Twenty-two people die every day in the United States waiting

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1 Doppler Ultrasonography of the Central Retinal Vessels in Children With Brain Death Becky J. Riggs, MD 1 ; Joanna S. Cohen, MD 2,3 ; Bhavana Shivakumar, MPH 1 ; Carmelina Trimboli-Heidler, COA, CDOS 4 ; Jason T. Patregnani, MD 2,5 ; Marijean M. Miller, MD 2,4 ; Michael C. Spaeder, MD 6 ; Nathan P. Dean, MD 2,7 Objective: The purpose of this observational study is to explore if bedside Doppler ultrasonography of the central retinal vessels has the potential to become an ancillary study to support the timely diagnosis of brain death in children. Design: Seventeen-month prospective observational cohort. Setting: Forty-four bed pediatric medical and surgical ICU in an academic teaching hospital. Patients: All children 0 18 years old who were clinically evaluated for brain death at Children s National Health Systems were enrolled and followed until discharge or death. Interventions: None. Measurements and Main Results: All patients had at least one ophthalmic ultrasound within 30 minutes of each brain death examination. The central retinal artery peak systolic blood flow velocity, resistive index, pulsatility index, and Doppler waveforms were 1 Division of Pediatric Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins University, Baltimore, MD. 2 Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC. 3 Division of Emergency Medicine, Children s National Health System, Washington, DC. 4 Division of Ophthalmology, Department of Surgery, Children s Hospital of Philadelphia, Philadelphia, PA. 5 Division of Cardiac Intensive Care Medicine, Children s National Health System, Washington, DC. 6 Division of Pediatric Critical Care, Department of Pediatrics, University of Virginia School of Medicine, Charlottesville, VA. 7 Division of Critical Care Medicine, Children s National Health System, Washington, DC. This work was performed at the Children s National Health System, Washington, DC. The authors have disclosed that they do not have any potential conflicts of interest. Address requests for reprints to: Becky J. Riggs, MD, Department of Anesthesiology and Critical Care Medicine, Division of Pediatric Anesthesiology and Critical Care Medicine, Charlotte Bloomberg Children s Center, 1800 Orleans Street Room 6321, Baltimore, MD rriggs6@jhmi.edu Copyright 2017 by the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies DOI: /PCC evaluated in each patient. Thirty-five ophthalmic ultrasounds were obtained on 13 patients, 3 months to 15 years old, who each had two clinical examinations consistent with brain death. The average systolic blood pressure during the ultrasound examinations was 102 mm Hg (± 28), diastolic blood pressure 65 mm Hg (± 24), mean arterial pressure 79 mm Hg (± 23), heart rate 133 beats/min (± 27), temperature 36 C (± 0.96), arterial Co 2 35 mm Hg (± 9), and end-tidal Co 2 23 mm Hg (± 6). For all examinations, the average peak systolic velocity of the central retinal artery was significantly decreased at 4.66 cm/s (± 3.2). Twelve of 13 patients had both resistive indexes greater than or equal to 1, average pulsatility indexes of 3.6 (± 3.5) with transcranial Doppler waveforms consistent with brain death. Waveform analysis of the 35 ultrasound examinations revealed 11% with tall systolic peaks without diastolic flow, 17% with oscillatory flow, 29% showed short systolic spikes, and 23% had no Doppler movement detected. A rippling tardus-parvus waveform was present in 20% of examinations. Conclusion: This study supports that the combination of qualitative waveform analysis and quantitative blood flow variables of the central retinal vessels may have the potential to be developed as an ancillary study for supporting the diagnosis of brain death in children. (Pediatr Crit Care Med 2017; XX:00 00) Key Words: brain death; ophthalmic Doppler ultrasonography Twenty-two people die every day in the United States waiting for organ transplants with over 123,000 remaining on the waiting list. Timely diagnosis of brain death (BD) is important to facilitate organ donation (1), allocate medical resources, and to relieve family members from end of life decisions. BD is defined as the irreversible cessation of functions of the entire brain, including the brain stem (2). In children, BD is diagnosed using two standardized neurologic examinations with apnea tests consistent with the absence of neurologic function and a known irreversible cause of coma (2). Ancillary studies may be used to determine BD when the clinical examination is unable to be adequately performed due to underlying medical conditions, findings are uncertain, there is concern for medication effect, or to reduce the time interval between examinations. Pediatric Critical Care Medicine 1

2 Riggs et al For over 40 years, transcranial Doppler (TCD) ultrasonography has been used with some technical difficulty as an ancillary study to identify intracranial sonographic patterns supporting the diagnosis of cerebral circulatory arrest (CCA) in the setting of BD in adults (3). In 2004, the American Academy of Neurology subcommittee on BD endorsed a type-a recommendation with a class-2 evidence level supporting the use of TCD to diagnose BD (4); however, these recommendations were not supported by the 2010 adult BD guidelines. Currently, the American Academy of Pediatrics does not endorse the use of TCD to confirm the diagnosis of BD in children due to the lack of pediatric research; however, they do endorse the use of electroencephalogram and radionuclide cerebral blood flow studies as having similar confirmatory value supporting the diagnosis of BD in children (2). Since this statement by the American Academy of Pediatrics in 2011, there have been several combined studies involving adult and pediatric patients that have demonstrated the high sensitivity and specificity of TCD in confirming the clinical diagnosis of BD; however, the actual number of pediatric patients was never specified in any of these studies (3, 5, 6). A study involving 623 adult and pediatric patients reported 91% sensitivity with 100% specificity for TCD in confirming the diagnosis of BD (7). More recent studies including adults and children have shown TCD with equal accuracy but superior speed in confirming the diagnosis of BD when compared with cerebral angiography and radionucleotide studies (8, 9). With further promising research, TCDs may become widely supported as an ancillary study to confirm the diagnosis of BD in children. The anatomy of the central retinal vessels (CRVs) is well suited for Doppler sonography because the ultrasound probe is easily positioned parallel to the axis of blood flow in the anterior portion of the optic nerve (10). In adults, spectral Doppler imaging has been used to study blood flow of the orbits in various pathologic states (10 12). In children, central retinal artery (CRA) resistance has been measured by spectral Doppler imaging in retinopathy of prematurity (13, 14), and the technology has been applied to diagnose orbital lesions (15). Normal blood flow velocity of the CRVs in healthy children has been identified (16), and pediatric studies have demonstrated significant alterations in CRV blood flow due to intracranial hypertension (17) (Fig. 1). Bedside ultrasound machines are portable, inexpensive, noninvasive, radiation-free, and widely available in PICUs. To our knowledge, there are no previous reports of Doppler ultrasonography of the CRVs being evaluated as a possible ancillary study to support the diagnosis of BD in children. The purpose of this observational study is to explore Doppler ultrasonography of the CRVs in BD children to determine if it has the potential to become an ancillary study to support the timely diagnosis of BD in children. METHODS Thirteen children, 3 months to 15 years old, who were clinically evaluated for BD at Children s National Health Systems, from November 2012 to April 2014, were enrolled in this Institutional Review Board approved, prospective observational cohort. All of these patients with suspected BD were mechanically ventilated Figure 1. Normal Doppler waveform produced by the central retinal artery (above the zero line) and the central retinal vein (below the zero line) (M-turbo; SonoSite, Bothell, WA). and had a Glasgow Coma Score of 3. Each patient had at least one ophthalmic ultrasound within 30 minutes of each BD examination, for a total of 35 ophthalmic ultrasound studies. Arterial blood pressure, heart rate, temperature, Pco 2, and end-tidal Co 2 (etco 2 ) levels were monitored during the ultrasound studies. The enrolling physician obtained parental consent prior to all ultrasound examinations. All examinations were conducted by a critical care fellow, with 1 year of prior ophthalmic ultrasound experience including 6 hours of direct ophthalmic ultrasound training and over 50 observed ophthalmic ultrasound studies. Examinations were conducted using a Sonosite M-TURBO ultrasound machine (SonoSite, Bothell, WA) with a high frequency linear array L25x 13-6 MHz probe set in ophthalmic safety mode. The probe was coated with GenTeal eye lubricant (Novartis Pharmaceuticals Corporation, East Hanover, NJ) and gently placed in the axial and the coronal plane over the closed eyelid with the probe positioned parallel to the axis of blood flow in the anterior portion of the optic nerve. The depth was set at cm depending on the age of the patient. The CRVs were located using duplex color sonography fully visualizing the lumens of the vessels in the most anterior portion of the optic nerve 2 4 mm prior to entering the orbit. Three separate Doppler spectrograms were taken for each study. After the spectrogram images were obtained, all measurements and analyses were determined by a blinded pediatric cardiologist. If no pulsatile Doppler movement was detected in the right eye, both eyes were imaged for a minimum of 15 minutes before concluding that no pulsatile Doppler signal was detectable by either color duplex sonography or Doppler sonography of the CRVs. Both qualitative analysis of spectrograms identifying characteristic flow patterns and quantitative variables including arterial peak systolic velocity, pulsatility index (PI), and resistive index (RI) were used to support the determination of CCA. TCD sonographic patterns supported by the Task Force of Neurosonology as markers of CCA are tall systolic peaks without diastolic flow (Fig. 2A), oscillating blood flow with diastolic reversal (Fig. 2B), a short systolic spike pattern (Fig. 2C), and a flat no pulsatile 2 XXX 2017 Volume XX Number XXX

3 Neurocritical Care Figure 2. All Doppler waveforms of the central retinal vessels. A, Initial stage of cerebral circulatory arrest showing systolic peaks without diastolic flow and respiratory-dependent changes in amplitude (waveform 1). B, As intracranial pressure rises, small vessels collapse and blood reverberates forward and backward in an oscillating flow pattern (waveform 2). C, Next short systolic spikes appear as the vessel vibrates with systole (waveform 3). D, No Doppler signal (waveform 4). E, Rippling tardus-parvus (waveform 5) (M-turbo; SonoSite, Bothell, WA). movement pattern (Fig. 2D) (18). These four identical Doppler patterns of the CRVs were identified as markers of CCA in this study. However, a fifth rippling tardus-parvus waveform, similar to the no movement pattern (Fig. 2E), not previously recognized as a sonographic pattern of CCA was identified as well. Waveforms over three cardiac cycles were analyzed at each sample point, and the mean was taken to obtain the average blood flow velocity, end-diastolic velocity, and peak systolic velocity for each spectrogram. Based on these raw data, the RI and PI were calculated for each spectrogram (19, 20). The average of each of these values for the three spectrograms was obtained as the final RI, PI, and peak systolic velocity for each study. SAS software (SAS Institute, Cary, NC) was used for data analysis. RESULTS Thirty-five ophthalmic ultrasounds were obtained on 13 patients. Each patient had two clinical examinations including apnea tests consistent with BD. Six patients were victims of abusive head trauma, three suffered accidental traumatic brain injuries, two were self-inflicted hangings, one had cerebral herniation secondary to oncologic cerebral edema, and one had sudden infant death syndrome (Table 1). The average systolic blood pressure during the ultrasound studies for all patients was 102 mm Hg (± 28) with a mean diastolic blood pressure of 65 mm Hg (± 24), giving a mean arterial pressure (MAP) of 79 mm Hg (± 23). The average heart rate was 133 beats/min (± 26.6), with a mean temperature of 36 C (± 0.96), a mean arterial Co 2 of 35 mm Hg (± 9), and a mean etco 2 of 23 mm Hg (± 6). The individual average values for each of these vital signs during the ultrasound examinations are reported in Table 1. The normal peak systolic blood flow velocity of the CRA in children is 9.1 cm/s (± 1.0) (Fig. 1) (16). Of the 35 Doppler studies, the average peak systolic velocity was significantly depressed at 4.6 cm/s (± 3.2) with a p value of less than when compared with normal values. When the eight studies without pulsatile Doppler flow are excluded, the remaining 27 studies also have a depressed peak systolic velocity of 6.0 cm/s (± 2.2) with a p value of less than (Table 2). If the arterial Doppler signal is not pulsatile, then the peak velocity defaults to zero; therefore, it is important to separate the pulsatile from the no pulsatile studies, because if all 35 studies are averaged, the nonpulsatile studies will artificially depress the average peak velocities. Thirty of the 35 Doppler studies showed a significantly decreased average peak systolic velocity of 3.7 cm/s (± 2.5) compared with normal values. Three Doppler studies revealed peak systolic velocity values that fall into the normal velocity range with the first having a velocity of 9.3 cm/s with waveform 5 described as a tardus-parvus waveform, the second with a velocity of 9.4 cm/s with waveform 1 described as tall systolic peaks without diastolic flow, and the third 9.6 cm/s again with waveform 5. Two Doppler studies showed increased peak systolic velocities of 10.5 cm/s associated with waveform 1 and 10.4 cm/s associated with waveform 5. Normal values for the CRA RI and PI were considered 0.70 (± 0.096) and 1.09 (± 0.21), respectively (16). Of the 35 Doppler studies, the average PI was significantly elevated at 2.9 (± 3.5) with a p value of and the RI was not significantly changed at 0.7 (± 0.5) with a p value of when compared with normal values. Doppler spectrograms without pulsatile patterns will always have a PI and RI of zero; therefore, the 27 Doppler studies with pulsatile flow must be evaluated separately as to not artificially depress the overall RI and PI values. Of the 27 examinations with pulsatile Doppler signal, the mean PI and RI were significantly elevated at 3.7 (± 3.6) and 0.91 (± 0.38), respectively, with a p values of less than No RIs and PIs fell within the normal range; however, they both had a bimodal distribution pattern either significantly elevated, which the majority were, or significantly reduced. All significantly reduced RI and PI values were associated with waveform 5. In all 35 Doppler studies, the RI and PI values followed the same trends of both either being elevated or reduced in all examinations, except for the first Doppler study on patient 12 where the PI was elevated at 1.42 but the RI was depressed at This single discrepancy with discoordination of RI and PI values is most likely due to extensive respiratory variability (Fig. 3). Further isolating the eight studies with pulsatility where the RI was reduced and the seven studies where the PI was reduced, the average RI value was 0.39 (± 0.16) with a Pediatric Critical Care Medicine 3

4 Riggs et al Table 1. Demographics, Hours From Injury to Brain Death, Cause of Injury, and Average Vital Signs During All Ophthalmic Doppler Flow Studies of the Central Retinal Vessels for Each Individual Patient ID Age Race a Sex Hours to Brain Death Cause of Injury Temperature ( C) Blood Pressure Mean Arterial Pressure Arterial Paco yr 1 Female 65 Hanging / yr 1 Male 47 TBI / yr 1 Male 41 Hanging / yr 1 Male 37 NAT / mo 2 Male 49 NAT / mo 1 Female 57 NAT / yr 2 Male 52 NAT / mo 1 Female 59 NAT / mo 1 Female 87 TBI / mo 2 Male 61 Sudden infant death syndrome / yr 3 Male 43 NAT / yr 1 Male 47 TBI / yr 1 Female 63 Herniation / NAT = nonaccidental trauma, TBI = traumatic brain injury. a Race: 1) African American, 2) Caucasian, and 3) Asian. p value of and the average PI value was 0.48 (± 0.22) with a p value of when compared with normal values. Twelve of 13 patients had both elevated RIs, elevated PIs, and spectrogram waveforms consistent with TCD waveforms that support the diagnosis of BD. Waveform analysis of the 35 ultrasound examinations revealed 11% with waveform 1 described as tall systolic peaks without diastolic flow (Fig. 2A), 17% with waveform 2 or an oscillatory pattern (Fig. 2B), and 29% with waveform 3 showing short systolic spikes (Fig. 2C), and 23% had waveform 4 without pulsatile Doppler movement detected (Fig. 2D). A rippling tardus-parvus waveform 5 was present in 20% of examinations (Fig. 2E), all of which were obtained from patients with Doppler spectrograms consistent with lost cerebral autoregulation showing severely elevated MAPs, depressed RIs and PIs. DISCUSSION Duplex Doppler ultrasonography is a noninvasive, radiationfree, cost-effective technique that can be easily performed and frequently repeated. Color Doppler ultrasonography eliminates the blinded transcranial approach necessary with TCD assuring excellent visualization of the correct vessel while obtaining Doppler spectrograms. Unlike TCD, there is no specialized machine or outside expertise required, and the technology is widely available and familiar to pediatric intensivists. Arterial systolic velocity of the CRA was significantly decreased in 30 of the 35 studies, within normal limits in three, and elevated in two examinations (Fig. 3). The variability in peak systolic flow velocities that fell within the normal to elevated range is explained by calculations based on Doppler spectrograms with extreme respiratory variability, which is classic for TCD waveforms supporting CCA. The spectrogram respiratory variability is produced by significant pressure changes influenced by both cardiopulmonary interactions with positive pressure ventilation and severe intracranial hypertension (Fig. 3). It is because of this significant respiratory variability associated with extreme intracranial hypertension that additional qualitative measures in addition to peak flow velocities are needed to more accurately evaluate the intravascular movement of blood. The RI reflects the resistance to blood flow in the vessel influenced by vasoconstriction, dilation, or external vascular compression. Hence, when the RI is less than 1, all flow is anterograde, but when the RI rises above 1, flow progressively becomes more retrograde. The PI measures the variability of blood velocity in a vessel during the cardiac cycle. As the PI rises, the pulse beat rises and falls more rapidly leading to a narrower waveform reflecting a significantly decreased volume of flow that will eventually represent atrial wall pulsation without blood flow. RIs and PIs are ratios that unlike measures of maximal and minimal velocities are not altered by the angle of the Doppler and take into account the direction and volume of flow. Therefore, the monitoring of RIs and PIs along with max velocities reduces interobserver bias between patients when conducting neurosonography (21). Specific intracranial TCD flow patterns consistent with CCA have been well established and supported in the evaluation of BD in adults (18, 22 25). BD clinically occurs when an insult 4 XXX 2017 Volume XX Number XXX

5 Neurocritical Care Table 2. Results and Timing of Each Doppler Flow Study of the Central Retinal Vessels and Additional Studies Supporting the Diagnosis of Brain Death Patient Number Ultrasound Study Central Retinal Artery Peak Systolic Velocity (cm/s) Resistive Index Pulsatility Index Wave Mean Arterial Pressure Ultrasound Timing With Brain Death Examinations Supporting Studies After 1st Electroencephalogram Before 2nd Before 1st Electroencephalogram After 1st TCD Before 2nd Before 1st TCD After 2nd Before 1st Electroencephalogram After 1st Before 2nd Before 1st Electroencephalogram After 1st Before 2nd After 2nd Before 1st Electroencephalogram After 1st Nuclear flow Before 2nd Before 1st Electroencephalogram After 1st Before 2nd Before 1st Electroencephalogram After 2nd Before 1st Electroencephalogram After 1st Nuclear flow Before 2nd Before 1st Electroencephalogram After 2nd Before 1st Electroencephalogram After 1st After 2nd Before 1st None Before 2nd Before 1st Electroencephalogram After 1st Before 2nd TCD = transcranial Doppler. Wave indicates Doppler waveforms identified in each study (1 = tall systolic peaks without diastolic flow, 2 = oscillatory pattern, 3 = short systolic spikes, 4 = no Doppler movement detected, rippling tardus-parvus waveform), and nuclear flow indicates nuclear medicine vascular flow study. Pediatric Critical Care Medicine 5

6 Riggs et al Figure 3. Doppler waveform of the central retinal vessels showing respiratory-dependent pressure changes causing great amplitude variations (M-turbo; SonoSite, Bothell, WA). causes the intracranial pressure (ICP) to rise above the systolic blood pressure leading to alterations in cerebral blood flow and eventual CCA. As ICP rises due to an intracranial insult, the peak systolic velocity decreases, diastolic perfusion pressure drops eventually reaching zero as the RI rises to a value of 1 (26) and the PI steadily climbs. As cerebral herniation evolves and ICP rises above diastolic blood pressure, the RI is greater than 1, and reversal of diastolic flow appears (waveform 1) as small intracranial vessels collapse and a to-and-fro oscillatory pattern of blood movement develops (waveform 2) from reverberations of the trapped blood in the intracranial vessels without significant anterograde or retrograde flow (Fig. 2B). With further cerebral herniation, a short systolic spike Doppler spectrogram (waveform 3) appears secondary to systolic arterial vessel vibration (Fig. 2C). Eventually with the completion of cerebral herniation, the ICP equals or exceeds perfusion pressure to the brain, vessel integrity decreases, cerebral blood flow terminates, and all pulsatile movement detectable by Doppler ultrasonography is lost (waveform 4) (Fig. 2D). The tall systolic peak without diastolic movement, the oscillating movement, short systolic spike, and no pulsatile Doppler movement sonographic patterns are all consistent with CCA and reflect zero net cerebral blood flow (25). CRV waveforms consistent with TCD waveforms that indicate CCA (4) were detected in 12 of 13 patients and in 80% of all Doppler studies obtained. Patient 9 is the single patient who did not have a Doppler spectrogram with a previously recognizable waveform consistent with CCA. Patient 9 had three consistent waveforms similar to a no pulsatile flow pattern but with a slight saw tooth ripple most likely indicative of slight vessel wall movement secondary to increased MAP in a profoundly vasodilated vessel (Fig. 2E). Patient 9 was a 19-month-old African American girl who was ejected from a roll-over motor vehicle accident causing extensive bilateral extra-axial hemorrhages, parenchymal contusions, and ventricular effacement causing intractable intracranial hypertension monitored with an externalized ventricular drain. During her first ophthalmic Doppler study, her ICP was 105 mm Hg with a MAP of 121 mm Hg providing a theoretical cerebral perfusion pressure (CPP) of 16 mm Hg. Her ICP was 87 mm Hg with a MAP of 100 mm Hg giving a CPP of 13 mm Hg during her second Doppler study. During her third Doppler study, her ICP was 67 mm Hg with a MAP of 85 mm Hg giving a CPP of 18 mm Hg. Despite full neuroprotective measures and maximal support a CPP of greater than 30 could not be sustained. She had lost cerebral autoregulation, efforts to increase her MAP with multiple vasoactive infusions would increase both the MAP and the ICP to similar degrees not allowing the CPP to increase. This patient had three ultrasound studies with Doppler spectrograms consistent with waveform 5 with an average RI of 0.27 (± 0.03), PI of 0.34 (± 0.005), and an average peak systolic velocity of 6.43 cm/s (± 2.8). This was the only patient in the study where all three examinations occurred over 72 hours after the neurologic insult. Along with having two clinical examinations consistent with BD, she also had an electroencephalogram and a Nuclear Medicine study both consistent with the diagnosis of BD. The saw tooth ripple effect seen in waveform 5 is most likely due to slight vessel wall movement influenced by elevated MAP secondary to multiple vasoactive infusions in the grossly vasodilated CRA, in a patient with multiple studies confirming the diagnosis of CCA. We hypothesize that this rippling tardus-parvus like waveform 5 would appear as the completely nonpulsatile waveform 4 if the MAP was not significantly elevated with vasoactive infusions. The seven Doppler studies from patients 3, 7, 9, and 13 where waveform 5 was identified all had grossly vasodilated CRVs and significantly elevated MAPs with an average MAP of 101 mm Hg (± 12) supported by vasoactive infusions. The RIs and PIs from these seven Doppler studies also had significantly depressed average RI values of 0.35 (± 0.11) and PI values of 0.48 (± 0.21), which is why both quantitative and qualitative spectrogram analysis is essential when determining CCA. We believe the combination of vascular vasodilatation due to the loss of cerebral autoregulation in the setting of vasoactive support elevating the blood pressure is what produces waveform 5 resulting in severely depressed RIs, PIs, and peak systolic velocities. It is also possible that waveform 5 is produced by compensatory arterial vasodilation secondary to obstruction or degradation of the arterial wall. Aside from how exactly this spectrogram is produced, this study suggests that waveform 5 should be considered a spectrogram consist with CCA. The greatest limitations of this prospective observational trial are the small sample size and lack of negative controls. Without including negative cases with a similar degree of injury, the sensitivity and specificity of Doppler flow of the CRVs to support the diagnosis of BD could not be determined. In addition, extreme respiratory variation and ICP waveforms impacting peak systolic velocities as well as RIs and PIs could potentially effect the subjective interpretation of these values (Fig. 3). In this study, the values were calculated by a blinded cardiologist and averaged over three cardiac cycles to enhance reproducibility and take into account respiratory variability. All bedside Doppler ultrasound studies were conducted by a 6 XXX 2017 Volume XX Number XXX

7 Neurocritical Care single provider making it difficult to determine reproducibility in obtaining these sonographic patterns. Additional studies evaluating the interrater reliability in both obtaining and interpreting the Doppler blood flow data of the CRVs must be conducted before this study could be considered as an ancillary study to support the diagnosis of BD in children. Further research must be conducted with a larger sample size including children with severe traumatic brain injuries as well as healthy negative controls before ophthalmic Doppler ultrasonography of the CRVs can be considered for evaluation as a possible bedside ancillary study to support the clinical diagnosis of BD in children. This study suggests that the combination of qualitative waveform analysis and quantitative blood flow variables of the CRVs may have the potential to be developed as an ancillary study for supporting the diagnosis of BD in children. 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