C. Ronco

Acute renal failure and multiple organ dysfunction in the ICU: from renal replacement therapy (RRT) to multiple organ support therapy (MOST).

Renal replacement therapy (RRT) has evolved from the concept that we need to treat the dysfunction of a single organ (the kidney). As intensive care units have become more and more complex, it has become clear that the majority of patients with acute renal failure often have dysfunction of several other organs. In order to facilitate single organ support in this setting, continuous renal replacement therapy (CRRT) techniques have been developed. However, CRRT has opened the door to the concept that targeting renal support as the only goal of extracorporeal blood purification may be a simplistic view of our therapeutic aims. In this article we argue that it is now time to move from the simple goal of achieving adequate renal support. The proper goal of extracorporeal blood purification in ICU should be multi-organ support therapy (MOST). We explain why MOST represents the most logical future conceptual and practical evolution of CRRT and illustrates the biological rationale, supplying animal and clinical evidence that confirms the need to move rapidly in this direction theoretically, practically and technologically.

Coupled Plasma Filtration Adsorption: Rationale, Technical Development and Early Clinical Experience

The adjuvant treatment of sepsis remains a major therapeutic challenge. Blood purification is theoretically appealing if the humoral theory of sepsis is accepted as the basis for intervention. In this setting, blood purification would provide a broad-based restoration of humoral homeostasis thereby avoiding both excessive inflammation and counterinflammation. Several techniques of blood purification have been tried or are under active investigation. One of these is the so-called coupled plasma filtration adsorption (CPFA). CPFA is a novel extracorporeal blood purification therapy aimed at nonselectively reducing the circulating levels and activities of both pro- and anti-inflammatory mediators during sepsis and multiorgan failure. In vitro studies have shown CPFA to be effective in binding a broad range of such mediators proving its technical efficacy. Subsequent animal models have shown a beneficial effect on survival in endotoxemia. These studies have provided the necessary technical developments and biologic rationale for initial human studies. Two phase I/IIa clinical studies have now been performed. Both studies have shown that CPFA improves blood pressure and restores immune function in patients with severe sepsis and multiorgan dysfunction. In this article, we will discuss some of the basic principles involved in sorbent technology, and how these may contribute to treatment efficacy, review animal experiments with CPFA and finally discuss the results of recent human studies and their implications.

Phosphatemic control during acute renal failure: intermittent hemodialysis versus continuous hemodiafiltration.

Background Achieving “adequacy of dialysis” includes the maintenance of normal serum phosphate concentrations and is an important therapeutic goal in the treatment of acute renal failure (ARF). It is unknown whether this goal is best achieved with intermittent or continuous renal replacement therapy. Methods We compared the effects of continuous veno-venous hemodiafiltration (CVVHDF) and intermittent hemodialysis (IHD) on serum phosphate concentrations using daily morning blood tests in 88 consecutive intensive care patients half of which were treated with IHD and half with CRRT. Results Mean patient age was 54 ± 14 years for IHD and 60 ± 14 years for CVVHDF (NS). However, patients who received CVVHDF were more critically ill (mean APACHE II scores: 24.4 ± 5.1 for IHD vs. 29.2 ± 5.7 for CVVHDF, p<0.003). Before treatment, the serum phosphate concentration was 2.04 ± 0.16 mmoll L for IHD and 1.96 ± 0.17 mmoll L for CVVHDF (NS), with abnormal values in 79.4% of IHD patients and in 64.8% of CVVHDF patients (NS). During treatment, CVVHDF induced a greater reduction in serum phosphate (p=0.02) during the first 48 hours and conferred superior subsequent control of hyperphosphatemia (achieved in 64.6% of observations during CVVHDF vs. 41.8% during IHD; p<0.0001). The serum phosphate concentration was also more likely to be within the normal range during CVVHDF (55.3% vs.36.2%; p<0.0001). There was a trend toward more frequent hypophosphatemia (9.3% vs. 5.6%; P<0.1) during CVVHDF. Conclusions Abnormal serum phosphate concentrations are frequent in ARF patients before and during renal replacement, however, normalization of phosphatemia is achieved more frequently with CVVHDF.

Impact of spacing filaments external to hollow fibers on dialysate flow distribution and dialyzer performance.

A new type of dialyzer (PAN 650 SF Asahi) is analyzed in terms of hydraulic properties, solute clearances and dialysate flow distribution. The new type of dialyzer is a polyacrylonitrile hollow fiber filter, equipped with spacing filaments placed externally to the fibers to facilitate dialysate distribution and avoid channeling. The new filter is compared with a similar filter without spacing filaments. For this purpose, blood and dialysate side clearances have been measured in sequential dialysis session carried out randomly in the same patients. Furthermore, a last generation helical scanner (X-Press / HS1, Toshiba) has been utilized to analyze in vitro the flow distribution of dialysate inside the dialyzer. A contrast medium was injected and a sequence of images has been achieved on a longitudinal section of the dialyzer. This new method permits to avoid any bias due to the cylindrical shape of the dialyzer, since a 10 mm thick rectangular section is analyzed and not the entire body of the filter. The dialyzers equipped with spacing filaments displayed a significant improvement of the dialysate distribution as demonstrated by the radiological pattern. In detail, despite a channeling phenomenon in the peripherical region of the bundle is still present, this is remarkably reduced in comparison with the channelling phenomenon observed in the standard dialyzers. This improved distribution is confirmed by a significant improvement of the solute clearances.

Studies on Brain Density in Hemodialysis and Peritoneal Dialysis

30 patients on hemodialysis or peritoneal dialysis have been investigated by computerized tomographic (CT) scan. To evaluate possible cerebral alterations induced by dialysis, CT examinations were carried out before, immediately after and 6 h after the end of dialysis with an Evaluskop, which provides an objective precise evaluation of even slight variations in brain density. No morphological variations were noted after dialysis, while the brain density fell significantly during and after the treatment. A decrease in density was not observed in normal subjects or in patients on continuous peritoneal dialysis. The changes in the densitometric values of brain tissue suggest that there is a postdialysis gain in cerebral water linked to the intermittent treatment. CT may represent a simple reliable method for studying uremic encephalopathy and investigating the pathogenesis of the dialysis disequilibrium syndrome.

Defining death in non-heart beating organ donors

Protocols for retrieving vital organs in consenting patients in cardiovascular arrest (non-heart beating donors, NHBD) rest on the assumptions that irreversible asystole a) identifies the instant of biological death, and b) is clinically assessable at the time when retrieval of vital organs is possible. Unfortunately both assumptions are flawed. We argue that traditional life/death definitions could be actually inadequate to represent the reality of dying under intensive support, and we suggest redefining NHBD protocols on moral, social, and antrhopological criteria, admitting that irreversible (however defined) asystole can only equate a clinically determinable point of no return in the process of dying, where organ retrieval can be morally and socially accepted in previously consenting patients.

The Role of Technology in Hemodialysis

The evolution of hemodialysis therapy has been characterized over the years by the search for reliable devices and supplies, for more efficient treatments and finally for a more tolerable therapy in long term dialysis patients. In this view, three steps can be identified: a) the first step was the creation of safe and reliable vascular access, dialyzers and machines. This step led to the birth of modern dialysis and treatment personalization was the logical consequence. Each patient is a single entity and he requires a specific therapy prescription and delivery. From this concept the search for adequacy and better outcomes has been generated, with the inevitable consequence that newer techniques were explored in the attempt to perform a more efficient and clinically tolerated dialysis therapy. b) The second step was the attempt to consider the intratreatment variations as possible source for dialytic morbidity. In this view, efforts were made to pre-set ultrafiltration and dialysate sodium profiles in the machine to counterbalance the negative effects of uncontrolled water and solute removal. However, this approach failed to provide significant results, because ultrafiltration and sodium profiles were predetermined and no adaptations could be made if the designed profile was inadequate. c) The third step in the evolution of dialysis was the understanding that on-line signals from the machine and from the patients were required in order to prepare and carry out the adequate response and variation of treatment parameters. For this reason a series of sensors have been developed including urea and blood volume sensors which are offering the most important signals from the patient. In this way, accurate responses could be made during treatment and from a simple manual feedback, we have today a completely automatic form of biofeedback. The question that now arises is where to find the financial resources to afford the upcoming technology. Another question is whether this new technology should be for everybody in routine dialysis or it should be designed for specific conditions. In other words, are these toys for nice experimental studies and speculations or are they tools to improve dialytic outcomes and morbidity? Probably, technology cannot be stopped in its evolution. What is exceptional today will probably be part of the routine of tomorrow. It seems that we are struggling more with the complex physiology of human body than with mechanical or electronic problems that certainly find their solution before or after. The increasing use of computers and the evolution of the applied software will certainly help in reducing the costs and improving the performances of our newer dialysis devices.

Ultrafiltration in Patients with Hypervolemia and Congestive Heart Failure

Fluid overload may occur in patients with myocardial dysfunction and different clinical problems. Myocoardial dysfunction may be a consequence of heart dilatation with reduced contractility, ventricular stiffness with diastolic dysfunction or the consequence of myocardial injury or circulating myocardial depressant factors as seen in sepsis. In all cases, cardiac support can be achieved by the optimization of fluid balance, the reduction in organ edema and the restoration of desirable levels of pre- and afterload. Several reports have shown that myocardial elastance can improve after hemofiltration with restoration of adequate fluid balance. In such conditions, continuous extracorporeal therapy may result in remarkable cardiovascular stability with maintenance of hemodynamic parameters, including mean arterial pressure, heart rate and systemic vascular resistance. Such stability, which is achieved through the slow continuous ultrafiltration and continuous refilling of the intravascular volume from the interstitium, enables the stability of the circulating blood volume and the preservation of organ perfusion. This is also crucial for renal recovery during acute renal failure.

ADQI 7: the clinical management of the Cardio-Renal syndromes: work group statements from the 7th ADQI consensus conference

Many patients with heart failure have underlying renal dysfunction, and similarly, patients with kidney failure are prone to cardiac failure. This has led to the concept of cardio-renal syndromes, which can be an acute or chronic cardio-renal syndrome, when cardiac failure causes deterioration in renal function, or acute and/or chronic Reno-Cardiac syndrome, when renal dysfunction leads to cardiac failure. Patients who develop these syndromes have increased risk of hospital admission and mortality. Although there are clinical guidelines for managing both heart failure and chronic kidney disease, there are no agreed guidelines for managing patients with cardio-renal and/or Reno-Cardiac syndromes, as these patients have typically been excluded from clinical trials. We have therefore reviewed the currently available published literature to outline a consensus of current best clinical practice for these patients.

Rasburicase therapy in acute hyperuricemia and renal dysfunction.

Neoplastic disorders may be complicated by acute renal failure (ARF). Different tumors may cause ARF: solid tumors involving the kidney, solid tumors not of hematological origin and not primarily involving the kidney or, more frequently, rapidly developing hematological tumors. The pathogenesis of ARF is different depending on the type of cancer, but the most frequent clinical feature is the acute tumor lysis syndrome, characterized by hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia and acute, frequently oliguric, ARF. The presence of a neoplastic disorder and associated acute illness may sometimes lead to the presence of immunodysfunction, septic complications and multiple organ dysfunction. In these settings patients develop systemic inflammation and diffuse endothelial damage, related to different mediators. Among these substances, in cancer patients, high circulating levels of uric acid are a common finding. Hyperuricemia is caused by the increase of purine metabolism, which is result of the increased cellular turnover or the aggressive cancer chemotherapy regimens that worsen cell lysis and release of purine metabolites. Even if hyperuricemia is not the first insult to the kidney, its development might represent a concomitant factor aggravating other previous or simultaneous insults. The most efficient therapy for lowering uric acid is rasburicase, a recombinant form of urate oxidase, a nonhuman proteolytic enzyme that oxidizes uric acid to allantoin. It is efficacious in reducing serum uric acid levels with associated diuresis more effectively and much faster than allopurinol, and to correct renal dysfunction more rapidly than allopurinol.