Brain Death: The Neurologist’s Perspective Stephen T. Mernoff, MD Clinical Assistant Professor of Neurology, Brown Medical School Medical Director, Neurorehabilitation Program, Rehabilitation Hospital of Rhode Island Staff Neurologist, Roger Williams Medical Center

Law & Order

I thought this would be easy i.e. a 15 minute discussion outlining the standard, uniformly accepted and applied criteria for brain death and the method for its determination

But… Not uniformly defined between institutions Not one universally accepted standard Not one universally and consistently applied algorithm for determination “If one subject in health law and bioethics can be said to be at once well settled and persistently unresolved, it is how to determine that death has occurred.” Rosenbaum, S. Ethical conflicts. Anesthesiology 1999;91:3-4

Versalius Madrid, 1564 Anatomist At autopsy: thorax openedheart beating! Forced to leave Spain This event and others  need for formal pronouncement of death

Death: traditional cardiopulmonary definition Asystole AND Apnea

Mollaret P and Goulon M. Le coma dépassé [“a state beyond coma”] Mollaret P and Goulon M. Le coma dépassé [“a state beyond coma”]. Rev Neurol 1959;101:3-15 Concept of Brain Death introduced: authors believed there was a definable condition from which recovery was impossible Criteria suggested Not recognized widely

“Harvard Criteria” Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. A definition of irreversible coma. JAMA 1968;205:337-340 Driving forces: advances in care mechanical ventilation and ICU’s Organ transplantation: cadaver (non-heart-beating) donors but some surgeons harvesting from patients with neurologic catastrophes: patients died after transplantation Many surgeons uncomfortable with this but “live donors” improved transplant outcomes When has irreversible loss of full brain function occurred? --premise: not idea that brain, therefore person, is dead; rather: coma irreversible and care futile

Harvard Criteria Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. A definition of irreversible coma. JAMA 1968;205:337-340 Purpose: “…to define irreversible coma as a new criterion for death.” “There are two reasons why there is need for a definition: 1) improvements in resuscitative and supportive measures…sometimes…only partial success…result is an individual whose heart continues to beat but whose brain is irreversibly damaged. The burdern is great on patients who suffer permanent loss of intellect, on their families, on the hositals, and those in need of hospital beds already occupied by those comatose patients.”

Harvard Criteria Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. A definition of irreversible coma. JAMA 1968;205:337-340 Note: presented in narrative rather than algorithmic form; stricter than ever before, but not strict enough (e.g. EEG duration criteria) Purpose: “…to define irreversible coma as a new criterion for death.” “There are two reasons why there is need for a definition: 2) Obsolete criteria for the definition of death can lead to controversy in obtaining organs for transplantation.”

Harvard Criteria Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. A definition of irreversible coma. JAMA 1968;205:337-340 “An organ, brain or other, that no longer functions and has no possibility of functioning again is for all practical purposes dead.” A. determine presence of “a permanently nonfunctioning brain.” 1. Unreceptivity and Unresponsitivity: “total unawareness to externally applied stimuli…even the most intensely painful stimuli evoke no vocal or other response, not even a groan, withdrawal of a limb, or quickening of respiration.” 2. No Movements or Breathing: no spontaneous movements or spontaneous respiration (turn off respirator for 3 minutes; prior to trial breathing room air for ≥10 minutes and pCO2 normal) or response to pain, touch, sound or light for an hour.

Harvard Criteria Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. A definition of irreversible coma. JAMA 1968;205:337-340 A. determine presence of “a permanently nonfunctioning brain.” 3. No reflexes: pupils fixed, dilated and absence of: Pupillary response to bright light ocular movement to head turning and ice water irrigation of ears blinking postural activity (decerebrate or other) Swallowing, yawning, vocalization Corneal reflexes Pharyngeal reflexes Deep tendon reflexes Respnse to plantar or noxious stimuli

Harvard Criteria Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. A definition of irreversible coma. JAMA 1968;205:337-340 B. confirmatory data 4. isoelectric EEG (specifies technique; have EKG and noncephalic leads to r/o confounders “At least 10 full minutes of recording are desirable, but twice that would be better.” [!]) EEG: “when available it should be utilized” If EEG unavailable, “the absence of cerebral function has to be determined by purely clinical signs…or by absence of circulation as judged by standstill of blood in the retinal vessels, or by absence of cardiac activity.” A and B all need to be repeated 24 hours later with no Δ AND in the absence of hypothermia (<90˚F [32.2˚C]) or CNS depressants, such as barbiturates, and determined only by a physician

Harvard Criteria Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. A definition of irreversible coma. JAMA 1968;205:337-340 If criteria are met, “Death is to be declared and then the respirator turned off. The decision to do this and the responsibility for it are to be taked by the physician-in-charge, in consultation with one or more physicians who have been directly involved in the case. It is unsound and undesirable to force the family to make the decision.”

Harvard Criteria Report of the Ad Hoc Committee of the Harvard Medical School to Examine the Definition of Brain Death. A definition of irreversible coma. JAMA 1968;205:337-340 Controversy Physicians concerned: desire to remove burden of decision off the transplant surgeon Public concern: press concerned that Brigham doctors were “playing god by removing organs.” Murray JE. Surgery of the soul: reflectins on a curious career. Canton, MA: Science History Publications, 2001. Subsequent literature concerned that criteria biased by participation of transplant surgeons on the committee whose programs could advance with brain death defined Wijdicks NEUROLOGY 2003;61:970-976 finds little basis for this in his review of the committee’s documents

Guidelines for the Determination of Death JAMA 11/13/1981;246(19),2184-2186 Report of the Medical Consultants on the Diagnosis of Death to the President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research Developed as an aid to implementation of the proposed “Uniform Determination of Death Act” (endorsed by: ABA, AMA, Nat’l Confernece of Commissioners on Uniform State Laws, President’s Commission for the Study of Ethical Problems in Medicine and Biomedical and Behavioral Research, AAN, AES

Guidelines for the Determination of Death JAMA 11/13/1981;246(19),2184-2186 “Uniform Determination of Death Act” “An individual who has sustained either (1) irreversible cessation of circulatory and respiratory functions, or (2) irreversible cessation of all functions of the entire brain, including the brain stem, is dead. A determination of death must be made in accordance with accepted medical standards.”

Guidelines for the Determination of Death JAMA 11/13/1981;246(19),2184-2186: Criteria Note: presented in somewhat narrative and somewhat algorithmic form; improvement from Harvard criteria but still room for interpretation of what to do and when. “An individual presenting the findings in either section A (Cardiopulmonary) or section B (neurological) is dead….a diagnosis of death requires that both cessation of functions and irreversibility…be demonstrated.”

Guidelines for the Determination of Death JAMA 11/13/1981;246(19),2184-2186: Criteria “A. An individual with irreversible cessation of circulatory and respiratory functions is dead. 1. Cessation is recognized by an appropriate clinical examination….at least absence of responsiveness, heartbeat, and respiratory effort….may require the use of…ECG.” 2. Irreversibility is recognized by persistent cessation of functions during an appropriate period of observation and/or trial of therapy.” [duration of observation period dependent on whether is expected vs. unexpected, whether resuscitation attempted, or moment of possible death is witnessed or not]

Guidelines for the Determination of Death JAMA 11/13/1981;246(19),2184-2186: Criteria “B. An individual with irreversible cessation of all functions of the entire brain, including the brain stem, is dead….” “1. Cessation is recognized when evaluation discloses findings of a and b: a. Cerebral functions are absent, and…” Deep coma (unreceptivity and unresponsivity) “Medical circumstances may require the use of confirmatory studies such as an EEG or blood-flow study.” [??Those circumstances not specified!] b. “Brainstem functions are absent” determined by testing pupillary light, corneal, oculocephalic, oculovestibular, oropharyngeal, and respiratory (apnea) reflexes;

Guidelines for the Determination of Death JAMA 11/13/1981;246(19),2184-2186: Criteria “B. An individual with irreversible cessation of all functions of the entire brain, including the brain stem, is dead….” “1. Cessation is recognized when evaluation discloses findings of a and b: b. “Brainstem functions are absent” determined by testing pupillary light, corneal, oculocephalic, oculovestibular, oropharyngeal, and respiratory (apnea) reflexes; “When these reflexes cannot be adequately assessed, confirmatory tests are recommended.” Apnea testing specified: O2 ventilation x 10 minutes then w/d ventilator with passive flow of O2,, confirm pCO2≥60 by ABG; “spontaneous breathing efforts indicate that part of the brain stem is functioning.”

Guidelines for the Determination of Death JAMA 11/13/1981;246(19),2184-2186: Criteria “B. An individual with irreversible cessation of all functions of the entire brain, including the brain stem, is dead….” “1. Cessation is recognized when evaluation discloses findings of a and b: “Peripheral nervous system activity and spinal cord reflexes may persist after death. True decerebrate or decorticate posturing or seizures are inconsistent with the diagnosis of death.”

Guidelines for the Determination of Death JAMA 11/13/1981;246(19),2184-2186: Criteria “B. An individual with irreversible cessation of all functions of the entire brain, including the brain stem, is dead….” “2. Irreversibility is recognized when evaluation discloses findings of a and b and c” or by absence of blood flow to the brain ≥10 minutes, shown by angiography : a. The cause of coma is established and is sufficient to account for the loss of brain functions, and… b. the possibility of recovery of any brain functions is excluded, and…” (i.e. rule out sedation, hypothermia <32.2˚C core temp, neuromuscular blockade, and shock) “c. the cessation of all brain functions persists for an appropriate period of observation and/or trial or therapy” (6 hours; 12 hours if no confirmatory tests; 24 hours if anoxic injury)

Practice parameters for determining brain death in adults (summary statement) NEUROLOGY 1995;45:1012-1014 Report of the Quality Standards Subcommittee of the American Academy of Neurology Brain Death Definition: “the irreversible loss of functin of the brain, including the brainstem.” Justification: “…need for standardization of the neurologic examination criteria for the diagnosis of brain death.” Process: based on review of literature 1976-1994; are GUIDELINES (class II evidence or strong consensus of class III evidence) Format: algorithm with precise definitions and precisely specified exam methods

Practice parameters for determining brain death in adults: (summary statement) NEUROLOGY 1995;45:1012-1014: I. Diagnostic Criteria A. “Prerequisites 1.Clinical or neuroimaging evidence of an acute CNS catastrophe that is compatible with the clinical diagnosis of brain death 2. Exclusion of complicating medical conditions” (electrolyte, acid-base, endocrine) “3.No drug intoxication or poisoning 4. Core temperature ≥32˚C(90˚F)”

B. Coma, lack of brainstem reflexes, and apnea Practice parameters for determining brain death in adults: (summary statement) NEUROLOGY 1995;45:1012-1014: I. Diagnostic Criteria B. Coma, lack of brainstem reflexes, and apnea 1.Coma or unresponsiveness… (defined specifically) 2. Absence of brainstem reflexes (defined specifically): Pupils Ocular movement Facial sensation and facial motor response Pharyngeal and tracheal reflexes

B. Coma, lack of brainstem reflexes, and apnea Practice parameters for determining brain death in adults: (summary statement) NEUROLOGY 1995;45:1012-1014: I. Diagnostic Criteria B. Coma, lack of brainstem reflexes, and apnea 3. Apnea: very specific description of apnea testing protocol e.g. core temp ≥ 36.5˚C; BP, volume, baseline PO2 and PCO2

B. Preexisting pupillary abonormalities Practice parameters for determining brain death in adults: (summary statement) NEUROLOGY 1995;45:1012-1014: II. Pitfalls in the diagnosis of brain death A. Severe facial trauma B. Preexisting pupillary abonormalities C. Toxic levels of any: sedatives, aminoglycosides, TCA’s, anticholinergics, AED’s, chemotherapeutic agents, or NM blocking agents D. Chronic CO2 retention

A. Spontaneous movements B. Respiratory-like movements Practice parameters for determining brain death in adults: (summary statement) NEUROLOGY 1995;45:1012-1014: III. Clinical observations compatible with the diagnosis of brain death A. Spontaneous movements B. Respiratory-like movements C. Sweating, blushing, tachycardia D. Normal BP without pressors E. Absence of diabetes insipidus F. DTR’s, superficial abdominal reflexes, triple flexion response G. Babinski reflex

Practice parameters for determining brain death in adults: (summary statement) NEUROLOGY 1995;45:1012-1014: IV. Confirmatory laboratory tests (Options) “Brain death is a clinical diagnosis. A repeat clinical evaluation 6 hours later is recommended, but this interval is arbitrary. A confirmatory test is not mandatory but is desirable in patients in whom specific components of clinical testing cannot be reliably performed or evaluated….most sensitive test [is listed] first:

A. Conventional Angiography B. EEG: no electrical activity over ≥30’ Practice parameters for determining brain death in adults: (summary statement) NEUROLOGY 1995;45:1012-1014: IV. Confirmatory laboratory tests (Options)(specific criteria described for all) A. Conventional Angiography B. EEG: no electrical activity over ≥30’ C. Transcranial Doppler U/S D. Technetium-99m HMPA brain scan E. Somatosensory evoked potentials

A. Etiology and irreversibility of condition Practice parameters for determining brain death in adults: (summary statement) NEUROLOGY 1995;45:1012-1014: V. Medical record documentation (Standard) A. Etiology and irreversibility of condition B. Absence of brainstem reflexes C. Absence of motor response to pain D. Absence of respiration with PCO2≥60 mm Hg E. Justification for confimatory test and result of confirmatory test F. Repeat neurologic examination Option: the interval is arbitrary, but a 6-hour period is reasonable

Canadian criteria Guidelines for the diagnosis of brain death Canadian criteria Guidelines for the diagnosis of brain death. Canadian Neurocritical Care Group. Can J Neurol Sci 1999;26:64-6 I haven’t obtained this reference yet but secondary report: Doesn’t require testing of oculocephalic reflex Permits core temperature as low as 32.2˚C during the apnea test Interval between exams as short as 2 hours; as long as 24 hours for anoxic-ischemic insult

“State Law” Practice parameters for determining brain death in adults (summary statement) NEUROLOGY 1995;45:1012-1014 “Regardless of the conclusions of this statement , the Quality Standards Subcommittee of the AAN recognizes the need to comply with state law.” Does RI have an applicable statute? RIDOH has no specific policy or guidelines for Brain Death determination; leaves it to institutions to develop their own should Ethics Network look into standardization across the state?

Brain Death Protocols in some RI hospitals Hospital #1: no protocol Hospital #2: based on President’s Commission but criteria somewhat vague and only semi-algorithmic Hospital #3: based on 1995 Practice Parameters; precise criteria and precise algorithm provided Other hospitals around the state?

Brain Death around the world Wijdicks EFM Brain Death around the world Wijdicks EFM. Brain death worldwide: Accepted fact but no global consensus in diagnostic criteria NEUROLOGY 2002;58:20-25 Guidelines of 80 countries reviewed Legal standards on organ transplantation present in 69% (55 of 80 countries) Practice guidelines for brain death for adults in 88% 50% guidelines require >1 physician to declare All guidelines specified exclusion of confounders, presence of irreversible coma, absent motor response, and absent brainstem reflexes Apnea testing required in 59% differences in time of observation and required expertise of examining physicians Confirmatory laboratory testing mandatory in 28 of 70 (40%) guidelines

Brain Death around the world Wijdicks EFM Brain Death around the world Wijdicks EFM. Brain death worldwide: Accepted fact but no global consensus in diagnostic criteria NEUROLOGY 2002;58:20-25 Conclusion: “uniform agreement on the neurologic exam with exception of the apnea test; but other major differences found in the procedures for diagnosing brain death in adults, and standardization should be considered.”

Misconceptions: 1. There is one nationally or internationally accepted standard for determination of brain death. In fact there is variability and inconsistency over time and at single points in time including the present: between published guidelines (differences between 1968 Harvard criteria, 1981 Presidents Commission, 1995 Practice Parameters; 1999 Canadian criteria) between jurisdictions (especially internationally) among patient populations in the use of confirmatory tests

Misconceptions: “Brain Death” Misconceptions: “Brain Death” ?sufficient for withdrawal of mechanical ventilation Case: ICU patient; multi-organ failure, comatose since cardiopulmonary arrest. Caregivers feel ongoing tx futile but family wants to continue. Neurology consult requested to determine if “Brain Death” applies to ?convince family to change to CMO. Implication also that if Brain Death determined, ICU could d/c vent even if family disagreed. No potential for organ donation. Hospital didn’t have Brain Death Protocol ?state law doesn’t define “brain death” (???) Consultant: don’t need “brain death” for this; need good communication with family so they understand fully the prognosis and valid option to withdraw interventions (even ventilation)

Misconceptions: “Brain Death” ?Misconceptions: “Brain Death” ?necessary for withdrawal of mechanical ventilation “brain death” originally motivated by potential for organ transplantation but concept often being invoked for decision-making even when there is no potential for organ donation

misconceptions All medical personnel, especially ICU staffs, have consistent and accurate understandings of brain death criteria 64% physicians and 28% of non-physician staff correctly identified clinical criteria for brain death and/or correctly identified patients as dead vs. alive in case scenarios Brain death ≡ loss of cortical function i.e. need loss of brainstem function as well

Pitfalls Incorrect application of accepted criteria Van Norman GA, A matter of life and death. Anesthesiology 1999;91:275-87 e.g. 2 patients with devastating brain injuries certified as brain dead and referred for organ donation despite the presence of spontaneous respirations and in one of them movement during organ retrieval leading to use of muscle relaxants and general anesthesia e.g. brain death determined after patient received IV muscle relaxants and Mg low (eventually patient discharged home alert and oriented)

Controversies Philosophically, why need loss of brainstem function as well? i.e. Harvard criteria based on irreversibility of coma and futility of care, not “death of the person.”

Going forward Are current Brain Death criteria satisfactory? Some are calling for additional study to see if they are as reliable as “conventional wisdom” suggests and many believe. Dead, or Dead Enough? Current algorithms use certain measures; but those just measure brain activity above a certain threshold along a continuum. Maybe some cells still functioning? How to determine that threshold?

Going Forward Doig CJ and Burgess E, Brain Death: resolving inconsistencies in the ethical declaration of death. Can J Anesth 2003;50(7):725-31 Are current Brain Death criteria satisfactory? Some are calling for additional study to see if they are as reliable as “conventional wisdom” suggests and many believe. Tests of cortical and subcortical brain function lack specificity Inconsistency of clinical criteria

Going forward A need for more uniform criteria: note difficulty I had in obtaining “front-line” (i.e. hospital) level information and variability between hospitals within the state! Within the state nationally ?internationally Ethics network look into this, determine what the various hospitals have and don’t have, andadvocate for more uniform criteria within Rhode Island?

Rosenbaum, S. Ethical conflicts. Anesthesiology 1999;91:3-4 “If one subject in health law and bioethics can be said to be at once well settled and persistently unresolved, it is how to determine that death has occurred.”