- Email: [email protected]
Brain-death diagnosis and organ procurement in misleading conditions
Brain-Death Diagnosis and Organ Procurement in Misleading Conditions M. de Tourtchaninoff and P. Hantson
T
HE necessity to define brain death (BD) arose from technological developments in medical science opened the way for organ donation. Today the increasing imbalance between the supply and demand for transplantation is becoming critical in most countries. Consequently surgeons are exploring organ donation from drug abusers and poison victims.1,2 Three main questions are encountered in this problem establishing the BD diagnosis, the selection of these organs, and the possibility of an increased risk of infection disease transmission. In most hospitals, a BD diagnosis is made according to precise criteria using a well-defined process to assure the safety for the recepient and to preserve the human dignity of the donor. Fitting these requirements to increase the rate of organ donation, BD diagnosis can be made more often and more rapidly if one has a reliable, accurate, and safe confirmatory test, especially in the presence of misleading conditions including hypothermia, drug intoxications, and metabolic disturbances. In our experience, multimodality evoked potentials (MEPS) can be rapidly performed at the patient’s bedside to assess both the brain stem and the cerebral cortex, in a fashion that is inocuous for the patient.3 Moreover, because MEPS are insensitive to the aforementioned misleading factors, they distinguish BD from clinical and EEG states that may mimic BD.4 Furthermore MEPS also yield an immediate diagnosis; no delay is required in BD confirmation. Using this technique for BD diagnosis we reviewed the outcome of 58 grafts procured from 21 poisoned donors (suicide or accident) over a 9-year period. We observed extremely encouraging results compared with outcomes of grafts from nonpoisoned donors.5,6 In conclusion, MEPs represent a safe, accurate, and reliable tool to confirm a BD diagnosis. Their application can improve the organ donation rate while preserving the patient safety. TECHNICAL IMPROVEMENTS
In medical science have modified old concepts. The possibility to sustain vital functions in critically ill patients allows maintenance of patients “alive” against “nature.” A new concept has been needed to define death to preserve the human dignity of the patient as well as to ensure his safety before making an irreversible decision. This is the foundation of the BD concept. Simultaneously, medical progress opened the way to organ transplantation. In the meantime
between the BD diagnosis and the cessation of resuscitation measures, BD patients represent an organ reservoir. Nowadays, the disparity between the number of organs available for transplantation and the demand is growing. In the light of epidemiological data,4,7–10 one can dissect the rate of BD diagnosis and the rate of donation with relation to the total number of ICU deaths as well as reasons for nongiving of organs, especially the types of medical contraindications. The percentage of BD among the total donors ICU deaths is rather similar among studies: around 10%. Except for one study,10 the percentage of BD patients who become donors is also consistent, around 50%. Medical reasons are more closely correlated with the nondonation rate than are family refusal, or cultural factors. These medical reasons are often misleading factors that impede safe, reliable, and rapid BD diagnosis. Improvement in the rate of organ donation may arise from philosophical, general, or practical levels. From a practical and technical point of view, enhanced BD diagnosis may improve the reliability and decrease the rate of medical contraindications thereby significantly modifying the number of available organs. BD diagnosis follows a well-defined process that only slightly differs from country to country but obeys general rules11: the presence of a well-defined clinical pattern including brain-stem death; the existence of a sufficient cause accounting for BD; the exclusion of states mimicking BD; the execution of a decision-making process that is accompanied by confirmatory tests. Minimal observational delay and repeated evaluation are often required. Confirmatory tests may be needed routinely depending on the local legislation that become mandatory when clinical features are unclear. Two kinds of BD confirmatory tests include: tests assessing cerebral blood flow (angiography, scintigraphy, and intracranial Do ¨ppler) and tests assessing the electrocerebral activity (EEG, EPs). The ideal confirmatory test assesses brain and brain-stem function is safe for the patient From the Clinical Neurophysiology Unit (M.D.T.) the Intensive Care Unit (P.H.), Medical School of Louvain, Brussels, Belgium. Address reprint requests to Marianne de Tourtchaninoff, Unite´ d’Explorations Electrophysiologiques du Syste`me Nerveux, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03430-9
Transplantation Proceedings, 34, 2575–2577 (2002)
2575
2576
DE TOURTCHANINOFF AND HANTSON Table 1. Brain-Death Diagnosis: Comparison Between Different Confirmatory Tests
BD Confirmatory Tests
Arteriography Scintigraphy Doppler EEG MEPs
Cost
Patient’s Bedside
Innocuousness
⫹⫹⫹ ⫹⫹ ⫹ ⫹ ⫹
⫺ ⫺ ⫹ ⫹ ⫹
⫺ ⫹/⫺ ⫹ ⫹ ⫹
and the recipient, is unambiguous and thus insensitive to misleading conditions, is performed at the patient’s bedside, and is as cheap as possible.3 Comparing these different parameters for each test (Table 1) EPs in multimodality show an interesting profile with low cost, the possibility to be performed at the patients’s bedside, an inocuos nature and a good assessment of the brain stem. Their relative insensitivity to misleading factors is discussed in the following section. EPS IN BD DIAGNOSIS
For more than 15 years we have used EPs to assess comatose patients in the ICU. Recording and stimulation parameters have been described elsewhere.4 Used in multimodality, EPs have the advantage of testing cortical as well as brain-stem functions. Flash VEPs and median nerve SEPs give rise to cortical activities over the frontal, parietal, central, and occipital areas. Median nerve SEPs and BAEPs reveal subcortical components originating from the brain stem. The BD pattern of MEPs is highly specific. It combines the absence of cortical and brain-stem activities with the persistence of peripheral activities (retinal activity, peripheral nerve action potential, spinal activities, and cochlea component). 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 must be excluded. Three criticisms have been raised against the use of EPs in BD diagnosis3: (1) some reports show persistence of intracranial activities in BD patients, (2) recovery of patients with an EP pattern of BD, and (3) the failure of EPs to test the entire CNS. Some EP activities described in BD patients can be of muscular origin and are easily suppressed by curarization. If genuine intracranial activities are still recordable, by definition the patient is not brain dead. Concerning the report of recovery of patients who display an EP pattern of BD, BAEPs were used without other modalities; specific misleading factors were present like anoxia, which may affect the cochlea or bilirubinemia, which can affect brain-stem auditory conduction. Thus the clinical and/or EEG pattern was not consistent with a BD diagnosis. Concerning the last criticism, no test, even the clinical examination, assesses the entire CNS. MEPS IN MISLEADING CONDITIONS
The three main categories of misleading conditions for BD diagnosis are: (1) hypothermia, (2) poisoning or drugs, and
Brain-Stem Assessment
⫹ difficult difficult ⫺ ⫹
Ambiguous Results
Misleading Factor Sensitivity
⫺ ⫹ ⫹ ⫹ ⫺
⫺ ⫺ ⫺ ⫹⫹ ⫺
(3) metabolic disturbances. Due to their high sensitivity to these misleading factors, almost similar to the EEG sensitivity, VEPs will be considered separately. From the literature and from our experience of monitoring of EPs during profound hypothermia for aorta repair surgery, we know: (1) that BAEPs are still present at body temperature around 20 to 22°C,12 (2) that SEP cortical components disappear at a mean temperature of 22°C and SEP lemniscal activities disappear around 18°C.13 These temperatures are rarely met in clinical practice. Concerning CNS depressant drugs, specialists in the field are unanimous14 –18: BAEPs and SEPs represent a good tool for examining the brain-stem function when these drugs are present. Actually, components are unchanged or slightly delayed in normal sedation and modified but still recordable in deep anesthesia or intoxication by CNS depressant drugs. Concerning other drugs and metabolic disturbances, whatever the mechanism is (anoxia, acidosis, hypoglycaemia, or other), the common pathway for determining BD is finally cerebral edema and acute intracranial hypertension.4 No specific toxicity on brain or brain-stem electrical activities has been described except for increased bilirubin on BAEPs. Between 1989 and 1997 in our center, 58 organs were transplanted from 21 poisoned donors. Taking into account the specific toxicity of each substance, some organs were not used (liver in paracetamol poisoning, heart in tricyclic antidepressant intoxication). For each case, discussion was performed with a toxicologist before transplantation. Follow-up of the survival rate at 1 month, 1 year, and 5 years is shown in Table 2. It is not possible to definitely conclude about outcomes for most organs owing to the small number of grafts. Nevertheless no significant difference was observed between the survival rates for patients from the poisoned group and those from the nonpoisoned group, especially for kidneys. On the other hand, the causes of death do not appear to be related to a specific graft problem.5,6 CONCLUSION
In our experience, MEPS show a highly interesting profile to make a rapid but safe BD diagnosis. They are rapidly performed at the patient’s bedside. They are inocuous for the patient as well as for the recipient. They assess the cortex and the brain stem and give a clear-cut BD pattern. Owing to their relative insensitivity to several misleading factors, they are safe and reliable, allowing an accurate and immediate diagnosis. It appears that they could increase the rate of organ donation by accelerating the BD diagnosis
BRAIN-DEATH DIAGNOSIS
2577
Table 2. Comparison of the Survival Rate (1 and 5 Years) of Recipients From Poisoned Donors and Recipients From Nonpoisoned Donors Organs
Survival Rate at 1 Month (%)
Survival Rate at 1 Year (%)
Survival Rate at 1 Year Nonpoisoned Donors (%)
Survival Rate at 5 Years (%)
Survival Rate at 5 Years Nonpoisoned Donors (%)
Kidney (n ⫽ 39) Liver (n ⫽ 9) Pancreas (n ⫽ 2) Heart (n ⫽ 6) Lungs (n ⫽ 1)
100 78 100 67 100
100 67 100 50 100
97.1 88.6 79.3 81 67
88 67 100 33 100
94 65.7 59 72 50
No statistical analysis can be performed due to the small number of organs in each category. So, the very good 5-year survival rate for lung and pancreas has to be carefully interpreted.
process and by allowing a safe BD diagnosis in misleading conditions. The follow-up of 58 grafts procured from 21 poisoned donors over a 9-year period gives encouraging results in comparison with grafts obtained from nonpoisoned donors.
REFERENCES 1. Jones AL, Simpson KJ: Q J Med 91:589, 1998 2. Hantson P, Mahieu P: Q J Med 92:415, 1999 3. Gue´rit JM: Eur J Med 1:233, 1992 4. de Tourtchaninoff M, Hantson P, Mahieu P, et al: Q J Med 92:407, 1999 5. Hantson P, de Tourtchaninoff M, Mahieu P, et al: Re´anim Urgences 9:197, 2000 6. Hantson P, de Tourtchaninoff M: In Brent J (ed): Critical Care Toxicology. In press. 7. Gore SM, Cable DJ, Holland AJ: BMJ 304:349, 1992 8. Navarro A: Transplant Proc 28:103, 1996
9. Rapport du Conseil Me´dical et Scientifique de l’Etablissement Franc¸ais des Greffes. 1996 10. Altinors N, Benli S, Caner H, et al: Transplant Proc 30:771, 1998 11. Ad Hoc Committee of the Harvard Medical School: JAMA 13:2184, 1981 12. Gue´rit JM, Meulders M: Electroencephalogr Clin Neurophysiol 52:S39, 1981 13. Gue´rit JM, Sove`ges L, Baele P, et al: Electroencephalogr Clin Neurophysiol 77:163, 1990 14. Jones SJ: In Halliday AM (ed): Evoked potentials in clinical testing. 2nd ed. Edinburgh: Churchill Livingstone; 1993, p 462 15. Picton TW: In Daly DD, Pedley TA (eds): Current Practice of Clinical Electroencephalography. 2nd ed. New York: Raven Press; 1990, p 642 16. Chiappa KH: In Chiappa KH (ed): Evoked Potentials in Clinical Medicine: 2nd ed. New York, Raven Press; 1990, p 218 17. Chiappa KH: In Chiappa KH (ed):Evoked Potentials in Clinical Medicine. 2nd ed. New York: Raven Press; 1990, p 368 18. Chatrian GE: In Daly DD, Pedley TA (eds): Current Practice of Clinical Electroencephalography. 2nd ed. New York: Raven Press; 1990, p 425
T
HE necessity to define brain death (BD) arose from technological developments in medical science opened the way for organ donation. Today the increasing imbalance between the supply and demand for transplantation is becoming critical in most countries. Consequently surgeons are exploring organ donation from drug abusers and poison victims.1,2 Three main questions are encountered in this problem establishing the BD diagnosis, the selection of these organs, and the possibility of an increased risk of infection disease transmission. In most hospitals, a BD diagnosis is made according to precise criteria using a well-defined process to assure the safety for the recepient and to preserve the human dignity of the donor. Fitting these requirements to increase the rate of organ donation, BD diagnosis can be made more often and more rapidly if one has a reliable, accurate, and safe confirmatory test, especially in the presence of misleading conditions including hypothermia, drug intoxications, and metabolic disturbances. In our experience, multimodality evoked potentials (MEPS) can be rapidly performed at the patient’s bedside to assess both the brain stem and the cerebral cortex, in a fashion that is inocuous for the patient.3 Moreover, because MEPS are insensitive to the aforementioned misleading factors, they distinguish BD from clinical and EEG states that may mimic BD.4 Furthermore MEPS also yield an immediate diagnosis; no delay is required in BD confirmation. Using this technique for BD diagnosis we reviewed the outcome of 58 grafts procured from 21 poisoned donors (suicide or accident) over a 9-year period. We observed extremely encouraging results compared with outcomes of grafts from nonpoisoned donors.5,6 In conclusion, MEPs represent a safe, accurate, and reliable tool to confirm a BD diagnosis. Their application can improve the organ donation rate while preserving the patient safety. TECHNICAL IMPROVEMENTS
In medical science have modified old concepts. The possibility to sustain vital functions in critically ill patients allows maintenance of patients “alive” against “nature.” A new concept has been needed to define death to preserve the human dignity of the patient as well as to ensure his safety before making an irreversible decision. This is the foundation of the BD concept. Simultaneously, medical progress opened the way to organ transplantation. In the meantime
between the BD diagnosis and the cessation of resuscitation measures, BD patients represent an organ reservoir. Nowadays, the disparity between the number of organs available for transplantation and the demand is growing. In the light of epidemiological data,4,7–10 one can dissect the rate of BD diagnosis and the rate of donation with relation to the total number of ICU deaths as well as reasons for nongiving of organs, especially the types of medical contraindications. The percentage of BD among the total donors ICU deaths is rather similar among studies: around 10%. Except for one study,10 the percentage of BD patients who become donors is also consistent, around 50%. Medical reasons are more closely correlated with the nondonation rate than are family refusal, or cultural factors. These medical reasons are often misleading factors that impede safe, reliable, and rapid BD diagnosis. Improvement in the rate of organ donation may arise from philosophical, general, or practical levels. From a practical and technical point of view, enhanced BD diagnosis may improve the reliability and decrease the rate of medical contraindications thereby significantly modifying the number of available organs. BD diagnosis follows a well-defined process that only slightly differs from country to country but obeys general rules11: the presence of a well-defined clinical pattern including brain-stem death; the existence of a sufficient cause accounting for BD; the exclusion of states mimicking BD; the execution of a decision-making process that is accompanied by confirmatory tests. Minimal observational delay and repeated evaluation are often required. Confirmatory tests may be needed routinely depending on the local legislation that become mandatory when clinical features are unclear. Two kinds of BD confirmatory tests include: tests assessing cerebral blood flow (angiography, scintigraphy, and intracranial Do ¨ppler) and tests assessing the electrocerebral activity (EEG, EPs). The ideal confirmatory test assesses brain and brain-stem function is safe for the patient From the Clinical Neurophysiology Unit (M.D.T.) the Intensive Care Unit (P.H.), Medical School of Louvain, Brussels, Belgium. Address reprint requests to Marianne de Tourtchaninoff, Unite´ d’Explorations Electrophysiologiques du Syste`me Nerveux, Cliniques Universitaires Saint-Luc, Avenue Hippocrate 10, 1200 Brussels, Belgium. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710
0041-1345/02/$–see front matter PII S0041-1345(02)03430-9
Transplantation Proceedings, 34, 2575–2577 (2002)
2575
2576
DE TOURTCHANINOFF AND HANTSON Table 1. Brain-Death Diagnosis: Comparison Between Different Confirmatory Tests
BD Confirmatory Tests
Arteriography Scintigraphy Doppler EEG MEPs
Cost
Patient’s Bedside
Innocuousness
⫹⫹⫹ ⫹⫹ ⫹ ⫹ ⫹
⫺ ⫺ ⫹ ⫹ ⫹
⫺ ⫹/⫺ ⫹ ⫹ ⫹
and the recipient, is unambiguous and thus insensitive to misleading conditions, is performed at the patient’s bedside, and is as cheap as possible.3 Comparing these different parameters for each test (Table 1) EPs in multimodality show an interesting profile with low cost, the possibility to be performed at the patients’s bedside, an inocuos nature and a good assessment of the brain stem. Their relative insensitivity to misleading factors is discussed in the following section. EPS IN BD DIAGNOSIS
For more than 15 years we have used EPs to assess comatose patients in the ICU. Recording and stimulation parameters have been described elsewhere.4 Used in multimodality, EPs have the advantage of testing cortical as well as brain-stem functions. Flash VEPs and median nerve SEPs give rise to cortical activities over the frontal, parietal, central, and occipital areas. Median nerve SEPs and BAEPs reveal subcortical components originating from the brain stem. The BD pattern of MEPs is highly specific. It combines the absence of cortical and brain-stem activities with the persistence of peripheral activities (retinal activity, peripheral nerve action potential, spinal activities, and cochlea component). 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 must be excluded. Three criticisms have been raised against the use of EPs in BD diagnosis3: (1) some reports show persistence of intracranial activities in BD patients, (2) recovery of patients with an EP pattern of BD, and (3) the failure of EPs to test the entire CNS. Some EP activities described in BD patients can be of muscular origin and are easily suppressed by curarization. If genuine intracranial activities are still recordable, by definition the patient is not brain dead. Concerning the report of recovery of patients who display an EP pattern of BD, BAEPs were used without other modalities; specific misleading factors were present like anoxia, which may affect the cochlea or bilirubinemia, which can affect brain-stem auditory conduction. Thus the clinical and/or EEG pattern was not consistent with a BD diagnosis. Concerning the last criticism, no test, even the clinical examination, assesses the entire CNS. MEPS IN MISLEADING CONDITIONS
The three main categories of misleading conditions for BD diagnosis are: (1) hypothermia, (2) poisoning or drugs, and
Brain-Stem Assessment
⫹ difficult difficult ⫺ ⫹
Ambiguous Results
Misleading Factor Sensitivity
⫺ ⫹ ⫹ ⫹ ⫺
⫺ ⫺ ⫺ ⫹⫹ ⫺
(3) metabolic disturbances. Due to their high sensitivity to these misleading factors, almost similar to the EEG sensitivity, VEPs will be considered separately. From the literature and from our experience of monitoring of EPs during profound hypothermia for aorta repair surgery, we know: (1) that BAEPs are still present at body temperature around 20 to 22°C,12 (2) that SEP cortical components disappear at a mean temperature of 22°C and SEP lemniscal activities disappear around 18°C.13 These temperatures are rarely met in clinical practice. Concerning CNS depressant drugs, specialists in the field are unanimous14 –18: BAEPs and SEPs represent a good tool for examining the brain-stem function when these drugs are present. Actually, components are unchanged or slightly delayed in normal sedation and modified but still recordable in deep anesthesia or intoxication by CNS depressant drugs. Concerning other drugs and metabolic disturbances, whatever the mechanism is (anoxia, acidosis, hypoglycaemia, or other), the common pathway for determining BD is finally cerebral edema and acute intracranial hypertension.4 No specific toxicity on brain or brain-stem electrical activities has been described except for increased bilirubin on BAEPs. Between 1989 and 1997 in our center, 58 organs were transplanted from 21 poisoned donors. Taking into account the specific toxicity of each substance, some organs were not used (liver in paracetamol poisoning, heart in tricyclic antidepressant intoxication). For each case, discussion was performed with a toxicologist before transplantation. Follow-up of the survival rate at 1 month, 1 year, and 5 years is shown in Table 2. It is not possible to definitely conclude about outcomes for most organs owing to the small number of grafts. Nevertheless no significant difference was observed between the survival rates for patients from the poisoned group and those from the nonpoisoned group, especially for kidneys. On the other hand, the causes of death do not appear to be related to a specific graft problem.5,6 CONCLUSION
In our experience, MEPS show a highly interesting profile to make a rapid but safe BD diagnosis. They are rapidly performed at the patient’s bedside. They are inocuous for the patient as well as for the recipient. They assess the cortex and the brain stem and give a clear-cut BD pattern. Owing to their relative insensitivity to several misleading factors, they are safe and reliable, allowing an accurate and immediate diagnosis. It appears that they could increase the rate of organ donation by accelerating the BD diagnosis
BRAIN-DEATH DIAGNOSIS
2577
Table 2. Comparison of the Survival Rate (1 and 5 Years) of Recipients From Poisoned Donors and Recipients From Nonpoisoned Donors Organs
Survival Rate at 1 Month (%)
Survival Rate at 1 Year (%)
Survival Rate at 1 Year Nonpoisoned Donors (%)
Survival Rate at 5 Years (%)
Survival Rate at 5 Years Nonpoisoned Donors (%)
Kidney (n ⫽ 39) Liver (n ⫽ 9) Pancreas (n ⫽ 2) Heart (n ⫽ 6) Lungs (n ⫽ 1)
100 78 100 67 100
100 67 100 50 100
97.1 88.6 79.3 81 67
88 67 100 33 100
94 65.7 59 72 50
No statistical analysis can be performed due to the small number of organs in each category. So, the very good 5-year survival rate for lung and pancreas has to be carefully interpreted.
process and by allowing a safe BD diagnosis in misleading conditions. The follow-up of 58 grafts procured from 21 poisoned donors over a 9-year period gives encouraging results in comparison with grafts obtained from nonpoisoned donors.
REFERENCES 1. Jones AL, Simpson KJ: Q J Med 91:589, 1998 2. Hantson P, Mahieu P: Q J Med 92:415, 1999 3. Gue´rit JM: Eur J Med 1:233, 1992 4. de Tourtchaninoff M, Hantson P, Mahieu P, et al: Q J Med 92:407, 1999 5. Hantson P, de Tourtchaninoff M, Mahieu P, et al: Re´anim Urgences 9:197, 2000 6. Hantson P, de Tourtchaninoff M: In Brent J (ed): Critical Care Toxicology. In press. 7. Gore SM, Cable DJ, Holland AJ: BMJ 304:349, 1992 8. Navarro A: Transplant Proc 28:103, 1996
9. Rapport du Conseil Me´dical et Scientifique de l’Etablissement Franc¸ais des Greffes. 1996 10. Altinors N, Benli S, Caner H, et al: Transplant Proc 30:771, 1998 11. Ad Hoc Committee of the Harvard Medical School: JAMA 13:2184, 1981 12. Gue´rit JM, Meulders M: Electroencephalogr Clin Neurophysiol 52:S39, 1981 13. Gue´rit JM, Sove`ges L, Baele P, et al: Electroencephalogr Clin Neurophysiol 77:163, 1990 14. Jones SJ: In Halliday AM (ed): Evoked potentials in clinical testing. 2nd ed. Edinburgh: Churchill Livingstone; 1993, p 462 15. Picton TW: In Daly DD, Pedley TA (eds): Current Practice of Clinical Electroencephalography. 2nd ed. New York: Raven Press; 1990, p 642 16. Chiappa KH: In Chiappa KH (ed): Evoked Potentials in Clinical Medicine: 2nd ed. New York, Raven Press; 1990, p 218 17. Chiappa KH: In Chiappa KH (ed):Evoked Potentials in Clinical Medicine. 2nd ed. New York: Raven Press; 1990, p 368 18. Chatrian GE: In Daly DD, Pedley TA (eds): Current Practice of Clinical Electroencephalography. 2nd ed. New York: Raven Press; 1990, p 425