Study design and population
We conducted a prospective clinical audit looking at the incidence of CIN in a number of patients with known renal impairment who underwent peripheral arterial interventions due to symptomatic peripheral arterial disease (PAD). The use of carbon dioxide (CO2) as an alternative contrast agent was formally initiated in patients with impaired renal function (eGFR<60mls/min/1.73 m2) undergoing peripheral endovascular interventions. All patients had both clinical assessment as well as a non-invasive imaging study (either Doppler ultrasound or non-contrast magnetic resonance angiography) before the procedure. During the 9-month study period, all patients suffering from critical limb ischemia (CLI) referred to the interventional radiology department for peripheral arterial intervention that were considered high risk for developing CIN, underwent either exclusively CO2 angiography or combined with supplementary use of small volumes of iodine CM which was recorded in detail and included in the analysis (CO2 group). Small volume of CM was administered in cases where images obtained with CO2 administration were inconclusive (degree and/or severity of post angioplasty dissection) to guide further treatment. Cases were matched (1:2) with a historical cohort of 100 consecutive patients treated solely with non-ionic low-osmolar iodinated contrast (Visipaque 320, Amersham; Control group). There were no exceptions made based on the arterial segment treated. This was a prospective service evaluation of carbon dioxide usage in peripheral interventions and a written informed consent prior to any intervention following detailed discussion of all the potential risks and benefits of CO2 use as an alternative to iodine-based contrast media. As per National Health Service Research and Ethics definitions (Institutional Review Board equivalent), this study is not classified as research and therefore formal ethics approval was waived.
Patients’ electronic medical records (electronic patient record-EPR, radiology information system-RIS) as well as relevant paper notes were retrospectively reviewed and analyzed for collection of baseline demographics, use of peri-procedure intravenous hydration and/or N-acetyl-cysteine (NAC). Baseline demographics included patients’ age at the time of the procedure, previous medical history including diabetes mellitus, hypertension, anemia and hypoalbuminemia. Cases that had received intravenous iodinated CM for other imaging investigations the week preceding the index angioplasty were excluded from inclusion in the present analysis. Patients under regular haemodialysis were also excluded from further analysis.
Procedure
The use of CO2 for peripheral angiography has been described in detail previously (Funaki, 2008). All procedures were done in a dedicated Interventional Radiology suite (Artis Zee, Siemens, Erlangen, Germany) using the CO2 –Angioset (OptiMed, Ettlingen, Germany). For imaging optimization as recommended all patients had their legs elevated by 10–15 degrees usually by tilt of the angiographic table. Prior to CO2 administration all patients were lightly sedated with a combination of intravenous Fentanyl and Midazolam to minimize discomfort during CO2 injection. Care was taken to safely purge the CO2 set and avoid any air contamination prior to connection to the patient. Selective close-up angiograms were performed as necessary in order to optimize the image quality. The antegrade approach was preferred for femoropopliteal and tibial segments, while the ipsilateral retrograde (up-and-over) approach was employed for aorto-iliac disease. Injected CO2 volume was 60 mls for the iliac segment, 40 mls for the femoropopliteal segment and 20 mls for selective imaging of the below-the-knee arterial segments. In cases of inadequate opacification of an arterial segment, as per operator decision, iodine CM angiogram was performed and the total volume of iodine contrast used was recorded.
Definitions, outcomes and statistical analysis
To date, there is no standard definition for reporting CIN. According to European Society of Urogenital Radiology (ESUR) guidelines, CIN may be defined as an increase in the creatinine (Cr) levels of more than 25% or 44 μmol (μmol)/L (0.5 mg/dl) compared to baseline within 3 days (72 h) following endovascular contrast administration (Guidelines E, 2015). Hence, this was adopted to for the purposes of this study to define the incidence of CIN (primary outcome). Secondary outcomes included differences (D) in serum creatinine values immediately and up to 30 days post procedure, total volume of iodinated CM used as well as calculation of a safe cut-off value of CM volume to be used in order to avoid CIN development based on receiver operating characteristics (ROC) curve analysis.
A univariate analysis of all potential covariates was performed in order to identify individual factors that may predict CIN development in the two study groups. These included patient age, diabetes mellitus, heart failure, hypertension, anaemia, CKD stages 4 or 5 (baseline eGFR < 30 mls/min/1.73 m2) versus CKD stage 3 (baseline eGFR > 30–59 mls/min/1.73 m2), hypoalbuminemia, total volume of carbon dioxide and finally total contrast volume below or above the cut-off value as calculated through the ROC curve analysis. Finally, any major complications associated with the use of CO2 were recorded. These included bowel ischemia, cardiac arrest, abdominal pain and nausea.
Statistical analysis was performed using the SPSS statistical software (SPSS, version 18.0 for Windows; SPSS Inc., Chicago, Il, USA.). Discrete and continuous variables are presented as counts and percentages, and as mean ± standard deviation respectively. Non-normal variables were expressed as medians and interquartile ranges (25th and 75th percentiles). The unpaired Student t test was used to identify statistical significant differences for variables that passed the normality test, while qualitative and continuous variables that did not pass the normality test were compared using the Mann-Whitney test. Receiver operating characteristics (ROC) curve analysis was used to identify the cut-off value of total CM volume in order to avoid CIN development.