Joost Wauters

Acute-on-chronic liver failure: current concepts on definition, pathogenesis, clinical manifestations and potential therapeutic interventions.

In recent years, acute-on-chronic liver failure has been recognized as a specific clinical form of liver failure associated with cirrhosis. The syndrome refers to an acute deterioration of liver function and subsequently of other end organs over a period of weeks following a precipitating event in a patient with previously well- or reasonably well-compensated cirrhosis. These precipitating events include either an indirect (e.g., variceal hemorrhage, sepsis) or a direct (e.g., drug-induced) hepatotoxic factor. The short-term mortality for this condition is more than 50%. At present, considerable efforts are ongoing to better characterize the syndrome, to gain further insight into its pathophysiology and to optimize therapy. This article aims to highlight the current concepts of these various aspects.

Critical illness evokes elevated circulating bile acids related to altered hepatic transporter and nuclear receptor expression.

Hyperbilirubinemia is common during critical illness and is associated with adverse outcome. Whether hyperbilirubinemia reflects intensive care unit (ICU) cholestasis is unclear. Therefore, the aim of this study was to analyze hyperbilirubinemia in conjunction with serum bile acids (BAs) and the key steps in BA synthesis, transport, and regulation by nuclear receptors (NRs). Serum BA and bilirubin levels were determined in 130 ICU and 20 control patients. In liver biopsies messenger RNA (mRNA) expression of BA synthesis enzymes, BA transporters, and NRs was assessed. In a subset (40 ICU / 10 controls) immunohistochemical staining of the transporters and receptors together with a histological evaluation of cholestasis was performed. BA levels were much more elevated than bilirubin in ICU patients. Conjugated cholic acid (CA) and chenodeoxycholic acid (CDCA) were elevated, with an increased CA/CDCA ratio. Unconjugated BA did not differ between controls and patients. Despite elevated serum BA levels, CYP7A1 protein, the rate‐limiting enzyme in BA synthesis, was not lowered in ICU patients. Also, protein expression of the apical bile salt export pump (BSEP) was decreased, whereas multidrug resistance‐associated protein (MRP) 3 was strongly increased at the basolateral side. This reversal of BA transport toward the sinusoidal blood compartment is in line with the increased serum conjugated BA levels. Immunostaining showed marked down‐regulation of nuclear farnesoid X receptor, retinoid X receptor alpha, constitutive androstane receptor, and pregnane X receptor nuclear protein levels. Conclusion: Failure to inhibit BA synthesis, up‐regulate canalicular BA export, and localize pivotal NR in the hepatocytic nuclei may indicate dysfunctional feedback regulation by increased BA levels. Alternatively, critical illness may result in maintained BA synthesis (CYP7A1), reversal of normal BA transport (BSEP/MRP3), and inhibition of the BA sensor (FXR/RXRα) to increase serum BA levels. (HEPATOLOGY 2011;)

Pathophysiology of renal hemodynamics and renal cortical microcirculation in a porcine model of elevated intra-abdominal pressure.

BACKGROUND Elevated intra-abdominal pressure (IAP) has been shown to impair renal perfusion and renal function. This study was designed to further investigate the effects of elevated IAP on renal venous hemodynamics and renal perfusion pressure (RPP). Another aim was to evaluate the renal cortical microcirculation by sidestream dark field (SDF) imaging in a porcine model of elevated IAP. METHODS In 11 pigs, IAP was increased stepwise while renal hemodynamics and urinary output were recorded. RPP (RPP = mean arterial pressure minus IAP) and renal filtration gradient (RFG = mean arterial pressure minus 2xIAP) were calculated. Renal cortical microcirculatory perfusion was assessed by calculating the microvascular flow index (MFI) based on SDF data. RESULTS With IAP elevated to 30 mm Hg, renal arterial and venous flow decreased in parallel by 34% (p < 0.05) and RPP decreased by 12% (p < 0.05). With increasing IAP, renal vascular resistance increased and MFI decreased significantly. RFG showed a moderate correlation with renal blood flow (r = 0.39, p < 0.05) and MFI (r = 0.46, p < 0.005), whereas RPP did not. CONCLUSIONS In a porcine model of IAP-induced renal impairment, we observed a parallel decrease in renal venous and arterial blood flow together with blood flow redistribution away from the kidney. SDF imaging was used for the first time to assess renal cortical microcirculation and MFI was found to decrease with increasing IAP. RFG, as a clinical estimator of renal perfusion, correlated moderately with renal blood flow and microcirculatory perfusion, whereas RPP did not. Increased renal vascular resistance with elevated IAP might account for this.

The Effect of Strict Blood Glucose Control on Biliary Sludge and Cholestasis in Critically Ill Patients

BACKGROUND AND AIMS Cholestatic liver dysfunction and biliary sludge are common problems in critically ill patients. No specific strategies have been described to prevent cholestasis and biliary sludge in the intensive care unit (ICU). We examined liver dysfunction and biliary sludge prospectively in a large medical long-stay ICU population and hypothesized that tight glycemic control with intensive insulin therapy (IIT) reduces cholestasis and biliary sludge. METHODS This study was a preplanned subanalysis of 658 long-stay (at least a fifth day) ICU patients out of a large randomized controlled trial (n = 1200), studying the effects of IIT on the outcome of medical critical illness. Patients were allocated to either IIT (glycemia 80-110 mg/dl) or conventional insulin therapy (CIT) requiring insulin above a glycemia of 215 mg/dl. Different patterns of liver dysfunction were studied based on daily blood sample analysis, and biliary sludge was evaluated by ultrasonography. RESULTS On admission, cholestasis was present in 17% of patients (n = 649), increasing to 20% on d 10 (n = 347), whereas ischemic hepatitis decreased from 3.4% (n = 588) to less than 1% (n = 328). IIT significantly decreased biliary sludge on d 5 (50.4 vs. 66.4%, P = 0.01; n = 250). The difference did not remain significant on d 10 (57.4 vs. 66.2%, P = 0.29; n = 136). IIT also lowered the cumulative risk of cholestasis (P = 0.03). CONCLUSIONS Cholestatic liver dysfunction and biliary sludge are very common during prolonged critical illness but are significantly reduced by IIT.

What is the best animal model for ACS

Abstract Introduction: Current treatment of the abdominal compartment syndrome (ACS) is based on consensus definitions but several questions regarding fluid regime or critical level of intra-abdominal hypertension (IAH)) remain unsolved. It is questionable whether these issues can be addressed in prospective randomized trials in the near future. This review aimed to summarize current animal models and to outline requirements for the best model. Methods: PubMed® data base was searched for articles describing animal models of ACS. Results: 25 articles were found. ACS in animals has not been defined yet. Investigations varied considerably regarding the experimental design. Animals were rats, rabbits, dogs and pigs with a bodyweight from 200g to 70 kg. IAP increase varied from 20 to 50 mmHg. The time period of IAH ranged between 30 min and 24h. The time between the IAH insult and organ dysfunction varied between 15 min and 18h. Investigations demonstrated that IAH is able to induce loss of intravascular volume, organ hypoperfusion, ischemic organ damage and multiple organ failure within 4 to 6h. Conclusion: In contrast to IAH or pneumoperitoneum for surgical exposure, ACS in an animal may be stated if an artificially increased IAP leads to circulatory, respiratory and renal insufficiency. A next step in animal research would be the development of a “pathological” model in which haemorrhage or systemic inflammation together with resuscitation lead to abdominal fluid accumulation and increased intra-abdominal pressure.

Relationship between Abdominal Pressure, Pulmonary Compliance, and Cardiac Preload in a Porcine Model

Rationale. Elevated intra-abdominal pressure (IAP) may compromise respiratory and cardiovascular function by abdomino-thoracic pressure transmission. We aimed (1) to study the effects of elevated IAP on pleural pressure, (2) to understand the implications for lung and chest wall compliances and (3) to determine whether volumetric filling parameters may be more accurate than classical pressure-based filling pressures for preload assessment in the setting of elevated IAP. Methods. In eleven pigs, IAP was increased stepwise from 6 to 30 mmHg. Hemodynamic, esophageal, and pulmonary pressures were recorded. Results. 17% (end-expiratory) to 62% (end-inspiratory) of elevated IAP was transmitted to the thoracic compartment. Respiratory system compliance decreased significantly with elevated IAP and chest wall compliance decreased. Central venous and pulmonary wedge pressure increased with increasing IAP and correlated inversely (r = −0.31) with stroke index (SI). Global end-diastolic volume index was unaffected by IAP and correlated best with SI (r = 0.52). Conclusions. Increased IAP is transferred to the thoracic compartment and results in a decreased respiratory system compliance due to decreased chest wall compliance. Volumetric filling parameters and transmural filling pressures are clearly superior to classical cardiac filling pressures in the assessment of cardiac preload during elevated IAP.

The use of bio-electrical impedance analysis (BIA) to guide fluid management, resuscitation and deresuscitation in critically ill patients: a bench-to-bedside review

The impact of a positive fluid balance on morbidity and mortality has been well established. However, little is known about how to monitor fluid status and fluid overload. This narrative review summarises the recent literature and discusses the different parameters related to bio-electrical impedance analysis (BIA) and how they might be used to guide fluid management in critically ill patients. Definitions are listed for the different parameters that can be obtained with BIA; these include among others total body water (TBW), intracellular water (ICW), extracellular water (ECW), ECW/ICW ratio and volume excess (VE). BIA allows calculation of body composition and volumes by means of a current going through the body considered as a cylinder. Reproducible measurements can be obtained with tetrapolar electrodes with two current and two detection electrodes placed on hands and feet. Modern devices also apply multiple frequencies, further improving the accuracy and reproducibility of the results. Some pitfalls and conditions are discussed that need to be taken into account for correct BIA interpretation. Although BIA is a simple, noninvasive, rapid, portable, reproducible, and convenient method of measuring body composition and fluid distribution with fewer physical demands than other techniques, it is still unclear whether it is sufficiently accurate for clinical use in critically ill patients. However, the potential clinical applications are numerous. An overview regarding the use of BIA parameters in critically ill patients is given, based on the available literature. BIA seems a promising tool if performed correctly. It is non-invasive and relatively inexpensive and can be performed at bedside, and it does not expose to ionising radiation. Modern devices have very limited between-observer variations, but BIA parameters are population-specific and one must be aware of clinical situations that may interfere with the measurement such as visible oedema, nutritional status, or fluid and salt administration. BIA can help guide fluid management, resuscitation and de-resuscitation. The latter is especially important in patients not progressing spontaneously from the Ebb to the Flow phase of shock. More research is needed in critically ill patients before widespread use of BIA can be suggested in this patient population.

ABDOMINO-THORACIC TRANSMISSION DURING ACS: FACTS AND FIGURES

Abstract Elevated intra-abdominal pressure (IAP) exerts effects not only on intra-abdominal organs, but also on organs distant to the abdominal compartment. Abdomino-thoracic interaction during intra-abdominal hypertension (IAH) or abdominal compartment syndrome (ACS) interferes with pulmonary, cardiovascular and cerebral function. In accordance with recent guidelines, IAH is defined as IAP above 12 mmHg and ACS as IAP more than 20 mmHg with one or more new organ failures. In this review we will first discuss the effects of elevated IAP on pulmonary dynamics and the relevance for interpreting airway pressures and adjusting ventilator settings. We will then discuss the interaction between abdomino-thoracic pressure transmission and global haemodynamics, the knowledge of which is necessary for correct assessment of cardiac preload and to optimize fluid therapy in the setting of IAH/ACS. A discussion on the relationship between increased IAP, increased intracranial pressure (ICP) and decreased cerebral perfusion pressure (CPP) will follow. Finally, we will review ventilator-induced thoracic pressure swings and their transmission to the abdominal compartment.

Protein-Binding Characteristics of Voriconazole Determined by High-Throughput Equilibrium Dialysis

Plasma protein binding (PPB) can possibly alter the already variable pharmacokinetics of voriconazole. Voriconazole PPB was determined only once, being 58%, according to equilibrium dialysis (ED). We investigated voriconazole PPB more in detail, with a convenient and newer high-throughput ED assay (HT-ED), in human blank plasma spiked with voriconazole and in plasma from intensive care unit (ICU) patients treated with voriconazole. HT-ED was conducted in a 96-well plate, setup against phosphate-buffered saline. Voriconazole concentrations were measured by liquid chromatography-tandem mass spectrometry. The median PPB was 47.6% [interquartile range (IQR) 45.3%-50%] in vitro, and 49.6% (IQR 42.5%-52.5%) in ICU samples (p = 0.35), and is not depending on total voriconazole concentration (0.7-11.2 mg/L, p = 0.65). The drug mainly binds to albumin (25.5 ± 5.1%), and to a lesser extent to α-1-acid glycoprotein (AAG; 4.8 ± 1.2%). The HT-ED assay can be performed at 37 °C or 25 °C (p = 0.44) and in batch: PPB variations during freeze-thaw cycles (p = 0.13) and during frozen storage up to 12 months (p = 0.10) were not clinically relevant. Voriconazole PPB is approximately 50%, according to HT-ED. As albumin and AAG only account for approximately 30% of total voriconazole PPB, other plasma components could influence PPB and therefore efficacy or toxicity because of variations in unbound fractions.

Impact of hypoalbuminemia on voriconazole pharmacokinetics in critically ill adult patients.

ABSTRACT Setting the adequate dose for voriconazole is challenging due to its variable pharmacokinetics. We investigated the impact of hypoalbuminemia (<35 g/liter) on voriconazole pharmacokinetics in adult intensive care unit (ICU) patients treated with voriconazole (20 samples in 13 patients) as well as in plasma samples from ICU patients that had been spiked with voriconazole at concentrations of 1.5 mg/liter, 2.9 mg/liter, and 9.0 mg/liter (66 samples from 22 patients). Plasma albumin concentrations ranged from 13.8 to 38.7 g/liter. Total voriconazole concentrations in adult ICU patients treated with voriconazole ranged from 0.5 to 8.7 mg/liter. Unbound and bound voriconazole concentrations were separated using high-throughput equilibrium dialysis followed by liquid chromatography-tandem mass spectrometry (LC-MSMS). Multivariate analysis revealed a positive relationship between voriconazole plasma protein binding and plasma albumin concentrations (P < 0.001), indicating higher unbound voriconazole concentrations with decreasing albumin concentrations. The correlation is more pronounced in the presence of elevated bilirubin concentrations (P = 0.05). We therefore propose to adjust the measured total voriconazole concentrations in patients with abnormal plasma albumin and total serum bilirubin plasma concentrations who show adverse events potentially related to voriconazole via a formula that we developed. Assuming 50% protein binding on average and an upper limit of 5.5 mg/liter for total voriconazole concentrations, the upper limit for unbound voriconazole concentrations is 2.75 mg/liter. Alterations in voriconazole unbound concentrations caused by hypoalbuminemia and/or elevated bilirubin plasma concentrations cannot be countered immediately, due to the adult saturated hepatic metabolism. Consequently, increased unbound voriconazole concentrations can possibly cause adverse events, even when total voriconazole concentrations are within the reference range.