BRAIN DEATH – CURRENT UNDERSTANDING & MANAGEMENT OF POSSIBLE ORGAN DONOR

Dr M N Chidananda Swamy, Senior Consultant, Transplant Anaesthesia & Critical Care,

BGS Global Hospitals, Bangalore

Death by neurological criteria, or “brain death,” came about in the 1950s when ventilators and resuscitation efforts in the intensive care unit (ICU) became widespread. Brain death criteria have been based on 3 cardinal features throughout history: coma, brainstem areflexia, and apnea, and thus have undergone little change. In response to a traumatic brain injury or physiological “insult” to the brain (e.g., hemorrhagic or ischemic stroke), some patients suffer global and irreversible loss of brain stem function, leading to the diagnosis of brain death.A major issue in a hospital’s neurocritical care unit (NCU) is management of the brain dead cadaver with a focus on optimizing the preservation and transfer of the donor organs. Managing the organ donor following determination of brain death involves a comprehensive system for medical care of the donor, which may include administering appropriate medications to maintain basic body and organ functions within physiological limits.Organ preservation includes but not limited to pharmacologic support of hemodynamics, ventilator support of respiration involves both monitoring and maintaining physiologic values within set parameters to avoid damage and maintain organ function. These parameters include blood pressure, respiratory rate, and fluid and electrolyte status.PRACTICAL GUIDANCE FOR DETERMINATION OF BRAIN DEATH: The determination of brain death can be considered to consist of 4 steps.I. The clinical evaluation (prerequisites).A. Establish irreversible and proximate cause of coma.The cause of coma can usually be established by history, examination, neuroimaging, and laboratory tests.Exclude –a. The presence of CNS depressant drugs (intoxicant, poison, sedative, hypnotic, narcotic, etc.) by history, drug screen, calculation of clearance using 5 times the drug’s half-life, or, if available, drug plasma levels below the therapeutic range. Alcohol Intoxication blood levels below 0.08%.b. Hypothermia c. Neuromuscular blocking drugsd. Severe metabolic disturbances – acid – base abnormality ( severe acidosis), severe electrolyte disturbances, or endocrine abnormality Hepatic coma, uremic coma, hypoglycaemia).e. Central nervous system pathology (Locked-in syndrome, Guillain- Barre syndrome, encephalitis, etc.)B. Achieve normal core temperature.C. Achieve normal systolic blood pressure. Neurologic examination is usually reliable with a systolic blood pressure > 100 mm Hg.4. Perform neurologic examination. As per THOA 1994, there is a need to perform two neurologic examinations at least six hours apart to exclude the possibility of recovery. Legally, all physicians are allowed to determine brain death. Neurologists, neurosurgeons, and intensive care specialists may have specialized expertise. It seems reasonable to require that all physicians making a determination of brain death be intimately familiar with brain death criteria and have demonstrated competence in this complex examination.II. The clinical evaluation (neurologic assessment).

1. Coma - Patients must lack all evidence of responsiveness to noxious stimuli.2. Absence of brain stem reflexes

o Pupils No response to bright light. A magnifying glass may be useful if response is

questionable.

Size: from mid-position (4 mm) to dilated (9 mm). Small or pinpoint pupils should alert the clinician to the possibility of narcotic intoxication (but may also be seen with pontine injury or ocular surgery/disease).

o Ocular movement No oculocephalic reflex (test only when the integrity of the cervical spine is

ensured) No oculovestibular reflex: deviation of the eyes to irrigation in each ear with 30-50

ml of ice water. Observe for 1 minute after irrigation and wait at least 5 minutes before testing on the opposite side. Testing may be confounded by blood or cerumen in the auditory canal, a disrupted tympanic membrane or injury to the globes or orbits. Perform otoscopy prior to calorics.

o Facial motor response to stimulation No corneal reflex to touch with a cotton swab No facial grimacing to any noxious stimulation, including insertion of a Q-tip into

the nares Facial myokymias (from denervation of the facial nerve) are permissible

o Pharyngeal and tracheal reflexes No response to stimulation of the posterior pharynx with tongue blade No coughing or significant bradyarrhythmia with bronchial suctioning.

3. Apnea Testing

A. Prerequisites-all prerequisites mentioned above plus the following: 1. Eucapnea (PaCO2 35-45 mmHg)

For patients with chronic CO2 retention (e.g., COPD, severe obesity), apnea testing may be performed with the baseline PaCO2 -if known-defined as eucapnia. Ancillary testing should be considered in such cases, especially if the baseline PaCO2 is unknown.

2. Euvolemia If the patient is requiring significant amounts of vasopressor agents for blood

pressure support, or is having unstable cardiac dysrhythmias, consider ancillary testing.

B. Preparation: 1. Place the patient on 100% oxygen and reduce positive end-expiratory pressure (PEEP) to 5

cm H2O and resoiratory frequency to 10 breaths per minute for > 10 minutes before beginning test. Oxygen desaturation or PaO2 < 200 mmHg with these settings may indicate difficulty with apnea testing.

2. Obtain baseline arterial blood gas C. Procedure:

1. Remove patient from ventilator 2. Provide oxygen via catheter at 10 L/min to the level of the carina 3. Watch closely for respiratory movements (defined as abdominal or chest excursions) 4. Monitor oxygen saturation and blood pressure 5. Draw arterial blood gas at 5 minutes and 10 minutes

D. Terminate test for: 1. Spontaneous respirations or respiratory effort (apnea test does not support brain death) 2. Cardiac ectopy 3. Pulse oximetry < 90% for > 30 seconds (can retry with T-piece, CPAP 10 cm H2O, and 100%

O2 at 12 L/min) 4. Systolic blood pressure < 100 mmHg

5. If apnea test aborted due to ectopy, oxygen desaturation, or hemodynamic instability, draw an ABG and restart artificial ventilation at original settings. Consider ancillary testing.

E. Interpretation:

1. If respiratory movements are absent and the final arterial blood gas shows: PaCO2 >= 60 mmHg OR for patients with known CO2 retention (e.g., COPD, severe obesity) > 20 mmHg increase from the pre-test baseline then apnea has been demonstrated, supporting the diagnosis of death by brain criteria.

2. If inconclusive after 10 minutes and the patient was stable for the duration of testing, the test may be repeated with the time extended to 12-15 minutes.

III. Ancillary tests. In clinical practice, EEG, cerebral angiography, nuclear scan, TCD, CTA, and MRI/MRA are currently used ancillary tests in adults. Ancillary tests can be used when uncertainty exists about the reliability of parts of the neurologic examination or when the apnea test cannot be performed. The interpretation of each of these tests requires expertise. In adults, ancillary tests are not needed for the clinical diagnosis of brain death and cannot replace a neurologic examination. Prior to ordering ancillary tests one should appreciate the disparities between tests and the potential for false-positives (i.e., the test suggests brain death, but the patient does not meet clinical criteria). Rather than ordering ancillary tests, physicians may decide not to proceed with the declaration of brain death if clinical findings are unreliable.Methods of ancillary testing for the determination of brain death :Cerebral angiography• The contrast medium should be injected in the aortic arch under high pressure and reach both anterior and posterior circulations.• No intracerebral filling should be detected at the level of entry of the carotid or vertebral artery to the skull.• The external carotid circulation should be patent.• The filling of the superior longitudinal sinus may be delayed.Electroencephalography• A minimum of 8 scalp electrodes should be used.• Interelectrode impedance should be between 100 and 10,000 • The integrity of the entire recording system should be tested.• The distance between electrodes should be at least 10 cm.• The sensitivity should be increased to at least 2 _V for 30 minutes with inclusion of appropriate calibrations.• The high-frequency filter setting should not be set below 30 Hz, and the low-frequency setting should not be above 1 Hz.• Electroencephalography should demonstrate a lack of reactivity to intense somatosensory or audiovisual stimuli.Transcranial Doppler ultrasonography• TCD is useful only if a reliable signal is found. The abnormalities should include either reverberating flow or small systolic peaks in early systole. A finding of a complete absence of flow may not be reliable owing to inadequate transtemporal windows for insonation. There should be bilateral insonation and anterior and posterior insonation. The probe should be placed at the temporal bone, above the zygomatic arch and the vertebrobasilar arteries, through the suboccipital transcranial window.• Insonation through the orbital window can be considered to obtain a reliable signal. TCD may be less reliable in patients with a prior craniotomy.Cerebral scintigraphy (technetium Tc 99m hexametazime(HMPAO)• The isotope should be injected within 30 minutes after its reconstitution.• Anterior and both lateral planar image counts (500,000) of the head should be obtained at several time points: immediately, between 30 and 60 minutes later, and at 2 hours.

• A correct IV injection may be confirmed with additional images of the liver demonstrating uptake (optional).• No radionuclide localization in the middle cerebral artery, anterior cerebral artery, or basilar artery territories of the cerebral hemispheres (hollow skull phenomenon).• No tracer in superior sagittal sinus (minimal tracer can come from the scalp).IV. Documentation.The time of brain death is documented in the medical records. Time of death is the time the arterial PCO2 reached the target value. In patients with an aborted apnea test, the time of death is when the ancillary test has been officially interpreted. As per THOA Form 6 and Form 8 ( Appendix A) need to be completed and signed by the team of doctors performing the clinical examination for declaring brain stem death.

THE LAW AND RULES GOVERNING ORGAN DONATION AND TRANSPLANTATION IN INDIA,THOA (passed by parliament in 1995 and amended in 2011)The legal issues binding the organ donation specific for India are clearly outlined in the Transplantation of Human Organs Act (THOA) guidelines. This Act is to provide guidelines for the regulation of removal, storage and transplantation of human organs for therapeutic purposes and for the prevention of commercial dealings in human organs.As defined in THOA : a. “brain-stem death” means the stage at which all functions of the brain stem have permanently and irreversibly ceased and is so certified under sub-section (6) of section 3;b. “deceased person” means a person in whom permanent disappearance of all evidence of life occurs, by reason of brain-stem death or in a cardio-pulmonary sense, at any time after live birth has taken place;The main provisions of the THO act and the newly passed Gazette by the Government of India include the following:

1. For living donation - it defines who can donate without any legal formalities. The relatives who are allowed to donate include mother, father, brothers, sisters, son, daughter, and spouse. Recently, in the new Gazette grandparents have been included in the list of first relatives. The first relatives are required to provide proof of their relationship by genetic testing and/or by legal documents. In the event of there being no first relatives, the recipient and donor are required to seek special permission from the government appointed authorization committee and appear for an interview in front of the committee to prove that the motive of donation is purely out of altruism or affection for the recipient.

2. Brain-death and its declaration - brain death is defined by the following criteria: two certifications are required 6 hours apart from doctors and two of these have to be doctors nominated by the appropriate authority of the government with one of the two being an expert in the field of neurology.

3. Regulation of transplant activities by forming an Authorization Committee (AC) and Appropriate Authority (AA.) in each State or Union Territory. Each has a defined role as follows:

a. Role of Authorization Committee (AC) - The purpose of this body is to regulate the process of authorization to approve or reject transplants between the recipient and donors other than a first relative. The primary duty of the committee is to ensure that the donor is not being exploited for monetary consideration to donate their organ. The joint application made by the recipient and donor is scrutinized and a personal interview is essential to satisfy to the AC the genuine motive of donation and to ensure that the donor understands the potential risks of the surgery. Information about approval or rejection is sent by mail to the concerned hospitals. The decision to accept or reject a donor is governed by Sub Clause (3), Clause 9 of Chapter II of the THO act.

b. Role of Appropriate Authority (AA): The purpose of this body is to regulate the removal, storage, and transplantation of human organs. A hospital is permitted to perform such activities only after being licensed by the authority. The removal of eyes from a dead body of

a donor is not governed by such an authority and can be done at other premises and does not require any licensing procedure. The powers of the AA include inspecting and granting registration to the hospitals for transplant surgery, enforcing the required standards for hospitals, conducting regular inspections of the hospitals to examine the quality of transplantation and follow-up medical care of donors and recipients, suspending or canceling the registrations or erring hospitals, and conducting investigations into complaints for breach of any provisions of the Act. The AA issues a license to a hospital for a period of 5 years at a time and can renew the license after that period. Each organ requires a separate license.

c. Brain stem death is certified, in such form and in such manner and on satisfaction of such conditions and requirements as may be prescribed, by a Board of medical experts consisting of the following namely:

(i) Registered medical practitioner in charge of the hospital in which brain-stem death has occurred;

(ii) An independent registered medical practitioner, being a specialist, to be nominated by the registered medical practitioner specified in cause (i), from the panel of names approved by the Appropriate authority;

(iii) A neurologist or a neurosurgeon to be nominated by the registered medical practitioner specified in clause (i), from the panel of names approved by the Appropriate Authority; and

(iv) The registered medical practitioner treating the person whose brain-stem death has occurred. (v) “Provided that where a neurologist or a neurosurgeon is not available, the registered medical

practitioner may nominate an independent registered medical practitioner, being a surgeon or a physician and an anaesthetist or intensivist subject to the condition that they are not members of the transplantation team for the concerned recipient and to such conditions as may be prescribed;”.

As per Transplantation of Human Organs Act (India) passed by parliament in 1995 and amended in 2011 the following forms need to be completed on

Form 6 - Certificate Of Consent By Person having Lawful possession of the Body in Event of Death (including Brain Death)

Form 8 - Brain Death Certificate

Medical Management of Brain Dead – Physiological Support:Significant and devastating physiologic changes may begin to evolve over several hours before brain death. The longer the duration of this process, the more likely complications will occur, with the potential to abort possible functional organ recovery. It is appropriate to prepare for a therapeutic shift from cerebral protective measures to optimizing donor organs immediately after brain death.Once the diagnosis is made, it is essential that the family understands that brain death is irreversible and that their loved one is “dead. The successful identification and conversion of the potential donor to an actual donation requires an integrated team approach. Basic Standard monitoring:• Fluid intake and output, hourly urine output• Pulse oximetry, ECG, temperature• Arterial blood pressure• Central venous pressure

Laboratory investigations: 12 hrly (+ more often if clinically indicated)• Full blood count• Urea and electrolytes• Liver enzymes, INR (or PT) and APPT• Blood glucose, arterial blood gases at least 6 hrly• Daily blood cultures, cultures of sputum and urineHaemodynamic monitoring and therapyGeneral targets:Heart rate: 60-120 / minBlood pressure: Systolic blood pressure 100 - 160mmHg ; MAP > 65 - 70 mmHgCardiac output; > 2.4 l /min /m2Urine output; 50 - 100 ml/hr +Central venous O2 saturation; > 70%Fluid administration; Adequate volume loading to maintain organ perfusion but avoid fluidoverload.May use CVP 6-10mmHg as a target provided organ perfusion is maintained.Oxygen saturation >95%Normocarbia (pCO2 40 mmHg)Arterial pH 7.35-7.45 Haematocrit 30%Platelets 50,000/cmmGlycemic control (at 80-200 mg/dL), IV insulin protocol as neededSodium 130-150 mEq/LPotassium 3.5–5.0 mEq/LMagnesium 1.8-4.5 mEq/LPhosphorus 2.0-4.5 mEq/LDrugs and Doses for Combined Hormonal Therapy:• T3 (tri-iodothyronine); 4 microgram bolus followed by infusion at 3 micrograms/hour.T3 is the most readily available agent for IV use and is preferable as the active agent. ( If T3 is not available, alternatively oral Thyroxin tablets 100 – 150 mcg may be used through the NG tube)• Vasopressin, 1 international unit bolus followed by 2.4 units/hr infusion (0.5 – 3units/hour)• Methylprednisolone, 15mg/kg bolus i.v. and every 24 hours• Insulin as indicated by blood sugars, minimum 1 unit/hrConclusion: Brain death has been defined previously in various ways. Current guidelines and diagnostic criteria are established with one common goal – unquestionable clinical diagnosis of irreversible loss of all brain functions Confirmatory studies, such as a cerebral angiogram, are not mandatory.Brain death has become established and accepted worldwide as a formal means of declaring a person legally dead. There are multiple implications, perhaps most importantly it allows for improved processes of organ donation.Increasing organ donation is an important and laudable objective. A large disparity exists between the number of patients waiting for transplantation and the number of available organs. Although the daunting task of resolving this incongruence seems practically impossible at present, we must make every effort to identify potential donors, obtain consent, and convert the potential donor into an actual organ donor. In many areas of the world, the largest numbers of organs retrieved follow conventional donation after brain death and it is imperative that these donors receive optimal care before and after the diagnosis of brain death.Many ethical and legal questions have been raised regarding brain death, and these are likely to remain areas of future research and debate for years to come.

References:1. Scripko PD, Greer DM. An Update on Brain Death Criteria; A Simple Algorithm With Complex Questions. The Neurologist 2011; 17: 237–240.2. Eelco F.M. Wijdicks, Panayiotis N. Varelas, Gary S. Gronseth, et al. Evidence-based guideline update: Determining brain death in adults: Report of the Quality Standards Subcommittee of theAmerican Academy of Neurology. Neurology 2010; 74: 1911–1918.3. Nathan, S, and Greer DM. Brain death; Seminars in Anesthesia, Perioperative Medicine and Pain 2006: 25, 225-2314. Linos K, John FraserJ, William D. Freeman, Carole Foot: Care of the brain-dead organ donor; Current Anaesthesia & Critical Care (2007) 18, 284–294. 5. Wood EK, McCartney J: Management of the potential organ donor; Transplantation Reviews 21 (2007) 204–218.6. THE TRANSPLANTATION OF HUMAN ORGANS ACT, 1994, No.42 OF 1994 [8th July, 1994].7. THE TRANSPLANTATION OF HUMAN ORGANS (AMENDMENT) BILL, 2011.

Who should test for brain death declaration?

THOA 1994 CHAPTER II AUTHORITY FOR THE REMOVAL OF HUMAN ORGANS

(6) Where any human organ is to be removed from the body of a person in the event of his brain stem death no such removal shall be undertaken unless such death is certified, in such form and in such manner and on satisfaction of such conditions and requirements as may be prescribed by a Board of medical experts consisting of the following, namely:-

i. The registered medical practitioner in charge of the hospital( Director Medical Services or Medical Superintendant) in which brain stem death has occurred;

ii. An independent registered medical practitioner, being a specialist, to be nominated by the registered medical practitioner specified in clause (i), from the panel of names approved by the Appropriate Authority

iii. A neurologist or a neurosurgeon to be nominated by the registered medical practitioner specified in clause (i) from the panel of names approved by the Appropriate Authority and

iv. The registered medical practitioner treating the person whose brain-stem death has occurred.

Inclusion criteria for imminent brain death – Who should be tested?

Only ventilator-dependent patients admitted to an ICU With a known origin of catastrophic brain damage (e.g. TBI, SAH, ICH). Condition is considered irreversible and for whom no treatment possibilities are left Establishing irreversibility requires repeated (at least twice) examinations and exclusion of

major confounders, such as: effects of sedation, metabolic causes, drug toxicity and hypothermia.

May include multidisciplinary assessment by physicians in intensive care medicine, neurology and neurosurgery.

Checklist for determination of brain death

o Prerequisites (all must be checked)o Coma, irreversible and cause knowno Neuroimaging explains comao CNS depressant drug effect absent (if indicated toxicology screen; if barbiturates given, serum level < 10 _g/mL). o No evidence of residual paralytics (electrical stimulation if paralytics used).o Absence of severe acid-base, electrolyte, endocrine abnormalityo Normothermia or mild hypothermia (core temperature _ 36°C)o Systolic blood pressure _ 100 mm Hgo No spontaneous respirationso Examination (all must be checked)o Pupils nonreactive to bright light.o Corneal reflex absento Oculocephalic reflex absent (tested only if C-spine integrity ensured)o Oculovestibular reflex absento No facial movement to noxious stimuli at supraorbital nerve, temporomandibular jointo Gag reflex absento Cough reflex absent to tracheal suctioningo Absence of motor response to noxious stimuli in all 4 limbs (spinally mediated reflexes are permissible)o Apnea testing (all must be checked)o Patient is hemodynamically stableo Ventilator adjusted to provide normocarbia (PaCo2 34–45 mm Hg)o Patient preoxygenated with 100% FiO2 for _ 10 minutes too PaO2 _ 200 mm Hgo Patient well-oxygenated with a PEEP of 5 cm of watero Provide oxygen via a suction catheter to the level of the carina at 6 L/min or attach T-piece with CPAP at 10 cm

H2Oo Disconnect ventilatoro Spontaneous respirations absento Arterial blood gas drawn at 8–10 minutes, patient reconnected to ventilatoro PCO2 _ 60 mm Hg, or 20 mm Hg rise from normal baseline valueo OR: Apnea test abortedo Ancillary testing (only 1 needs to be performed; to be ordered only if clinical examination cannot be fully

performed due to patient factors, or if apnea testing inconclusive or aborted)o Cerebral angiogramo HMPAO SPECTo EEGo TCDo Time of death (DD/MM/YY) _______________________o Name of physician and signature ___________________

FORM 8

[Refer rule 4(3) (a) and (b)]

We, the following members of the Board of Medical Experts after careful personal examination, hereby certify that Shri/ Smt. / Km ........................... aged about ................... ....…………. s / o, w /o, d / o, Shri .............................. resident of ............................... is dead on ac- count of permanent and irreversible cessation of all functions of the brain-stem. The tests carried out by us and the findings therein are recorded in the brain-stem death certificate annexed hereto.

Date ............................ Signature ...........................

R.M.P. Incharge of the Hospital in which brain-stem death has occurred.

1. R.M.P. nominated from the panel of names approved by the Appropriate Authority.2. Neurologist / Neuro-Surgeon nominated from the panel of names approved by the Appropriate

Authority.3. R.M.P. treating the aforesaid deceased person.

BRAIN-STEM DEATH CERTIFICATE

(A) Patient Details:

1. Name of the Patient Shri/ Smt ./ Km. .................…..

S.O. / W.O. / D.O. Shri .................................……

Sex................. Age...........…….

2. Home Address ......................................……..

3.. Hospital Number ................................................................

4. Name and address of next of kin or person .............................

responsible for the patient (if none exists, this ..................................................... must be specified) ..................................

5. Has the patient or next of kin agreed to any transplant? ............................

6. Is this a Police Case? Yes................ No..............

(B) Pre-Conditions:

1. Diagnosis: Did the patient suffer from any illness or accident that led to irreversible brain damage? Specify details: ......................... ..........................................................................................

Date and time of accident/onset of illness .................................

Date and onset of non-responsible coma ...................................

2. Findings of Board of Medical Experts:

(1) The following reversible cause of coma have been excluded:-

First Examination Second Examination

Intoxication (Alcohol) Y/N Y/N

Depressant Drugs Y/N Y/N

Relaxants (Neuromuscular blocking agents) Y/N Y/N

Primary hypothermia Y/N Y/N

Hypovolaemic shock Y/N Y/N

Metabolic of endocrine disorder shock Y/N Y/N

Test for absence of brain-stem functions Y/N Y/N

(2) Coma Y/N Y/N

(3) Cessation of spontaneous breathing Y/N Y/N

(4) Pupillary size

(5) Pupillary light reflexes Y/N Y/N

(6) Doll’s head eye movements Y/N Y/N

(7) Corneal reflexes (Both sizes) Y/N Y/N

(8) Motor response in any cranial nerve distribution,

any responses to stimulation of face, limb or trunk Y/N Y/N

(9) Gag reflex Y/N Y/N

(10) Cough (Tracheal) Y/N Y/N

(11) Eye movements on coloric testing bilaterally Y/N Y/N

(12) Apnoea tests as specified Y/N Y/N

(13) Were any respiratory movements seen ? Y/N Y/N

Date and time of first testing: .................................................

Date and time of second testing: ............................................

This is to certify that the patient has been carefully examined twice after an interval of six hours and on the basis of findings recorded above,

Shri / Smt / Km................................................. is declared brain-steam dead.

1. Medical Administrator Incharge of the hospital.

2. Authorised Specialist.

3. Neurologist / Neuro-Surgeon.

4. Medical Officer treating the patientN.B

I. The Minimum time interval between the first testing and second testing will be six hours.

II. No. 2 and No. 3 will be co-opted by the Administrator Incharge of the hospital from the panel of experts approved by the Appropriate Authority.

FORM 6[(See rule 4(2) (b)]

I................................... s/o,d/o,w/o ....................... aged ...................resident of. ..............................having lawful possession of the dead body Sri/Smt/km ...........................................s/o,d/o,w/o .................................. aged........... resident of..................................................... having known that the deceased has not expressed any objection to his/her organ/organs being removed for therapeutic purposes after his/her death and also having reasons to believe that no near relative of the said deceased person has objection to any of his/her organs being used for therapeutic purposes authorise removal of his/her body organs,

Signature..................... Name........................Dated.......................... Place …………………. ......... Person in lawful possession of the dead body Address................................................................................................................................................