1. بسم الله الرحمن الرحیم

2. Brain Death

3. Because advancements in medicine have changed the definition and concept of death, legislation must also change accordingly.

4. This issue results from progress in organ transplantation and the increasing number of patients who have a living body but non functioning brain, a consequence of discoveries in resuscitative and life support.

5. So the neurologists and neurosurgeons and anesthesiologist must be able to make an appropriate diagnosis of death.

6. Diagnostic criteria for the clinical diagnosis of brain death

8. A. Prerequisites. Brain death is the absence of clinical brain function when the proximate cause is known and demonstrably irreversible. 1. Clinical or neuroimaging evidence of an acute central nervous system catastrophe that is compatible with the clinical diagnosis of brain death 2. Exclusion of complicating medical conditions that may confound clinical assessment (no severe electrolyte, acid-base, or endocrine disturbance) 3. No drug intoxication or poisoning 4. Core temperature ≥32°C (90°F)

9. The three cardinal findings in brain death are
coma or unresponsiveness
absence of brainstem reflexes
apnea.

10. Coma or unresponsiveness: no cerebral motor response to pain in all extremities (nail-bed pressure and supraorbital pressure)

11. Absence of brainstem reflexes
a. Pupils
1. No response to bright light
2. Size: mid position (4 mm) to dilated (9 mm)
b. Ocular movement
1. No oculocephalic reflex (testing only when no fracture or instability of the cervical spine is apparent)
2. No deviation of eyes to irrigation in each ear with 50 mL of cold water (allow 1 minute after injection and at least. 5 minutes between testing on each side)

12. c. Facial sensation and facial motor response
1. No corneal reflex to touch with a throat swab
2. No jaw reflex
3. No grimacing to deep pressure on nail bed, supraorbital ridge, or temporomandibular joint
d. Pharyngeal and tracheal reflexes
1. No response after stimulation of the posterior pharynx with tongue blade
2. No cough response to bronchial suctioning

13. Apnea-testing performed as follows:
a. Prerequisites
1. Core temperature ≥ 36.5°C or 97°F
2. Systolic blood pressure ≥ 90mm Hg
3. Euvolemia. Option: positive fluid balance in the previous 6 hours
4. Normal Paco2. Option: arterial PCo2 ≥ 40mm Hg
5. Normal Pao2. Option: preoxygenation to obtain arterial Pao2 ≥ 200 mm Hg

14. Apnea-testing performed as follows:
b. Connect a pulse oximeter and disconnect the ventilator.
c. Deliver 100% O2, 6 L/min, into the trachea. Option: place a cannula at the level of the carina.
d. Look closely for respiratory movements (abdominal or chest excursions that produce adequate tidal volumes)

15. Apnea-testing performed as follows:
e. Measure arterial Pao2, PCo2, and pH after approximately 8 minutes, and reconnect the ventilator.
f. If respiratory movements are absent and arterial PCo2 is ≥ 60 mm Hg (option≥ 20 mm Hg increase in PCo2 over a baseline normal PCo2), the apnea test result is positive (i.e., it supports the diagnosis of brain death).

16. Apnea-testing performed as follows:
g. If respiratory movements are observed, the apnea test result is negative (i.e., it goes not support the clinical diagnosis of brain death), the test should be repeated.

17. Apnea-testing performed as follows:
h. Connect the ventilator if, during testing, the systolic blood pressure becomes ≤ 90 mm Hg or the pulse oximeter indicates significant oxygen desaturation and cardiac arrhythmias are present; immediately draw an arterial blood sample and analyze arterial blood gas.

18. Apnea-testing performed as follows:
If PCo2 is ≥ 60 mm Hg or PCo2 increase is ≥ 20mm Hg over baseline normal Pco2, the apnea test result is positive (it supports the clinical diagnosis of brain death); if Pco2 is <60 mm Hg or PCo2 increase is <20 mm Hg over baseline normal Pco2, the result is indeterminate, and an additional confirmatory test can be considered.

19. THE CONCEPT OF BRAIN DEATH

20. The organism is an aggregation of living cells, although an aggregation of living cells does not necessarily constitute an organism.
An organism exists only when the cell aggregation is under the control of modulating systems such as CNS, the endocrine system, and the immune system.
After anyone of these systems ceases to function, death is inevitable unless artificial measures can be taken.

21. Brain death represents death of the organism, and without CNS harmonious functioning of individual cells as constituents of the whole organism ceases.

22. Previously, cessation of respiration was equivalent to immediate death of the organism, but artificial ventilation can now prolong the life of a body for a certain period.

23. The physiologic significance of brain death and cardiac death are essentially equal, and both represent an irreversible loss of communication between the control center and peripheral cells and tissues.

24. The brainstem contains the main tracts for neural communication between the control center and peripheral tissues.
All the motor outputs from the hemispheres have to travel through the brainstem, as do all the sensory inputs to the brain except sight and smell.

25. When respiration stops; drugs, computers can maintain the circulatory functions.
For example arginine vasopressin prolongs the cardiovascular functions for months in brain death patients.

26. In brain death we can’t provide humanity or personality which both are products of the telencephalon.

27. the current concept of brain death adopts the conclusions of modern biologic science: Cessation of CNS functions represents cessation of the harmony of life, and that without CNS control, the living organism is nothing more than an aggregation of living cells.

28. Mechanism of Brain Death

29. Brain death sources Traumatic Cerebrovascular injury
Generalized hypoxia
In all we have brain edema

30. Brain Edema
Vasogenic: an increase in cerebrovascular permeability and leaking of serum proteins into brain parenchyma.
Cytotoxic: occurs in hypoxic and ischemic condition. Disturbances of osmoregulation of cells. Entry of water into brain parenchyma.

31. Brain edema may be focal at first but it then spreads throughout the whole brain.
Brain is covered by a rigid bony skull. So we have increase in ICP.
The cerebral circulation ceases, aseptic necrosis of the brain ensues.

32. Within 3 to 5 days, the brain becomes a liquefied mass
Within 3 to 5 days, the brain becomes a liquefied mass. A condition known as respirator brain.

33. Neurophysiologic Basis of Brain death
Brain death is a total irreversible cessation of functioning of the brain.
Brain includes all the CNS structures except the spinal cord.
It is generally agreed that brain death does not include lower portions of the spinal cord (caudal from C2), because their location outside the skull spares them from compression during brain edema.

34. Histologic studies of human spinal cord in cases of brain death revealed divergent pathologic findings ranging from histologically intact tissues to complete destruction.

35. In U. K, no confirmatory test(including an EEG) is required
In U.K, no confirmatory test(including an EEG) is required. The rationale for excluding the cerebral cortices is the fact that the brainstem, not the cerebral cortices, plays the major role in controlling whole-body vital activities such as respiration, circulation, and other homeostatic functions.
We believe that if the cerebral cortices were excluded, assessment of brainstem functions would be more accurate, and the danger of mistaking the vegetative state for brain death could be avoided.

36. Consciousness & EEG
It was believed that ascending reticular activating system (ARAS) regulate the state of consciousness.
Before, that it was restricted to reticular nuclei
Maintenance of wakefulness or control of the sleep-wake cycle does not depend exclusively and unalterably on any single region of the brain.

37. In brain death, the patient is believed to have no consciousness, no intellectual activity, and therefore no true humanity.

38. Significant EEG changes occur when blood flow falls below 18 mL /100 g/min, and it becomes isoelectric when blood flow is in the range of 12 to 15 mL/100 g/min. However, Paolin and associates reported that 7 of 15 patients with clinical diagnosis of brain death showed persistent electrical activity, although cerebral blood flow measurements with xenon 133 and selective cerebral angiography showed intracranial circulatory arrest.

39. Respiration
The primary respiratory center, consisting of the inspiratory and expiratory neurons, is located in the reticular core of the medulla oblongata. Although the other respiratory neurons distributed in the pons are believed to affect the activities of these neurons.

40. In brain death, spontaneous respiration does not occur in patients even when arterial carbon dioxide partial pressure reaches 55 to 60 mm Hg. Mechanical stimulation of the carina to induce the cough reflex may be helpful in detecting residual functioning of the medullary respiratory neurons.

41. Cardiovascular function
The central neurons that control the circulatory system distribute diffusely in the pontine and medullary reticular core.
Of these neurons, the vasomotor and cardioaccelerating neurons undergo negative-feedback control through the carotid and aortic sinus nerves.

42. When the entire cerebrum was ischemic, vagal activation with resultant decrease in heart rate, mean arterial pressure, and cardiac output was observed.

43. As ischemia progresses rostrally to approach the pons, sympathetic stimulation was added to vagal stimulation, leading to bradycardia and hypertension (Cushing phenomenon).

44. When the entire brainstem became ischemic, there was unopposed sympathetic stimulation, leading to tachycardia, hypertension, and high blood levels of catecholamine (autonomic storm).

45. Some authorities think that myocardial damage may occur at this stage of autonomic storm, which may contribute to the early failure of some transplants .

46. When intracranial pressure is elevated arterial blood pressure suddenly decreases. This sudden decrease is the sign of tonsillar herniation through the foramen magnum on the cervical spinal cord, in which outflow of the cardioaccelerating and vasomotor neurons to the spinal cord suddenly ceases.

48. The vasomotor & cardioaccelerating neurons of spinal cord (located in the lateral horn) obtain automaticity within several days of disconnection from the supraspinal structures, and arterial blood pressure returns to normal without supplementation with vasopressors.

49. Temperature
The heat-sensitive center consists of the heatloss center in the anterior hypothalamus and the heatproducing center in the posterior hypothalamus.

50. In brain death, the neural connection between the temperature-regulating center and peripheral body tissues is lost, and the patient becomes poikilothermic.

51. Even if infection occurs, fever should not develop in cases of brain death, because the temperature-regulating centers no longer function.

52. The Immune System
Increased levels of cytokines in blood and in organs are observed in brain dead patients, and it is thought that these cytokines are responsible for some of the endocrine and acute-phase reactant abnormalities found in these patients and for the low success rates after organ transplantation.

53. Various brainstem reflexes are used to diagnose brain death, such as pupillary, oculocephalic, oculovestibular, and cough reflexes. Preservation of the cough reflex indicates preservation of the brainstem respiratory center.
All the brainstem reflexes (except those of the respiratory centers) need not be present for the organism to be said to be alive, but they are tested to confirm preservation of brainstem functions.

54. CRITERIA AND TESTS FOR DETERMINING BRAIN DEATH

55. Loss of consciousness and unresponsiveness
The patient should be in coma
GCS = 3
No response of the limbs and facial muscles to painful supraorbital pressure
Spontaneous movement during apnea test may have spinal origin (Lazarus sign).

56. Pupils The shape of the pupils can be round, oval, or irregular.
The size of the pupils may vary from 4 to 9 mm, but most cases show 4 to 6 mm.
Sympathetic cervical pathways can be intact in the state of brain death, connect with the radially arranged fibers of the dilator muscle, and dilate the pupils.

57. Apnea Test
Apnea testing is mandatory for the determination of brain death, but there have been controversies about it.
Its safety is a major issue.
During it, severe changes in vital sign, marked hypotension, severe cardiac arrhythmias, and pneumothorax may occur

58. Apnea Test
The apnea test should be performed as the last test after the other tests fulfill the criteria of brain death.
Preoxygenation with 100 % oxygen for 10 minutes before apnea testing if Pao2 is less than 200 mm Hg.

59. Several disorders mimic brain death and can lead to an erroneous diagnosis. The absence of these conditions must be confirmed.

60. Deep coma
The patient must be in deep coma and the cause of the coma must be identified.
Organic brain damage must be confirmed.
Drug intoxication, sever electrolyte, acid-base or endocrine disturbances, hypothermia and other common treatable disorders should be ruled out.

61. Before diagnosis of brain death hypothermia must be corrected because hypothermia suppress CNS function and leads to misdiagnosis of brain death.

62. CLINICAL DIAGNOSIS OF BRAIN DEATH
clinical diagnosis of brain death should be performed in three steps:
1. Establishing the cause of disease
2. Excluding certain potentially reversible syndromes that may produce signs similar to brain death
3. Demonstrating clinical signs of brain death: coma, brainstem areflexia, and apnea

63. Confirmatory tests are not always mandatory but they are desirable, especially when the clinical picture is confusing.
In general, two examinations separated by at least 6 hours are required to establish the diagnosis of brain death.
Most codes mandate that the clinical diagnosis be confirmed by 2 or 3 physicians, independent of the transplantation team, and at least one of the physicians is required to be a specialist in neurology, neurosurgery, or anesthesiology.

64. Cerebral Death: Persistent Vegetative State
Cerebral death, the so-called persistent vegetative state, refers to cessation of the functions of the cerebral cortices.
Brainstem functions governing the respiratory centers, autonomic nervous system, endocrine system, and immune system, which are vital for maintaining life, are preserved.

65. The term cerebral death is occasionally used by mistake to indicate brain death, which include brain stem.
Severe dementia

66. Spinal Cord Reflexes and Surgery
Spontaneous and reflex movements are found in brain death patients.
Spontaneous body movements may be observed during the apnea test, while the body is being prepared for transport, at the time of a skin incision for the retrieval of organs.

67. Spinal Cord Reflexes and Surgery
In 5 of 60 cases of brain death after terminally turning off the ventilator or during apnea tests, reported bizarre, seemingly purposeful movements of the upper extremities, called the Lazarus sign, in which the arms flexed quickly to the chest from the patient's side, the shoulders adducted, and in some patients, the hands crossed or opposed just below the chin .

69. Considerations Regarding Children
infants and young children may recover substantial brain functioning after periods of unresponsiveness that are longer than those from which adults could recover.
Open fontanelles and open sutures.

72. CONFIRMATORY TESTS FOR BRAIN DEATH
Optional for adults but strongly recommended for children, especially younger than 1 year
In the United States, the choice of tests is left to the discretion of the physician.
In all cases, confirmatory tests should be used in conjunction with appropriate clinical judgment.

77. Evoked Responses Brainstem auditory evoked potentials (BAEP) and median nerve somatosensory evoked potentials (SSEP) are used for the diagnosis of brain death.

78. Wave I represents the eighth nerve compound action potential;
wave II, the eight nerve & cochlear nerves
wave III, the lower pons including the superior olive
waves IV and V, the upper pons and the midbrain, as high as the inferior colliculus.
The loss of waves III to V, II to V, or no reproducible BAEP on both sides is usually regarded as brain death, although wave I
sometimes remains.

79. Measurement of Blood Flow
Possible mechanisms for brain death include an obstruction of circulation by cerebral swelling.
The demonstration of absent intracranial circulation indicates irreversible cerebral damage.

80. Measurement of Blood Flow
Contrast Angiography
Radionuclide Angiography
Computed Tomography
Magnetic Resonance
Transcranial Doppler Sonography
Positron Emission Tomography

81. ANESTHESIOLOGISTS IN ORGAN DONATION
Because of their intact spinal cord and the presence of somatic and visceral reflexes, brain-dead patients require special anesthetic management, including use of muscle relaxants, vasodilators, and perhaps sedation and analgesia.