Editorials REFERENCES 1. Cullen SC, Gross EG: The anesthetic properties of xenon in animals and human beings, with additional observations on krypton. Science 1951; 1 1 3 :5 8 0 -5 8 2 2. Dickinson R, Franks NP: Bench-to-bedside review: Molecular phar macology and clinical use of inert gases in anesthesia and neuropro tection. Crit Care 2010; 14:229 3. Homi HM, Yokoo N, Ma D, et al: The neuroprotective effect of xenon administration during transient middle cerebral artery occlusion in mice. Anesthesiology 2003; 99 :876-881 4. Schmidt M, Marx T, Gloggl E, et al; Xenon attenuates cerebral dam age after ischemia in pigs. Anesthesiology 2005; 1 0 2 :9 2 9 -9 3 6 5. Ma D, Hossain M, Chow A, et al: Xenon and hypothermia combine to provide neuroprotection from neonatal asphyxia. Ann Neurol 2005; 5 8 :1 8 2 -1 9 3 6. Yang YW, Cheng WP, Lu JK, et al: Timing of xenon-induced delayed postconditioning to protect against spinal cord ischaemia-reperfusion injury in rats. Br J Anaesth 2014; 1 1 3 :1 6 8 -1 7 6 7. Banks P, Franks NP, Dickinson R: Competitive inhibition at the gly cine site of the A/-methyl-o-aspartate receptor mediates xenon
neuroproteotion against hypoxia-ischemia. Anesthesiology 2010; 1 1 2 :61 4-6 22 8. Natale G, Cattano D, Abramo A, et al: Morphological evidence that xenon neuroprotects against /V-methyl-DL-aspartic acid-induced dam age in the rat arcuate nucleus: A time-dependent study. Ann N Y Acad Sci 2006; 1 0 7 4 :6 50 -658 9. Campos-Pires R, Armstrong SP, Sebastiani A, et al: Xenon Improves Neurologic Outcome and Reduces Secondary Injury Following Trauma in an In Vivo Model of Traumatic Brain Injury. Crit Care Med 2 0 1 5 ;4 3 :1 4 9 -1 5 8 10. Harris K, Armstrong SP, Campos-Pires R, et al: Neuroprotection against traumatic brain injury by xenon, but not argon, is medi ated by inhibition at the A/-methyl-D-aspartate receptor glycine site. Anesthesiology 2013; 1 1 9 :1 1 3 7 -1 1 4 8 11. Marklund N, Hillered L: Animal modelling of traumatic brain injury in preclinical drug development: Where do we go from here? Br J Pharmacol 2011; 1 6 4 :1 2 0 7 -1 2 2 9 12. Esencan E, Yuksel S, Tosun YB, et al: XENON in medical area: Emphasis on neuroprotection in hypoxia and anesthesia. Med Gas Res 2013; 3:4
Strength by Sheer Numbers: Electroencephalogram Gathers Momentum as a Positive Predictor* Tommaso Pellis, M D Anesthesia, Intensive Care and Emergency Medical Service Santa Maria Degli Angeli Hospital Pordenone, Italy
he introduction of therapeutic hypothermia, and then of the broader concept of temperature management, has profoundly changed the gameplay of prognostica tion after resuscitation. Physicians must now rely on a limodal approach and should refrain from the temptation of establishing prognosis earlier than 72 hours (1). Most recently, practical recommendations and a large postresuscitation trial on temperature management further delayed prognostication to 72 hours after reestablishing normothermia (2,3). As a con sequence, treating physicians, and families alike, face a painful stall in a possible end-of-life decision-making process. Recently, electroencephalogram has been investigated with growing interest for its potential role in providing clues to positive prognostication. In the contrary, in the multimodal approach to patients who do not regain consciousness, clinical
T
*See also p. 159. Key Words: cardiac arrest; neurologic outcome; postresuscitation care; prognostication; target temperature management Dr. Pellis lectured for Bard Medical. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM .0000000000000661
Critical Care Medicine
evaluation, somatosensory evoked potentials, biomarkers, and neuroimaging are all more reliable as negative than positive predictors (2,4). Another element that contributes to make extremely attrac tive the use of electroencephalogram is the timing with which it becomes informative. Despite hypothermia and ongoing sedation, several studies have highlighted early patterns of electroencephalogram activity associated with good outcome (5-7). In particular, a continuous background, even if slow, and reactivity should strongly reinforce motivation in con muttinuing aggressive postresuscitation care. The ramifications of the contribution of electroencephalogram as an early positive predictor should not be underestimated because in the first days the prevailing causes of death are postresuscitation myo cardial dysfunction and multiorgan failure (8). In this context, for example, electroencephalogram could positively contribute to the discussion on escalation of care such as with mechanical support. On the other hand, a perceived poor expectation may lead to early limitation of care, thus contributing to the main cause of death after resuscitation, which is neurological injury. Early positive indicators may counterbalance lurking skepti cism toward resuscitated patients. Yet, the available data so far suffered from the limitations deriving from low numbers and the retrospective nature of some studies (5-7, 9). In this scenario, Tjepkema-Cloostermans et al (10) should be complimented for presenting the largest prospective study so far on electroencephalogram for early prognostication. The authors analyzed a 5-minute section of a continuous electroencephalogram recording at 12 and 24 hours after cardiac arrest in 142 patients. A positive prediction w w w .c c m jo u r n a l.o r g
251
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was possible as early as 12 hours in patients with normally or diffusely slow electroencephalogram patterns (sensitivity of 56% and a specificity of 96%). Interestingly, the 12-hour mark was more informative than the 24 hours, bearing a posi tive likelihood ratio of 14 (i.e., often conclusive results) and positive predicted value of 93 (Cl, 78-99). Instead at 24 hours, other electroencephalogram patterns were predictive of poor outcome (sensitivity, 48%; specificity, 100%) (10). The authors provide a pragmatic approach to a heterogenous cardiac arrest population—i.e., in- and out-of-hospital car diac arrest from cardiac and noncardiac causes—as commonly encountered in daily ICU practice. An effort is made to overcome other shortcomings of previous studies by setting a clear tim ing for electroencephalogram analysis. A fix reference timepoint is of key importance. Although many often rely on continuous electroencephalogram, it is not clear at which exact point in time electroencephalogram readings were analyzed, thus hampering comparison because electroencephalogram activity changes over time and leaving the influence of temperature on brain activity a possible confounder. By analyzing electroencephalogram at 12 and 24 hours, all patients were at 33°C of core temperature. In addition to what previously reported by others, there has been an attempt to quantify sedatives. The impact of sedatives on electroencephalogram has been an important limitation so far and matter of concern in attempting comparisons. Despite in this study, the precise dose being received by the patient at the time of electroencephalogram evaluation is unknown, follow ing a conservatory approach the authors were able to provide the maximum dose of medication during the first 24 hours after cardiac arrest (10). Most of the patients were treated with pro pofol or a combination of propofol and midazolam. Although influencing electroencephalogram patterns, sedatives did not affect the predictive values of the specific electroencephalogram patterns. Thus again Tjepkema-Cloostermans et al (10) were able to provide a framework to ensure reproducibility. Among other strengths, the study relies on a solid endpoint: blind evaluation of best cerebral performance category during the first 6 months. Electroencephalogram were also analyzed by two blinded reviewers, with a substantial interobserver agreement rate (k = 0.66 and 0.7). However, studies on prognostication all share an inheriting risk of a self fulfilling prophecy. In this instance, treating physi cians were not blinded to electroencephalograms. Efforts were made to standardize limitation of care, and physicians were encouraged not to rely on electroencephalogram for prog nostication or treatment decisions. Yet, once again a study on prognostication cannot rule out such bias. Moreover, predictive tools, such as electroencephalogram, still suffer from insufficient international standards. The lack
252
w w w . c c m jo u r n a l. o r g
of a generally accepted electroencephalogram classification system for epileptiform activity and for postanoxic encepha lopathy remains an issue. The authors partially fill the gap with the use of a different nomenclature. For example, a distinction is made between burst suppressions with or without identical bursts, which is reflected by substantial differences in outcome. Yet, additional strength to the results might have been deliv ered by testing for reactivity and anterior-posterior differen tiation. Reactivity, in particular, has been previously described in prospective cohort as promising positive indicator (9). Overall, the study by Tjepkema-Cloostermans et al (10) con tributes to generate momentum and add to the interest on elec troencephalogram as an early predictor of positive and negative outcome. With the growing appreciation of early patterns and reconsidering limitations, such as the effect of sedation, electro encephalogram is a step closer to represent the Holy Grail of tools with which to stratify patients and possibly in the future tailor temperature management and postresuscitation care in general.
REFERENCES 1. Nolan JP, Neumar RW, Adrie C, et al: Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation 2008; 7 9 :350 -37 9 2. Cronberg T, Brizzi M, Liedholm LJ, et al: Neurological prognosti cation after cardiac arrest-recommendations from the Swedish Resuscitation Council. Resuscitation 2013; 8 4 :8 6 7 -8 7 2 3. Nielsen N, Wetterslev J, Cronberg T, et al: Targeted temperature man agement at 33 degrees c versus 36 degrees c after cardiac arrest. N Engl J Med 2013; 3 6 9 :2 1 9 7 -2 2 0 6 . 4. Oddo M, Rossetti AO: Predicting neurological outcome after cardiac arrest. Curr Opin Crit Care 2011; 1 7 :2 5 4 -2 5 9 5. Rundgren M, Rosbn I, Friberg H: Amplitude-integrated EEG (aEEG) predicts outcome after cardiac arrest and induced hypothermia. Intensive Care Med 2006; 3 2 :8 3 6 -8 4 2 6. Cloostermans MC, van Meulen FB, Eertman CJ, et al: Continuous electroencephalography monitoring for early prediction of neurologi cal outcome in postanoxic patients after cardiac arrest: A prospective cohort study. Crit Care Med 201 2; 4 0 :2 8 6 7 -2 8 7 5 7. Crepeau AZ, Rabinstein AA, Fugate JE, et al: Continuous EEG in therapeutic hypothermia after cardiac arrest: Prognostic and clinical value. Neurology 2013; 8 0 :3 3 9 -3 4 4 8. Dragancea I, Rundgren M, Englund E, et al: The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest. Resuscitation 2013; 8 4 :3 3 7 -3 4 2 9. Rossetti AO, Oddo M, Logroscino G, Kaplan PW : Prognostication after cardiac arrest and hypothermia: A prospective study. Ann Neurol 2010; 67:301 -3 0 7 10. Tjepkema-Cloostermans MC, Hofmeijer J, Trof RJ, et al: Electroencephalogram Predicts Outcome in Patients With Postanoxic Coma During Mild Therapeutic Hypothermia. Crit Care Med 2015; 4 3 :1 5 9 -1 6 7
January 2015 • Volume 43 • Number 1
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
neuroproteotion against hypoxia-ischemia. Anesthesiology 2010; 1 1 2 :61 4-6 22 8. Natale G, Cattano D, Abramo A, et al: Morphological evidence that xenon neuroprotects against /V-methyl-DL-aspartic acid-induced dam age in the rat arcuate nucleus: A time-dependent study. Ann N Y Acad Sci 2006; 1 0 7 4 :6 50 -658 9. Campos-Pires R, Armstrong SP, Sebastiani A, et al: Xenon Improves Neurologic Outcome and Reduces Secondary Injury Following Trauma in an In Vivo Model of Traumatic Brain Injury. Crit Care Med 2 0 1 5 ;4 3 :1 4 9 -1 5 8 10. Harris K, Armstrong SP, Campos-Pires R, et al: Neuroprotection against traumatic brain injury by xenon, but not argon, is medi ated by inhibition at the A/-methyl-D-aspartate receptor glycine site. Anesthesiology 2013; 1 1 9 :1 1 3 7 -1 1 4 8 11. Marklund N, Hillered L: Animal modelling of traumatic brain injury in preclinical drug development: Where do we go from here? Br J Pharmacol 2011; 1 6 4 :1 2 0 7 -1 2 2 9 12. Esencan E, Yuksel S, Tosun YB, et al: XENON in medical area: Emphasis on neuroprotection in hypoxia and anesthesia. Med Gas Res 2013; 3:4
Strength by Sheer Numbers: Electroencephalogram Gathers Momentum as a Positive Predictor* Tommaso Pellis, M D Anesthesia, Intensive Care and Emergency Medical Service Santa Maria Degli Angeli Hospital Pordenone, Italy
he introduction of therapeutic hypothermia, and then of the broader concept of temperature management, has profoundly changed the gameplay of prognostica tion after resuscitation. Physicians must now rely on a limodal approach and should refrain from the temptation of establishing prognosis earlier than 72 hours (1). Most recently, practical recommendations and a large postresuscitation trial on temperature management further delayed prognostication to 72 hours after reestablishing normothermia (2,3). As a con sequence, treating physicians, and families alike, face a painful stall in a possible end-of-life decision-making process. Recently, electroencephalogram has been investigated with growing interest for its potential role in providing clues to positive prognostication. In the contrary, in the multimodal approach to patients who do not regain consciousness, clinical
T
*See also p. 159. Key Words: cardiac arrest; neurologic outcome; postresuscitation care; prognostication; target temperature management Dr. Pellis lectured for Bard Medical. Copyright © 2014 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins DOI: 10.1097/CCM .0000000000000661
Critical Care Medicine
evaluation, somatosensory evoked potentials, biomarkers, and neuroimaging are all more reliable as negative than positive predictors (2,4). Another element that contributes to make extremely attrac tive the use of electroencephalogram is the timing with which it becomes informative. Despite hypothermia and ongoing sedation, several studies have highlighted early patterns of electroencephalogram activity associated with good outcome (5-7). In particular, a continuous background, even if slow, and reactivity should strongly reinforce motivation in con muttinuing aggressive postresuscitation care. The ramifications of the contribution of electroencephalogram as an early positive predictor should not be underestimated because in the first days the prevailing causes of death are postresuscitation myo cardial dysfunction and multiorgan failure (8). In this context, for example, electroencephalogram could positively contribute to the discussion on escalation of care such as with mechanical support. On the other hand, a perceived poor expectation may lead to early limitation of care, thus contributing to the main cause of death after resuscitation, which is neurological injury. Early positive indicators may counterbalance lurking skepti cism toward resuscitated patients. Yet, the available data so far suffered from the limitations deriving from low numbers and the retrospective nature of some studies (5-7, 9). In this scenario, Tjepkema-Cloostermans et al (10) should be complimented for presenting the largest prospective study so far on electroencephalogram for early prognostication. The authors analyzed a 5-minute section of a continuous electroencephalogram recording at 12 and 24 hours after cardiac arrest in 142 patients. A positive prediction w w w .c c m jo u r n a l.o r g
251
Editorials
was possible as early as 12 hours in patients with normally or diffusely slow electroencephalogram patterns (sensitivity of 56% and a specificity of 96%). Interestingly, the 12-hour mark was more informative than the 24 hours, bearing a posi tive likelihood ratio of 14 (i.e., often conclusive results) and positive predicted value of 93 (Cl, 78-99). Instead at 24 hours, other electroencephalogram patterns were predictive of poor outcome (sensitivity, 48%; specificity, 100%) (10). The authors provide a pragmatic approach to a heterogenous cardiac arrest population—i.e., in- and out-of-hospital car diac arrest from cardiac and noncardiac causes—as commonly encountered in daily ICU practice. An effort is made to overcome other shortcomings of previous studies by setting a clear tim ing for electroencephalogram analysis. A fix reference timepoint is of key importance. Although many often rely on continuous electroencephalogram, it is not clear at which exact point in time electroencephalogram readings were analyzed, thus hampering comparison because electroencephalogram activity changes over time and leaving the influence of temperature on brain activity a possible confounder. By analyzing electroencephalogram at 12 and 24 hours, all patients were at 33°C of core temperature. In addition to what previously reported by others, there has been an attempt to quantify sedatives. The impact of sedatives on electroencephalogram has been an important limitation so far and matter of concern in attempting comparisons. Despite in this study, the precise dose being received by the patient at the time of electroencephalogram evaluation is unknown, follow ing a conservatory approach the authors were able to provide the maximum dose of medication during the first 24 hours after cardiac arrest (10). Most of the patients were treated with pro pofol or a combination of propofol and midazolam. Although influencing electroencephalogram patterns, sedatives did not affect the predictive values of the specific electroencephalogram patterns. Thus again Tjepkema-Cloostermans et al (10) were able to provide a framework to ensure reproducibility. Among other strengths, the study relies on a solid endpoint: blind evaluation of best cerebral performance category during the first 6 months. Electroencephalogram were also analyzed by two blinded reviewers, with a substantial interobserver agreement rate (k = 0.66 and 0.7). However, studies on prognostication all share an inheriting risk of a self fulfilling prophecy. In this instance, treating physi cians were not blinded to electroencephalograms. Efforts were made to standardize limitation of care, and physicians were encouraged not to rely on electroencephalogram for prog nostication or treatment decisions. Yet, once again a study on prognostication cannot rule out such bias. Moreover, predictive tools, such as electroencephalogram, still suffer from insufficient international standards. The lack
252
w w w . c c m jo u r n a l. o r g
of a generally accepted electroencephalogram classification system for epileptiform activity and for postanoxic encepha lopathy remains an issue. The authors partially fill the gap with the use of a different nomenclature. For example, a distinction is made between burst suppressions with or without identical bursts, which is reflected by substantial differences in outcome. Yet, additional strength to the results might have been deliv ered by testing for reactivity and anterior-posterior differen tiation. Reactivity, in particular, has been previously described in prospective cohort as promising positive indicator (9). Overall, the study by Tjepkema-Cloostermans et al (10) con tributes to generate momentum and add to the interest on elec troencephalogram as an early predictor of positive and negative outcome. With the growing appreciation of early patterns and reconsidering limitations, such as the effect of sedation, electro encephalogram is a step closer to represent the Holy Grail of tools with which to stratify patients and possibly in the future tailor temperature management and postresuscitation care in general.
REFERENCES 1. Nolan JP, Neumar RW, Adrie C, et al: Post-cardiac arrest syndrome: epidemiology, pathophysiology, treatment, and prognostication. A Scientific Statement from the International Liaison Committee on Resuscitation; the American Heart Association Emergency Cardiovascular Care Committee; the Council on Cardiovascular Surgery and Anesthesia; the Council on Cardiopulmonary, Perioperative, and Critical Care; the Council on Clinical Cardiology; the Council on Stroke. Resuscitation 2008; 7 9 :350 -37 9 2. Cronberg T, Brizzi M, Liedholm LJ, et al: Neurological prognosti cation after cardiac arrest-recommendations from the Swedish Resuscitation Council. Resuscitation 2013; 8 4 :8 6 7 -8 7 2 3. Nielsen N, Wetterslev J, Cronberg T, et al: Targeted temperature man agement at 33 degrees c versus 36 degrees c after cardiac arrest. N Engl J Med 2013; 3 6 9 :2 1 9 7 -2 2 0 6 . 4. Oddo M, Rossetti AO: Predicting neurological outcome after cardiac arrest. Curr Opin Crit Care 2011; 1 7 :2 5 4 -2 5 9 5. Rundgren M, Rosbn I, Friberg H: Amplitude-integrated EEG (aEEG) predicts outcome after cardiac arrest and induced hypothermia. Intensive Care Med 2006; 3 2 :8 3 6 -8 4 2 6. Cloostermans MC, van Meulen FB, Eertman CJ, et al: Continuous electroencephalography monitoring for early prediction of neurologi cal outcome in postanoxic patients after cardiac arrest: A prospective cohort study. Crit Care Med 201 2; 4 0 :2 8 6 7 -2 8 7 5 7. Crepeau AZ, Rabinstein AA, Fugate JE, et al: Continuous EEG in therapeutic hypothermia after cardiac arrest: Prognostic and clinical value. Neurology 2013; 8 0 :3 3 9 -3 4 4 8. Dragancea I, Rundgren M, Englund E, et al: The influence of induced hypothermia and delayed prognostication on the mode of death after cardiac arrest. Resuscitation 2013; 8 4 :3 3 7 -3 4 2 9. Rossetti AO, Oddo M, Logroscino G, Kaplan PW : Prognostication after cardiac arrest and hypothermia: A prospective study. Ann Neurol 2010; 67:301 -3 0 7 10. Tjepkema-Cloostermans MC, Hofmeijer J, Trof RJ, et al: Electroencephalogram Predicts Outcome in Patients With Postanoxic Coma During Mild Therapeutic Hypothermia. Crit Care Med 2015; 4 3 :1 5 9 -1 6 7
January 2015 • Volume 43 • Number 1
Copyright of Critical Care Medicine is the property of Lippincott Williams & Wilkins and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
