Inne Hendrickx

Effects of N-acetylcysteine on Microalbuminuria and Organ Failure in Acute Severe Sepsis : Results of a Pilot Study

STUDY OBJECTIVE The level of microalbuminuria is thought to reflect the severity of inflammation-induced systemic vascular permeability and may have prognostic value with regard to organ dysfunction and survival. N-acetylcysteine (NAC) has been shown to decrease capillary leakage in experimental sepsis. The present study investigated the effect of early treatment with NAC on microalbuminuria and organ dysfunction in severe clinical sepsis. DESIGN Prospective, randomized, placebo-controlled study. SETTING A 24-bed multidisciplinary ICU in a university teaching hospital. PATIENTS Thirty-five patients included within 4 h of fulfilling consensus criteria of severe sepsis. INTERVENTIONS Patients were randomly assigned to receive either NAC (continuous infusion starting with 50 mg/kg/4 h followed by 100 mg/kg/24 h for 44 h; n = 18) or placebo (n = 17) in addition to standard therapy. MEASUREMENTS AND RESULTS Urine samples for measurement of microalbuminuria/creatinine ratio (MACR) were collected on inclusion and after 4 h, 24 h, and 48 h. Severity of illness and degree of organ failure were determined by using, respectively, the APACHE (acute physiology and chronic health evaluation) II score and the sequential organ failure assessment (SOFA) score. The MACR did not differ over time between the placebo- and the NAC-treated groups. SOFA scores were comparable between both treatment groups at baseline (6.2 +/- 3.9 vs 6.5 +/- 2.7, NAC vs placebo; p = 0.6) and increased during treatment in the NAC-treated patients but not in the placebo group (7.9 +/- 3.7 vs 5.9 +/- 2.5, p = 0.09 and 7.7 +/- 3.8 vs 5.1 +/- 2.1, p < 0.05; NAC vs placebo, respectively, at 24 h and at 48 h). The cardiovascular SOFA score progressively increased during NAC treatment, reaching higher values as compared to time-matched scores in the placebo group. CONCLUSIONS Early NAC administration does not influence the course of MACR in severe clinical sepsis, suggesting that NAC might not attenuate endothelial damage in this condition. NAC treatment even aggravated sepsis-induced organ failure, in particular cardiovascular failure.

Prevention and treatment of sepsis-induced acute kidney injury: an update

Sepsis-induced acute kidney injury (SAKI) remains an important challenge in critical care medicine. We reviewed current available evidence on prevention and treatment of SAKI with focus on some recent advances and developments. Prevention of SAKI starts with early and ample fluid resuscitation preferentially with crystalloid solutions. Balanced crystalloids have no proven superior benefit. Renal function can be evaluated by measuring lactate clearance rate, renal Doppler, or central venous oxygenation monitoring. Assuring sufficiently high central venous oxygenation most optimally prevents SAKI, especially in the post-operative setting, whereas lactate clearance better assesses mortality risk when SAKI is present. Although the adverse effects of an excessive “kidney afterload” are increasingly recognized, there is actually no consensus regarding an optimal central venous pressure. Noradrenaline is the vasopressor of choice for preventing SAKI. Intra-abdominal hypertension, a potent trigger of AKI in post-operative and trauma patients, should not be neglected in sepsis. Early renal replacement therapy (RRT) is recommended in fluid-overloaded patients’ refractory to diuretics but compelling evidence about its usefulness is still lacking. Continuous RRT (CRRT) is advocated, though not sustained by convincing data, as the preferred modality in hemodynamically unstable SAKI. Diuretics should be avoided in the absence of hypervolemia. Antimicrobial dosing during CRRT needs to be thoroughly reconsidered to assure adequate infection control.

‘Biomarking’ infection during continuous renal replacement therapy: still relevant?

We greatly appreciated the recent research article by Park and colleagues in Critical Care showing that procalcitonin (PCT) is not superior to C-reactive protein (CRP) as a marker for infection in renal impairment [1]. Additionally, we would like to comment on the validity of CRP and PCT measurement during continuous renal replacement therapy (CRRT). Both acute-phase proteins are indeed effectively cleared by CRRT. CRP is predominantly present as a monomer (mCRP) in the blood [2] and is removed by all forms of CRRT because its molecular weight (22-25 kDa) lies below the cutoff permeability limits of all classic dialysis membranes [3]. Most of the PCT mass is easily eliminated by convection [4]. However, although mCRP and PCT are adequately filtered, substantial amounts of both are adsorbed on the dialysis membrane [3, 4]. Therein lies a clinically relevant but poorly recognized problem! In fact, highly adsorptive dialysis membranes are increasingly applied to CRRT in many intensive care units worldwide. The use of such membranes will inherently accentuate mCRP and PCT removal. As a result, plasma levels of both biomarkers risk becoming falsely low during CRRT and thereby losing all potential to help clinicians diagnose or evaluate infection. The recently introduced sepsis biomarkers brain natriuretic peptide and N-terminal pro-brain natriuretic peptide have been proclaimed to be superior to CRP and PCT, but whether they perform better under CRRT is doubtful because their molecular weights (3.5 and 8.5 kDa, respectively) already predict highly effective clearance by both high- and low-flux membranes [5].

Statins and the Kidney: Friend or Foe?

Statins essentially are cholesterol-lowering drugs that are extensively prescribed for primary and secondary prevention of cardiovascular disease. Compelling evidence suggests that the beneficial effects of statins may not only be due to controlling cholesterol levels but also due to a pleiotropic cholesterol-independent anti-inflammatory, antioxidant, endothelial-protective and plaque-stabilizing activity. Along this line, statins may also exert acute and long-term effects on renal function. We present a narrative literature review that summarizes arguments in favour or against the preventive and/or therapeutic use of statins in kidney-related diseases or complications. We also highlight the ongoing controversy regarding statin therapy in chronic and end-stage kidney disease.

Biomarkers in critical illness: have we made progress?

Biomarkers have emerged as exemplary key players in translational medicine. Many have been assessed for timely recognition, early treatment, and adequate follow-up for a variety of pathologies. Biomarker sensitivity has improved considerably over the last years but specificity remains poor, in particular when two “marker-sensitive” conditions overlap in one patient. Biomarker research holds an enormous potential for diagnostic and prognostic purposes in postoperative and critically ill patients who present varying degrees of inflammation, infection, and concomitant (sub)acute organ dysfunction or failure. Despite a remarkable progress in development and testing, biomarkers are not yet ready for routine use at the bedside.

Regional Citrate Anticoagulation for Continuous Renal Replacement Therapy: All Citrates Are Not Created Equal!

also compared 2 low-concentration or diluted citrate solutions (C18 with a C10/2 (i.e. C10 + 2 mmol/l citric acid)) formula in patients treated with CVVH. None of the C10/2 patients reached a pH >7.5 but 25% had an SIDa >45 mmol/l. In the C18 group, 10% of the patients had pH values >7.5, whereas 93% were diagnosed with an SIDa >45 mmol/l. This is also reflected by the BEaRRS data. Looking only at pH, a low overall incidence of metabolic alkalosis was noticed with no difference between citrate groups. In contrast, applying the Stewart approach allowed more early identification of substantially more cases of metabolic alkalosis, particularly in the C18 group [2] . Metabolic alkalosis related to RCA is a ‘child with many fathers’. Obviously, it is directly linked to the increased SID due to the significant load of sodium from trisodium citrate, during citrate metabolization. Egi et al. [8] compared a C14 with a C11 solution (also low concentration or diluted citrate) and found more metabolic alkalosis in the C14 arm. Daily infused citrate was higher in patients receiving C14, which translated into a corresponding additional bicarbonate load that shifted acid–base balance toward metabolic alkalosis. Metabolic alkalosis, however, may also be related to the electrolyte composition of the chosen citrate liquids. Patients who received C18 in the Jacobs et al. [7] study developed hypochloremic metabolic alkalosis, which stemmed from the lower chloride content of the C18 as compared with the C10/2 solution (86 vs. 106 mmol/l). In the BEaRRS study, the 2 studied citrate solutions had similar chloride content (99 mmol/l). Yet, the C18 solution contained more sodium (152 vs.143 mmol/l), resulting in higher sodium levels throughout the study. This relative ‘hypernatremia’ significantly increased SIDa uncovering metabolic alkalosis [2, 5, 7] . Counteracting metabolic alkalosis thus depends on the inciting culprit. If citrate flow is implicated, a less concentrated citrate solution should be preferred. If hypochloremia or hypernatremia are key determinants, changing post-dilution bicarbonate substiRegional citrate anticoagulation (RCA) is increasingly preferred over unfractionated heparin (UFH) for anticoagulation during continuous renal replacement therapy (CRRT) because it improves circuit and filter lifespan (FLS) with less bleeding risk [1] . However, citrate is often blamed for creating unwarranted metabolic effects, particularly when different concentrations are used in a frail critically ill population. This is illustrated by the Base Excess and Renal Substitution Solution (BEaRSS) trial published in the same issue of Blood Purification [2] . In this study, patients on continuous veno-venous hemofiltration (CVVH) were randomly assigned to receive RCA with solutions containing either 15 mmol/l (C15) or 18 mmol/l (C18) of sodium citrate [2] . It has to be stressed that this study compares 2 different concentrations of an already low concentration (or diluted) citrate solution (15 and 18 mmol/l) as opposed to more concentrated approaches (up to >135 mm/l) used by some centers. From this study, 2 findings stand out that are relevant for RCA-CRRT practice. First, the more concentrated C18 (although low concentration or diluted citrate) formula produced a significant rise in serum sodium concentration and subsequent metabolic alkalosis [2] . Metabolic alkalosis is defined as a pH above 7.45 and becomes clinically significant when pH exceeds 7.5 [3] . At this cut-off, the dissociation of oxygen from hemoglobin gets thwarted and tissue oxygen supply decreases [3, 4] . Sustained alkalosis then may cause a reduction in coronary blood flow, hypoventilation with hypercapnia, and a systemic and cerebral blood oxygenation deficit [3, 4] . The BEaRSS investigators also assessed metabolic alkalosis by measuring pH, but concomitantly calculated the apparent strong ion difference (SIDa) according to the simplified Stewart equation ([Na + ] + [K + ] + [Mg 2+ ] + [Ca 2+ ]) – ([Cl – ] + [lactate – ]). Many clinicians consider the SIDa (normal range 40–44 mmol/l) as a more sensitive tool than pH for evaluating the incidence and severity of metabolic alkalosis in RCA-CRRT patients [5] . Jacobs et al. [6, 7] Received: June 21, 2016 Accepted: August 2, 2016 Published online: August 17, 2016

Nebulized colistin for treatment of ventilator-associated pneumonia caused by multidrug-resistant Gram-negative bacteria: we still need to straighten out the dose!

We applaud the extensive systematic review and meta-analysis by Zampieri and colleagues on inhaled antibiotics for ventilator-associated pneumonia (VAP) [1] but would like to add some comments regarding inhaled colistin for treatment of VAP caused by multidrug-resistant Gram-negative bacteria (MDR-GNB). In patients with cystic fibrosis, the equivalent of 160 mg colistimethate sodium (CMS) produced high and therapeutic endobronchial concentrations [2]. However, to be effective in VAP caused by MDR-GNB, colistin must attain pulmonary concentrations that substantially exceed minimal plasma inhibitory levels for these microorganisms. Colistin aerosols used in the predominantly retrospective and observational studies summarized by Zampieri and colleagues contained CMS doses ranging from 80 to 300 mg [1]. These doses may be insufficient to grant any significant or additional therapeutic value to inhaled colistin, especially when used together with intravenous antibiotics. Indeed, a total daily inhaled dose of 240 mg CMS was found to be inadequate to treat lung infection caused by MDR-GNB [3]. A recent review recommended inhalation of 160 mg CMS every 8 h for severe pulmonary infections [4]. Finally, a daily dose of 1,200 mg inhaled CMS used in monotherapy or associated with a 3-day course of intravenous aminoglycosides cured VAP caused by MDR-GNB as effectively as VAP caused by β-lactam susceptible GNB [5]. In contrast with intravenous administration, high doses of nebulized colistin are not associated with an increased risk of kidney injury, even when given for a prolonged period of time [5]. We strongly salute aerosolized colistin as an important alternative or adjunct therapy to treat VAP caused by MDR-GNB, provided that the daily inhaled dose is sufficiently high.

Is neutrophil gelatinase-associated lipocalin unaffected by convective continuous renal replacement therapy? Definitely … maybe

Two recent studies published in Critical Care reported that plasma [1] and urinary [2] levels of neutrophil gelatinase-associated lipocalin (NGAL), an important biomarker for prediction and diagnosis of acute kidney injury, were not affected by continuous renal replacement therapy (CRRT). The investigators assessed NGAL elimination during continuous venovenous hemofiltration [1] and hemodiafiltration [2] using respectively a cellulose triacetate [1] and a polysulfone [2] membrane filter. Of note is that these filters both have notoriously low adsorption capacity [3]. Recently, the proinflammatory high-mobility group box 1 protein, a cytokine with a molecular weight approximating that of NGAL, was also found to be unaffected by convective CRRT. However, it was significantly (up to 90 %!) cleared from the circulation when highly adsorptive membranes (i.e., surface-treated acrylonitrile 69 and polymethylmethacrylate) were used [4]. These membranes are increasingly applied for hemofiltration in critically ill patients [4]. Thus, it is imperative to evaluate NGAL clearance during convective CRRT performed with highly adsorptive membranes before definitively accepting that CRRT leaves the sensitivity of this biomarker intact.

Presepsin and sepsis-induced acute kidney injury treated with continuous renal replacement therapy: will another promising biomarker bite the dust?

A recent meta-analysis published in Critical Care proposed presepsin as a novel valuable biomarker for discriminating systemic inflammation from true sepsis [1]. Unfortunately, this excellent paper did not provide information about the occurrence and eventual treatment of acute kidney injury (AKI) in the studied population. The kidney is one of the most frequently afflicted organs during sepsis and AKI may complicate up to half of the cases of blood culture-positive septic shock [2].

Lactate: the Black Peter in high-risk gastrointestinal surgery patients

Lactate arises from metabolisation of glucose to pyruvate. Pyruvate either is transformed to or from lactate in the cytosol or converted by pyruvate dehydrogenase in mitochondria to acetyl coenzyme A which enters the Krebs cycle to produce energy for cellular metabolism. Any switch to anaerobic metabolism will reduce activity of the highly oxygen-dependent Krebs cycle and shunt “redundant” pyruvate towards lactate (1).