, poor judgment or euphoria) and delirium to coma [10], depending on the injury on subcortical and brainstem functions. Symptoms observed in the first hours and days may also include other manifestations of neurological dysfunction, such as seizures, myoclonus status epilepticus and other forms of movement disorders including post-anoxic myoclonus. In the most severe cases, coma may be irreversible or evolve towards a minimally conscious state, a vegetative state or even brain death. These severe conditions represent the leading cause of mortality and disability in such patients. In a recent French cohort, while 66% of patients died after ICU admission – a rate that is consistent with studies from other Western countries [1–5] –, brain damages accounted for around two thirds of fatalities. In survivors, longterm symptoms may be very various and include memory and cognitive impairment, late-onset seizures and cerebral palsy. 4. Prevention of post-CA brain damages In the recent years, the evidence of further cerebral damage occurring during the reperfusion phase encouraged intense research aiming to limit the worsening of the neurological lesions occurring during the post-CA period. This culminated 10 years ago with the demonstration that post-CA cooling was an effective treatment in these patients. 4.1. Therapeutic hypothermia Many experimental data previously showed that mild hypothermia can exert neuroprotective effects through multiple mechanisms of action, i.e. decrease of cerebral metabolism, reduction of apoptosis and mitochondrial dysfunction, reduction of the cerebral excitatory cascade, decrease of local inflammatory response, reduction of free oxygen radicals production, and decrease of vascular and membrane permeability. These convergent experimental effects were confirmed by two landmark clinical studies published in 2002 [12,13]. In both trials, the implementation of mild hypothermia permitted to achieve a survival rate without major sequel in around 40–50% of a highly ‘‘selected’’ population (out-of-hospital CA with an initial rhythm of ventricular fibrillation in front of a bystander). Their publication was decisive and led to a rapid change in international recommendations on the management of patients surviving after CA. It is now strongly recommended to routinely induce moderate hypothermia (32 to 34 8C) for 12 to 24 hours in any comatose adult successfully resuscitated after out-of-hospital CA caused by ventricular fibrillation/tachycardia [14]. If numerous clinical studies further confirmed the benefit of this treatment in shockable patients, the level of evidence remains weaker in patients presenting an initial non-shockable rhythm [15]. In these patients, some recent data suggest a lack of neurological benefit [16]. Considering that the risk-benefit ratio is sufficiently favorable, guidelines recommend discussing its use on a caseby-case basis.
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4.2. Neuroprotective treatments Despite encouraging animal data and numerous attempts, no drug has at this time demonstrated its ability to reduce the consequences of cerebral anoxo-ischemia after CA. Several molecules, which previously showed experimental neuroprotective effects during ischemia-reperfusion phenomena (cyclosporine, erythropoietin), are currently investigated [17,18]. 4.3. Prevention of secondary cerebral damages Achieving and maintaining an optimal metabolic homeostasis is a major goal of post-CA management. In particular, all factors susceptible to affect cerebrovascular function should be adequately controlled. The correction of electrolyte disturbances is essential and special attention should be given to the one that may participate in the recurrence of CA or worsening of organ dysfunction. Regarding arterial blood gases, recent clinical data suggest that both normoxia and normocapnia should be targeted, as abnormally high or low levels of arterial oxygen and carbon dioxide may be associated with worse outcome in this population [19,20]. There is also a strong association between high blood glucose levels and adverse neurological outcome after CA, but causality is not established. Moreover converging data underline that blood glucose variability more seriously impairs the outcome of critically ill patients rather than the mean level of glycemia [21]. At this time, it is not possible to recommend the use of tight control glycemia in patients in post-CA population as this attitude must first be studied in terms of benefit-risk ratio. 5. Early outcome prediction Accurate assessment of prognosis is mandatory to identify patients who will really benefit from intensive care and to avoid extending unnecessary life-sustaining treatments to those who do not have a reasonable chance of recovery. At this time, prognostication of poor outcome is still mainly based on a rigorous clinical evaluation coupled with neuro-physiological investigations, i.e. electro-encephalogram (EEG) and somato-sensatory evoked potentials (SSEP) recording. A recent meta-analysis indicated that in comatose resuscitated patients who have not been cooled, presence of myoclonus or myoclonus status at 24– 48 hours, bilateral absence of SSEP N20 wave or absence of EEG activity >20–21 V at 24–72 hours and absence of pupillary light reflex at 72 hours each predicted death or vegetative state with 0% false positive rate and narrow confidence intervals. In addition, the absence of SSEP N20 wave at 24 hours predicted death, vegetative state or severe disability with 0% false positive rate and narrow confidence intervals [22]. When used, hypothermia is of particular importance since sedation and neuromuscular blockade may interfere with these prognostication tools [23]. A recent metaanalysis focusing on cooled patients strongly indicates that not all currently used clinical parameters can be applied to patients after hypothermia [24]. In these patients, the Glasgow Coma Scale (GCS) motor score and the corneal reflexes at 72 hours after the arrest are unreliable parameters to predict a poor outcome. On the other hand, bilaterally absent pupillary reflexes and a bilaterally absent cortical N20 response both have low false positive rate, with narrow confidence intervals. Thus the validity of the SSEP and the pupillary reflexes is comparable to that reported in patients not treated with hypothermia [24]. To note, the usual evaluation, which can be performed at day 3 in the absence of cooling, should be postponed at least 72 hours after normothermia achievement in cooled patients. Regarding routine neuroimaging techniques, CT-scan imaging adds little information regarding prognostication, unless stroke,
bleeding or trauma is initially suspected. Preliminary reports suggest that magnetic resonance imaging (MRI) could be used to determine the prognosis of patients with diffuse cerebral anoxia [25,26], but this requires further investigations. Similarly, if major hopes had been placed into specific cerebral biomarkers like Neuron Specific Enolase (NSE), or S-100 proteins, therapeutic hypothermia has greatly modified their roles, with uncertainty on the optimal threshold and sampling period. Moreover, clinical or paraclinical tools cannot be conceived as isolated pieces of the prognostication puzzle, but rather as a multi-faceted evaluation that should converge towards accurate appreciation of outcome. The lack of firm prognostication tools in the first 3 ICU days also implies that adequate level of care should be provided in all patients, regardless of CA characteristics, and should not be restricted on the basis of perceived poor outcome. 6. Ethical considerations The growing number of patients admitted to ICU after resuscitated CA is associated with several ethical questions regarding futility of care. The widespread assumption is that poor outcome can be defined as death, vegetative state, or severe neurological impairment (precluding independent living). Even if for most patients and families severe neurological impairment is not considered to be a desirable outcome, the decision to forgo or to withdraw life-sustaining treatments cannot only be based on caregivers’ personal convictions and should systematically be discussed with all persons involved in the situation. Health care professionals must consider that some families and patients may have different perceptions of what constitutes an acceptable neurological outcome. A multidisciplinary approach, involving psychologists, ethicists and experts in communication with families, should be developed to improve the decision process. 7. What about CA survivors? A common perception is that both survival rate and health status of these patients are satisfactory [27,28]. Among 681 patients discharged after CA and followed over a 6-month period, 69% of them were considered to have a good neurological outcome [29]. For 70% of patients, the neurological status remained stable during follow-up, or even improved in 12% of cases; only 1% of the patients exhibited a decrease in neurological performance. In this cohort, the 6-month mortality rate of 17% was mainly due to cardiovascular causes. However, quality of life, psychological wellbeing and social activity are most often poorly taken into consideration. Hypoxic insult may result in a number of disorders considered as minor, but having a strong impact on quality of life such as memory problems. A fine evaluation of the quality of life was performed 3 years after CA, using the standardized questionnaire SF-36 [30], which explores both physical and mental aspects. Results obtained in survivors were quite similar to those of a matched healthy population, but CA survivors displayed a lower sense of vitality. CA survivors also represent an important potential source for development of posttraumatic stress disorder (PTSD). In a study that compared the psychological status of patients 9 months after in-hospital CA or acute myocardial infarction, CA survivors complained more frequently from anxiety (30% vs. 7%), depression (15% vs. 0%) and PTSD (19% vs. 7%) [31]. This study highlights the frailty of CA survivors and the significant risk of emotional disorders [32]. Another study showed that PTSD occurred in one third of CA survivors 45 months after the event [33]. Interestingly, this study displayed that the only risk factor for PTSD was young age.
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8. Conclusion In the near future, improvement in cardiac resuscitation will undoubtedly enhance the number of CA survivors admitted to hospital, with minimization of neurological sequels as the main objective of care. During ICU stay, cerebral protection (particularly through therapeutic hypothermia and homeostasis maintenance) is now an essential part of patient management in association with life-supportive treatments [34]. Research projects focusing on survivors should be encouraged in order to assess the mid- and long-terms outcome and to evaluate the impact of new treatments or strategies. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Lemiale V, Dumas F, Mongardon N, Giovanetti O, Charpentier J, Chiche JD, et al. Intensive care unit mortality after cardiac arrest: the relative contribution of shock and brain injury in a large cohort. Intensive Care Med 2013;39:1972–80. [2] Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 2004;30:2126–8. [3] Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-ofhospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2010;3:63–81. [4] Bouwes A, Binnekade JM, Kuiper MA, Bosch FH, Zandstra DF, Toornvliet AC, et al. Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Ann Neurol 2012;71:206–12. [5] Nolan JP, Laver SR, Welch CA, Harrison DA, Gupta V, Rowan K. Outcome following admission to UK intensive care units after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database. Anaesthesia 2007;62:1207–16. [6] Walters EL, Morawski K, Dorotta I, Ramsingh D, Lumen K, Bland D, et al. Implementation of a post-cardiac arrest care bundle including therapeutic hypothermia and hemodynamic optimization in comatose patients with return of spontaneous circulation after out-of-hospital cardiac arrest: a feasibility study. Shock 2011;35:360. [7] Illievich UM, Zornow MH, Choi KT, Scheller MS, Strnat MA. Effects of hypothermic metabolic suppression on hippocampal glutamate concentrations after transient global cerebral ischemia. Anesth Analg 1994;78:905–11. [8] Chio CC, Kuo JR, Hsiao SH, Chang CP, Lin MT. Effect of brain cooling on brain ischemia and damage markers after fluid percussion brain injury in rats. Shock 2007;28:284–90. [9] Ames 3rd A, Wright RL, Kowada M, Thurston JM, Majno G. Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol 1968;52:437–53. [10] Xiong W, Hoesch RE, Geocadin RG. Post-cardiac arrest encephalopathy. Semin Neurol 2011;31:216–25. [11] Greer DM. Mechanisms of injury in hypoxic-ischemic encephalopathy: implications to therapy. Semin Neurol 2006;26:373–9. [12] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63. [13] Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56. [14] Nolan JP, Soar J, Zideman DA, Biarent D, Bossaert LL, Deakin C, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary. Resuscitation 2010;81:1219–76.
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[15] Kim YM, Yim HW, Jeong SH, Klem ML, Callaway CW. Does therapeutic hypothermia benefit adult cardiac arrest patients presenting with non-shockable initial rhythms?: a systematic review and meta-analysis of randomized and non-randomized studies. Resuscitation 2012;83:188–96. [16] Dumas F, Grimaldi D, Zuber B, Fichet J, Charpentier J, Pe`ne F, et al. Is hypothermia after cardiac arrest effective in both shockable and nonshockable patients?: insights from a large registry. Circulation 2011;123:877–86. [17] Cariou A, Claessens YE, Pe`ne F, Marx JS, Spaulding C, Hababou C, et al. Early high-dose erythropoietin therapy and hypothermia after out-of-hospital cardiac arrest: a matched control study. Resuscitation 2008;76:397–404. [18] Cour M, Loufouat J, Paillard M, Augeul L, Goudable J, Ovize M, et al. Inhibition of mitochondrial permeability transition to prevent the post-cardiac arrest syndrome: a pre-clinical study. Eur Heart J 2011;32:226–35. [19] Kilgannon JH, Jones AE, Shapiro NI, Angelos MG, Milcarek B, Hunter K, et al. Association between arterial hyperoxia following resuscitation from cardiac arrest and in-hospital mortality. JAMA 2010;303:2165–71. [20] Roberts BW, Kilgannon JH, Chansky ME, Mittal N, Wooden J, Trzeciak S. Association between postresuscitation partial pressure of arterial carbon dioxide and neurological outcome in patients with post-cardiac arrest syndrome. Circulation 2013;127:2107–13. [21] Cueni-Villoz N, Devigili A, Delodder F, Cianferoni S, Feihl F, Rossetti AO, et al. Increased blood glucose variability during therapeutic hypothermia and outcome after cardiac arrest. Crit Care Med 2011;39:2225–31. [22] Sandroni C, Cavallaro F, Callaway CW, Sanna T, D’Arrigo S, Kuiper M, et al. Predictors of poor neurological outcome in adult comatose survivors of cardiac arrest: a systematic review and meta-analysis. Part 1: patients not treated with therapeutic hypothermia. Resuscitation 2013;84:1310–23. http:// dx.doi.org/10.1016/j.resuscitation.2013.05.013. pii: S0300-9572(13)00294-3. [23] Oddo M, Rossetti AO. Predicting neurological outcome after cardiac arrest. Curr Opin Crit Care 2011;17:254–9. [24] Kamps MJ, Horn J, Oddo M, Fugate JE, Storm C, Cronberg T, et al. Prognostication of neurologic outcome in cardiac arrest patients after mild therapeutic hypothermia: a meta-analysis of the current literature. Intensive Care Med 2013;39:1671–82. [25] Weiss N, Galanaud D, Carpentier A, Naccache L, Puybasset L. Clinical review: prognostic value of magnetic resonance imaging in acute brain injury and coma. Crit Care 2007;11:230. [26] Luyt CE, Galanaud D, Perlbarg V, Vanhaudenhuyse A, Stevens RD, Gupta R, et al. Diffusion tensor imaging to predict long-term outcome after cardiac arrest: a bicentric pilot study. Anesthesiology 2012;117:1311–21. [27] Eisenburger P, List M, Scho¨rkhuber W, Walker R, Sterz F, Laggner AN. Longterm cardiac arrest survivors of the Vienna emergency medical service. Resuscitation 1998;38:137–43. [28] Nichol G, Stiell IG, Hebert P, Wells GA, Vandemheen K, Laupacis A. What is the quality of life for survivors of cardiac arrest? A prospective study. Acad Emerg Med 1999;6:95–102. [29] Arrich J, Zeiner A, Sterz F, Janata A, Uray T, Richling N, et al. Factors associated with a change in functional outcome between one month and six months after cardiac arrest: a retrospective cohort study. Resuscitation 2009;80:876–80. [30] Bunch TJ, White RD, Gersh BJ, Meverden RA, Hodge DO, Ballman KV, et al. Longterm outcomes of out-of-hospital cardiac arrest after successful early defibrillation. N Engl J Med 2003;348:2626–33. [31] O’Reilly SM, Grubb N, O’Carroll RE. Long-term emotional consequences of inhospital cardiac arrest and myocardial infarction. Br J Clin Psychol 2004;43(Pt 1):83–95. [32] Ladwig KH, Schoefinius A, Dammann G, Danner R, Gu¨rtler R, Herrmann R. Long-acting psychotraumatic properties of a cardiac arrest experience. Am J Psychiatry 1999;156:912–9. [33] Gamper G, Willeit M, Sterz F, Herkner H, Zoufaly A, Hornik K, et al. Life after death: posttraumatic stress disorder in survivors of cardiac arrest – prevalence, associated factors, and the influence of sedation and analgesia. Crit Care Med 2004;32:378–83. [34] Mongardon N, Bougle´ A, Geri G, Daviaud F, Morichau-Beauchant T, Tissier R, et al. Syndrome post-arreˆt cardiaque : aspects physiopathologiques, cliniques et the´rapeutiques Pathophysiology and management of post-cardiac arrest syndrome Ann Fr Anesth Reanim 2013;32:779–86. http://dx.doi.org/10.1016/ j.annfar.2013.07.818.
Anarlf meeting
Neurological consequences of cardiac arrest: Where do we stand?§,§§ Conse´quences neurologiques post-arreˆt cardiaque : ou` en sommes-nous ? G. Geri a,d,f, N. Mongardon c,e, F. Daviaud a,d, J.-P. Empana d,f, F. Dumas b,d,f, A. Cariou a,*,d,f a
Medical Intensive Care Unit, Cochin Hospital, Assistance publique des Hoˆpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France Emergency Department, Cochin Hospital, Assistance publique des Hoˆpitaux de Paris, 27, rue du Faubourg-Saint-Jacques, 75014 Paris, France Department of Anesthesiology and Surgical Intensive Care, Henri-Mondor Hospital, Assistance publique des Hoˆpitaux de Paris, 51, avenue du Mare´chal-de-Lattre-de-Tassigny, 94000 Cre´teil, France d Faculte´ de me´decine, universite´ Paris Descartes & Sorbonne Paris Cite´, 15, rue de l’E´cole-de-Me´decine, 75006 Paris, France e Faculte´ de me´decine, universite´ Paris Est, 8, avenue du Ge´ne´ral-Sarrail, 94000 Cre´teil, France f Paris Cardiovascular Research Center, European Georges-Pompidou Hospital, INSERM U970, 56, rue Leblanc, 75015 Paris, France b c
A R T I C L E I N F O
A B S T R A C T
Keywords: Cardiac arrest Prognostication Therapeutic hypothermia Cardio-pulmonary resuscitation
With increasing public education in basic life support and with the widespread use of automated defibrillators, post-cardiac arrest comatose patients represent a growing part of ICU admissions. However the prognosis remains very poor and only a very low proportion of these resuscitated patients will recover and will leave the hospital without major neurological impairments. Neurological dysfunction predominantly includes disorders of consciousness, and may also include other manifestations such as seizures, myoclonus status epilepticus and other forms of movement disorders including post-anoxic myoclonus. In the most severe cases, coma may be irreversible or evolve towards a minimally conscious state, a vegetative state or even brain death. These severe conditions represent by far the leading cause of mortality and disability in such patients. Currently, early use of mild therapeutic hypothermia is the only treatment that demonstrated its ability to decrease neurological consequences and to improve the prognosis. Prognostication outcome is still mainly based on a rigorous clinical evaluation coupled with neuro-physiological investigations, but brain functional imaging could become a valuable tool in the near future. Clinical research focusing on survivors should be strongly encouraged in order to assess the mid- and long-terms outcome of survivors and to evaluate the impact of new treatments or strategies. ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved. R E´ S U M E´
Mots cle´s : Arreˆt cardiaque E´valuation pronostique Hypothermie the´rapeutique Re´animation cardiopulmonaire
La prise en charge de patients re´anime´s avec succe`s d’un arreˆt cardiaque extrahospitalier repre´sente une part d’activite´ de plus en plus importante en re´animation, graˆce notamment aux progre`s re´alise´s en matie`re d’e´ducation du grand publique pour la re´animation cardiopulmonaire et la diffusion des de´fibrillateurs semi-automatiques. Cependant, le pronostic reste sombre et seulement une faible proportion de ces patients re´anime´s avec succe`s sortiront de l’hoˆpital sans se´quelle neurologique majeure et retrouveront leur e´tat neurologique ante´rieur. Les se´quelles neurologiques sont domine´es par les troubles de la conscience, mais peuvent e´galement se pre´senter sous la forme de crises convulsives, d’e´tat de mal e´pileptique et d’autres formes de mouvements anormaux comme les myoclonies postanoxiques. Dans les cas les plus se´ve`res, le coma est irre´versible ou e´volue vers un e´tat pauci-relationnel, un e´tat ve´ge´tatif ou la mort ence´phalique. Ces se´quelles lourdes repre´sentent la principale cause de mortalite´ et de handicap chez ces patients. Actuellement, l’hypothermie the´rapeutique est le seul traitement ayant de´montre´ son efficacite´ pour la diminution des se´quelles neurologiques et l’ame´lioration du pronostic. Pre´dire l’e´volution neurologique est toujours actuellement base´e sur une e´valuation neurologique clinique rigoureuse, associe´e aux explorations neurophysiologiques, mais
French NeuroAnesthesia and Intensive Care society Meeting, Paris, November 2013, 21st and 22nd: ‘‘The acutely brain-injured patient: consciousness and neuroethic’’. This article is published under the responsibility of the Scientific Committee of the ‘‘35e Journe´e de l’Association des neuro-anesthe´sistes re´animateurs de langue franc¸aises’’ de la SFAR. The editorial board of the Annales franc¸aises d’anesthe´sie et de re´animation was not involved in the conception and validation of its content. * Corresponding author. E-mail address: [email protected] (A. Cariou). §
§§
0750-7658/$ – see front matter ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Published by Elsevier Masson SAS. All rights reserved. http://dx.doi.org/10.1016/j.annfar.2013.11.003
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l’imagerie fonctionnelle ce´re´brale pourrait devenir un outil pertinent a` l’avenir. Les e´tudes s’inte´ressant particulie`rement aux survivants doivent eˆtre soutenues afin d’e´valuer le devenir a` moyen et long termes de ces patients et l’impact des nouvelles strate´gies the´rapeutiques. ß 2013 Socie´te´ franc¸aise d’anesthe´sie et de re´animation (Sfar). Publie´ par Elsevier Masson SAS. Tous droits re´serve´s.
1. Scope of the problem Sudden cardiac death remains a major public health issue, as highlighted by epidemiological data showing that nearly 40,000 people are supported for out-of-hospital cardiac arrest (CA) in France each year. Even more problematic, only a very low proportion of resuscitated patients will recover and will leave the hospital without major neurological impairments [1–6]. Across the different studies focusing on early prognostic factors, a common finding is that the frequency and intensity of post-CA complications depend mainly on the quality and duration of cardio-pulmonary resuscitation (CPR). Nevertheless, with increasing public education in basic life support and with the widespread use of automated defibrillators, post-CA comatose patients have now become more and more frequent among ICU population. After traumatic brain injury and drug overdose, CA is considered to be the third cause of coma in Western countries, a fact that is associated with a multitude of medical, ethical, and economic questions. In parallel, experimental and clinical research has focused on a better comprehension of the mechanisms responsible for post-CA brain damages, as well as on the development of several neuroprotective strategies able to improve outcome of these patients. 2. Pathophysiology of brain damages Contrary to traumatic or focal ischemic causes of coma, CA provokes a global ischemic insult to the brain. The extent of cerebral damage is largely influenced by the duration of interrupted cerebral blood flow. Accordingly, minimizing both the arrest time (‘‘noflow’’) and CPR time (‘‘low-flow’’) are key issues. Schematically, cerebral oxygen stores and consciousness are lost within 20 seconds of the onset of CA, while glucose and adenosine triphosphate (ATP) stores are lost within 5 minutes. Cerebral ischemia then triggers a complex cascade of pathways, which lead to neuronal death and clinically translates in post-CA coma [7]. Of importance, it is now well demonstrated that brain injury continues even after restoration of cerebral perfusion and oxygenation, in a process known as ‘‘reperfusion injury’’. The injurious mechanisms involved in this process are partially modulated by brain temperature, as hyperthermia may worsen the anoxic insult [8]. Finally, even after the restoration of adequate blood supply and cellular energy stores, a global hypoperfusion state is commonly observed, called the ‘‘no reflow phenomenon’’, which results from the combination of increased blood viscosity, microvascular alterations and altered cerebral flow regulation [9]. This hypoperfusion, potentially associated with other secondary injuries, such as alterations in blood glucose concentrations, abnormal carbon dioxide levels, seizures and hyperthermia, may further lead to secondary brain injury and may worsen initial brain damages. 3. Clinical consequences of post-CA brain damages CA and subsequent brain damages may result in heterogeneous neurological signs and symptoms, reflecting the different susceptibility of cerebral areas to anoxia. These differences could be related either to the poor circulation, to the higher energy requirement and glutamate release of cerebral cells or to the
lower expression of some proteins, such as heat-shock proteins, which confer a relative tolerance to ischemia, in certain vulnerable brain regions [10,11]. Nevertheless, neurological dysfunction in post-CA patients predominantly includes disorders of consciousness, which ranges from mild confusion (difficult concentrating, poor judgment or euphoria) and delirium to coma [10], depending on the injury on subcortical and brainstem functions. Symptoms observed in the first hours and days may also include other manifestations of neurological dysfunction, such as seizures, myoclonus status epilepticus and other forms of movement disorders including post-anoxic myoclonus. In the most severe cases, coma may be irreversible or evolve towards a minimally conscious state, a vegetative state or even brain death. These severe conditions represent the leading cause of mortality and disability in such patients. In a recent French cohort, while 66% of patients died after ICU admission – a rate that is consistent with studies from other Western countries [1–5] –, brain damages accounted for around two thirds of fatalities. In survivors, longterm symptoms may be very various and include memory and cognitive impairment, late-onset seizures and cerebral palsy. 4. Prevention of post-CA brain damages In the recent years, the evidence of further cerebral damage occurring during the reperfusion phase encouraged intense research aiming to limit the worsening of the neurological lesions occurring during the post-CA period. This culminated 10 years ago with the demonstration that post-CA cooling was an effective treatment in these patients. 4.1. Therapeutic hypothermia Many experimental data previously showed that mild hypothermia can exert neuroprotective effects through multiple mechanisms of action, i.e. decrease of cerebral metabolism, reduction of apoptosis and mitochondrial dysfunction, reduction of the cerebral excitatory cascade, decrease of local inflammatory response, reduction of free oxygen radicals production, and decrease of vascular and membrane permeability. These convergent experimental effects were confirmed by two landmark clinical studies published in 2002 [12,13]. In both trials, the implementation of mild hypothermia permitted to achieve a survival rate without major sequel in around 40–50% of a highly ‘‘selected’’ population (out-of-hospital CA with an initial rhythm of ventricular fibrillation in front of a bystander). Their publication was decisive and led to a rapid change in international recommendations on the management of patients surviving after CA. It is now strongly recommended to routinely induce moderate hypothermia (32 to 34 8C) for 12 to 24 hours in any comatose adult successfully resuscitated after out-of-hospital CA caused by ventricular fibrillation/tachycardia [14]. If numerous clinical studies further confirmed the benefit of this treatment in shockable patients, the level of evidence remains weaker in patients presenting an initial non-shockable rhythm [15]. In these patients, some recent data suggest a lack of neurological benefit [16]. Considering that the risk-benefit ratio is sufficiently favorable, guidelines recommend discussing its use on a caseby-case basis.
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4.2. Neuroprotective treatments Despite encouraging animal data and numerous attempts, no drug has at this time demonstrated its ability to reduce the consequences of cerebral anoxo-ischemia after CA. Several molecules, which previously showed experimental neuroprotective effects during ischemia-reperfusion phenomena (cyclosporine, erythropoietin), are currently investigated [17,18]. 4.3. Prevention of secondary cerebral damages Achieving and maintaining an optimal metabolic homeostasis is a major goal of post-CA management. In particular, all factors susceptible to affect cerebrovascular function should be adequately controlled. The correction of electrolyte disturbances is essential and special attention should be given to the one that may participate in the recurrence of CA or worsening of organ dysfunction. Regarding arterial blood gases, recent clinical data suggest that both normoxia and normocapnia should be targeted, as abnormally high or low levels of arterial oxygen and carbon dioxide may be associated with worse outcome in this population [19,20]. There is also a strong association between high blood glucose levels and adverse neurological outcome after CA, but causality is not established. Moreover converging data underline that blood glucose variability more seriously impairs the outcome of critically ill patients rather than the mean level of glycemia [21]. At this time, it is not possible to recommend the use of tight control glycemia in patients in post-CA population as this attitude must first be studied in terms of benefit-risk ratio. 5. Early outcome prediction Accurate assessment of prognosis is mandatory to identify patients who will really benefit from intensive care and to avoid extending unnecessary life-sustaining treatments to those who do not have a reasonable chance of recovery. At this time, prognostication of poor outcome is still mainly based on a rigorous clinical evaluation coupled with neuro-physiological investigations, i.e. electro-encephalogram (EEG) and somato-sensatory evoked potentials (SSEP) recording. A recent meta-analysis indicated that in comatose resuscitated patients who have not been cooled, presence of myoclonus or myoclonus status at 24– 48 hours, bilateral absence of SSEP N20 wave or absence of EEG activity >20–21 V at 24–72 hours and absence of pupillary light reflex at 72 hours each predicted death or vegetative state with 0% false positive rate and narrow confidence intervals. In addition, the absence of SSEP N20 wave at 24 hours predicted death, vegetative state or severe disability with 0% false positive rate and narrow confidence intervals [22]. When used, hypothermia is of particular importance since sedation and neuromuscular blockade may interfere with these prognostication tools [23]. A recent metaanalysis focusing on cooled patients strongly indicates that not all currently used clinical parameters can be applied to patients after hypothermia [24]. In these patients, the Glasgow Coma Scale (GCS) motor score and the corneal reflexes at 72 hours after the arrest are unreliable parameters to predict a poor outcome. On the other hand, bilaterally absent pupillary reflexes and a bilaterally absent cortical N20 response both have low false positive rate, with narrow confidence intervals. Thus the validity of the SSEP and the pupillary reflexes is comparable to that reported in patients not treated with hypothermia [24]. To note, the usual evaluation, which can be performed at day 3 in the absence of cooling, should be postponed at least 72 hours after normothermia achievement in cooled patients. Regarding routine neuroimaging techniques, CT-scan imaging adds little information regarding prognostication, unless stroke,
bleeding or trauma is initially suspected. Preliminary reports suggest that magnetic resonance imaging (MRI) could be used to determine the prognosis of patients with diffuse cerebral anoxia [25,26], but this requires further investigations. Similarly, if major hopes had been placed into specific cerebral biomarkers like Neuron Specific Enolase (NSE), or S-100 proteins, therapeutic hypothermia has greatly modified their roles, with uncertainty on the optimal threshold and sampling period. Moreover, clinical or paraclinical tools cannot be conceived as isolated pieces of the prognostication puzzle, but rather as a multi-faceted evaluation that should converge towards accurate appreciation of outcome. The lack of firm prognostication tools in the first 3 ICU days also implies that adequate level of care should be provided in all patients, regardless of CA characteristics, and should not be restricted on the basis of perceived poor outcome. 6. Ethical considerations The growing number of patients admitted to ICU after resuscitated CA is associated with several ethical questions regarding futility of care. The widespread assumption is that poor outcome can be defined as death, vegetative state, or severe neurological impairment (precluding independent living). Even if for most patients and families severe neurological impairment is not considered to be a desirable outcome, the decision to forgo or to withdraw life-sustaining treatments cannot only be based on caregivers’ personal convictions and should systematically be discussed with all persons involved in the situation. Health care professionals must consider that some families and patients may have different perceptions of what constitutes an acceptable neurological outcome. A multidisciplinary approach, involving psychologists, ethicists and experts in communication with families, should be developed to improve the decision process. 7. What about CA survivors? A common perception is that both survival rate and health status of these patients are satisfactory [27,28]. Among 681 patients discharged after CA and followed over a 6-month period, 69% of them were considered to have a good neurological outcome [29]. For 70% of patients, the neurological status remained stable during follow-up, or even improved in 12% of cases; only 1% of the patients exhibited a decrease in neurological performance. In this cohort, the 6-month mortality rate of 17% was mainly due to cardiovascular causes. However, quality of life, psychological wellbeing and social activity are most often poorly taken into consideration. Hypoxic insult may result in a number of disorders considered as minor, but having a strong impact on quality of life such as memory problems. A fine evaluation of the quality of life was performed 3 years after CA, using the standardized questionnaire SF-36 [30], which explores both physical and mental aspects. Results obtained in survivors were quite similar to those of a matched healthy population, but CA survivors displayed a lower sense of vitality. CA survivors also represent an important potential source for development of posttraumatic stress disorder (PTSD). In a study that compared the psychological status of patients 9 months after in-hospital CA or acute myocardial infarction, CA survivors complained more frequently from anxiety (30% vs. 7%), depression (15% vs. 0%) and PTSD (19% vs. 7%) [31]. This study highlights the frailty of CA survivors and the significant risk of emotional disorders [32]. Another study showed that PTSD occurred in one third of CA survivors 45 months after the event [33]. Interestingly, this study displayed that the only risk factor for PTSD was young age.
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8. Conclusion In the near future, improvement in cardiac resuscitation will undoubtedly enhance the number of CA survivors admitted to hospital, with minimization of neurological sequels as the main objective of care. During ICU stay, cerebral protection (particularly through therapeutic hypothermia and homeostasis maintenance) is now an essential part of patient management in association with life-supportive treatments [34]. Research projects focusing on survivors should be encouraged in order to assess the mid- and long-terms outcome and to evaluate the impact of new treatments or strategies. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] Lemiale V, Dumas F, Mongardon N, Giovanetti O, Charpentier J, Chiche JD, et al. Intensive care unit mortality after cardiac arrest: the relative contribution of shock and brain injury in a large cohort. Intensive Care Med 2013;39:1972–80. [2] Laver S, Farrow C, Turner D, Nolan J. Mode of death after admission to an intensive care unit following cardiac arrest. Intensive Care Med 2004;30:2126–8. [3] Sasson C, Rogers MA, Dahl J, Kellermann AL. Predictors of survival from out-ofhospital cardiac arrest: a systematic review and meta-analysis. Circ Cardiovasc Qual Outcomes 2010;3:63–81. [4] Bouwes A, Binnekade JM, Kuiper MA, Bosch FH, Zandstra DF, Toornvliet AC, et al. Prognosis of coma after therapeutic hypothermia: a prospective cohort study. Ann Neurol 2012;71:206–12. [5] Nolan JP, Laver SR, Welch CA, Harrison DA, Gupta V, Rowan K. Outcome following admission to UK intensive care units after cardiac arrest: a secondary analysis of the ICNARC Case Mix Programme Database. Anaesthesia 2007;62:1207–16. [6] Walters EL, Morawski K, Dorotta I, Ramsingh D, Lumen K, Bland D, et al. Implementation of a post-cardiac arrest care bundle including therapeutic hypothermia and hemodynamic optimization in comatose patients with return of spontaneous circulation after out-of-hospital cardiac arrest: a feasibility study. Shock 2011;35:360. [7] Illievich UM, Zornow MH, Choi KT, Scheller MS, Strnat MA. Effects of hypothermic metabolic suppression on hippocampal glutamate concentrations after transient global cerebral ischemia. Anesth Analg 1994;78:905–11. [8] Chio CC, Kuo JR, Hsiao SH, Chang CP, Lin MT. Effect of brain cooling on brain ischemia and damage markers after fluid percussion brain injury in rats. Shock 2007;28:284–90. [9] Ames 3rd A, Wright RL, Kowada M, Thurston JM, Majno G. Cerebral ischemia. II. The no-reflow phenomenon. Am J Pathol 1968;52:437–53. [10] Xiong W, Hoesch RE, Geocadin RG. Post-cardiac arrest encephalopathy. Semin Neurol 2011;31:216–25. [11] Greer DM. Mechanisms of injury in hypoxic-ischemic encephalopathy: implications to therapy. Semin Neurol 2006;26:373–9. [12] Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, et al. Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002;346:557–63. [13] Hypothermia after Cardiac Arrest Study Group. Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest. N Engl J Med 2002;346:549–56. [14] Nolan JP, Soar J, Zideman DA, Biarent D, Bossaert LL, Deakin C, et al. European Resuscitation Council Guidelines for Resuscitation 2010 Section 1. Executive summary. Resuscitation 2010;81:1219–76.
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