Introduction
At present, organ supply still proceeds mainly from cadavers with brain death. The main difficulty involved in the development of organ transplant programs is the insufficient amount of organs available for transplantation.. For this reason, the diagnosis of brain death is an essential step for the procurement of organs for transplantation.
It is advisable that all the health professionals involved in the donation transplantation process have enough knowledge of all ethical and social aspects besides the concepts of Brain death. This information will help them to: “1. - Improve the information on brain death, needed to increase transplant programs, 2. - Improve contact with the relatives of potential donors, giving accurate answers to the questions that they may have concerning brain death, 3. - Assess all health professionals not acquainted with the diagnostic methods of brain death, and 4. - Collaborate logistically (instrument management, serum drug levels, etc.) in difficult cases that may need more atypical methods of diagnosis, 5. -Comprehend the ethical aspects of the diagnosis of death, since nowadays brain death is synonymous of death; therefore all patients diagnosed of brain death must nor be submitted to any further measures to prolong their lives.
2- The concepts and definition of brain death
2.1 Death as a process
The death of a human being, defined biologically, is not instantaneous but an evolutionary process during which the different organ functions are gradually extinguished, ending when all the body's cells irreversibly cease to function.
Although death is accepted to be a process, society requires that doctors not only provide a biological confirmation of death, but also establish an exact time of death.
The lack of any kind of body movement (including respiratory movements and heart pulse) has been, during millenniums, the most accepted sign to distinguish the beginning of death in the individual. This was justified because the lack of cardiac and respiratory movements was followed by rapid and irremediable development of multiple processes of organic decomposition (rigidity, putrefaction, etc.) identified with death.
The development of life support techniques (cardiac and ventilatory assistance, etc.) has changed the prognosis of a vast amount of processes that ended in death. Currently, certain diseases previously considered fatal (cardiogenic shock, severe respiratory failure, etc.) can be controlled by life support techniques (extracorporeal circulation pumps, membrane oxygenators, etc.) capable of completely replacing the patient's cardiac and respiratory functions. After the resolution of the acute process, the patient may not depend on the mechanical support elements and will then be able to return to normal life. This has caused a change in the concepts of organic failure used to establish the frontier between life and death since, up to now, the presence of severe cardiocirculatory, respiratory or neurological failure inevitably ended in death because of a lack of substitutes for these organic functions.
At present, the complete and irreversible failure of central nervous system functions constitutes the authentic frontier between life and death of human beings. The main reason for this affirmation is that complete neurological failure is irremediably associated to the cease of cardiac and respiratory functions and, consequently, the immediate start to the death process. However, thanks to the support techniques mentioned above, the cease of cardiac function can be deferred hours or days. This situation of irreversible absence of central nervous system functions, the inability to maintain body homeostasis spontaneously, with spontaneous cardiocirculatory function (although sometimes supported pharmacologically) and assisted ventilation, is defined as brain death, and accepted in many countries of the world as the legal death of the individual.
The concepts in brain death
Nowadays, not all-medical schools accept the same concept of brain death.Consequently the criteria for diagnosis are different according the concept of brain death used. The three main concepts are:
Whole brain death concept. The whole brain death concept means the irreversible cessation of hemispheric and brainstem neurological functions. It is the most wide-spread concept. Diagnosis criteria include: clinical examination, and several tests that examine central nervous system functions (electroencephalogram, etc.) or phenomena related to brain death (cerebral circulatory arrest using cerebral blood flow tests, etc.).
Brainstem death. It is defined as the irreversible loss of the capacity to remain conscious combined with an irreversible loss of the capacity to breath spontaneously. Diagnosis can be established based on the absence of clinical brainstem activity by means of a clinical examination. No instrumental tests are required for the diagnosis.
Higher brain death formulation or neocortical death. This new formulation has emerged in recent years. There are two main elements of the consciousness: The content of the consciousness and the arousal. In individuals in Neocortical death, there are an absence of content of the consciousness, but the arousal and other neurological functions can persist. A clinical examination is the basis for diagnosis.
The diagnosis of brain death applied to the brainstem death concept and the whole brain death concept
The brain in brain death
The brain of a patient with brain death is an organ that has lost all its intrinsically neurological functions. However, certain non-specifically neurological functions (neuroendocrine, etc.) may persist for a short period of time. In most patients there may also be, for a period of time, a certain degree of metabolic activity (oxygen consumption, glucose consumption, etc...) , due to the persistence of glial cell and the activity of the basal metabolism of some neuronal groups.
Who should carry out the diagnosis of brain death?
The legislation of different countries and several guidelines suggest a widespread number of doctors (one to five) to perform the diagnosis of brain death. From a medical point of view is not needed more than one doctor to perform the diagnosis of death. The physicians attending the patient should make the diagnosis of brain death. These doctors must have enough experience not also for performing the diagnosis but also for the management of the patient when alive.
They need to be experienced in neurological diagnosis. If instrumental tests are required for diagnosis (EEG, evoked potentials, arteriography), they are best carried out and interpreted by specialists (neurophysiologists, radiologists, etc.), although this is not essential. In some countries, legal requirements demand the participation of three doctors in this diagnosis, one of whom must be a neurologist or neurosurgeon, and another a doctor in the unit where the patient is admitted.
How should the diagnosis of brain death be done?
Irrespective of the brain death concept used, an essential condition before diagnosing brain death is to identify: The cause of the brain damage (head injury, stroke, brain tumor, anoxia, etc.).
It is also necessary to exclude certain conditions that could simulate the clinical examination of a brain dead patient. (table 1) So, it is essential to discard any physical agents affecting the patient, such as induced hypothermia (remember that brain death is frequently associated to spontaneous hypothermia), neurodepressor drugs or neuromuscular blockers. It is important to emphasize that the prior administration of barbiturates (thiopental, phenobarbital), benzodiazepines (midazolam), neuromuscular blockers (atracurium, pancuronium, etc.) and anticholinergic drugs (atropine, etc.) could simulate the physical examination of a patient with brain death. In the cases of drugs that can be antagonised, the use of antagonists (flumazenil, etc.) is recommended.
Sometimes a reasonable time should be left for the drug to be eliminated (table 2). In case of doubt, instrumental tests refractory to the drug effect will be necessary for diagnosis, primarily tests that demonstrate cerebral circulatory arrest (conventional arteriography, perfusion studies using radioisotopes, transcranial Doppler sonography), or multimodal evoked potentials (all of them refractors to barbiturates and sedatives)
The hemodynamic situation must be normal, especially blood pressure, before considering the possible diagnosis of brain death, since severe arterial hypotension generates a severe decrease of cerebral perfusion pressure, and this may also simulate brain death.
Elements that support the diagnosis of brain death
To demonstrate the cessation of brainstem´s neurological functions, the best diagnostic tool is a clinical examination. However, several intracranial phenomena follow (table 3) whole brain death. The demonstration of such phenomena can be very useful for establishing the diagnosis of whole brain death and the irreversibility of the process. Its important to stress that the presence of such phenomena is not synonymous with brain death. So you can find, for instance, a flat electroencephalogram in a patient with neurological brainstem activity. However it is also important to stress that not all these tests have the same accuracy for diagnosing brain death. The neurophysiological tests, and the cerebral blood flow test, are the tests that are most accurate in relation to the development of whole brain death.
Clinical examination of the patient with brain death
Before carrying out diagnostic tests that may have a negative effect on the brain, it is advisable to run tests that do not have such an effect, thus preventing further damage if death is not confirmed. Therefore, the apnea test (which produces intracranial hypertension) should be the last clinical examination performed.
In patients in whom brain death is suspected, but who are under effect of depressor drug therapy (barbiturates, sedatives, etc.), before withdrawal the treatment, it is advisable to carry out diagnostic tests for brain death that are not affected by these drugs (evoked potentials, arteriography, doppler, etc.), which can also back up treatment withdrawal.
If a neurological clinical examination is performed in patients who have died from cardiac arrest, the results of it will be similar as those found in patients in brain death. The only noteworthy difference is the possibility of encountering spinal reflexes in patients with brain death.
It is, however, convenient to systematise the neurological examination of the patients. A clinical examination protocol (table 4) should include the following aspects:
Absence of photomotor reflex
The II and the III cranial nerve participate in the photomotor reflex. In brain-dead patients, when pupils are illuminated with a strong light there is no change in size. There is total absence of spontaneous or provoked ocular movements. There is also absence of spontaneous blinking. Eyelids are flaccid and without any movement. They do not necessarily cover the eye.
Absence of corneal reflex
When the cornea is stimulated (use a cotton swab) there is no motor (no blinking, no withdrawal) or vegetative (no tearing, no reddening) response.
Absence of facial movements
There are no facial movements due to the lack of activity of the nucleus of the seventh cranial nerves in the brainstem. Consequently no kind of facial movement is observed:
1.- No spontaneous movements
2.- No movement produced by a painful stimulus on the face
3.- No movements produced by a painful stimulus on the neck, thorax, limbs or abdomen.
Absence of spontaneous muscle movements
We must divide the clinical examination of motor responses into two parts.
A.- After stimulation of trigeminus area. No corporal motor or facial motor responses are observed after stimulus in the area nerved by the trigeminus.
B.- After stimulation spinal territories. In most patients with brain death there are no somatic motor responses (in neck, thorax, abdomen and limb muscle groups) after stimulating somatic territories. It is possible, however, to detect somatic motor responses (sometimes extremely complex) in certain patients with brain death when the stimulus occurs in any of the previously mentioned territories (neck, thorax, abdomen or limbs). These are spinal cord reflexes, the presence of which does not invalidate a diagnosis of brain death (table 4). These motor responses can also be found in a situation of ischaemia-anoxia of the spinal cord (for example, when clamping the aorta during organ extraction), and are similar to a cough response (sudden contraction of all the respiratory muscles), not invalidating, however, the diagnosis of brain death since the stimulus is produced in spinal territory.
Absence of oculovestibular reflexes
After elevating the head 30º, 50 ml. of freezing water is injected into the external auditory conduct (previously eliminating any existing earwax and assuring the integrity of the tympanum membrane). With the eyelids open, no ocular movements are observed after irrigation.
Absence of oculocephalic reflexes
The eyelids are kept open when the head is turned abruptly from side to side, maintaining the end positions briefly. Unlike the normal response, the eyes follow the head movement.
Absence of nausea reflex
No response is obtained when stimulating the base of the tongue and the posterior wall of the pharynx with a probe.
Absence of cough reflex
No type of response is obtained when repeatedly introducing a probe through the endotraqueal tube down to the lower respiratory tract. This is usually the last reflex to disappear.
The atropine test
The lack of response to atropine. In patients with brain death, when they are administered 0.04 mg/Kg of intravenous atropine, the increase in cardiac frequency is 10% or less of baseline frequency. The test examines the brainstem nucleus of the vagus nerve, located in the lower part of the brainstem. It should be performed after clinical examination and always after examining the photomotor reflex. The atropine should be injected in an independent venous line, without mixing with other drugs that could interfere with the test results, especially chronotropic drugs (dopamine, dobutamine, etc).
Apnea test
This test shows the lack of brainstem respiratory centre function. There are several ways to perform this test. One of them is: the patient is given 100% oxygen for 20 minutes, then withdrawn from the respirator and provided with a 6 l/min flow of oxygen through the endotraqueal tube. We wait until the pCO2 reaches 60 mmHg (the mean elevation in blood is of 3 mmHg/min) or less than 50 mmHg of pO2 patients with a possible dependence on hypoxic stimuli for ventilation. No kind of respiratory movement is observed. This should be the last clinical examination to be performed. Movements of the diaphragm because of the heart beat should not be mistaken for a positive ventilatory response.
Practical considerations about the use of clinical examinations for the diagnosis of brain death.
If we are using the brainstem death concept, the clinical prerequisites are fulfilled (No pharmacological, or physical factors influencing above the clinical exam), the mechanism of brain damage is well-known, and the clinical examination is completed according to the previous protocol, a diagnosis of brainstem death can be established.
If we are using the Whole Brain death concept, besides the previous clinical examination, diagnosis of death requires the demonstration of at least one of the phenomena more clinically related to brain death (cerebral circulatory arrest, or absence of bioelectric activity in the central nervous system). It is therefore necessary to confirm the lack of cerebral circulation and/or the absence of electric activity in the brain by means of instrumental tests.
Instrumental tests in the patient with brain death
There is no single instrumental test that demonstrates the absence of all neurological functions in the central nervous system. However, there are different instrumental tests that are capable of demonstrating the presence of phenomena closely related to brain death, such as cerebral circulatory arrest, absence of bioelectric activity or the decrease of cerebral aerobic metabolism. These tests (table 6) are complementary to those used to document the neurological function.
Electroencephalogram
An electroencephalographic register obtained over 30 min., with amplification characteristics of 2 microv/mm, frequency bands between 0.3 and 30 Hz, electrodes spaced at least 10 cm apart, placed at frontal, temporal, occipital and parietal regions, and with painful stimulation of the patient, will document existing cerebral electrical activity. No activity is considered as electric brain silence, a null recording or other synonyms such as a flat EEG.
In the electroencephalogram of some brain dead patients it is possible to register electrical activity due to cardiac activity. In those cases, there are spikes in the EEG that coincide with the QRS complex of the electrocardiogram.
Multimodal evoked potentials
The multimodal evoked responses to luminous, sound and electrical stimuli examine the visual, auditory and somatosensorial pathways at different levels. They provide information regarding the indemnity of the pathways or their exclusive functional extension to the peripheral nervous system. Evoked responses that identify the spinal cord as the highest level of nerve signal processing are compatible with brain death . Evoked responses are resistant to central nervous system depressor drugs, such as barbiturates, as shown in many clinical and experimental studies. The persistence of evoked responses has also been demonstrated, although with modifications of the latency period, in induced hypothermia.
Transcranial doppler sonography
Besides its use in the management of patients with cerebrovascular and traumatic processes, it is very useful in the diagnosis of progressive circulatory cessation of the large intracranial arteries found in brain death. In these patients the flow wave shows a pattern of high resistance that determines the absence or inversion of the diastolic flow or small or isolated systolic spikes. Decrease in the mean velocity and a significant elevation of the pulsatility index are associated to these modifications. The use of transcranial Doppler sonography has the advantage of being able to be performed at the patient’s bedside frequently, or even by permanent monitoring. This has verified that the cessation of cerebral circulation is a process that begins (especially in supratentorial pathology with intracranial hypertension) with a progressive decrease in diastolic flow speed, followed by a separation of the diastolic and systolic wave , an inversion of the diastolic flow wave (reverberanting flow), a disappearance of the diastolic wave and, finally, and especially in patients with an over 24 hr cerebral circulatory arrest, the impossibility of obtaining signs of cerebral flow.
 |
| Transcranial Doppler of middle cerebral artery in a brain dead patient, showing a Reverberating Flow Pattern. |
Cerebral arteriography
Cerebral arteriography of the 4 vessels in patients with brain death can be extremely valuable for the diagnosis of cerebral circulatory arrest. Cessation of circulation is not instantaneous, but progressive. Different patterns, all compatible with brain death, can be seen:
a- Total arrest of arterial contrast and lack of vein filling. The contrast material disappears retrogradely
b- The cessation of cerebral circulation at Willis´ polygon,
c- Extreme slowing of arteriovenous circulation time. A lengthening of over 15 seconds is not compatible with cerebral function.
Digital subtraction intravenous angiography is also successfully used to verify cerebral circulatory arrest and based on the same principles as conventional arteriography. The movement of patients out of intensive care units (with less monitoring and possibility of treatment) is one of the greatest disadvantages of these techniques.
Isotope perfusion studies
Nuclear medicine also has interesting possibilities for confirming cerebral circulatory arrest, particularly since the recent development of lypophillic radiosubstances. These tracers, capable of crossing the intact blood-brain barrier, present high extraction in the first step and prolonged brain retention. I123IMP and Tc99mHMPAO are those mainly used to study brain death.
They show no differences regarding results, although Tc99mHMPAO is used more often because of higher availability. These radiotracers do not have the disadvantages of the nondiffusible tracers used previously (depending on the correct bolus, with poor spatial resolution and capacity for posterior fosse evaluation). Angiogammagraphy with Tc99mHMPAO consists of 2 phases: the first evaluating cerebral blood flow, and the second phase, 5-10 minutes after injection, when static images are obtained in anterior, lateral right and lateral left projection, evaluating parenchymal capture. Gammagraphy with Tc99mHMPAO is easy to perform, highly sensitive and specific, with no interference by the patient's clinical conditions or the administration of central nervous system depressor drugs. This permits an exact, quick and early diagnosis of brain death, especially important in patients treated with barbiturates, benzodiacepines, etc. Another additional advantage, in potential organ donors, is the possibility of evaluating the perfusion of other organs.
Other instrumental tests
Other instrumental tests, such as the analysis of cerebral oxygen consumption by means of a catheter positioned in the bulb of the internal jugular vein, or the estimation of cerebral perfusion pressure by measuring intracranial pressure and mean arterial pressure, are useful data to complement a brain death diagnosis, although it is not accurate enough for the technique to be instrumental for diagnosis purposes.
Are all these tests necessary to diagnose brain death?
When we are working with the whole brain death concept, it is not always necessary to use some of the previously described instrumental methods for the diagnosis of brain death. Like any other medical diagnosis, the methods should be selected according to the sound judgement of the clinicians making the diagnosis. Because of their accessibility and widely extended use, there must be a complete clinical examination, an electroencephalogram and/or any of the tests that demonstrate the arrest of cerebral circulation (Doppler, angiography, gammagraphy, etc.). However, because of the implications of the diagnosis, one should use the methods available at the center where the patient is admitted.
What time period is needed to establish a diagnosis of brain death?
When the first criteria of brain death were described (Criteria of the Harvard Medical School), the clinical and complementary signs had to be maintained for at least 24 hours before confirming the diagnosis of brain death. Today we can say that, after excluding the agents that could interfere with the diagnosis and complying with all the prerequisites, with a patient in a coma of known etiology, presenting brain death on clinical examination, a flat EEG and the absence of cerebral flow, brain death can be diagnosed.
Conflictive situations in the diagnosis of brain death
The most frequent conflicts in the diagnosis of brain death are the following: diagnosis in children and in patients under the effects of central nervous system depressor drugs.
In new born children, diagnostic criteria are applicable after 7 days of brain injury; in patients between 7 days and 2 months of age, the observation period should cover 48 hours; in patients between 2 months and 1 year of age, two separate examinations, at least 24 hours apart, are recommended. Longer periods of clinical observation are also wisely recommended when there is difficulty in confirming the irreversibility of the lesion, as in the case of ischaemic-anoxic encephalopathy. The use of techniques that study cerebral perfusion for the verification of cerebral circulatory arrest can shorten these observation periods.
The administration of high doses of barbiturates can interfere with the clinical examination and EEG of patients in whom brain death is suspected. There is no unanimously accepted approach. While certain authors wait until the plasmatic levels of barbiturates decrease to certain levels, others wait until these levels reach zero. It is true that certain cases of barbiturate therapy or intoxication have been reported to present reversible electric brain silence. However, it is also true that the plasmatic levels of the barbiturates at the moment of recording were approximately 100 microgram/ml. Since, in our experience, the plasmatic levels of thiopental (used for the control of intracranial hypertension) were never greater than 10 microgram/ml, the safety range is wide enough to consider a decrease of the barbiturates down to therapeutic levels as sufficient. However, the use of techniques such as multimodal evoked potentials or techniques examining cerebral blood flow is justified for confirming diagnosis, since they are refractory to barbiturate therapy.
TABLE 1
DIAGNOSIS OF BRAIN DEATH.
ESSENTIAL PRECONDITIONS AND NECESSARY PREREQUISITES
1.- ESSENTIAL PRECONDITION: COMA OF KNOWN ORIGIN
2.- NECESSARY PREREQUISITES:
TABLE 2
HALF LIFE OF SOME NEURODEPRESSOR DRUGS FREQUENTLY USED IN ICU
| Midazolam | 1-4 hours |
| Diazepam | 20-70 hours |
| Morfine | 2-3 hours |
| Droperidol | 1,5-2 hours |
| Fentanyl | 30 min-90 min |
| Remifentanyl | 8-15 min |
| Thiopental | 6-80 hours |
| Propofol | 30 min-4 hours |
TABLE 3
INTRACRANIAL PHENOMENA RELATED TO WHOLE BRAIN DEATH
1.- CEREBRAL CIRCULATORY ARREST
2.- ABSENCE OF BIOELECTRICAL ACTIVITY OF THE CENTRAL NERVOUS SYSTEM
3.- DECREASE OF CEREBRAL OXYGEN CONSUMPTION
4.- OTHERS
TABLE 4
CLINICAL EXAMINATION PROTOCOL
TO DEMONSTRATE BRAIN DEATH
1.- ABSENCE OF PHOTOMOTOR REFLEX
2,. ABSENCE OF CORNEAL REFLEX
3.- ABSENCE OF FACIAL MOVEMENTS
4.- ABSENCE OF SPONTANEOUS MUSCLE MOVEMENTS
5.- ABSENCE OF OCULOVESTIBULAR REFLEXES
6.- ABSENCE OF OCULOCEPHALIC REFLEXES
7.- ABSENCE OF NAUSEA REFLEX
8.- ABSENCE OF COUGH REFLEX
9.- ABSENCE OF RESPONSE TO ATROPINE
10.- ABSENCE OF SPONTANEOUS BREATHING
TABLE 5
REFLEX AND SPONTANEOUS MOVEMENTS SPINAL –CORD MEDIATED
| Flexor plantar reflex |
| Flexor withdrawal reflex |
| Abdominal reflex |
| Cremasteric reflex |
| Anal reflex |
| Bulbocavernous reflex |
| Cervicoabdominal reflex |
| Bringing one or both arms up to the face |
| Sitting up (Lazarus sign) |
TABLE 6
INSTRUMENTAL TESTS USEFUL FOR THE DIAGNOSIS
OF BRAIN DEATH
1.- ELECTROENCEPHALOGRAM
2.- MULTIMODAL EVOKED POTENTIALS
3.- TRANSCRANIAL DOPPLER SONOGRAPHY
4.- CEREBRAL ARTERIOGRAPHY
5.- CEREBRAL ISOTOPIC STUDIES
6.- OTHERS
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hi jose maria
it is very informative ...