1. Technical Assistance for Alignment in Organ Donation- EuropeAid/131052/D/SER/TR Key Points in Brain Death Diagnosis Clinical aspects and Confirmation Francesco Procaccio ISS – CNT - Rome Neuro Intensive Care Unit University City Hospital, Verona - Italy University City Hospital, Verona - Italy

2. Total Brain Infarct 2 What is Brain Death?

3. Brain Death is the irreversible loss of capacity for consciousness combined with the irreversible loss of all brainstem functions including the capacity to breathe. The Canadian Neurocritical Care Group, 1999 BD Definition

4. F Procaccio 2012 Certainty of death: Irreversibility Karnice-Karnicki, 1896 Brain Death or Brain Dying? Death is a process Neurological functions must have ceased irreversibly

5. “Irreversible loss of all cerebral functions” (Brain) Death

6. Brainstemdeath 6

7. Why Brain death is the only death ? Pathophysiological reasons 7

8. When a person is dead? Definitive, irreversible total damage of the brain Cerebral functions are totally lost Due to two different mechanisms: 1)Respiratory and circulatory arrest causing secondary irreversible damage of brain (non Heart Beating cadaver) 2)Devastating cerebral lesions which cause total irreversible damage of the brain (Brain Death – Heart Beating cadaver) 8

9. Definition of death (Universal death) Capron, May 2012 Montreal Forum Simple uniform reliable concepts & definitions may increase public confidence and trust 9

10. Heart, Lung, Liver, Kidneys etc. are vital organs but can be supported by technology or replaced by transplantation. except The Brain Why only Brain death is death ? 10

11. Who may become brain dead ? Only patients with acute cerebral lesion under mechanical ventilation in ICU Brain injury – Cerebral Hemorrhage Ischemic Stroke – Brain Tumour Anoxia – Cerebral Infection etc.

12. Determination of death by neurological criteria

13. “All the cerebral functions are irreversibly lost” ClinicalREFLEXES EEG Determination of Death by Neurological criteria CBF

14. 14

15. Total Brain Infarct Absence of cerebral blood flow Death 15

16. Harvard Criteria - 1968 The Neurological Standard 16

17. Wijdicks E. N Engl J Med 2001 N Engl J Med 2001 17

18. Brain Death Diagnosis Milestones 1.The etiology of the brain lesion is known 2.Exclude all potential confounding factors 3.The neurological examination is complete and all clinical criteria are fulfilled 18

19. Etiology 19

20. NMR 20

21. Clinical examination

22. Prerequisites Etiology must be known Imaging of irreversible cerebral damage Temp. >32 °C (“Normal” BP – SO 2 – Na + ) Exclusion of medical confounding factors Exclusion of drug effects on CNS Exclusion of drug effects on clinical exam (muscle relaxant agents, atropine etc.) 22

23. The Brainstem 23

24. II III V VIVII VIII X XI Light response Corneal Oculocephalic Oculovestibular Brainstem reflexes: pathways Painful stimuli Tracheal 24

25. 25

26. Pupillary response to light Methodology & clinical experience 26

27. APNEA TEST Absence of respiratory drive 130 98 130 78 23 PaCO2 > 60mmHg 100% Oxygen 27

28. Why brain dead patients may move ?

29. Spinal reflexes in Brain Death Brain infarct Spine without superior control SpinalShock Spinal function recovery recovery Hyperexcitability 1 2 3 29

30. Are there factors that may cause unreliable brain death diagnosis?

31. CONFOUNDING FACTORS Severe derangement in temperature, blood pressure, oxygenation, electrolytes, glusose, cortisol, T4) Drugs (sedative/anesthetic - barbiturates ! – muscle relaxants ) Facial trauma – Cranial nerves lesions 31

32. Facial Trauma 32

33. If potentially confounding factors may be present confirmatory tests must be used

34. The absence of cerebral perfusion is a simple, clear, acceptable criteria, easily to be understood and demonstrated.

35. Cerebral angiogram. Arch injection Wijdicks, 2001 35

36. 36

37. TCD Brain Death patterns Trans Cranial Doppler 37

38. F Procaccio 2012 Girlanda R Angio-CT scan BD standard – no confounding factors

39. Persistence of cerebral blood “flow” after brain death Flowers WM et al. Southern Medical Journal 93:364,2000 Decompressing fracturesDecompressing fractures Ventricular shuntsVentricular shunts Reperfusion (post-anoxic !)Reperfusion (post-anoxic !) Decompressive HemicraniectomyDecompressive Hemicraniectomy 39

40. F Procaccio 2012 Possible Pitfalls in BD diagnosis 1.the BD declared patient is not Dead zero mistake must be ensured 2.the BD person is not BD declared silent BD – Death is not equal - missing PODs

41. Mimicking Disorders HypothermiaHypothermia BarbituratesBarbiturates Acute poisoningAcute poisoning Endocrine crisisEndocrine crisis (glucose – cortisol – T4) neurological diseasesneurological diseases 41

42. “ Neurological ” conditions that may be confused with Brain Death Locked-in syndromeLocked-in syndrome Guillain-Barré syndromeGuillain-Barré syndrome Demyelinating conditionsDemyelinating conditions Post-anoxic comaPost-anoxic coma Brainstem encephalitisBrainstem encephalitis “ Medulla man ”“ Medulla man ” 42

43. The Medulla Man Wijdicks E. J Neurol Neurosurg Psych 2001 43

44. F Procaccio 2012

45. Post-anoxic BD Neuro ICU, Verona - 2005 swelling“flow” 6 hours 45

46. 46

47. F Procaccio 2012 Possible Pitfalls in BD diagnosis 1.the BD declared patient is not Dead zero mistake must be ensured 2.the BD person is not BD declared

49. 49 Brain Death Declaration Certain diagnosis plus Legal procedures

50. Clinical Diagnosis simple and reliable simple and reliable Must be complete complete methodical methodicalrigorous 50

51. Deceased Organ Donation Dead Donor Rule Death determination (diagnosis) Threshold of irreversibilityThreshold of irreversibility Clinical standardClinical standard Confirmatory testsConfirmatory tests Dying process (legal) Death declaration Adherence to guidelinesAdherence to guidelines Legal proceduresLegal procedures The moment of DeathThe moment of Death 51

52. Brain death diagnosis (clinical criteria) etiologyComaBrainstemreflexes+apneaMandatoryEEGMandatoryCBFCBFInDefined Condition s children All pts or only potential donors? other xxxnoxxall >24hrs anoxic BD declaration (legal procedures) BD declaration (legal procedures)ObservationperiodN°MD Repeated clincial tests RepeatedEEG Repeated CBF Children All pts Or only PotentialDonors? 6 hrs 322noxallItaly Law –Decree ?!x! National Guidelines ?!x! Country: Italy Death determination by neurological criteria 52

53. ICUAdmission VegetativeStorm(coning) Brain Death Declaration 12 3 4 Patient treatment Timing in Death declaration BDcriteria observation Death 53

54. Common Principles for present/future ? Citizens equal in death: Death declaration independent from organ donation Clear, simple and acceptable definitions, criteria and procedures in death diagnosis A «Universal death» independent from clinical and (new) technical aspects Clear legal procedures for death declaration 54

55. 1.Treating physicians (Intensivists!) should be more involved in BD diagnosis and potential donor identification. 2.BD Pathophysiology based guidelines should guide BD diagnosis and donor treatment. 2.BD Pathophysiology based guidelines should guide BD diagnosis and donor treatment. 3.Law and decrees should have (few) technical details aimed to BD (legal) declaration Suggestions 55

56. 1.Specific education and common language are needed. 2.Quality of critical care may facilitate BD diagnosis. 3.The probability of success in organ donation reflects the capacity of declaring brain death in all the patients fulfilling BD criteria. Key factors Key factors 56

57. 57 Case study Reversible Brain Death

58. A 55-yr-old man presented with cardiac arrest preceded by respiratory arrest. Cardiopulmonary resuscitation was performed, spontaneous perfusion restored, and therapeutic hypothermia was attempted for neural protection. After rewarming to 36.5°C, neurologic examination showed no eye opening or response to pain, spontaneous myoclonic movements, sluggishly reactive pupils, absent corneal reflexes, and intact gag and spontaneous respirations.

59. Day 1 Facial Myoclonus

60. Over 24 hours, remaining cranial nerve function was lost. The neurologic examination was consistent with brain death. Apnea test and repeat clinical examination after a duration of 6 hrs confirmed brain death. Death was pronounced and the family consented to organ donation.

61. Are there factors that may cause unreliable brain death diagnosis?

62. Twenty-four hrs after brain death pronouncement, on arrival to the operating room for organ procurement, the patient was found to have regained corneal reflexes, cough reflex, and spontaneous respirations. The care team faced the challenge of offering an adequate explanation to the patient's family and other healthcare professionals involved.

63. 63

66. 66 Would you consider propofol/fentanyl a potential confounding factor at hour 80 ? 1)Yes 2)No 3)maybe

67. The ideal practice is to use confirmatory tests to use confirmatory tests only if necessary to confirm the clinical examination. Physicians should not go far as to place blind faith in machinery and as to place blind faith in machinery and the clinical diagnosis remains the clinical diagnosis remains a sacrosant principle. a sacrosant principle. EFM Wijdicks, 2001 67

68. 68 Is an ancillary test 1) Useful 1) Mandatory 1) Unreliable

69. F Procaccio 2012 SEPs NMR CBF CCA 170 170 195 200202 ventilationwithdrawal Operating room 1°- 2° clinical exam + apnea test HypothermiaSedation

70. Although the reversal was transient and did not impact the patient's prognosis, it impacted his eligibility for organ donation and cast doubt about the ability to determine irreversibility of brain death findings in patients treated with hypothermia after cardiac arrest. CONCLUSIONS: We strongly recommend caution in the determination of brain death after cardiac arrest when induced hypothermia is used. Confirmatory testing should be considered and a minimum observation period after rewarming before brain death testing ensues should be established.