Ancillary Cerebral Blood Flow Testing for Brain Death: Used, But Usefulness (Specificity) Far From Clear*

Ancillary testing for brain death (BD) when required, according to 2023 recommendations by the American Academy of Neurology (AAN) and the Canadian clinical practice guideline, can be with a nuclear medicine cerebral blood flow (CBF) test (1,2). A lipophilic radionuclide (technetium 99m-hexamethylpropyleneamine oxime [99mTc-HMPAO] or -ethyl cysteinate dimer [ECD]) is preferred as this tracer crosses the blood-brain barrier and uptake by viable brain cells provides a delayed image of brain perfusion. If a lipophilic radionuclide is not available, a lipophobic tracer (99mTc diethylene-triamine-pentaacetate) can be used in children (in the Canadian guideline) and in children and adults (in the AAN guideline) to provide vascular-flow planar imaging (1,2). There is little information on use of CBF ancillary tests in infants under 2 months of age, and the Canadian guideline recommends against using CBF tests at this age (3). More information on CBF testing in infants is clearly needed. In this issue of Pediatric Critical Care Medicine, Bach et al (4) in their retrospective study from Children’s Hospital of Philadelphia aimed to fill some of this gap. The authors report on the use of 99mTc-ECD as an ancillary CBF test for determination of BD from 2005 to 2022 in 10 infants younger than 12 months. This ancillary test was done in five infants as the apnea test was “unable to be completed,” three due to confounders to examination, and two at clinician discretion. Overall, 9 of 10 ancillary tests were consistent with BD and the patients were therefore diagnosed with BD. One ancillary test showed persistent good brain perfusion in a patient aged younger than 2 months who had corneal clouding and chemosis confounding clinical determination of BD, leading to withdrawal of life support without the diagnosis of BD. The authors concluded that “prospective studies are needed to further characterize the diagnostic accuracy of these studies when used to augment the clinical evaluation of BD/death determination by neurologic criteria (DNC) in infants and children” (4). I will first briefly discuss my opinion about some terminology issues. The radionuclide CBF perfusion test was said to be “ancillary” and to “augment” the “clinical” evaluation of BD. The authors used this wording because it is recommended terminology. However, the test most surely is confirmatory, and labeling it “ancillary” is misleading. Patients who have a confounder to examination for BD, or who cannot have the apnea test, and who then have this ancillary test consistent with BD are diagnosed as dead. How that test did not act as a confirmation of the diagnosis of BD is unclear to me. In addition, BD is most certainly not a “clinical” diagnosis, the recommended wording meant to convey that only clinical bedside testing is needed to make the diagnosis. To make the diagnosis of BD, many laboratory (e.g., electrolytes, glucose, liver and renal function tests, endocrine tests, drug levels, arterial blood gases, etc) and imaging (CT or MRI of brain demonstrating injury severe enough to cause irreversible BD) tests are required to rule out confounders. The ancillary test is not the only nonclinical test used, and claiming otherwise is misleading. I will now focus on how useful the reported use of the ancillary CBF test actually was. In my opinion, whether any of these infants were BD is far from clear. This is because the data to determine the specificity of radionuclide CBF testing used to confirm BD are extremely limited, with surprisingly small numbers, at all ages (Table 1) (5–16). The data for specificity are even more limited than these very small numbers suggest, for several reasons. TABLE 1. - Sensitivity and Specificity of Radionuclide Cerebral Blood Flow Testing in Recent Guidelines Systematic Review Ancillary Test Sensitivity (95% CI) Specificity (95% CI) No. of Studies for Specificity, n/n (%) of Patients With Flow Comments on Studies Contributing to Specificity Calculationa Canadian consensus guideline: adults (2) HMPAO planar (p. 215–216) 92% (71–98) 100% (96–100) Three studies, 13/13 (100%) Macdonald et al (5): one patient of unstated severity.Mhrac et al (6): all had clinical BD; the authors may have included five patients (two of whom “survived”) who did not have BD “confirmed” by CBF testing (hence may have had only one set of full clinical BD testing).Schlake et al (7): three patients with “deep coma” and “slight triggering of breath on the ventilator,” and four with PVS and “clinically intact brainstem.”Did not include Laurin et al, as incorrectly denoted it as an HMPAO SPECT study, which would add another five adult patients.Unclear how specificity 95% CI was so narrow given the few numbers. HMPAO SPECT (p. 213–214) 91% (64–99) 100% (97–100) Two studies, 21/21 (100%) Facco et al (8): 12 “deeply comatose,” two whose “only sign of not having BD was breathing on apnea test,” and three surviving with PVS.Laurin et al (9): nine in “deep coma” with “residual brainstem function,” eight of whom had “no response to central pain,” one surviving in PVS; four of nine were younger than 18 yr (i.e., not adults). All had planar imaging, and none had SPECT, and therefore this study should not be included here in their meta-analysis.Unclear how specificity 95% CI was so narrow given the few numbers. 99mTc pertechnetate (p. 211–212) 99% (93–100) 99% (55–100) Two studies, 8/13 (61.5%) Unclear how the reported specificity of 99% was determined. Canadian consensus guideline: children (2) HMPAO planar (p. 247) 99% (87–100) 97% (65–100) Three studies, 5/5 (100%) Kraft et al (10): six aged younger than 18 years, all had clinically “established BD.”Laurin et al (9): included nine children, four were in “deep coma” with “residual brainstem function” and did not have clinical BD.Wilson et al (11): one infant 6 wk old did not have clinical brain death (breathing on apnea test and no EEG or vestibulo-ocular testing done); two were unclear about clinical BD: one child with “silent EEG” and no apnea test or vestibulo-ocular testing done, and one with EEG activity and no apnea test or vestibulo-ocular testing done. HMPAO SPECT (p. 245) 100% (40–100) Not estimable One study, all had BD Erbengi et al (12): all four children had clinical BD. This reference could not be obtained by this author. HMPAO planar or SPECT (p. 246) 99% (89–100) 97% (65–100) Three studies, 5/5 (100%) Same as for planar HMPAO (see above). Unclear on how the specificity of 97% was calculated. Radionuclide flow imaging (p. 242) 95% (89–98) 88% (67–98) Eight studies Canadian consensus guideline: infants (3) Radionuclide flow imaging 10 infants in 6 studies, 5 had confirmed BD, 1 without BD had flow “This neonate initially had a clinical assessment and flow study consistent with DNC (true-positive) but 24 h later, after mannitol, dexamethasone, and acetazolamide, had a clinical examination NOT consistent with DNC and had detectable flow on a radionuclide study (true negative)” (3). More accurately, the first flow study gave a false-positive diagnosis of BD. AAN Guideline (1): all ages, based upon Joffe et al (13) HMPAO planar 77.8% (70.5–83.7) 100% (92.6–100) Five studies, 41/41 (100%) “Most of these data for specificity come from 1 study in children that poorly describes [i.e., gave no detail] the severity of brain injury in a group of 22 patients without BD” (13, 14). HMPAO SPECT 88.4% (81.4–93.1) 100% (78.4–100) One study, 12/12 (100%) Facco et al (8): see above. Radionuclide flow imaging 50% One study, 5/10 (50%) “There is another report of two patients with electrocerebral silence, spontaneous respirations on apnea testing, and no cerebral blood flow on planar nondiffusable radionuclide study” (13, 15). BD = brain death, DNC = death determination by neurologic criteria, EEG = electroencephalogram, HMPAO = 99mTc-hexamethylpropyleneamine oxime, p. = page numbers in the supplemental appendix to the Canadian consensus guideline (2), PVS = persistent vegetative state, now better called unresponsive wakefulness syndrome, SPECT = single-photon emission CT.aNote that the radionuclide flow imaging studies from reference (2) were not reviewed by this author (as opposed to the HMPAO with/without SPECT studies), so no comment was made on the specific studies included. First, most reports on specificity have unclear or high risk of bias, often because the reference standard (i.e., the clinical neurologic examination) “may have been inaccurate in studies where confounders to the examination had not been clearly excluded” (i.e., confounders are the main reason for doing the ancillary test in the first place) (16). The Canadian consensus guideline systematic review had “reliance on data provided by studies with unclear or high risk of bias, which calls into question the validity of our meta-analysis estimates” (16). In the review by Joffe et al (13), “all studies had referral bias, where patients were usually referred for brain blood flow testing only after BD was strongly suspected, potentially limiting the ability to define specificity of the test. Most studies had many patients where confounding factors made clinical confirmation of BD impossible, and therefore, lack of brain blood flow was assumed to confirm BD, leading again to limited ability to define the specificity of the test” (13). Furthermore, the severity of brain injury in patients contributing to calculation of specificity was poorly described, a major limitation because the test should differentiate those close to BD from those with BD (i.e., having CBF detected in the vegetative state is not very informative, as those patients are not suspected of having BD) (13,16). Second, “brainstem uptake of lipophilic RPs (radiopharmaceuticals) remains poorly resolved on either planar or tomographic (single-photon emission CT [SPECT]) imaging,” and because the “brainstem [is] not well visualized… Specificity for DNC [is] not adequately characterized” (17). This likely explains the published reports of brainstem function after absent flow or uptake on CBF radionuclide testing. This includes a child with spontaneous breathing after diagnosis of BD supplemented with a nondiffusible radionuclide CBF test with no detectable flow; an adult with breathing, cough, and extensor posturing after no detectable uptake on Tc-99-ECD SPECT imaging; and an adult with spontaneous breathing noted after an HMPAO planar CBF test with no detectable uptake (18–20). Of concern, absent uptake on CBF studies is often used to define complex movements as “spinal reflexes” despite these almost certainly being of brainstem origin (21). This includes cases with absent uptake yet “myoclonic limb movements, flexion and extension jerking movement of the upper extremities, penile erection and flexion of lower extremities,” “upper extremity extensor posturing,” sternal rub elicited “movement of the arms, legs, head, and back… the patient’s head turned to the left and his left arm rose slightly off the bed, flexed at the elbow approximately 15 degrees, and tremored for several seconds” (as quoted in [16]). Third, the “thresholds of minimal detectable [brain] perfusion have never been determined” (16). It is quite possible that CBF tests cannot detect perfusion in the global ischemic penumbra range—that is, perfusion below the threshold for neuronal function, yet above the necrosis/apoptosis threshold. Global ischemic penumbra is a mathematical necessity occurring along the course to possible BD, yet if reversed would lead to maintained brain structure and function. This likely explains studies that demonstrated lack of pathologic global brain necrosis in over 20% of BD patients (21,22). In the case of Jahi McMath, brain MRI 9.5 months after being declared BD demonstrated “gross integrity of the cortex, basal ganglia, thalamus, cerebellum, and upper brainstem,” incompatible with the absent detected CBF and uptake on her earlier Tc-99-ECD confirmatory test (23). It is likely that Jahi McMath emerged to minimally conscious state with her intermittent ability to follow commands (21,23). There are several cases of electroencephalogram activity despite absent flow on nondiffusible radionuclide CBF tests, which would not be possible if there was sustained absent perfusion to brain tissue (15,24,25). Fourth, hypothalamic osmoregulatory function remains in approximately 50% of patients diagnosed with BD, indicating blood flow to at least parts of the diencephalon (22). This is sometimes hypothesized as due to the posterior pituitary (which releases vasopressin) being supplied by the inferior hypophyseal artery that takes a pathway outside the dura, possibly protected from high intracranial pressure. However, this cannot be the explanation because osmoregulation requires the function of cell bodies with blood supply from intradural coursing vessels unprotected from high intracranial pressure. The cell bodies for axons in the posterior pituitary that release vasopressin locate in magnocellular neurons in hypothalamic (paraventricular and supraoptic) nuclei of the diencephalon (22). To release vasopressin, these magnocellular neurons require additive glutamatergic input from circumventricular areas in basal forebrain (22). Furthermore, anterior pituitary function can remain (e.g., thyroid stimulating hormone not detectable in 16%, adrenocorticotropic hormone not detectable in 29%, and cases of pubertal sexual development) in BD (22). These anterior pituitary hormonal functions rely on cell bodies in hypothalamic nuclei that project to the median eminence, perfused by vessels unprotected from high intracranial pressure. The implication requires emphasis: “hypothalamic-pituitary function entails false-positive diagnosis of absent brain blood flow” (22). Bach et al (4) describe their use of 99mTc-ECD radionuclide brain perfusion as an “ancillary” test for BD in 10 infants at a large children’s hospital over a period of 17 years. However, in my opinion and as argued above, the usefulness of their having used this test to confirm BD is, at best, unclear, as this depends on the test specificity. “[A] single occurrence of misdiagnosis has catastrophic implications for the patient, their family, and the public’s trust in the medical system” (3). The lack of sufficiently robust study of radionuclide ancillary testing may explain the inconsistency between guidelines in the United States and Canada (Table 2) (1,2). I suggest more robust study of the specificity of CBF testing in confirming suspected BD at all ages, and more transparency in guideline recommendations regarding CBF testing in confirming BD. Only then will we learn whether the test is useful in cases of suspected BD. TABLE 2. - Radionuclide Cerebral Blood Flow Ancillary Testing: Comparison of Indications From the American and Canadian 2023 Guidelines Recommendation American Academy of Neurology Guideline (1)a Canadian Consensus Guideline (2)a Comments on Differences Confounders If metabolic derangements are unable to be adequately corrected.Must not use ancillary tests to assist in the diagnosis of BD/DNC in the setting of hypothermia or high levels of sedating medications. If these derangements [severe metabolic, acid-base, and endocrine] cannot be corrected and are judged to be potentially contributing to the loss of brain function, ancillary investigation should be considered.If there is uncertainty about reduced drug clearance or unknown drug exposures additional time is required or performing ancillary investigation may be considered.Confounding conditions that cannot be resolved. In Canada, but not the United States, an ancillary test may be used in the setting of suspected high levels of sedating medications. Inadequate examination When the accurate evaluation of a component of the BD/DNC neurologic examination cannot be assessed safely.Finding may be difficult to interpret, such as limb movements that may or may not be spinally mediated. Inability to complete a [full] valid clinical assessment.Uncertainty in interpretation of possible spinally mediated movements. No practical differences.Ancillary test is sufficient to assign complex movements as being spinally mediated. Inadequate apnea test Known or suspected to have chronic hypercarbia but the patient’s chronic baseline Paco 2 level is not known.Hypoxemia during apnea testing: So 2 < 85%.Hypotension during apnea testing: SBP ≤ 100 or MAP ≤ 75 in adults, or ≤ fifth percentile in children.Cardiac arrhythmia with hemodynamic instability. For patients who are dependent on hypoxic drive or have a history suggestive of chronic respiratory insufficiency and responsiveness to only supranormal levels of CO2, physicians must exercise caution in interpreting apnea test results. If the physician cannot be sure of the validity of the apnea test, an ancillary investigation should be performed.Hypotension: SBP < 100 or MAP < 60 despite titration of fluids/inotropes/vasopressors… Pediatric patients should have age-appropriate targets.Hypoxia: sustained desaturation < 85%.Unstable arrhythmia. The instruction in chronic hypercarbia is vague in Canada.In adults, the definition of hypotension is different (e.g., MAP cutoff of 75 in United States and 60 in Canada).In children, the definition of hypotension is not well specified: fifth percentile in United States, and “age-appropriate” in Canada. Primary posterior fossa injury Clinicians should ensure that the posterior fossa process has also led to catastrophic supratentorial injury as demonstrated on a conventional neuroimaging study. In patients with isolated infratentorial brain injury without supratentorial involvement. Ancillary investigation is required to determine death. In Canada, but not the United States, isolated infratentorial injury on conventional neuroimaging may be diagnosed with BD/DNC with ancillary testing. Radionuclide test Clinicians may use either SPECT radionuclide perfusion scintigraphy with a blood-brain barrier (BBB)-crossing agent or planar radionuclide angiography, preferably with a BBB-crossing agent or, if necessary, a non-BBB-crossing agent, as an ancillary test. A radionuclide brain perfusion study using a lipophilic radiopharmaceutical (with or without tomographic imaging) in adult patients… We suggest against performing… a radionuclide brain flow only study employing a lipophobic radiopharmaceutical… in adult patients.A lipophilic radiopharmaceutical… (which incorporates both a flow and parenchymal phase) with or without tomographic imaging in pediatric patients… We suggest performing a radionuclide brain flow study employing a lipophobic radiopharmaceutical… (which incorporate only a flow phase) when a study employing a lipophilic radiopharmaceutical cannot be performed, in pediatric patients.Against performing ancillary investigation in infants under 2 mo corrected gestational age who require ancillary investigation for DNC. In the United States a lipophobic (flow phase only) radionuclide test is acceptable at all ages, whereas in Canada this is acceptable only in pediatric patients (despite known poor specificity at all ages []).In Canada, but not the United States, ancillary testing is not acceptable in infants younger than 2 mo of age. BD/DNC = brain death/death determination by neurologic criteria, MAP = mean arterial pressure, SBP = systolic blood pressure, SPECT = single-photon emission CT.aThese columns are direct verbatim quotations from the respective guidelines.

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