Microangiography: An Alternative Tool for Assessing Severe Frostbite Injury

Microangiography: An Alternative Tool for Assessing Severe Frostbite Injury Abstract Assessment of frostbite injury typically relies on computed tomography, angiography, or nuclear medicine studies to detect perfusion deficits prior to thrombolytic therapy. The aim of this study was to evaluate the potential of a novel imaging method, microangiography, in the assessment of severe frostbite injury. Patients with severe frostbite were included if they received a post-thrombolytic Technetium 99 (Tc99) bone scan, a Tc99 bone scan without thrombolytic therapy, and/or post-thrombolytic microangiography (MA) study. We included all patients from the years 2006 to 2018 with severe frostbite injury who had received appropriate imaging for diagnosis: Tc99 scan alone (N = 82), microangiography alone (N = 22), and both Tc99 and microangiography (N = 26). The majority of patients received thrombolytic therapy (76.2%), and the average time to thrombolytics was 6.9 hours. Tc99 scans showed strong correlation with amputation level (r = .836, P < .001), and microangiography showed a slightly stronger positive correlation with amputation level (r = .870, P < .001). In the subset who received both Tc99 scan and microangiography (N = 26), we observed significant differences in the mean scores of perfusion deficit (z = 3.20, P < .001). In this subset, a moderate correlation was found between level of perfusion deficit on Tc99 bone scan and amputation level (r = .525, P = .006). A very strong positive correlation was found between the microangiography studies and the amputation level (r = .890, P < .001). These results demonstrate that microangiography is a reliable alternative method of assessing severe frostbite injury and predicting amputation level. Severe frostbite injury is a well-known disease process, but the diagnosis and treatment of this disease remains highly variable. Current known practices for diagnosis include physical exam, angiography, computed tomography (CT), Technetium 99 (Tc99) bone scans, and other studies.1,2 These imaging modalities all have variable accuracy and predictive value that have not been directly compared. Currently, the Tc99 triple-phase bone scan is a standard method of diagnosis, as it shows absent perfusion in limbs/digits affected by severe frostbite injury.3 The absence of perfusion indicates that the patient may benefit from early treatment with thrombolytics. This has proved a reliable, consistent method for diagnosis of frostbite injury and is used at our institution. Limitations inherent to currently available imaging studies include access to the imaging modality, cost, need for specialized medical personnel to conduct the test and interpret the results, and radiation exposure. The only currently available diagnostic method unaffected by these factors is physical exam, but this is subject to significant inter-rater variability depending on physician training and experience. There is a need for an imaging modality that is rapid, low-cost, nonionizing, and can be used at the bedside with minimal training. With severe frostbite injury, “time is tissue”: the faster a patient can receive a definitive diagnosis, the sooner thrombolytic treatment can be started and the greater the tissue salvage.4 Microangiography (MA) is a novel imaging modality that uses peripherally injected indocyanine green (IcG) and ultraviolet light to assess perfusion in the vasculature of soft tissue. IcG is a safe drug, with the only major contraindications being iodine sensitivity and caution in renal failure patients. MA has been used in multiple settings including the assessment of limb perfusion, bowel anastomoses, and free flaps among many other applications.5–7 This test can typically be performed in less than 30 minutes at the bedside and involves no radiation, specialized technicians, arterial sheaths, or other invasive procedures. Another method of microangiography that is currently emerging is optical coherence tomography–based microangiography, which does not use IcG or any other intravenous contrast. So far, this method has demonstrated utility in retinal imaging and dermatologic imaging.8,9 Although optical coherence tomography–based microangiography provides exquisite detail of microvasculature, it can only penetrate a maximum of a 1 to 2 mm. Frostbite injury often involves the deeper tissues, and IcG-based microangiography demonstrates a greater depth of imaging as demonstrated in several burn depth studies.10 Given this difference in imaging modalities and our institution’s currently available tools, we use IcG-based imaging and have been doing so since 2016. Our aim was to determine whether microangiography had the potential to diagnose severe frostbite injury, by comparing microangiography to Tc99 scans and assessing the predicted tissue at risk for amputation to final amputation levels. At the start of this study, the exact specificity and sensitivity for the Tc99 scan and microangiography scans to determine final amputation level was unknown. METHODS This study received Institutional Review Board (IRB) approval at our institution. We included all patients from the years 2006 to 2018 with a diagnosis of severe frostbite injury who had received appropriate imaging for diagnosis: Tc99 scan alone (N = 82), microangiography alone (N = 22), and both Tc99 and microangiography (MA) (N = 26). Patients with severe frostbite injury are admitted to our American Burn Association (ABA) verified Burn Unit, either through the Emergency Department or as direct admissions. On admission, our practice is to perform a Tc99 triple-phase bone scan to confirm the diagnosis of severe frostbite by demonstrating a perfusion deficit in the deeper tissues. The treatment is then a loading dose and infusion of intravenous alteplase after confirming the patient has no contraindications to receiving thrombolytics. The patients included in this retrospective and prospective observational data analysis had either a Tc99 triple-phase bone scan, a Tc99 triple-phase bone scan and a microangiography study, or a microangiography study alone. These imaging studies were performed after completion of thrombolytic therapy (if given). In patients who received both the microangiography study and the Tc99 study, both of these studies were performed within 12 hours of each other and after completion of thrombolytic therapy. For this analysis, the imaging studies were reviewed by radiology staff (for Tc99 scans) and hyperbaric medicine staff (for MA studies). Our hyperbaric medicine staff have undergone appropriate training for reading and interpreting microangiography studies. The perfusion deficits were quantified using the Hennepin Frostbite Score11 as a “Tissue at Risk” score. If surgery was performed, the operating surgeon filled out a Hennepin Frostbite Score worksheet to indicate the final amputation levels. The Hennepin Frostbite Score allows for quantification of the percent of tissue salvaged by medical treatment. We then compared the amount of assessed tissue at risk on the imaging studies to the final amputation level to determine the accuracy of each imaging modality in predicting amputation. Statistical analysis included ANOVA for continuous variables and the Fisher’s exact test for categorical variables. A P value of less than or equal to .05 was considered to be statistically significant. Wilcoxon matched-pairs sign test was used for comparison of MA and Tc99 bone scans. Pearson correlation assessed microangiography and Tc99 bone scan at risk level to amputation level. All analyses were conducted using STATA 15.1 (StataCorp, College Station, TX). RESULTS Patients with severe frostbite injury treated at our institution between 2006 and 2018 were included in this analysis. Overall, the patient demographics were consistent with typical demographics associated with urban frostbite injury (Table 1). They were mostly male (83.1%) with a mean age of 40.4 years. A large proportion (86.2%) had social factors associated with frostbite injury including substance abuse and homelessness. Across the three imaging groups (Tc99 only, MA only, and Tc99 and MA), the cohorts were mostly similar with the exception that the MA-only group had fewer medical comorbidities (P = .010). These medical comorbidities included diabetes, chronic kidney disease, and coronary artery disease. There were no differences in measured tissue at risk between the groups (Table 1). Significantly more MA-only patients received thrombolytics (Table 1). Time to thrombolytics does not differ between the groups. Salvage percentage was significantly higher for the MA alone cohort as would be expected given that this group had a higher rate of thrombolytic treatment. Table 1. Demographics, injury characteristics, and outcomes Cohort Tc99 Scan alone MA alone Tc99 & MA N = 130 N = 82 N = 22 N = 26 P valuea Age, y, mean (SD) 40.4 (14.3) 40.7 (14.0) 41.0 (16.3) 39.0 (14.1) .865 Gender M, N (%) 108 (83.1) 64 (78.1) 20 (90.9) 24 (92.3) .135 Comorbidityb, N (%) 46 (35.4) 31 (37.8) 2 (9.1) 13 (50.0) .010 Socialc, N (%) 112 (86.2) 72 (87.8) 19 (86.4) 21 (80.8) .664 At riskd (pre-tPA Tc99 scan), mean (SD) 11.6 (10.5) 12.0 (11.7) 9.7 (8.9) 11.9 (6.3) .67 At riskd (post-tPA Tc99 scan), mean (SD) 8.4 (10.0) 8.6 (11.0) — 7.9 (6.0) .766 At riskd (post-tPA MA scan), mean (SD) 2.6 (3.6) — 1.8 (2.9) 3.3 (4.0) .147 tPA, N (%) 99 (76.2) 56 (68.3) 21 (95.5) 22 (84.6) .012 Time to tPA, h, mean (SD) 6.9 (3.0) 7.3 (3.1) 6.7 (3.2) 6.3 (2.6) .369 Salvaged %, mean (SD) 71.7 (40.0) 66.2 (43.5) 90.0 (21.6) 73.8 (36.3) .043 Cohort Tc99 Scan alone MA alone Tc99 & MA N = 130 N = 82 N = 22 N = 26 P valuea Age, y, mean (SD) 40.4 (14.3) 40.7 (14.0) 41.0 (16.3) 39.0 (14.1) .865 Gender M, N (%) 108 (83.1) 64 (78.1) 20 (90.9) 24 (92.3) .135 Comorbidityb, N (%) 46 (35.4) 31 (37.8) 2 (9.1) 13 (50.0) .010 Socialc, N (%) 112 (86.2) 72 (87.8) 19 (86.4) 21 (80.8) .664 At riskd (pre-tPA Tc99 scan), mean (SD) 11.6 (10.5) 12.0 (11.7) 9.7 (8.9) 11.9 (6.3) .67 At riskd (post-tPA Tc99 scan), mean (SD) 8.4 (10.0) 8.6 (11.0) — 7.9 (6.0) .766 At riskd (post-tPA MA scan), mean (SD) 2.6 (3.6) — 1.8 (2.9) 3.3 (4.0) .147 tPA, N (%) 99 (76.2) 56 (68.3) 21 (95.5) 22 (84.6) .012 Time to tPA, h, mean (SD) 6.9 (3.0) 7.3 (3.1) 6.7 (3.2) 6.3 (2.6) .369 Salvaged %, mean (SD) 71.7 (40.0) 66.2 (43.5) 90.0 (21.6) 73.8 (36.3) .043 M, male; h, hour; SD, standard deviation; tPA, thrombolytic; y, year; Tc99, Technetium 99. aANOVA for continuous variables and Fisher’s exact test for categorical variables. bComorbidities include documented heart disease, diabetes, peripheral vascular disease, or renal disease. cSocial factors include drug abuse, alcohol abuse, mental health issues, or home insecurity. dPMID: 26536540. View Large Table 1. Demographics, injury characteristics, and outcomes Cohort Tc99 Scan alone MA alone Tc99 & MA N = 130 N = 82 N = 22 N = 26 P valuea Age, y, mean (SD) 40.4 (14.3) 40.7 (14.0) 41.0 (16.3) 39.0 (14.1) .865 Gender M, N (%) 108 (83.1) 64 (78.1) 20 (90.9) 24 (92.3) .135 Comorbidityb, N (%) 46 (35.4) 31 (37.8) 2 (9.1) 13 (50.0) .010 Socialc, N (%) 112 (86.2) 72 (87.8) 19 (86.4) 21 (80.8) .664 At riskd (pre-tPA Tc99 scan), mean (SD) 11.6 (10.5) 12.0 (11.7) 9.7 (8.9) 11.9 (6.3) .67 At riskd (post-tPA Tc99 scan), mean (SD) 8.4 (10.0) 8.6 (11.0) — 7.9 (6.0) .766 At riskd (post-tPA MA scan), mean (SD) 2.6 (3.6) — 1.8 (2.9) 3.3 (4.0) .147 tPA, N (%) 99 (76.2) 56 (68.3) 21 (95.5) 22 (84.6) .012 Time to tPA, h, mean (SD) 6.9 (3.0) 7.3 (3.1) 6.7 (3.2) 6.3 (2.6) .369 Salvaged %, mean (SD) 71.7 (40.0) 66.2 (43.5) 90.0 (21.6) 73.8 (36.3) .043 Cohort Tc99 Scan alone MA alone Tc99 & MA N = 130 N = 82 N = 22 N = 26 P valuea Age, y, mean (SD) 40.4 (14.3) 40.7 (14.0) 41.0 (16.3) 39.0 (14.1) .865 Gender M, N (%) 108 (83.1) 64 (78.1) 20 (90.9) 24 (92.3) .135 Comorbidityb, N (%) 46 (35.4) 31 (37.8) 2 (9.1) 13 (50.0) .010 Socialc, N (%) 112 (86.2) 72 (87.8) 19 (86.4) 21 (80.8) .664 At riskd (pre-tPA Tc99 scan), mean (SD) 11.6 (10.5) 12.0 (11.7) 9.7 (8.9) 11.9 (6.3) .67 At riskd (post-tPA Tc99 scan), mean (SD) 8.4 (10.0) 8.6 (11.0) — 7.9 (6.0) .766 At riskd (post-tPA MA scan), mean (SD) 2.6 (3.6) — 1.8 (2.9) 3.3 (4.0) .147 tPA, N (%) 99 (76.2) 56 (68.3) 21 (95.5) 22 (84.6) .012 Time to tPA, h, mean (SD) 6.9 (3.0) 7.3 (3.1) 6.7 (3.2) 6.3 (2.6) .369 Salvaged %, mean (SD) 71.7 (40.0) 66.2 (43.5) 90.0 (21.6) 73.8 (36.3) .043 M, male; h, hour; SD, standard deviation; tPA, thrombolytic; y, year; Tc99, Technetium 99. aANOVA for continuous variables and Fisher’s exact test for categorical variables. bComorbidities include documented heart disease, diabetes, peripheral vascular disease, or renal disease. cSocial factors include drug abuse, alcohol abuse, mental health issues, or home insecurity. dPMID: 26536540. View Large When the Tc99 scan was compared against final amputation level, Tc99 scans showed strong correlation with amputation level (r = .836, P < .001) (Figure 1A). Meanwhile, microangiography demonstrated slightly stronger positive correlation with amputation level (r = .870, P < .001; Figure 1B). In a comparison of patients who received both Tc99 scan and microangiography (N = 26), we observed significant differences in the mean scores of perfusion deficit (z = 3.20, P < .001). In this same cohort, a moderate correlation was found between level of perfusion deficit on Tc99 bone scan and amputation level (r = .525, P = .006; Figure 2A). Whereas a strong positive correlation was found between the microangiography studies and the amputation level (r = .890, P < .001; Figure 2B). Figure 1. View largeDownload slide Bland–Altman plot. A. Tc99 scan versus final amputation (N = 108). B. Microangiography versus final amputation (N = 48). Figure 1. View largeDownload slide Bland–Altman plot. A. Tc99 scan versus final amputation (N = 108). B. Microangiography versus final amputation (N = 48). Figure 2. View largeDownload slide Bland–Altman plot subgroup analysis of cohort of patients with Tc99 and microangiography scans. A. Tc99 scan versus final amputation (N = 26). B. Microangiography versus final amputation (N = 26). Figure 2. View largeDownload slide Bland–Altman plot subgroup analysis of cohort of patients with Tc99 and microangiography scans. A. Tc99 scan versus final amputation (N = 26). B. Microangiography versus final amputation (N = 26). DISCUSSION Early and accurate diagnosis of severe frostbite injury is required for effective treatment with thrombolytics. In our study, microangiography had a strong correlation with final amputation level. This suggests that microangiography can provide a reliable method of identifying the perfusion deficits seen in severe frostbite injury. Microangiography has many advantages over traditional methods of assessing the extent of tissue injury in severe frostbite. It is significantly quicker than the Tc99 scan (which can take several hours to complete) and does not require the use of a radioisotope, radiation exposure, or a specialized technician. Use and interpretation of microangiography can be performed by at the patient’s bedside. This could result in a much more expeditious diagnosis and a shorter warm ischemia time before the patient receives thrombolytics, thereby saving more tissue. Other methods of imaging include angiography and single-proton emission CT, which are used at other institutions.1 Angiography allows for direct arterial instillation of thrombolytics.2 This requires skilled personnel for performing the procedure but also exposure to contrast dye, the risk associated with an arterial puncture, and the patient must lay flat during and after the procedure. Single-proton emission CT is a newer method of imaging that involves fusing the images provided on a nuclear medicine scan with a low-dose CT to allow for better anatomic delineation of ischemia caused by severe frostbite injury.12 This is a promising technology, but, similar to Tc99 scans, it requires the use of specialized technicians a radiation exposure. Diagnosing frostbite more quickly using a bedside imaging technique could contribute to a shorter warm ischemia time and shorter time to therapy. By salvaging more tissue through earlier treatment, the burden of frostbite injury could be reduced.2,4,13 Frostbite patients already have increased critical care needs and longer lengths of stay than other burn injuries. Any intervention to decrease the severity of injury could potentially decrease the length of stay and thereby decrease the cost treating this disease.14 In addition, with microangiography being a more affordable imaging option, this also could decrease costs associated with treatment. Limitations of this study include those innate to single-center, retrospective studies. All microangiography studies were in patients who had either already received thrombolytic therapy or were not eligible for thrombolytic therapy. In future studies, it would be ideal to obtain a microangiography study on admission prior to thrombolytic therapy and compare this with the admission technetium 99 scan, as this would validate the microangiography study as a diagnostic tool. Ongoing data collection will continue with this novel imaging modality at our institution. CONCLUSIONS Microangiography provides a safe and accurate method of predicting final amputation level in severe frostbite injury and may be useful in rapid diagnosis of frostbite. ACKNOWLEDGMENTS We thank all of the staff at our Burn Unit, Hyperbaric Medicine Unit, Radiology, and Emergency Department for their dedicated care to frostbite patients on ongoing work in improving care for these patients. Conflicts of interest: None. REFERENCES 1. Millet JD , Brown RK , Levi B , et al. Frostbite: spectrum of imaging findings and guidelines for management . Radiographics 2016 ; 36 : 2154 – 69 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Gonzaga T , Jenabzadeh K , Anderson CP , Mohr WJ , Endorf FW , Ahrenholz DH . Use of intra-arterial thrombolytic therapy for acute treatment of frostbite in 62 patients with review of thrombolytic therapy in frostbite . J Burn Care Res 2016 ; 37 : e323 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Cauchy E , Marsigny B , Allamel G , Verhellen R , Chetaille E . The value of technetium 99 scintigraphy in the prognosis of amputation in severe frostbite injuries of the extremities: a retrospective study of 92 severe frostbite injuries . J Hand Surg Am 2000 ; 25 : 969 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Nygaard RM , Lacey AM , Lemere A , et al. Time matters in severe frostbite: assessment of limb/digit salvage on the individual patient level . J Burn Care Res 2017 ; 38 : 53 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 5. Braun JD , Trinidad-Hernandez M , Perry D , Armstrong DG , Mills JL Sr . Early quantitative evaluation of indocyanine green angiography in patients with critical limb ischemia . J Vasc Surg 2013 ; 57 : 1213 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Jafari MD , Lee KH , Halabi WJ , et al. The use of indocyanine green fluorescence to assess anastomotic perfusion during robotic assisted laparoscopic rectal surgery . Surg Endosc 2013 ; 27 : 3003 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Holm C , Tegeler J , Mayr M , Becker A , Pfeiffer UJ , Mühlbauer W . Monitoring free flaps using laser-induced fluorescence of indocyanine green: a preliminary experience . Microsurgery 2002 ; 22 : 278 – 87 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Baran U , Choi WJ , Wang RK . Potential use of OCT-based microangiography in clinical dermatology . Skin Res Technol 2016 ; 22 : 238 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Zhi Z , Yin X , Dziennis S , et al. Optical microangiography of retina and choroid and measurement of total retinal blood flow in mice . Biomed Opt Express 2012 ; 3 : 2976 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Thatcher JE , Squiers JJ , Kanick SC , et al. Imaging techniques for clinical burn assessment with a focus on multispectral imaging . Adv Wound Care (New Rochelle) 2016 ; 5 : 360 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Nygaard RM , Whitley AB , Fey RM , Wagner AL . The Hennepin score: quantification of frostbite management efficacy . J Burn Care Res 2016 ; 37 : e317 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Kraft C , Millet JD , Agarwal S , et al. SPECT/CT in the evaluation of frostbite . J Burn Care Res 2017 ; 38 : e227 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Bruen KJ , Ballard JR , Morris SE , Cochran A , Edelman LS , Saffle JR . Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy . Arch Surg 2007 ; 142 : 546 – 51; discussion 551 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Nygaard R , Endorf F . Frostbite vs burns: increased cost of care and use of hospital resources . J Burn Care Res 2018 ; 39 : 676 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat © American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Burn Care & Research Oxford University Press

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Abstract

Abstract Assessment of frostbite injury typically relies on computed tomography, angiography, or nuclear medicine studies to detect perfusion deficits prior to thrombolytic therapy. The aim of this study was to evaluate the potential of a novel imaging method, microangiography, in the assessment of severe frostbite injury. Patients with severe frostbite were included if they received a post-thrombolytic Technetium 99 (Tc99) bone scan, a Tc99 bone scan without thrombolytic therapy, and/or post-thrombolytic microangiography (MA) study. We included all patients from the years 2006 to 2018 with severe frostbite injury who had received appropriate imaging for diagnosis: Tc99 scan alone (N = 82), microangiography alone (N = 22), and both Tc99 and microangiography (N = 26). The majority of patients received thrombolytic therapy (76.2%), and the average time to thrombolytics was 6.9 hours. Tc99 scans showed strong correlation with amputation level (r = .836, P < .001), and microangiography showed a slightly stronger positive correlation with amputation level (r = .870, P < .001). In the subset who received both Tc99 scan and microangiography (N = 26), we observed significant differences in the mean scores of perfusion deficit (z = 3.20, P < .001). In this subset, a moderate correlation was found between level of perfusion deficit on Tc99 bone scan and amputation level (r = .525, P = .006). A very strong positive correlation was found between the microangiography studies and the amputation level (r = .890, P < .001). These results demonstrate that microangiography is a reliable alternative method of assessing severe frostbite injury and predicting amputation level. Severe frostbite injury is a well-known disease process, but the diagnosis and treatment of this disease remains highly variable. Current known practices for diagnosis include physical exam, angiography, computed tomography (CT), Technetium 99 (Tc99) bone scans, and other studies.1,2 These imaging modalities all have variable accuracy and predictive value that have not been directly compared. Currently, the Tc99 triple-phase bone scan is a standard method of diagnosis, as it shows absent perfusion in limbs/digits affected by severe frostbite injury.3 The absence of perfusion indicates that the patient may benefit from early treatment with thrombolytics. This has proved a reliable, consistent method for diagnosis of frostbite injury and is used at our institution. Limitations inherent to currently available imaging studies include access to the imaging modality, cost, need for specialized medical personnel to conduct the test and interpret the results, and radiation exposure. The only currently available diagnostic method unaffected by these factors is physical exam, but this is subject to significant inter-rater variability depending on physician training and experience. There is a need for an imaging modality that is rapid, low-cost, nonionizing, and can be used at the bedside with minimal training. With severe frostbite injury, “time is tissue”: the faster a patient can receive a definitive diagnosis, the sooner thrombolytic treatment can be started and the greater the tissue salvage.4 Microangiography (MA) is a novel imaging modality that uses peripherally injected indocyanine green (IcG) and ultraviolet light to assess perfusion in the vasculature of soft tissue. IcG is a safe drug, with the only major contraindications being iodine sensitivity and caution in renal failure patients. MA has been used in multiple settings including the assessment of limb perfusion, bowel anastomoses, and free flaps among many other applications.5–7 This test can typically be performed in less than 30 minutes at the bedside and involves no radiation, specialized technicians, arterial sheaths, or other invasive procedures. Another method of microangiography that is currently emerging is optical coherence tomography–based microangiography, which does not use IcG or any other intravenous contrast. So far, this method has demonstrated utility in retinal imaging and dermatologic imaging.8,9 Although optical coherence tomography–based microangiography provides exquisite detail of microvasculature, it can only penetrate a maximum of a 1 to 2 mm. Frostbite injury often involves the deeper tissues, and IcG-based microangiography demonstrates a greater depth of imaging as demonstrated in several burn depth studies.10 Given this difference in imaging modalities and our institution’s currently available tools, we use IcG-based imaging and have been doing so since 2016. Our aim was to determine whether microangiography had the potential to diagnose severe frostbite injury, by comparing microangiography to Tc99 scans and assessing the predicted tissue at risk for amputation to final amputation levels. At the start of this study, the exact specificity and sensitivity for the Tc99 scan and microangiography scans to determine final amputation level was unknown. METHODS This study received Institutional Review Board (IRB) approval at our institution. We included all patients from the years 2006 to 2018 with a diagnosis of severe frostbite injury who had received appropriate imaging for diagnosis: Tc99 scan alone (N = 82), microangiography alone (N = 22), and both Tc99 and microangiography (MA) (N = 26). Patients with severe frostbite injury are admitted to our American Burn Association (ABA) verified Burn Unit, either through the Emergency Department or as direct admissions. On admission, our practice is to perform a Tc99 triple-phase bone scan to confirm the diagnosis of severe frostbite by demonstrating a perfusion deficit in the deeper tissues. The treatment is then a loading dose and infusion of intravenous alteplase after confirming the patient has no contraindications to receiving thrombolytics. The patients included in this retrospective and prospective observational data analysis had either a Tc99 triple-phase bone scan, a Tc99 triple-phase bone scan and a microangiography study, or a microangiography study alone. These imaging studies were performed after completion of thrombolytic therapy (if given). In patients who received both the microangiography study and the Tc99 study, both of these studies were performed within 12 hours of each other and after completion of thrombolytic therapy. For this analysis, the imaging studies were reviewed by radiology staff (for Tc99 scans) and hyperbaric medicine staff (for MA studies). Our hyperbaric medicine staff have undergone appropriate training for reading and interpreting microangiography studies. The perfusion deficits were quantified using the Hennepin Frostbite Score11 as a “Tissue at Risk” score. If surgery was performed, the operating surgeon filled out a Hennepin Frostbite Score worksheet to indicate the final amputation levels. The Hennepin Frostbite Score allows for quantification of the percent of tissue salvaged by medical treatment. We then compared the amount of assessed tissue at risk on the imaging studies to the final amputation level to determine the accuracy of each imaging modality in predicting amputation. Statistical analysis included ANOVA for continuous variables and the Fisher’s exact test for categorical variables. A P value of less than or equal to .05 was considered to be statistically significant. Wilcoxon matched-pairs sign test was used for comparison of MA and Tc99 bone scans. Pearson correlation assessed microangiography and Tc99 bone scan at risk level to amputation level. All analyses were conducted using STATA 15.1 (StataCorp, College Station, TX). RESULTS Patients with severe frostbite injury treated at our institution between 2006 and 2018 were included in this analysis. Overall, the patient demographics were consistent with typical demographics associated with urban frostbite injury (Table 1). They were mostly male (83.1%) with a mean age of 40.4 years. A large proportion (86.2%) had social factors associated with frostbite injury including substance abuse and homelessness. Across the three imaging groups (Tc99 only, MA only, and Tc99 and MA), the cohorts were mostly similar with the exception that the MA-only group had fewer medical comorbidities (P = .010). These medical comorbidities included diabetes, chronic kidney disease, and coronary artery disease. There were no differences in measured tissue at risk between the groups (Table 1). Significantly more MA-only patients received thrombolytics (Table 1). Time to thrombolytics does not differ between the groups. Salvage percentage was significantly higher for the MA alone cohort as would be expected given that this group had a higher rate of thrombolytic treatment. Table 1. Demographics, injury characteristics, and outcomes Cohort Tc99 Scan alone MA alone Tc99 & MA N = 130 N = 82 N = 22 N = 26 P valuea Age, y, mean (SD) 40.4 (14.3) 40.7 (14.0) 41.0 (16.3) 39.0 (14.1) .865 Gender M, N (%) 108 (83.1) 64 (78.1) 20 (90.9) 24 (92.3) .135 Comorbidityb, N (%) 46 (35.4) 31 (37.8) 2 (9.1) 13 (50.0) .010 Socialc, N (%) 112 (86.2) 72 (87.8) 19 (86.4) 21 (80.8) .664 At riskd (pre-tPA Tc99 scan), mean (SD) 11.6 (10.5) 12.0 (11.7) 9.7 (8.9) 11.9 (6.3) .67 At riskd (post-tPA Tc99 scan), mean (SD) 8.4 (10.0) 8.6 (11.0) — 7.9 (6.0) .766 At riskd (post-tPA MA scan), mean (SD) 2.6 (3.6) — 1.8 (2.9) 3.3 (4.0) .147 tPA, N (%) 99 (76.2) 56 (68.3) 21 (95.5) 22 (84.6) .012 Time to tPA, h, mean (SD) 6.9 (3.0) 7.3 (3.1) 6.7 (3.2) 6.3 (2.6) .369 Salvaged %, mean (SD) 71.7 (40.0) 66.2 (43.5) 90.0 (21.6) 73.8 (36.3) .043 Cohort Tc99 Scan alone MA alone Tc99 & MA N = 130 N = 82 N = 22 N = 26 P valuea Age, y, mean (SD) 40.4 (14.3) 40.7 (14.0) 41.0 (16.3) 39.0 (14.1) .865 Gender M, N (%) 108 (83.1) 64 (78.1) 20 (90.9) 24 (92.3) .135 Comorbidityb, N (%) 46 (35.4) 31 (37.8) 2 (9.1) 13 (50.0) .010 Socialc, N (%) 112 (86.2) 72 (87.8) 19 (86.4) 21 (80.8) .664 At riskd (pre-tPA Tc99 scan), mean (SD) 11.6 (10.5) 12.0 (11.7) 9.7 (8.9) 11.9 (6.3) .67 At riskd (post-tPA Tc99 scan), mean (SD) 8.4 (10.0) 8.6 (11.0) — 7.9 (6.0) .766 At riskd (post-tPA MA scan), mean (SD) 2.6 (3.6) — 1.8 (2.9) 3.3 (4.0) .147 tPA, N (%) 99 (76.2) 56 (68.3) 21 (95.5) 22 (84.6) .012 Time to tPA, h, mean (SD) 6.9 (3.0) 7.3 (3.1) 6.7 (3.2) 6.3 (2.6) .369 Salvaged %, mean (SD) 71.7 (40.0) 66.2 (43.5) 90.0 (21.6) 73.8 (36.3) .043 M, male; h, hour; SD, standard deviation; tPA, thrombolytic; y, year; Tc99, Technetium 99. aANOVA for continuous variables and Fisher’s exact test for categorical variables. bComorbidities include documented heart disease, diabetes, peripheral vascular disease, or renal disease. cSocial factors include drug abuse, alcohol abuse, mental health issues, or home insecurity. dPMID: 26536540. View Large Table 1. Demographics, injury characteristics, and outcomes Cohort Tc99 Scan alone MA alone Tc99 & MA N = 130 N = 82 N = 22 N = 26 P valuea Age, y, mean (SD) 40.4 (14.3) 40.7 (14.0) 41.0 (16.3) 39.0 (14.1) .865 Gender M, N (%) 108 (83.1) 64 (78.1) 20 (90.9) 24 (92.3) .135 Comorbidityb, N (%) 46 (35.4) 31 (37.8) 2 (9.1) 13 (50.0) .010 Socialc, N (%) 112 (86.2) 72 (87.8) 19 (86.4) 21 (80.8) .664 At riskd (pre-tPA Tc99 scan), mean (SD) 11.6 (10.5) 12.0 (11.7) 9.7 (8.9) 11.9 (6.3) .67 At riskd (post-tPA Tc99 scan), mean (SD) 8.4 (10.0) 8.6 (11.0) — 7.9 (6.0) .766 At riskd (post-tPA MA scan), mean (SD) 2.6 (3.6) — 1.8 (2.9) 3.3 (4.0) .147 tPA, N (%) 99 (76.2) 56 (68.3) 21 (95.5) 22 (84.6) .012 Time to tPA, h, mean (SD) 6.9 (3.0) 7.3 (3.1) 6.7 (3.2) 6.3 (2.6) .369 Salvaged %, mean (SD) 71.7 (40.0) 66.2 (43.5) 90.0 (21.6) 73.8 (36.3) .043 Cohort Tc99 Scan alone MA alone Tc99 & MA N = 130 N = 82 N = 22 N = 26 P valuea Age, y, mean (SD) 40.4 (14.3) 40.7 (14.0) 41.0 (16.3) 39.0 (14.1) .865 Gender M, N (%) 108 (83.1) 64 (78.1) 20 (90.9) 24 (92.3) .135 Comorbidityb, N (%) 46 (35.4) 31 (37.8) 2 (9.1) 13 (50.0) .010 Socialc, N (%) 112 (86.2) 72 (87.8) 19 (86.4) 21 (80.8) .664 At riskd (pre-tPA Tc99 scan), mean (SD) 11.6 (10.5) 12.0 (11.7) 9.7 (8.9) 11.9 (6.3) .67 At riskd (post-tPA Tc99 scan), mean (SD) 8.4 (10.0) 8.6 (11.0) — 7.9 (6.0) .766 At riskd (post-tPA MA scan), mean (SD) 2.6 (3.6) — 1.8 (2.9) 3.3 (4.0) .147 tPA, N (%) 99 (76.2) 56 (68.3) 21 (95.5) 22 (84.6) .012 Time to tPA, h, mean (SD) 6.9 (3.0) 7.3 (3.1) 6.7 (3.2) 6.3 (2.6) .369 Salvaged %, mean (SD) 71.7 (40.0) 66.2 (43.5) 90.0 (21.6) 73.8 (36.3) .043 M, male; h, hour; SD, standard deviation; tPA, thrombolytic; y, year; Tc99, Technetium 99. aANOVA for continuous variables and Fisher’s exact test for categorical variables. bComorbidities include documented heart disease, diabetes, peripheral vascular disease, or renal disease. cSocial factors include drug abuse, alcohol abuse, mental health issues, or home insecurity. dPMID: 26536540. View Large When the Tc99 scan was compared against final amputation level, Tc99 scans showed strong correlation with amputation level (r = .836, P < .001) (Figure 1A). Meanwhile, microangiography demonstrated slightly stronger positive correlation with amputation level (r = .870, P < .001; Figure 1B). In a comparison of patients who received both Tc99 scan and microangiography (N = 26), we observed significant differences in the mean scores of perfusion deficit (z = 3.20, P < .001). In this same cohort, a moderate correlation was found between level of perfusion deficit on Tc99 bone scan and amputation level (r = .525, P = .006; Figure 2A). Whereas a strong positive correlation was found between the microangiography studies and the amputation level (r = .890, P < .001; Figure 2B). Figure 1. View largeDownload slide Bland–Altman plot. A. Tc99 scan versus final amputation (N = 108). B. Microangiography versus final amputation (N = 48). Figure 1. View largeDownload slide Bland–Altman plot. A. Tc99 scan versus final amputation (N = 108). B. Microangiography versus final amputation (N = 48). Figure 2. View largeDownload slide Bland–Altman plot subgroup analysis of cohort of patients with Tc99 and microangiography scans. A. Tc99 scan versus final amputation (N = 26). B. Microangiography versus final amputation (N = 26). Figure 2. View largeDownload slide Bland–Altman plot subgroup analysis of cohort of patients with Tc99 and microangiography scans. A. Tc99 scan versus final amputation (N = 26). B. Microangiography versus final amputation (N = 26). DISCUSSION Early and accurate diagnosis of severe frostbite injury is required for effective treatment with thrombolytics. In our study, microangiography had a strong correlation with final amputation level. This suggests that microangiography can provide a reliable method of identifying the perfusion deficits seen in severe frostbite injury. Microangiography has many advantages over traditional methods of assessing the extent of tissue injury in severe frostbite. It is significantly quicker than the Tc99 scan (which can take several hours to complete) and does not require the use of a radioisotope, radiation exposure, or a specialized technician. Use and interpretation of microangiography can be performed by at the patient’s bedside. This could result in a much more expeditious diagnosis and a shorter warm ischemia time before the patient receives thrombolytics, thereby saving more tissue. Other methods of imaging include angiography and single-proton emission CT, which are used at other institutions.1 Angiography allows for direct arterial instillation of thrombolytics.2 This requires skilled personnel for performing the procedure but also exposure to contrast dye, the risk associated with an arterial puncture, and the patient must lay flat during and after the procedure. Single-proton emission CT is a newer method of imaging that involves fusing the images provided on a nuclear medicine scan with a low-dose CT to allow for better anatomic delineation of ischemia caused by severe frostbite injury.12 This is a promising technology, but, similar to Tc99 scans, it requires the use of specialized technicians a radiation exposure. Diagnosing frostbite more quickly using a bedside imaging technique could contribute to a shorter warm ischemia time and shorter time to therapy. By salvaging more tissue through earlier treatment, the burden of frostbite injury could be reduced.2,4,13 Frostbite patients already have increased critical care needs and longer lengths of stay than other burn injuries. Any intervention to decrease the severity of injury could potentially decrease the length of stay and thereby decrease the cost treating this disease.14 In addition, with microangiography being a more affordable imaging option, this also could decrease costs associated with treatment. Limitations of this study include those innate to single-center, retrospective studies. All microangiography studies were in patients who had either already received thrombolytic therapy or were not eligible for thrombolytic therapy. In future studies, it would be ideal to obtain a microangiography study on admission prior to thrombolytic therapy and compare this with the admission technetium 99 scan, as this would validate the microangiography study as a diagnostic tool. Ongoing data collection will continue with this novel imaging modality at our institution. CONCLUSIONS Microangiography provides a safe and accurate method of predicting final amputation level in severe frostbite injury and may be useful in rapid diagnosis of frostbite. ACKNOWLEDGMENTS We thank all of the staff at our Burn Unit, Hyperbaric Medicine Unit, Radiology, and Emergency Department for their dedicated care to frostbite patients on ongoing work in improving care for these patients. Conflicts of interest: None. REFERENCES 1. Millet JD , Brown RK , Levi B , et al. Frostbite: spectrum of imaging findings and guidelines for management . Radiographics 2016 ; 36 : 2154 – 69 . Google Scholar Crossref Search ADS PubMed WorldCat 2. Gonzaga T , Jenabzadeh K , Anderson CP , Mohr WJ , Endorf FW , Ahrenholz DH . Use of intra-arterial thrombolytic therapy for acute treatment of frostbite in 62 patients with review of thrombolytic therapy in frostbite . J Burn Care Res 2016 ; 37 : e323 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat 3. Cauchy E , Marsigny B , Allamel G , Verhellen R , Chetaille E . The value of technetium 99 scintigraphy in the prognosis of amputation in severe frostbite injuries of the extremities: a retrospective study of 92 severe frostbite injuries . J Hand Surg Am 2000 ; 25 : 969 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat 4. Nygaard RM , Lacey AM , Lemere A , et al. Time matters in severe frostbite: assessment of limb/digit salvage on the individual patient level . J Burn Care Res 2017 ; 38 : 53 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat 5. Braun JD , Trinidad-Hernandez M , Perry D , Armstrong DG , Mills JL Sr . Early quantitative evaluation of indocyanine green angiography in patients with critical limb ischemia . J Vasc Surg 2013 ; 57 : 1213 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 6. Jafari MD , Lee KH , Halabi WJ , et al. The use of indocyanine green fluorescence to assess anastomotic perfusion during robotic assisted laparoscopic rectal surgery . Surg Endosc 2013 ; 27 : 3003 – 8 . Google Scholar Crossref Search ADS PubMed WorldCat 7. Holm C , Tegeler J , Mayr M , Becker A , Pfeiffer UJ , Mühlbauer W . Monitoring free flaps using laser-induced fluorescence of indocyanine green: a preliminary experience . Microsurgery 2002 ; 22 : 278 – 87 . Google Scholar Crossref Search ADS PubMed WorldCat 8. Baran U , Choi WJ , Wang RK . Potential use of OCT-based microangiography in clinical dermatology . Skin Res Technol 2016 ; 22 : 238 – 46 . Google Scholar Crossref Search ADS PubMed WorldCat 9. Zhi Z , Yin X , Dziennis S , et al. Optical microangiography of retina and choroid and measurement of total retinal blood flow in mice . Biomed Opt Express 2012 ; 3 : 2976 – 86 . Google Scholar Crossref Search ADS PubMed WorldCat 10. Thatcher JE , Squiers JJ , Kanick SC , et al. Imaging techniques for clinical burn assessment with a focus on multispectral imaging . Adv Wound Care (New Rochelle) 2016 ; 5 : 360 – 78 . Google Scholar Crossref Search ADS PubMed WorldCat 11. Nygaard RM , Whitley AB , Fey RM , Wagner AL . The Hennepin score: quantification of frostbite management efficacy . J Burn Care Res 2016 ; 37 : e317 – 22 . Google Scholar Crossref Search ADS PubMed WorldCat 12. Kraft C , Millet JD , Agarwal S , et al. SPECT/CT in the evaluation of frostbite . J Burn Care Res 2017 ; 38 : e227 – 34 . Google Scholar Crossref Search ADS PubMed WorldCat 13. Bruen KJ , Ballard JR , Morris SE , Cochran A , Edelman LS , Saffle JR . Reduction of the incidence of amputation in frostbite injury with thrombolytic therapy . Arch Surg 2007 ; 142 : 546 – 51; discussion 551 . Google Scholar Crossref Search ADS PubMed WorldCat 14. Nygaard R , Endorf F . Frostbite vs burns: increased cost of care and use of hospital resources . J Burn Care Res 2018 ; 39 : 676 – 9 . Google Scholar Crossref Search ADS PubMed WorldCat © American Burn Association 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/open_access/funder_policies/chorus/standard_publication_model)

Journal

Journal of Burn Care & ResearchOxford University Press

Published: Aug 14, 2019

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