Sensitivity and specificity of plasma disappearance rate of indocyanine green as a prognostic indicator in acute liver failure

Acute liver failure (ALF) is a rare condition in which rapid deterioration of liver function occurs in previously healthy individuals. The most prominent causes include drug-induced liver injury, viral or autoimmune hepatitis, Wilson disease, ischemia, or unknown reasons [1]. The most widely accepted definition of ALF includes evidence of coagulopathy, usually an INR ≥ 1.5, and any degree of encephalopathy in a patient without pre-existing liver disease and with an illness of <26 weeks duration [2]. Liver transplantation is the treatment of choice, but because this is only clearly justifiable in patients who would otherwise die, criteria for determining such patients have been established. Prognostic scoring systems still fail to achieve success, given the wide variety of aetiologies that lead to this end stage syndrome. The decision as to whether a patient will recover with conservative management or require transplantation has been the subject of many different reports and case series; however, the King's College Criteria remain the current standard for many clinicians [3].

Indocyanine green (ICG) is a water-soluble, inert anionic compound. After intravenous injection it mainly binds to albumin and β-lipoproteins in the plasma. ICG is not metabolized and is almost completely excreted into the bile without enterohepatic recirculation [4]. Because of these features, ICG has been studied in assessing liver function before hepatectomy, in liver transplantation donors and recipients, in patients with chronic liver failure, and in critically ill patients as a prognostic factor [5‐11]. Plasma disappearance rate of ICG (ICG-PDR) is the most commonly used ICG-derived parameter for clinical and experimental assessment of liver function and should physiologically be >18%/min [12]. ICG-PDR depends on ICG uptake by hepatocytes, its excretion into the bile, blood flow-dependent liver metabolism, and energy status. It does not represent the liver blood flow alone. There are various techniques to assess ICG-PDR in vivo. The gold standard relies on serial blood sampling after ICG injection with spectrophotometric analysis of concentration [9, 10]. However, this method is invasive, expensive and time-consuming. In contrast, a non-invasive pulsedensitometric method uses a transcutaneous system adapted from pulse oxymetry and a peripheral or central venous access for ICG injection. This method correlates well with the invasive method in hemodynamically stable and mechanically ventilated critically ill patients as well as hemodynamic unstable patients undergoing liver transplantation [13, 14].

Using ICG-PDR we measured residual liver function in patients with acute liver failure non-invasively. We evaluated the relationship between ICG-PDR and non-spontaneous recovery, to serve as a diagnostic marker to identify candidates who have to be transplanted. We then assessed the usefulness of this test by examining the correlations between the results of ICG-PDR and other markers of liver function.

Based upon the available data, the current prognostic scoring systems have not consistently demonstrated reliable accuracy in predicting outcome from ALF and the subsequent need for liver transplantation [16]. In this study we prospectively evaluated ICG-PDR in predicting outcome in 25 patients with ALF.

ICG-PDR measured at day 1 (after inclusion in the study) below 6.3%/min had a sensitivity of 85.7% and a specificity of 88.9% in predicting outcome in ALF patients. When analyzing the lowest ICG-PDR values obtained in each individual patient during the study period (day 1 to 7 or until liver transplantation, death, or discharge from intensive care unit, respectively) the sensitivity remained high, but specificity was slightly lower. Our results coincide with a previously published retrospective analysis of ICG-PDR in seven patients presenting with acute liver failure [17]. In this report ICG-PDR values greater than 5%/min were a prognostic factor for hepatic recovery. However, although in our cohort the predictive value of ICG-PDR is promising, caution has to be taken with the interpretation of single ICG-PDR measurement as ICG-PDR may vary from day to day (Figure 1). One could speculate that the observed variation of ICG-PDR values may in part be caused by an - to date speculative - additional extrahepatic ICG elimination or decay. This hypothesis is supported by the previously published observation of ICG clearance even in anhepatic patients [18]. Nevertheless, our results suggest that ICG-PDR measured early during the course of ALF is a valuable prognostic marker for predicting outcome of ALF. One advantage is its prognostic value early in the course of ALF. Thus, measurement of ICG-PDR might help to timely identify those patients with ALF who are likely to benefit from liver transplantation.

To date the most widely used criteria are the King's college criteria [3]. In a recent meta-analysis, Bailey et al. [16] compared different prognostic criteria used to determine the need for liver transplantation and found that all prognostic models presently available lack sensitivity and may miss patients requiring transplantation. In this meta-analysis King's college criteria performed best, with a sensitivity of 69% and a specificity of 92%. In our study sensitivity and specificity of King's college criteria in predicting outcome in ALF patients were 85.7% and 83.3%, and thus in the range of the results of the studies included in the meta-analysis of Bailey et al. [16]. Compared to the results obtained in the meta-analysis of Bailey et al. [16] the prognostic value of ICG-PDR in our recent study is superior to King's college criteria with respect to its sensitivity and equal with respect to its specificity. However, the evaluation of the performance of King's College criteria in our and other studies must be interpreted with care as fulfilment of the criteria has most likely influenced the clinical decision whether to transplant a patient or not. In addition the number of patients analyzed in our present study is limited. Thus, future studies in larger cohorts will have to follow.

Clinical studies in ALF patients are often limited because of heterogeneous aetiologies, the small number of cases, and difficulties in predicting the patient's outcome without transplantation. In our present study predicting the spontaneous outcome of six of the seven patients not recovering spontaneously and receiving liver transplantation can only be assumed fatal. However, as the fatal outcome in these is only an assumption and part may have survived without liver transplantation the calculated ICG-PDR test performances may be inferior to that stated.

In general, ICG removal from blood depends on liver blood flow, parenchymal cellular function and biliary excretion [19, 20]. ICG-PDR is a complex measure of both, sinusoidal perfusion as well as hepatic cell membrane function, and thus, reflects a functional reserve of intact hepatocytes which participate in maintained nutritional perfusion [21]. In our study, ICG-PDR allowed early and sensitive detection of spontaneous recovery from ALF, which might be helpful in clinical management. A non-spontaneous recovery from ALF was associated with high ICG retention rates. The advantage of the method used in our study is that ICG-PDR can be measured noninvasively at the bedside by a transcutaneous system even in critically ill patients and results can be obtained within 6-8 minutes [13]. Normal values for ICG-PDR are considered to be over 18%/min. In our study only one patient presenting with ALF had an ICG-PDR in the normal range. ICG is known to be a safe substance, as side effects are very rare (1:40000). Since ICG contains iodine, however, it should not be used in patients with iodine allergy or thyreotoxicosis.

ICG-PDG is a valuable dynamic liver function tool to predict outcome in patients suffering from ALF early during its course. Because of the possibility of its user-friendly non-invasive bedside assessment, we suggest to use ICG-PDR together with other clinical variables to monitor progress or reversal of liver failure.