Statistical Multi-State Modelling of Progression from Acute Liver Failure to Intracranial Hypertension and Death

Abstract

Background and Aims: The clinical course of patients with acute liver failure (ALF) is associated with a high risk of intracranial hypertension and death. Efforts to investigate risk factors for developing intracranial hypertension (ICH) are challenged by the competing risk situation given by the high mortality. In this study we aim to identify risk factors of development of intracranial hypertension in a cohort of high-risk ALF patients by the use of multi-state modelling. Patients and methods: 44 patients (26 females) with ALF and persistent hyperammonaemia (>150 μM for 24 h) or clinical signs of ICH were included over a ten year period. Cerebral microdialysis and monitoring of intracranial pressure (ICP) was initiated while the patients were mechanically ventilated and sedated. Baseline values of ICP, arterial lactate and ammonia were measured upon inclusion. Furthermore the need for renal replacement therapy and/or vasopressors was registered. The concentration of lactate, pyruvate and glutamine was measured in the microdialysate. ICH was defined as ICP > 20 mmHg for more than one hour. Time (hours) to ICH and/or death measured from initiation of ICP-monitoring was registered. A multi-state model was fitted and covariates with discriminative power (P > 0.15) in univariate analysis were included as binary predictors. Results: A four-state model (ALF, ICH, liver transplantation (LTX) or death) was fitted and state occupation probabilities for the first seven days are given in Figure 1. An elevated baseline brain glutamine (above 3.7 mM) and ICP (above 10.6 mmHg) had significant hazard ratios (HR) related to the transition from ALF to ICP (HR 6.7 and 11.7 respectively). Baseline ammonia above 195 μM had a significant negative effect on survival in patients with ICH (HR 2.0). Conclusion: ICH and death were common complication in this selected group of patients with ALF. Baseline ICP and brain glutamine concentration were significant predictors of development of ICH. Baseline ammonia was a significant predictor of death of patients with subsequent development of ICH. The authors have none to declare.