A Novel Fluorescent Clinical Method to Rapidly Quantify Plasma Volume

Abstract

Objectives: To determine the performance of a rapid fluorescent indicator technique for measuring plasma volume (PV). Methods: This was an open-label, observational evaluation of a two-component intravenous visible fluorescent dye technique to rapidly measure PV in 16 healthy subjects and 16 subjects with chronic kidney disease (8 stage 3 and 8 stage 4 CKD), at 2 clinical research sites. The method consisted of a single intravenous injection of 12 mg of a large 150-kDa carboxy-methyl dextran conjugated to a fluorescent rhodamine-derived dye as the PV marker (PVM), and 35 mg of a small 5-kDa carboxy-methyl dextran conjugated to fluorescein, the renal clearance marker. Dye concentrations were quantified 15 min after the injections for initial PV measurements using the indicator-dilution principle. Additional samples were taken over 8 h to evaluate the stability of the PVM as a determinant of PV. Blood volumes (BV) were calculated based on PV and the subject’s hematocrit. Pharmacokinetic parameters were calculated from the plasma concentration data taken over several days using noncompartmental methods (Phoenix WinNonlin®). Linear correlation and Bland-Altman plots were used to compare visible fluorescent injectate-measured PV compared to Nadler’s formula for estimating PV. Finally, 8 healthy subjects received 350 mL infusion of a 5% albumin solution in normal saline over 30 min and a repeat PV determination was then carried out. Results: PV and BV varied according to weight and body surface area, with PV ranging from 2,115 to 6,234 mL and 28.6 to 41.9 mL/kg when weight adjusted. Both parameters were stable for > 6 h with repeated plasma measurements of the PVM. There was no difference between healthy subjects and CKD subjects. Overall, there was general agreement with Nadler’s estimation formula for the mean PV in subjects. A 24-h repeat dose measurement in 8 healthy subjects showed PV variability of 98 ± 121 mL (mean = 3.8%). Additionally, following an intravenous bolus of 350 mL of a 5% albumin solution in normal saline in 8 healthy subjects, the mean (SD) measured increase in PV was 356 (±50.0) mL post-infusion. There were no serious adverse events reported during the study. Conclusions: This minimally invasive fluorescent dye approach safely allowed for rapid, accurate, and reproducible determination of PV, BV, and dynamic monitoring of changes following fluid administration.

Serum creatinine and cystatin C‐based estimates of glomerular filtration rate are misleading in acute heart failure

“…Though no severe adverse events were considered related to the VFI compound, a subset of patients exhibited mild or moderate events suggestive of allergic reactions, including two cases of transient pruritus and urticaria, which resolved within 30–60 min after antihistamine treatment. A previously published study using VFI reported no serious adverse events 24,31 . Placebo‐controlled data on the VFI compound are currently limited to one small Phase 1 study, in which VFI or placebo was administered in 32 healthy subjects.…”

Estimated plasma volume status in heart failure: clinical implications and future directions

“…PV is calculated from the measured blood volume, venous hematocrit, corrected for the trapped plasma and mean body hematocrit. 29 Recently, a non-isotopic (fluorescent) method to rapidly quantify PV and renal function was developed. The method consists of 12mg of a 150-kDa carboxy-methylated dextran, conjugated to a rhodamine dye (plasma volume marker), and 35mg of a 5-kDa carboxy-methylated dextran, conjugated to fluorescein (renal clearance marker), in a total volume of 3.0 ml.…”

“…The injectate is infused intravenously over 30s. Dye concentrations are quantified at only 1-time point, 15 min after the injections for initial PV measurements using the indicator-dilution principle, and this timing may have less influence on the value of PV 29 . Blood volumes are calculated based on PV and the subject's hematocrit.…”

“…Blood volumes are calculated based on PV and the subject's hematocrit. Samples are also taken at 60 and 170 min for determination of glomerular filtration rate by the FAST BioMedical technique 29 . Validation results were recently published using data from 16 healthy subjects and 16 subjects with chronic kidney disease.…”

“…Additionally, this technique accurately tracked dynamic changes in PV induced by a volume challenge following an intravenous bolus of 350 mL of a 5% albumin solution in normal saline in 8 healthy subjects 29 . The ongoing EMPAKT-CHF (Estimating versus Measuring Plasma Volume and Kidney Function in Acute Decompensated Congestive Heart Failure) study is a one-armed, phase 2 clinical trial using (VFI)™ to assay and assess measured PV and measured glomerular filtration rate in hospitalized patients with acute decompensated congestive HF (NCT03808948).…”