Functional molecular imaging holds the key to improved diagnosis, treatment selection, and treatment monitoring. Combined structural and functional scanning, such as MRI/optical or PET/CT combinations, unite the benefits of physical structural imaging and functional measures. We propose a hybrid optical and ultrasound device that will bring functional molecular imaging to the clinic. A previous 1-year feasibility study has allowed successful prototype construction, which we now propose to manufacture and validate. In this 5-year study, we extend our prior feasibility study to test the hypothesis that very-low-birth- weight neonates (VLBW) who develop necrotizing enterocolitis (NEC) can be reliably detected early in the process using broadband optical spectroscopy sensitive to changes in perfusion of the gut. Such perfusion changes result in regional tissue hypoxemia, which we have demonstrated to be detectable by combined broadband visible/near-infrared tissue oximetry, a real-time method that can assess the adequacy of deep tissue oxygenation. Initially this will be an optical-only device; then combining it with ultrasound will be studied in years 2-5, first on the benchtop, and then in the intensive care unit. Necrotizing enterocolitis (NEC) is the most common life-threatening surgical emergency encountered in the neonatal intensive care unit [1]. NEC is a multi-factorial (infectious, inflammatory, and ischemic) disease of the gastrointestinal (GI) tract of newborns and neonates. The end result is mucosal injury and/or transmural necrosis of the intestine. Currently, there is no test to diagnose NEC in the early stages of the disease, before the later and ominous clinical signs appear. The mortality of NEC ranges from 10% to 50%, approaching 100% for neonates with severe forms of the disease characterized by full-thickness necrosis of the intestine, followed by rupture and sepsis. Ninety percent of NEC cases occur in infants born before 36 weeks' gestational age, occurring in up to 10% of all very-low-birth-weight (VLBW, <1500g) neonates [2]. A diagnosis of NEC increases the NICU length of stay by 22-60 days, and increases the total hospital charges by $76,000-$186,000 per case [3]. Finally, Neonates recovering from NEC often incur additional serious complications (malnutrition, liver dysfunction). NEC requiring surgery carries increased risk of cerebral palsy, cognitive or psychomotor impairment, or both. Repeated attempts to use clinical signs to reliably identify neonates most likely to progress to severe NEC have been unsuccessful. Broadband oximetry appears to offer a solution. Developed by the PI and others, broadband oximetry is sensitive to ischemia. It differs from typical near-infrared spectroscopy (NIRS) methods that generally use only 2-4 wavelengths in that broadband oximetry measures hundreds of wavelengths. Broadband approaches, have shown significantly tighter normal ranges, lower noise, and better reproducibility in vivo. Further, typical NIRS fails to account for shifts in water, fat, blood volume, and stool, any of which can affect oxygenation measurements if not specifically accounted for, making NIRS unreliable for quantitative studies of the gut. In contrast, in our just-completed 1-year feasibility R43 trial, we demonstrated that NEC can be detected using broadband methods. The question remains: how will this new device perform clinically in a multicenter study? By incorporating broadband oximetry monitoring into the management of VLBW neonates, we may detect NEC at its earliest stages and prevent the cascade that leads to bowel necrosis. Success should lead quickly to clinical use, as this team has previously developed, received FDA approval for, and commercialized two biomedical devices.
The Specific Aims are:
Aim 1 : (Technology Innovation) Reduce to manufacture a broadband optical-only system to assess oxygenation of the gut, and a hybrid optical/ultrasound device and regionally co-register gut oxygenation values with ultrasound Doppler imaging, testing whether a hybrid device improves diagnostic accuracy.
Aim 2 : (Clinical Study) Perform a prospective, blinded observational trial of 240 VLBW premature neonates starting with (a) reducing to manufacturing the prototype broadband oximeter from the prior feasibility study to identify patients at increased risk of NEC due to inadequate perfusion, either prior to the development of NEC or early in the course; and (b) subsequently, extend the study to include a hybrid optical/ultrasound molecular imaging device.
Aim 3 : (Dissemination) Submit and receive FDA approval for broadband optical scanning of the gut, including water, fat, and stool correction. Submit ultrasound/optical device if combination improves accuracy.

Public Health Relevance

We are studying a disease called 'necrotizing enterocolitis' (or 'NEC' for short), which affects premature infants. It is the most common surgical emergency involving neonates admitted to Newborn Intensive Care Units. Currently, clinicians are unable to identify which infants will go on to develop NEC before they become ill. Clinical signs of illness occur relatively late in the course of the condition, making NEC more difficult to treat. We will test a new probe that uses safe levels of visible and infrared light, with and without ultrasound imaging, to see if we can identify infants before they get sick using a simple, noninvasive test, This test will be repeated through at least one feeding (which stresses the gut) each day. If successful, the health benefit will be large, as it is estimated that treating NEC alone (not including treating its later complications) adds $650 million to the annual health bill.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
High Priority, Short Term Project Award (R56)
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Special Emphasis Panel (ZDK1-GRB-1 (O3))
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Hamilton, Frank A
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Spectros Corporation
Portola Valley
United States
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