- Email: [email protected]
Can Mismatch Negativity Reduce Uncertainty in the Prediction of Awakening From Coma During Extracorporeal Membrane Oxygenation?
CASE REPORT
Can Mismatch Negativity Reduce Uncertainty in the Prediction of Awakening From Coma During Extracorporeal Membrane Oxygenation? Rosendo A. Rodriguez, MD, PhD,* Michel Shamy, MD,† Dar Dowlatshahi, MD, PhD,†§ and Howard J. Nathan, MD‡
E
XTRACORPOREAL MEMBRANE OXYGENATION (ECMO) has been associated with a risk of neurologic injury that may be related to the precipitating event or to the ECMO therapy itself.1–3 In ECMO patients who progress into coma in particular, the use of extracorporeal circulation serves as a confounder because it increases the uncertainty surrounding the prediction of awakening and the potential for neurologic recovery.1,2 This uncertainty may lead to inappropriate decisions about continuation or withdrawal of life support even in cases in which the patient’s cardiopulmonary function has been re-established under ECMO.2,4 Auditory event-related potentials (ERPs) are neurophysiologic techniques that have been associated with higher-level cognitive functions, such as arousal or attention,5–7 and their recording during coma may identify those patients whose auditory preattentive memory remains active.8 Recent studies8–14 have documented that the mismatch negativity (MMN), an electrophysiologic marker of the auditory ERPs, can offer a valuable addition to routine clinical examination and other neurophysiologic methods in the early assessment and prediction of awakening from coma. The presence of MMN in the course of coma indicates the likelihood of awakening, and it may encourage the continuation of life support in those patients for whom clinical prognosis is uncertain. This report describes 2 comatose patients during ECMO, whose continuation of life support was questioned because of the uncertainty of their neurologic prognosis, and results of the MMN and other auditory evoked potentials (AEPs; brainstem and middlelatency) informed medical decisions about the continuation or withdrawal of intensive care after the patient’s cardiopulmonary function had improved under ECMO.
least 12 hours, her Glasgow coma score (GCS) remained 6, suggestive of severe neurologic dysfunction. A noncontrast head CT scan did not show any signs of stroke or intracranial hemorrhage. Then, a severe, diffuse, hypoxic-ischemic encephalopathy was diagnosed. In considering that the results of the head CT scan did not support the clinical unresponsiveness of this patient and that the residual effects of previous sedation associated with her metabolic derangements could be potential confounders, neurologic prognosis remained doubtful. Because of this uncertainty, continuation of life support was questioned. As a result, consent from family members was obtained to perform AEPs. The recording, analysis, and interpretation of the AEPs have been described elsewhere.8–16 Table 1 summarizes the parameters used for delivering the stimuli and recording the AEPs in these 2 cases. Performed off-sedation (12 hours with no sedation), the AEPs revealed normal bilateral configurations of brainstem (waves I, III, and V) and middle-latency (Pa wave) AEPs (Fig 1A and 1B). The ERPs were obtained in the same session using the classic odd-ball paradigm technique,6,7 in which an occasional acoustic stimulus deviating in duration (“deviant”) was interspersed in a train of identical auditory stimuli (“standard”).9,12 The most distinctive components in the standard and deviant ERPs were identified, including the first negative wave (called N100) in the latency range between 100 and 150 ms. The MMN was obtained by subtracting the single standard averaged waveform from the single deviant averaged waveform, and the resultant negative wave in the range between 150 to 250 ms was defined as the MMN.6 The ERPs in this case showed clearly defined N100 waves in both standard and deviant recordings, and their difference waveforms (Fig 1C) showed a reproducible broad negative wave identified as the MMN. Although the results of the preserved brainstem and middlelatency AEPs indicated an intact auditory pathway, the detection of the MMN suggested residual higher order function. As a consequence, a decision was made to continue circulatory support by weaning the patient off ECMO and providing support through an intra-aortic balloon pump (IABP). In the next 4 days, cardiac function improved significantly, and the patient was weaned off the IABP. After sedation
CASE REPORT
Case 1 A 38-year-old woman with deep vein thrombosis in the right leg and previous bariatric surgery developed shortness of breath and was admitted in respiratory distress and cardiogenic shock. A lung computerized tomography (CT) scan showed massive pulmonary embolism and a cystic lesion in the right lung. Cardiac catheterization found normal coronary circulation with multiple areas of akinesis (cardiac output: 40%) suggestive of severe right and left ventricular dysfunction and no significant embolus in the main branches of the pulmonary arteries. During the procedure, the patient developed cardiac arrest due to ventricular fibrillation. Cardiopulmonary resuscitation was prolonged (20 minutes), and she was transferred urgently to the operating room for initiation of ECMO. After 6 days on ECMO, cardiac function improved slowly but the patient remained unresponsive to external stimulation. After the discontinuation of sedatives for at
From the *Department of Medicine, †Division of Neurology, and ‡Department of Anaesthesia, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada; and the §Ottawa Hospital Research Institute, Ottawa, ON, Canada. Address reprint requests to Rosendo A. Rodriguez, MD, PhD, Department of Medicine, The Ottawa Hospital, General Campus, OBDC, Room L-2217, Box 180, 501 Smyth Road, Ottawa, ON, K1H, 8L6 Canada. E-mail: [email protected] © 2014 Elsevier Inc. All rights reserved. 1053-0770/2602-0033$36.00/0 http://dx.doi.org/10.1053/j.jvca.2014.09.019 Key words: coma, extracorporeal membrane oxygenation, auditory evoked potentials, mismatch negativity, event-related potentials, awakening
Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2014: pp ]]]–]]]
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RODRIGUEZ ET AL
Table 1. Stimulation and Recording Parameters of Brainstem, Middle-Latency Auditory Evoked Potentials and Event-Related Potentials Parameter
Stimulation
Recording
Brainstem AEP
Stimulus Frequency Polarity Duration Rise/Fall times Intensity Rate Proportion Presentation Delay (ms) Band-pass filters Time window Number of averages per trial Number of trials Artifact rejection level
click wide þ/100 ms n/a 80 dB nHL 11.3/s 100% Unilateral 0 100-3000 Hz 15 ms 2,000 2 90%
Middle-Latency AEPs
click wide þ/100 ms n/a 80 dB nHL 11.3/s 100% Unilateral 0 10-3000 Hz 90 ms 1,500 2 90%
Event-Related Potentials
Standard Tone-burst 800 Hz
Deviant Tone-burst 800 Hz
75 ms 5 ms 80 dB nHL 1.6/s 85% Bilateral 0 1-150 Hz 500 ms 850 2 90%
30 ms 5 ms 80 dB nHL 1.6/s 15% Bilateral 0 1-150 Hz 500 ms 150 2 90%
Abbreviations: AEP, auditory evoked potentials; n/a, not applicable; þ, condensation; –, rarefaction.
was discontinued (5 days after AEP examination), the patient showed spontaneous eye opening and visible and consistent motor and verbal responses to commands. Clinical examination indicated that the patient was oriented and capable of communicating verbally with no focal neurologic deficits identified (GCS: 15).
Case 2 A 61-year-old man with a history of type-2 diabetes and hypertension was admitted for an elective angiogram after an acute coronary syndrome. During the procedure, he developed cardiac arrest due to ventricular fibrillation. Cardiopulmonary resuscitation was prolonged ( 20 min), and an IABP was inserted. This was followed by stenting of the distal and mid-right and left main coronary arteries but it was unsuccessful for the mid-left anterior descending artery. Because of persistent cardiogenic shock, he was taken urgently for ECMO. After 24 hours, cardiac function improved, and it was decided to discontinue ECMO and maintain circulatory support via IABP and inotropes. Following a 24-hour period without sedation, the patient remained minimally responsive to external stimulation (GCS: 6) and a noncontrast head CT scan did not reveal stroke or intracranial hemorrhage. At this point, the patient’s neurologic status was consistent with a severe, diffuse, hypoxic-ischemic encephalopathy. Consent from family members was obtained to perform AEPs after 24 hours off sedation. This examination showed the presence of bilateral brainstem AEPs but absence of Pa waves bilaterally (Fig 2A and 2B). The N100 waves of the ERPs for both standard and deviant stimuli were absent and no MMN wave was identified in the subtracted waveform (Fig 2C). An EEG showed a burst suppression pattern with 2-second high amplitude burst activity followed by 5 to 6 seconds of suppression and no background activity. In the next 72 hours, his neurologic status deteriorated and a new AEP recording showed absence of waves III and V of the brainstem AEPs. Neurologic examination (GCS: 4) showed absence of corneal, pupillary, oculocephalic, oculovestibular (cold caloric test: negative), and gag reflexes. His overall clinical course was discussed with family members, and it was agreed to prioritize comfort measures. The patient died within 24 hours of extubation. DISCUSSION
Caring for the unconscious and unresponsive ECMOsupported patient after resuscitation from prolonged cardiac arrest due to severe cardiac or lung injury presents physicians,
family members, and the healthcare system with major challenges. The limited ability to determine to what degree a patient may recover consciousness and brain function impairs appropriate decision-making.13,17,18 In the present two ECMO patients, awakening was delayed and there were no reliable signs at an early stage that would have indicated the likelihood for recovery of consciousness and neurologic function. The results of AEPs in these patients were felt to decrease uncertainty about the decision to continue or withdraw support. Although brainstem AEPs were preserved in both patients in the course of coma, only 1 displayed intact MMN and bilateral Pa waves before awakening and these findings encouraged continuation of care. The persistence of brainstem and middle-latency AEPs in this patient supported the assumption that intact functioning of the brainstem and cortical areas involved in the generation of AEPs made the recovery of consciousness more likely. The fact that MMN was detected 5 days before regaining consciousness provided further evidence that recording of MMN early in the course of coma can predict awakening.11,14 In contrast, the initial absence of both MMN and Pa waves in patient 2 and the extended absence of waves III and V in the brainstem AEPs suggested poor prognosis, and this was supported by the clinical examination and EEG. In light of all of these factors, the clinical care team and the family elected to withdraw care in patient 2. Several studies8–14,18 have shown that MMN is an AEP waveform with a high specificity to predict the return of consciousness in patients with coma from different etiologies. A recent pooled analysis of cases from 5 publications14 determined that the presence of MMN had 91% specificity for predicting awakening during coma but 38% sensitivity for predicting poor outcome (PPV: 88% and NPV: 46%). Fisher et al9 reported that 30 of their 33 comatose patients (GCS: o8) who showed MMN regained consciousness 6.3 ⫾ 4 days after AEP examination. Their study found that Pa waves also were highly specific, but brainstem AEPs were not. Although all their patients with MMN displayed Pa waves, the Pa wave was normal in only 9 patients, delayed in 16 and with small
AWAKENING AFTER COMA IN ECMO
3
Fig 1. Auditory evoked potentials (AEPs) recorded in the course of coma 5 days before awakening (case 1). Acoustic stimuli for all modalities of AEPs were delivered through insert earphones. Gold-plated clip and cup electrodes recorded the electroencephalogram from the scalp between A1 and A2 referred to Fz and Cz grounded to the forehead. Latency and amplitude measurements included waves I, III, and V for the brainstem and Pa wave for the middle-latency AEPs. All components of the brainstem AEPs (A) were preserved in this case. Peak latencies for waves I, III, and V were 2.5, 4.8, and 6.8 ms (amplitudes: 0.22, 0.30, and 0.75 lV) on the left side and 2.7, 4.8, and 7.0 ms (amplitudes: 0.30, 0.32, 0.65 lV) on the right side. Recording of the middle-latency AEPs (panel B) showed a reproducible Pa wave (black arrow) with average peak latency of 40 ms (Na-Pa: 0.40 lV) and 42 ms (Na-Pa: 0.38 lV), respectively. Auditory event-related potentials (ERPs) to bilateral standard and deviant stimuli (panel C) showed a reproducible N100 wave (unfilled triangle) with an average latency of 102 and 105 ms (amplitudes: 2.0 and 2.2 lV), respectively. The subtracted waveform (deviant ERPs minus standard ERPs) displayed a broad-negative wave (C, left-upper) identified as mismatch negativity (filled triangle) with an average latency of 218 ms (amplitude: 4.4 lV). The 4 overlapped traces in the subtracted responses represent the differences between standard and deviant ERPs for each pair of electrodes. Notice the different scales for brainstem, middle latency, and ERPs.
amplitude in 8 patients. In a recent study of 17 comatose patients after cardiac arrest or cardiogenic shock,12 MMN was present early in the course of coma in all 7 patients who awakened and in only 2 of the 10 who did not regain consciousness. In addition, all awakened patients had intact brainstem and middle-latency AEPs, but in nonawakened patients, Pa waves and brainstem AEPs were detected in 50% and 90% of the patients, respectively. Although the absence of
brainstem and middle-latency AEPs are very good markers of poor outcome,9 the presence of middle-latency AEPs is a better predictor of awakening than brainstem AEPs.9–12 However, the value of the MMN as a predictor of awakening is even higher than middle-latency AEPs.9–12 Although the detection of MMN may indicate the likelihood for awakening, it currently is unknown which characteristics of the MMN (ie, latency, amplitude) would be associated with a
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RODRIGUEZ ET AL
Fig 2. Auditory evoked potentials (AEPs) recorded 72 hours after coma onset (case 2). The waves I, III, and V of the brainstem AEPs (A) were identified clearly with peak latencies of 2.5, 5.0, and 7.0 ms (amplitude: 0.14, 0.21, and 0.48 lV) on the left side and 2.3, 4.8, and 6.8 ms (amplitude: 0.12, 0.15, and 0.36 lV) on the right side. Recording of middle-latency AEPs (B) did not show Pa waves and the auditory eventrelated potentials (ERPs) to standard and deviant stimuli did not demonstrate N100 waves (C). The subtracted response between both waveforms did not reveal any mismatch negativity. The 4 overlapped traces in the subtracted responses represent differences between standard and deviant ERPs for each pair of electrodes. Notice the different scales for brainstem, middle latency, and ERPs.
complete functional recovery. This requires further investigation. In addition, since the extension and type of the brain injury are related to the probability of awakening, the cause of coma may affect the rate of detecting MMN.14,18 Traumatic and postoperative etiologies of coma are associated with the greatest chance of awakening, whereas the lowest rate occurs with anoxia and metabolic encephalopathy.14 In the metaanalysis by Daltrozzo et al,14 the estimated odds ratio for predicting awakening by the MMN in coma due to traumatic brain injury was 2.81, and for anoxic brain injury, it was only 0.23. As documented in the authors’ previous research12 and as illustrated in case 1, the presence of MMN in comatose patients
makes the recovery of consciousness more likely. Should its accuracy for predicting awakening be further demonstrated in future studies, MMN could be highly useful as a tool to determine whether comatose patients will awaken before the clinical exam becomes reliable. Thus, it may prevent the occurrence of a premature termination of cardiorespiratory support. To achieve its best predictive value, MMN recordings need to be performed off sedation. However, in cases of impaired metabolism and previously prolonged sedation, the potential residual effects of sedatives on the amplitude of the MMN should be taken into account, and then the possibility of repeating the test could be considered. In that they are easy to perform at the patient’s bedside, are inexpensive to obtain, and
5
AWAKENING AFTER COMA IN ECMO
do not require active attention or a behavioral response from the subject, these neurophysiologic markers can complement
the information provided by other modalities to better prognosticate outcome in comatose patients.
REFERENCES 1. Massetti M, Gaudino M, De Paulis S, et al: Extracorporeal membrane oxygenation for resuscitation and cardiac arrest management. Heart Fail Clin 10:S85-S93, 2014 (suppl) 2. Matteen FJ, Muralidharan R, Shinohara RT, et al: Neurological injury in adults treated with extracorporeal membrane oxygenation. Arch Neurol 68:1543-1549, 2011 3. Lan C, Tsai PR, Chen YS, et al: Prognostic factors for adult patients receiving extracorporeal membrane oxygenation as mechanical circulatory support—A 14-year experience at a medical center. Artif Organs 34:E59-E64, 2010 4. Rodriguez RA, Nair S, Bussière M, et al: Long-lasting functional disabilities in patients who recover from coma after cardiac operations. Ann Thorac Surg 95:884-890, 2013 5. Rodriguez RA: Human auditory evoked potentials in the assessment of brain function during major cardiovascular surgery. Semin Cardiothorac Vasc Anesth 8:85-99, 2004 6. Picton TW, Bentin S, Berg P, et al: Guidelines for using human event-related potentials to study cognition: recording standards and publication criteria. Psychophysiology 37:127-152, 2000 7. Näätänen R: The mismatch negativity: A powerful tool for cognitive neuroscience. Ear Hear 16:6-18, 1995 8. Vanhaudenhuyse A, Laureys S, Perrin F: Cognitive event-related potentials in comatose and post-comatose states. Neurocrit Care 8: 262-270, 2008 9. Fischer C, Morlet D, Bouchet P, et al: Mismatch negativity and late auditory evoked potentials in comatose patients. Clinical Neurophysiol 110:1601-1610, 1999
10. Fischer C, Morlet D, Giard MH: Mismatch negativity and N100 in comatose patients. Audiol Neurootol 5:192-197, 2000 11. Fischer C, Luauté J, Némoz C, et al: Improved prediction of awakening or nonawakening from severe anoxic coma using tree-based classification analysis. Crit Care Med 34:1520-1524, 2006 12. Rodriguez RA, Boussière M, Froeschl M, et al: Auditory evoked potentials during coma: Do they improve our prediction of awakening in comatose patients? J Crit Care 29:93-100, 2014 13. Friberg H, Cronberg T: Prognostication after cardiac arrest. Best Pract Res Clin Anaesthesiol 27:359-372, 2013 14. Daltrozzo J, Wioland N, Mutschler V, et al: Predicting coma and other low responsive patients outcome using event-related brain potentials: A meta-analysis. Clin Neurophysiol 118: 606-614, 2007 15. Chiappa KH: Methodology and interpretation of brainstem evoked potentials, in Chiappa KH (ed). Evoked Potentials in Clinical Medicine. New York, Raven Press, 1983, pp. 105-323 16. Spehlmann H: The middle latency auditory evoked potentials, in Spehlmann R (ed). Evoked Potential Primer. Visual, Auditory and Somatosensory Evoked Potentials in Clinical Diagnosis. Boston, Butterworth Publishers, 1985, pp. 240-251 17. Young GB: Outcome after cardiac arrest: Are the feet of our predictors made of clay? Resuscitation 84:1300-1301, 2013 18. Van der Stelt O, van Boxtel GJ: Auditory P300 and mismatch negativity in comatose states. Clin Neurophysiol 119: 2172-2174, 2008
Can Mismatch Negativity Reduce Uncertainty in the Prediction of Awakening From Coma During Extracorporeal Membrane Oxygenation? Rosendo A. Rodriguez, MD, PhD,* Michel Shamy, MD,† Dar Dowlatshahi, MD, PhD,†§ and Howard J. Nathan, MD‡
E
XTRACORPOREAL MEMBRANE OXYGENATION (ECMO) has been associated with a risk of neurologic injury that may be related to the precipitating event or to the ECMO therapy itself.1–3 In ECMO patients who progress into coma in particular, the use of extracorporeal circulation serves as a confounder because it increases the uncertainty surrounding the prediction of awakening and the potential for neurologic recovery.1,2 This uncertainty may lead to inappropriate decisions about continuation or withdrawal of life support even in cases in which the patient’s cardiopulmonary function has been re-established under ECMO.2,4 Auditory event-related potentials (ERPs) are neurophysiologic techniques that have been associated with higher-level cognitive functions, such as arousal or attention,5–7 and their recording during coma may identify those patients whose auditory preattentive memory remains active.8 Recent studies8–14 have documented that the mismatch negativity (MMN), an electrophysiologic marker of the auditory ERPs, can offer a valuable addition to routine clinical examination and other neurophysiologic methods in the early assessment and prediction of awakening from coma. The presence of MMN in the course of coma indicates the likelihood of awakening, and it may encourage the continuation of life support in those patients for whom clinical prognosis is uncertain. This report describes 2 comatose patients during ECMO, whose continuation of life support was questioned because of the uncertainty of their neurologic prognosis, and results of the MMN and other auditory evoked potentials (AEPs; brainstem and middlelatency) informed medical decisions about the continuation or withdrawal of intensive care after the patient’s cardiopulmonary function had improved under ECMO.
least 12 hours, her Glasgow coma score (GCS) remained 6, suggestive of severe neurologic dysfunction. A noncontrast head CT scan did not show any signs of stroke or intracranial hemorrhage. Then, a severe, diffuse, hypoxic-ischemic encephalopathy was diagnosed. In considering that the results of the head CT scan did not support the clinical unresponsiveness of this patient and that the residual effects of previous sedation associated with her metabolic derangements could be potential confounders, neurologic prognosis remained doubtful. Because of this uncertainty, continuation of life support was questioned. As a result, consent from family members was obtained to perform AEPs. The recording, analysis, and interpretation of the AEPs have been described elsewhere.8–16 Table 1 summarizes the parameters used for delivering the stimuli and recording the AEPs in these 2 cases. Performed off-sedation (12 hours with no sedation), the AEPs revealed normal bilateral configurations of brainstem (waves I, III, and V) and middle-latency (Pa wave) AEPs (Fig 1A and 1B). The ERPs were obtained in the same session using the classic odd-ball paradigm technique,6,7 in which an occasional acoustic stimulus deviating in duration (“deviant”) was interspersed in a train of identical auditory stimuli (“standard”).9,12 The most distinctive components in the standard and deviant ERPs were identified, including the first negative wave (called N100) in the latency range between 100 and 150 ms. The MMN was obtained by subtracting the single standard averaged waveform from the single deviant averaged waveform, and the resultant negative wave in the range between 150 to 250 ms was defined as the MMN.6 The ERPs in this case showed clearly defined N100 waves in both standard and deviant recordings, and their difference waveforms (Fig 1C) showed a reproducible broad negative wave identified as the MMN. Although the results of the preserved brainstem and middlelatency AEPs indicated an intact auditory pathway, the detection of the MMN suggested residual higher order function. As a consequence, a decision was made to continue circulatory support by weaning the patient off ECMO and providing support through an intra-aortic balloon pump (IABP). In the next 4 days, cardiac function improved significantly, and the patient was weaned off the IABP. After sedation
CASE REPORT
Case 1 A 38-year-old woman with deep vein thrombosis in the right leg and previous bariatric surgery developed shortness of breath and was admitted in respiratory distress and cardiogenic shock. A lung computerized tomography (CT) scan showed massive pulmonary embolism and a cystic lesion in the right lung. Cardiac catheterization found normal coronary circulation with multiple areas of akinesis (cardiac output: 40%) suggestive of severe right and left ventricular dysfunction and no significant embolus in the main branches of the pulmonary arteries. During the procedure, the patient developed cardiac arrest due to ventricular fibrillation. Cardiopulmonary resuscitation was prolonged (20 minutes), and she was transferred urgently to the operating room for initiation of ECMO. After 6 days on ECMO, cardiac function improved slowly but the patient remained unresponsive to external stimulation. After the discontinuation of sedatives for at
From the *Department of Medicine, †Division of Neurology, and ‡Department of Anaesthesia, The Ottawa Hospital and University of Ottawa, Ottawa, ON, Canada; and the §Ottawa Hospital Research Institute, Ottawa, ON, Canada. Address reprint requests to Rosendo A. Rodriguez, MD, PhD, Department of Medicine, The Ottawa Hospital, General Campus, OBDC, Room L-2217, Box 180, 501 Smyth Road, Ottawa, ON, K1H, 8L6 Canada. E-mail: [email protected] © 2014 Elsevier Inc. All rights reserved. 1053-0770/2602-0033$36.00/0 http://dx.doi.org/10.1053/j.jvca.2014.09.019 Key words: coma, extracorporeal membrane oxygenation, auditory evoked potentials, mismatch negativity, event-related potentials, awakening
Journal of Cardiothoracic and Vascular Anesthesia, Vol ], No ] (Month), 2014: pp ]]]–]]]
1
2
RODRIGUEZ ET AL
Table 1. Stimulation and Recording Parameters of Brainstem, Middle-Latency Auditory Evoked Potentials and Event-Related Potentials Parameter
Stimulation
Recording
Brainstem AEP
Stimulus Frequency Polarity Duration Rise/Fall times Intensity Rate Proportion Presentation Delay (ms) Band-pass filters Time window Number of averages per trial Number of trials Artifact rejection level
click wide þ/100 ms n/a 80 dB nHL 11.3/s 100% Unilateral 0 100-3000 Hz 15 ms 2,000 2 90%
Middle-Latency AEPs
click wide þ/100 ms n/a 80 dB nHL 11.3/s 100% Unilateral 0 10-3000 Hz 90 ms 1,500 2 90%
Event-Related Potentials
Standard Tone-burst 800 Hz
Deviant Tone-burst 800 Hz
75 ms 5 ms 80 dB nHL 1.6/s 85% Bilateral 0 1-150 Hz 500 ms 850 2 90%
30 ms 5 ms 80 dB nHL 1.6/s 15% Bilateral 0 1-150 Hz 500 ms 150 2 90%
Abbreviations: AEP, auditory evoked potentials; n/a, not applicable; þ, condensation; –, rarefaction.
was discontinued (5 days after AEP examination), the patient showed spontaneous eye opening and visible and consistent motor and verbal responses to commands. Clinical examination indicated that the patient was oriented and capable of communicating verbally with no focal neurologic deficits identified (GCS: 15).
Case 2 A 61-year-old man with a history of type-2 diabetes and hypertension was admitted for an elective angiogram after an acute coronary syndrome. During the procedure, he developed cardiac arrest due to ventricular fibrillation. Cardiopulmonary resuscitation was prolonged ( 20 min), and an IABP was inserted. This was followed by stenting of the distal and mid-right and left main coronary arteries but it was unsuccessful for the mid-left anterior descending artery. Because of persistent cardiogenic shock, he was taken urgently for ECMO. After 24 hours, cardiac function improved, and it was decided to discontinue ECMO and maintain circulatory support via IABP and inotropes. Following a 24-hour period without sedation, the patient remained minimally responsive to external stimulation (GCS: 6) and a noncontrast head CT scan did not reveal stroke or intracranial hemorrhage. At this point, the patient’s neurologic status was consistent with a severe, diffuse, hypoxic-ischemic encephalopathy. Consent from family members was obtained to perform AEPs after 24 hours off sedation. This examination showed the presence of bilateral brainstem AEPs but absence of Pa waves bilaterally (Fig 2A and 2B). The N100 waves of the ERPs for both standard and deviant stimuli were absent and no MMN wave was identified in the subtracted waveform (Fig 2C). An EEG showed a burst suppression pattern with 2-second high amplitude burst activity followed by 5 to 6 seconds of suppression and no background activity. In the next 72 hours, his neurologic status deteriorated and a new AEP recording showed absence of waves III and V of the brainstem AEPs. Neurologic examination (GCS: 4) showed absence of corneal, pupillary, oculocephalic, oculovestibular (cold caloric test: negative), and gag reflexes. His overall clinical course was discussed with family members, and it was agreed to prioritize comfort measures. The patient died within 24 hours of extubation. DISCUSSION
Caring for the unconscious and unresponsive ECMOsupported patient after resuscitation from prolonged cardiac arrest due to severe cardiac or lung injury presents physicians,
family members, and the healthcare system with major challenges. The limited ability to determine to what degree a patient may recover consciousness and brain function impairs appropriate decision-making.13,17,18 In the present two ECMO patients, awakening was delayed and there were no reliable signs at an early stage that would have indicated the likelihood for recovery of consciousness and neurologic function. The results of AEPs in these patients were felt to decrease uncertainty about the decision to continue or withdraw support. Although brainstem AEPs were preserved in both patients in the course of coma, only 1 displayed intact MMN and bilateral Pa waves before awakening and these findings encouraged continuation of care. The persistence of brainstem and middle-latency AEPs in this patient supported the assumption that intact functioning of the brainstem and cortical areas involved in the generation of AEPs made the recovery of consciousness more likely. The fact that MMN was detected 5 days before regaining consciousness provided further evidence that recording of MMN early in the course of coma can predict awakening.11,14 In contrast, the initial absence of both MMN and Pa waves in patient 2 and the extended absence of waves III and V in the brainstem AEPs suggested poor prognosis, and this was supported by the clinical examination and EEG. In light of all of these factors, the clinical care team and the family elected to withdraw care in patient 2. Several studies8–14,18 have shown that MMN is an AEP waveform with a high specificity to predict the return of consciousness in patients with coma from different etiologies. A recent pooled analysis of cases from 5 publications14 determined that the presence of MMN had 91% specificity for predicting awakening during coma but 38% sensitivity for predicting poor outcome (PPV: 88% and NPV: 46%). Fisher et al9 reported that 30 of their 33 comatose patients (GCS: o8) who showed MMN regained consciousness 6.3 ⫾ 4 days after AEP examination. Their study found that Pa waves also were highly specific, but brainstem AEPs were not. Although all their patients with MMN displayed Pa waves, the Pa wave was normal in only 9 patients, delayed in 16 and with small
AWAKENING AFTER COMA IN ECMO
3
Fig 1. Auditory evoked potentials (AEPs) recorded in the course of coma 5 days before awakening (case 1). Acoustic stimuli for all modalities of AEPs were delivered through insert earphones. Gold-plated clip and cup electrodes recorded the electroencephalogram from the scalp between A1 and A2 referred to Fz and Cz grounded to the forehead. Latency and amplitude measurements included waves I, III, and V for the brainstem and Pa wave for the middle-latency AEPs. All components of the brainstem AEPs (A) were preserved in this case. Peak latencies for waves I, III, and V were 2.5, 4.8, and 6.8 ms (amplitudes: 0.22, 0.30, and 0.75 lV) on the left side and 2.7, 4.8, and 7.0 ms (amplitudes: 0.30, 0.32, 0.65 lV) on the right side. Recording of the middle-latency AEPs (panel B) showed a reproducible Pa wave (black arrow) with average peak latency of 40 ms (Na-Pa: 0.40 lV) and 42 ms (Na-Pa: 0.38 lV), respectively. Auditory event-related potentials (ERPs) to bilateral standard and deviant stimuli (panel C) showed a reproducible N100 wave (unfilled triangle) with an average latency of 102 and 105 ms (amplitudes: 2.0 and 2.2 lV), respectively. The subtracted waveform (deviant ERPs minus standard ERPs) displayed a broad-negative wave (C, left-upper) identified as mismatch negativity (filled triangle) with an average latency of 218 ms (amplitude: 4.4 lV). The 4 overlapped traces in the subtracted responses represent the differences between standard and deviant ERPs for each pair of electrodes. Notice the different scales for brainstem, middle latency, and ERPs.
amplitude in 8 patients. In a recent study of 17 comatose patients after cardiac arrest or cardiogenic shock,12 MMN was present early in the course of coma in all 7 patients who awakened and in only 2 of the 10 who did not regain consciousness. In addition, all awakened patients had intact brainstem and middle-latency AEPs, but in nonawakened patients, Pa waves and brainstem AEPs were detected in 50% and 90% of the patients, respectively. Although the absence of
brainstem and middle-latency AEPs are very good markers of poor outcome,9 the presence of middle-latency AEPs is a better predictor of awakening than brainstem AEPs.9–12 However, the value of the MMN as a predictor of awakening is even higher than middle-latency AEPs.9–12 Although the detection of MMN may indicate the likelihood for awakening, it currently is unknown which characteristics of the MMN (ie, latency, amplitude) would be associated with a
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RODRIGUEZ ET AL
Fig 2. Auditory evoked potentials (AEPs) recorded 72 hours after coma onset (case 2). The waves I, III, and V of the brainstem AEPs (A) were identified clearly with peak latencies of 2.5, 5.0, and 7.0 ms (amplitude: 0.14, 0.21, and 0.48 lV) on the left side and 2.3, 4.8, and 6.8 ms (amplitude: 0.12, 0.15, and 0.36 lV) on the right side. Recording of middle-latency AEPs (B) did not show Pa waves and the auditory eventrelated potentials (ERPs) to standard and deviant stimuli did not demonstrate N100 waves (C). The subtracted response between both waveforms did not reveal any mismatch negativity. The 4 overlapped traces in the subtracted responses represent differences between standard and deviant ERPs for each pair of electrodes. Notice the different scales for brainstem, middle latency, and ERPs.
complete functional recovery. This requires further investigation. In addition, since the extension and type of the brain injury are related to the probability of awakening, the cause of coma may affect the rate of detecting MMN.14,18 Traumatic and postoperative etiologies of coma are associated with the greatest chance of awakening, whereas the lowest rate occurs with anoxia and metabolic encephalopathy.14 In the metaanalysis by Daltrozzo et al,14 the estimated odds ratio for predicting awakening by the MMN in coma due to traumatic brain injury was 2.81, and for anoxic brain injury, it was only 0.23. As documented in the authors’ previous research12 and as illustrated in case 1, the presence of MMN in comatose patients
makes the recovery of consciousness more likely. Should its accuracy for predicting awakening be further demonstrated in future studies, MMN could be highly useful as a tool to determine whether comatose patients will awaken before the clinical exam becomes reliable. Thus, it may prevent the occurrence of a premature termination of cardiorespiratory support. To achieve its best predictive value, MMN recordings need to be performed off sedation. However, in cases of impaired metabolism and previously prolonged sedation, the potential residual effects of sedatives on the amplitude of the MMN should be taken into account, and then the possibility of repeating the test could be considered. In that they are easy to perform at the patient’s bedside, are inexpensive to obtain, and
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AWAKENING AFTER COMA IN ECMO
do not require active attention or a behavioral response from the subject, these neurophysiologic markers can complement
the information provided by other modalities to better prognosticate outcome in comatose patients.
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10. Fischer C, Morlet D, Giard MH: Mismatch negativity and N100 in comatose patients. Audiol Neurootol 5:192-197, 2000 11. Fischer C, Luauté J, Némoz C, et al: Improved prediction of awakening or nonawakening from severe anoxic coma using tree-based classification analysis. Crit Care Med 34:1520-1524, 2006 12. Rodriguez RA, Boussière M, Froeschl M, et al: Auditory evoked potentials during coma: Do they improve our prediction of awakening in comatose patients? J Crit Care 29:93-100, 2014 13. Friberg H, Cronberg T: Prognostication after cardiac arrest. Best Pract Res Clin Anaesthesiol 27:359-372, 2013 14. Daltrozzo J, Wioland N, Mutschler V, et al: Predicting coma and other low responsive patients outcome using event-related brain potentials: A meta-analysis. Clin Neurophysiol 118: 606-614, 2007 15. Chiappa KH: Methodology and interpretation of brainstem evoked potentials, in Chiappa KH (ed). Evoked Potentials in Clinical Medicine. New York, Raven Press, 1983, pp. 105-323 16. Spehlmann H: The middle latency auditory evoked potentials, in Spehlmann R (ed). Evoked Potential Primer. Visual, Auditory and Somatosensory Evoked Potentials in Clinical Diagnosis. Boston, Butterworth Publishers, 1985, pp. 240-251 17. Young GB: Outcome after cardiac arrest: Are the feet of our predictors made of clay? Resuscitation 84:1300-1301, 2013 18. Van der Stelt O, van Boxtel GJ: Auditory P300 and mismatch negativity in comatose states. Clin Neurophysiol 119: 2172-2174, 2008