Ongoing pulmonary capillary hemorrhage (PCH) induced by pulmonary diagnostic ultrasound (PDUS) in mammals is displayed as growing comet-tail artifacts in the image. This phenomenon represents the only clearly demonstrated biological effect of (non-contrast enhanced) diagnostic ultrasound in medicine. When discovered in 1990 using laboratory exposure systems, only harmless incidental diagnostic ultrasound exposure was expected, and no useful safety strategies arose from authoritative reviews in 2000 and 2008. However, direct PDUS now is becoming routine in formal and bedside clinical settings. Point-of-care ultrasonography often involves pulmonary examination by physicians not necessarily aware of PCH or the deficiency in safety. As bedside PDUS becomes routine worldwide, many patients will receive direct lung exposure and suffer a risk of PCH injury. Our objective is to fully understand PDUS-PCH and find solutions for this uniquely important safety issue. Novel and unexpected findings thus far have thoroughly revised our understanding of pulmonary injury by PDUS. PCH thresholds are virtually independent of ultrasound frequency and well below the Mechanical Index safety limit. Physiological factors, such as clinical sedatives, can be as important as physical exposure parameters. These worrisome findings overturn present PDUS safety assumptions and imply that sick people or patients taking certain medications may be most vulnerable to injury. Initial consideration of my hypothesis of acoustical radiation surface pressure for the physical mechanism of PCH only partly explained this bioeffect. Our central hypothesis is that PDUS-PCH arises from the interaction of ultrasound pulses with susceptible alveolar blood-air-barrier structures, generating capillary stress and failure. Our research has set the stage for rapid progress and three specific aims are planned using rigorous scientific method to ensure validity and reproducibility: First, the physiological susceptibility to PDUS- PCH will be determined for inhalation restriction, widely used medications, inflammation by pneumonia and sex. Second, the remaining physics of PDUS-PCH will be characterized, including the relative efficacy of imaging modes, the sites of initiation and progression of PCH in microscopical observations and the temporal evolution of PCH from nanoseconds to minutes. Finally, the propagation and interaction of ultrasound pulses within lung will be characterized by acoustical modeling at the scale of the acinus, by micro-scale finite element analysis of alveolar capillary architecture and blood-air-barrier stresses, and by research in swine, together with chest-wall dosimetry, for realistic translation of risk estimation to human patients. The outcomes expected from achieving these aims are an understanding of lung susceptibility in different patients, the elucidation of the physical mechanism causing PDUS-PCH, and a path to clinical safety assurance, with minimal loss of image quality, suitable for sonographer education and guidance. The overall impact of this project will be the initiation of new safety concepts for PDUS and the proactive solution of this emergent public health problem.

Public Health Relevance

Diagnostic ultrasound examination of lung is rapidly becoming routine in critical care medicine and other clinical settings, which will subject many patients to a risk of pulmonary injury. Unbeknown to many point-of-care sonographers, pulmonary capillary hemorrhage is the only bioeffect of (non-contrast) diagnostic ultrasound proven to occur in mammals. In order to mitigate this potentially important public health problem, our research will examine the poorly understood risk of pulmonary injury and create a dosimetric model suitable for sonographer education and safety guidance.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL116434-06
Application #
9612564
Study Section
Biomedical Imaging Technology Study Section (BMIT)
Program Officer
Reineck, Lora A
Project Start
2013-08-01
Project End
2021-11-30
Budget Start
2018-12-01
Budget End
2019-11-30
Support Year
6
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Radiation-Diagnostic/Oncology
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Miller, Douglas L; Dong, Zhihong; Dou, Chunyan et al. (2018) Pulmonary Capillary Hemorrhage Induced by Diagnostic Ultrasound in Ventilated Rats. Ultrasound Med Biol 44:1810-1817
Miller, Douglas L; Dong, Zhihong; Dou, Chunyan et al. (2018) Pulmonary Capillary Hemorrhage Induced by Different Imaging Modes of Diagnostic Ultrasound. Ultrasound Med Biol 44:1012-1021
Miller, Douglas L; Dong, Zhihong; Dou, Chunyan et al. (2018) Does Intravenous Infusion Influence Diagnostic Ultrasound-Induced Pulmonary Capillary Hemorrhage? J Ultrasound Med 37:2021-2028
Rice, John D; Tsodikov, Alex (2017) Semiparametric profile likelihood estimation for continuous outcomes with excess zeros in a random-threshold damage-resistance model. Stat Med 36:1924-1935
Miller, Douglas L (2016) Mechanisms for Induction of Pulmonary Capillary Hemorrhage by Diagnostic Ultrasound: Review and Consideration of Acoustical Radiation Surface Pressure. Ultrasound Med Biol 42:2743-2757
Miller, Douglas L; Dou, Chunyan; Dong, Zhihong et al. (2016) The Influence of Dexmedetomidine on Ultrasound-induced Pulmonary Capillary Hemorrhage in Rats. Ultrasound Med Biol 42:964-70
Miller, Douglas L; Dong, Zhihong; Dou, Chunyan et al. (2016) Influence of Scan Duration on Pulmonary Capillary Hemorrhage Induced by Diagnostic Ultrasound. Ultrasound Med Biol 42:1942-50
Miller, Douglas L; Dou, Chunyan; Raghavendran, Krishnan (2015) Comparison of Thresholds for Pulmonary Capillary Hemorrhage Induced by Pulsed-wave and B-mode Ultrasound. Phys Procedia 70:1087-1090
Miller, Douglas L; Dou, Chunyan; Raghavendran, Krishnan (2015) Pulmonary Capillary Hemorrhage Induced by Fixed-Beam Pulsed Ultrasound. Ultrasound Med Biol 41:2212-9
Miller, Douglas L; Dou, Chunyan; Raghavendran, Krishnan (2015) Anesthetic techniques influence the induction of pulmonary capillary hemorrhage during diagnostic ultrasound scanning in rats. J Ultrasound Med 34:289-97

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