Renal blood flow in sepsis

INTRODUCTION: To assess changes in renal blood flow (RBF) in human and experimental sepsis, and to identify determinants of RBF. METHOD: Using specific search terms we systematically interrogated two electronic reference libraries to identify experimental and human studies of sepsis and septic acute renal failure in which RBF was measured. In the retrieved studies, we assessed the influence of various factors on RBF during sepsis using statistical methods. RESULTS: We found no human studies in which RBF was measured with suitably accurate direct methods. Where it was measured in humans with sepsis, however, RBF was increased compared with normal. Of the 159 animal studies identified, 99 reported decreased RBF and 60 reported unchanged or increased RBF. The size of animal, technique of measurement, duration of measurement, method of induction of sepsis, and fluid administration had no effect on RBF. In contrast, on univariate analysis, state of consciousness of animals (P = 0.005), recovery after surgery (P < 0.001), haemodynamic pattern (hypodynamic or hyperdynamic state; P < 0.001) and cardiac output (P < 0.001) influenced RBF. However, multivariate analysis showed that only cardiac output remained an independent determinant of RBF (P < 0.001). CONCLUSION: The impact of sepsis on RBF in humans is unknown. In experimental sepsis, RBF was reported to be decreased in two-thirds of studies (62 %) and unchanged or increased in one-third (38%). On univariate analysis, several factors not directly related to sepsis appear to influence RBF. However, multivariate analysis suggests that cardiac output has a dominant effect on RBF during sepsis, such that, in the presence of a decreased cardiac output, RBF is typically decreased, whereas in the presence of a preserved or increased cardiac output RBF is typically maintained or increased

Großporige Hämofiltration bei septischen Patienten im akuten Nierenversagen

Zirkulierende inflammatorische Mediatoren spielen eine zentrale Rolle in der Induktion und Unterhaltung eines septischen Multiorganversagens (MOV). Tritt im Rahmen eines septischen MOV ein akutes Nierenversagen auf, so wird der Einsatz einer Nierenersatztherapie notwendig. Kontinuierliche Nierenersatztherapieverfahren (CRRT) haben sich hier bewährt. Der Einsatz von CRRT zur adjuvanten Therapie des septischen MOV ist in den neunziger Jahren aufgekommen. Grundlage bildet die Hypothese, dass durch die Reduktion von Spitzenpegeln pro- and anti-inflammatorischer Mediatoren im Blutplasma die Homöostase der Immunabwehr wiederhergestellt werden kann. Kommerziell erhältlichen Hämofilter weisen aufgrund ihrer Konstruktion nur eine geringe Clearanceleistung für inflammatorische Mediatoren auf. In Kooperation mit der Industrie (Gambro, Medical Research, Hechingen, Germany) entwickelten wir einen neuartigen, großporigen Hämofilter für den klinischen Einsatz. Der Hämofilter wurde konzipiert, um Moleküle in einer Größe von bis zu 60 kD aus dem Blut septischer Patienten zu eliminieren. In einer ersten Pilotstudie wurde der Hämofilter auf seine klinische Verwendbarkeit untersucht. Untersucht wurde die hämodynamische Verträglichkeit, der Verlust an Bluteiweißen und Gerinnungsfaktoren sowie die Effektivität der Mediatorelimination am Beispiel von Interleukin-6 (IL-6) und Tumornekrosefaktor-alpha (TNF-alpha). Wir konnten zeigen, dass die großporige Hämofiltrationstherapie ein sicheres und effizientes Nierenersatzverfahren darstellt. Es erwies sich als hämodynamisch verträglich. Der kumulative Eiweißverlust lag bei 8 g/Tag. Signifikante Verluste an essentiellen Gerinnungsfaktoren wurden nicht beobachtet. Es zeigte sich zudem eine signifikante Filtration von im Blut zirkulierendem IL-6. Die Clearancekapazität für TNF-alpha war jedoch gering. In Folgestudien konnten wir zeigen, dass die großporige Hämofiltration immunmodulatorische Eigenschaften ausübt. Sowohl die Phagozytose-Aktivität zirkulierender polymorphkerniger Leukozyten und Monozyten, als auch die Proliferationseigenschaften von T-Lymphozyten wurden günstig beeinflusst. Um den Verlust an Bluteiweißen durch den großporigen Hämofilter zu reduzieren, wurden verschiedene Nierenersatzstrategien experimentiert. Der diffusive Stofftransport scheint dem konvektiven Verfahren hinsichtlich der Mediatorelimination, bei deutlich günstigerem Effekt auf den Proteinhaushalt, gleichwertig zu sein. In wieweit die großporige Hämofiltration den Krankheitsverlauf septischer Patienten beeinflussen kann, ist Gegenstand aktueller Studien.Inflammatory mediators play a pivotal role in the induction and maintenance of a septic syndrome. In the course of a septic multiorgan dysfunction syndrome, acute renal failure (ARF) often necessitates the use of renal replacement therapy. Continuous renal replacement therapy (CRRT) is the treatment of choice in this regard, and convection (hemofiltration) has become the most common used purification technique. Apart from representing a valuable renal replacement modality, CRRT also allows the elimination of inflammatory mediators. Since the early nineties CRRT has been used as an adjuvant treatment strategy in the septic multiorgan failure syndrome. It has been hypothesized that CRRT may re-institute the immunologic and hemostasilogic homeostasis by reducing the peak cytokine concentration in circulating blood. Commercially available hemofilters do not allow for a substantial elimination of inflammatory mediators. Their clearance capacity for septic mediators is poor. In cooperation with an industry company (Gambro, Medical Research, Hechingen, Germany), we developed a high cut-off hemofilter for clinical use in septic patients. The hemofilter was developed in order to allow the elimination of septic mediators in the molecular weight range up to 60 kilodaltons (kD). In a first pilot study the newly developed hemofilter was analyzed for clinical feasibility. We studied the hemodynamic impact, the transmembrane loss of plasma proteins and coagulation parameters as well as the efficacy in regard to mediator elimination. For mediator elimination Interleukin-6 (IL-6) and tumor-necrosis-factor-alpha (TNF-alpha) were chosen. We were able to show, that high cut-off hemofiltration is a safe and effective renal replacement procedure. Hemodynamically high cut-off hemofiltration was well tolerated. The cumulative transmembrane total plasma protein loss was around 8g/day. Coagulation parameters were not effected. We further demonstrated, that high cut-off hemofiltration is able to significantly eliminate substantial amounts of circulating IL-6. However, the elimination capacity for TNF-alpha was poor. We were also able to show, that high cut-off hemofiltration exerts immunomodulatory properties. The phagocytotic activity of polymorphnuclear leukocytes and monocytes as well as proliferative capacity of lymphocytes were positively influenced. In order to reduced transmembrane protein losses through the high cut-off hemofilter, a variety of different renal replacement strategies were tested. Diffusive purification techniques were comparable to convective techniques in regard to the mediator elimination capacity, but were associated with significantly lower transmembrane protein losses. Whether high cut-off hemofiltration can positively influence the course of critically ill septic patients is still under investigation

N-acetylcysteine does not artifactually lower plasma creatinine concentration

Background. All randomized controlled trials of N-acetylcysteine (NAC) in contrast media-induced nephropathy used creatinine as a marker of renal function. However, it has been suggested that NAC may lower plasma creatinine levels independent of any effects on glomerular filtration rate (GFR). Methods. At a tertiary hospital 110 cardiac surgical patients were randomly allocated to peri-operative infusion of NAC (300 mg/kg over 24 h, N = 30) or placebo (N = 80). We compared the plasma concentrations of creatinine, cystatin C and urea, the plasma creatinine/plasma cystatin C ratio and the estimated GFR at baseline and at 24 and 72 h after commencement of the infusion. We measured urinary creatinine concentration at 24 h. Results. At baseline, the plasma creatinine/plasma cystatin C ratio did not differ between the NAC and placebo group (0.90 versus 0.92; P = 0.94). There was no significant difference in the plasma creatinine/plasma cystatin C ratio for the NAC and placebo group either during or after NAC infusion at 24 h (1.03 versus 1.00; P = 0.78) and 72 h (0.94 versus 0.89; P = 0.09). Those allocated to NAC showed no difference in urinary creatinine excretion when compared to placebo (P = 0.24). Conclusions. The results of our study do not demonstrate that NAC artifactually lowers creatinine measured using the Jaffé method. (ClinicalTrials.gov, NCT00332631, NCT00334191)

Phase II, randomized, controlled trial of high-dose N-acetylcysteine in high-risk cardiac surgery patients

OBJECTIVE: To assess the effect of high-dose N-acetylcysteine on renal function in cardiac surgery patients at higher risk of postoperative renal failure. DESIGN: Multiblind, placebo-controlled, randomized, phase II clinical trial. SETTING: Operating rooms and intensive care units of two tertiary referral hospitals. PATIENTS: A total of 60 cardiac surgery patients at higher risk of postoperative renal failure. INTERVENTIONS: Patients were allocated to either 24 hrs of high-dose N-acetylcysteine infusion (300 mg/kg body weight in 5% glucose, 1.7 L) or placebo (5% glucose, 1.7 L). MEASUREMENTS AND MAIN RESULTS: The primary outcome measure was the absolute change in serum creatinine from baseline to peak value within the first five postoperative days. Secondary outcomes included the relative change in serum creatinine, peak serum creatinine level, serum cystatin C, and in urinary output. Further outcomes were needed for renal replacement therapy, length of ventilation, and length of stay in the intensive care unit and hospital. Randomization was successful and patients were well balanced for preoperative and intraoperative characteristics. There was no significant attenuation in the increase in serum creatinine from baseline to peak when comparing N-acetylcysteine with placebo (64.5 ± 91.2 and 38.0 ± 42.4 μmol/L, respectively; p = .15). Also, there was no attenuation in the increase in serum cystatin C from baseline to peak for N-acetylcysteine compared with placebo (0.45 ± 0.43 and 0.30 ± 0.33 mg/L, respectively; p = .40). Likewise, there was no evidence for differences in any other clinical outcome. CONCLUSIONS: In this phase II, randomized, controlled trial, high-dose N-acetylcysteine was no more effective than placebo in attenuating cardiopulmonary bypass-related acute renal failure in high-risk cardiac surgery patients

Diuretics and mortality in acute renal failure

According to recent research, diuretics may increase mortality in acute renal failure patients. The administration of diuretics in such patients has been discouraged. Our objective was to determine the impact of diuretics on the mortality rate of critically ill patients with acute renal failure. Prospective, multiple-center, multinational epidemiologic study. Intensive care units from 54 centers and 23 countries. Patients were 1,743 consecutive patients who either were treated with renal replacement therapy or fulfilled predefined criteria for acute renal failure. Three distinct multivariate models were developed to assess the relationship between diuretic use and subsequent mortality: a) a propensity score adjusted multivariate model containing terms previously identified to be important predictors of outcome; b) a new propensity score adjusted multivariate model; and c) a multivariate model developed using standard methods, compensating for collinearity. Approximately 70% of patients were treated with diuretics at study inclusion. Mean age was 68 and mean Simplified Acute Physiology Score II was 47. Severe sepsis/septic shock (43.8%), major surgery (39.1), low cardiac output (29.7), and hypovolemia (28.2%) were the most common conditions associated with the development of acute renal failure. Furosemide was the most common diuretic used (98.3%). Combination therapy was used in 98 patients only. In all three models, diuretic use was not associated with a significantly increased risk of mortality. Diuretics are commonly prescribed in critically ill patients with acute renal failure, and their use is not associated with higher mortality. There is full equipoise for a randomized controlled trial of diuretics in critically ill patients with renal dysfunctio

Acute renal failure in critically ill patients: a multinational, multicenter study

Although acute renal failure (ARF) is believed to be common in the setting of critical illness and is associated with a high risk of death, little is known about its epidemiology and outcome or how these vary in different regions of the world. To determine the period prevalence of ARF in intensive care unit (ICU) patients in multiple countries; to characterize differences in etiology, illness severity, and clinical practice; and to determine the impact of these differences on patient outcomes. Prospective observational study of ICU patients who either were treated with renal replacement therapy (RRT) or fulfilled at least 1 of the predefined criteria for ARF from September 2000 to December 2001 at 54 hospitals in 23 countries. Occurrence of ARF, factors contributing to etiology, illness severity, treatment, need for renal support after hospital discharge, and hospital mortality. Of 29 269 critically ill patients admitted during the study period, 1738 (5.7%; 95% confidence interval [CI], 5.5%-6.0%) had ARF during their ICU stay, including 1260 who were treated with RRT. The most common contributing factor to ARF was septic shock (47.5%; 95% CI, 45.2%-49.5%). Approximately 30% of patients had preadmission renal dysfunction. Overall hospital mortality was 60.3% (95% CI, 58.0%-62.6%). Dialysis dependence at hospital discharge was 13.8% (95% CI, 11.2%-16.3%) for survivors. Independent risk factors for hospital mortality included use of vasopressors (odds ratio [OR], 1.95; 95% CI, 1.50-2.55; P <.001), mechanical ventilation (OR, 2.11; 95% CI, 1.58-2.82; P <.001), septic shock (OR, 1.36; 95% CI, 1.03-1.79; P = .03), cardiogenic shock (OR, 1.41; 95% CI, 1.05-1.90; P = .02), and hepatorenal syndrome (OR, 1.87; 95% CI, 1.07-3.28; P = .03). In this multinational study, the period prevalence of ARF requiring RRT in the ICU was between 5% and 6% and was associated with a high hospital mortality rat

Discontinuation of continuous renal replacement therapy: A post hoc analysis of a prospective multicenter observational study

Objectives: To describe current practice for the discontinuation of continuous renal replacement therapy in a multinational setting and to identify variables associated with successful discontinuation. The approach to discontinue continuous renal replacement therapy may affect patient outcomes. However, there is lack of information on how and under what conditions continuous renal replacement therapy is discontinued. Design: Post hoc analysis of a prospective observational study. Setting. Fifty-four intensive care units in 23 countries. Patients: Five hundred twenty-nine patients (52.6%) who survived initial therapy among 1006 patients treated with continuous renal replacement therapy. Interventions: None. Measurements and Main Results., Three hundred thirteen patients were removed successfully from continuous renal replacement therapy and did not require any renal replacement therapy for at least 7 days and were classified as the ""success"" group and the rest (216 patients) were classified as the ""repeat-RRT"" (renal replacement therapy) group. Patients in the ""success"" group had lower hospital mortality (28.5% vs. 42.7%, p < .0001) compared with patients in the ""repeat-RRT"" group. They also had lower creatinine and urea concentrations and a higher urine output at the time of stopping continuous renal replacement therapy. Multivariate logistic regression analysis for successful discontinuation of continuous renal replacement therapy identified urine output (during the 24 hrs before stopping continuous renal replacement therapy: odds ratio, 1.078 per 100 mL/day increase) and creatinine (odds ratio, 0.996 per mu mol/L increase) as significant predictors of successful cessation. The area under the receiver operating characteristic curve to predict successful discontinuation of continuous renal replacement therapy was 0.808 for urine output and 0.635 for creatinine. The predictive ability of urine output was negatively affected by the use of diuretics (area under the receiver operating characteristic curve, 0.671 with diuretics and 0.845 without diuretics). Conclusions. We report on the current practice of discontinuing continuous renal replacement therapy in a multinational setting. Urine output at the time of initial cessation (if continuous renal replacement therapy was the most important predictor of successful discontinuation, especially if occurring without the administration of diuretics. (Crit Care Med 2009; 37:2576-2582)Austin Hospital Anaesthesia and Intensive Care Trust Fun

Continuous renal replacement therapy: a worldwide practice survey. The beginning and ending supportive therapy for the kidney (B.E.S.T. kidney) investigators

Little information is available regarding current practice in continuous renal replacement therapy (CRRT) for the treatment of acute renal failure (ARF) and the possible clinical effect of practice variation. Prospective observational study. A total of 54 intensive care units (ICUs) in 23 countries. A cohort of 1006 ICU patients treated with CRRT for ARF. Collection of demographic, clinical and outcome data. All patients except one were treated with venovenous circuits, most commonly as venovenous hemofiltration (52.8%). Approximately one-third received CRRT without anticoagulation (33.1%). Among patients who received anticoagulation, unfractionated heparin (UFH) was the most common choice (42.9%), followed by sodium citrate (9.9%), nafamostat mesilate (6.1%), and low-molecular-weight heparin (LMWH; 4.4%). Hypotension related to CRRT occurred in 19% of patients and arrhythmias in 4.3%. Bleeding complications occurred in 3.3% of patients. Treatment with LMWH was associated with a higher incidence of bleeding complications (11.4%) compared to UFH (2.3%, p = 0.0083) and citrate (2.0%, p = 0.029). The median dose of CRRT was 20.4 ml/kg/h. Only 11.7% of patients received a dose of > 35 ml/kg/h. Most (85.5%) survivors recovered to dialysis independence at hospital discharge. Hospital mortality was 63.8%. Multivariable analysis showed that no CRRT-related variables (mode, filter material, drug for anticoagulation, and prescribed dose) predicted hospital mortality. This study supports the notion that, worldwide, CRRT practice is quite variable and not aligned with best evidenc