From the earliest times the process of dying has preoccupied men.The definition and diagnosis of death itself, however, have changed over time.Although the absence of respiration, heart sounds and a palpable pulse was used to diagnose death,this diagnosis was not always certain and the fear of premature buriel gave rise to a variety of means to alert watchers to any signs of life.One of such device invented by Count Karnice-Karnicki in 1897,consisted of glass ball resting on the chest of the burried corpse that was attached by a tube to a flag and a bell above ground.(2)
However,with the advent of the modern ressucitative techniques and cardiopulmonary support in the intensive care unit(ICU) ,cessation of brain function became recognizable as a distinct entity that may precede cardio pulmonary arrest for a significant periode of time if other systemic organ functions are maintained.(1)
In 1968 an adhoc commitee of the Harvard Medical School first published criteria to define irreversible coma as death. Half a year later,the brain death commitee at the University of Pittsburgh, School of Medicine published its criteria, leading to the first hospital approved brain death policy in the United States at Presbyterian University Hospital in Pittsburgh. In 1981 the medical consultants to the Presidents Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research published guidelines
on the determination of death based on neurologic criteria.The American Bar and American Medical Ascociations,at a National Conference on Uniform State Laws,also agreed on the Uniform Determination of Death Act(UDDA) which has since become federal law.The UDDA concludes that an individual is dead
if there is either irreversible cessation of circulatory and respiratory functions or irreversible cessation of the entire brain,including the brain stem.These guidelines and statues form the current medicolegal basis for the definition and certification of brain death. Most hospital require two physicians to independently confirm brain death;usually one of the two physicians
must be trained in the neurosciences either neurology or neurosurgery.
THE CLINICAL EXAMINATION :(3)
The clinical examination yields the most important information.Once it is determined that patient :
1.has no toxic drug levels that could interfere with the examination.
2.near normoptherrmic > 32,3 C.
3.has no significant metabolic or endocrinologic disturbances e.g.severe hypoglycaemia, metabolic encephalitis.
4.has adquate perfussion pressure (absence of shock or hypotension).
5.has a sufficiently irreversible and sufficient cause for brain death,the neurologic examination should be performed.(e.g.primary brain injury).
Prior to the examination of patients suspected of brain death it is necessary to exclude the precense of confounding factors that may render this examination invalid as mentioned above.(1)
The assesment includes mental status looking for urresponsiveness,pupillary response,corneal reflex, cervicoocular reflex(occulocephalic or dolls eye response),vestibuloocular reflex(oculovestibular response or cold water calorics),if the cervicooculo refles is absent and gag reflex. When these response are lacking an apnoe test is performed.(3)
The patient is preoxygenated with 100% FiO2 for ten minutes with normocapnic ventilation. Then mechanical ventilation is stopped;modes that can be used include a T-piece with tracheal canula delivering a 10L/min flow of oxygen or continous positive airway pressure(CPAP) alone.
The test is prematurely terminated if the patient becomes hemodinamically unstable or has evidence of oxygen desaturation.The patient is declared apneic if there is no ventilatory effort after PaCO2 reaches 60 torr.
Most institution require observation of a patient for at least 6 hours before this determination is made. However confirmatory test such as absent CBF on angiograhy or nuclear medicine scanning can establish the irreversibility of the patients condition and obviate the need for futher observation.
In the evaluation of the patient it must be determined that significant hypothermia or sedative or hypnotic medication overdose are not contributing factors Paralytic agents will completely abolish the neurologic examination (except that pupillary response will still be intact).
Electrocerebral silence on EEG is problematic because it occurs transiently within 6-8 hours after circulatory arrest and will be present in cases of severe hypothermia (<27C) or massive barbiturat overdose. The EEG should be perfomed 8 hours or more after the precipitating event.
In neonates the EEG is used with great caution because transient electrocerebral silence has occured with good neurologic condition. In addition apparent EEG activity is sometimes seen in the absence of CBF and the EEG can be technically very difficult requiring considerable technical expertise.Thus EEG is being used less frequently in determination of brain death.
On motor examination decerebrate or decorticate posturing or withdrawal to painful stimuli are not consistent with brain death.However, a streotyped triple-flexion in response to a painful stimulus to the foot and other reflexes that are spinalcord mediated,will persist after brain death has occured. Criteria for declaring brain death in children are slightly different needed 24 hours of observation because children can tolerate hypothermia better than adults, longer periods of observation are especially need after cold drowning.(3)
A mistaken diagnosis of brain death must never occur and although established criteria are objective and unambiguous,a physician experienced in the subtleties of brain death certification should always be involved in the process.
The physicians should be aware of state laws governing determination of braindeath.(4)
CLINICAL CRITERIA FOR BRAIN DEATH CERTIFICATION:(4)
1.Identifiable cause of coma
2.Exclusion of reversible CNS depression
- absence of hypothermia >34 C
- absence of drugs (e.g.ethanol,barbiturates)
- absence of metabolic perturbations that could potentiate CNS depression (e.g.abnormalities in electrolytes,osmolarity,serum ammonia,creatinine, hypercapnia,hypoxemia).
3.Absence of cortical function :
- unresponsive to painful stimuli
- no spontaneous muscular movement (in the absence of muscle relaxant)
- no posturing,shivering,or seizure activity(in the absence of relaxant)
4.Absence brainstem function
- pupil nonreactive
- no corneal reflex
- no gag or cough reflex.
- no oculocphalic reflex
- no oculovestibular reflex.
5.Documentation of apnea
- absence of spontaneous breathing for 30 secs after PaCO2 >50 torr with pH <7,35.
6.Additional confirmatory studies (optional).
- Cerebral blood flow study (radionucleic imaging)---absence CBF
- Electroencephalogram----no activity recorded at full gain.
The peripheral nervous system activity and simple or complex spinal cord reflexes may persist after established brain death.(1)
The pupils must be non reactive to light stimulation but need not be equal or dilated. It is important to exclude preexisting facial weakness as a cause for an absent corneal reflex, Absence of response to painful stimulus to the face is tested by firm supraorbital pressure.(1)
The oculocephalic reflex is tested by rapidly turning the head from side to side. Any eye movement indicates residual brain stem function.This test omitted in patients with concurent cervical spine injury. The oculovestibular reflex is tested by instilling 50 ml of ice water irrigated into each external auditory canal,cleared of cerument after elevating the patients head to 30 degrees.Ocular motion in response to this powerful labyrinthine stimulus imply presence of brainstem function.This reflex may be altered by labyrinthine injury or disease,anticholinergics,anticonvulsant,tricyclic antidepressant,barbiturat and other sedatives.
Pharyngeal reflexes,indicative of glossopharyngeal and vagal nerve function are tested by inserting pharyngeal and endotracheal catheters.Any gagging or coughing indicates persistent brainstem function. Vagus nerve function is further tested by administering intravenous atropine in a dose 0,04 mg/kg.
Atropine would oppose the action of any underlying vagal tone that normally slows heart rate. An increase in the pulse rate thus indicates baseline vagal activity that is inconsistent with brainstem death.
The apnea test is performed only if prior test of brainstem reflexes are found to be abscent since increased arterial carbondioxide tension (PaCO2) may increase intracranial pressure and potential for futher compromise of residual
brain function.The test is performed by disconnection from mechanical ventilation and observing for spontaneous respiration after the PaCO2 is allowed to increase to levels greater than 60 mmHg for at least 30 secs.This extremely powerful stimulus has no effect on the respiratory center in non functioning brainstem.As PaCO2 accumulates at a rate of 4 to 6 mmHg per min of apnea,the apneic test could last from 3 to 6 min,during which time hypoxemia must be avoided to prevent cardiac arrest or organ injury, especially in potential organ donors.
This may be prevented by ventilating the patient with 100% oxygen for 5 minutes before the test and insuflating 4 to 6 liters/min of oxygen through the endotracheal tube while patient is disconected from the ventilator. Conversely in patients with known chronic respiratory failure,who are dependent on hypoxic stimulus for respirtory drive, the PaO2 must be less than 50 mmHg at the end of the apnea test. Arterial blood samples are drawn to document oxygen and carbondixide levels on completion of the test.(1)
UNITED KINGDOM ROYAL COLLEGE GUIDELINES FOR DETERMINATION OF BSD.(2)
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The criteria for diagnosis of brain death published by the Honorary Secretary of Royal Colleges and their faculties in the United Kingdom and the Harvard Report in the United States became the basis for the confirmation of brain death in many other countries.However,the exact criteria upon which brain death is diagnosed vary between countries with some but not all countries requiring confirmatory test of absent brain function, such EEG or cerebral angiography.
There are three sequential steps in making the diagnosis of brainstem death. To avoid unnecessary testing and to eliminate the chance of making an incorrect diagnosis.
It is essensial that steps 1 and 2 are completed before beginning step 3.
Step 1: PRECONDITIONS
The patient is deeply comatose and being maintained on a ventilator because spontaneous ventilation had previously been inadequate or had ceased altogether. There should be no doubt that the patient's condition is due to irremediable brain damage of known etiology.
An accurate history of events before and after the onset of the coma is essential.
Step 2: EXCLUSIONS
If step 1 have been fulfilled the necessary exclusions must be considered.
There are to ensure that neither the state of apnoea nor coma is contributed to or caused by reversible condition.
The mayor groups of conditions that may produce this clinical picture are :
- hypothermia, <35C depressant drugs both therapeutic and non therapeutic.
- metabolic disorders,e.g.hyponatraemia endocrineabnormalities,e.g.myxoedema.
In the absence of toxicological screening, it has been suggested that three days is a reasonable time to allow potential drug effects to disappear.
Metabolics and endocrine abnormalities may be suspected from the history, examination and routine blood test,i.e.full blood count,arterial blood gas,electrolyte and blood glucoe measurements,although sophisticated test may be necessary.
Certain abnormalities accompanying BSD(Brain Stem Death) (e.g hyponatraemia) do not preclude the diagnosis of BSD. Spesific conditions such as the Locked in syndrome, and brainstem encephalitis (Bickerstatt's encephalitis,or the Miller Fisher Syndrome), may produce a clinical picture to that seen in BSD.
The Locked in syndrome, is produced by a leison in the pons which paralyses the limbs, respiratory muscles, and lower cranial nerves.
Patient are concious and able to blink,and produce vertical eye movements. Brainstem encephalitis may produce a comatose,areflexic,apnoeic patient,with motor and central nerve paralysis including internal and external opthalmoph-
legia.
Full recovery from brain encephalitis is possible.
Therefore,the importance of obtaining an adequate history consistent with the clinical picture together with strict adherence to the preconditions and exclusions before BSD testings can not be overemphasized.If any doubt exist as to the cause of patient condition, BSD test should not be performed.
Step 3 : THE TEST
The test should not be perfomed unless steps 1 and 2 has been fulfilled.
WHO AND WHEN :
BSD test should be perfomed by two medical practioners who have been registered for more than five years and are competent in this field.
At least one of the practioners should be a consultant and neither practioner should be a member of the transplant team. Two sets of tests should be performed;the two practioners may perform the test separately or together.
The test should be repeated to ensure no observer error has occured.
The timing of this second set of test is a matter for the doctors involved but should be adequate for the reassurance of all those directly concerned.
The interval between the two sets of tests can be used to discuss the possibility organ donation with the relatives if they have not already raised the subject.
HOW ?
For confirmation of BSD,five tests of the brainstem reflexes and testing for apnoea are required,The test are easily performed at the bedside and have an unambigous endpoints.In the United Kingdom there is no requirement to perform cerebral angiography or electro encephalography for the confirmation of BSD.
The five tests of brainstem relexes are :
Test
|
BSD Criteria
|
Cranial nerved tested
| |
| 1. | A Bright Light Shine into | No Reaction in either pupil | II and III |
| Both Pupil | |||
| 2. | A Strong Stimulus | No blinking applied to the | V and VII |
| cornea | |||
| 3. | 20 ml of iced water is | No Eye Movement | III, VI and VIII |
| injected into both external | |||
| auditory meateae | |||
| 4. | Painful stimulus is applied | No Motor response in the cra- | III,IV,V,VI,IX,X,XI and XII |
| supra orbital pressure | cranial nerve distribution | ||
| 5. | Suction Catether is passed | No coughing or gagging | IX and X |
| into the trachea |
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PRESBYTERIAN UNIVERSITY HOSPITAL(PUH) GUIDELINES FOR DETERMINATION OF BRAIN DEATH.(1)
================================
The clinical diagnosis of brain death in adults at PUH is made in accordance with standards recomended by the President's Commision for the study of Ethical Problems in Medicine.
The etiology of brain death must be well estabilshed using historical and adjunctive testing(e.g. CT scanning when indicated).The brain death evaluation should only be perfomed after all correctable abnormalities that might contribute to abnormal brain function(e.g.hypothermia,shock,hypoxaemia) have been adressed.
The patient should be observed for a reasonable period of time after he/she is first noted to be brain death to the time that brain death is formally declared.The duration of observation is a matter of clinical judgement and depends on the nature and severity of injury as well as certainty of prognosis.Two clinical examinations at least two hours apart must be perfomed by two physicians licensed in Pennsylvania.Finally the barin check list must be filled out.
1. ABSENCE OF CONFOUNDING FACTORS:
Before the clinical examination for brain death can be perfomed,systolic blood pressure (with or without vasopressors) must be at least 90 mmHg with eviden
ce of adequate peripheral perfusion.
The following conditions must be excluded before a clinical diagnosis of brain death can be made without confirmation of absent circulation: hypothermia <32C,presence of CNS depressant in toxic or therapeutic concentration (opiates,benzodiazepenes,phenothiazines,lithium,tricyclic anti depressants barbiturates,glutethimide,methaqualone) alcohol level >= 100 mg%,or the presence of neuromuscular blockers.
Brain death may be declared in patients sedative levels in subtherapeutic range,or when alcohol is present at level <100mg% without confirmation of absent circulation as long as the cause of brain death is not due to global brain ischemia/anoxia and sedative and alcohol are not present in combination.
If uremia,hepatic encephalopathy, meningitis, encephalitis or other metabolics encephalopathies are present,an EEG must be obtained to confirm the clinical diagnosis of brain death.
If there is clinical suspicion of the presence of sedative, alcohol or other CNS depressants,toxicological studies must be obtained to exclude their presence.The results of toxicological studies must be recorded in the comments section of the check list along with the time at which the sample was obtained.
II.THERE MUST BE DEMONSTRABLE EVIDENCE OF ABSENT CEREBRAL AND BRAIN STEM FUNCTION:
The clinical exam must demonstrate :
A. Cerebral unresponsitivity and unreceptivity.
B. Absent brainstem reflexes including a test for apnoe.
1. Apnea is confirmed by the absence of spontaneous breathing movements at PaCO2 above 60 torr at the end of the test.If the history suggests dependence on hypoxic stimulation for ventilation (e.g.a COPD patient ),the PaO2 at the end of the test must be less than 50 torr.
2. Atropine test -heart rate changes less than five beats per minute after 2 mg iv.
III. CONFIRMATORY TEST:
A. An EEG demonstrating electrocerebral silence is required for the diagnosis of brain death under following circumtances:
1. When at least one of the clinical examination is not perfomed by neurologist neurosurgeon,or critical care medicine physician.
2. When apnea testing cannot be perfomed because of the potential cardiac arrest due to hypoxaemia.
3. When the cause of death uncertain or is due to global ischemia/anoxic brain injury and the patient has been observed for less than 24 h.
4. When uremia,hepatic encephalopathy or other metabolic encephalopathy are present.
B. A four vessels cerebral angiogram demonstrating absent intrcranial circulation must be obtained when the brain death evaluation is confounded by hypothermia, the presence of CNF depressants,sedative,alcohol,sedatives and alcohol in combination,or neuro muscular blocking agents.
CERTIFICATION PROCESS: (1)
Brain death certification shoud be perfomed according to an individual institution's policy. This should include a protocol detailing clinical and confirmatory test, their frequency,and interval between test. Two or more appropriately licensed physicians with experiences in brain death certification should perform the examination.Transplant physicians are generally not involved in brain death certification of a potential organ donor to avoid conlict of interest.
Brain death certification is equivalen to the pronouncement of death and the time documented for this certification is considered the time of death medically and legally.
Certification of death is the physicians's duty.Seeking consent is inappropriate but the family must be informed of the certification process. In cases which lie within a coroner's jurisdiction, permission is not required for that certification or termination of medical therapy,but consent of the coroner and the next of kin must be obtained for the removal of organs for transplantation.
MANAGEMENT OF PATIENTS WITH BRAIN DEATH:(2)
After declaration of brain death, continuation of therapy is indicated if organs are to be removed for transplantation.Care of the brain death organ donor awaiting organ procurement provides many clinical challenges.Progressive hemodynamic instability, leading eventually to cardiac arrest, is inevitable after brain death may occur within hours to days. After permission for organ donation has been obtained from the patient's relative the intensivist in charge of the patient's care should contact the local transplant coordinator to discuss spesific treatment which may be requested by transplant team the transplant team(e.g.hormone therapy). A continued high standard of nursing care, the use of invasive monitoring and prompt treatment to preserve organ function will increase the chances of successful organ donation.
OPTIMIZED CARDIAC OUTPUT AND TISSUE OXYGEN DELIVERY:
Cardiac output is optimized by volume loading guided by central venous and/or pulmonary artery wedge pressure. Blood,coloid and crystaloid solution are used as appropriate to maintain volume of circulation. A combination of inotropes and peripheral vasoconstrictors is usually required to improve cardiac contractility and to increase organ perfusion pressure. Although dopamine is the most
commonly used agent,dobutamine,epinephrine and nor epinephrine may be required depending on the cardiac index and systemic vascular resistance at the time.The transplant team may specify their most favoured regiment as shown in table
PHYSIOLOGICAL GOALS FOR HEART OR HEART-LUNG DONATION :
Criteria Goal
----------------------------------------------------------
Mean arterial pressure > 60 mmHg
Left ventricular stroke work index > 15 g/m2
Cardiac index > 2,1 l/min
Pulmonary artery wedge pressure 12 mmHg
Central venous pressure 12 mmHg
Inotropic support 5 mg/kg/min
The rule of 100's has been suggested as a guide to treatment.
Systolic blood pressure > 100 mmHg
Urine output > 100 ml/h
PaO2 > 100 mmHg
Haemoglobine > 100 g/l
ADEQUATE OXYGENATION :
As these patients are intubated and ventilated they are risk of atelectasis retained secretions and nosocomial pneumonia. Physiotherapy, aseptic tracheobronchial suction and low levels of positive end expiratory pressure(PEEP) of 5 cm H2O may be used to prevent basal atelectasis and improve gas exchange. Bronchoscopy may be necessary to facilitate clearance of secretions but care must be taken to avoid damaging the lungs if lung donation is being considered.To minimize the risk of barotrauma and volutrauma, the peak inspiratory ventilatory pressure should be kept below 35cm H2O and tidal volume less than 10 ml/kg.The lower concentration of inspired oxygen that give adequate haemoglobine saturation should be used to reduce the risk of oxygen toxicity. The end-tidal CO2 should be kept within normal limits.However, this may be difficult as CO2 production is low in brain dead patients and dead space may have to be added to the ventilator circuit.
MAINTAINANCE OF HAEMOSTASIS WITH FAILING AUTONOMIC AND HORMONAL SYSTEMS.
Diabetes insipidus is treated with intravenous or subcutaneous boluses of desmopressine 0,5-4 microgram or if the patient is hypotensive,intravenous vasopressine (pitressine) 5-20 units. Repeat doses should be given to keep the urine output < 200 ml/h.
Rapid treatment is essential to prevent the development of electrolyte abnormalities and hypotension.Urine losses should be replaced with the appropriate crystaloid solutions according to plasma and urine electrolyte measurements.Infusion of insuline should be used to maintain blood glucose concentration within normal limits. By using a combination of hormone replacements, it is possible to increase the number of suitable donors.
HORMONE REPLACEMENT COMBINA
HORMONE/DRUG DOSE
Methylprednisolone 15 mg/kg/ bolus
Triodothyronine 4 mcg bolus + 3 mcg/h,infusion
ADH(Pitressin) 1 IU bolus + 1,5 IU/h,infusion
Insulin Minimum 1 IU/h to maintain blood glu-
cose of 6-11 mmol/dL.
Epinephrine 1 mcg/min,to maintain Systemic Vas
cular Resistance(SVR) 800-1200 dyne/
s/cm-5.
Hypothermia should be prevented by keeping the patient covered, the use of a warm air blanket warmed fluid and humidification of the breathing circuit.
OPTIMIZATION OF DONOR ORGAN FUNCTION BEFORE HARVEST:(4)
-----------------------------------------------------------
Systolic blood pressure >90 mmHg or mean arterial pressure >65 mmHg (adults)
Dopamine < 10 mcg/kg/min
Central venous pressure 8-12 mmHg
Urine output 100-200 ml/hr,or 2-4 ml/kg/hr
SaO2 > 95%or PaO2 > 100 torr
Hematocriet > 30%
Temperature > 35 C
Normalize electrolytes
Serum glucose 100-200 mg/dL
Tape eyelids shut/ eye drops.
AGE GUIDELINES FOR ORGAN AND TISSUE DONATION USED AT THE PITTSBURGH TRANSPLANTATION INSTITUTE:(1)
==============================
Organ/tissue Age
================================
Heart < 60 years
Heart-lungs < 60
Lungs < 60
Kidney 1 mo - 75 y
Liver < 75 y
Pancreas < 65 y
Intestine
Bone 15 - 65 y
Marrow < 75 y
Cornea 1 - 65 y
Skin 15 - 65 y
Heart valves < 55 y
================================
Donors beyond these ages limits could be accepted on the basis of the individual organ function.No age limits have been set for intestinal donors.
Intestines should be available from most organ donors and are always evaluated on an individual basis.
Contra indications to organ Procurement: (1)
A.Systemic, absolute
1.Severe trauma to spesific organ
2.Malignancy (except for primary CNS tumors)
3.Active infections :
a.Systemic sepsis
b.Active tuberculosis
c.Viral encephalitis
d.Guillian Barre syndrome
e.Active hepatitis,presence of hepatitis B surface antigen,
f. Human immunodeficiency virus carrier
B.Systemic relative
1.Severe hypotension or prolonged cardiac arrest.
2.Long standing systemic diseases
a.Hypertension
b.Cardiac
c. Peripheral vascular
d. Diabetes mellitus
C.Organ spesific :
1.Kidney
a.Chronic renal disease
b.Consistently elevated serum creatinine and blood urea nitrogen.
2.Liver
a.Elevated serum aspartate aminotransferase (AST),serum alanine aminotransferasew(ALT),bilirubine,prothrombine time.
3.Pancreas
a. Diabetes mellitus
4.Intestine
a. Unstable hemodynamics
b. Dopamine requirements > 10 mcg/kg/min
5.Heart
a.Systolic blood pressure < 90 mmHg
b.Dopamine requirements > 10 mcg/kg/min
c.Significant coronary artery disease
d.Severe cardiac hypertrophy,valvular defects,global myocardial dysfunction, or segmental wall motion abnormalities(by transoesophageal echocardiography)
6.Heart-lung or isolated single or double lung
a.As in section 5,a-d
b.History of heavy smooking
c.Chronic lung disease
d.Pulmonary aspiration
e.PaO2/FiO2 ratio < 250 mmHg
f. Peak airway pressure > 30 cm H2O at 15 ml/kg tidal volume and 5 cmH2O positive end expiratory pressure
CONCLUSION : (2)
The change from the idea of a cardiovascular death to the concept of brain death arose as a result of advances in medical technology.Death of the brainstem,which can be reliably diagnosed by clinical test,implies death of the whole brain and thus death of the individual.
The preconditions must be fulfilled before a diagnosis of brainstem death can be considered are essential to prevent any errors in the diagnosis.
Brainstem death results in a loss homeostasis and therefore succesful organ transplantation is only possible after careful management of the organ donor.
REFERENCES :
1.Lew W.K.Thomas ,Grenvik Ake: Brain deathh ,Vegetative management Cessation of Theraphy;Maurice S Albin;Neuroanesthesia with Neurosurgical and Neurosciense Perspectives ,The MCGrawHill Companies,Newyork, St. Louis San Franscisco etc 1997. pp.1363- 69.
2.Seigne R,Gunning E.J K: Brainstem death and Management of the organ donor, Matta F.B; Neuroanaesthesia and Critical Care,Greenwich Medical Media Ltd, London 2000.pp,383 388-394.
3. Chang W.J.Cherylee,Bleck P Thomas; Neurosciense Intensive Care, Brain death,Stone J.D et all;Neuroanesthesia Handbook,Mosby-Year-Book Inc.
USA,1996. pp.464-466.
4. Society of Crirical Care Medicine ;Brain Death and Organ Donation,in Course Syllabus Fundamental Critical Care Support,USA,1996 pp265-6.
