Alessandra Brendolan

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 patients bodyweight and should reach at least 35 mL h(-1) kg(-1).

A pilot study of coupled plasma filtration with adsorption in septic shock

ObjectiveTo test the hypothesis that nonselective plasma adsorption by a hydrophobic resin (coupled plasmafiltration and adsorption) could improve hemodynamics and restore leukocyte responsiveness in patients with septic shock. DesignProspective, pilot, crossover clinical trial. SettingGeneral intensive care unit in a teaching hospital. SubjectsTen patients with hyperdynamic septic shock. InterventionsPatients were randomly allocated to 10 hrs of either coupled plasma filtration adsorption plus hemodialysis (treatment A) or continuous venovenous hemodiafiltration (treatment B) in random order. We measured the change in mean arterial pressure, norepinephrine requirements, and leukocyte tumor necrosis factor-&agr; (TNF-&agr;) production (both spontaneous and lipopolysaccharide-stimulated) after 10 hrs of each treatment. We also tested TNF-&agr; production from normal human adherent monocytes incubated with patients’ plasma obtained before and after the resin, both with or without incubation with an anti-interleukin-10 monoclonal antibody. ResultsMean arterial pressure increased after 10 hr by 11.8 mm Hg with treatment A and by 5.5 mm Hg with treatment B (p = .001). There was an average decrease of norepinephrine requirement of 0.08 &mgr;g/kg/min with treatment A and 0.0049 &mgr;g/kg/min with treatment B (p = .003). All patients but one survived. Spontaneous and lipopolysaccharide-induced TNF-&agr; production from patients’ whole blood increased over time with treatment A. This increase was more marked in blood drawn after the device (plasmafiltrate-sorbent plus hemodialyzer) (p = .009). Preresin plasma suppressed lipopolysaccharide-stimulated production of TNF-&agr; by 1 × 106 cultured adherent monocytes from healthy donors. This suppressive effect was significantly reduced after passage of plasma through the resin (p = .019) and after incubation with anti-interleukin-10 monoclonal antibodies (p = .028). ConclusionsIn patients with septic shock, coupled plasmafiltration-adsorption combined with hemodialysis was associated with improved hemodynamics compared with continuous venovenous hemodiafiltration. This result might be related to its ability to restore leukocyte responsiveness to lipopolysaccharide. These findings suggest a potential role for blood purification in the treatment of septic shock.

Pulse high-volume haemofiltration for treatment of severe sepsis: effects on hemodynamics and survival

IntroductionSevere sepsis is the leading cause of mortality in critically ill patients. Abnormal concentrations of inflammatory mediators appear to be involved in the pathogenesis of sepsis. Based on the humoral theory of sepsis, a potential therapeutic approach involves high-volume haemofiltration (HVHF), which has exhibited beneficial effects in severe sepsis, improving haemodynamics and unselectively removing proinflammatory and anti-inflammatory mediators. However, concerns have been expressed about the feasibility and costs of continuous HVHF. Here we evaluate a new modality, namely pulse HVHF (PHVHF; 24-hour schedule: HVHF 85 ml/kg per hour for 6–8 hours followed by continuous venovenous haemofiltration 35 ml/kg per hour for 16–18 hours).MethodFifteen critically ill patients (seven male; mean Acute Physiology and Chronic Health Evaluation [APACHE] II score 31.2, mean Simplified Acute Physiology Score [SAPS] II 62, and mean Sequential Organ Failure Assessment 14.2) with severe sepsis underwent daily PHVHF. We measured changes in haemodynamic variables and evaluated the dose of noradrenaline required to maintain mean arterial pressure above 70 mmHg during and after pulse therapy at 6 and 12 hours. PHVHF was performed with 250 ml/min blood flow rate. The bicarbonate-based replacement fluid was used at a 1:1 ratio in simultaneous pre-dilution and post-dilution.ResultsNo treatment was prematurely discontinued. Haemodynamics were improved by PHVHF, allowing a significant reduction in noradrenaline dose during and at the end of the PHVHF session; this reduction was maintained at 6 and 12 hours after pulse treatment (P = 0.001). There was also an improvement in systolic blood pressure (P = 0.04). There were no changes in temperature, cardiac index, oxygenation, arterial pH or urine output during the period of observation. The mean daily Kt/V was 1.92. Predicted mortality rates were 72% (based on APACHE II score) and 68% (based on SAPS II score), and the observed 28-day mortality was 47%.ConclusionPHVHF is a feasible modality and improves haemodynamics both during and after therapy. It may be a beneficial adjuvant treatment for severe sepsis/septic shock in terms of patient survival, and it represents a compromise between continuous renal replacement therapy and HVHF.

Continuous renal replacement therapy in neonates and small infants: Development and first-in-human use of a miniaturised machine (CARPEDIEM)

BACKGROUND Peritoneal dialysis is the renal replacement therapy of choice for acute kidney injury in neonates, but in some cases is not feasible or effective. Continuous renal replacement therapy (CRRT) machines are used off label in infants smaller than 15 kg and are not designed specifically for small infants. We aimed to design and create a CRRT machine specifically for neonates and small infants. METHODS We prospectively planned a 5-year project to conceive, design, and create a miniaturised Cardio-Renal Pediatric Dialysis Emergency Machine (CARPEDIEM), specifically for neonates and small infants. We created the new device and assessed it with in-vitro laboratory tests, completed its development to meet regulatory requirements, and obtained a licence for human use. Once approved, we used the machine to treat a critically ill neonate FINDINGS The main characteristics of CARPEDIEM are the low priming volume of the circuit (less than 30 mL), miniaturised roller pumps, and accurate ultrafiltration control via calibrated scales with a precision of 1 g. In-vitro tests confirmed that both hardware and software met the specifications. We treated a 2·9 kg neonate with haemorrhagic shock, multiple organ dysfunction, and severe fluid overload for more than 400 h with the CARPEDIEM, using continuous venovenous haemofiltration, single-pass albumin dialysis, blood exchange, and plasma exchange. The patients 65% fluid overload, raised creatinine and bilirubin concentrations, and severe acidosis were all managed safely and effectively. Despite the severity of the illness, organ function was restored and the neonate survived and was discharged from hospital with only mild renal insufficiency that did not require renal replacement therapy. INTERPRETATION The CARPEDIEM CRRT machine can be used to provide various treatment modalities and support for multiple organ dysfunction in neonates and small infants. The CARPEDIEM could reduce the range of indications for peritoneal dialysis, widen the range of indications for CRRT, make the use of CRRT less traumatic, and expand its use as supportive therapy even when complete renal replacement therapy is not indicated. FUNDING Associazione Amici del Rene di Vicenza.

On-Line Urea Monitoring: A Further Step towards Adequate Dialysis Prescription and Delivery

The Aim Of This Study Is To Present A Clinical Experience Carried Out With A New Device Designed To Measure On-Line Urea Nitrogen Concentration In The Effluent Dialysate. The Biostat 1000® Urea Monitor (Baxter Healthcare, Dirfield, Iii, Usa) Was Utilized In The Present Study. The Monitor Is Based On The Principle That Multiple Urea Measurements In The Dialysate Effluent From The Dialyzer, Permit To Built A Double Exponential Regression Leading To The Urea Kinetic Parameters Of The Dialysis Session. Data Obtained With The Urea Monitor Were, In The Present Study, Compared With Those Obtained By Direct Measurements Carried Out In Blood And Dialysate And By The Collection Of The Whole Amount Of Spent Dialysate. The Monitor Provided An Accurate Value Of Predialysis Bun Without Any Blood Drawing. Urea Kinetics Were Established From Multiple Dialysate Measurements And No Blood Drawing Was Necessary. The Double Pool Kinetics Were Taken Into Account And Kt/V, Pcr And Sri° Obtained Were Comparable To Those Obtained From Direct Measurement. Since A Projected Value Of Kt/V Can Be Obtained, The Monitor Could Represent A Potential Source Of Information To Detect Possible Filter And Machine Dysfunction, As Well As High Rate Of Recirculation.

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.

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.

Phosphate Kinetics during Different Dialysis Modalities

Background: An abnormal serum phosphate concentration is common in acute renal failure patients, with a reported incidence of 65–80%. Phosphate removal and kinetics during intermittent hemodialysis (IHD) have been investigated, but there is no information on its kinetics during slow low-efficiency dialysis (SLED) and continuous renal replacement therapy (CRRT). Methods: Eight IHD, 8 SLED, and 10 continuous venovenous hemofiltration (CVVH) patients with a residual renal clearance of <4.0 ml/min were studied during a single treatment to evaluate phosphate removal and kinetics. CVVH was studied the first 24 h after initiation. Dialysis/replacement fluid contained no phosphate. Kt/V, clearance of urea (Ku), inorganic phosphate (Kp) and solute removal was determined by direct dialysate quantification (DDQ). Results: Kp recorded with the three techniques were: IHD, 126.9 ± 18.4 ml/min; SLED, 58.0 ± 15.8 ml/min, and CVVH, 31.5 ± 6.0 ml/min. However, in shorter dialysis treatment the total removal of phosphate was significantly lower than in longer dialysis (IHD, 29.9 ± 7.7 mmol; SLED, 37.6 ± 9.6 mmol; CVVH, 66.7 ± 18.9 mmol, p = 0.001). The duration of treatment is the only factor determining phosphate removal (r = 0.7, p < 0.0001 by linear correlation model). Like IHD, phosphate kinetics during SLED could not be explained by the two-pool kinetic model, and the rebound of phosphate extended beyond 1 h after dialysis. Rebound, however, is less marked than in short dialysis. Conclusion: These results are reliable evidence about amount of phosphate removal and behavior of intradialytic phosphate kinetics in renal failure patients undergoing different dialysis modalities. These data will help clinicians plan phosphate supplementation and treatment intensity.

Dialysate flow distribution in hollow fiber hemodialyzers with different dialysate pathway configurations.

The efficiency of a hemodialyzer is largely dependent on its ability to facilitate diffusion, since this is the main mechanism by which small solutes are removed. The diffusion process can be impaired if there is a mismatch between blood and dialysate flow distribution in the dialyzer. The objective of the paper was to study the impact of different dialysate compartment designs on dialysate flow distribution and urea clearances. Eighteen hollow fiber 1.3 m2 hemodialyzers were studied, 6 each of 3 designs: Type A- standard fiber bundle (PAN 65DX Asahi Medical, Tokyo, Japan); Type B - spacing filaments external to the fibers (PAN 65SF Asahi Medical, Tokyo, Japan); Type C - fibers waved to give Moiré structure (FB130 Nissho-Nipro, Osaka, Japan). In vitro studies: 3 dialyzers of each type were studied following dye injection into the dialysate compartment. Dynamic sequential imaging of longitudinal sections of the dialyzer were undertaken, using a new generation helical CT scanner (X-Press/HS1 Toshiba Corporation, Tokyo, Japan). In vivo studies: 3 dialyzers of each type were studied, in randomized sequence, in 3 different patients under standardized dialysis conditions. Blood- and dialysate-side urea clearances were measured at 30 and 150 minutes of treatment. Macroscopic and densitometrical analysis revealed that flow distribution was most homogeneous in the dialyzer with Moiré structure (Type C) and least homogeneous in the standard dialyzer (Type A). Space yarns (Type B) gave an intermediate dialysate flow distribution. Significantly increased urea clearances (p<0.001) were seen with Types B and C, compared to the standard dialyzer. Type C (Moiré) had the highest clearances although these were not significantly greater than Type B (space yarns). In conclusion, more homogeneous dialysate flow distribution and improved small solute clearances can be achieved by use of spacing yarns or waved (Moiré structure) patterns of fiber packing in the dialyzer. These effects are achieved probably as a result of reduced dialysate channeling resulting in a lower degree of mismatch between blood and dialysate flows. The new radiological technique using the helical CT scanner allows detailed flow distribution analysis and has the potential for testing future modifications to dialyzer design.

Pulse High-Volume Hemofiltration in Critically Ill Patients: A New Approach for Patients with Septic Shock

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 shockgiving 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 patientsthe procedureas routinely performeddoes not have a substantial impact on their plasma levels. More intensive plasma water exchangeas high‐volume hemofiltration (HVHF)can reduce levels of these mediators and potentially improve clinical outcomes. Howeverthere 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 kineticsand 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 techniqueits effects on hemodynamicsand 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.