The KCC24 provides a well-validated method for predicting death without transplantation in APAP-induced ALF,27 although they have been criticized for low sensitivity28 and low negative predictive value (NPV).29 KCC used an initial dataset of 310 patients to identify statistically significant prognostic indicators to distinguish survivors and nonsurvivors and used a validation set of 121 patients

to identify cutoff values associated with survival rates less than 20% for the statistically significant prognostic indicators, with no physiologically defined selleck inhibitor model of mortality. Many modifications of the KCC have been suggested,30–35 perhaps most importantly the addition of arterial lactate.36 Arterial lactate has consistently been shown to be associated with survival, although its prognostic value has been questioned.37

In contrast to other modifications of the KCC, MALD is novel because we build upon the KCC by utilizing an understanding of the dynamics of hepatocyte damage following APAP overdose in the form of a dynamic mathematical model. Hepatic necrosis is directly related to the extent of covalent binding of NAPQI to intracellular components,2, 4, 6, 7 which causes hepatocyte lysis and release of AST and ALT into the blood. This produces a characteristic time course of injury with an early rise and predictable U0126 decay of AST, ALT, and INR. We have developed a system of differential equations based on the principles of APAP-induced liver damage. All parameters in MALD were estimated from the literature, except six that were adjusted to match general properties of AST and ALT dynamics, and two that were scaled to the dosages thought to cause hepatotoxicity and death. Survival information from University of Utah patients was

not used in model development or parameterization. The equations describe how AST, ALT, and INR levels change Buspirone HCl over time as a function of overdose amount. Because these curves over time are only a function of initial overdose amount, AST, ALT, and INR levels in the model only depend on initial overdose amount and time since overdose. Our method works by fitting measured AST, ALT, and INR values to the curves described by our differential equations to estimate overdose timing and amount (Fig. 4). An outcome of death is predicted when the estimate of overdose amount is sufficiently high and the estimate of timing predicts N-Ac to be ineffectual, or when serum creatinine measurements are sufficiently high. If the outcome is predicted to be poor, liver transplantation may be the only life-saving treatment. Previous studies have not found absolute aminotransferase levels to be significant predictors of outcome in cases of APAP-induced ALF.24 This is not surprising because aminotransferase levels will be low, even with a high dose, both early and late in the course of the injury based on known mechanisms of liver damage following APAP overdose.