Abstract
Purpose
Patients with peripheral arterial disease (PAD) or critical limb ischemia (CLI) require revascularization. Traditionally, endovascular therapy (EVT) is performed with iodinated contrast agent (ICM), which can provoke potential deterioration in renal function. CO2 is a safe negative contrast agent to guide vascular procedures, but interpretation of CO2 angiography is challenging. Changes in blood flow following iodine-aided EVT are assessable with 2D-perfusion angiography (2D-PA). The aim of this study was to evaluate 2D-PA as a tool to monitor blood flow changes during CO2-aided EVT.
Material and Methods
2D-PA was performed before and after ten EVTs (nine stents; one endoprosthesis; 10/2012–02/2020) in nine patients (six men; 65 ± 10y) with Fontaine stage IIb (n = 8) and IV (n = 1). A reference ROI (ROIINFLOW) was placed in the artery before the targeted obstruction and a target ROI (ROIOUTFLOW) distally. Corresponding ROIs were used pre- and post-EVT. Time to peak (TTP), peak density (PD) and area under the curve (AUC) were computed. The reference/target ROI ratios (TTPOUTFLOW/TTPINFLOW; PDOUTFLOW/PDINFLOW; AUCOUTFLOW/AUCINFLOW) were calculated.
Results
2D-PA was technically feasible in all cases. A significant increase of 82% in PDOUTFLOW/PDINFLOW (0.44 ± 0.4 to 0.8 ± 0.63; p = 0.002) and of 132% in AUCOUTFLOW/AUCINFLOW (0.34 ± 0.22 to 0.79 ± 0.59; p = 0.002) was seen. A trend for a decrease in TTPOUTFLOW/TTPINFLOW was observed (− 24%; 5.57 ± 3.66 s–4.25 ± 1.64 s; p = 0.6).
Conclusion
The presented 2D-PA technique facilitates the assessment of arterial flow in CO2-aided EVTs and has the potential to simplify the assessment of immediate treatment response.
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Introduction
Peripheral arterial disease (PAD) is a major public health problem with rising prevalence and considerable socioeconomic impact [1,2,3]. Current guidelines recommend an “endovascular first” strategy for stenosed or occluded vessels in patients with claudication and critical limb ischemia, which leads to an increase in endovascular therapy (EVT) [1, 2, 5, 6]. Coexisting renal, diabetic, vascular and other chronic comorbidities are common in patients with PAD, which can complicate disease management [2, 7, 8]. Carbon dioxide (CO2) has long been acknowledged as a safe intravascular, negative contrast agent to guide vascular procedures in patients with chronic kidney disease (CKD), hypersensitivities to iodinated contrast agent (ICM) or hyperthyroidism [1, 4, 9,10,11]. Nevertheless, CO2 is reported to be underutilized in the past [12]—mainly due to the discrepancy between CO2 and ICM regarding application and image analysis. The unsteady image quality in this infrequently used technique can limit the interpretation of contrast flow changes following EVT. This might negatively affect EVT with CO2, as the angiographic endpoint in EVT depends on the visual comparison of blood flow before and after revascularization.
2D-perfusion angiography (2D-PA) is a newly available technique for the assessment of blood flow and tissue perfusion. This technique relies on dedicated post-processing of standard digital subtraction angiography (DSA) images and computes time–density curves, which represent the flow of contrast agent within a region of interest (ROI) throughout the entire DSA run [2, 18,19,20,21,22]. Thus, it allows us to assess the perfusion distal to occluded vessels [2, 13,14,15,16,17] before, during and after endovascular revascularization. This might offer an opportunity to predict and evaluate clinical outcomes. 2D-PA used in CO2-guided interventions might increase the diagnostic confidence and thus support the visual interpretation. The aim of this study was to evaluate the feasibility of 2D-PA as a tool to monitor perfusion changes after CO2-aided EVT in patients with PAD.
Material and Methods
Patient Population
In total, 857 diagnostic and interventional DSA of the lower extremity, performed at our institution between 10/2014 and 02/2020, were screened for CO2-aided imaging. Out of these, we included all consecutive studies with paired pre- and post-interventional DSA series performed with CO2. In total, ten interventions in nine patients with PAD admitted for EVT of the pelvic/lower extremity arteries were assessed. Indications for CO2 as contrast agent were severe CKD with preserved urine excretion in all patients (n = 9/9; 100%) and additional allergy to ICM and hyperthyroidism in one patient each (n = 1/9; 11%).
Angiography
The DSA images were acquired using a monoplane, ceiling-mounted angiographic system equipped with a 30 × 40 cm flat-panel detector (Artis Q® or Artis pheno, Siemens Healthcare, Forchheim, Germany). Intra-arterial CO2 was administered using a dedicated angiography set (CO2-Angioset nach Schmitz-Rode/Alzen, Optimed, Ettlingen, Germany) via transfemoral approach.
For each DSA of the pelvic or the femoral arteries, 60–80 ml of pure CO2 was administered with a constant injection pressure of 1.3 bar [21]. Imaging parameters included a tube voltage of 60–80 kV and a tube current of 50–450 mA. Images were acquired at 7.5 frames/second with a range of 10–20 s, commencing at the same time as contrast injection. Interventions were performed with FOV adjusted to the investigated region using the 30 × 40 cm detector with collimation. Spatial resolution is 125 µm.
In patients with a known severe iodinated contrast agent allergy, CO2 was the only contrast agent used. In patients without absolute contraindications for ICM, hybrid angiographies were performed at the discretion of the interventionalist (n = 7). In hybrid angiography, ICM-based images were acquired in between a mainly CO2-aided intervention if image quality was insufficient and the interventionalist was not comfortable with sole CO2-based imaging.
Residual stenosis of < 30% of the vessel diameter after EVT by visual assessment of the performing interventionalist was set as the endpoint [2].
Image Analysis
Post-processing of the original angiographic DICOM dataset was computed on a dedicated workstation using a commercially available software package (syngo X Workplace®VD10A, iFlow®, Siemens Healthcare). One reference region of interest (ROI) was placed in the artery proximal to the vascular lesion (to assess the arterial inflow; ROIINFLOW), and a second ROI (ROIOUTFLOW) was placed distal to the vascular lesion to assess arterial outflow. All ROIs were fitted to at least 2/3 of the vessel diameter. As shape and positioning of the ROIs might influence the results [14], we used circular ROIs on the pre-interventional DSA, which were semiautomatically copied to the corresponding DSA following revascularization in order to ensure that shape and position of the ROIs were comparable.
Numeric density values for the time to peak (TTP), peak density value (PD) and area under the time–density curve (AUC) were computed [2, 13,14,15,16,17,18]. The following ratios were calculated pre- and post-intervention: TTPOUTFLOW/TTPINFLOW, PDOUTFLOW/PDINFLOW and AUCOUTFLOW/AUCINFLOW. Comparison of the pre- and post-intervention 2D-perfusion parameter ratios was performed. Patient motion during an angiographic run was analyzed, based on visual impressions.
Statistical Analysis
Descriptive statistical analyses of the patient demographics and angiographic data were performed. Comparisons between pre- and post-intervention data were tested using pairwise Wilcoxon signed-rank test. A p value of ≤ 0.05 was defined as statistically significant. Statistical analyses were computed using commercially available software (JMP 14, SAS Institute, JMP Office Germany, Böblingen, Germany).
Results
In total, this study included ten interventions in nine patients (six men, three women; mean age 65 ± 10 years), who were admitted for CO2-aided EVT due to clinically relevant PAD (Fontaine stage IIB (9/10) and IV (1/10)) of the pelvis (6/10; 60%) or lower extremity (4/10; 40%). In 7/9 patients, leading indication for EVT was intermittent claudication. In total, 5/9 patients (55%) had a previous kidney transplant. Of those, 2/9 (22%) presented with acute renal deterioration due to PAD-associated perfusion changes in the transplanted kidney. All patients suffered from CKD stage 4 (n = 7/9; 78%) or stage 5 (n = 2/9; 22%). In addition to CKD, one patient (1/9; 11%) suffered from a severe allergy to ICM and another patient (1/9; 11%) presented with hyperthyroidism. For detailed patient characteristics, refer to Table 1.
Revascularization (nine stents, one endoprosthesis) was successfully achieved in all patients (common iliac artery (n = 6), superficial femoral artery (n = 4)). In 7/10 interventions, hybrid angiography was performed. In 3/10 interventions (performed in 2/9 patients), administration of additional ICM was not necessary. No patient had to be excluded due to motion artifacts. In the two patients admitted with acute transplant dysfunction, serum creatinine decreased and eGFR increased following revascularization (serum creatinine of patient 1: 406 μmol/l (eGFR 15 ml/min) before and 195 μmol/l (eGFR 33 ml/min) 1 week after EVT; serum creatinine of patient 2: 338 μmol/l (eGFR 15 ml/min) pre- and 303 μmol/l (eGFR 18 ml/min) 1 week post-intervention) (Table 2).
2D-PA facilitated detection of blood flow changes following recanalization in all procedures. After revascularization, PDOUTFLOW/PDINFLOW significantly increased compared with the pre-interventional values (0.44 ± 0.4–0.8 ± 0.63; p = 0.002). Concordantly, AUCOUTFLOW/AUCINFLOW presented significantly higher values following EVT (0.34 ± 0.22–0.79 ± 0.59; p = 0.002) indicating a higher amount of contrast passing through the treated lesion. A trend for a decrease in TTPOUTFLOW/TTPINFLOW after the interventions was observed, but without reaching statistical significance (5.57 ± 3.66 s–4.25 ± 1.64 s; p = 0.6). Treatment results are summarized in Table 3; an example of 2D-PA is shown in Fig. 1 for iliac EVT and in Fig. 2 for femoral EVT.
Discussion
In this study, we evaluated the feasibility of 2D-PA as a tool to monitor perfusion changes following EVT in CO2-guided interventions. Angiographies during EVT in PAD have traditionally used ICM to accurately visualize the target arteries [12, 22]. However, ICM has significant associated risks, including hypersensitivity reactions, thyrotoxicosis and an increased danger of acute renal deterioration in patients with CKD. CO2 has been acknowledged as a low-risk contrast agent to guide vascular interventions in patients with CKD, hyperthyroidism or hypersensitivities to ICM [1, 4, 9,10,11]. Nonetheless, the image quality in CO2 angiographies is unsteady [1, 12, 23], and obtaining diagnostically valuable images in CO2 angiography can be more challenging than in conventional angiography [24], especially as CO2 angiographies are still less common compared with ICM. Generally, the assessment of blood flow and thus identification of occluded/stenotic arteries during EVT are highly subjective and operator-dependent [18]. The combination of the aforementioned difficulties in the evaluation of blood flow changes using CO2 might aggravate and lead to a significantly decreased diagnostic confidence.
2D-PA assigns density values to each area within an ROI and calculates mean values in each frame. These density values over time have been used to retrieve knowledge about flow rates, flow time and maximum values [2, 13,14,15,16,17]. In our study, we retrospectively assessed pre- and post-interventional blood flow through stenotic vessels using 2D-PA, evaluating it for possible assistance in CO2-based angiographies. As previously described, PD characterizes the maximum mean density within the ROI. The AUC is calculated from each density value at each time point using integration of successive values [2, 13,14,15,16,17]. The significant increases in PDOUTFLOW/PDINFLOW and AUCOUTFLOW/AUCINFLOW following EVT imply an intra-individually increased perfusion of the treated artery. TTPOUTFLOW/TTPINFLOW, equaling the time from the start of the DSA run until maximum density, decreased following EVT, as expected, indicating an accelerated speed of blood flow after removal of the intravascular obstruction. We attribute the lack of significance regarding TTPOUTFLOW/TTPINFLOW to the small sample size. However, despite the preliminary trendsetting results, the definition of endpoints for a successful EVT based on 2D-PA requires further evaluation with larger study populations.
This study has several limitations. The major limitation is the small number of patients admitted for EVT that received CO2-aided DSA before and after revascularization. Therefore, larger studies are necessary to support our findings.
Conclusion
Evaluation of blood flow changes following EVT in CO2-guided interventions using 2D-PA is feasible. This technique has the potential to objectify immediate treatment response and might result in the definition of objective, user-independent interventional endpoints.
Abbreviations
- 2D-PA:
-
2D-perfusion angiography
- AUC:
-
Area under the time–density curve
- CKD:
-
Chronic kidney disease
- CO2:
-
Carbon dioxide
- DSA:
-
Digital subtraction angiography
- eGFR:
-
Estimated glomerular filtration rate
- EVT:
-
Endovascular therapy
- ICM:
-
Iodinated contrast medium
- PAD:
-
Peripheral arterial disease
- PD:
-
Peak density value
- ROI:
-
Region of interest
- TTP:
-
Time to peak
References
Stegemann E, Tegtmeier C, Bimpong-Buta NY, Sansone R, Uhlenbruch M, Richter A. Carbondioxide-aided angiography decreases contrast volume and preserves kidney function in peripheral vascular interventions. Angiology. 2016;67(9):875–81.
Hinrichs JB, Murray T, Akin M, Lee M, Brehm MU, Wilhelmi M. Evaluation of a novel 2D perfusion angiography technique independent of pump injections for assessment of interventional treatment of peripheral vascular disease. Int J Cardiovasc Imaging. 2017;33(3):295–301.
Krause D, Burghaus I, Thiem U, Trampisch US, Trampisch M, Klaassen-Mielke R. The risk of peripheral artery disease in older adults - seven-year results of the get ABI study. Vasa. 2016;45(5):403–10.
Fujihara M, Kawasaki D, Shintani Y, Fukunaga M, Nakama T, Koshida R. Endovascular therapy by CO2 angiography to prevent contrast-induced nephropathy in patients with chronic kidney disease: a prospective multicenter trial of CO2 angiography registry: EVT by CO2 angiography in CKD patients. Catheter Cardiovasc Interv. 2015;85(5):870–7.
Endorsed by: the European Stroke Organisation (ESO), Authors/Task Force Members, Tendera M, Aboyans V, Bartelink M-L, Baumgartner I, ESC Guidelines on the diagnosis and treatment of peripheral artery diseases: Document covering atherosclerotic disease of extracranial carotid and vertebral, mesenteric, renal, upper and lower extremity arteries * The Task Force on the Diagnosis and Treatment of Peripheral Artery Diseases of the European Society of Cardiology (ESC). Eur Heart J 2011;32(22):2851–906.
Norgren L, Hiatt WR, Dormandy JA, Nehler MR, Harris KA, Fowkes FGR. Inter-society consensus for the management of peripheral arterial disease (TASC II). J Vasc Surg. 2007;45(1):S5-67.
Dua A, Lee CJ. Epidemiology of peripheral arterial disease and critical limb ischemia. Tech Vasc Interv Radiol. 2016;19(2):91–5.
Belch JJF. Critical issues in peripheral arterial disease detection and managementa call to action. Arch Intern Med. 2003;163(8):884.
Cho KJ. Carbon dioxide angiography: scientific principles and practice. Vasc Spec Int. 2015;31(3):67–80.
Miller FJ, Mineau DE, Koehler PR, Nelson JA, Luers PD, Sherry RA. Clinical intra-arterial digital subtraction imaging. Use of small volumes of iodinated contrast material or carbon dioxide. Radiology. 1983;148(1):273–8.
Krasny R, Hollmann J, Günther R. Erste Erfahrungen mit CO2 als gasförmiges Kontrastmittel in der DSA. RöFo - Fortschritte Auf Dem Geb Röntgenstrahlen Bildgeb Verfahr. 1987;146(04):450–4.
Gupta A, Dosekun AK, Kumar V. Carbon dioxide-angiography for patients with peripheral arterial disease at risk of contrast-induced nephropathy. World J Cardiol. 2020;12(2):76–90.
Maschke SK, Renne J, Werncke T, Olsson KM, Hoeper MM, Wacker FK. Chronic thromboembolic pulmonary hypertension: evaluation of 2D-perfusion angiography in patients who undergo balloon pulmonary angioplasty. Eur Radiol. 2017;27(10):4264–70.
Dewald CLA, Meine TC, Winther HMB, Kloeckner R, Maschke SK, Kirstein MM. Chemosaturation percutaneous hepatic perfusion (CS-PHP) with melphalan: evaluation of 2D-perfusion angiography (2D-PA) for leakage detection of the venous double-balloon catheter. Cardiovasc Intervent Radiol. 2019;42(10):1441–8.
Maschke SK, Werncke T, Renne J, Kloeckner R, Marquardt S, Kirstein MM. Transjugular intrahepatic portosystemic shunt (TIPS) dysfunction: quantitative assessment of flow and perfusion changes using 2D-perfusion angiography following shunt revision. Abdom Radiol. 2018;43(10):2868–75.
Maschke SK, Werncke T, Klöckner R, Rodt T, Renne J, Kirstein MM. Quantification of perfusion reduction by using 2D-perfusion angiography following transarterial chemoembolization with drug-eluting beads. Abdom Radiol. 2018;43(5):1245–53.
Becker LS, Stahl K, Meine TC, von Falck C, Meyer BC, Dewald CLA. Non-occlusive mesenteric ischemia (NOMI): evaluation of 2D-perfusion angiography (2D-PA) for early treatment response assessment. Abdom Radiol Internet. 2020. https://doi.org/10.1007/s00261-020-02457-y.
Murray T, Rodt T, Lee MJ. Two-dimensional perfusion angiography of the foot: technical considerations and initial analysis. J Endovasc Ther. 2016;23(1):58–64.
Jens S, Marquering HA, Koelemay MJW, Reekers JA. Perfusion angiography of the foot in patients with critical limb ischemia: description of the technique. Cardiovasc Intervent Radiol. 2015;38(1):201–5.
Reekers JA, Koelemay MJW, Marquering HA, van Bavel ET. Functional imaging of the foot with perfusion angiography in critical limb ischemia. Cardiovasc Intervent Radiol. 2016;39(2):183–9.
Arendt CT, Leithner D, Lenga L, Wichmann JL, Albrecht MH, Czwikla R. Multi-observer comparison study between unenhanced quiescent-interval single-shot magnetic resonance angiography and invasive carbon dioxide angiography in patients with peripheral arterial disease and chronic renal insufficiency. Eur J Radiol. 2018;108:140–6.
Mehran R, Dangas GD, Weisbord SD. Contrast-associated acute kidney injury. N Engl J Med. 2019;380(22):2146–55.
Rolland Y, Duvauferrier R, Lucas A, Gourlay C, Morcet N, Rambeau M. Lower limb angiography: a prospective study comparing carbon dioxide with iodinated contrast material in 30 patients. Am J Roentgenol. 1998;171(2):333–7.
Hawkins IF, Cho KJ, Caridi JG. Carbon dioxide in angiography to reduce the risk of contrast-induced nephropathy. Radiol Clin North Am. 2009;47(5):813–25.
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The authors of this manuscript declare relationships with the following companies: Siemens Healthcare and ProMedicus (Bernhard Meyer and Frank Wacker; outside the submitted work). The remaining authors declare no relationships with any companies whose products or services may be related to the subject matter of the article.
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Dewald, C.L.A., Becker, L.S., Maschke, S.K. et al. 2D-Perfusion Angiography Using Carbon Dioxide (CO2): A Feasible Tool to Monitor Immediate Treatment Response to Endovascular Therapy of Peripheral Arterial Disease?. Cardiovasc Intervent Radiol 44, 635–641 (2021). https://doi.org/10.1007/s00270-020-02722-z
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DOI: https://doi.org/10.1007/s00270-020-02722-z