Federico Nalesso

Effectiveness of polymyxin B-immobilized fiber column in sepsis: a systematic review

IntroductionSevere sepsis and septic shock are common problems in the intensive care unit and carry a high mortality. Endotoxin, one of the principal components on the outer membrane of gram-negative bacteria, is considered important to their pathogenesis. Polymyxin B bound and immobilized to polystyrene fibers (PMX-F) is a medical device that aims to remove circulating endotoxin by adsorption, theoretically preventing the progression of the biological cascade of sepsis. We performed a systematic review to describe the effect in septic patients of direct hemoperfusion with PMX-F on outcomes of blood pressure, use of vasoactive drugs, oxygenation, and mortality reported in published studies.MethodsWe searched PubMed, the Cochrane Collaboration Database, and bibliographies of retrieved articles and consulted with experts to identify relevant studies. Prospective and retrospective observational studies, pre- and post-intervention design, and randomized controlled trials were included. Three authors reviewed all citations. We identified a total of 28 publications – 9 randomized controlled trials, 7 non-randomized parallel studies, and 12 pre-post design studies – that reported at least one of the specified outcome measures (pooled sample size, 1,425 patients: 978 PMX-F and 447 conventional medical therapy).ResultsOverall, mean arterial pressure (MAP) increased by 19 mm Hg (95% confidence interval [CI], 15 to 22 mm Hg; p < 0.001), representing a 26% mean increase in MAP (range, 14% to 42%), whereas dopamine/dobutamine dose decreased by 1.8 μg/kg per minute (95% CI, 0.4 to 3.3 μg/kg per minute; p = 0.01) after PMX-F. There was significant intertrial heterogeneity for these outcomes (p < 0.001), which became non-significant when analysis was stratified for baseline MAP. The mean arterial partial pressure of oxygen/fraction of inspired oxygen (PaO2/FiO2) ratio increased by 32 units (95% CI, 23 to 41 units; p < 0.001). PMX-F therapy was associated with significantly lower mortality risk (risk ratio, 0.53; 95% CI, 0.43 to 0.65). The trials assessed had suboptimal method quality.ConclusionBased on this critical review of the published literature, direct hemoperfusion with PMX-F appears to have favorable effects on MAP, dopamine use, PaO2/FiO2 ratio, and mortality. However, publication bias and lack of blinding need to be considered. These findings support the need for further rigorous study of this therapy.

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.

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.

Comparison and Reproducibility of Techniques for Fluid Status Assessment in Chronic Hemodialysis Patients.

Background: Several methods have been developed to assess the hydration status in chronic hemodialysis (HD) patients. The aim of this study was to compare body bioimpedance spectroscopy (BIS) with ultrasound (US) lung comet score (ULCs), B-type natriuretic peptide (BNP) and inferior vena cava diameter (IVCD) by US for the estimation of dry weight before and after HD and to analyze all methods in terms of fluid status variations induced by HD. An additional aim of this study was to establish the interoperator reproducibility of these methods. Methods: Two nephrologists evaluated BIS, ULCs, IVCD during inspiration (min) and expiration (max), the inferior vena cava collapsibility index (IVCCI) as well as BNP before and after HD in 30 patients. The same operators measured BIS, ULCs and IVCD in 28 HD patients in a blinded fashion. Results: There was a significant reduction in BIS, ULCs, IVCD and BNP after HD (p < 0.001), but a less significant reduction in IVCCI (p = 0.13). There was a significant correlation between BIS and ULCs, BNP and indexed IVCD (IVCDi)min (p < 0.05) before and after HD, and between BIS and IVCDimax only before HD. Conclusion: All methods were able to describe hyperhydration before and after HD, except for IVCCI after HD. All techniques correlated with BIS before HD. After HD, ULCs correlated better with BIS than IVCD in terms of evaluation of fluid status. It could be expected that the ULCs can give a real-time evaluation of interstitial water. The reproducibility of the measurement of BIS, IVCD and ULCs between the two operators was high.

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.

HLA-DR expression and apoptosis: a cross-sectional controlled study in hemodialysis and peritoneal dialysis patients.

Background: Altered HLA-DR expression and apoptosis have been described to reflect a state of immunological dysfunction in uremia. Here, we performed a cross-sectional, controlled study to evaluate monocyte HLA-DR expression and apoptosis in dialyzed chronic kidney disease patients. Methods: Monocyte HLA-DR expression was determined in 81 hemodialysis (HD) and 51 peritoneal dialysis (PD) patients and 40 healthy controls. By triple-color flow cytometry, we analyzed the percentage of monocytes in whole blood, the percentage of HLA-DR+ monocytes and the mean fluorescence intensity. Using U937 cell line incubated with the patients’ plasma, we analyzed the percentage of apoptosis induced after 96 h. Results: Both HD and PD patients had lower, but statistically not significant, monocyte HLA-DR expression compared to controls (96.47 ± 3.83% and 96.64 ± 3.29% respectively, versus 98.42 ± 1.05%). However, mean fluorescence intensity of HLA-DR was significantly higher in PD (149.35 ± 80.96) than in HD (99.20 ± 40.46), and controls (73.25 ± 27.78, p < 0.001). Apoptosis was higher in both HD and PD (35.14 ± 6.77 and 14.37 ± 5.03%) compared to controls (11.30 ± 2.03%, p < 0.001), and significantly higher in HD compared to PD. Conclusion: A reduced inflammatory state and the continuous solute removal in PD may attenuate immune dysfunction in uremia. In HD but not in PD patients, there was a significant correlation between the percentage of HLA-DR+ monocytes with apoptosis (R = 0.230, p = 0.04).

Removal of neutrophil gelatinase-associated lipocalin by extracorporeal therapies

Neutrophil gelatinase‐associated lipocalin (NGAL) protein is an early biomarker for acute kidney injury (AKI). It is unknown if extracorporeal therapies (EC) have an effect on circulating NGAL levels. This study was designed to describe the kinetics of NGAL molecule in different EC techniques and to evaluate NGAL clearance in different operational conditions. A mock hemofiltration (HF) and hemoperfusion (HP) setup was used. NGAL was added to the blood reservoir and then measured at 30‐minute intervals from arterial, venous, and ultrafiltrate (UF) lines. Removal kinetics and NGAL sieving coefficient were calculated. In our experiments, baseline NGAL concentration averaged 452 μg/L. There was a consistent downward trend throughout the experiment. NGAL concentration in the UF was between 80 and 90 μg/L, though it showed a slight increase in the second hour. The sieving coefficient of NGAL ranged from 0.2 to 0.4 during HF and it appeared to increase with time, suggesting an initial effect of membrane adsorption. HP proved clearly that there was adsorption of NGAL by the membrane and the point of saturation occured at approximately 60 minutes from the start of circulation. Our evaluation demonstrates that NGAL can be adsorbed and ultrafiltrated with polysulfone membranes. This should be taken into consideration when using NGAL as an AKI biomarker in patients undergoing EC circulation.

A wearable artificial kidney: technical requirements and potential solutions

Recently, new approaches for miniaturization and transportability of medical devices have been developed, paving the way for wearability and the possibility of implantation, for renal replacement therapies. A wearable artificial kidney (WAK) is a medical device that supports renal function during ambulation or social activities out of hospital. With the aim of improving dialysis patients’ quality of life, WAK systems have been developed for several decades. However, at present there are a lot of technical issues confronting the attempt to apply WAK systems in clinical practice. This article focuses on technical requirements and potential solutions for WAKs and reviews up-to-date approaches related to dialysis membrane, dialysate regeneration, vascular access, patient-monitoring systems and power sources for WAKs.

Extracorporeal CO2 removal--a way to achieve ultraprotective mechanical ventilation and lung support: the missing piece of multiple organ support therapy.

Extracorporeal therapies are able to sustain life through different mechanisms. This approach, called multiple organ support therapy, can in fact obtain blood purification by hemodialysis/hemofiltration to replace kidney function, temperature control, electrolyte and acid-base control to mimic homeostatic regulation of the kidney and circulation, fluid balance control to support the right hydration and cardiac performance, cardiac support removing cardiodepressant substances and equilibrating potassium levels, blood detoxification and liver support by coupled plasma filtration and adsorption or direct adsorption on blood (hemoperfusion), immunomodulation and endothelial support in the presence of sepsis by cutting the peaks of pro- and anti-inflammatory mediators, and immunoadsorption or adsorption of specific substances such as endotoxin. A missing piece of this group of therapies was the protective lung support. Today this is made possible by removal of CO(2) either by complete extracorporeal membrane oxygenation or by using decapneization in conjunction with hemofiltration in a system called DECAP/DECAPSMART. In conclusion, circulating blood outside the body and treating it with different filters or cartridges in a multiple organ support therapy may represent an important support for multiple organ dysfunction conditions induced by sepsis, acute respiratory distress syndrome and in recent times by complicated H1N1-related infections.

Oxidative stress and 'monocyte reprogramming' after kidney transplant: a longitudinal study.

Uremia has been implicated in increased oxidative stress (OS) and decreased monocyte HLA-DR expression in chronic kidney disease (CKD) patients. Thus, one would expect normalization of these parameters after successful kidney transplant (KTx). Our aim was to describe patterns of OS and HLA-DR expression after KTx and to explore the effect of renal function and different immunosuppression regimens. 30 KTx patients (20 male; 48 ± 11 years) were enrolled and compared with 20 healthy controls. We measured advanced oxidation protein products (AOPP) and the percentage of monocytes expressing HLA-DR (%DR+) before (preKTx) and after KTx (on days 2, 30, 90, 180 and after 1 year). Compared to controls, patients had a higher preKTx AOPP (152.6 vs. 69.3 µmol/l; p < 0.001). AOPP decreased at 48 h after KTx, achieving values similar to controls. Thereafter, it increased again and remained significantly higher compared to controls, returning to preKTx levels at 90 days. Prior to KTx there was a trend for lower %DR+ in KTx patients compared to controls (96 vs. 98%; NS). Following KTx, patients had a lower %DR+ in the 1st month; then it gradually returned to preKTx levels during the 1st year; at no time did it reach a value similar to controls. Cyclosporine (CyA)-treated patients had a significantly higher AOPP (161.5 vs. 99.5 µmol/l; p = 0.03) and a lower %DR+ (91.7 vs. 96.4; p < 0.05) at 30 days than patients on tacrolimus (FK). Patients on mycophenolate mofetil (MMF) showed a low AOPP (106.9 vs. 168.1 µmol/l; p = 0.05) and a high %DR+ (96.7 vs. 88.2%; p = 0.001) than those on everolimus. After 3 months, CyA-treated patients had a non-significant increase in AOPP levels, whereas those on FK showed a decrease (p < 0.05) as did those treated with MMF (p < 0.05). Successful KTx reduced but did not normalize AOPP, suggesting ongoing OS, perhaps due to persistent mild renal dysfunction and the effects of immunosuppression. HLA-DR expression remained low after KTx, which may be a possible contributing factor to infectious complications after transplantation. Immunosuppressive agents appear to have diverse effects on OS and HLA-DR expression.