Hepatic PPARs: their role in liver physiology, fibrosis and treatment.

Complex molecular and cellular mechanisms are involved in the pathway of liver fibrosis. Activation and transformation of hepatic stellate cells (HSCs) are considered the two main reasons for the cause and development of liver fibrosis. The peroxisome proliferator-activated receptors (PPARs) belonging to the family of ligand-activated transcription factors play a key role in liver homeostasis, regulating adipogenesis and inhibiting fibrogenesis in HSCs. Normal transcriptional function of PPARs contributes to maintain HSCs in quiescent phase. A reduced expression of PPARs in HSCs greatly induces a progression of liver fibrosis and an increased production of collagen. Here, we discuss role and function of PPARs and we take into consideration molecular factors able to reduce PPARs activity in HSCs. Finally, although further validations are needed, we illustrate novel strategies available from in vitro and animal studies on how some PPARs-agonists have been proved effective as antifibrotic substances in liver disease.

Prospective multicenter study on epidemiology of acute kidney injury in the ICU: a critical care nephrology Italian collaborative effort (NEFROINT).

Acute kidney injury (AKI) is an independent risk factor for mortality in critically ill patients whose epidemiology has been made unclear in the past by the use of different definitions across various studies. The RIFLE consensus definition has provided a unifying definition for AKI leading to large retrospective studies in different countries. The present study is a prospective observational multicenter study designed to prospectively evaluate all incident admissions in 10 Intensive Care Units (ICUs) in Italy and the relevant epidemiology of AKI. A simple user-friendly web-based data collection tool was created with the scope to serve for this study and to facilitate future multicenter collaborative efforts. We enrolled 601 consecutive patients into the study; 25 patients with End-Stage Renal Disease were excluded leaving 576 patients for analysis. The median age was 66 (IQR 53-76) years, 59.4% were male, while median SAPS II and APACHE II scores were 43 (IQR 35-54) and 18 (IQR 13-24), respectively. The most common diagnostic categories for ICU admission were: respiratory (27.4%), followed by neurologic (17%), trauma (14.4%), and cardiovascular (12.1%). Crude ICU and hospital mortality were 21.7% and median ICU length of stay was 5 days (IQR 3, 14). Of 576 patients, 246 patients (42.7%) had AKI within 24 hours of ICU admission while 133 developed new AKI later during their ICU stay. RIFLE-initial class was Risk in 205 patients (54.1%), Injury in 99 (26.1%) and Failure in 75 (19.8%). Progression of AKI to a worse RIFLE class was seen in 114 patients (30.8% of AKI patients). AKI patients were older, with higher frequency of common risk factors. 116 AKI patients (30.6%) fulfilled criteria for sepsis during their ICU stay, compared to 33 (16.7%) of non-AKI patients (P<0.001). 48 patients (8.3%) were treated with renal replacement therapy (RRT) in the ICU. Patients were started on RRT a median of 2 (IQR 0-6) days after ICU admission. Among AKI patients, they were started on RRT a median of 1 (IQR 0-4) days after fulfilling criteria for AKI. Median duration of RRT was 5 (IQR 2-10) day. AKI patients had a higher crude ICU mortality (28.8% vs. non-AKI 8.1%, P<0.001) and longer ICU length of stay (median 7 days vs. 3 days [non-AKI], P<0.001). Crude ICU mortality and ICU length of stay increased with greater severity of AKI. Two hundred twenty five patients (59.4% of AKI patients) had complete recovery of renal function, with a SCr at time of ICU discharge which was ≤120% of baseline; an additional 51 AKI patients (13.5%) had partial renal recovery, while 103 (27.2%) had not recovered renal function at the time of death or ICU discharge. Septic patients had more severe AKI, and were more likely to receive RRT with less frequency of renal function recovery. Patients with sepsis had higher ICU mortality and longer ICU stay. The study confirms previous analyses describing RIFLE as an optimal classification system to stage AKI severity. AKI is indeed a deadly complication for ICU patients where the level of severity correlated with mortality and length of stay. The tool developed for data collection resulted user friendly and easy to implement. Some of its features including a RIFLE class alert system, may help the treating physician to collect systematically AKI data in the ICU and possibly may guide specific decision on the institution of renal replacement therapy.

End of life in the Intensive Care Unit.

A bio-social revolution has been prompted by the capacity of artificial organ support technology to effectively sustain and/or replace many of the functions of vital organs. The consequent possibility of manipulating the dying process has generated many problems, which range from the necessity of rationing scarce and expensive resources to the definition of optimal care for dying people and the necessity of redefining death itself. In all of these situations, facts and values are strictly interconnected, and actions should be accompanied by careful bioethical reflection. In this text, we will briefly explore these issues in an attempt to illustrate the main problems related to the management of end-of-life care in the intensive care environment. We also present the protocol we use to make and implement difficult end-of-life decisions in our intensive care unit.

[A pilot study comparing pulse high volume hemofiltration (pHVHF) and coupled plasma filtration adsorption (CPFA) in septic shock patients]. / Coupled plasma filtration adsorption (CPFA) versus emofiltrazione continua con regime intermittente di alti volumi (pHVHF) nel trattamento dello shock settico: uno studio pilota.

High-volume hemofiltration (HVHF) and coupled plasma filtration adsorption (CPFA) have shown potential to improve the treatment of sepsis in animals, but there have been no studies comparing these two treatments in humans. Our aim was to compare the hemodynamic effects of HVHF and CPFA in septic shock patients with acute kidney injury (AKI) undergoing continuous renal replacement therapy (CRRT). We performed a cross-over study enrolling patients with septic shock and AKI who were receiving CRRT. Patients were treated with pulse HVHF and continuous veno-venous hemofiltration (CVV H) on day 1 and CPFA and CVV H on day 2 or vice versa. HVHF was performed for 8-10 hours with a replacement fluid rate of 85 mL/kg/h. CPFA was performed for 8-10 hours with a plasma flow rate of 15%. CVV H was performed for the rest of the day with a replacement fluid rate of 35 mL/kg/h. The primary endpoints were changes in mean arterial pressure, vasopressor requirement (expressed as vasopressor score, VS), and noradrenaline dose after pulse HVHF and CPFA. The two treatments were compared using nonparametric tests. We enrolled 8 patients (median age 70.5 years, SOFA 12.5, SAPS II 69.5). There was a trend towards a reduction in VS with HVHF and CPFA (HVHF p=0.13, CPFA p<0.05). There was no significant difference between the two treatments in terms of percentage change in VS score (p=0.22). The data from this pilot study provide no evidence for a difference in hemodynamic effects between pulse HVHF and CPFA in patients with septic shock already receiving CRRT. A larger sample size is needed to adequately explore this issue.

The epidemiology of cardiac surgery-associated acute kidney injury.

PURPOSE: To describe current knowledge on the epidemiology of cardiac surgery-associated acute kidney injury (CSA-AKI) and to formulate recommendations for clinical practice and a research agenda. METHODS: After a modified Delphi analysis by the Acute Dialysis Quality Initiative (ADQI), 4 questions on the epidemiology of CSA-AKI and recommendations for clinical practice and a research agenda were formulated and addressed. RESULTS: Existing studies on CSA-AKI use over 35 different definitions for CSA-AKI. In addition, there may be important differences in patient characteristics and procedures. This explains the significant variations in reported incidence. Most studies report on CSA-AKI as defined by the need for renal replacement therapy. However, even small decreases in kidney function are associated with a worsened outcome. The workgroup formulated the recommendation to use the AKIN consensus criteria for AKI. One should differentiate early CSA-AKI, caused by the procedure, and late CSA-AKI, associated with the procedure. There may be different clinical scenarios: acute on chronic CSA-AKI, AKI prior to CS, and AKI occurring post CS. Risk factors should be differentiated between pre-, intra-, and post-CS, and between patient-, process-, and procedure-related. Endpoints should include both short-term and long-term outcomes. CONCLUSIONS: Existing data on the epidemiology of CSA-AKI are difficult to compare due to variations in definition and patient cohort. A modified Delphi analysis resulted in a series of recommendations for future research on CSA-AKI.

First clinical trial for a new CRRT machine: the Prismaflex.

A new CRRT machine has been designed to fulfill the expectations of nephrologists and intensivists operating in the common ground of critical care nephrology. The new equipment is called "Prismaflex" (Gambro-Dasco, Mirandola, Modena) and it is the natural evolution of the Prisma machine that has been utilized worldwide for CRRT in the last decade. We performed a preliminary "alfa trial" to establish usability, flexibility and realiability of the new device. Accuracy was also tested by recording various operational parameters during different intermittent and continuous renal replacement modalities. Forty-one runs were conducted on 13 patients and the difference between delivered and prescribed parameters was always lower than 2%. We concluded that the new Prismaflex is a well designed new machine for CRRT and can be safely and effectively utilized in the critical care nephrology setting.

When the ICU patient refuses vital supports.

The aim of this paper is to discuss the problem of caring for ICU patients who request forgoing of intensive supports; in particular, evaluating their competence and building effective relationships among the patients themselves, their relatives and the health care team. The histories of 2 adult competent ICU patients 2 asked that vital intervention be forgone are presented, together with the discussion of problems posed by such a request and of possible solutions which respect patients' autonomy and bystanders needs. These patients were hospitalized in an Italian general 14 bed ICU. The patients' request were weighted against their prognosis and their view of life, in order to evaluate their reliability. Also the refusal of either treatment or outcome was evaluated, in order to effectively safeguard the patients' interests. The request of one patient was satisfied and he was allowed to die, after all the involved people had understood and accepted the final decision. The second patient, who was somehow forced to undergo intensive treatment, is alive and satisfied with having been cured. In Italy too, autonomy is an increasingly applied principle in end-of-life decisions in ICUs. It is usually tempered by a consideration about the patients' best interest as perceived by involved bystanders.

Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial.

BACKGROUND: Continuous veno-venous haemofiltration is increasingly used to treat acute renal failure in critically ill patients, but a clear definition of an adequate treatment dose has not been established. We undertook a prospective randomised study of the impact of different ultrafiltration doses in continuous renal replacement therapy on survival. METHODS: We enrolled 425 patients, with a mean age of 61 years, in intensive care who had acute renal failure. Patients were randomly assigned ultrafiltration at 20 ml/h-1/kg(-1) (group 1, n = 146), 35 ml/h(-1)/kg(-1) (group 2, n = 139), or 45 ml/h(-1)/ kg(-1) (group 3, n = 140). The primary endpoint was survival at 15 days after stopping haemofiltration. We also assessed recovery of renal function and frequency of complications during treatment. Analysis was by intention to treat. RESULTS: Survival in group 1 was significantly lower than in groups 2 (p = 0.0007) and 3 (p = 0.0013). Survival in groups 2 and 3 did not differ significantly (p = 0.87). Adjustment for possible confounding factors did not change the pattern of differences among the groups. Survivors in all groups had lower concentrations of blood urea nitrogen before continuous haemofiltration was started than non-survivors. 95%, 92% and 90% of survivors in groups 1, 2 and 3, respectively, had full recovery of renal function. The frequency of complications was similarly low in all groups. INTERPRETATION: Mortality among these critically ill patients was high, but increase in the rate of ultrafiltration improved survival significantly We recommend that ultrafiltration should be prescribed according to patient's bodyweight and should reach at least 35 ml/h(-1)/kg(-1).

Assessment of adequacy of ICU admission.

BACKGROUND: Direct costs of critical care are increasing more than in other health care sectors. Tools are needed to evaluate adequacy of ICU admission in order to have a proper allocation of ICU resources. OBJECTIVE: evaluation of different ways used to assess adequacy of ICU admission. STUDY TYPE: 12 months prospective descriptive study. SETTING: 24 Intensive Care beds of a 1000 beds tertiary hospital in Italy. PATIENTS: 2314 patients admitted to Cardiac Surgery, General and Postoperative Intensive Care Units. INTERVENTIONS: all patients admitted to the ICUs were studied. Information was collected for the patients' age, source of admission, diagnoses, surgical status, reason for admission, SAPS II score, NEMS daily score, LOS, ICU outcome. The number of available beds (ventilated or not) and nurse working hours were obtained. RESULTS: 2373 patients were admitted to the ICs, with an overall readmission rate of 2.5%, and a total amount of 8084 NEMS record. The mean Work Utilization Ratio was significantly different between the three IC and between working and weekend days in PACU and CSU. The 49.7% of the NEMS points is scored by the SAPS II 43-78 patients, corresponding to the 29.2% of >24 h admissions. The level of care provided and the trend of each admission was derived from NEMS score according to Iapichino. The proportion of HT records in each IC was 88.3% in ICU, 73.1% in PACU and 91.2% in CSU; the outcome (dead/discharged) was significantly different between LT and HT. CONCLUSIONS: Despite the difficulties imposed by he rigid nurses' work organization in Italy, a daily data collection about level of care, severity of illness, workload utilization could provide, together with standard administrative indexes, the necessary framework to assess and to improve adequacy of ICU admission.

Principles, protocols and patients: the practical management of a limit in ICU.

The definition and management of a limit is a common but sometimes extremely complex problem in the Intensive Care Unit (ICU). Guidelines and consensus documents have been published in order to help clinicians. Yet, many controversial issues are brought into question. Legal rules are sometimes vague and derive more from the interpretation of various and unrelated principles (which vary from country to country) than from a clear ad hoc law. In this sense, the practical management of a limit in ICU is usually run by a dual normativity: an external one, which derives from the cultural, moral and legal values of the society, and an internal one, which depends on the particular clinical and human situation, namely the values of everybody involved in (the patient, his/her relatives, the health staff) and the relationships among these people. The considerable freedom left for the decision by an open communication is a great and favourable potential which must be used in the interest of the patient's and of his/her family.

Adsorption in sepsis.

The pathophysiology of sepsis offers a highly complicated scenario. In sepsis, endotoxin or other gram-positive-derived products induce a complex and dynamic cellular response, giving rise to several mediators known to be relevant in the pathogenesis of septic shock such as specific mediators, substances responsible for up- or down-regulation of cytokine receptors and cytokine antagonists, inactivators of translational or transductional pathways, and precursor molecules. In this review, we delve into some new concepts stemming up from the use of sorbents in continuous plasma filtration. Nonspecific simultaneous removal of several mediators of the inflammatory cascade have led to improved outcomes in animal models of septic shock and to improved hemodynamics in a pilot clinical study. It seems of great importance to explore all possible treatment techniques that may have a direct impact on circulating mediators of sepsis and that also may interfere with the imbalance between proinflammatory and anti-inflammatory substances in the critically ill patient with multiple organ failure. In this view, the application of sorbents appears to open new and interesting therapeutic options. The search for innovative treatments specifically targeted to the special needs of the critically ill patients seems therefore more important than the attempt to adjust concepts and technologies that are normally applied to patients with chronic renal failure.

Effects of different doses in continuous veno-venous haemofiltration on outcomes of acute renal failure: a prospective randomised trial.

BACKGROUND: Continuous veno-venous haemofiltration is increasingly used to treat acute renal failure in critically ill patients, but a clear definition of an adequate treatment dose has not been established. We undertook a prospective randomised study of the impact different ultrafiltration doses in continuous renal replacement therapy on survival. METHODS: We enrolled 425 patients, with a mean age of 61 years, in intensive care who had acute renal failure. Patients were randomly assigned ultrafiltration at 20 mL h(-1) kg(-1) (group 1, n=146), 35 mL h(-1) kg(-1) (group 2, n=139), or 45 mL h(-1) kg(-1) (group 3, n=140). The primary endpoint was survival at 15 days after stopping haemofiltration. We also assessed recovery of renal function and frequency of complications during treatment. Analysis was by intention to treat. RESULTS: Survival in group 1 was significantly lower than in groups 2 (p=0.0007) and 3 (p=0.0013). Survival in groups 2 and 3 did not differ significantly (p=0.87). Adjustment for possible confounding factors did not change the pattern of differences among the groups. Survivors in all groups had lower concentrations of blood urea nitrogen before continuous haemofiltration was started than non-survivors. 95%, 92%, and 90% of survivors in groups 1, 2, and 3, respectively, had full recovery of renal function. The frequency of complications was similarly low in all groups. INTERPRETATION: Mortality among these critically ill patients was high, but increase in the rate of ultrafiltration improved survival significantly. We recommend that ultrafiltration should be prescribed according to patient's bodyweight and should reach at least 35 mL h(-1) kg(-1).

Bioethical issues related to continuous renal replacement therapy in intensive care patients.

OBJECTIVE: To examine the ethical approach of intensivists and nephrologists to continuous renal replacement therapy (CRRT). DESIGN: A questionnaire. SETTING: The First International Course on Critical Care Nephrology. PARTICIPANTS: The participants in the course (around 500). RESULTS: Most participants think that establishing ethical criteria for managing CRRT is a medical task, as clinicians have adequate criteria for defining futility. However, many responders would grant the request of starting futile CRRT or would maintain it if requested by the family. Only 55% believe that informed consent is necessary for initiating CRRT; one out of four would start or maintain unwanted life-saving CRRT. In case of lack of equipment, the majority would select the patients, excluding the worst one or on a "first-come, first-served" basis. Withholding and withdrawing are regarded differently by most responders. Again, most think that every vital support should be withdrawn when futile, but practical and psychological aspects still influence the final decision. Responders think that ethics critical care committees can help in the management of ethical problems in ICU. CONCLUSIONS: Our results show that several ethical questions are still unsolved and that practical and psychological aspects of the treatment process can be stronger than bioethical principles.

Use of adsorptive mechanisms in continuous renal replacement therapies in the critically ill.

The pathophysiology of sepsis is becoming a more complicated scenario. In sepsis, endotoxin or other gram-positive derived products induce a complex and dynamic cellular response giving rise to several mediators known to be relevant in the pathogenesis of septic shock, such as specific mediators. substances responsible for up- or down-regulation of cytokine receptors and cytokine antagonists, inactivators of nuclear factor-kappaB or signal transduction pathways, and precursor molecules. In this article, we delve into some new concepts stemming from the use of sorbents in continuous plasma filtration. The rationale is based on the assumption that the nonspecific removal of several mediators of the inflammatory cascade and cytokine network may improve outcome in a rabbit model of septic shock and hemodynamics in a pilot clinical study. The importance of looking for innovative treatments specifically targeted for the special needs of the critically ill patients rather than using concepts and technology applied to the treatment of chronic renal failure is underlined.

Present and future options in continuous renal replacement therapies of sepsis and MOF.

Conventional continuous extracorporeal treatments such as hemofiltration and hemodiafiltration have not achieved significant reduction in cytokine plasma levels, in spite of their increasing popularity mainly related to the unnecessary fluid restriction thereby rendering adequate caloric intake possible (Actualités Nephrologiques, 1994). This is mainly due to reduced filtration, to saturability of the adsorption-related phenomena and to the absence of a convective mass transfer. New approaches have been more recently introduced. The concept of blood purification has been applied in some new innovative techniques that use non-selective or selective sorbents. We will focus on the criteria used by others and us to assess the efficiency in vitro and in animal models of sepsis of more recently introduced non-selective and selective devices. Among the innovative techniques, modalities aimed at the plasma treatment will receive emphasis. These modalities that are based on plasma filtration with the use of different sorbents. The preliminary results obtained from ongoing clinical trials will be presented. We will also expand on the technical, biological and clinical aspects that should be addressed in order to establish a new modality as innovative in the treatment of sepsis.