1. Brain death
Dr. J.R.Prajwala Reddy.

2. Introduction
The concept of Brain death and brain-stem death, its relevance to organ donation and its legal implications are new to most of the general population and are still unclear to many medical students and practitioners.
India enacted a law in 1994 to legalize brain- stem death.

3. Historically before 1960, death was defined as the complete and irreversible cessation of spontaneous cardiac and respiratory functions.
Refinement of cardiopulmonary resuscitation techniques and the advent of ICUs with mechanical ventilators enabled temporary support of cardiopulmonary function in the absence of brain function.
Hence, the cardiopulmonary definition of death lost relevance in such cases.

4. In 1968, an Ad Hoc Committee of Harvard Medical School on Brain Death published a landmark report, “the definition of irreversible coma.”
It defined the criteria for determining brain death as apneic coma and absence of elicitable brain-stem reflexes for a period of 24 h as confirmed by an EEG.

5. In 1995, American Academy of Neurology (AAN) published practice parameters for diagnosis of brain-death.
The parameter emphasizes on irreversible coma (with a known cause), absence of brain-stem reflexes and irreversible apnea.

6. Causes and pathophysiology
Direct traumatic injury to the head (e.g. road accident), subarachnoid hemorrhage and ischemic stroke are the most common causes of brain-death.
Others include intracerebral hemorrhage, hypoxic-ischemic encephalopathy .
These cause severe damage of neuronal tissue leading to edema and increase in ICP.
Elevated ICP in turn reduces cerebral perfusion pressure and cerebral blood flow.

7. A vicious cycle is established in which decreasing cerebral perfusion and increasing ICP reinforce one another until blood no longer enters the cranial cavity and transtentorial herniation and coning at foramen magnum occurs.
This herniation crush the brain-stem.
At this point, the brain including brain-stem is rendered permanently dysfunctional.
Late neuronal injury can be explained by reperfusion mechanism associated with hypoxic-ischemic brain injury.

8. Diagnosis of Brain-Stem Death In India
Brain-stem death is medically and legally def ned as the total and irreversible cessation of all brain-stem functions.
Diagnosis of brain-stem death is required to discontinue artificial ventilation and to ask legal consent for organ donation from relatives.
In India the THO Act 1994 and the THO Rules, are the only laws wherein brain-death certification procedures have been laid down.

9. Team of four medical experts should be included in diagnosing BD
• Medical Administrator In charge of the hospital.
• Authorized Specialist
• Authorized Neurologist/Neuro-Surgeon
• Medical Officer treating the patient.
Amendments in the THO Act (2011) have allowed selection of a surgeon/physician and an anesthetist/intensivist, in the event of the nonavailability of approved neurosurgeon/ neurologist.

10. Exclusion of potential reversible causes of coma and apnoea

11. The specified core temperature thresholds range from 32. 2°C to 36
The specified core temperature thresholds range from 32.2°C to 36.0°C without clear evidence base for any of these limits.
While Canadian guidelines permit a core temperature as low as 32.2°C during the apnea test, the American require a core temperature of more than 36°C.

12. Criteria for Diagnosis of Brain-stem Death in India
Patient should be deeply comatose (due to irreversible brain damage of known etiology); exclude reversible causes of coma
Patient should be on a ventilator because of the cessation of spontaneous respiration.
Exclude neuromuscular blocking agents as a cause of respiratory failure.

13. All brain-stem reflexes should be absent:
Pupillary light reflex - Pupils are dilated, fixed and do not react to light
Doll’s head eye movements (oculocephalic reflex) absence of conjugate deviation of eyes when head is fully rotated to one side Performed only when there is no fracture or instability of the cervical spine
Corneal reflex is absent.
No motor response to stimulation within any cranial nerve distribution (e.g. no response to the supraorbital pressure)

14. No Gag (Pharyngeal) reflex (to stimulation of pharynx)
No Cough reflex (to suction catheter in the trachea)
Vestibulo-occular reflex (oculovestibular reflex/caloric testing) is absent (No eye movements after installation of 50 ml of ice cold water into each external acoustic meatus for 1 min)

15. Apnea test - absence of respiratory movements after disconnection from the ventilator for sufficient duration to have pCO2 rise above threshold (>50-60 mmHg) for stimulating respiration.
All the prescribed tests are required to be repeated, after minimum interval of 6h, “to ensure that there has been no observer error” and persistence of the clinical state can be documented.

16. Apnea Test
Apnea must be demonstrated as part of any brain-death declaration.
Prerequisites for the apnea test
Core body temperature of minimum 36°C,
blood pH ,
systolic blood pressure of at least 100 mmHg,
euvolemia and
eucapnia (PaCO mmHg).
There should be absence of hypoxia and prior CO2 retention.
Apnea test should not be performed when the subject is under the influence of paralyzing drugs.

17. The patient is first preoxygenated with 100% oxygen for 15 min, and an arterial ABG is obtained.
The patient is then disconnected from MV and continued to oxygenate through a catheter placed in the trachea with oxygen flow at 6–10 L/min.
Alternatives include using a T-piece system with oxygen flow at 12 L/min or using continuous positive airway pressure (CPAP) at 10 cm H2O with FiO2 titrated to keep oxygen saturation above 95%.

18. PaCO2 is allowed to climb (usually at a rate of 3mmHg/min).
The threshold for maximal stimulation of the respiratory center is thought to be PaCO2 of 60 mmHg or a PaCO2 of 20 mmHg above the normal baseline value.
ABG is repeated within about 8–10 min of disconnection from the mechanical ventilation, and the increase in the PaCO2 is documented.
Visual observation is the standard method for detecting respiratory movement.

19. About 8–10 min with no observable respiratory effort is a standard observation period.
During this period of observation, if the subject does not have spontaneous respiration and arterial PCO2 is 60mmHg (or 20 mmHg increase over the baseline arterial PCO2 ), the apnea test result is positive (i.e., supports the clinical diagnosis of brain death).
This test should not be performed or should be terminated if the patient becomes hemodynamically unstable or hypoxemic.

20. If the test is inconclusive but the patient is hemodynamically stable during the procedure, it may be repeated for a longer period (10–15 min) after the patient is again adequately preoxygenated.

21. confirmatory tests
These tests are optional in adults but recommended in children younger than 1 year.
In certain countries, these tests are required by law to confirm brain death:
Cerebral angiography (conventional or CT)
Angiography of both the anterior and posterior circulations has to be carried out.
The absence of contrast flow into the intracerebral portions of the carotid and vertebral arteries at the level of their entry into the skull is taken as a sign of brain death.
External carotid circulation should be patent.
Limitation of the test is the need for transporting the patient.

22. Electroencephalography (EEG)
A complete absence of EEG activity to intense somatosensory and audiovisual stimulation is taken as a sign of brain death.
It is important to ensure that EEG recordings are done in a standardized manner.
Limitations are presence of artifacts leading to an EEG pattern for false negative brain death diagnosis.

23. Transcranial Doppler (TCD) ultrasound
The TCD abnormalities that indicate brain death are a lack of diastolic or reverberating flow and the documentation of small systolic peaks in early systole.
Complete absence of flow in the TCD may not be reliable owing to inadequate transtemporal windows.
Limitation is the need for expertise and appropriate interpretation of the flow pattern.

24. Cerebral scintigraphy
Demonstration of absent cerebral blood flow using radiolabeled (99mTclabeled) hexamethylpropyleneamine oxime (HMPAO), followed by single photon emission computerized tomography (SPECT) scanning, provides a confirmatory test in the diagnosis of brain death.
The absence of isotope uptake (“hollow skull phenomenon”) indicates no brain perfusion and supports the diagnosis of brain death.
Limitation is lack of availability and need for transportation.

25. DIAGNOSING BRAIN DEATH IN SPECIAL CIRCUMSTANCES
SEDATIVE DRUGS AND HYPOTHERMIA
The effects of high-dose sedative infusions may persist for several days after discontinuation, particularly in critically ill patients.
During this time the patient fails to satisfy the preconditions for the clinical confirmation of brain death.
This is particularly an issue following infusion of barbiturates, which are increasingly being used to treat intractable intracranial hypertension.

26. As with other sedatives, plasma barbiturate levels may not reflect clinical effect, particularly in the context of brain injury, and there is no consensus regarding a minimal plasma concentration at which brain death can be diagnosed.
Although the effects of high-dose barbiturates can mimic brain death, particularly in the presence of hypothermia, this is rare except in children.

27. Therefore, in the presence of other stigmata of brain death, such as dilated unreactive pupils, characteristic cardiovascular changes and diabetes insipidus, the diagnosis is rarely in doubt.
Confirmatory tests may have a role when the diagnosis of brain death using clinical criteria is complicated by the effects of prolonged sedation, particularly in the context of hypothermia.

28. INABILITY TO COMPLETE THE APNOEA TEST
In patients with high spinal cord injury the possibility that apnoea might be related to the cord injury itself brings some uncertainty to the diagnosis of brain death.
The degree of any spinal cord injury must therefore be quantified clinically,structurally and functionally by meticulous clinical examination, MRI and electrophysiological tests.

29. OTHER CONDITIONS
Other brain death mimics, including baclofen and valproic acid overdose, snake bite and some neurological conditions
Cranial nerve involvement and respiratory paralysis are features of Guillain–Barré syndrome and may cause diagnostic confusion, although pupil dilatation is rare.
Brainstem reflexes may also be absent in brainstem encephalitis but the patient is usually drowsy rather than comatose.

30. The preconditions for the diagnosis of brain death are not met in any of these conditions and meticulous application of the clinical criteria and careful examination will ensure that they cannot be mistaken for brain death.

31. CHILDREN
Special care is recommended in diagnosing brain death in children younger than 5 years of age.
In those over 2 months, the general criteria are the same as for adults but the period of observation should be longer and confirmatory investigations, such as EEG or cerebral angiography, are often conducted.
A higher PaCO2 target is also recommended during the apnoea test.
As in adults the tests must be undertaken by two competent clinicians but, in the case of young children, one should be a paediatrician and one not directly involved in the child’s care.

32. Managing a Brain-Dead Patient
Adequate monitoring is essential for managing a potential organ donor.
If not already placed, an arterial line, a central venous line, and a urinary catheter will be useful.
These will help in assessing resuscitation and monitoring the hemodynamic status closely.
Adequate volume status should be maintained.

33. Replace hormones
Brain death is associated with a panhypopituitary state that can lead to refractory hypotension.
Hormone replacement therapy not only helps in correcting this but also decreases cardiovascular instability and improves organ protection and graft function.
Levothyroxine:
Thyroxine (T4) is initially given at 20 mcg IV bolus.
T4 has been shown to be more beneficial than using T3.

34. Bolus administration of T4 can cause hyperkalemia, and it is advisable to administer 10 units of regular insulin and 50 mL of 50% dextrose prior to bolus administration of T4, unless the serum glucose is greater than 300 mg/dL.
If intravenous preparation is not available, thyroxine needs to be replaced enterally

35. Methylprednisolone:
Methylprednisolone is given as 15 mg/kg IV bolus and repeated on a daily basis.
This has been shown to improve the potential for lung donation.
Insulin:
The aim should be to maintain the blood glucose level below 140 mg/dL.
Insulin is initiated at the rate of 1 unit/h IV infusion, and the infusion rate is adjusted appropriately to achieve this target.
Frequent blood glucose analysis (hourly) may be required to maintain the target.

36. Vasopressin:
Diabetes insipidus (DI) should be suspected in a brain-dead patient when urine output is greater than 5 mL/kg/h for two consecutive hours, and this can be associated with hemodynamic instability.
If urine-specific gravity is <1.005, urine osml <200 mOsm/kg, serum osmolality >300mOsm/kg, and serum sodium >145mEq/L, a diagnosis of DI can be confirmed.
Once the diagnosis of DI is confirmed, vasopressin needs to be started.

37. Therapy is usually initiated with an infusion of vasopressin at 0
Therapy is usually initiated with an infusion of vasopressin at 0.5 unit/h and titrated to a maximum of 6 units/h with an aim of bringing urine output down to 0.5–3 mL/kg/h and serum sodium to 135–145 mEq/L.
Caution—serum sodium values should be checked every 6h to assist with titration.
Side effects of vasopressin include hyponatremia, digital vasoconstriction, and thrombosis.

38. Desmopressin (DDAVP) can be an alternative choice.
It is usually given at a dose of 1–4 mcg IV followed by 1–2 mcg IV every 6 h until the above-mentioned targets are met.
However, its drawbacks are that it is more difficult to titrate and does not provide significant hemodynamic support.

39. There is still no clear consensus about when to initiate hormonal replacement therapy.
Some prefer to initiate methylprednisolone and insulin components of hormonal replacement therapy soon after the first brain death declaration, while levothyroxine and/or vasopressin are initiated only if the patient becomes hypotensive or has diabetes insipidus.
Others start all hormones simultaneously as soon as brain death is declared, even if they are hemodynamically stable.