J Neurocrit Care.  2021 Dec;14(2):63-77. 10.18700/jnc.210016.

Brain injury in extracorporeal cardiopulmonary resuscitation: translational to clinical research

• Wilcox C
• Choi CW
• Cho SM

• KMID: 2523716
• DOI: http://doi.org/10.18700/jnc.210016

Abstract

The addition of extracorporeal membrane oxygenation (ECMO) to conventional cardiopulmonary resuscitation (CPR), termed extracorporeal cardiopulmonary resuscitation (ECPR), has significantly improved survival in selected patient populations. Despite this advancement, significant neurological impairment persists in approximately half of survivors. ECPR represents a potential advancement for patients who experience refractory cardiac arrest (CA) due to a reversible etiology and do not regain spontaneous circulation. Important risk factors for acute brain injury (ABI) in ECPR include lack of perfusion, reperfusion, and altered cerebral autoregulation. The initial hypoxic-ischemic injury caused by no-flow and low-flow states after CA and during CPR is compounded by reperfusion, hyperoxia during ECMO support, and nonpulsatile blood flow. Additionally, ECPR patients are at risk for Harlequin syndrome with peripheral cannulation, which can lead to preferential perfusion of cerebral vessels with deoxygenated blood. Lastly, the oxygenator membrane is prothrombotic and requires systemic anticoagulation. The two competing phenomena result in thrombus formation, hemolysis, and thrombocytopenia, increasing the risk of ischemic and hemorrhagic ABI. In addition to clinical studies, we assessed available ECPR animal models to identify the mechanisms underlying ABI at the cellular level. Standardized multimodal neurological monitoring may facilitate early detection of and intervention for ABI. With the increasing use of ECPR, it is critical to understand the pathophysiology of ABI, its prevention, and the management strategies for improving the outcomes of ECPR. Translational and clinical research focusing on acute ABI immediately after ECMO cannulation and its short- and long-term neurological outcomes are warranted.

Keyword

Extracorporeal membrane oxygenation; Acute brain injuries; Extracorporeal cardiopulmonary resuscitation

Figure

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  Fig. 1. Extracorporeal cardiopulmonary resuscitation (ECPR) model with associated risk factors for brain injury. This figure represents the model for the proposed timing for ECPR. ECPR should be considered if return of spontaneous circulation (ROSC) is not obtained within 10–15 minutes or after 3 shocks for ventricular tachycardia (VT)/ventricular fibrillation (VF). The cannulation goal is <60 minutes. Perfusion is restored after cannulation; however, ROSC may not be achieved until the underlying cause is addressed. The left column shows proposals of brain injury mechanisms during different stages of resuscitation. Flow time refers to duration in minutes. Bystander cardiopulmonary resuscitation (CPR) refers to life support measures initiated by on-scene persons before the arrival of emergency medical services (EMS) or health care agents before the arrival of the code team. ECMO, extracorporeal membrane oxygenation.

• 

  Fig. 2. Components of neurologic complications, monitoring, and prognostication in extracorporeal cardiopulmonary resuscitation (ECPR). NIRS, near-infrared spectroscopy; TCD, transcranial Doppler; CT, computed tomography; NSE, neuron-specific enolase; GFAP, glial fibrillary acidic protein; S100B, calcium-binding protein B; ICAM-5, intercellular adhesion molecule 5; MCP-1/CCL2, monocyte chemoattractant protein 1/chemokine (C-C motif) ligand-2; BDNF, brain-derived neurotrophic factor; SSEP, somatosensory evoked potential; ECMO, extracorporeal membrane oxygenation; EEG, electroencephalography.

Reference

1. Kennedy JH. The role of assisted circulation in cardiac resuscitation. JAMA. 1966; 197:615–8.

2. Phillips SJ, Ballentine B, Slonine D, Hall J, Vandehaar J, Kongtahworn C, et al. Percutaneous initiation of cardiopulmonary bypass. Ann Thorac Surg. 1983; 36:223–5.

3. Mooney MR, Arom KV, Joyce LD, Mooney JF, Goldenberg IF, Von Rueden TJ, et al. Emergency cardiopulmonary bypass support in patients with cardiac arrest. J Thorac Cardiovasc Surg. 1991; 101:450–4.

4. del Nido PJ, Dalton HJ, Thompson AE, Siewers RD. Extracorporeal membrane oxygenator rescue in children during cardiac arrest after cardiac surgery. Circulation. 1992; 86(5 Suppl):II300–4.

5. Mégarbane B, Leprince P, Deye N, Résière D, Guerrier G, Rettab S, et al. Emergency feasibility in medical intensive care unit of extracorporeal life support for refractory cardiac arrest. Intensive Care Med. 2007; 33:758–64.

6. Dembitsky WP, Moreno-Cabral RJ, Adamson RM, Daily PO. Emergency resuscitation using portable extracorporeal membrane oxygenation. Ann Thorac Surg. 1993; 55:304–9.

7. Wollborn J, Siemering S, Steiger C, Buerkle H, Goebel U, Schick MA. Phosphodiesterase-4 inhibition reduces ECLS-induced vascular permeability and improves microcirculation in a rodent model of extracorporeal resuscitation. Am J Physiol Heart Circ Physiol. 2019; 316:H751–61.

8. Liu B, Zhang Q, Liang Y, Zhang Y, Yuan X, Ling J, et al. Extracorporeal membrane oxygenation mitigates myocardial injury and improves survival in porcine model of ventricular fibrillation cardiac arrest. Scand J Trauma Resusc Emerg Med. 2019; 27:82.

9. Yuan XL, Li CS, Zhang Y, Ling JY, Zhang Q, Liang Y, et al. Extracorporeal membrane oxygenation improving survival and alleviating kidney injury in a swine model of cardiac arrest compared to conventional cardiopulmonary resuscitation. Chin Med J (Engl). 2018; 131:1840–8.

10. McCarthy FH, McDermott KM, Kini V, Gutsche JT, Wald JW, Xie D, et al. Trends in U.S. extracorporeal membrane oxygenation use and outcomes: 2002-2012. Semin Thorac Cardiovasc Surg. 2015; 27:81–8.

11. Yam N, McMullan DM. Extracorporeal cardiopulmonary resuscitation. Ann Transl Med. 2017; 5:72.

12. Extracorporeal Life Support Organization. ECMO registry of the Extracorporeal Life Support Organization (ELSO), 2020. Ann Arbor, MI: ELSO Registry;2020.

13. Ahn C, Kim W, Cho Y, Choi KS, Jang BH, Lim TH. Efficacy of extracorporeal cardiopulmonary resuscitation compared to conventional cardiopulmonary resuscitation for adult cardiac arrest patients: a systematic review and meta-analysis. Sci Rep. 2016; 6:34208.

14. Kim SJ, Kim HJ, Lee HY, Ahn HS, Lee SW. Comparing extracorporeal cardiopulmonary resuscitation with conventional cardiopulmonary resuscitation: a meta-analysis. Resuscitation. 2016; 103:106–16.

15. Lamhaut L, Hutin A, Puymirat E, Jouan J, Raphalen JH, Jouffroy R, et al. A pre-hospital Extracorporeal Cardio Pulmonary Resuscitation (ECPR) strategy for treatment of refractory out hospital cardiac arrest: an observational study and propensity analysis. Resuscitation. 2017; 117:109–17.

16. Andersen LW, Holmberg MJ, Berg KM, Donnino MW, Granfeldt A. In-hospital cardiac arrest: a review. JAMA. 2019; 321:1200–10.

17. Hayashi M, Shimizu W, Albert CM. The spectrum of epidemiology underlying sudden cardiac death. Circ Res. 2015; 116:1887–906.

18. Myat A, Song KJ, Rea T. Out-of-hospital cardiac arrest: current concepts. Lancet. 2018; 391:970–9.

19. Myerburg RJ. Cardiac and noncardiac causes of apparent sudden arrhythmic deaths: shadows in a spectrum. Circulation. 2018; 137:2701–4.

20. Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, Callaway CW, Carson AP, et al. Heart disease and stroke statistics: 2020 update: a report from the American Heart Association. Circulation. 2020; 141:e139–596.

21. Nichol G, Thomas E, Callaway CW, Hedges J, Powell JL, Aufderheide TP, et al. Regional variation in out-of-hospital cardiac arrest incidence and outcome. JAMA. 2008; 300:1423–31.

22. Gräsner JT, Herlitz J, Tjelmeland IB, Wnent J, Masterson S, Lilja G, et al. European Resuscitation Council Guidelines 2021: epidemiology of cardiac arrest in Europe. Resuscitation. 2021; 161:61–79.

23. Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of-hospital cardiac arrest and survival rates: systematic review of 67 prospective studies. Resuscitation. 2010; 81:1479–87.

24. Ong ME, Shin SD, Tanaka H, Ma MH, Khruekarnchana P, Hisamuddin N, et al. Pan-Asian Resuscitation Outcomes Study (PAROS): rationale, methodology, and implementation. Acad Emerg Med. 2011; 18:890–7.

25. Ong ME, Shin SD, De Souza NN, Tanaka H, Nishiuchi T, Song KJ, et al. Outcomes for out-of-hospital cardiac arrests across 7 countries in Asia: the Pan Asian Resuscitation Outcomes Study (PAROS). Resuscitation. 2015; 96:100–8.

26. Doctor NE, Ahmad NS, Pek PP, Yap S, Ong ME. The Pan-Asian Resuscitation Outcomes Study (PAROS) clinical research network: what, where, why and how. Singapore Med J. 2017; 58:456–8.

27. The Brain Resuscitation Clinical Trial II Study Group. A randomized clinical trial of calcium entry blocker administration to comatose survivors of cardiac arrest. Design, methods, and patient characteristics. Control Clin Trials. 1991; 12:525–45.

28. Schluep M, Gravesteijn BY, Stolker RJ, Endeman H, Hoeks SE. One-year survival after in-hospital cardiac arrest: a systematic review and meta-analysis. Resuscitation. 2018; 132:90–100.

29. Goto T, Morita S, Kitamura T, Natsukawa T, Sawano H, Hayashi Y, et al. Impact of extracorporeal cardiopulmonary resuscitation on outcomes of elderly patients who had out-of-hospital cardiac arrests: a single-centre retrospective analysis. BMJ Open. 2018; 8:e019811.

30. Richardson AS, Tonna JE, Nanjayya V, Nixon P, Abrams DC, Raman L, et al. Extracorporeal cardiopulmonary resuscitation in adults: interim guideline consensus statement from the Extracorporeal Life Support Organization. ASAIO J. 2021; 67:221–8.

31. Yannopoulos D, Bartos JA, Martin C, Raveendran G, Missov E, Conterato M, et al. Minnesota resuscitation consortium's advanced perfusion and reperfusion cardiac life support strategy for out-of-hospital refractory ventricular fibrillation. J Am Heart Assoc. 2016; 5:e003732.

32. Bartos JA, Grunau B, Carlson C, Duval S, Ripeckyj A, Kalra R, et al. Improved survival with extracorporeal cardiopulmonary resuscitation despite progressive metabolic derangement associated with prolonged resuscitation. Circulation. 2020; 141:877–86.

33. Sakamoto T, Morimura N, Nagao K, Asai Y, Yokota H, Nara S, et al. Extracorporeal cardiopulmonary resuscitation versus conventional cardiopulmonary resuscitation in adults with out-of-hospital cardiac arrest: a prospective observational study. Resuscitation. 2014; 85:762–8.

34. Napp LC, Sanchez Martinez C, Akin M, Garcheva V, Kühn C, Bauersachs J, et al. Use of extracorporeal membrane oxygenation for eCPR in the emergency room in patients with refractory out-of-hospital cardiac arrest. PLoS One. 2020; 15:e0239777.

35. Wang CH, Chou NK, Becker LB, Lin JW, Yu HY, Chi NH, et al. Improved outcome of extracorporeal cardiopulmonary resuscitation for out-of-hospital cardiac arrest: a comparison with that for extracorporeal rescue for in-hospital cardiac arrest. Resuscitation. 2014; 85:1219–24.

36. Kim SJ, Jung JS, Park JH, Park JS, Hong YS, Lee SW. An optimal transition time to extracorporeal cardiopulmonary resuscitation for predicting good neurological outcome in patients with out-of-hospital cardiac arrest: a propensity-matched study. Crit Care. 2014; 18:535.

37. Panchal AR, Bartos JA, Cabañas JG, Donnino MW, Drennan IR, Hirsch KG, et al. Part 3: adult basic and advanced life support: 2020 American Heart Association Guidelines for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2020; 142(16_suppl_2):S366–468.

38. Lott C, Truhlář A, Alfonzo A, Barelli A, González-Salvado V, Hinkelbein J, et al. European Resuscitation Council Guidelines 2021: cardiac arrest in special circumstances. Resuscitation. 2021; 161:152–219.

39. Thiagarajan RR, Brogan TV, Scheurer MA, Laussen PC, Rycus PT, Bratton SL. Extracorporeal membrane oxygenation to support cardiopulmonary resuscitation in adults. Ann Thorac Surg. 2009; 87:778–85.

40. Yannopoulos D, Bartos J, Raveendran G, Walser E, Connett J, Murray TA, et al. Advanced reperfusion strategies for patients with out-of-hospital cardiac arrest and refractory ventricular fibrillation (ARREST): a phase 2, single centre, open-label, randomised controlled trial. Lancet. 2020; 396:1807–16.

41. Pusswald G, Fertl E, Faltl M, Auff E. Neurological rehabilitation of severely disabled cardiac arrest survivors. Part II. Life situation of patients and families after treatment. Resuscitation. 2000; 47:241–8.

42. Migdady I, Rice C, Deshpande A, Hernandez AV, Price C, Whitman GJ, et al. Brain injury and neurologic outcome in patients undergoing extracorporeal cardiopulmonary resuscitation: a systematic review and meta-analysis. Crit Care Med. 2020; 48:e611–9.

43. Writing Group Members, Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, et al. Heart disease and stroke statistics: 2016 update: a report from the American Heart Association. Circulation. 2016; 133:e38–360.

44. Raina KD, Rittenberger JC, Holm MB, Callaway CW. Functional outcomes: one year after a cardiac arrest. Biomed Res Int. 2015; 2015:283608.

45. de Vos R, de Haes HC, Koster RW, de Haan RJ. Quality of survival after cardiopulmonary resuscitation. Arch Intern Med. 1999; 159:249–54.

46. Belohlávek J. Hyperinvasive approach in refractory out-of-hospital cardiac arrest. Prague OHCA study: a randomized clinical trial. Washington, DC: American College of Cardiology;2021.

47. Bol ME, Suverein MM, Lorusso R, Delnoij TS, Brandon Bravo Bruinsma GJ, Otterspoor L, et al. Early initiation of extracorporeal life support in refractory out-of-hospital cardiac arrest: design and rationale of the INCEPTION trial. Am Heart J. 2019; 210:58–68.

48. Sekhon MS, Ainslie PN, Griesdale DE. Clinical pathophysiology of hypoxic ischemic brain injury after cardiac arrest: a "two-hit" model. Crit Care. 2017; 21:90.

49. 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.

50. Madathil RJ, Hira RS, Stoeckl M, Sterz F, Elrod JB, Nichol G. Ischemia reperfusion injury as a modifiable therapeutic target for cardioprotection or neuroprotection in patients undergoing cardiopulmonary resuscitation. Resuscitation. 2016; 105:85–91.

51. Böttiger BW, Krumnikl JJ, Gass P, Schmitz B, Motsch J, Martin E. The cerebral 'no-reflow' phenomenon after cardiac arrest in rats: influence of low-flow reperfusion. Resuscitation. 1997; 34:79–87.

52. Jean WC, Spellman SR, Nussbaum ES, Low WC. Reperfusion injury after focal cerebral ischemia: the role of inflammation and the therapeutic horizon. Neurosurgery. 1998; 43:1382–96.

53. 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.

54. 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.

55. Weiser C, Weihs W, Holzer M, Testori C, Kramer AM, Kment C, et al. Feasibility of profound hypothermia as part of extracorporeal life support in a pig model. J Thorac Cardiovasc Surg. 2017; 154:867–74.

56. Kim YS, Cho YH, Sung K, Ryu JA, Chung CR, Suh GY, et al. Target temperature management may not improve clinical outcomes of extracorporeal cardiopulmonary resuscitation. J Intensive Care Med. 2019; 34:790–6.

57. Kagawa E, Dote K, Kato M, Sasaki S, Oda N, Nakano Y, et al. Do lower target temperatures or prolonged cooling provide improved outcomes for comatose survivors of cardiac arrest treated with hypothermia? J Am Heart Assoc. 2015; 4:e002123.

58. Beylin ME, Perman SM, Abella BS, Leary M, Shofer FS, Grossestreuer AV, et al. Higher mean arterial pressure with or without vasoactive agents is associated with increased survival and better neurological outcomes in comatose survivors of cardiac arrest. Intensive Care Med. 2013; 39:1981–8.

59. Janiczek JA, Winger DG, Coppler P, Sabedra AR, Murray H, Pinsky MR, et al. Hemodynamic resuscitation characteristics associated with improved survival and shock resolution after cardiac arrest. Shock. 2016; 45:613–9.

60. McDonald CI, Fraser JF, Coombes JS, Fung YL. Oxidative stress during extracorporeal circulation. Eur J Cardiothorac Surg. 2014; 46:937–43.

61. Thangappan K, Cavarocchi NC, Baram M, Thoma B, Hirose H. Systemic inflammatory response syndrome (SIRS) after extracorporeal membrane oxygenation (ECMO): incidence, risks and survivals. Heart Lung. 2016; 45:449–53.

62. Vereczki V, Martin E, Rosenthal RE, Hof PR, Hoffman GE, Fiskum G. Normoxic resuscitation after cardiac arrest protects against hippocampal oxidative stress, metabolic dysfunction, and neuronal death. J Cereb Blood Flow Metab. 2006; 26:821–35.

63. Hazelton JL, Balan I, Elmer GI, Kristian T, Rosenthal RE, Krause G, et al. Hyperoxic reperfusion after global cerebral ischemia promotes inflammation and long-term hippocampal neuronal death. J Neurotrauma. 2010; 27:753–62.

64. Trittenwein G, Rotta AT, Gunnarsson B, Steinhorn DM. Lipid peroxidation during initiation of extracorporeal membrane oxygenation after hypoxia in endotoxemic rabbits. Perfusion. 1999; 14:49–57.

65. Mach WJ, Thimmesch AR, Pierce JT, Pierce JD. Consequences of hyperoxia and the toxicity of oxygen in the lung. Nurs Res Pract. 2011; 2011:260482.

66. ICU-ROX Investigators and the Australian and New Zealand Intensive Care Society Clinical Trials Group, Mackle D, Bellomo R, Bailey M, Beasley R, Deane A, et al. Conservative oxygen therapy during mechanical ventilation in the ICU. N Engl J Med. 2020; 382:989–98.

67. Itoh H, Ichiba S, Ujike Y, Douguchi T, Obata H, Inamori S, et al. Effect of the pulsatile extracorporeal membrane oxygenation on hemodynamic energy and systemic microcirculation in a piglet model of acute cardiac failure. Artif Organs. 2016; 40:19–26.

68. Ostadal P, Mlcek M, Gorhan H, Simundic I, Strunina S, Hrachovina M, et al. Electrocardiogram-synchronized pulsatile extracorporeal life support preserves left ventricular function and coronary flow in a porcine model of cardiogenic shock. PLoS One. 2018; 13:e0196321.

69. Short BL, Walker LK, Bender KS, Traystman RJ. Impairment of cerebral autoregulation during extracorporeal membrane oxygenation in newborn lambs. Pediatr Res. 1993; 33:289–94.

70. Wang S, Izer JM, Clark JB, Patel S, Pauliks L, Kunselman AR, et al. In vivo hemodynamic performance evaluation of novel electrocardiogram-synchronized pulsatile and nonpulsatile extracorporeal life support systems in an adult swine model. Artif Organs. 2015; 39:E90–101.

71. Passmore MR, Fung YL, Simonova G, Foley SR, Diab SD, Dunster KR, et al. Evidence of altered haemostasis in an ovine model of venovenous extracorporeal membrane oxygenation support. Crit Care. 2017; 21:191.

72. Luo Y, Fritz C, Hammache N, Grandmougin D, Kimmoun A, Orlowski S, et al. Low versus standard-blood-flow reperfusion strategy in a pig model of refractory cardiac arrest resuscitated with Extra Corporeal Membrane Oxygenation. Resuscitation. 2018; 133:12–17.

73. Cashen K, Reeder R, Dalton HJ, Berg RA, Shanley TP, Newth CJ, et al. Hyperoxia and hypocapnia during pediatric extracorporeal membrane oxygenation: associations with complications, mortality, and functional status among survivors. Pediatr Crit Care Med. 2018; 19:245–53.

74. Munshi L, Kiss A, Cypel M, Keshavjee S, Ferguson ND, Fan E. Oxygen thresholds and mortality during extracorporeal life support in adult patients. Crit Care Med. 2017; 45:1997–2005.

75. Roberts BW, Kilgannon JH, Hunter BR, Puskarich MA, Pierce L, Donnino M, et al. Association between early hyperoxia exposure after resuscitation from cardiac arrest and neurological disability: prospective multicenter protocol-directed cohort study. Circulation. 2018; 137:2114–24.

76. Cho SM, Canner J, Chiarini G, Calligy K, Caturegli G, Rycus P, et al. Modifiable risk factors and mortality from ischemic and hemorrhagic strokes in patients receiving venoarterial extracorporeal membrane oxygenation: results from the Extracorporeal Life Support Organization Registry. Crit Care Med. 2020; 48:e897–905.

77. Modine T, Azzaoui R, Ouk T, Fayad G, Lacroix D, Warembourg H, et al. Changes in cerebral vascular reactivity occur early during cardiopulmonary bypass in the rat. Ann Thorac Surg. 2006; 82:672–8.

78. O'Neil MP, Fleming JC, Badhwar A, Guo LR. Pulsatile versus nonpulsatile flow during cardiopulmonary bypass: microcirculatory and systemic effects. Ann Thorac Surg. 2012; 94:2046–53.

79. Salameh A, Kühne L, Grassl M, Gerdom M, von Salisch S, Vollroth M, et al. Protective effects of pulsatile flow during cardiopulmonary bypass. Ann Thorac Surg. 2015; 99:192–9.

80. Ostadal P, Mlcek M, Kruger A, Hala P, Lacko S, Mates M, et al. Increasing venoarterial extracorporeal membrane oxygenation flow negatively affects left ventricular performance in a porcine model of cardiogenic shock. J Transl Med. 2015; 13:266.

81. Veraar CM, Rinösl H, Kühn K, Skhirtladze-Dworschak K, Felli A, Mouhieddine M, et al. Non-pulsatile blood flow is associated with enhanced cerebrovascular carbon dioxide reactivity and an attenuated relationship between cerebral blood flow and regional brain oxygenation. Crit Care. 2019; 23:426.

82. Groner W, Winkelman JW, Harris AG, Ince C, Bouma GJ, Messmer K, et al. Orthogonal polarization spectral imaging: a new method for study of the microcirculation. Nat Med. 1999; 5:1209–12.

83. Mehra MR, Uriel N, Naka Y, Cleveland JC Jr, Yuzefpolskaya M, Salerno CT, et al. A fully magnetically levitated left ventricular assist device: final report. N Engl J Med. 2019; 380:1618–27.

84. Risnes I, Wagner K, Nome T, Sundet K, Jensen J, Hynås IA, et al. Cerebral outcome in adult patients treated with extracorporeal membrane oxygenation. Ann Thorac Surg. 2006; 81:1401–6.

85. Cho SM, Canner J, Caturegli G, Choi CW, Etchill E, Giuliano K, et al. Risk factors of ischemic and hemorrhagic strokes during venovenous extracorporeal membrane oxygenation: analysis of data from the Extracorporeal Life Support Organization Registry. Crit Care Med. 2021; 49:91–101.

86. Cho SM, Farrokh S, Whitman G, Bleck TP, Geocadin RG. Neurocritical care for extracorporeal membrane oxygenation patients. Crit Care Med. 2019; 47:1773–81.

87. Cho SM, Geocadin RG, Caturegli G, Chan V, White B, Dodd-O J, et al. Understanding characteristics of acute brain injury in adult extracorporeal membrane oxygenation: an autopsy study. Crit Care Med. 2020; 48:e532–6.

88. Wilcox C, Etchill E, Giuliano K, Mayasi Y, Gusdon AM, Choi CW, et al. Acute brain injury in postcardiotomy shock treated with venoarterial extracorporeal membrane oxygenation. J Cardiothorac Vasc Anesth. 2021; 35:1989–96.

89. Cho SM, Ziai W, Geocadin R, Choi CW, Whitman G. Arterial-sided oxygenator clot and transcranial doppler ultrasound emboli in venoarterial extracorporeal membrane oxygenation. Ann Thorac Surg. 2019; 107:326–7.

90. Cho SM, Deshpande A, Pasupuleti V, Hernandez AV, Uchino K. Radiographic and clinical brain infarcts in cardiac and diagnostic procedures: a systematic review and meta-analysis. Stroke. 2017; 48:2753–9.

91. Zwischenberger JB, Nguyen TT, Upp JR, Bush PE, Cox CS Jr, Delosh T, et al. Complications of neonatal extracorporeal membrane oxygenation: collective experience from the Extracorporeal Life Support Organization. J Thorac Cardiovasc Surg. 1994; 107:838–48.

92. Horton AM, Butt W. Pump-induced haemolysis: is the constrained vortex pump better or worse than the roller pump? Perfusion. 1992; 7:103–8.

93. Hwang J, Caturegli G, White B, Chen L, Cho SM. Cerebral microbleeds and intracranial hemorrhages in adult patients on extracorporeal membrane oxygenation-autopsy study. Crit Care Explor. 2021; 3:e0358.

94. Ong BA, Geocadin R, Choi CW, Whitman G, Cho SM. Brain magnetic resonance imaging in adult survivors of extracorporeal membrane oxygenation. Perfusion. 2020; Nov. 12. [Epub]. https://doi.org/10.1177/0267659120968026.

95. Liebeskind DS, Sanossian N, Sapo ML, Saver JL. Cerebral microbleeds after use of extracorporeal membrane oxygenation in children. J Neuroimaging. 2013; 23:75–8.

96. Le Guennec L, Bertrand A, Laurent C, Roze H, Chastre J, Combes A, et al. Diffuse cerebral microbleeds after extracorporeal membrane oxygenation support. Am J Respir Crit Care Med. 2015; 191:594–6.

97. Greenberg SM, Vernooij MW, Cordonnier C, Viswanathan A, Al-Shahi Salman R, Warach S, et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 2009; 8:165–74.

98. Frenckner B, Broman M, Broomé M. Position of draining venous cannula in extracorporeal membrane oxygenation for respiratory and respiratory/circulatory support in adult patients. Crit Care. 2018; 22:163.

99. Kitamura M, Shibuya M, Kurihara H, Akimoto T, Endo M, Koyanagi H. Effective cross-circulation technique of venoarterial bypass for differential hypoxia condition. Artif Organs. 1997; 21:786–8.

100. Contento C, Battisti A, Agrò B, De Marco M, Iaiza A, Pietraforte L, et al. A novel veno-arteriovenous extracorporeal membrane oxygenation with double pump for the treatment of Harlequin syndrome. Perfusion. 2020; 35(1_suppl):65–72.

101. Rupprecht L, Lunz D, Philipp A, Lubnow M, Schmid C. Pitfalls in percutaneous ECMO cannulation. Heart Lung Vessel. 2015; 7:320–6.

102. Lorusso R, Taccone FS, Belliato M, Delnoij T, Zanatta P, Cvetkovic M, et al. Brain monitoring in adult and pediatric ECMO patients: the importance of early and late assessments. Minerva Anestesiol. 2017; 83:1061–74.

103. Cho SM, Ziai W, Mayasi Y, Gusdon AM, Creed J, Sharrock M, et al. Noninvasive neurological monitoring in extracorporeal membrane oxygenation. ASAIO J. 2020; 66:388–93.

104. Cho SM, Ritzl EK. Neurological prognostication using electroencephalogram in adult veno-arterial extracorporeal membrane oxygenation: limitations and recommendations. Neurocrit Care. 2020; 33:652–4.

105. Khan I, Rehan M, Parikh G, Zammit C, Badjatia N, Herr D, et al. Regional cerebral oximetry as an indicator of acute brain injury in adults undergoing veno-arterial extracorporeal membrane oxygenation: a prospective pilot study. Front Neurol. 2018; 9:993.

106. Marinoni M, Migliaccio ML, Trapani S, Bonizzoli M, Gucci L, Cianchi G, et al. Cerebral microemboli detected by transcranial doppler in patients treated with extracorporeal membrane oxygenation. Acta Anaesthesiol Scand. 2016; 60:934–44.

107. Hunt MF, Clark KT, Whitman G, Choi CW, Geocadin RG, Cho SM, et al. The use of cerebral NIRS monitoring to identify acute brain injury in patients with VA-ECMO. J Intensive Care Med. 2020; Oct. 15. [Epub]. https://doi.org/10.1177/0885066620966962.

108. Callaway CW, Donnino MW, Fink EL, Geocadin RG, Golan E, Kern KB, et al. Part 8: post-cardiac arrest care: 2015 American Heart Association Guidelines update for cardiopulmonary resuscitation and emergency cardiovascular care. Circulation. 2015; 132(18 Suppl 2):S465–82.

109. Cho SM, Choi CW, Whitman G, Suarez JI, Martinez NC, Geocadin RG, et al. Neurophysiological findings and brain injury pattern in patients on ECMO. Clin EEG Neurosci. 2019; Dec. 11. [Epub]. https://doi.org/10.1177/1550059419892757.

110. Magalhaes E, Reuter J, Wanono R, Bouadma L, Jaquet P, Tanaka S, et al. Early EEG for prognostication under venoarterial extracorporeal membrane oxygenation. Neurocrit Care. 2020; 33:688–94.

111. Ryu JA, Chung CR, Cho YH, Sung K, Suh GY, Park TK, et al. The association of findings on brain computed tomography with neurologic outcomes following extracorporeal cardiopulmonary resuscitation. Crit Care. 2017; 21:15.

112. Floerchinger B, Philipp A, Foltan M, Keyser A, Camboni D, Lubnow M, et al. Neuron-specific enolase serum levels predict severe neuronal injury after extracorporeal life support in resuscitation. Eur J Cardiothorac Surg. 2014; 45:496–501.

113. Ferraro S, Braga F, Luksch R, Terenziani M, Caruso S, Panteghini M. Measurement of serum neuron-specific enolase in neuroblastoma: is there a clinical role? Clin Chem. 2020; 66:667–75.

114. Nguyen DN, Huyghens L, Wellens F, Schiettecatte J, Smitz J, Vincent JL. Serum S100B protein could help to detect cerebral complications associated with extracorporeal membrane oxygenation (ECMO). Neurocrit Care. 2014; 20:367–74.

115. Gazzolo D, Masetti P, Meli M, Grutzfeld D, Michetti F. Elevated S100B protein as an early indicator of intracranial haemorrhage in infants subjected to extracorporeal membrane oxygenation. Acta Paediatr. 2002; 91:218–21.

116. Bembea MM, Savage W, Strouse JJ, Schwartz JM, Graham E, Thompson CB, et al. Glial fibrillary acidic protein as a brain injury biomarker in children undergoing extracorporeal membrane oxygenation. Pediatr Crit Care Med. 2011; 12:572–9.

117. Mattsson N, Zetterberg H, Nielsen N, Blennow K, Dankiewicz J, Friberg H, et al. Serum tau and neurological outcome in cardiac arrest. Ann Neurol. 2017; 82:665–75.

118. Kirschen MP, Yehya N, Graham K, Kilbaugh T, Berg RA, Topjian A, et al. Circulating neurofilament light chain is associated with survival after pediatric cardiac arrest. Pediatr Crit Care Med. 2020; 21:656–61.

119. Moseby-Knappe M, Mattsson N, Nielsen N, Zetterberg H, Blennow K, Dankiewicz J, et al. Serum neurofilament light chain for prognosis of outcome after cardiac arrest. JAMA Neurol. 2019; 76:64–71.

120. Gul SS, Huesgen KW, Wang KK, Mark K, Tyndall JA. Prognostic utility of neuroinjury biomarkers in post out-of-hospital cardiac arrest (OHCA) patient management. Med Hypotheses. 2017; 105:34–47.