Carnitine Deficiency after Long-Term Continuous Renal Replacement Therapy.

A 60-year-old man was admitted in the intensive care unit (ICU) for a rapidly progressive respiratory failure due to SARS-CoV-2 infection. He developed numerous complications including acute kidney injury (AKI) requiring prolonged continuous renal replacement therapy (CRRT). Enteral feeding was initiated on day 8. Despite nutritional management, there was a remarkable amyotrophy and weight loss. On day 85 in the ICU, the patient became progressively unresponsive. An extensive metabolic workup was performed, and blood results showed hyperammoniemia and hypertriglyceridemia. Plasma free carnitine level was low, as was also copper. After carnitine supplementation, the neurological condition rapidly improved, and metabolic perturbations regressed. Prolonged CRRT may be complicated by clinically significant deficiency in micronutrients and trace elements.

New Agents in Development for Sepsis: Any Reason for Hope?

Sepsis is a syndrome which is defined as a dysregulated host response to infection leading to organ failure. Since it remains one of the leading causes of mortality worldwide, numerous drug candidates have already been tested, and continue to be developed, as potential adjunct therapies. Despite convincing mechanisms of action and robust pre-clinical data, almost all drug candidates in the field of sepsis have failed to demonstrate clinical efficacy in the past two decades. Accordingly, the development of new sepsis drugs has markedly decreased in the past few years. Nevertheless, thanks to a better understanding of sepsis pathophysiology and pathways, new promising drug candidates are currently being developed. Instead of a unique sepsis profile as initially suspected, various phenotypes have been characterised. This has  resulted in the identification of multiple targets for new drugs together with relevant biomarkers, and a better understanding of the most appropriate time to intervention. Within the entire sepsis drugs portfolio, those targeting the immune response are probably the most promising. Monoclonal antibodies targeting either cytokines or infectious agents are undoubtedly part of the potential successful therapeutic classes to come.

The impact of a rapid molecular identification test on positive blood cultures from critically ill with bacteremia: A pre-post intervention study.

OBJECTIVES: Bloodstream infections in critically ill require a speeded-up microbiological diagnosis to improve clinical outcomes. In this pre-post intervention study, we evaluated how a molecular identification test directly performed on positive blood cultures of critically ill improves patient's therapeutic management. METHODS: All adult patients staying at the intensive care unit (ICU) at the time of positive blood culture detection were study-eligible. In the 8-month pre-intervention period (P0), standard positive blood culture management was performed. In the 10-month intervention period (P1), a BioFire® FilmArray® blood culture identification (FA-BCID) test (bioMérieux) was additionally performed 24/7 at detection. The evaluated clinical outcome was time to optimal antimicrobial treatment of the bloodstream infection. FA-BCID microbiological test performances were also analysed. RESULTS: 163 positive blood culture episodes were allocated to P0 and 166 to P1. After the withdrawal of episodes in accordance with defined exclusion criteria, outcome analysis was performed on 110 bloodstream infections both in P0 and P1. Time to optimal antimicrobial treatment in P0 was 14h41 compared to 4h39 in P1. FA-BCID test results led to a treatment adjustment in 35/110 (31.8%) P1 episodes including 26 where the adjustment was the optimal antimicrobial treatment. FA-BCID testing identified 96.2% of the on-panel microorganisms thereby covering 85.2% of our ICU-strain epidemiology. Time to identification with FA-BCID testing was calculated at 1h35. Resistance detection was in complete concordance with routine results. Considering 150 FA-BCID tests were initially performed in P1, 4,3 tests were required to have 1 test leading to an improved therapeutic outcome. CONCLUSIONS: FA-BCID testing drastically reduced time to optimal antimicrobial treatment in critically ill with bloodstream infections.

Pharmacokinetics of a loading dose of amikacin in septic patients undergoing continuous renal replacement therapy.

Data on the optimal amikacin regimen during continuous renal replacement therapy (CRRT) are scarce and the proposed loading dose of 10mg/kg may result in inadequate drug levels. The aim of this study was to describe the pharmacokinetics of a 25 mg/kg first dose of amikacin in septic shock patients treated with CRRT. Serum samples were collected before (t=0 h) and at 1 (peak), 1.5, 4.5, 8 and 24 h after a 30-min amikacin infusion in 13 consecutive patients treated with a combination of amikacin and ß-lactam. Blood amikacin levels were measured using a validated fluorescence polarisation immunoassay method. In 9 patients (69%) the peak concentration was >64 mg/L, which corresponds to eight times the minimal inhibitory concentration breakpoints defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST) for Enterobacteriaceae and Pseudomonas aeruginosa (susceptible <8 mg/L, resistant >16 mg/L). The median (range) total volume of distribution was 0.50 L/kg (0.22-4.05 L/kg), the elimination half-life was 6.5h (4.5-279.6h) and total drug clearance (CL) was 1.26 mL/min/kg (0.1-3.30 mL/min/kg). Only three patients had drug concentrations at 24h (C(min)) of <5mg/L and the median predicted time needed to reach this value was 34 h (14-76 h). There was no correlation between CRRT parameters and C(min), CL or the time to C(min)<5mg/L. In septic shock patients treated with CRRT, a first dose of ≥ 25 mg/kg amikacin is therefore required to reach therapeutic peak concentrations. However, as drug clearance is reduced, amikacin concentrations remained above the threshold of renal toxicity at 24h. The therapeutic benefit of high-dose aminoglycoside therapy should be balanced with its potential renal effects in septic patients receiving CRRT.

Electrical vagus nerve stimulation and nicotine effects in peritonitis-induced acute lung injury in rats.

The cholinergic anti-inflammatory pathway has been identified as playing a key role in the communication between the central nervous system and the immune system during inflammation. The potential beneficial role of vagus nerve stimulation (VNS) remains to be clarified in established sepsis. We hypothesized that VNS or nicotine administration would reduce lung injury and mortality in established sepsis. We conducted a prospective, randomized experimental study. Four hours after peritonitis induction by cecal ligation and puncture (CLP), rats were randomized into three groups of seven animals according to the intervention: control group, VNS group (15 V, 2 ms, 5 Hz during 20 min), and nicotine group (400 µg/kg intraperitoneal). Survival was determined as lung injury score 4 and 8 h after CLP. Tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, IL-10, cytokine-induced neutrophil chemoattractant (CINC)-3 and thrombin-antithrombin complexes (TATc) were measured at baseline and at 4 and 8 h after CLP. Survival at 8 h was 71.4%, 100%, and 23.8% in the control, VNS, and nicotine groups, respectively (p < 0.05). All animals had lung damage but without significant difference between groups even if nicotine-treated animals tended to have a higher score than the controls (p = 0.09). Neutrophil polymorphonuclear (PMN) infiltration was more pronounced in the nicotine group compared with the VNS group (p = 0.015) but not with the controls. TNF-α, IL-6, IL-10, CINC-3, and TATc were elevated in all groups (NS). In this model of established sepsis, posttreatment by VNS was associated with increased survival, while nicotine administration increased lung PMN infiltration and mortality. Nicotine-induced bacterial clearance impairment and nicotine systemic effects may explain these observations.

Insufficient ß-lactam concentrations in the early phase of severe sepsis and septic shock.

INTRODUCTION: Altered pharmacokinetics (PK) in critically ill patients can result in insufficient serum ß-lactam concentrations when standard dosages are administered. Previous studies on ß-lactam PK have generally excluded the most severely ill patients, or were conducted during the steady-state period of treatment. The aim of our study was to determine whether the first dose of piperacillin-tazobactam, ceftazidime, cefepime, and meropenem would result in adequate serum drug concentrations in patients with severe sepsis and septic shock. METHODS: Open, prospective, multicenter study in four Belgian intensive care units. All consecutive patients with a diagnosis of severe sepsis or septic shock, in whom treatment with the study drugs was indicated, were included. Serum concentrations of the antibiotics were determined by high-pressure liquid chromatography (HPLC) before and 1, 1.5, 4.5 and 6 or 8 hours after administration. RESULTS: 80 patients were treated with piperacillin-tazobactam (n = 27), ceftazidime (n = 18), cefepime (n = 19) or meropenem (n = 16). Serum concentrations remained above 4 times the minimal inhibitory concentration (T > 4 × MIC), corresponding to the clinical breakpoint for Pseudomonas aeruginosa defined by the European Committee on Antimicrobial Susceptibility Testing (EUCAST), for 57% of the dosage interval for meropenem (target MIC = 8 µg/mL), 45% for ceftazidime (MIC = 32 µg/mL), 34% for cefepime (MIC = 32 µg/mL), and 33% for piperacillin-tazobactam (MIC = 64 µg/mL). The number of patients who attained the target PK profile was 12/16 for meropenem (75%), 5/18 for ceftazidime (28%), 3/19 (16%) for cefepime, and 12/27 (44%) for piperacillin-tazobactam. CONCLUSIONS: Serum concentrations of the antibiotic after the first dose were acceptable only for meropenem. Standard dosage regimens for piperacillin-tazobactam, ceftazidime and cefepime may, therefore, be insufficient to empirically cover less susceptible pathogens in the early phase of severe sepsis and septic shock.