Abstract
Imaging diagnosis of brain death is performed with either four-vessel cerebral angiography or radionuclide cerebral blood flow studies. Unfortunately, timely performance of either study at a critically ill period is not only cumbersome but not feasible in many cases. We present a case of a 6-month-old male three hours status post-cardiac arrest of unknown etiology who underwent contrast-enhanced ultrasound (CEUS) for diagnosis of near absent perfusion, or near brain death. The patient passed away 30 minutes after the exam and clinical diagnosis of brain death was confirmed. The case report highlights the utility of CEUS for diagnosis of brain death. This can have significant clinical implications in neonates who may not be eligible for commonly used, cumbersome radiologic studies for diagnosis of brain death.
Keywords: Contrast-enhanced ultrasound, brain death, neonate
Background
Contrast-enhanced ultrasonography (CEUS) is an imaging technique in which gas-filled microbubbles, smaller than red blood cells, generate increased signal because of the acoustic impedance mismatch. Injection of ultrasound (US) contrast agents into the medium increases the echogenicity, allowing enhanced visualization of a blood vessel. US contrast agents have been approved for use in Europe for almost two decades. The Food and Drug Administration in the United States just recently approved the use of Lumason for evaluation of focal hepatic lesions and evaluation of the urinary tract in pediatric patients with known or suspected vesicoureteral reflux. For the remainder of clinical applications, US contrast agents are being used off-label.
Unlike computed tomography (CT) or magnetic resonance (MR) imaging contrast agents, US contrast agents have no associated renal toxicity, and there is no need for accompanying ionizing radiation or sedation. The risk of adverse events is the lowest of all contrast agents available, with CT contrast being the highest (0.6%), followed by MR contrast (0.0088%) and US contrast (0.0086%).1 Studies detailing the safety profile of US contrast agents in children have shown minor adverse events including altered taste, tinnitus, light-headedness, and nausea.2–4
The major clinical benefit of CEUS, in comparison to other radiologic modalities used for brain death, is safety, convenience, and low cost. Because the scans can be performed at the bedside, neonates needing diagnosis of brain death can benefit from the lack of need for transport and radiation, high-cost exams such as four-vessel cerebral angiography, and radionuclide cerebral blood flow studies (CBFs). The presented case details the first application of CEUS for diagnosis of near absent brain perfusion, or near brain death in a neonate status post-cardiac arrest.
Case presentation
We present a CEUS image that demonstrates near absent perfusion of the intracranial vessels with the exception of a few central vessels in a 6-month-old male three hours after he suffered a prolonged cardiac arrest of unknown etiology.
Brain CEUS data were acquired by a sonographer, D.S., with more than 20 years of scanning experience, using an EPIQ scanner (Philips Healthcare, Bothell, WA). A C5-1 13-MHz center-frequency transducer with a low mechanical index of 0.06 was used. The anterior fontanel was used as the acoustic window. Transducer position and gain settings were initially optimized and maintained throughout scanning. A board-certified pediatric radiologist with three years of experience performed the contrast agent injection. The scan required approximately 40 minutes of total examination time, including two minutes of contrast agent preparation from the US contrast-agent kit (Lumason; Bracco Diagnostics Inc). Nurse staff connected a three-way stopcock to the patient’s existing peripheral intravenous line for saline flush and contrast agent administration, while the radiologist obtained parental consent for off-label use of the contrast agent.
One bolus of contrast agent was administered (0.03 ml/kg). A cine clip of two minutes in the midcoronal scan plane including the basal ganglia and thalami were obtained. Coronal and sagittal sweeps through the brain were then acquired to assess the perfusion in the remainder of the brain. Owing to the delayed washout of contrast related to injury, intermittently delayed cine clips of 30 seconds were obtained for 30 minutes.
A midcoronal CEUS image (Figure 1(a)) shows avid enhancement of the cervical extracranial vessels. For comparison, Figure 1(b) is a coronal slice from a 2-month-old male admitted for respiratory distress but without intracranial injury showing normal enhancement of brain. Within seven minutes of administration, the contrast had a near complete washout in the comparison case; however, washout from few intracranial vessels had not occurred 30 minutes after administration in the post-cardiac arrest patient, signifying extremely poor cerebral circulation. Unfortunately, the 6-month-old passed away before any further imaging could be obtained. The patient was declared dead as per clinical assessment of brain death.
Figure 1.
(a) Contrast-enhanced ultrasound: near absent perfusion of the intracranial vessels. (b) Contrast-enhanced ultrasound: normal enhancement of the brain.
Discussion and conclusions
Brain death is a clinical diagnosis, but infants’ inability to tolerate the apnea test often forces clinicians to rely on ancillary studies to confirm cerebral circulatory arrest (CCA). According to the 2011 revised pediatric brain death guidelines, the two most supported and commonly used ancillary studies to confirm CCA are radionuclide CBFs and four-vessel cerebral angiography.5 Cerebral angiography is invasive, requires patient transportation out of the intensive care unit (ICU), and is technically challenging in infants. CBF is less invasive but requires transportation out of the ICU and administration of a radioisotope. Bedside CEUS is rapid, noninvasive, inexpensive, and does not require patient transportation, a potentially ideal ancillary study to confirm CCA in neonates/infants with open fontanelles.
US contrast agents do not pose a need for accompanying radiation or sedation, and are not associated with renal toxicity. The risk of adverse events with US contrast is 0.0086%, the lowest of all contrast agents available for other imaging modalities such as CT and MR, with a risk of 0.6% and 0.0088% respectively.1 CEUS has been studied in pediatric populations, showing a favorable safety profile; the potential adverse effects that have been described in children comprise tinnitus, nausea, altered taste, and light-headedness.2–4 One rare severe reaction in a child documented symptoms of generalized pruritus, nausea, and hypotension with tachycardia initially then bradycardia.6 This patient was treated with oxygen, intravenous epinephrine, and fluids (0.9% normal saline) with resolution of symptoms in two hours. The extensive evidence supporting CEUS safety has contributed to the expansion of CEUS clinical use in the neonatal population.
While the present case showed the diagnostic utility of CEUS in assessing brain death, the neonate unfortunately passed away before any formal radiologic evaluation for diagnosis of brain death could be made. Future studies comparing the more novel CEUS with gold-standard radiologic tools for diagnosis of brain death will be needed to advance the CEUS technique for this particular clinical application. In this case, there was still perfusion to very few cerebral vessels, suggesting near brain death rather than brain death. In brain death, one would expect complete absence of brain perfusion. In keeping with this radiologic finding, the clinically declared time of death for the neonate was 30 minutes after the CEUS exam.
With further research, bedside CEUS has the potential to replace CBF and cerebral angiography to confirm the diagnosis of brain death in infants. CEUS can provide qualitative and quantitative assessment of brain perfusion in infants with open fontanelles.7,8 CEUS can be repeated serially with immediate interpretation. This real-time, noninvasive, bedside cerebral perfusion scan can reveal critical diagnostic information to guide patient care and provide objective markers of severe brain injury.
In summary, CEUS has the potential to become the alternative, bedside cerebral perfusion tool available to support the diagnosis of brain death in infants with open fontanelles.
Acknowledgments
All authors have contributed to the design of the study, data collection, and manuscript writing. The authors have read and approved the final manuscript.
The CEUS scan was performed after approval by the institutional review board of Johns Hopkins Hospital. Written informed consent was obtained from the guardian of the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the editor-in-chief of this journal.
This study was approved by the institutional review board of Johns Hopkins Hospital.
Funding
The work was supported by the Radiological Society of North America Research Scholar Grant, grant number: RSCH1705.
Conflict of interest
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
References
- 1.Sidhu PS, Cantisani V, Deganello A, et al. Role of contrast-enhanced ultrasound (CEUS) in paediatric practice: An EFSUMB position statement. Ultraschall Med 2017; 38: 33–43. [DOI] [PubMed] [Google Scholar]
- 2.McMahon CJ, Ayres NA, Bezold LI, et al. Safety and efficacy of intravenous contrast imaging in pediatric echocardiography. Pediatr Cardiol 2005; 26: 413–417. [DOI] [PubMed] [Google Scholar]
- 3.Coleman JL, Navid F, Furman WL, et al. Safety of ultrasound contrast agents in the pediatric oncologic population: A single-institution experience. AJR Am J Roentgenol 2014; 202: 966–970. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.McCarville MB, Coleman JL, Guo J, et al. Use of quantitative dynamic contrast-enhanced ultrasound to assess response to antiangiogenic therapy in children and adolescents with solid malignancies: A pilot study. AJR Am J Roentgenol 2016; 206: 933–939. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Nakagawa TA, Ashwal S, Mathur M, et al. Guidelines for the determination of brain death in infants and children: An update of the 1987 Task Force recommendations. Crit Care Med 2011; 39: 2139–2155. [DOI] [PubMed] [Google Scholar]
- 6.Piskunowicz M, Kosiak W, Batko T, et al. Safety of intravenous application of second-generation ultrasound contrast agent in children: Prospective analysis. Ultrasound Med Biol 2015; 41: 1095–1099. [DOI] [PubMed] [Google Scholar]
- 7.Hwang M, De Jong RM, Jr, Herman S, et al. Novel contrast-enhanced ultrasound evaluation in neonatal hypoxic ischemic injury: Clinical application and future directions. J Ultrasound Med 2017; 36: 2379–2386. [DOI] [PubMed] [Google Scholar]
- 8.Hwang M, Riggs BJ, Katz J, et al. Advanced pediatric neurosonography techniques: Contrast-enhanced ultrasonography, elastography, and beyond. J Neuroimaging 2018; 28: 150–157. [DOI] [PubMed] [Google Scholar]