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special article NEUROLOGY 1995;45: 003 0 1

Determining brain death in adultsEelco F.M. Wijdicks, MD

Overview. The Quality Standards Subcommitteeof the American Academy of Neurology (AAN) ischarged with developing guidelines for neurologistsfor diagnostic procedures, tr eat me nt modalities,and clinical disorders. The present document is in-tended t o provide background for the report “Prac-tice Parameters for Determining Brain Death inAdults” (in this issue), which has been produced bythe Quality Standards Subcommittee of the AANand approved by the AAN Executive Board. Thisdocument outlines diagnostic criteria for the c h i -cal diagnosis of brain death in patients older than18 years. The recommendations for diagnosis inneonates and children have been published as a po-sition paper by the American Academy of Pedi-atrics’; in addition, a review paper can be con-sulted.‘ The sensitivity and specificity of laboratorytests that confirm the clinical diagnosis of braindeath are discussed.

Justification. Brain death is seen frequently as aresult of severe head injury, aneurysmal subarach-noid hemorrhage, and intracerebral he m ~ r r ha g e. ~ . ~In medical and surgical intensive care units, largeischemic strokes associated with brain swelling

and herniation, hypoxic-ischemic encephalopathyafter prolonged cardiac resuscitation or asphyxia,and massive brain edema in patients with fulmi-nant hepatic necrosis a re th e most common causesof bra in death.7-9 n large referral hospitals, neurol-ogists or neurosurgeons may diagnose brain deathfrom 25 t o 30 times a year.1°-14

The clinical diagnosis of brain death has neverbeen easy for most physicians, including neurolo-gists and neurosurgeons.

Brain death was selected as a topic for practiceparameters because of a perceived need for stan-dardized clinical examination criteria for the diag-nosis of brain death in adults, large differences inpractice in performing the apnea tes t,” and contro-versies over appropriate utilization of confirmatorytests.” In addition, government and third-pa rtypayers are demanding well-defined practice param-eters in the clinical examination or confirmatorytesting. New parameters are needed t o add to the

report of the medical consultants on the diagnosisof death submitted t o the President’s Commissionfor the Study of Ethical Problems in Medicine andBiomedical and Behavioral Research, published in1981.15 The ar eas of need are as follows:

1. Unequivocal definition of clinical testing ofbrainstem function;

2. Description of conditions that may completelyor partly mimic brain death;

3. Interp retation of clinical observations that arecompatible with brain death but initially may sug-gest otherwise;

4. Clear description of apnea testing procedure;5 . Indications of confirmatory laboratory tests;6. Validity and reproducibility of confirmatory

7. Initial practice guidelines for organ procure-laboratory tests ; and

ment.

Development of practice parameters. All liter-ature pertaining to brain death was identified byMEDLINE for the years 1976 t o 1994. Key wordsused were “brain d e a t h and “apnea test” with thesubheadin g “adu lt.” Peer-reviewed articles withoriginal work were selected. Selection for this docu-

ment was based on the quality of the original work.Current textbooks and handbooks of neurology,medicine, intensive care, pulmonology, and anes-thesia were reviewed for opinion. References werecategorized as class I1 (well-designed clinical stud-ies) or class I11 (case reports, uncontrolled studies,and expert opinion). (Class I1 or I11 studies areidentified by a “IZ” or “IIZ” in the list of references.)Class I studies (randomized clinical trials) were notavailable. The committee defined practice param-eters as s tandards (generally accepted principlesfor patient management that reflect a high degreeof clinical certainty); guidelines (recommendationsfor patient management that may identify a partic-ular strategy and th at reflect moderate clinical cer-tainty); and options (strategies for patient manage-ment for which certainty is unclear). All sugges-tions in this document should be considered guide-lines unless otherwise specified. Consensus w a sachieved by group discussion.

I See also page 101 2From the Depar tmen t of Neurology Mayo Clinic and Mayo Foundatio n Rochester MN.

Portions of this manuscript were published in Wijdicks EFM Neurology of critical illness. Philadelphia: F.A. Davis Co 1995 :chapter 18. By permission ofMayo Foundation.

Received October 4, 1994. Accepted in final form October 10, 1994

Address correspondence and reprint requests to Dr. Eelco F.M. Wijdicks Depa rtm ent of Neurology Mayo Clinic 200 First Street SW, Rochester MN55905.

M a y 1995 NEUROLOGY 45 1003.


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Background. The President’s Commission for theS t u d y of Eth ica l P rob lems in Medic ine andBiomedical an d B ehavioral Research15 defined“brain death” as irreversible cessation of all func-tions of the entire brain, including the brainstem.The clinical diagnosis of brain death is equivalentt o irreversible loss of all brainstem function. Of

particular importance in the clinical examination ofpatients who are brain-dead are 1) documentationof loss of consciousness, (2) no motor response t opain sti muli, (3) no brainstem reflexes, and (4 )apnea. In the vast majority of patients, CT docu-ments an abnormality that explains loss of brainand brainstem function. The clinical diagnosis ofbrain death should be in doubt in patients withnormal CT o r CSF findings. Nonetheless, occa-sional patients have an ischemic-anoxic insult tothe brain that results in brain death without CTabnormality. In these patien ts, t he clinical diagno-sis of brain death should be made only if there is ahigh degree of certainty about the mechanism thatled t o brain death.

The diagnosis of brain death in patients withcoma of undetermined origin is very complex. Nostudies have been reported that address this spe-cific clinical dilemma. If a patient meets the clinicalcriteria, has a prolonged period of observation (>24hours), and has no cerebral blood flow, and if con-founding factors have been excluded, it is reason-able t o make a diagnosis of brain death. Organ do-nation can be allowed if no transmittable disease(eg, rabies encephalitis) is present.

Confounding factors that mimic or partly mimicbrain death should be excluded. Firs t, hypothermia

may blunt brainstem reflexes but only when rectaltemperatures are below 32 “C. Brainstem reflexeshave been absent in patients with rectal tempera-tur es below 27 O C 1 6 It is not known whether pa-tients with a major CNS catastrophe are suscepti-ble at higher core temperatures. Second, drug in-toxication should be excluded if the history is sug-gestive. In this situation, routine drug screens maybe helpful but probably only when testing is re-quested for a specific drug or poison. The diagnosisof brain death most likely can be made when levelsof barbiturates in the blood are subtherapeutic, al-though data in adults are sparse. In brain-deadchildren with therapeutic levels of barb iturate s, nochange in isoelectric EEGs was noted during de-crease of barbiturates in the blood t o subtherapeu-tic or undetectable 1e~els.l~ hird, the clinical diag-nosis of brain death is probably not reliable in pa-tients investigated at the time of an acute meta-bolic or endocrine derangement. 5,18-20

A n impor tant component of th e clinical diagnosisof brain death is the demonstration of apnea. Mis-conceptions about the procedure are frequently en-countered in clinical practice.ll Loss of brainstemfunction produces loss of breathing and vasomotorcontrol that results in apnea and hypotension. Hy-potension is frequently present at the time of theclinical diagnosis of brain death, but patients may1004 NEUROLOGY 45 May 1995

have normal blood pressure despite fulfilling theclinical criter ia of brain death.21

The respiratory neurons are controlled by cen-tral chemoreceptors that sense changes in the PCO,and pH of the CSF, and these accurately reflectchanges in plasma P c o , . ~ ~ here are many othermechanical and chemical stimuli and inhibitory in-

fluences on the respiratory neurons of the brain-stem.

It is not known at what arterial PCO, evel thechemoreceptors of the respiratory center are maxi-mally stimulated in hyperoxygenated patients withbrainstem destruction. Target arterial PCO, evelsare derived from a small number of patients whohad respiratory efforts after induction of hypercar-bia but who otherwise fulfilled the criteria for theclinical diagnosis of brain death.,’ The advisoryguidelines for the determination of death submit-ted t o the President’s Commission for the Study ofEthical Problems in Medicine and Biomedical andBehavioral Research are based on these observa-t i o n ~ . ’ ~ hat document recommends Paco, levelsgreater than 60 mm Hg for maximal s timulation ofthe brainstem. Lower target levels have been sug-gested because four patients made effective normalbreathing efforts at lower PCO, alues (range, 30 to37 mm Hg; mean, 34 mm Hg). At higher PCO, Val-ues ( range, 41 to 51 mm Hg), respiratory-likemovem ents have been observed.21 These move-ments are ineffective for ventilation and consist ofshoulder elevation and adduction, back arching,and intercostal expansion. These respiratory-likeefforts produce negligible tidal volumes and virtu-ally no inspiratory force.21 Less reliable targets for

Pco, may be obtained from anesthetized subjects(Pco, of 30 mm Hg)23,24 r in experiments withbreath-holding (Pco, of 40 o 45 mm Hg).25-27

The target PCO, evels of the apnea tes ts in braindeath determination may be higher in patientswith chronic hypercapnia. Typically, these patientshave severe chronic obstructive pulmonary disease,bronchiectasis, sleep apnea, and morbid o b e ~ i t y . ~ ~ , ~ ~If metabolic acidosis is not present, chronic hyper-carbia (“GO, retainer s”) can be suspected in pa-tients with high initial serum concentrations of bi-carbonate. When initial arterial blood gas determi-nation confirms chronic hypercarbia, additionalnoninvasive confirmatory tests are strongly encour-aged.

Low arterial PCO, alues can be expected in pa-tients with acute catastrophic structural CNS dam-age. In many instances, hypocarbia is caused by hightidal volumes associated with mechanical ventilation,by hyperventilation instituted to decrease intracra-nial pressure, or by hypothermia. Hypocarbia can becorrected by changing the minute volume by decreas-ing either rate o r tidal volume for several minutes.Correction of hypocarbia probably should not be donewith GO, mixtures. Although administration of 5CO, in oxygen will elevate PCO, y 17.3 mm Hg in 1to 2 minutes, this procedure may rapidly lead to se-vere hypercarbia and respiratory


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Clinical/Neuroimaging/CSFevidence of cause of coma

I

‘igure 1. Proposed gu idelin es for the clinical diag nosis 1rain death.

Apnea testing is easy with a starting arterialPCO, alue of 40 mm Hg because the target level of60 mm Hg is reached af ter 6 t o 8 minutes of discon-nection from t h e v e n t i l a t ~ r . ’ ~ . * ~ - ~ ~he estimated

PCO, ncrease is from 3 t o 6 mm Hg per minute andvaries with the rate of CO, production. Cardiac ar-rhythmias are side effects of hypercarbia and respi-ratory acidosis, occurring mostly in patients withh y p o ~ i a . ~ ~he most common abnormalities ar e pre-mature ventricular contractions and ventriculart a ~ h y c a r d i a . ~ ~evere hypotension (change in meanarterial blood pressure of more than 15%) has beenobserved in well-oxygenated patien ts in whom Pco,values reached very high levels (average, 90 mmHg) from acidosis alone.34 Administration of 100%0, through a cathete r placed at the level of the ca-rina secures adequate oxygenation during apneatesting. A recent study of 70 apnea tests found nosignificant hypoxemia after previous oxygenationand placement of a catheter inside the endotra-cheal Oxygenation may be inadequ ate, forexample, in patients with severe pulmonary dis-ease, acute respiratory distress syndrome, o r neu-rogenic pulmonary edema.33

The clinical diagnosis of brain death includesapnea with an arterial PCO, f 60 mm Hg. How-ever, ther e have been only a few studies of t hemethods of testing, and th e lit erature does not pro-vide evidence to favor one method over th e other.

Clinical diagnosis of brain death. Brain deathis the absence of clinical brain function when the

proximate cause is known and demonstrably irre-versible. To overcome the possible pitfalls of mak-ing the diagnosis of brain death, the following pre-requisites are proposed (figure 1): 1) there m ust bedefinite clinical or neuroimaging evidence of anacute CNS catastrophe that is compatible withbrain death; (2) complicating medical conditions

that may confound clinical assessment should beexcluded (no severe electrolyte, severe acid-base, orsevere endocrine disturbance); 3) drug intoxicationo r poisoning must be absent; and (4) core tempera-ture must be at least 32 “C. Tes t ing of b ra ins temfu n c t i o n c an p r oce ed on ly a f t e r t h e se p r e c a u ti o n shave been taken.

The three cardinal findings in brain death arecoma or unresponsiveness, absence of brainstemreflexes, and apnea. The clinical examination of thebrainstem includes testing of brainstem reflexes,determination of the patient’s ability t o breathspontaneously, and evaluation of motor responsest o pain.

I.

11.

Coma or unresponsivenessA. Motor responses of the limbs

1. Testinp. Motor responses of the limbs topainful s t imul i should be absent af tersupraorbital pressure and nail-bed pres-sure stimulus.

2. Pitfal ls. Motor responses (“Laza rus sign”)14may occur spontaneously during apneatesting, often during hypoxic or hypoten-sive episodes, and are of spinal origin. Neu-romuscular blocking agents can produceprolonged weakness.35 If neuromuscularblocking agents have recently been admin-istered, examination with a bedside periph-eral nerve stimulator is needed.36 A train-of-four s t im ulu s should resu l t in fourthumb twitches.

Absence of brainstem reflexesA. Pupils

1. Testinn. The response to bright light shouldbe absent in both eyes. Round, oval, or ir-regularly shaped pupils are compatiblewith brain death. Most pupils in braindeath are in middle position 4 t o 6 mm),but the size of the pupils may vary from 4to 9 mm. Dilated pupils a re compatible withbrain death because intact sympathetic cer-vical pathways connected with the radiallyarranged fibers of the dilator muscle mayremain i n t a ~ t . ~ . ~ ~

2. Pitfalls. Many drugs can influence pupilsize, but light response remains intact. Inconventional doses, atropine given intra-venously has no marked influence onpupillary r e s p o n ~ e . ~ ~ ~ ~ ~report of fixed,dilated pupils after extremely high dosesof dopamine has not been confirmed.40

Because nicotine receptors are absen t inthe iris, neuromuscular blocking drugs do

not noticeably influence pupil size. TopicalMay 1995 NEUROLOGY 45 1005


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ocular instillation of drugs and trauma tothe cornea or bulbus oculi may cause ab-normalities in pupil size and can producenonreactive pupils. Preexisting anatomicabnormalities of the iris or effects of previ-ous surgery should be exchckd.

B. Ocular movements

1. Testing;, Ocular movements are absentafter head-turn ing and caloric testing withice ~ a t e r . ~ . ~Testing is done only when nofracture or instability of the cervical spineis apparent, and in patients with head in-jury, the cervical spine must be imaged toexclude potential fractures o r instability o rboth.) The oculocephalic reflex, elicited byfast and vigorous turning of the head frommiddle position to 90 on both sides, nor-mally results in eye deviation to the oppo-site side of the head-turning. Vertical eyemovements should be tested with briskneck flexion. Eyelid opening and verticaland horizontal eye movements must be ab-sent in brain death.

Caloric testing should be done with thehead elevated t o 30 during irrigation ofthe tympanum on each side with 50 ml ofice water. Tympanum irrigation can bebest accomplished by ins er tin g a sma llsuction catheter into th e external auditorycanal and connecting it to a 50-ml syringefilled with ice water. Tonic deviation of theeyes directed to the cold caloric stimulus isabsent. The investigator should allow upto 1 minute after injection, and the time

between stimulation on each side shouldbe at least 5 minutes.

2. Pitfalls. Drugs that can diminish o r com-pletely abolish the caloric response aresedatives, aminoglycosides, tricyclic anti-depressants, anticholinergics, antiepilepticdrugs, and chemotherapeutic agent^.^^,^^After closed head injury or facial trauma,lid edema and chemosis of th e conjunctivamay restrict movement of the globes. Clot-ted blood or cerumen may diminish thecaloric response, and repeat testing is re-quired after direct inspection of the tympa-num. Basal fracture of the petrous boneabolishes the caloric response only unilat-erally and may be identified by an ecchy-motic mastoid process.

C. Facial sensation and facial motor response1. Testing. Corneal reflexes should be tested

with a throat swab. Corneal reflex and jawreflex should be absent. Grimacing to paincan be tested by applying deep pressurewith a blunt object on the nail beds, pres-sur e on the s upra orbit al ridge, or deeppressure on both condyles at the level ofthe temporomandibular joint.

2. Pitfall. Severe facial trauma may limit in-terpretation of all brainstem reflexes.

1006 NEUROLOGY 45 May 1995

Absent brain stem reflex es7 yes

Severe COPD. morbid obesity 7- Contirmatov testKI 1 Warm blanket

t YesSystolic blood pressure 290 mm g.-

--

Positive fluid balance 2 6 hours Fix vampressin/0.9 NaCl

Fi02 = 1.0 or 10 mm

. Decrease mlnuteventilation

Connect to pulse oximeter

Figure 2. Prerequisites for the apnea tes t in b ra in death .COPD = chronic obstructive pulm ona ry disease.

D. Pharyngeal and tracheal reflexes1. Testing. The gag response, tested by stim-

ulation of the posterior pharynx with atongue blade, should be absent. Lack ofcough response t o bronchial suctioningshould be demonstrated.

2. Pitfall. In orally intubated patients, thegag response may be difficult to interpret.

111. ApneaA. Apnea test (guidelines for testing)

1. Prereauisites (figure 2). Important changesin vital signs (eg, marked hypotension, se-vere cardiac arrhythmias) during the apneatest may be related to lack of adequate pre-cautions, although they may occur sponta-neously during increasing acidosis. There-

fore, th e following prerequisites ar e sug-gested: 1) core temperature greater than orequal to 36 5 C (4.5 C higher than the re-quired 32 C for clinical diagnosis of braindeath), 2) systolic blood pressure greaterthan or equal to 90 mm Hg, 3) euvolemia(option: preferably positive fluid balance inthe previous 6 hours), 4) ucapnia (option:arterial PCO, reater than or equal to 40mm Hg), and 5 ) normoxemia (option: arte-rial Po, greater than o r equal to 200 mmHg). A pulse oximeter is connected to thepatient.

Disconnect th e ventilator.Deliver 100% 0,, 6 Vmin. Option: place acannula a t the level of the carina.Look closely for respiratory movements.Respiration is defined as abdominal orchest excursions that produce adequatetidal volumes. If present, respiration canbe expected early in the apnea test. Whenrespiratory-like movements occur, theycan be expected at the end of the apneatest, when oxygenation may becomemarginal. When the result is in doubt, aspirometer can be connected to the patientto confirm tha t tidal volumes are absent.

2. Testing (figure 3)


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Figure 3 Procedure fo r the apnea test in brain dea th,

Measure art eria l Po,, Pco,, and pH afterapproximately 8 minutes and reconnectthe ventilator.If respiratory movements are absent andarterial PCO, s equal to or greater than60 mm Hg option: 20 mm Hg increase inPco, over a baseline normal Pco,), theapnea test result is positive ie, it supportsthe clinical diagnosis of brain death).If respiratory movements are observed,the apnea test result is negative ie, it doesnot support the clinical diagnosis of braindeath), and the test should be repeated.If, during apnea testing, the systolic bloodpressure becomes 19 mm Hg, the pulse

oximeter indicates marked desaturation,and cardiac arrhythmias occur, immedi-ately draw a sample, connect the ventilator,and analyze arterial blood gas. he apneatest result is posi t ive if arterial Pco, isgreater than or equal to 60 mm Hg o r PCO,increase is equal to or greater th n 20 mmHg above baseline normal Pco,. If arterialPCO, s less than 60 mm Hg or Pco2 in-crease is less than 20 mm Hg over baselinenormal Pco,, the result is indeterminate. Inthis situation of cardiovascular instabilitytogether with uncertainty about the upperlimit of Pco2 at which maximal stimulationof the respiratory center occurs it is left tothe discretion of the physician whether aconfirmatory test is needed to finalize theclinical diagnosis of brain death.If no respiratory movements are observed,PCO, s less than 60 mm Hg, nd no signif-icant cardiac arrhythmia or hypotension isobserved, the test may be repeated with10 minutes of apnea.

Clinical observations compatible with the diagnosis of brain death. Respiratory acidosis,hypoxia, o r brisk neck flexion may generate spinal

cord responses.4 3 4 3 9 4 4

Spont aneou s movements of th e limbs fromspinal mechanisms can occasionally occur and aremore frequent in young adults. These spinal re-flexes include rapid flexion in arms, raising of alllimbs off the bed, grasping movements, sponta-neous jerking of one leg, walking-like movements,and movements of the arms up to the point of

reaching the endotracheal tube.I4Respiratory-like movements may also occur andare typical agonal breathing patterns. They arecharacterized by shoulder elevation and adduction,back arching, and intercostal expansion withoutany significant tidal volume.

Other responses are profuse sweating, blushing,tachycardia, and sudden increases in blood pres-sure.33s46 hese hemodynamic responses can some-times be elicited by neck flexion, and they can be elim-inated by ganglion blockers eg, trimethaphan).44 Nor-mal blood pressure and absence of diabetes insipiduswithout pharmacologic support are compatible withbrain death. Muscle stretch reflexes, superficial ab-dominal reflexes, and Babinski reflexes are of spinalorigin and do not invalidate a diagnosis of braindeath. Patients may have initial plantar flexion of thegreat toe followed by sequential brief plantar flexionof the second, third, fourth, and fifth toes after s n a pping of one of the toes “undulating t o flexion sign”).45

Confirmatory laboratory tests. Brain death is aclinical diagnosis. A repeat clinical evaluation 6hours later is advised option), but a firm recom-mendation cannot be given and the interval is arbi-trary.I5 A confirmatory test is not mandatory inmost situations. All clinical tests are needed to de-

clare brain death and are likely equally essential.One should not prioritize individual brainstemtests.) A confirmatory test is needed for patients inwhom specific components o clinical testing cannotbe reliably evaluated. In some countries other tha nthe United States, confirmatory tests are requiredby law eg, germ an^ .^ Clinical experience withconfirmatory tests other than EEG, transcranialDoppler ultrasonography, and conventional angiog-raphy is limited. Many studies did not use blind as-sessment of the r esul ts , d id not assess inte r-observer variation, and did not perform tests incontrol subjects. In addition, many tests needcostly equipment and well-trained technicians.

Confirmatory tests th at ar e generally acceptedare conventional angiography and EEG. Consen-sus criteria are reported only for EEG and somatosensory evoked potential^.^ The Therapeuticsand Technology Assessment Subcommittee of theAAN ha s accepted transcrani al Doppler ultr a-sonography as a reliable procedure for confirmationof brain death.48

Conventional angiography.49-54Techniaue. A selective four-vessel angiogram is

done in the radiology suite. Iodinated contrastmedium is injected under high pressure in both the

anterior and the posterior circulations. The proce-May 1995 NEUROLOGY 45 1 7


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dure takes a few hours.Result. Intracerebral filling is absent a t the level

of the carotid bifurcation or circle of Willis. The ex-ternal carotid circulation is patent, and at timesdelayed filling of the superior longitudinal sinus isseen.

Validitv. Interobserver studies have not been

published. The procedure has the potential t o yieldconflicting results because no guidelines for inter-pretation have been developed.

Disadvantage. Repeated contrast injections mayincrease the risk of nephrotoxicity and decrease theacceptance rate in organ recipients, but in generaldo not result in refusal of kidney donation.

Electroencephalography. 47~55 62Techniaue. Usually a 16- or 18-channel instru-

ment is used with guidelines developed by theAmerican Electroencephalographic Society forrecording brain death.47j55

Result. No electrical activity occurs above 2 pVat a sensitivity of 2 pV/mm with filter setting a t 0.1or 0.3 second and 70 Hz. Recording should continuefor at least 30 minutes.

Validity. Most patients meeting the clinical cri-teria for brain death have isoelectric EEGs. Never-theless, in one consecutive series of patient s fulfill-ing the clinical diagnosis of brain death, 20% of 56patients had residual EEG activity that lasted upto 168 hours.60

Disadvantage. Considerable artifacts in the in-tensive care unit can limit interpretation.62

Isotope angiography. i3-65Technique. Rapid intravenous injection of serum

albumin labeled with technetium 99m is followedby bedside imaging with a portable gamma camera.

Result. Intracranial radioisotope activity is ab-sent. Filling of sagitt al and transver se sinuses mayoccur in delayed images from connections betweenthe extracranial circulation and the venous system.

Validity. The sensitivity and specificity of lack ofintracranial radioisotopes have not been defined inadults.

Disadvantage. The posterior cerebral circulationis not visualized.

Tech netiu m-9 9m hexamethylpropyleneamine-oxime 99mTc-HMPAO).66-s9

Techniaue. The procedure can be performed atthe bedside and takes approximately 15 minutes.The isotope should be injected within 30 minutes ofreconstitution. A portable gamma camera producesplanar views within 5 t o 10 minutes. Correct intra-venous injection can be checked by taking addi-tional chest and abdominal images.

Result. N o uptake occurs in the brain paren-chyma.

Validity. Experience with this technique is lim-ited. Sensitivity of the brainstem has been reportedto be as low as 94% with a specificity of Re-producibility has been tested in only a few patients.In one study, a correlation between cerebral an-1008 NEUROLOGY45 May 1995

giography and 99mTc-HMPA0 cintigraphy was ex-cellent.66

Disadvantages. The tracer should be injected im-mediately. Because the costs are currently highand the technique is not widely available, expertiseis limited.

Transc ranial Doppler ultrasonography.13.fi3s70 74Technique. A portable 2-MHz pulsed Doppler in-

strument can be used at the bedside. Intracranialarteries should be insonated bilaterally (eg, middlecerebral artery through the temporal bone abovethe zygomatic arch and the vertebral or basilar ar-teries through the suboccipital transcranial win-~ o w ~ ~ J O ; lternatively, a combination of one oph-thalmic artery through the transorbital windowand the middle cerebral artery can be tried13-70).

Result. Transcranial Doppler signals that havebeen reported in brain dea th a re a s follows: 1) Ab-sent diastolic or reverberating flow that indicatesflow only through systole or retrograde diastolicflow. This pattern is caused by the contractiveforces of the arteries. (2) Small systolic peaks inearly systole that indicate very high vascular resis-tance. This pattern is associated with greatly in-creased intracranial pressure. Lack of transcranialDoppler signals cannot be interpreted as confirma-tory of brain death, because 10 of patients maynot have temporal insonation windows. An excep-tion possibly can be made in patients who hadtranscrania l Doppler signals during admission tha tdisappeared a t the time of brain death.

Validity. There is a comparatively large experi-ence with tr anscranial Doppler ultrasonography inthe confirmation of brain death.13,70,71s75 he sensi-tivity of the procedure is 91.3% and the specificityis 100%. Transcranial Doppler ultrasonography oc-casionally demonstrates “brain death patterns” inpatients who ar e clinically brain-dead an d whohave EEG a c t i ~ i t y . l ~ , ~ ~mall systolic peaks and in-creased diastolic flow may occur as transient phe-nomena in pat ients with aneurysmal r e r ~ p t u r e . ~ ~Transcranial Doppler signals can be normal in pa-tients with primary infratentorial lesions and inpatients with anoxic-ischemic damage after cardiacarrest.13

Disadvantages. Transcranial Doppler velocities

can be affected by marked changes in Pco,, hemat-ocr it , and cardiac 0u t p ~ t . l ~ ranscr anial Dopplerultrasonography requires considerable practice andskill.

Somatosensory evoked potentials.Technique. A portable instrument can be used a t

the bedside. Median nerve st imulation is per-formed on both sides.

Result. N20-P22 response is bilaterally absent.Validity. Somatosensory evoked potentials and

auditory brainstem responses were tested in pa-tients with brain death, and most patients werefound t o have no response^.^^-^^One claimedth at both flat brainstem auditory evoked potentials


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and absence of somatosensory evoked potentials be-yond Erb’s point were unique in patients withbrain death and not found in comatose patientswho still had preserved brainstem function. Thisstud y has not been confirmed or refuted.

Miscel laneous tes t s . Many of these tests havebeen done in small series of patients only and are

not widely adopted as confirmatory tests .Contrast CT with a bolus of meglumine diatri-zoate, 1 mWkg of body weight, followed by drip infu-sion of 0.02 mWkg per minute, does not visualize in-tr ac ra ni al v e s s e l ~ . ~ 7 - ~ ~ good correlation with cere-bral angiography has been demonstrated in a fewanecdotal reports.89

Many other confirmatory tests are variants ormodifications. Experience is limited, or these testsproduce similar results in patients with neurologiccatastrophes who do not fulfill the clinical criteriafor brain death.

Recommendations after th e diagnosis ofbrain death. It is prudent to discuss organ dona-tion with family members only after the clinical di-agnosis of brain death. The following approach issuggested. The family should be told in unequivo-cal terms th at the patient died. Mechanical ventila-tion, fluids, and blood pressure medication are ad-ministered only to procure organs in th e event th atpermission for donation is given. Refusal by familymembers t o harvest organs removes the rationalefor supportive therapy, and mechanical ventilationis discontinued after the family has been allowedadequate time for consideration and visitation.When the family permits organ procurement, a

local transplantatio n coordinator is notified.Management of a brain-dead patient in prepara-

tion for donation is complicated, and advice from aneurologist specialized in neurologic critical care orfrom an anesthesiologist should be strongly consid-ered.91-94

Major immediate threats to organs are (1) pul-m o n a r y e d e m a , r e q u i r i n g p u l m o n a r y a r t e r ycatheter placement and treatment with positiveend-expiratory pressure ventilation, (2) hypoten-sion, requiring adequate fluid resuscitation andvasopressors (dopamine to 10 pg/kg per millime-ter), 3) polyuria from diabetes insipid~s,~5 equir-ing l-desamino-8-o-arginine vasopressin 1 o 4 g)or desmopressin (0.5 to 2 pg) intravenously every 8hours and guidance by urine output. Use of hor-mone substitution and prophylactic administrationof antibiotics is c o n t r o v e r ~ i a l . ~ ~ - ~ ~

Recommendation for future research. Data onapnea testing are incomplete, and careful evalua-tion of respiratory efforts and the level of Pco, a twhich apnea occurs is necessary. Confirmatory testresults need t o be validated.

Acknowledgments

Many neurologists have reviewed the manuscript. I am particu-

larly grateful for the critical reviews by Drs. S. Ashwal, J.L.Bernat, T.P. Bleck, J.R. Daube, M. Diringer, D. Hanley, A.H.Ropper, and M.R. Nuwer. Joanne F. Okagaki’s expertise isgreatly acknowledged.

References roman num bers i n parenthesesidentify class II or I I I studies)

1. fZZZ) American Academy of Pediatrics. Report of special taskforce: guidelines for the determination of brain death in chil-dren . Pediatr ics 1987;80:298-300.

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DOI 10.1212/WNL.45.5.10031995;45;1003-1011 Neurology

Eelco F.M. WijdicksDetermining brain death in adults

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