Modeling ¹⁸F-FDG Kinetics during Acute Lung Injury: Experimental Data and Estimation Errors

Background: There is increasing interest in Positron Emission Tomography (PET) of 2-deoxy-2-[18F]flouro-D-glucose (¹⁸F-FDG) to evaluate pulmonary inflammation during acute lung injury (ALI). We assessed the effect of extra-vascular lung water on estimates of ¹⁸F-FDG-kinetics parameters in experimental and simulated data using the Patlak and Sokoloff methods, and our recently proposed four-compartment model. Methodology/Principal Findings: Eleven sheep underwent unilateral lung lavage and 4 h mechanical ventilation. Five sheep received intravenous endotoxin (10 ng/kg/min). Dynamic ¹⁸F-FDG PET was performed at the end of the 4 h period. ¹⁸F-FDG net uptake rate (Ki), phosphorylation rate (k₃), and volume of distribution (F_e) were estimated in three isogravitational regions for each method. Simulations of normal and ALI ¹⁸F-FDG-kinetics were conducted to study the dependence of estimated parameters on the transport rate constants to (k₅) and from (k₆) the extra-vascular extra-cellular compartment. The four-compartment model described 85.7% of the studied ¹⁸F-FDG-kinetics better than the Sokoloff model. Relative to the four-compartment model the Sokoloff model exhibited a consistent positive bias in Ki (3.32 [1.30-5.65] 10^-4/min, p<0.001) and showed inaccurate estimates of the parameters composing Ki (k₃ and F_e), even when Ki was similar for those methods. In simulations, errors in estimates of Ki due to the extra-vascular extra-cellular compartment depended on both k₅ and k₅/k₆, with errors for the Patlak and Sokoloff methods of 0.02 [-0.01-0.18] and 0.40 [0.18-0.60] 10^-3/min for normal lungs and of -0.47 [-0.89-0.72] and 2.35 [0.85-3.68] 10^-3/min in ALI. Conclusions/Significance: ¹⁸F-FDG accumulation in lung extra-vascular fluid, which is commonly increased during lung injury, can result in substantial estimation errors using the traditional Patlak and Sokoloff methods. These errors depend on the extra-vascular extra-cellular compartment volume and its transport rates with other compartments. The four-compartment model provides more accurate quantification of ¹⁸F-FDG-kinetics than those methods in the presence of increased extra-vascular fluid.