Mathematics57

Abstract
The necessity of defining brain death (BD) arose from technological development in medical science. The definition of this concept had practical consequences and opened the way to organ donation from BD patients. Nowadays, the imbalance between the number of organs available for transplantation and the size of the demand is becoming critical. In most laboratories, a BD diagnosis is made according to precise criteria and in a well-defined process. BD diagnosis should be improved, not only to assure the safety and to preserve the human dignity of the patient, but also in order to increase the rate of organ donation. By analysing some epidemiological parameters in BD diagnosis and organ donation, it appears that BD diagnoses can be made more often and more rapidly if one has a reliable, accurate, and safe confirmatory test, especially under misleading conditions (hypothermia, drugs, metabolic disturbances). In our experience, the use of multimodality evoked potentials (MEPs) to confirm a BD diagnosis has many advantages: MEPs can be rapidly performed at the patient’s bedside, assess the brain stem as well as the cerebral cortex, and are innocuous for the patient. Moreover, their insensitivity to the aforementioned misleading factors is sufficient to distinguish BD from clinical and EEG states that mimic BD. They give an immediate diagnosis, and no delay is required in BD confirmation if there is sufficient cause to account for BD. MEPs are a safe, accurate, and reliable tool for confirming a BD diagnosis, and their use can improve the organ donation rate while preserving the safety of the patient.
Introduction
The increasing imbalance between the number of organs available for transplantation and the demand is becoming critical in most countries. Enlarging the organ reservoir could reduce the problem. In a recent article,1 Jones and Simpson analysed the problem of organ donation from drug abusers and poison victims. For the authors, three main problems are encountered: the brain death (BD) diagnosis in such patients, the fitness and the selection of these organs, and the higher risk of infectious disease transmission.

The last two problems are qualitatively the same, but quantitatively more important than in other cases of transplantation when toxicity and infection are not present. As suggested by Jones and Simpson,1 they could be solved, or at least minimized, by measures such as pre-transplant biopsy of the organs, thorough infectious disease screening prior to transplantation, and extended perfusion of the organs. The first problem is quite different in nature and requires specific measures in cases of hypothermia or metabolic disturbances. It can be extended to the general problem of anaesthetized or sedated patients in the Intensive Care Unit (ICU).

From our experience, multimodality evoked potentials (MEPs) could be a safe diagnosis tool of BD in such situations thanks to their relative insensitivity to these misleading factors. Moreover, the 24-h delay recommended by the Ad Hoc Committee of the Harvard Medical School2 in order to avoid a false-positive BD diagnosis in doubtful conditions could be short-circuited by the use of MEPs, since they can confirm BD diagnosis unambiguously in most cases.
Brain death diagnosis
BD is a modern concept engendered by technological developments in medical science, especially the advent of the respirator. For R.M. Taylor,3 it is also `a social construct that was created for utilitarian purposes’, and its preservation `is necessary to the continuation of our current program of organ transplantation’. Without being so restrictive (first of all the need for a BD diagnosis is a matter of human dignity for the patient), we are forced to accept that BD diagnosis and organ transplantation are closely related. So BD diagnosis improvements could have beneficial outcomes for organ transplantation while preserving the safety of the patient.

Depending on the approach, BD is defined as the complete and irreversible loss of all brain and brain-stem function (whole brain formulation), or as the complete and irreversible loss of the brain-stem function, irrespective of the state of the cerebral cortex.4 Whatever concept we consider, brain-stem death is a feature common to both approaches. Absence of cerebral responses and brain-stem-mediated reflexes, including apnoea, occur in BD. However, this clinical pattern is not sufficient to confirm BD in all cases. A BD diagnosis needs a prerequisite (sufficient cause to account for BD) and comprises a differential-diagnosis process to exclude states mimicking BD (hypothermia, metabolic disorders, drugs, or neurological diseases). It ends with a decision-making process accompanied or not by confirmatory tests, even if BD is basically a clinical diagnosis. A well-defined process and BD criteria are applied by most laboratories, usually in function of local legislation. A minimal observation delay is often required, and repeated tests are needed to avoid false-positive BD diagnosis, particularly in the presence of misleading factors.2,,5 Nevertheless, a delay in BD diagnosis can affect the quality of the organs, or make them unsuitable for transplantation by permitting the occurrence of events such as multi-organ failure or cardiac arrest. Confirmatory tests can be required either routinely or only when potentially misleading factors like hypothermia, drugs or metabolic disturbances are present. In case of BD, these tests demonstrate either the absence of cerebral blood flow or the absence of electrocerebral activity.
Epidemiology of brain death and organ donation
In England and Wales6 in the years 1989 and 1990, brain-stem death was suspected in 13.6% of the ICU deaths, and was confirmed in 10% of them; 50% of them led to organ donation. In the Madrid study,7 performed from 1991 to 1993, BD accounted for 0.8% of all deaths, 2% of hospital deaths and 13.4% of ICU deaths, of which 48% of the patients eventually became effective donors. In 1996 in France,8 less than 1% of all deaths were diagnosed as BD, and 55% of these patients became donors. In our hospital, the rate of BD diagnosis was 2.7% of all in-hospital deaths and 9% of ICU deaths from 1993 to 1996; from 1993 to 1997, of the 105 diagnosed cases of BD, 58% gave rise to organ transplantation.

According to these studies, medical problems prevented the organ donation in 18%,6 24%,7 13%,8 or 53%9 of the BD cases. Family refusal occurred in 17%,7 30%,8 and 28%9 of the BD cases. Cardiac arrest occurred before organ donation in 9% of the cases in the Madrid study. Other causes (logistical problems and miscellaneous) impeded transplantation in 2%.6,,7 In our experience, medical contraindications prevented organ donation in 4% of the cases of BD, family refusal in 15% and other causes in 1% (Table 1). Among our patients, the low rate of medical contraindication is partially due to the high number of cases without an identified cause for impeding the organ transplantation (22%).

Enlarge table
Table 1 
Epidemiological data in brain death diagnosis and organ donation

Studies Years BD BD/ICUM Donors Medical reasons Cardiac arrest Family refusal
The rate of brain death (BD) diagnosis compared to the ICU mortality (ICUM) is quite constant whatever study we consider. Slight differences are linked (i) to the different approaches of the BD concept (systemic approach for Gore et al.6 or whole brain formulation for others) and (ii) to the degree of certainty of BD diagnosis (suspected BD in Navarro7 and confirmed BD by others). The rate of donors and the frequency of medical contraindications (multi-organ failure, sepsis, drugs, etc) are significantly different from one study to another, probably due to different approaches to BD diagnosis and organ-donation procedure. The use of a fast and reliable confirmatory tool in BD diagnosis could decrease the rate of medical contraindications and the occurrence of deleterious events like cardiac arrest or multi-organ failure. * Unpublished data.
England and Wales5 1989–90 2389 10% 50% 18% 23%
Madrid6 1991–93 855 13.4% 48% 24% 9% 17%
France7 1996 1600 55% 13% 30%
Ankara8 1996–97 32 8.3% 19% 53% 28%
St-Luc* 1993–97 105 9% 58% 4% 15%
By studying these differents parameters, we defined several levels of improvement in BD diagnosis and BD management. From philosophical reflections (changing or extending the concept of brain death or death) to practical solutions (improving the efficiency of the system), improvements could increase the number of organ donations (Figure 1). Gore et al.6 particularly regretted the number of undiagnosed probable BD cases (3.6% of the ICU deaths) due to the unavailability of a confirmatory test. On the other hand, for the same authors,6 `action on general medical contraindications to organ donation could diminish a … major barrier’. Upstream as well as downstream of the final BD diagnosis, the improvement of the diagnosis tools will increase the number of potential donors. In fact, by accelerating the BD diagnosis, and avoiding uncontrollable complications (multi-organ failure or cardiac arrest) and increasing the certainty of the BD diagnosis in some categories of patients (poison victims or drug abusers), the number of potential donors may be expected to increase. It is our opinion that MEPs can provide a helpful tool in this setting.

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Figure 1.
Improvement of BD diagnosis and BD management: points of intervention. MEPs can act at different levels either by accelerating the BD diagnosis or by decreasing the rate of medical contraindications. MEPs can also improve the safety of the presumed BD patient by invalidating BD.

Confirmatory tests for brain death: contributions and limits
Ideally the confirmatory tests must be (i) rapidly performed at the patient’s bedside, (ii) innocuous for the patient (and for the potential recipient), and (iii) insensitive to misleading factors.10 These tests are either cerebral blood flow evaluation techniques (four-vessel arteriography, radioisotopic techniques, and transcranial doppler) or electrophysiological tests (EEG, EPs). In case of BD, the former demonstrates the absence of cerebral blood flow and the latter shows the absence of electrocerebral activity.

Four-vessel arteriography gives clear-cut results in misleading conditions, but its total innocuity has not been proven either for the patient (hazardous transportation, contrast-product injection11,,12 or for the potential recipient (contrast-product injection11,,12). It can be inefficient (false-negative) in cases of open-head trauma.

Radioisotopic techniques also show some weaknesses (non-quantitative character, inability to image the flow of the posterior fossa and possible persistent filling of venous sinuses). In our opinion, the discrepancies between radioisotope-based BD diagnosis and EEG results13,,14 have to be interpreted more in terms of radioisotope technique failure in diagnosing persistent brain activity than in terms of EEG failure in diagnosing BD. Ashwall and Schneider13 interpret their results as the possible persistence of isolated islands of cortex perfused by leptomeningeal collateral circulation. Actually, at least in the whole-brain formulation, the persistence of electrocerebral activity is sufficient to invalidate the BD diagnosis, whatever the blood flow source may be.

Transcranial doppler is a promising technique but highly operator-dependent, and, assessment of the vertebrobasilar system is particularly difficult in comatose patients.15 More studies are needed to confirm the current results.

The EEG is by far the most used confirmatory test in the BD diagnosis. Nevertheless, this technique is very sensitive to hypothermia, drugs, and metabolic disorders, and therefore has the same limitations as the clinical examination. Drugs such as barbiturates, diazepam, metaqualone, meprobamate, and trichlorethylene, in particular, can cause reversible electrocerebral silence (ECS).16 Thus the EEG does not allow one to short-circuit the observation delay often required in guidelines for BD diagnosis.2,,5 Moreover, in the whole-brain formulation as well as in the brain-stem-death approach, one can reproach the EEG for its absence of brain-stem testing. Finally, EEG results can be ambiguous in the highly artifactual environment of the ICU.

In our hospital, MEPs (BAEPs, flash VEPs, median SEPs) have been used as a confirmatory tool of BD for more than 15 years. They are easily and rapidly recordable at the patient’s bedside and evaluate the brain stem as well as the cerebral cortex. Brain-stem auditory EPs (BAEPs) are recorded in the 10 ms following the application of auditory clicks and consist of seven peaks. Peaks I to V are studied in most clinical settings: peak I (and partially peak II) corresponding to the cochlear nerve, and peaks II to V corresponding to the pontine auditory pathways. Upper-limb somatosensory EPs (SEPs) are obtained after electrical stimulation of the median nerve at the wrist. Multilevel recordings can be done at (i) a peripheral level (Erb’s point) corresponding to the afferent volley in the brachial plexus (N10), (ii) a cervical level (C6 spinous process) corresponding to a segmental activity in the dorsal cervical horn (N13), (iii) a low brain-stem level (scalp recording referred to linked ears) corresponding to a lemniscal activity (P14), and (iv) a double cortical level, parietal (N20-P27-P45 complex) and frontal (N30). Flash-visual EPs are obtained after LED (light-emitting diode) stimulation, and consist of seven peaks occurring in the 250 ms following the stimulation. Peak I corresponds to retina activation, while peaks III to VI correspond to the visual occipital projections and peak VII to associative areas. Detailed recording and stimulation parameters are described elsewhere.17 The three-modality EP pattern of BD is highly specific, and associates the disappearance of all cortical and brain-stem activities to the persistence of retinal, peripheral, and spinal activities (Figure 2). It is unequivocal in most situations mimicking BD. Only the association of a bilateral optic-nerve section, a spinal-cord interruption at the cervical level, and a bilateral auditory-nerve section could mimic the MEP pattern of BD. In case of trauma, this possibility has to be ruled out by appropriate testing (skull and spinal X-ray, CT scan or MRI). MEPs can differentiate BD from primary brain-stem death or from neurological disease such as the Guillain-Barré syndrome by the persistence of flash VEPs (and by the presence of a severe peripheral neuropathy affecting sometimes the auditory nerves in the Guillain-Barré syndrome) and from misleading factors such as hypothermia, drugs, and metabolic disturbances, or from vegetative state by the persistence of brain-stem activities (waves from II to V in BAEPs and P14 in median nerve SEPs).

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Figure 2.
MEP pattern in a BD patient. MEPs were recorded from a 33-year-old man. At the time of recording, clinical examination was consistent with BD diagnosis. Flash VEPs show only a retinal component (wave I) on the cortical channel as well as on the periocular recording. Median-nerve somatosensory responses are only represented by peripheral (Erb) and by spinal (N13) components, while brain-stem and cortical components are bilaterally absent. BAEPs are limited to a cochlear nerve component (wave I).

Critiscisms of the use of EPs in the BD diagnosis are mainly of three kinds:4 the persistence of activities of intracranial origin in BD patients, the recovery of patients with EP pattern of BD, and the fact that EPs do not test the entire central nervous system (CNS). The persistence of presumed intracranial activities per se precludes total brain destruction; in some cases these activities are not of neural but only of muscular origin and can be suppressed by patient curarization.18 In all the reports concerning recovery of patients with EP pattern of BD,19–,21 BAEPs were used alone, but we recommend the use of three-modality EPs. Moreover, in most cases, other causes of BAEP alterations were present, such as anoxia or kernicterus, which are known to give possibly reversible BAEP abnormalities. Finally, the clinical (or EEG) pattern was not consistent with BD diagnosis in most cases, and in no case was the cause of coma sufficient to provoke BD. The third argument against the EP use in BD diagnosis is more theoretical. No test, even clinical examination, assesses the entire CNS. In other respects, BD diagnosis can raise from the results of a confirmatory test as MEPs only when the cause of coma is clearly identified as sufficient to provoke brain death and the results of clinical examination are completely compatible with BD.
MEPs and misleading factors
VEPs show the same sensitivity to misleading factors as the EEG, however, their lower sensitivity to environmental artifacts due to the averaging process is a significant advantage over the EEG and makes their interpretation easier.4

Hypothermia per se or relative hypothermia due to drugs is often experienced in comatose patients. BAEPs are still present as long as the body temperature exceeds 20 °C to 22 °C.22 From our experience in recording SEPs during profound hypothermia for surgical aorta repair,23 the lemniscal P14 of median nerve SEPs only disappeared at 18 °C, while cortical SEP activities can be recorded at temperatures around 22 °C. In most clinical situations, the hypothermia level is less marked and does not interfere with MEP interpretation.

Drugs affecting consciousness can be divided into three major groups: the CNS-depressant drugs, the drugs giving rise to anoxia and the drugs impairing important metabolic functions. The CNS depressant drugs act directly at the neuronal level interfering with neurotransmission. Other groups have a systemic effect leading to metabolic disturbances and cerebral oedema in the extreme cases.

With regard to CNS-depressant drugs, there is a large consensus among the authors that BAEPs and SEPs are a good tool for examining brain-stem function when CNS-depressant drugs are present. For Jones,24 EPs are the most useful alternative test in the clinical assessment of the neurological status in comatose patients when sedating or paralysing drugs are present. They can be simply and repeatedly applied at the patient’s bedside in the ICU and might be included in the BD criteria.24 BAEPs are unchanged under normal sedative medications (chloral hydrate or diazepam) and remain detectable in anaesthesia with barbiturates or nitrous oxide and halothane. BAEPs can thus be considered as relatively insensitive to pharmacological factors.25 For Chiappa,26 clinical interpretation of BAEP results are not affected by the presence of CNS-depressant drugs or variations in intrinsic metabolic factors, and the brain-stem function can be assessed by BAEPs in such situations. In the presence of CNS-depressant drugs, BAEPs are either unchanged at therapeutic levels (thiopental, barbiturates, ketamine, halothane, isoflurane, chloralose, phenothiazine, benzodiazepines) or delayed at therapeutic or toxic levels (thiopental, barbiturates, alcohol, phenytoin, nitrazepam, amitryptillin, meprobamate). Amplitude or morphological changes can occur with enflurane, cholinergic and serotoninergic agents, phentolamine, and propranolol.27 Mauguière et al.28 showed deep reversible BAEP alterations following the association of barbiturates and xylocaine in one case. Nevertheless, for Chiappa, BAEPs provide a sufficient safety margin to be used in comatose patients and remain an indicator of preserved brain-stem function in difficult clinical situations.27 SEPs are also poorly affected by CNS-depressant drugs. Increased latencies with increased central conduction time (as measured between cervical N13 and parietal N20) have been observed in amitryptilline, meprobamate and nitrazepam overdose.29

For Chatrian30 too, electrophysiological tests provide objective proof of permanent loss of brain function in difficult clinical situations. The main advantage of EPs compared to EEG is their insensitivity to most medications in the dosages and concentrations commonly used in the comatose patient.30 In our experience, barbiturate intoxication sufficient to provoke a clinical and EEG pattern of BD is associated with well-preserved BAEPs and persistent P14 in the median nerve SEPs (Figure 3). Thus, the MEP pattern in BD is clearly distinct from that observed in CNS-depressant intoxication.

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Figure 3.
Electrophysiological study in a 5-year-old epileptic girl under barbiturate. At the time of recording, blood level of thiopental was 53 μg/ml and all cephalic reflexes were absent. The EEG was isoelectric during long periods. Median-nerve SEPs show delayed but recognizable lemniscal (P14) and cortical (N20) activities. The BAEPs are well-preserved but slightly delayed.

Except for CNS-depressant drugs, substances involved in poisoning are (i) those giving rise to anoxia either by affecting the respiratory or cardiovascular systems (e.g. antiarrhythmic drugs, tricyclic antidepressants) or by acting directly at the cellular level (CO, CN) and (ii) those impairing other important functions (paracetamol or acetaminophen hepatotoxicity, methanol acidosis, insulin-induced hypoglycaemia).31 There is little information in the literature about the effect of lethal doses of these substances on EEG and EPs. In animal studies, most of the isoelectric-EEG recordings obtained after acute poisoning were linked to anoxia, and no EP recordings were performed. In the cat, insulin-induced hypoglycaemia with isoelectric EEG was described in association with persistent BAEP and SEP components.32 In humans the physiopathogenic mechanisms in these intoxications are mainly anoxia and metabolic disturbances. In our experience, pure anoxia seldom gives rise to brain death, except when associated with brain oedema leading to acute intracranial hypertension. Indeed, the brain-stem sensitivity to anoxia is almost the same as that of the myocardium. When anoxia is sufficient to provoke brain-stem death, cardiac failure occurs simultaneously. However, the high sensitivity of the cochlea to anoxia may provoke an early disappearance of BAEPs from wave I. Simultaneous recording of SEPs and VEPs will avoid a misdiagnosis in such cases.

Hepatic encephalopathy (paracetamol or acetaminophen poisoning) and metabolic acidosis (methanol poisoning) can also give rise to severe cerebral oedema and acute intracranial hypertension.31 It has been reported that insulin-induced hypoglycaemia provokes shifts of water from the extracellular to the intracellular compartment, as does ischaemia.33 Indeed, the occurrence of a severe cerebral oedema with the subsequent development of intracranial hypertension leading to irreversible brain-stem damage is the common pathway of all these physiopathogenic mechanisms. In our experience, brain oedema consistently preceded BD in poisoned patients in whom a cerebral CT scan was performed.31 Drug intoxication cannot account for a complete MEP pattern of BD, if BD is not really present. Subcortical (and even cortical) activities persist in high doses of CNS-depressant drugs sufficient to give rise to a clinical and EEG pattern of BD. The MEP pattern of BD is encountered in other drug intoxication only when irreversible damage occurs at the brain stem and the cerebral cortex.
Conclusion
The diagnosis of BD may be difficult when misleading factors like hypothermia, drugs, or metabolic disturbances interfere with the clinical examination or confirmatory tests. From the literature, it appears that MEPs, by testing the brain stem as well as the cerebral cortex, and thanks to their relative insensitivity to these misleading factors, are a safe confirmatory test for BD diagnosis. In our experience, MEPs are innocuous, rapidly performed at the patient’s bedside and do not require any delay in diagnosing BD, provided that a sufficient cause to account for BD is present. Their general use could improve the accuracy of the diagnosis of BD, especially in the presence of misleading factors, and so increase the number of organ donations while assuring the safety of the potential donor.
© Association of Physicians 1999
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