Zaccaria Ricci

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.

Clinical review: RIFLE and AKIN – time for reappraisal

In recent years, the use of the consensus definitions of acute kidney injury (RIFLE and AKIN) in the literature has increased substantially. This indicates a highly encouraging acceptance by the medical community of a unifying definition for acute kidney injury. This is a very important and positive step in the right direction. There remains some variation in how the criteria are interpreted and used in the literature, including use/nonuse of urine output criteria, use of change in estimated glomerular filtration rate rather than change in creatinine, and choice of baseline creatinine. The present review is intended to aid the reader in critically appraising studies using these consensus definitions. Since no single definition will be perfect, a logical next step would be to reconcile existing definitions, moving the medical community towards using a single consensus definition as has been done with sepsis and acute lung injury/acute respiratory distress syndrome. As new data emerge, integration of novel biomarkers into the consensus definition will be a welcome refinement.

Classification and staging of acute kidney injury: beyond the RIFLE and AKIN criteria

Acute kidney injury (AKI) is often overlooked in hospitalized patients, despite the fact that even mild forms are strongly associated with poor clinical outcomes such as increased mortality, morbidity, cardiovascular failure and infections. Research endorsed by the Acute Dialysis Quality Initiative led to the publication of a consensus definition for AKI—the RIFLE criteria (Risk, Injury, Failure, Loss of function, and End-stage renal disease)—which was designed to standardize and classify renal dysfunction. These criteria, along with revised versions developed by the AKI Network (AKIN), can detect AKI with high sensitivity and high specificity and describe different severity levels that aim to predict the prognosis of affected patients. The RIFLE and AKIN criteria are easy to use in a variety of clinical and research settings, but have several limitations: both utilize an increase in serum creatinine level from a hypothetical baseline value and a decrease in urine output, but these surrogate markers of renal impairment manifest relatively late after injury has occurred and do not consider the nature or site of the kidney injury. New biomarkers for AKI have shown promise for early diagnosis and prediction of the prognosis of AKI. As more data become available, they could, in the future, be incorporated into improved definitions or criteria for AKI.

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.

Prophylactic fenoldopam for renal protection in sepsis: a randomized, double-blind, placebo-controlled pilot trial.

Objective:Acute renal failure is common in septic patients. Fenoldopam, a dopamine-1 receptor agonist, increases renal blood flow and may, therefore, reduce the risk of acute renal failure in such patients. Accordingly, we sought to determine the safety and efficacy of fenoldopam for the prevention of acute renal failure in septic patients. Design:Prospective, double-blind, placebo-controlled trial. Setting:Three multidisciplinary intensive care units at a university hospital. Patients:Three hundred septic patients with baseline serum creatinine concentrations <150 &mgr;mol/L. Interventions:We randomized patients to a continuous infusion of either fenoldopam (n = 150) at 0.09 &mgr;g·kg−1·min−1 or placebo (n = 150) while in the intensive care unit. The primary outcome measure was the incidence of acute renal failure, defined as a serum creatinine concentration increase to >150 &mgr;mol/L, during study drug infusion. Measurements and main results:The incidence of acute renal failure was significantly lower in the fenoldopam group compared with the control group (29 vs. 51 patients; p = .006). The odds ratio of developing acute renal failure for patients treated with fenoldopam was estimated to be 0.47 (p = .005). The difference in the incidence of severe acute renal failure (creatinine >300 &mgr;mol/L), however, failed to achieve statistical significance (10 vs. 21; p = .056). The length of intensive care unit stay in surviving patients was significantly lower in the fenoldopam group compared with the control group (10.64 ± 9.3 vs. 13.4 ± 14.0; p < .001). There were no complications of fenoldopam infusion. A direct effect of treatment on the probability of death, beyond its effect on acute renal failure, was not significant (odds ratio = 0.68, p = .1). Conclusions:Compared with placebo, low-dose fenoldopam resulted in a smaller increase in serum creatinine in septic patients. The clinical significance of this finding is uncertain. A large multiple-center trial is now needed to confirm these findings.

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.

Extracorporeal Therapies in Non-Renal Disease: Treatment of Sepsis and the Peak Concentration Hypothesis

In the setting of intensive care, patients with acute renal failure often present a clinical picture of the systemic inflammatory response syndrome (SIRS). SIRS can be caused by bacterial stimuli or by non-microbiological stimuli that induce a significant inflammatory response. When this response is exaggerated, the patient experiences multiple organ system failure and a condition of sepsis also defined as a systemic malignant inflammation. This is mostly characterized by an invasion of cytokines and other pro-inflammatory mediators into the systemic circulation where major biological effects take place, including vasopermeabilization, hypotension and shock. At the same time, the monocyte of the septic patient seems to be hyporesponsive to inflammatory stimuli to a certain extent. In this condition, the patient faces a situation of hyperinflammation but at the same time of immunodepression expressing a clinical entity defined as counter anti-inflammatory response syndrome. The general picture of the clinical disorder is therefore better characterized by an immunodysregulation than by a simple pro- or anti-inflammatory disorder. Due to the short half-life of cytokines and other mediators spilled over into the circulation, it is extremely difficult to approach the problem at the right moment with the right pharmacological agent. For these reasons, the peak concentration hypothesis suggests that continuous renal replacement therapies, due to their continuity and unspecific capacity of removal, might be beneficial in cutting the peaks of the concentrations of both pro- and anti-inflammatory mediators, restoring a situation of immunohomeostasis. Thus the patient may benefit from a lesser degree of immunodysregulation and he/she may restore a close-to-normal capacity of response to exogenous stimuli.

Renal replacement therapy in acute kidney injury: controversy and consensus.

Renal replacement therapies (RRTs) represent a cornerstone in the management of severe acute kidney injury. This area of intensive care and nephrology has undergone significant improvement and evolution in recent years. Continuous RRTs have been a major focus of new technological and treatment strategies. RRT is being used increasingly in the intensive care unit, not only for renal indications but also for other organ-supportive strategies. Several aspects related to RRT are now well established, but others remain controversial. In this review, we review the available RRT modalities, covering technical and clinical aspects. We discuss several controversial issues, provide some practical recommendations, and where possible suggest a research agenda for the future.

Extracorporeal Ultrafiltration for the Treatment of Overhydration and Congestive Heart Failure

Fluid overload may occur in patients with congestive heart failure. Under normal conditions, this is treated with inotropic support and diuretics. However, when diuretics fail, fluid removal becomes uncontrolled and other therapeutic options must be undertaken. Extracorporeal ultrafiltration is a possible solution to restore a status of fluid balance close to normal. Several new technologies have made ultrafiltration available today in all centers and easy to be instituted. Acute isolated schedules of ultrafiltration may, however, be too aggressive and result in severe hemodynamic instability. For this reason, continuous extracorporeal techniques have been applied in such patients and the therapy is generally carried out with success. Excellent hemodynamic stability, a good cardiovascular response and often diuresis restoration are the most common effects encountered using continuous forms of extracorporeal fluid removal. The potential for a home-based application of these techniques represents a further stimulating concept to be investigated.

High-dose fenoldopam reduces postoperative neutrophil gelatinase-associated lipocaline and cystatin C levels in pediatric cardiac surgery

IntroductionThe aim of the study was to evaluate the effects of high-dose fenoldopam, a selective dopamine-1 receptor, on renal function and organ perfusion during cardiopulmonary bypass (CPB) in infants with congenital heart disease (CHD).MethodsA prospective single-center randomized double-blind controlled trial was conducted in a pediatric cardiac surgery department. We randomized infants younger than 1 year with CHD and biventricular anatomy (with exclusion of isolated ventricular and atrial septal defect) to receive blindly a continuous infusion of fenoldopam at 1 μg/kg/min or placebo during CPB. Perioperative urinary and plasma levels of neutrophil gelatinase-associated lipocaline (NGAL), cystatin C (CysC), and creatinine were measured to assess renal injury after CPB.ResultsWe enrolled 80 patients: 40 received fenoldopam (group F) during CPB, and 40 received placebo (group P). A significant increase of urinary NGAL and CysC levels from baseline to intensive care unit (ICU) admission followed by restoration of normal values after 12 hours was observed in both groups. However, urinary NGAL and CysC values were significantly reduced at the end of surgery and 12 hours after ICU admission (uNGAL only) in group F compared with group P (P = 0.025 and 0.039, respectively). Plasma NGAL and CysC tended to increase from baseline to ICU admission in both groups, but they were not significantly different between the two groups. No differences were observed on urinary and plasma creatinine levels and on urine output between the two groups. Acute kidney injury (AKI) incidence in the postoperative period, as indicated by pRIFLE classification (pediatric score indicating Risk, Injury, Failure, Loss of function, and End-stage kidney disease level of renal damage) was 50% in group F and 72% in group P (P = 0.08; odds ratio (OR), 0.38; 95% confidence interval (CI), 0.14 to 1.02). A significant reduction in diuretics (furosemide) and vasodilators (phentolamine) administration was observed in group F (P = 0.0085; OR, 0.22; 95% CI, 0.07 to 0.7).ConclusionsThe treatment with high-dose fenoldopam during CPB in pediatric patients undergoing cardiac surgery for CHD with biventricular anatomy significantly decreased urinary levels of NGAL and CysC and reduced the use of diuretics and vasodilators during CPB.Trial registrationClinical Trial.Gov NCT00982527.