Critically ill patients with acute kidney injury (AKI) present high mortality rates. The magnitude of inflammatory response could determine the prognosis of such patients. Continuous renal replacement therapy (CRRT) may play an important role in removing inflammatory mediators in patients with AKI.

To investigate whether the magnitude of inflammatory mediator's removal is associated with mortality among critically ill patients on CVVHDF, a CRRT modality.

This study consisted of 64 critically ill patients requiring CVVHDF. Plasma levels of C3a, TNF-α, IL-10, IL-6, IL-1β, sTNFRI and sTNFRII were determined by enzyme-linked immunosorbent assay (ELISA) at the beginning of CVVHDF and after 24h (outlet). Clearance of cytokines during the first 24h of CVVHDF was calculated. Clinical and laboratory data were acquired from patient's records data.

Mean age of patients requiring CVVHDF was 63years, 67.2% were men and 87.3% were Caucasian. Thirty-five (35) patients (54.7%) died. Comparing non-survivors with the group of survivors we observed higher incidence of sepsis (68.6 versus 37.9%, p<0.05), higher APACHE II score (34.8±7.6 versus 29.2±7.1, p<0.05) and higher lactate levels (23.2±17.6 versus 16.4±6.6, p<0.05). According to the inter-tertile range of TNF-α clearance (ITR1 (<0.54); ITR2 (0.54-2.93); ITR3 (>2.93)) we found that those patients with higher TNF-α removal by RRT (ITR3) had a better survival. Multivariable analysis showed that lower clearance of TNF-α remained independently associated with high mortality after adjustment for sex, age, use of vasoactive drugs, APACHE II score sepsis, creatinine and lactate before CVVHDF (HR: 0.179, 95% IC: 0.049-0.661, p<0.01).

The attenuation of inflammatory response may be related to the lower mortality observed on those patients with higher TNF-α removal by CVVHDF.

Therapeutic plasma exchange (TPE) is an extracorporeal blood purification technique designed for the removal of large molecular weight substances. Examples of these substances include pathogenic autoantibodies, immune complexes, cryoglobulins, myeloma light chains, endotoxin and cholesterol containing lipoproteins. The basic premise of the treatment is that removal of these substances will allow for the reversal of the pathologic processes related to their presence. This review will cover the techniques for performing TPE, the kinetics of the removal of large molecules from the plasma and the benefits and risks of the different types of replacement fluids.

Attempts at achieving cytokine homeostasis include blood purification to deliver cytokine removal. Assessment of ex vivo studies for optimal operating conditions is a vital step.

We conducted a systematic search for ex vivo studies on cytokine removal using known modalities of extracorporeal circulation. We selected 29 articles and analyzed data according to clearance, sieving coefficient, ultrafiltrate concentration and percentage removal.

We identified four main techniques for cytokine removal: standard techniques, high cut-off (HCO) techniques, adsorption techniques and combined plasma filtration adsorption. HCO hemofiltration (HCO/HF) showed greatest consistency in cytokine removal among all approaches. Mean albumin clearance with HCO filters was 3.74 ml/min.

Ex vivo data support the view that HCO/HF is the most consistently effective approach in terms of sieving and clearance. Further investigation of HCO/HF in randomized controlled trials in animal models and humans seems desirable.

We hypothesized that the use of hemofiltration (HF) to reduce cytokines may attenuate the hyperbilirubinemia that often develops after left ventricular assist system (LVAS) implantation. Four patients with hyperbilirubinemia after LVAS implantation underwent HF continuously for 7 days. Blood samples were collected and the serum concentrations of total bilirubin (T-Bil), interleukin (IL)-6, and IL-8 were measured. We also measured the serum concentrations of IL-6 and IL-8 in the blood flowing into and out of the filter. Two patients had reduced serum concentrations of IL-6, IL-8, and T-Bil, but the other two did not, despite the effective filtration of these cytokines. Our findings suggest that the reduction of cytokines by HF may assist in the treatment of hyperbilirubinemia after LVAS placement in some patients.

Mortality rates in septic shock remain unacceptably high despite advances in our understanding of the syndrome and its treatment. Humoral factors are increasingly recognized to participate in the pathogenesis of septic shock, giving a biological rationale to therapies that might remove varied and potentially dangerous humoral mediators. While plasma water exchange in the form of hemofiltration can remove circulating cytokines in septic patients, the procedure, as routinely performed, does not have a substantial impact on their plasma levels. More intensive plasma water exchange, as high-volume hemofiltration (HVHF)can reduce levels of these mediators and potentially improve clinical outcomes. However, there are concerns about the feasibility and costs of HVHF as a continuous modality--very high volumes are difficult to maintain over 24 hours and solute kinetics are not optimized by this regimen. We propose pulse HVHF (PHVHF)-HVHF of 85 ml/kg/hr for 6-8 hours followed by continuous venovenous hemofiltration (CVVH) of 35 ml/kg/hr for 16-18 hours-as a new method to combine the advantages of HVHFimprove solute kinetics, and minimize logistic problems. We treated 15 critically ill patients with severe sepsis and septic shock using daily PHVHF in order to evaluate the feasibility of the technique, its effects on hemodynamics, and the impact of the treatment on pathologic apoptosis in sepsis. Hemodynamic improvements were obtained after 6 hours of PHVHF and were maintained subsequently by standard CVVHas demonstrated by the reduction in norepinephrine dose. PHVHFbut not CVVHsignificantly reduces apoptotic plasma activity within 1 hour and the pattern was maintained in the following hours. PHVHF appears to be a feasible modality that may provide the same or greater benefits as HVHFwhile reducing the workload and cost.

To evaluate the effect of veno-venous continuous renal replacement therapy (CRRT) on the plasma levels of endotoxin and cytokines in severely burned patients with sepsis.

Twenty adult severely burned patients with sepsis were studied. For the diagnosis of sepsis, patients were randomly divided into CRRT (n=10) and Control (n=10). Both groups received conventional therapy after admission. Veno-venous CRRT was administered to 10 patients in the CRRT group whenever patients were determined to be septic. The plasma level of endotoxin, TNF-alpha, IL-1 beta, IL-6 and IL-8 were measured at 0, 1, 2, 6, 12, 36 and 60 h after CRRT initiation, and at 0, 12, 36 and 60 h after the patients were diagnosed as having sepsis in the Control group.

Plasma level of endotoxin and all the cytokines after CRRT initiation were significantly lower than those before the treatment (P<0.01). The serial change of endotoxin, IL-1 beta, IL-6 and IL-8 was significantly lower at 12, 36 and 60 h after treatment compared with Control groups (P<0.01). A significant decrease in plasma TNF-alpha levels was seen at 36 and 60 h after treatment compared with Control groups (P<0.01).

Plasma endotoxin and cytokines (TNF-alpha, IL-1 beta, IL-6 and IL-8) can be removed effectively with CRRT in severely burned patients with sepsis.

The purpose of this study was to evaluate the effect of high volume continuous venovenous hemofiltration (HVCVVH) on hemodynamic and outcome in patients with septic shock. The primary end point was mortality at 28 days. Study design was a prospective case series, and study setting was a 12 bed intensive care unit at a university hospital. A total of 24 consecutive patients with septic shock were included, with dysfunction of more than two organs. All patients were treated by HVCVVH with ultrafiltration rate between 40 ml x kg(-1) x hr(-1) and 60 ml x kg(-1) x hr(-1) for 96 hours. In all patients, the increase in hemodynamic parameters was statistically significant (p < 0.05), with a significant linear decrease in norepinephrine doses (p < 0.05). The predicted 28 day mortality by three different severity scores was more than 70%, and the mortality in the hemofiltration group was 46% (p < 0.075). In the present study of septic shock patients with organ dysfunction, the hemodynamic parameters increased regularly during treatment by HVCVVH. This study suggests a beneficial effect of HVCVVH on 28 day mortality (46% vs. 70%), and further studies with larger cohorts are required.

Group II A phospholipase A2 (PLA2) produces many inflammatory lipid mediators, and the elevation in the level during sepsis has been correlated positively with the decrease in the arterial blood pressure. We studied the effect of large-pore continuous venovenous hemodiafiltration (LP-CVVHDF) on the plasma PLA2 concentration and the clearance mechanism during septic acute renal failure. The subjects were 10 consecutive patients with septic acute renal failure receiving CVVHDF. Simultaneous samples of arterial, and filter inlet and outlet blood, and ultradiafiltrate were collected before starting CVVHDF (0 hr), and 4 hr, 12 hr and 24 hr after starting CVVHDF. PLA2 activity was measured in plasma and ultradiafiltrate. We eluted PLA2 bound to hemofilter from patient and the classification of PLA2 type of eluting solution and ultradiafiltrate was done using Western blot analysis. Plasma clearance (mL/min) was 28.1+/-7.6 at 4 hr, 23.2+/-8.9 at 12hr and 17.5+/-8.0 at 24 hr. Plasma clearance at 4 hr was higher than that at either 12 hr or 24 hr. Plasma clearance mainly consisted of adsorption by LP-CVVHDF. The changes in arterial plasma PLA2 activity were not statistically significant. One mg/mL of heparin eluted PLA2 bound to the large-pore hemofilter. The PLA2 in eluting solution and in ultradiafiltrate were identified as an approximately 70 kD band in Western blot analysis using anti-human secretory II A-PLA2 monoclonal antibody. The results show that circulating PLA2 can be removed by adsorption with LP-CVVHDF to some extent and that plasma PLA2 activity is not significantly decreased. Because PLA2 clearance with LP-CVVHDF is estimated as <1% of total body PLA2 clearance, LP-CVVHDF could not be a clinically efficient therapy to remove the circulating PLA2.

Severe sepsis is frequently associated with inflammation, multiple-organ dysfunction syndrome, and the accumulation of excess fluid that can be removed by continuous renal replacement therapy. Appropriate therapy for sepsis requires knowledge of the antibiotic susceptibility of the causative organism. However, bacterial isolation and identification are often unsuccessful. The objective of this study was to determine whether bacteria could be recovered from continuous renal replacement therapy ultrafiltrates of clinically septic patients who were either blood culture positive or repeatedly culture negative.

Clinical study.

Adult medical intensive care unit.

Six clinically septic, blood culture-positive or repeatedly culture-negative patients and four clinically nonseptic patients.

We performed continuous renal replacement therapy on patients. In addition, we devised an in vitro system mimicking human bacteremia to determine whether bacteria traverse the hemofilter. In these experiments, a reservoir containing reconstituted blood was inoculated with Enterococcus faecalis and hemofiltered. The ultrafiltrates were centrifuged or secondarily filtered for bacterial recovery.

Bacterial pathogens were recovered in culture from ultrafiltrates of all the clinically septic patients. Ultrafiltrates of the nonseptic patients were sterile. E. faecalis, the bacterium inoculated into the reconstituted blood, was the only organism recovered from the in vitro-derived ultrafiltrates.

Pathogenic bacteria were shown to traverse the hemofilter. Culture of ultrafiltrates of clinically septic, blood culture-negative patients may be useful in recovery of the etiological organism and confirmation of the clinical diagnosis and management of sepsis.

The aim of our study was to examine renal replacement therapies (RRT) that have been used for acute renal failure (ARF) in our intensive care unit (ICU) patients and to compare their outcomes. Sixteen patients who underwent intermittent hemodialysis (IHD), 14 patients who underwent continuous hemofiltration (CHF) in combination with IHD (CHF + IHD), and 38 patients who underwent continuous hemodiafiltration (CHDF) were evaluated. Regarding the effects of blood purification on hemodynamics and renal function, the percentage increase in blood pressure and percent rapid increase in urinary output were the greatest in the CHDF group. The hourly urinary output after the start of initial blood purification increased only in the CHDF group. The survival rate was significantly higher in the CHDF group. These results suggest that CHDF should be the first-line therapy for patients with ARF and that we are moving in the right direction regarding the application of RRT to treat ARF in ICU patients.

Cytokines play important roles in the pathophysiology of systemic inflammatory response syndrome (SIRS) and sepsis. Therefore, some effective measures to remove cytokines from the bloodstream could be effective in the treatment of SIRS and sepsis. The aim of this study was to evaluate the cytokine adsorptive property of various adsorbents for the purpose of the development of new selective cytokine adsorption columns.

The cytokine adsorptive property of adsorbent in a CF-X column, which consists of cellulose beads cross-linked with hexamethylene-di-isocyanate, was compared with those of various adsorbents in currently available immunoadsorption columns, such as Immusorba TR, Immusorba PH, Selesorb, and Lixelle, in vitro batchwise test using patients' plasma. A newly developed adsorbent, MPCF-X, which was modified by coating the surface of the adsorbent in CF-X with 2-methacryloyloxyethyl phosphorylcholine (MPC), was also tested for its cytokine adsorptive property.

The adsorbent in CF-X showed a significantly higher adsorption rate for TNF-alpha, interleukin (IL)-6 and IL-10 compared with other adsorbents (p < 0.05). Adsorbent in Lixelle showed good affinity to TNF-alpha and IL-8. Especially, the adsorbent in CF-X almost completely removed TNF-alpha, whereas it also had considerable affinity to normal IgG. MPCF-X showed decreased affinity to IgG with considerable adsorptive properties to cytokines.

Selective cytokine adsorption columns could be developed with improvement of currently available adsorbents. Such a new selective cytokine adsorption column could be clinically applied for the treatment of SIRS/sepsis.

During the past 3 years new insights have been gained into the fundamental elements that underlie the pathogenesis of sepsis, and after years of frustrating failures, progress in the basic understanding of sepsis has translated into successful new therapies. These new treatment strategies have significantly improved the outcome of patients experiencing the puzzling syndrome of severe sepsis. More effective supportive therapies with early, goal-oriented therapy including volume resuscitation, catecholamine therapy and transfusion improve the chances for survival in septic shock. Novel endocrine management with hydrocortisone replacement therapy for relative adrenal insufficiency in septic shock patients and strict blood glucose control provide a survival advantage in critically ill patients. Administering appropriate antimicrobial therapy, nutritional support and ventilation protocols with low tidal volumes have now been shown to benefit septic patients. Finally, human recombinant activated protein C (drotrecogin alfa), which ameliorates sepsis-induced disseminated intravascular coagulation and exerts several other favourable effects on endothelial cells, has been shown to reduce mortality in patients with severe sepsis. On the basis of newly discovered pathophysiological mechanisms of sepsis, several other adjuvant therapies for sepsis are in various stages of preclinical and clinical development. Individualised and optimal supportive care with efforts to reverse the precipitating cause of sepsis remains the mainstay of therapy for severe sepsis. How these new and often expensive regimens will fit into the standard treatment approach to sepsis remains to be defined by future clinical investigations.

Severe sepsis and septic shock are the primary causes of multiple organ dysfunction syndrome (MODS), which is the most frequent cause of death in intensive care unit patients. Many water-soluble mediators with pro- and anti-inflammatory action such as TNF, IL-6, IL-8, and IL-10 play a strategic role in septic syndrome. In intensive care medicine, blocking any one mediator has not led to a measurable outcome improvement in patients with sepsis. CRRT is a continuously acting therapy, which removes in a nonselective way pro- and anti-inflammatory mediators; "the peak concentration hypothesis" is the concept of cutting peaks of soluble mediators through continuous hemofiltration. Furthermore, there is evidence of increased efficacy of high-volume hemofiltration compared to conventional CVVH, and other blood purification techniques that utilize large-pore membranes or sorbent plasmafiltration are conceptually interesting.

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.

Sepsis remains the major cause of mortality worldwide, claiming millions of lives each year. The past decade has seen major advances in the understanding of the biological mechanisms involved in this complex process. Unfortunately, no definitive therapy yet exists that can successfully treat sepsis and its complications. At variance with targeting single mediators, therapeutic intervention aimed at the nonselective removal of pro- and anti-inflammatory mediators seems a rational concept and a possible key to successful extracorporeal therapies. A further advantage may lie in the continuous nature of such therapy. With such continuous therapy, sequentially appearing peaks of systemic mediator overflow may be attenuated and persistently high plasma levels reduced. This theoretical framework is proposed as the underlying biological rationale for a series of innovative modalities in sepsis. In this editorial, we will review recent animal and human trials that lend support to this concept. We will also review the importance of treatment dose during continuous renal replacement therapy as a major factor affecting survival in critically ill patients with acute renal failure. Additionally, we will review novel information related to other blood purification techniques using large pore membranes or plasma filtration with adsorbent perfusion. Although these approaches are still in the early stages of clinical testing, they are conceptually promising and might represent an important advance.

The effectiveness of plasma exchange (PE) with continuous hemodiafiltration (CHDF) in the treatment of critically ill patients was evaluated based on changes in cytokine levels. Twenty-six patients with acute hepatic failure were treated with PE (PE group) or PE and CHDF (PE+CHDF group), and the levels of cytokines such as tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-8 were determined before and after treatment. Bilirubin levels were significantly lower after treatment in both the PE and PE+CHDF groups. There were no significant differences in TNF-alpha levels before and after treatment in the PE group, but the TNF-alpha level was significantly lower after treatment in the PE+CHDF group. There were no significant differences in the IL-6 levels before and after treatment in both the PE and PE+CHDF groups. There were no significant differences in IL-8 levels before and after treatment in the PE group, but the IL-8 level was significantly lower after treatment in the PE+CHDF group. PE with CHDF therapy was given to 5 patients with acutely aggravated autoimmune diseases, 2 patients with hemorrhagic shock and encephalopathy syndrome, and 3 patients with thrombotic microangiopathy. The results suggested that PE with CHDF therapy are useful in critically ill patients with suspected hypercytokinemia.

To test the hypothesis that dialysis using a new large pore membrane would achieve effective cytokine removal, blood from six volunteers was incubated with endotoxin (1 mg) and then circulated through a closed circuit with a polyamide membrane (nominal cut-off: 100 kDa). Hemodialysis was conducted at 1 or 9 L/hr of dialysate flow at the start of circulation and after 2 and 4 hours. The peak dialysate/plasma concentration ratios were 0.92 for interleukin (IL)-1beta, 0.67 for IL-6, 0.94 for IL-8, 0.33 for tumor necrosis factor (TNF)-a, and 0.11 for albumin. The dialysate/plasma ratios for all cytokines and albumin were decreased with increased dialysate flow from 1 to 9 L/hr (p < 0.05). Clearances for IL-1beta, IL-6, and IL-8, however, were significantly improved with increased dialysate flow (p < 0.01). There was no increase in TNF-a clearance (not significant) and a decrease in albumin clearance (p < 0.01). The peak clearance at 9 L/hr was 33 ml/min for IL-1beta, 19 for IL-6, 51 for IL-8, 11 for TNF-alpha, and 1.2 for albumin. No adsorption of cytokines was observed. We conclude that cytokine dialysis is achievable through a membrane with a high cut-off point with negligible albumin loss. These findings support the technical feasibility of this new approach to blood purification in sepsis.

Continuous arteriovenous haemofiltration (CAVH) is the first example of continuous renal replacement therapy (CRRT). CAVH was first applied for the treatment of diuretic unresponsive fluid overload. Subsequently, CRRT has undergone a remarkable growth, and it is now performed with pump technology (CVVH) and via double-lumen central venous catheters. In many intensive care units, especially in Australia and in Europe, CRRT has become the dominant, if not exclusive, form of artificial renal support. Continuous haemofiltration is now used beyond the original indications of blood purification, for the treatment of certain drug intoxications, for severe cardiac failure, for volume control during, after cardiopulmonary bypass, and to decrease the toxicity of chemotherapy. Furthermore, there is strong ongoing research into its role or that of derived techniques as possible adjuvant therapies during severe sepsis. Despite its large use, the current state of CRRT is surrounded by some controversies, and an effort should be made to give a dispassionate distillation of the literature for a final common definition of what is based on opinions and what carries sufficient evidence.

Procalcitonin (PCT), interleukin-6 (IL-6), tumour necrosis factor a (TNFalpha), and interleukin-1beta (IL-1beta) are important clinical prognostic markers in ICU septic patients. The goal of the study was to determine whether continuous venovenous haemofiltration (CWH), using an AN69 haemofilte, leads to elimination of PCT, TNFalpha, IL-6 and IL-1beta in 13 septic patients with multi-organ failure. At the start of haemofiltration (0), 6 and 12 hours the mean afferent plasma concentration +/- SD of PCT (10.1 +/- 9.1, 7 +/- 6, 5.9 +/- 5.7 ng/ml), IL-6 (804.6 +/- 847.6, 611.7 +/- 528.4, 575.2 +/- 539.2 pg/ml), and that of TNFalpha (4.5 +/- 2.6, 4 +/- 3.1, 3.8 +/- 2.9 pg/ml) significantly declined during CVVH. The efferent plasma concentrations were significantly lower than the corresponding afferent concentrations. PCT; IL-6 and TNFalpha were detectable in the ultrafiltrate of all patients. IL-1beta was only detectable in the plasma of eight patients and the ultrafiltrate of five patients. The plasma clearance of PCT, IL-6 and TNFalpha significantly decreased after 12 hours as a result of a decline in the adsorptive elimination of the mediators due to progressive membrane saturation. We demonstrated that if PCT, IL-6 and TNFalpha are used as clinical prognostic markers in septic patients who are treated with CWIH using an AN69 membrane, one should be aware that their plasma level could be modified by the therapy. In addition CWH could represent an appropriate tool to remove a broad spectrum of proinflammatory mediators, if such removal is required in septic patients.

Continuous hemofiltration and continuous hemodiafiltration (CHF/CHDF) were developed as continuous renal replacement therapy for patients with severe conditons and has come to be widely performed mainly in critical care, taking the place of intermittent hemodialysis. The membrane pore size of a hemofilter used for CHF/CHDF allows passage of substances ranging from 30,000 to 50,000 Da, and the method for solute removal in CHF/CHDF employs the principle of convection, which is advantageous for removing middle- to high-molecular-weight substances. As apheresis therapy to remove pathogenic substances in blood, CHF/CHDF is therefore being investigated for its possible effect on various morbid conditions. It has recently been found that CHF/CHDF removes humoral mediators including cytokines, particularly in severe systemic inflammatory response syndromes such as septic shock and severe acute pancreatitis. CHF/CHDF is thus beginning to be performed for the prevention and treatment of organ dysfunction secondary to septic shock, trauma, or acute pancreatitis. CHF/CHDF is also efficacious as artificial liver support in preventing adverse effects caused by plasma exchange (PE) and for continuous removal of hepatic coma-inducing substances. CHF/CHDF is effective for various morbid conditions not only as renal replacement therapy, but also as apheresis therapy and is expected to be applied more widely in critical care in the future.

Extracorporeal blood detoxification by sorbent therapy long has been applied in treatment of hepatic failure and encephalopathy, starting with hemoperfusion columns and more recently with the currently marketed Liver Dialysis Unit. Liver Dialysis employs hemodiabsorption (dialysis of blood against powdered sorbents including charcoal and cation exchanger) to remove selectively numerous small-molecular-weight toxins of hepatic failure. Liver Dialysis is used in treatment of acute hepatic encephalopathy (AHE) because of decompensation of chronic liver disease (A-on-C) or fulminant hepatic failure (FHF). Controlled, prospective and randomized studies of daily 6-hour Liver Dialysis have shown physiologic and neurologic improvement of patients with AHE, regardless of etiology. Liver dialysis significantly improved the incidence of positive outcomes (recovery of hepatic function or improvement for transplant) of A-on-C patients versus controls (71.5% treated, and 35.7% control, P =.036), but had an insignificant improvement in outcome of patients with FHF as compared with the control group. Other extracorporeal sorbent devices are now in clinical testing phase. The molecular adsorbent regenerating system (MARS) device employs a polysulfone high-permeability dialyzer with albumin on the dialysate side to aid transfer of protein-bound toxins such as bilirubin and bile acids across the membranes. Sorbent columns of charcoal and an anion exchanger remove hepatic toxins from the albumin dialysate, and a second dialyzer removes water-soluble toxins, such as ammonium. Clinical results of daily MARS treatments of patients with hepatic failure are similar to that of Liver Dialysis, with neurologic and physical improvement occurs in most patients with AHE, and improved outcome for patients with A-on-C. The system extends the life of patients with hepatorenal syndrome. PF-Liver Dialysis is an experimental device combining hemodiabsorption with push-pull sorbent-based pheresis with powdered sorbent surrounding plasmafilters. PF-Liver Dialysis (Hemocleanse, Inc, W. Lafayette, IN) has been tested in a few patients with hepatic failure, grade 3-4 encephalopathy, and respiratory and kidney insufficiency. Treatments appeared to be safe and resulted in marked decreases in plasma levels of bilirubin, aromatic amino acids, ammonium, creatinine, and interleukin-1beta (IL-1beta). The PF add-on module adds the capability to Liver Dialysis to remove bilirubin, bile acids, and other strongly protein-bound toxins from treated patients and may be of clinical benefit in management of patients with the most severe hepatic failure and encephalopathy, including patients with FHF or concomitant sepsis.

An FDA-approved Phase 1 feasibility study was performed in two centers to determine the safety of the BioLogic-DTPF (detoxifier/plasma filter) system for the treatment of patients with systemic inflammatory response syndrome (SIRS). This device combines hemodiabsorption (dialysis of blood against powdered sorbents with the BioLogic-DT system) with push-pull sorbent-based pheresis (the PF add-on module). Eight adult ICU patients with both SIRS and multiple organ failure participated in the study. One 6 h treatment was planned for each patient with powdered charcoal as sorbent for 4 patients and a combination of charcoal/silica in the PF sorbent bag for 4 patients. The treatments appeared to have no negative effects in 7 patients, but 1 patient died during treatment due to progressive cardiac failure. Sepsis was resolved in 5 of the 8 patients. However, there were only 2 long-term survivors of the group. The addition of the PF module should improve the chemical function of the BioLogic-DT by allowing removal of protein-bound toxins such as cytokines. The selected patients tolerated treatment by the DTPF system well, but proof of benefit of the device remains to be proven in a Phase 2 clinical trial with randomized controls.

The Liver Dialysis Unit (the Unit) is a liver-assist device that employs hemodiabsorption (dialysis of blood against powdered sorbents) to selectively remove numerous small molecular weight toxins of hepatic failure. The Unit has been cleared by the Food and Drug Administration and is indicated and marketed for treatment of acute hepatic encephalopathy (AHE) due to decompensation of chronic liver disease (A-on-C) or fulminant hepatic failure (FHF). Controlled, prospective, and randomized studies of liver dialysis were conducted at several centers, enrolling 56 patients with AHE, grades II-IV with or without renal and respiratory insufficiency or failure. Liver dialysis treatments were for 6 h daily, 1-5 days with similar observation periods for control patients. Physiologic status, neurologic status, and outcome (recovery of hepatic function, improvement for transplant, or death) were measured, and results were compared for treated patients versus controls for patients with A-on-C and patients with FHF. Liver dialysis resulted in physiologic and neurologic improvement of patients with AHE, regardless of etiology. Liver dialysis significantly improved the incidence of positive outcomes (recovery of hepatic function or improvement for transplant) of A-on-C patients versus controls (71.5% treated, 35.7% control, p = 0.036), but had an insignificant improvement in the outcome of patients with FHF as compared with the control group. Among the overall 31 treated patients, 51.6% survived. Outcome was not negatively affected by the presence of kidney failure or respiratory failure. The plasmafilter unit (PF-Unit) combines hemodiabsorption with push-pull sorbent-based pheresis (the PF add-on module, with powdered sorbent surrounding plasmafilters). At blood flow rates of 200 ml/min, the system clears creatinine and aromatic amino acids at 120-160 ml/min, unconjugated bilirubin at 20-40 ml/min, and cytokines at 15-25 ml/min. The PF-Unit has been tested in a few patients with hepatic failure with Grades III and IV encephalopathy, and respiratory, and kidney insufficiency. Treatment appeared to be safe, and there were no significant hematologic changes. Physiologic changes included improved blood pressure, and encephalopathy, and stable urine output. Chemical changes included a decrease in the plasma levels of bilirubin, aromatic amino acids, ammonium, creatinine, and IL-1beta. The PF add-on module adds the capability to the Unit to remove bilirubin and other strongly protein-bound toxins from treated patients and may be of clinical benefit in the management of patients with the most severe hepatic failure and encephalopathy, including patients with FHF or concomitant sepsis.

Acute renal failure is a common clinical problem in the intensive care unit (ICU) and is associated with significant morbidity and mortality. There is no "magic bullet" to prevent acute renal failure or to modify the clinical course of established renal failure. The approach to therapy is directed to the early initiation of dialysis therapy. Continuous dialysis therapy is becoming the preferred form of dialysis in the ICU.

To evaluate the effects of short-term, high-volume hemofiltration (STHVH) on hemodynamic and metabolic status and 28-day survival in patients with refractory septic shock.

Prospective, interventional.

Intensive care unit (ICU), tertiary institution.

Twenty patients with intractable cardiocirculatory failure complicating septic shock, who had failed to respond to conventional therapy.

STHVH, followed by conventional continuous venovenous hemofiltration. STHVH consisted of a 4-hr period during which 35 L of ultrafiltrate is removed and neutral fluid balance is maintained. Subsequent conventional continuous venovenous hemofiltration continued for at least 4 days.

Cardiac index, systemic vascular resistance, pulmonary vascular resistance, oxygen delivery, mixed venous oxygen saturation, arterial pH, and lactate were measured serially. Fluid and inotropic support were managed by protocol. Therapeutic endpoints were as follows during STHVH: a) by 2 hrs, a > or =50% increase in cardiac index; b) by 2 hrs, a > or =25% increase in mixed venous saturation; c) by 4 hrs, an increase in arterial pH to >7.3; d) by 4 hrs, a > or =50% reduction in epinephrine dose. Patients who attained all four goals (11 of 20) were considered hemodynamic "responders"; patients who did not (9 of 20) were considered hemodynamic "nonresponders." There were no differences in baseline hemodynamic, metabolic, and Acute Physiology and Chronic Health Evaluation and Simplified Acute Physiology Scores between responders and nonresponders. Survival to 28 days was better among responders (9 of 11 patients) than among nonresponders (0 of 9). Factors associated with survival were hemodynamic-metabolic response status, time interval from ICU admission to initiation of STHVH, and body weight.

These data suggest that STHVH may be of major therapeutic value in the treatment of intractable cardiocirculatory failure complicating septic shock. Early initiation of therapy and adequate dose may improve hemodynamic and metabolic responses and 28-day survival.

Continuous renal replacement therapy (CRRT) was first described in 1977 for the treatment of diuretic-unresponsive fluid overload in the intensive care unit (ICU). Since that time this treatment has undergone a remarkable technical and conceptual evolution. It is now available in most tertiary ICUs around the world and has almost completely replaced intermittent haemodialysis (IHD) in some countries. Specially made machines are now available, and venovenous therapies that use blood pumps have replaced simpler techniques. Although, it remains controversial whether CRRT decreases mortality when compared with IHD, much evidence suggests that it is physiologically superior. The use of CRRT has also spurred renewed interest in the broader concept of blood purification, particularly in septic states. Experimental evidence suggests that this is a promising approach to the management of septic shock in critically ill patients. The evolution and use of CRRT is likely to continue and grow over the next decade.

To study the removability of pro-inflammatory cytokines by hemofiltration (HF), we performed experimental HF with various high-flux membranes (HFM) using a closed circuit system filled with monocyte-free human plasma, which contained TNFalpha, IL-1beta, and IL-6. Plasma and filtrate samples were taken before and 1, 2, 3, and 4 hours after the initiation of HF, and each cytokine was determined by enzyme-linked immunosorbent assay. IL-1beta was well removed through filtration during experimental HF using HFM (PAN>CTA>PMMA>PS). TNFalpha and IL-6 were only minimally filtered out by HF using HFM. TNFalpha was removed to some extent by using PS, and IL-6 was partially removed by using PMMA during experimental HF through other mechanisms, such as adsorption, than the filtration. IL-1beta and IL-6 were effectively removed by HA using charcoal adsorbent column, especially during the first 2 hours, while TNFalpha was only partly removed.

The only natural reservoir of Neisseria meningitidis is the human nasopharyngeal mucosa. Depending on age, climate, country, socioeconomic status, and other factors, approximately 10% of the human population harbors meningococci in the nose. However, invasive disease is relatively rare, as it occurs only when the following conditions are fulfilled: (i) contact with a virulent strain, (ii) colonization by that strain, (iii) penetration of the bacterium through the mucosa, and (iv) survival and eventually outgrowth of the meningococcus in the bloodstream. When the meningococcus has reached the bloodstream and specific antibodies are absent, as is the case for young children or after introduction of a new strain in a population, the ultimate outgrowth depends on the efficacy of the innate immune response. Massive outgrowth leads within 12 h to fulminant meningococcal sepsis (FMS), characterized by high intravascular concentrations of endotoxin that set free high concentrations of proinflammatory mediators. These mediators belonging to the complement system, the contact system, the fibrinolytic system, and the cytokine system induce shock and diffuse intravascular coagulation. FMS can be fatal within 24 h, often before signs of meningitis have developed. In spite of the increasing possibilities for treatment in intensive care units, the mortality rate of FMS is still 30%. When the outgrowth of meningococci in the bloodstream is impeded, seeding of bacteria in the subarachnoidal compartment may lead to overt meningitis within 24 to 36 h. With appropriate antibiotics and good clinical surveillance, the mortality rate of this form of invasive disease is 1 to 2%. The overall mortality rate of meningococcal disease can only be reduced when patients without meningitis, i.e., those who may develop FMS, are recognized early. This means that the fundamental nature of the disease as a meningococcus septicemia deserves more attention.

The only natural reservoir of Neisseria meningitidis is the human nasopharyngeal mucosa. Depending on age, climate, country, socioeconomic status, and other factors, approximately 10% of the human population harbors meningococci in the nose. However, invasive disease is relatively rare, as it occurs only when the following conditions are fulfilled: (i) contact with a virulent strain, (ii) colonization by that strain, (iii) penetration of the bacterium through the mucosa, and (iv) survival and eventually outgrowth of the meningococcus in the bloodstream. When the meningococcus has reached the bloodstream and specific antibodies are absent, as is the case for young children or after introduction of a new strain in a population, the ultimate outgrowth depends on the efficacy of the innate immune response. Massive outgrowth leads within 12 h to fulminant meningococcal sepsis (FMS), characterized by high intravascular concentrations of endotoxin that set free high concentrations of proinflammatory mediators. These mediators belonging to the complement system, the contact system, the fibrinolytic system, and the cytokine system induce shock and diffuse intravascular coagulation. FMS can be fatal within 24 h, often before signs of meningitis have developed. In spite of the increasing possibilities for treatment in intensive care units, the mortality rate of FMS is still 30%. When the outgrowth of meningococci in the bloodstream is impeded, seeding of bacteria in the subarachnoidal compartment may lead to overt meningitis within 24 to 36 h. With appropriate antibiotics and good clinical surveillance, the mortality rate of this form of invasive disease is 1 to 2%. The overall mortality rate of meningococcal disease can only be reduced when patients without meningitis, i.e., those who may develop FMS, are recognized early. This means that the fundamental nature of the disease as a meningococcus septicemia deserves more attention.

While there is clear support for the use of continuous renal replacement therapy (CRRT) in critically ill acute renal failure patients, there are other illnesses without renal involvement where CRRT might be of value. These include sepsis and other inflammatory syndromes such as acute respiratory distress syndrome (ARDS) and cardiopulmonary bypass where removal of inflammatory mediators by hemofiltration is hypothesized to improve outcome. Adsorption appears to be the predominant mechanism of mediator elimination. However, the observed hemodynamic improvement can, at least partially, be attributed to a reduction of body temperature or to fluid removal, and the evidence for a clinically important removal of proinflammatory cytokines remains limited. Continuous and therefore smooth fluid removal may improve organ function in ARDS, after surgery with cardiopulmonary bypass, and in patients with refractory congestive heart failure. Continuous removal of endogenous toxins, eventually combined with intermittent hemodialysis, is probably beneficial in inborn errors of metabolism, severe lactic acidosis, or tumor lysis syndrome.

The serum levels of proinflammatory cytokines were investigated in three patients with severe burn injuries complicated by sepsis and pulmonary edema, who were treated with continuous hemofiltration (CHF) using a polymethylmethacrylate (PMMA) membrane. All patients had suffered burn injuries to more than 30% of their total body surface area (TBSA) and had burn indexes of 20 or more. Both interleukin (IL)-6 and tumor necrosis factor-alpha were detectable in one patient, while the serum IL-6 levels were elevated in the remaining two patients. The serum cytokines decreased 24 h after the initiation of CHF. Determinations of IL-6 in inflow and outflow blood samples as well as in the filtration fluid revealed that IL-6 was ultrafiltrated and/or adsorbed by the filter. Two of the three patients did not survive. Nevertheless, the results of this study indicate that since burn injuries are frequently associated with hypercytokinemia, the removal of cytokines by CHF with a PMMA membrane may be effective in the management of severe burn injuries.