title: Noninvasive Multimodal Imaging to Predict Recovery of Locomotion after Extended Limb Ischemia.
abstract: Acute limb ischemia is a common cause of morbidity and mortality following trauma both in civilian centers and in combat related injuries. Rapid determination of tissue viability and surgical restoration of blood flow are desirable, but not always possible. We sought to characterize the response to increasing periods of hind limb ischemia in a porcine model such that we could define a period of critical ischemia (the point after which irreversible neuromuscular injury occurs), evaluate non-invasive methods for characterizing that ischemia, and establish a model by which we could predict whether or not the animal's locomotion would return to baselines levels post-operatively. Ischemia was induced by either application of a pneumatic tourniquet or vessel occlusion (performed by clamping the proximal iliac artery and vein at the level of the inguinal ligament). The limb was monitored for the duration of the procedure with both 3-charge coupled device (3CCD) and infrared (IR) imaging for tissue oxygenation and perfusion, respectively. The experimental arms of this model are effective at inducing histologically evident muscle injury with some evidence of expected secondary organ damage, particularly in animals with longer ischemia times. Noninvasive imaging data shows excellent correlation with post-operative functional outcomes, validating its use as a non-invasive means of viability assessment, and directly monitors post-occlusive reactive hyperemia. A classification model, based on partial-least squares discriminant analysis (PLSDA) of imaging variables only, successfully classified animals as "returned to normal locomotion" or "did not return to normal locomotion" with 87.5% sensitivity and 66.7% specificity after cross-validation. PLSDA models generated from non-imaging data were not as accurate (AUC of 0.53) compared the PLSDA model generated from only imaging data (AUC of 0.76). With some modification, this limb ischemia model could also serve as a means on which to test therapies designed to prolong the time before critical ischemia.
authors.affiliation: Department of Surgery, Uniformed Services University of Health Sciences, Bethesda, MD, United States of America.
authors.forename: Jason S
authors.initials: JS
authors.lastname: Radowsky
authors.affiliation: General Surgery, Walter Reed National Military Medical Center, Bethesda, MD, United States of America.
authors.forename: Joseph D
authors.initials: JD
authors.lastname: Caruso
authors.affiliation: Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States of America.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Luthra
authors.affiliation: Department of Surgery, Uniformed Services University of Health Sciences, Bethesda, MD, United States of America; General Surgery, Walter Reed National Military Medical Center, Bethesda, MD, United States of America; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States of America.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Bradley
authors.affiliation: Department of Surgery, Uniformed Services University of Health Sciences, Bethesda, MD, United States of America; General Surgery, Walter Reed National Military Medical Center, Bethesda, MD, United States of America.
authors.forename: Eric A
authors.initials: EA
authors.lastname: Elster
authors.affiliation: Department of Surgery, Uniformed Services University of Health Sciences, Bethesda, MD, United States of America; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States of America; Orthopaedics and Rehabilitation, Walter Reed National Military Medical Center, Bethesda, MD, United States of America.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Forsberg
authors.affiliation: Department of Surgery, Uniformed Services University of Health Sciences, Bethesda, MD, United States of America; Regenerative Medicine Department, Naval Medical Research Center, Silver Spring, MD, United States of America; Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States of America.
authors.forename: Nicole J
authors.initials: NJ
authors.lastname: Crane
mesh_terms: D000818:Animals; D016207:Cytokines / Q000097:blood; D005121:Extremities / Q000098:blood supply* / Q000502:physiology; D005260:Female; D006940:Hyperemia / Q000473:pathology; D007511:Ischemia / Q000150:complications*; D064847:Multimodal Imaging / Q000379:methods; D018482:Muscle, Skeletal / Q000473:pathology; D016491:Peripheral Vascular Diseases / Q000097:blood / Q000473:pathology / Q000503:physiopathology*; D020127:Recovery of Function; D012039:Regional Blood Flow; D013552:Swine
chemical_list: D016207:Cytokines