1. BRAIN DEATH AND STATES OF CONSCIOUSNESS Laurence Tancredi, MD, JD New York University School of Medicine

2. TWO BASIC QUESTIONS Does the essence of life reside throughout all organs or is it represented in a single organ of the body? How can we avoid the inaccurate diagnosis of death with maximum certainty?

3. REASONS FOR SHIFT TO BRAIN DEATH The mechanical ventilator (Bjorn Ibsen: mid-20 th. Century) especially combination of mechanical ventilator and new cardiac stimulation measures) The creation of intensive care units (ICUs) The issue of organ procurement for transplantation purposes.

4. FORMULATIONS OF BRAIN DEATH Whole-brain: complete and irreversible cessation of all brain function, including that of the brain stem Brain-stem formulation: complete and irreversible cessation of brain-stem function alone

5. LOCATION OF BRAIN STEM

6. BRAIN STEM

7. HARVARD CRITERIA (1968) Unreceptivity and unresponsivity No movements or breathing No reflexes Flat electroencephalogram (EEG) All of the above four tests are to be repeated at, at least, 24 hrs with no change. Exclusion of hypothermia (below 90 F or 32.2 C) or Central nervous system depressants

8. American Academy of Neurology Guidelines (1995) Demonstration of coma Evidence for the cause of coma Absence of confounding factors, including hypothermia, drugs, electrolyte, and endocrine disturbances Absent brainstem reflexes Absent motor responses Apnea A repeat evaluation in 6 hrs is advised, but the time period is considered arbitrary Confirmatory laboratory tests are only required when specific components of the clinical testing cannot reliably be evaluated.

9. PREREQUISITES BEFORE DETERMINATION OF BRAIN DEATH Acute catastrophic event involving both hemispheres or brainstem and irreversibility Exclusion: medical conditions that may confound clinical assessment, particularly severe electrolyte, acid-base, or endocrine disturbances Core temperature equal to or greater than 32 degrees C No documented evidence of drug intoxication, poisoning, or neuromuscular blocking agents

10. CONFIRMATORY TESTS OF BRAIN DEATH IN ADULTS Electroencephalography (EEG) Cerebral Angiogram Transcranial Doppler Sonography Magnetic Resonance Imaging (MRI) Single Photon Emission Computed Tomography (SPECT) Evoked Potentials Brainstem Auditory Evoked Potentials (BAEP) Somatosensory Evoked Potentials (SSEP) Spiral Computed Tomography Scan (Spiral CT Scan)

11. BRAIN DEATH DETERMINATION IN CHILDREN No reports of children recovering neurological function who have met adult brain death criteria on clinical examination Guidelines for children emphasize history and clinical examination in determining etiology of coma to eliminate reversible conditions Age-related observation periods and need for specific tests recommended in guidelines for children under 1 year of age 7 days to 2 months: Two examinations and EEGs 48 hrs apart 2 months to 1 year: Two examinations and EEGs 24 hrs apart, or one examination and an initial EEG showing ECS combined with a radionuclide angiogram showing no CBF or both More than 1 year: Two examinations 12-24 hrs apart, EEG and isotope angiography are optional

12. NEUROLOGIC STATES RESEMBLING BRAIN DEATH Hypothermia Acute Poisoning Acute Metabolic Encephalopathies Akinetic Mutism Persistent Vegetative State Locked-in-Syndrome

13. PERSISTENT PERMANENT VEGETATIVE STATE Time Duration: 1 month; if persistent more than 1 year, almost always permanent Function lost: No cognition: consistent responses to linguistic, symbolic, or mimetic instruction are absent No semantically meaningful sounds or goal-directed movements No sustained head-ocular pursuit activity

14. PERSISTENT PERMANENT VEGETATIVE STATE Function usually or often preserved: Brainstem and autonomically controlled visceral functions: homeothermia; osmolar homeostasis; breathing; circulation; gastrointestinal functions Pupillary and oculovestibular reflexes usually remain and are accentuated Brief, inconsistent shifting of head or eyes toward new sounds or sights may occur Smiles, tears, or rage reactions may occur either spontaneously or to nonverbal sounds Reflex postural responses to noxious stimuli remain

15. HYPOTHERMIA: CLINICAL FEATURES Body Core Temperature 35 – 32 degrees C Central Nervous System: apathy; dysarthria, impaired judgment Cardiovascular: tachycardia, then progressive bradycardia; cardiac cycle prolongation; vasoconstriction Respiratory: tachypnia, to progressive bradypnea; bronchorrhea; bronchospasm

16. HYPOTHERMIA: CLINICAL FEATURES 32 – 28 degrees C Central Nervous System: decreased level of consciousness; hallucinations; papillary dilation Cardiovascular: Progressive decrease in pulse and cardiac output; increased cardiac arrhythmias; Respiratory: Hypoventilation; 50% decrease in carbon dioxide production per 8 degree C drop in temperature; absence of protective airway reflexes; 50% decrease in oxygen consumption Neuromuscular: hyporeflexia; diminishing shivering, rigidity

17. HYPOTHERMIA: CLINICAL FEATURES Under 28 degrees C Central Nervous System: coma; absent oculocephalic, corneal and bulbar reflexes Cardiovascular: hypotension, bradycardia, dysrhythmias, decreased ventricular arrhythmia, asystole Respiratory: pulmonic congestion and edema; apnea Neuromuscular: amobile; areflexia

18. RESEARCH DIRECTIONS FOR BRAIN DEATH Improvements in use of MRI and MRI angiography Use of multimodality evoked potentials (MEPs), which test cerebral cortex as well as the brain stem, and include: brain-stem auditory evoked potentials (BAEP) flash-visual evoked potentials (flash VEPs), and median somatosensory evoked potentials (median SEPs) Refinements of imaging technologies (PET, MRI, SPECT) to achieve greater sensitivity and specificity Improvements in MEG (magnetoencephalography) to detect cellular activity in the brain stem

19. FUTURE DEVELOPMENTS AND BRAIN DEATH Use of electrodes on motor cortex to translate motor control commands, opens possibilities of translating and transferring ideas to a computer during process of dying Use of electrodes may also provide means for determining that any organized activity doesn’t exist, which in the absence of mechanical disruption, would demonstrate the brain is dead. Understanding the process of neuronal death (apoptosis) may provide opportunities for intervention

20. SOURCES Wijdicks EFM., (ed.): Brain Death. Philadelphia, Lippincott Williams & Wilkins (2001) Faymonville ME, Pantke KH, Berre J et. Al (2004): Cerebral functions in brain-damaged patients. What is meant by coma, vegetative state, minimally conscious state, locked-in syndrome and brain death? Anaesthesist 53: 1195-1202 Karantanas AH, Hadjigeorgiou GM, Paterakis K et al. (2002: Contribution of MRI and MR angiography in early diagnosis of brain death. Eur Radiol 2710-2716. Munari M, Zuchetta P, Carollo C et al. (2005): Confirmatory tests in the diagnosis of brain death: Comparison between SPECT and contrast angiography. Critical Care Medicine 33: 2068-2073 Yuan J, Yanker BA (2000): Apoptosis in the nervous system. Nature 407: 802-809