Abstract
Background
Computed tomography angiography (CTA) has been investigated as a confirmatory study (CS) for the diagnosis of brain death (BD). International consensus regarding its use, study parameters, and evaluation criteria is lacking. In the German BD guideline, a CTA protocol was first introduced in 2015.
Methods
The authors obtained a comprehensive dataset of all BD examinations in adults from the German organ procurement organization to investigate implementation, results, and impact of CTA on BD determination during the first 4 years.
Results
In 5152 patients with clinically absent brain function, 1272 CTA were reported by 676 hospitals. Use of CTA increased from 17.2% of patients in the first year to 29.7% in the final year. CTA replaced other CS such as electroencephalography without increasing overall CS frequency. Technical failure was rare (0.9%); 89.3% of studies were positive. Negative results (9.8%) were more frequent with secondary brain injury, longer duration of the clinical BD syndrome, or unreliable clinical assessment. Median time to diagnosis was longer with CTA (2.6 h) versus other CS (1.6 h). CTA had no differential impact on the rate of confirmed BD and did not improve access of small hospitals to CS for BD determination.
Conclusions
CTA expands the range of available CS for the diagnosis of BD in adults. Real‐world evidence from a large cohort confirms usability of the German CTA protocol within the guideline‐specified context.
Keywords: ancillary tests, brain death, CT angiography, electroencephalography, guidelines
INTRODUCTION
Brain death (BD) is defined as the complete and permanent loss of brain function following catastrophic brain injury [1]. In many countries, BD is legally equivalent to the death of the individual and allows for postmortem organ donation and withdrawal of life support. Diagnosis of BD is regulated by country‐specific guidelines [2], often including mandatory observation periods or confirmatory studies (CS). Digital subtraction angiography (DSA) or computed tomography angiography (CTA), transcranial Doppler (TCD), or radionucleotide imaging may provide evidence of absent brain perfusion.
Currently, there is no international consensus regarding the use of CTA in BD determination or on a specific protocol and criteria [3]. A UK consensus guideline recommended CTA as a diagnostic standard [4], whereas a recent international panel suggested that CTA should not be used pending further research into its sensitivity and specificity [1].
In Germany, diagnosis of BD is regulated by the guideline of the national Chamber of Physicians. In its fourth update in July 2015, a specific CTA protocol was first approved as a CS for adults [5, 6, 7, 8, 9]. The CTA protocol was retained in the most recent 2022 update [10]. The present study investigates the implementation of CTA as a CS during the first 4 years after its introduction as well as its utility and impact on BD determination in Germany.
METHODS
Diagnostic standard for BD in Germany
Diagnosis of BD in Germany requires demonstration of permanent and complete loss of cerebral, cerebellar, and brain stem function. Using a three‐step approach, a proximate cause is established and confounding effects are ruled out [10]. Second, coma, loss of all brain stem reflexes, and a positive apnea test are documented by two qualified physicians with several years of neuro‐intensive care experience. At least one must be a board‐certified neurologist or neurosurgeon. Third, irreversibility is established by clinical reassessment after at least 12 h for primary brain injuries or 72 h for secondary hypoxic brain injury. As an alternative to clinical reassessment, a CS may be performed.
Isolated brain stem death does not fulfill German BD criteria. If primary supratentorial lesions or hypoxic brain damage result in transforaminal herniation, clinically absent brain stem function implies loss of whole brain function. In contrast, a CS indicating absent brain perfusion or electroencephalography (EEG) activity is mandatory with primary infratentorial brain injury. Demonstration of absent brain perfusion can be used to override confounding factors or when a complete assessment of brain stem reflexes or an apnea test are not possible. CS include EEG, somatosensory evoked potentials (SEP) or brainstem acoustic evoked potentials (AEP), TCD, and brain nuclear scans. DSA may confirm BD but is not indicated as a CS due to its invasiveness. CTA was added in 2015 [5]. While not confirmative, negative CS findings do not rule out BD, and a different CS may be applied immediately. Outside the scope of this study, additional diagnostic rules apply to children younger than 14 years.
CTA protocol
CTA is approved by the German guideline as a CS in patients aged 18 years or above [5, 10]. A mean arterial pressure of at least 60 mmHg must be documented during the study. With the gantry adjusted in parallel to the orbitomeatal line, a native spiral scan from scull base to vertex is obtained at 120 kV, 170 mA, and reconstructed as 5 mm axial slices. Via a peripheral or central venous catheter, 65 mL of highly concentrated non‐ionic contrast medium are pressure infused at 3.5 mL/s, followed by 30 mL of saline. CTA is started by bolus tracking 5 s after reaching 150 Hounsfield units in the common carotid artery (CCA). A spiral scan is performed from the 6th cervical vertebra to the vertex at 120 kV, 200 mA, and a table feed of 4 cm/s. Axial 2 mm slices are reconstructed. Alternatively, a simultaneous volume scan from the 6th cervical vertebra to vertex can be performed 15 s after arrival of the bolus.
Diagnosis of cerebral circulatory arrest requires absence of contrast in the basilar artery and in both M1, A1, and P1 segments as well as presence of contrast in both CCA and in external carotid arteries with their branches, including the superficial temporal arteries. Proximal portions of the intradural internal carotid arteries (ICA), of the V4 segments, or of the inferior posterior cerebellar arteries may show contrast due to stasis filling without contradicting cerebral circulatory arrest. Evaluation and reporting must be performed by a neuroradiologist or a radiologist with several years of experience in neuroradiological diagnostics.
Patient data
The national organ procurement organization (Deutsche Stiftung Organtransplantation [DSO]) collects reports on patients who died from cerebral causes during mechanical ventilation on an intensive care unit. This documentation includes any formal BD diagnostics, regardless of whether BD was diagnosed, or organs were donated. The authors obtained a dataset including all reported BD studies that were performed between July 2015 and June 2019. Anonymization was applied beforehand to preclude identification of individuals, hospitals, or regions. Only patients aged 18 years or above were included in this study.
Evaluated information included patient age, the diagnosis leading to BD and its categorization as primary versus secondary hypoxic brain injury, the hospital category (A, university hospitals; B, other hospitals with neurosurgical departments; C, other hospitals without neurosurgical departments); time and result of all clinical examinations and CS for BD; duration of the diagnostic process, and outcomes including confirmation of BD, termination of the diagnostic process, permanent circulatory failure, and organ donation.
Based on the chronological sequence, clinical examinations and associated CS were retrospectively assigned to examination rounds. A distinction was made between core working hours (weekdays 08:00–17:00) and on‐call time (remaining hours and public holidays), and between examinations by employees of the hospital versus external consultants.
The underlying data were derived exclusively from the official BD protocol form. Here, information on confounding variables is incomplete since confounders are marked as ruled out if absence of brain perfusion has been demonstrated by a guideline‐specified CS.
Statistical evaluation
Statistical evaluation was carried out using Access and Excel (Microsoft, Redmond, CA, USA) and SPSS for Windows 29.0 (IBM Corp., Armonk, NY, USA). For descriptive statistics, absolute numbers with mean ± standard deviation, median and ranges, and percentages are reported. Effects of hospital size on the frequency of BD diagnostics and use of CTA, results of different CS modalities, and effects on diagnosis of BD, premature circulatory failure, and organ donation were examined using nonparametric ANOVA or chi‐square tests. To compare frequencies between multiple groups, an omnibus chi‐square test was followed by z‐tests with Bonferroni's correction for multiple levels. Time‐dependent probabilities were evaluated using Kaplan–Meier analysis with log‐rank tests for group comparisons. Logistic regression was performed to investigate multivariable predictors of negative CTA results. Values of p < 0.05 were considered significant.
RESULTS
Patients
From July 2015 to June 2019, 5152 patients underwent BD diagnostics (Table 1). The annual number increased from 1240 and 1237 in the first 2 years to 1296 and 1379 in the final 2 years. There were 6350 clinical examinations and 4626 CS. BD was diagnosed in 4904 patients (95.2%); 64.1% donated organs. Primary brain injuries, mostly non‐traumatic, were the proximate cause in 76.2% of cases. On average, patients with secondary brain damage were 8 years older than those with primary brain damage (mean ± SD 58.4 ± 15.8 vs. 50.1 ± 15.9 years).
TABLE 1.
Characteristics of patients studied with computed tomography angiography, other confirmatory studies, or no confirmatory studies.
| Characteristic | CTA | Other CS | No CS | |||
|---|---|---|---|---|---|---|
| Patients, n | 1248 | 3052 | 852 | |||
| Age (years) | ||||||
| Mean (SD) | 56.1 | (16.1) | 56.2 | (16.3) | 57.7 | (15.8) |
| Median (range) | 57 | (18–92) | 57 | (18–95) | 57 | (18–92) |
| Hospital type, n (%) | ||||||
| A | 552 | (31.3) | 906 | (51.4) | 303 | (17.2) |
| B | 484 | (22.9) | 1210 | (57.2) | 423 | (20.0) |
| C | 212 | (16.6) | 936 | (73.5) | 126 | (9.9) |
| Patients per year, n (%) | ||||||
| Year 1 | 213 | (17.2) | 813 | (65.6) | 214 | (17.3) |
| Year 2 | 271 | (21.9) | 754 | (61.0) | 212 | (17.1) |
| Year 3 | 354 | (27.3) | 740 | (57.1) | 202 | (15.6) |
| Year 4 | 410 | (29.7) | 745 | (54.0) | 224 | (16.2) |
| Cause of BD, n (%) | ||||||
| Primary brain injury | 956 | (76.6) | 2175 | (71.3) | 793 | (93.1) |
| Spontaneous ICH | 647 | (51.8) | 1431 | (46.9) | 496 | (58.2) |
| TBI | 159 | (12.7) | 342 | (11.2) | 165 | (19.4) |
| Ischemic stroke | 106 | (8.5) | 304 | (10.0) | 100 | (11.7) |
| Other | 44 | (3.5) | 98 | (3.2) | 32 | (3.8) |
| Secondary hypoxic brain injury | 292 | (23.4) | 877 | (28.7) | 59 | (6.9) |
| Clinical examinations, n (%) | ||||||
| Number per patient, mean (SD) | 1.1 | (0.4) | 1.1 | (0.3) | 1.9 | (0.3) |
| n = 1 | 1155 | (92.5) | 2787 | (91.3) | 69 | (8.1) |
| n = 2 | 72 | (5.8) | 245 | (8.0) | 772 | (90.6) |
| n = 3 | 18 | (1.4) | 19 | (0.6) | 10 | (1.2) |
| n = 4 | 3 | (0.2) | 1 | (0.0) | 1 | (0.1) |
| During on‐call time | 450 | (33) | 1282 | (38) | 657 | (40) |
| External consultation | 267 | (19.6) | 1044 | (31.3) | 268 | (16.3) |
| Confirmatory studies | ||||||
| n = 1 per patient | 1151 | (92.2) | 2871 | (94.1) | – | – |
| n = 2 per patient | 82 | (6.6) | 155 | (5.1) | – | – |
| n = 3 per patient | 11 | (0.9) | 24 | (0.8) | – | – |
| n = 4 per patient | 4 | (0.3) | 1 | (0.0) | – | – |
| n = 5 per patient | – | – | 1 | (0.0) | – | – |
| During on‐call time | 540 | (39.6) | 1366 | (41.9) | – | – |
| External consultation | 49 | (3.6) | 1711 | (52.5) | – | – |
| CTA | 1272 | – | – | |||
| EEG | 49 | 1990 | – | |||
| TCD | 35 | 1012 | – | |||
| Brain nuclear scan | 3 | 164 | – | |||
| AEP | 1 | 32 | – | |||
| SEP | 3 | 57 | – | |||
| DSA | 1 | 7 | – | |||
| BD not diagnosed, n (%) | ||||||
| Total | 72 | (5.8) | 98 | (3.2) | 78 | (9.2) |
| Medical decision | 48 | (3.8) | 51 | (1.7) | 15 | (1.8) |
| Organ donation denied | 13 | (1.0) | 29 | (1.0) | 39 | (4.6) |
| Circulatory failure | 10 | (0.8) | 16 | (0.5) | 23 | (2.7) |
| Unknown | 1 | (0.1) | 2 | (0.1) | 1 | (0.1) |
| BD confirmed, n (%) | ||||||
| Total | 1176 | (94.2) | 2954 | (96.8) | 774 | (90.8) |
| Organ donation | 797 | (63.9) | 1973 | (64.6) | 531 | (62.3) |
| Organ donation denied | 299 | (24.0) | 755 | (24.7) | 194 | (22.8) |
| Medical contraindication | 66 | (5.3) | 190 | (6.2) | 36 | (4.2) |
| Circulatory failure | 7 | (0.6) | 10 | (0.3) | 3 | (0.4) |
| Outcome unknown | 7 | (0.6) | 26 | (0.9) | 10 | (1.2) |
Note: Hospital categories: A, university hospitals; B, other hospitals with neurosurgical departments; C, other hospitals without neurosurgical departments.
Abbreviations: AEP, brainstem auditory evoked potentials; BD, brain death; CS, confirmatory studies; CTA, computed tomography angiography; DSA, digital subtraction agiography; EEG, electroencephalography; ICH, intracranial hemorrhage; SD, standard deviation; SEP, somatosensory evoked potentials; TBI, traumatic brain injury; TCD, transcranial Doppler ultrasound.
The frequency of BD diagnostics and the use of CTA were dependent on the hospital category (p < 0.001; nonparametric ANOVA; Table 2). In A and B hospitals, clinical examinations were generally performed by employees of the hospital (92.5% and 93.8%), whereas a higher proportion was performed by external consultants in C hospitals (29.4%; p < 0.05). More examinations were conducted during on‐call time in C hospitals (48.4%) than in A or B hospitals (37.1% and 32.0%; all p < 0.05). Most external consultations (55.5%) took place during on‐call time.
TABLE 2.
Implementation of computed tomography angiography by hospitals of different categories.
| Hospital category | A | B | C | |||
|---|---|---|---|---|---|---|
| Hospitals, n (%) | 38 | (5.6) | 122 | (18.1) | 514 | (76.3) |
| Patients examined for BD, n (%) | 1761 | (34.2) | 2117 | (41.1) | 1274 | (24.7) |
| Patients with secondary hypoxic brain injury, n (%) | 320 | (18.2) | 317 | (15.0) | 591 | (46.4) |
| Patients per hospital | ||||||
| Mean (SD) | 46.3 | (21.7) | 17.4 | (13.7) | 2.5 | (2.7) |
| Median (range) | 42.5 | (17–93) | 14 | (1–66) | 2 | (1–24) |
| CTA studies, n (%) | ||||||
| Year 1 | 104 | (47.9) | 77 | (35.5) | 36 | (16.6) |
| Year 2 | 117 | (42.2) | 114 | (41.2) | 46 | (16.6) |
| Year 3 | 163 | (45.4) | 140 | (39.0) | 56 | (15.6) |
| Year 4 | 183 | (43.7) | 161 | (38.4) | 75 | (17.9) |
| Patients with CTA, n (%) | 552 | (31.3) | 484 | (22.9) | 212 | (16.6) |
| Positive CTA studies, n (%) | 501 | (88.4) | 445 | (90.4) | 191 | (89.7) |
| Hospitals that have used CTA, n (%) | ||||||
| Year 1 | 27 | (71.1) | 40 | (32.8) | 33 | (6.4) |
| Years 1–2 | 31 | (81.6) | 58 | (47.5) | 59 | (11.5) |
| Years 1–3 | 35 | (92.1) | 76 | (62.3) | 88 | (17.1) |
| Years 1–4 | 35 | (92.1) | 86 | (70.5) | 120 | (23.3) |
| CTA studies per hospital | ||||||
| Mean (SD) | 14.5 | (13.6) | 4 | (5.7) | 0.4 | (1.1) |
| Median (range) | 12.0 | (0–64) | 2 | (0–33) | 1 | (0–13) |
Note: Hospital categories: A, university hospitals; B, other hospitals with neurosurgical departments; C, other hospitals without neurosurgical departments.
Abbreviations: BD, brain death; CTA, computed tomography angiography; SD standard deviation.
Use and results of CTA
After inclusion in the guideline, use of CTA showed a steady increase year on year. Implementation in A and B hospitals was much faster and more comprehensive than in C hospitals (p < 0.001; chi‐square test; Table 2). Overall, 1272 CTA were performed in 1248 patients, mostly during core working hours (n = 782; 61.5%). Technical failure was reported in only 11 studies (0.9%), whereas 1136 (89.3%) were positive and 125 (9.8%) negative. When used as the first CS (n = 1212), CTA was positive in 90.8%, compared with 58.3% after an earlier negative or inconclusive CS (p < 0.001). Negative CTA was also more frequent with secondary versus primary brain injury (13.5% vs. 8.7%; p = 0.004), and with incomplete clinical assessment or in the presence of confounders (n = 74; 23.3% vs. 9.0%; p < 0.001). Negative CTA results were more frequent with longer delays since the first documentation of the clinical BD syndrome (Figure 1a). In a multivariable analysis, secondary hypoxic brain injury, incomplete or inconclusive clinical assessment, non‐confirmatory findings in an earlier CS, and more than 48 h delay before CTA were significant predictors of a negative result (Figure 1b). There was no significant effect of the hospital category or the number of previously performed CTA for BD at the hospital.
FIGURE 1.
(a) Kaplan–Meier analysis of the probability of a positive finding on the first computed tomography angiography (CTA) study dependent on the time since first fulfilling clinical brain death (BD) criteria. Censored events indicate CTA studies with positive results. The difference between patients with primary versus secondary brain injury was not significant (log‐rank test). (b) Predictors of a negative result of the first CTA. Odds ratios with 95% confidence intervals and p values were calculated using multivariable logistic regression analysis. Studies with inconclusive results were not included in panel (a) or (b).
Excluding repeat studies and technical failure, 114 of 1237 CTA did not meet the criteria of absent brain perfusion. Of these, 18 patients underwent a second CTA study. Of these, 11 remained negative. Similarly, 5 of 9 TCD studies were negative, whereas 24 of 30 EEG and 3 of 3 brain nuclear scans were positive. A single SEP study was reported as negative.
Comparison with other confirmatory studies
A comparison of all modalities when used as the first CS is depicted in Figure 2a. Technical failure was less frequent with CTA versus TCD (0.9% vs. 2.8%; p < 0.05; z‐test), but not different from the general failure rate of all modalities (1.0%). Compared with CTA, positive results were more frequent with EEG and nuclear scans, and less frequent with TCD.
FIGURE 2.
Comparison of computed tomography angiography (CTA) and other confirmatory studies. (a) Comparison of the results of confirmatory studies (CS), including CTA, digital subtraction angiography (DSA), electroencephalography (EEG), brainstem auditory evoked potentials (AEP), somatosensory evoked potentials (SEP), and transcranial Doppler ultrasound (TCD), in patients fulfilling clinical criteria of brain death (BD). *p < 0.05 versus CTA; chi‐square test followed by z‐tests. (b) Number of CS per modality that were performed in house versus by external consultants during core working time (08:00–17:00) versus on‐call time (other times, weekends, and holidays) in university hospitals (A hospitals), other hospitals with neurosurgical departments (B hospitals), and other hospitals without neurosurgical departments (C hospitals). (c) Kaplan–Meier analysis of the time to confirmed diagnosis of BD, starting after conclusion of the first positive clinical examination. Censored events indicate death before diagnosis of BD due to permanent circulatory failure. Group differences between patients studied with CTA, other CS, or no CS were compared using log‐rank tests; all comparisons were p < 0.001.
In only eight patients, both CTA and TCD were performed within 12 h. Three of these had inconclusive results in one study. In three patients, both studies were negative. In the remaining two, the earlier study was negative whereas the later study was positive. A combination of CTA with DSA or nuclear scan was not reported.
Frequency and timing of CS modalities differed between hospital categories (Figure 2b). EEG was used most frequently; fewer than 5% of hospitals reported a nuclear scan. CS was applied more often when an external diagnostic team was involved (77.8% vs. 68.7%; p < 0.001). Compared with other CS, use of CTA was less likely in B and C hospitals, during core working hours, or by an external diagnostic team (all p < 0.001; multivariable logistic regression).
The median delay between conclusion of the clinical examination and conclusion of a CS was 2.0 h for CTA (mean ± SD 5.2 ± 9.6 h) versus 1.5 h for other CS (5.2 ± 11.3 h). Except for nuclear scans (median 3 h; mean ± SD 9.6 ± 17.8 h), waiting times were shorter for all other modalities (p < 0.01, one‐way ANOVA). The delay was longer for a CS during core working hours (p < 0.05, log‐rank tests) except for nuclear scans. This additional delay was longer for CTA versus other CS (81 vs. 45 min).
Procedural effects of CTA in BD determination
During the first 4 years, the proportion of patients studied with CTA increased significantly, whereas other CS declined (p < 0.001; chi‐square test; Table 1). EEG studies declined from 48.5% of all CS in year 1 to 39.4% in year 4, and TCD studies decreased from 26.5% to 20.9% (p < 0.05). The proportion examined without CS did not change. These effects did not differ between hospital categories.
BD was diagnosed in 94.2% of the patients who underwent CTA, in 96.8% of those who received other CS, and in 90.8% of those with a purely clinical diagnostic approach (all p < 0.05).
The median diagnostic duration was 2.6 h (95% CI 2.5–2.8 h) with CTA compared to 1.6 h (1.6–1.7 h) with other CS (p < 0.001, log‐rank test; Figure 2c). For reference, duration was 21.2 h (95% CI 20.7–21.7 h) when BD was confirmed by clinical follow‐up only.
With CTA, 1.4% of patients died from circulatory failure before diagnosis of BD or before organ donation compared with 0.9% with other CS (p = n.s.). This risk was higher in patients who did not receive CS (3.1%; p < 0.05, z‐test). The proportion of organ donation was not dependent on whether CTA, other CS, or no CS were performed (p = n.s., chi‐square test).
DISCUSSION
Reporting on 1272 CTA examinations, this study provides real‐world insight into the routine use of CTA in the diagnosis of BD, its implementation across hospital categories, and its impact on the diagnostic process in Germany.
The guideline‐specified CTA protocol was validated in an earlier study of 71 patients [6]. To minimize false negative results from stasis filling of intracranial arteries, bolus tracking is applied to capture the early arterial phase [11, 12]. In the authors' experience, sources of error include misplacement of the trigger volume and failed infusion of the contrast agent. The study cannot be repeated before the contrast agent has been eliminated. Given these considerations, the low reported rate of inconclusive studies is remarkable.
CTA was rarely applied in parallel with other CS, precluding a case‐based assessment of its validity. There were no cases where a positive CTA was contradicted later. Amongst the CS measuring cerebral perfusion, the positive rate of CTA was lower than that of nuclear scans, and higher than that of DSA and TCD. Details on negative studies were not available. Possible explanations include method‐specific criteria. The German guideline demands absence of contrast in proximal arterial segments, while other protocols focus on more distal arteries or cerebral veins [4, 13, 14, 15]. The positive rate is in the upper range of studies using a criterion of absent opacification of all intracranial arteries on arterial phase CTA (75%–94%) [3]. In CTA and DSA, stasis filling of proximal intracranial arteries may occur [7, 11, 12, 13, 16, 17, 18], being more frequent on late‐ than early‐phase CTA [19]. If present, expert judgement is required on whether criteria are met, potentially leading to false‐negative reports. Limited stasis filling may occur on single‐photon emission computed tomography (SPECT) [16], but absent parenchymal perfusion and tracer uptake in the static phase provide additional clear criteria. Negative findings on TCD despite positive CTA have been reported previously [8, 20]. On TCD, the ICA may show directional flow despite absent cerebral perfusion when feeding the ophthalmic artery [21]. This finding is incompatible with the German guideline. Although the potential of false‐negative results has been recognized, these criteria were upheld in the most recent update to avoid a higher risk of false‐positives [10, 22]. Moreover, patient‐related factors such as decompressive craniectomy or other skull defects may play a role [23]. Related information was not available in the dataset.
Since perfusion studies may also be applied to override confounders, a comparison to neurophysiological studies is not informative. However, EEG, SEP, and AEP offer additional information by investigating brain function rather than perfusion. In recent discussions, EEG is given lower priority, citing a high rate of false‐negative findings or failure due to artifacts [1]. With a failure rate of 0.6% and 4.7% negative results, the present data from more than 2000 EEG studies do not support this view. The German BD guideline requires supervision of the recording by an experienced physician, thereby reducing the risk of artifacts [10].
The rate of positive CTA was higher in the original implementation study (94%) than in the present study (90.8%) [6]. Similarly, the same study reported a much higher rate of positive TCD (92% vs. 82.2%). While this could indicate an impact of individual expertise, the number of previously performed BD CTA at the hospital or its category were not significant predictors. It is advisable to set up the specific CTA protocol at the local scanner and formulate a local standard procedure ahead of its use [9].
A negative CTA was more likely with secondary brain damage or when CTA was delayed for more than 48 h after documented loss of clinical brain function. Absent flow in the large intracerebral arteries is expected when cerebral perfusion pressure (CPP) is near zero due to a massive increase in intracranial pressure (ICP). In secondary brain damage, ICP may rise more slowly than in patients with acute space‐occupying lesions. Peak ICP and negative CPP are frequently recorded hours before diagnosis of BD, whereas at the time of diagnosis a relevant proportion of patients shows positive CPP [24, 25]. ICP is expected to decrease over time due to resolving edema and dissolution of tissue. CTA was less often positive when used second line after a negative CS. Repeat CTA studies in particular often remained negative. Instead, switching to a different CS, not investigating blood flow, seems preferable. A follow‐up CTA may be more promising if fewer than 36 h have passed since documentation of the clinical signs of BD [26]. Interestingly, a previous study of 104 patients reported a higher negative rate when CTA was performed within 6 h after clinical diagnosis compared with after 12 h [27].
Compared with other CS, CTA prolonged the time to diagnosis by about 1 h. Potential reasons include scheduling issues, preparation, transport, and positioning of the patient in the scanner. BD CTA studies usually require more time than routine examinations. Another major factor may be a competition with other patients for the scanner, as suggested by the longer waiting time during routine hours. Other than suggested [4], CTA may not be the first choice if a bedside CS is applicable and available.
In contrast to other CS, CTA is available at all times at virtually every hospital. Hence, CTA should be ideal to provide smaller hospitals with access to CS and improve their ability to diagnose BD. However, the larger A and B hospitals introduced CTA much faster and used it in a higher proportion of patients than C hospitals, where only one in six patients underwent CTA. In A and B hospitals, this may seem counterintuitive, considering the resources involved in transporting ventilated patients to the CT facility, when bedside CS are available and require a shorter time until diagnosis. While not captured in the source data, we speculate that presence of sedatives may be an important motive [28, 29, 30]. Due to the higher proportion of primary brain injuries, this situation is more likely to occur in A and B hospitals. Here, CTA may be particularly useful in avoiding delays until sedatives have been eliminated [31]. Conversely in many C hospitals, the limiting factor for BD diagnostics is less the availability of CS and more the need for qualified clinical examiners. Upon request, the organ procurement organization coordinates external consultations by neurointensive care specialists, who also perform bedside CS on mobile devices, thus reducing the likelihood of CTA in C hospitals.
Consistent with these considerations, increasing use of CTA did not reduce the proportion of patients studied without CS, independent of the hospital category. Instead, the higher frequency of CTA was compensated by a lower frequency of other CS, particularly EEG. As in many countries, inclusion of CS is required in Germany only in specific situations. Instead, they are mostly applied on a facultative basis to substitute for clinical observation [32]. Clinical observation periods should be avoided since they increase the risk of permanent circulatory failure before diagnosis [32].
Conclusions from this study are limited by the retrospective evaluation of routine data. Source data were verified by the DSO only in cases proceeding to organ donation. There is a risk of incomplete reporting of negative or inconclusive examinations, which may be greater when an external diagnostic team was not involved. Underreporting may also concern patients who did not consent to organ donation. Regarding process duration and time effects, the first positive formal documentation of the clinical signs of BD was available rather than the actual time when BD was first suspected. Factors with potential relevance to the CTA results, including decompressive craniectomy [12, 23] or the presence of a posterior fossa lesion, were not reported in the dataset, and case‐specific reasons behind the individual diagnostic approach remain unknown.
To summarize our findings, CTA was readily accepted and progressively implemented across all hospital types following its introduction in the German BD guideline. Within the framework and definitions of irreversible loss of whole brain function, CTA had no differential effect on the probability of a final diagnosis of BD, permanent circulatory failure, and postmortal organ donation. Compared with other CS, CTA prolonged the time until diagnosis. CTA was less utilized by smaller hospitals and had no apparent impact on their ability to perform BD diagnostics. As an important advantage, CTA may facilitate an earlier diagnosis of BD in patients in whom sedatives or other confounders compromise clinical assessment, thereby reducing the risk of permanent circulatory failure before diagnosis. Effects may be underestimated due to a risk of underreporting.
AUTHOR CONTRIBUTIONS
Olaf Hoffmann: Conceptualization; data curation; formal analysis; writing – original draft; writing – review and editing. Farid Salih: Conceptualization; writing – review and editing. Florian Masuhr: Conceptualization; writing – review and editing.
CONFLICT OF INTEREST STATEMENT
O.H., F.S., and F.M. perform diagnostics for suspected brain death as external consultants. They receive per‐case compensation from the local branch of the national organ procurement organization (Deutsche Stiftung Organtransplantation, Region Nordost).
ETHICS STATEMENT
This study does not include experiments on human subjects or animals.
ACKNOWLEDGMENTS
No funding was obtained for this study. Open Access funding enabled and organized by Projekt DEAL.
Hoffmann O, Salih F, Masuhr F. Computed tomography angiography in the diagnosis of brain death: Implementation and results in Germany. Eur J Neurol. 2024;31:e16209. doi: 10.1111/ene.16209
DATA AVAILABILITY STATEMENT
Research data are not shared.
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