Caroline E. Fife

Lymphatic imaging in humans with near-infrared fluorescence

While the lymphatic system is increasingly associated with diseases of prevalence, study of these diseases is difficult owing to the paucity of imaging techniques with the sensitivity and temporal resolution to discriminate lymphatic function. Herein, we review the known, pertinent features of the human lymphatic system in health and disease and set the context for a number of emerging studies that use near-infrared fluorescence imaging to non-invasively assess tumor draining lymphatic basins in cancer patients, intraoperatively guide resection of first draining lymph nodes, and to interrogate the difference between normal and aberrant lymphatic structure and function.

The predictive value of transcutaneous oxygen tension measurement in diabetic lower extremity ulcers treated with hyperbaric oxygen therapy: a retrospective analysis of 1144 patients

The objective of this retrospective analysis was to determine the reliability of transcutaneous oxygen tension measurement (TcPO2) in predicting outcomes of diabetics who underwent hyperbaric oxygen therapy for lower extremity wounds. Six hyperbaric facilities provided TcPO2 data under several possible conditions: breathing air, breathing oxygen at sea level, and breathing oxygen in the chamber. Overall, 75.6% of the patients improved after hyperbaric oxygen therapy. Baseline sea‐level air TcPO2 identified the degree of tissue hypoxia but had little statistical relationship with outcome prediction because some patients healed after hyperbaric oxygen therapy despite very low prehyperbaric TcPO2 values. Breathing oxygen at sea level was unreliable for predicting failure, but 68% reliable for predicting success after hyperbaric oxygen therapy. TcPO2 measured in chamber provides the best single discriminator between success and failure of hyperbaric oxygen therapy using a cutoff score of 200 mmHg. The reliability of in‐chamber TcPO2 as an isolated measure was 74% with a positive predictive value of 58%. Better results can be obtained by combining information about sea‐level air and in‐chamber oxygen. A sea‐level air TcPO2 < 15 mmHg combined with an in‐chamber TcPO2 < 400 mmHg predicts failure of hyperbaric oxygen therapy with a reliability of 75.8% and a positive predictive value of 73.3%. (WOUND REP REG 2002;10:198–207)

Near-Infrared Fluorescence Imaging in Humans with Indocyanine Green: A Review and Update.

Near-infrared (NIR) fluorescence imaging clinical studies have been reported in the literature with six different devices that employ various doses of indocyanine green (ICG) as a non-specific contrast agent. To date, clinical applications range from (i) angiography, intraoperative assessment of vessel patency, and tumor/metastasis delineation following intravenous administration of ICG, and (ii) imaging lymphatic architecture and function following subcutaneous and intradermal ICG administration. In the latter case, NIR fluorescence imaging may enable new discoveries associated with lymphatic function due to (i) a unique niche that is not met by any other conventional imaging technology and (ii) its exquisite sensitivity enabling high spatial and temporal resolution. Herein, we (i) review the basics of clinical NIR fluorescence imaging, (ii) survey the literature on clinical application of investigational devices using ICG fluorescent contrast, (iii) provide an update of non-invasive dynamic lymphatic imaging conducted with our FDPM device, and finally, (iv) comment on the future NIR fluorescence imaging for non-invasive and intraoperative use given recent demonstrations showing capabilities for imaging following microdose administration of contrast agent.

Incidence of pressure ulcers in a neurologic intensive care unit.

ObjectivesTo determine the risk factors for pressure ulceration in an intensive care setting, to evaluate the Braden scale as a predictor of pressure ulcer risk in critically ill patients, and to determine whether pressure ulcers are likely to occur early in the hospital stay. DesignCohort study of patients with no preexisting ulcers with a 3-month enrollment period. SettingThe neurologic intensive care unit and the neurologic intermediate unit at a primary care/referral hospital with a level I trauma center. PatientsA total of 186 patients entered the study. InterventionWithin 12 hrs of admittance, initial assessment, photographs, and Braden score were completed. Patients were re-examined every 4 days or at discharge from the unit, whichever came first. Main Outcome MeasuresDetermining risk factors for pressure ulcers, performing detailed statistical analyses, and testing the usefulness of the Braden score as a predictor of pressure ulcer risk. ResultsTwenty-three of 186 patients developed at least one pressure ulcer (incidence = 12.4%) after an average stay of 6.4 days. The Braden scale, which measures six characteristics of skin condition and patient status, proved to be a primary predictor of ulcer development. No ulcers developed in the 69 patients whose Braden score was 16 or higher. The likelihood of developing a pressure sore was predicted mathematically from the Braden score. However, being underweight was a significant and distinct factor in pressure ulcer development. ConclusionsPressure ulcers may develop within the first week of hospitalization in the intensive care unit. Patients at risk have Braden scores of ≤16 and are more likely to be underweight. These results suggest that aggressive preventive care should be focused on those patients with Braden scores of ≤13 and/or a low body mass index at admission.

Guidelines for the treatment of arterial insufficiency ulcers

1. Co-chaired panel 2. University of Utah, Salt Lake City, UT 3. University of Texas, San Antonio, TX 4. Sinai Hospital/Johns Hopkins Medical Institutions, Baltimore, MD 5. GKT School of Medicine, King’s College, London, UK 6. University of Texas Health Science Center at Houston, TX 7. Sequoia Hospital, Redwood City, CA 8. Maricopa Medical Center, Phoenix, AZ 9. Tufts-New England Medical Center, Boston, MA 10. Southampton University Hospitals Trust NHS, Southampton, UK 11. Penrose–St. Francis Health Services, Colorado Springs, CO 12. Beverly Surgical Associates, Beverly, MA 13. Saint Francis Memorial Hospital, San Francisco, CA 14. Northbay Center for Wound Care, Vacaville, CA, and 15. University of California, San Francisco, CA

Assessment of Lymphatic Contractile Function After Manual Lymphatic Drainage Using Near-Infrared Fluorescence Imaging

OBJECTIVE To investigate the feasibility of assessing the efficacy of manual lymphatic drainage (MLD), a method for lymphedema (LE) management, by using near-infrared (NIR) fluorescence imaging. DESIGN Exploratory pilot study. SETTING Primary care unit. PARTICIPANTS Subjects (N=10; age, 18-68y) with a diagnosis of grade I or II LE and 12 healthy control subjects (age, 22-59y). INTERVENTION Indocyanine green (25 μg in 0.1 mL each) was injected intradermally in bilateral arms or legs of subjects. Diffused excitation light illuminated the limbs, and NIR fluorescence images were collected by using custom-built imaging systems. Subjects received MLD therapy, and imaging was performed pre- and posttherapy. MAIN OUTCOME MEASURES Apparent lymph velocities and periods between lymphatic propulsion events were computed from fluorescence images. Data collected pre- and post-MLD were compared and evaluated for differences. RESULTS By comparing pre-MLD lymphatic contractile function against post-MLD lymphatic function, results showed that average apparent lymph velocity increased in both the symptomatic (+23%) and asymptomatic (+25%) limbs of subjects with LE and control limbs (+28%) of healthy subjects. The average lymphatic propulsion period decreased in symptomatic (-9%) and asymptomatic (-20%) limbs of subjects with LE, as well as in control limbs (-23%). CONCLUSIONS We showed that NIR fluorescence imaging could be used to quantify immediate improvement of lymphatic contractile function after MLD.

Direct evidence of lymphatic function improvement after advanced pneumatic compression device treatment of lymphedema

Lymphedema affects up to 50% of all breast cancer survivors. Management with pneumatic compression devices (PCDs) is controversial, owing to the lack of methods to directly assess benefit. This pilot study employed an investigational, near-infrared (NIR) fluorescence imaging technique to evaluate lymphatic response to PCD therapy in normal control and breast cancer-related lymphedema (BCRL) subjects. Lymphatic propulsion rate, apparent lymph velocity, and lymphatic vessel recruitment were measured before, during, and after advanced PCD therapy. Lymphatic function improved in all control subjects and all asymptomatic arms of BCRL subjects. Lymphatic function improved in 4 of 6 BCRL affected arms, improvement defined as proximal movement of dye after therapy. NIR fluorescence lymphatic imaging may be useful to directly evaluate lymphatic response to therapy. These results suggest that PCDs can stimulate lymphatic function and may be an effective method to manage BCRL, warranting future clinical trials.

Lymphatic abnormalities are associated with RASA1 gene mutations in mouse and man

Mutations in gene RASA1 have been historically associated with capillary malformation–arteriovenous malformation, but sporadic reports of lymphatic involvement have yet to be investigated in detail. To investigate the impact of RASA1 mutations in the lymphatic system, we performed investigational near-infrared fluorescence lymphatic imaging and confirmatory radiographic lymphangiography in a Parkes–Weber syndrome (PKWS) patient with suspected RASA1 mutations and correlated the lymphatic abnormalities against that imaged in an inducible Rasa1 knockout mouse. Whole-exome sequencing (WES) analysis and validation by Sanger sequencing of DNA from the patient and unaffected biological parents enabled us to identify an early-frameshift deletion in RASA1 that was shared with the father, who possessed a capillary stain but otherwise no overt disease phenotype. Abnormal lymphatic vasculature was imaged in both affected and unaffected legs of the PKWS subject that transported injected indocyanine green dye to the inguinal lymph node and drained atypically into the abdomen and into dermal lymphocele-like vesicles on the groin. Dermal lymphatic hyperplasia and dilated vessels were observed in Rasa1-deficient mice, with subsequent development of chylous ascites. WES analyses did not identify potential gene modifiers that could explain the variability of penetrance between father and son. Nonetheless, we conclude that the RASA1 mutation is responsible for the aberrant lymphatic architecture and functional abnormalities, as visualized in the PKWS subject and in the animal model. Our unique method to combine investigatory near-infrared fluorescence lymphatic imaging and WES for accurate phenoptyping and unbiased genotyping allows the study of molecular mechanisms of lymphatic involvement of hemovascular disorders.

Factors influencing the outcome of lower-extremity diabetic ulcers treated with hyperbaric oxygen therapy

The objectives of this study were to report outcomes of a large number of patients receiving hyperbaric oxygen therapy (HBO2T) for diabetic lower‐extremity ulcers, and to identify likely outcome predictors. Five hyperbaric facilities supplied data on 1,006 patients. A sixth clinic served as a validation sample for the regression‐based prediction model, and later additional data from Memorial Hermann Hospital were added. The severity of lower‐extremity lesions was assessed upon initiation of HBO2T using the Modified Wagner scale, and the outcome described as healed, partially healed, not improved, amputated, or died. Overall, 73.8% of patients improved (granulated or healed). Factors significantly related to outcome included renal failure, pack‐year smoking history, transcutaneous oximetry, number of HBO2T treatments, and interruption of treatment regimen. Number of treatments per week and treatment pressure (2.0 vs. 2.4 atmospheres absolute) were not significant factors in outcome. Concomitant administration of autologous growth factor gel did not improve outcome. A multiple regression model was fitted to the data that can be used to predict the outcome of diabetic patients undergoing HBO2T. Given the high cost of amputation and rehabilitation, these data suggest that hyperbaric oxygen treatment should be an important adjunctive therapy to heal lower‐extremity lesions, especially those with a Wagner grade of 3 or higher.

Lipedema: a frequently misdiagnosed and misunderstood fatty deposition syndrome.

PURPOSE: To enhance the learners competence in caring for patients with lipedema through understanding the differential diagnoses, pathophysiology, and treatment/management options. TARGET AUDIENCE: This continuing education activity is intended for physicians and nurses with an interest in skin and wound care. OBJECTIVES: After participating in this educational activity, the participant should be better able to: Differentiate lipedema from other similar diagnoses. Tell patients with lipedema and their caregivers about treatment of this condition. Construct assessments, treatment plans, and management options for patients with lipedema.