Pasquale Piccinni

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).

North East Italian Prospective Hospital Renal Outcome Survey on Acute Kidney Injury (NEiPHROS-AKI): Targeting the Problem with the RIFLE Criteria

Acute kidney injury (AKI) in the intensive care unit (ICU) is associated with an enhanced mortality. The Acute Dialysis Quality Initiative group has proposed the RIFLE (Risk-Injury-Failure-Loss-ESRD) classification to standardize the approach to AKI. This study was performed to estimate the AKI incidence in ICU patients in northeastern Italy and describe clinical characteristics and outcomes of patients with AKI on the basis of their RIFLE class. A prospective multicenter observational study was performed of patients who fulfilled AKI criteria in 19 ICU in northeastern Italy. Data were analyzed using multivariate logistic regression and survival curve analysis. Of 2164 ICU patients who were admitted during the study period, 234 (10.8%; 95% confidence interval 9.5 to 12.1%) developed AKI; 19% were classified as risk (R), 35% as injury (I), and 46% as failure (F). Preexisting kidney disease was present in 36.8%. The most common causes of AKI were prerenal causes (38.9%) and sepsis (25.6%). At diagnosis of AKI, median serum creatinine and urine output were 2.0 mg/dl and 1100 ml/d, respectively. ICU mortality was 49.5% in class F, 29.3% in I, and 20% in R. Independent risk factors for mortality included RIFLE class, sepsis, and need for renal replacement therapy, whereas a postsurgical cause of AKI, exposure to nephrotoxins, higher serum creatinine, and urine output were associated with lower mortality risk. In this study, AKI incidence in the ICU was between 9 and 12%, with 3.3% of ICU patients requiring renal replacement therapy. Sepsis was a significant contributing factor. Overall mortality was between 30 and 42%, and was highest among those in RIFLE class F.

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.

Fluid balance and urine volume are independent predictors of mortality in acute kidney injury

IntroductionIn ICUs, both fluid overload and oliguria are common complications associated with increased mortality among critically ill patients, particularly in acute kidney injury (AKI). Although fluid overload is an expected complication of oliguria, it remains unclear whether their effects on mortality are independent of each other. The aim of this study is to evaluate the impact of both fluid balance and urine volume on outcomes and determine whether they behave as independent predictors of mortality in adult ICU patients with AKI.MethodsWe performed a secondary analysis of data from a multicenter, prospective cohort study in 10 Italian ICUs. AKI was defined by renal sequential organ failure assessment (SOFA) score (creatinine >3.5 mg/dL or urine output (UO) <500 mL/d). Oliguria was defined as a UO <500 mL/d. Mean fluid balance (MFB) and mean urine volume (MUV) were calculated as the arithmetic mean of all daily values. Use of diuretics was noted daily. To assess the impact of MFB and MUV on mortality of AKI patients, multivariate analysis was performed by Cox regression.ResultsOf the 601 included patients, 132 had AKI during their ICU stay and the mortality in this group was 50%. Non-surviving AKI patients had higher MFB (1.31 ± 1.24 versus 0.17 ± 0.72 L/day; P <0.001) and lower MUV (1.28 ± 0.90 versus 2.35 ± 0.98 L/day; P <0.001) as compared to survivors. In the multivariate analysis, MFB (adjusted hazard ratio (HR) 1.67 per L/day, 95%CI 1.33 to 2.09; <0.001) and MUV (adjusted HR 0.47 per L/day, 95%CI 0.33 to 0.67; <0.001) remained independent risk factors for 28-day mortality after adjustment for age, gender, diabetes, hypertension, diuretic use, non-renal SOFA and sepsis. Diuretic use was associated with better survival in this population (adjusted HR 0.25, 95%CI 0.12 to 0.52; <0.001).ConclusionsIn this multicenter ICU study, a higher fluid balance and a lower urine volume were both important factors associated with 28-day mortality of AKI patients.

RIFLE-Based Data Collection/Management System Applied to a Prospective Cohort Multicenter Italian Study on the Epidemiology of Acute Kidney Injury in the Intensive Care Unit

The epidemiology of acute kidney injury (AKI) has been difficult to explore in the past, due to different definitions across various studies. Nevertheless, this is a very important topic today in light of the high morbidity and mortality of critically ill patients presenting renal dysfunction during their stay in the intensive care unit (ICU). The case mix has changed over the years, and AKI is a common problem in critically ill patients often requiring renal replacement therapy (RRT). The RIFLE and AKIN initiatives have provided a unifying definition for AKI, making possible large retrospective studies in different countries. The present study aims at validating a unified web-based data collection and data management tool based on the most recent AKI definition/classification system. The interactive database is designed to elucidate the epidemiology of AKI in a critically ill population. As a test, we performed a prospective observational multicenter study designed to prospectively evaluate all incident admissions in ten ICUs in Italy and the relevant epidemiology of AKI. Thus, 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 incident 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 Simplified Acute Physiology Score II and Acute Physiology and Chronic Health Evaluation 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 (IQR 3–14) days. Of 576 patients, 246 patients (42.7%) had AKI within 24 h 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 RRT in the ICU. Patients were started on RRT a median of 2 (IQR 0–6) days after ICU admission. AKI patients were started on RRT a median of 1 (IQR 0–4) day after fulfilling criteria for AKI. Median duration of RRT was 5 (IQR 2–10) days. AKI patients had a higher crude ICU mortality (28.8 vs. 8.1%, non-AKI; p < 0.001) and longer ICU length of stay (median 7 vs. 3 days, non-AKI; p < 0.001). Crude ICU mortality and ICU length of stay increased with greater severity of AKI. 225 (59.4% of AKI patients) had complete recovery of renal function, with a serum creatinine 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. The study supports the use of RIFLE as an optimal classification system to stage AKI severity. AKI is indeed a deadly complication for ICU patients, where the level of severity is correlated with mortality and length of stay. The tool developed for data collection was user-friendly and easy to implement. Some of its features, including a RIFLE class alert system, may help the treating physician to systematically collect AKI data in the ICU and possibly may guide specific decisions on the institution of RRT.

Selection of endpoints for clinical trials of acute renal failure in critically ill patients

The selection of appropriate outcome measures is essential to the design of clinical trials of the prevention or treatment of acute renal failure in critically ill patients. In this paper, we present the consensus opinion from the second Acute Dialysis Quality Initiative Conference held in Vicenza, Italy, in May 2002, regarding the issues that should guide the selection of endpoints in clinical intervention trials of acute renal failure. Important criteria for the selection of these outcome measures include their clinical importance, responsiveness to experimental intervention, precision of definition, accuracy of measurement, and completeness of ascertainment. Although the most appropriate endpoints for individual studies are dependent on specific hypotheses and study designs, the primary endpoint in prevention trials should be based on an assessment of renal function, whereas mortality or renal functional assessment may serve as the primary endpoint in studies of established acute renal failure.

The role of advanced oxidation protein products in intensive care unit patients with acute kidney injury.

INTRODUCTION Oxidative stress (OS) is an imbalance between the production of oxidizing chemical species and the antioxidant defense. It is known that OS increases in critically ill patients with acute kidney injury (AKI). Measurement of advanced oxidation protein products (AOPPs) has been found to be a simple tool for monitoring OS. AIMS The aims of this study were to evaluate OS in intensive care unit (ICU) patients by AOPP levels and compare its levels between patients with and without AKI; we also wanted to assess the ability of AOPP to predict the development of AKI in this population. PATIENTS, MATERIAL, AND METHODS: We performed a prospective cohort study to compare AOPP levels between critically ill AKI (as defined by Risk-Injury-Failure-Loss-End Stage Renal Disease [RIFLE] criteria) and non-AKI patients. Blood samples were collected from all consecutively admitted patients upon arrival to ICU and daily for up to 4 days. We collected 234 blood samples from 86 adult medical and surgical ICU patients. The levels of AOPP were determined in the plasma and measured by spectrophotometry at 340 nm and compared between non-AKI (n = 71) and AKI patients (n = 15). We further subdivided the AKI patients according to severity of AKI (worst RIFLE class attained in ICU). RESULTS Among the 86 patients, 15 (17.44%) developed AKI during their stay in ICU, whereas 71 patients (82.56%) did not. Among the AKI patients, 5 had AKI on ICU admission, whereas 10 developed it later. The levels of AOPP were significantly higher among AKI patients compared with non-AKI patients (153.8 ± 117.8 versus 129.0 ± 114.9 μmol/L, respectively; P = .034). Patients with the most severe AKI (RIFLE class Failure) had markedly elevated AOPP levels compared with RIFLE class Risk and Injury patients (P = .012). Area under the curve of receiver operating characteristic for prediction of AKI within 48 hours after first blood sample collection was 0.5835 (P = not significant). CONCLUSIONS This is the first study to explore the relationship between severity of AKI and AOPP. In our adult ICU population, AOPP levels were higher in AKI compared with non-AKI critically ill patients. On the other hand, AOPP levels were not found to be a useful biomarker for AKI, as it was unable to identify patients who developed AKI within 24, 48, 76, and 96 hours.

Oliguria, Creatinine and Other Biomarkers of Acute Kidney Injury

Acute kidney injury (AKI) and fluid overload are conditions that require an early diagnosis and a prompt intervention. The recognition of these pathologic conditions is possible in the early stages if specific signs and symptoms are taken into account. Among them, oliguria represents an important sign. Reduced urine output for a certain number of hours may be an important sign of kidney dysfunction. This must be evaluated in conjunction with other factors such as hydration status and use of drugs. At the same time, traditional markers of kidney function such as urea nitrogen and creatinine must be evaluated in light of a possible altered balance. Increased levels may be due to reduced kidney function but also increased generation or altered solute distribution space due to non-optimal hydration status. Finally, novel biomarkers for renal tissue damage are becoming popular. Molecules such as NGAL or cystatin C may become altered well before creatinine or oliguria signal a condition of reduced kidney function. Here, the difference between insult and dysfunction becomes evident. Novel biomarkers seem to enable the clinician to make early diagnosis of kidney damage, distinguishing between AKI and acute kidney failure. Reduced glomerular filtration rate is, in fact, a late event in the continuum of the AKI syndrome.

Rationale of Extracorporeal Removal of Endotoxin in Sepsis: Theory, Timing and Technique

Several signs and symptoms in sepsis are due to the presence of endotoxin in the circulation. Both in animal and human models, there is an evident immunological response to the endotoxin insult. Furthermore, altered cardiovascular function, lung dysfunction and acute kidney injury are common in sepsis and endotoxemia. In these circumstances it would be extremely important to identify patients with sepsis in the early phases and to characterize the humoral alterations involved with it, including the identification and quantification of circulating endotoxin. Once this is obtained, it seems logical to try to remove as much of the circulating endotoxin as possible in order to mitigate the clinical effects of this condition. This can be achieved today with a very specific hemoperfusion process utilizing cartridges with immobilized polymixin B in an extracorporeal circuit. This approach seems to provide a significant removal of endotoxin with a significant reduction of its circulating levels. The clinical consequences of this approach can be summarized in a mitigation of the septic cascade in the early phases, with improvement of outcome. Recent clinical results seem to confirm these expectations showing a reduction of mortality in patients with early signs of abdominal sepsis due to recent surgery. This opens a new avenue for intervention in sepsis.