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Background: Rezafungin is an echinocandin approved in the US and EU to treat candidaemia and/or invasive candidiasis. This post-hoc, pooled analysis of the Phase 2 STRIVE and Phase 3 ReSTORE trials assessed rezafungin versus caspofungin in patients with candidaemia and/or invasive candidiasis (IC) in the intensive care unit (ICU) at randomisation., Methods: STRIVE and ReSTORE were randomised double-blind trials in adults with systemic signs and mycological confirmation of candidaemia and/or IC in blood or a normally sterile site ≤ 96 h before randomisation. Data were pooled for patients in the ICU at randomisation who received intravenous rezafungin (400 mg loading dose then 200 mg once weekly) or caspofungin (70 mg loading dose then 50 mg once daily) for ≤ 4 weeks. Outcomes were Day 30 all-cause mortality (primary outcome), Day 5 and 14 mycological eradication, time to negative blood culture, mortality attributable to candidaemia/invasive candidiasis, safety, and pharmacokinetics., Results: Of 294 patients in STRIVE/ReSTORE, 113 were in the ICU at randomisation (rezafungin n = 46; caspofungin n = 67). At baseline, ~ 30% of patients in each group had impaired renal function and/or an Acute Physiologic Assessment and Chronic Health Evaluation II score ≥ 20. One patient (in the caspofungin group) was neutropenic at baseline. Day 30 all-cause mortality was 34.8% for rezafungin versus 25.4% for caspofungin. Day 5 and 14 mycological eradication was 78.3% and 71.7% for rezafungin versus 59.7% and 65.7% for caspofungin, respectively. Median time to negative blood culture was 18 (interquartile range, 12.6-43.0) versus 38 (interquartile range, 15.9-211.3) h for rezafungin versus caspofungin (stratified log-rank P = 0.001; nominal, not adjusted for multiplicity). Candidaemia/IC-attributable deaths occurred in two rezafungin patients versus one caspofungin patient. Safety profiles were similar between groups. Overall, 17.4% (rezafungin) versus 29.9% (caspofungin) of patients discontinued due to treatment-emergent adverse events. Rezafungin exposure following the initial 400-mg dose was comparable between patients in the ICU at randomisation (n = 50) and non-ICU patients (n = 117)., Conclusions: Rezafungin was well tolerated and efficacious in critically ill, mainly non-neutropenic patients with candidaemia and/or IC. This analysis provides additional insights into the efficacy and safety of rezafungin in the ICU population., (© 2024. The Author(s).)

Background: Acute kidney injury (AKI) after surgery is associated with increased mortality and healthcare costs. Fenoldopam is a selective dopamine-1 receptor agonist with renoprotective properties. We conducted a systematic review and meta-analysis of randomised controlled trials comparing fenoldopam with placebo to prevent AKI after major surgery., Methods: We searched EMBASE, PubMed, meta-Register of randomised controlled trials and Cochrane CENTRAL databases for trials comparing fenoldopam with placebo in patients undergoing major surgery. The primary outcome was incidence of new AKI. Secondary outcomes were requirement for renal replacement therapy and hospital mortality., Results: Eighty-three publications were screened; 23 studies underwent full data extraction and scoring. Six trials were suitable for inclusion in the data synthesis (total of 507 subjects undergoing cardiovascular surgery, partial nephrectomy, liver transplant surgery). Five studies were rated at high risk of bias. Data on post-operative incidence of AKI were available in five of the six trials (total of 471 patients) but definitions of AKI varied between studies. Of the 238 patients receiving fenoldopam, 45 (18.9%) developed AKI compared to 62 (26.6%) of the 233 patients who received placebo (p = 0.004, I (2) = 0 %; random-effects model odds ratio 0.46, 95% confidence interval 0.27-0.79). In patients treated with fenoldopam, there was no difference in renal replacement therapy (n = 478; p = 0.11, I (2) = 47%; fixed-effect model odds ratio 0.27, 95% confidence interval 0.06-1.19) or hospital mortality (p = 0.60, I (2) = 0 %; fixed-effect model odds ratio 1.0, 95% confidence interval 0.14-7.37)., Conclusions: In this analysis, peri-operative treatment with fenoldopam was associated with a significant reduction in post-operative AKI but it had no impact on renal replacement therapy or hospital mortality. Equipoise remains for further large trials in this area since the studies were conducted in three types of surgery, the majority of studies were rated at high risk of bias and the criteria for AKI varied between trials.

Introduction: High-volume hemofiltration (HVHF) is an attractive therapy for the treatment of septic acute kidney injury (AKI). Small experimental and uncontrolled studies have suggested hemodynamic and survival benefits at higher doses of HVHF than those used for the high-intensity arms of the RENAL and ATN studies. Our aim was to evaluate the effects of high-volume hemofiltration (HVHF) compared with standard-volume hemofiltration (SVHF) for septic AKI., Methods: A systematic review and meta-analysis of publications between 1966 and 2013 was performed. The review was limited to randomized-controlled trials that compared HVHF (effluent rate greater than 50 ml/kg per hour) versus SVHF in the treatment of sepsis and septic shock. The primary outcome assessed was 28-day mortality. Other outcomes assessed were recovery of kidney function, lengths of ICU and hospital stays, vasopressor dose reduction, and adverse events., Results: Four trials, including 470 total participants, were included. Pooled analysis for 28-day mortality did not show any meaningful difference between HVHF compared with SVHF (OR, 0.76; 95% CI, 0.45 to 1.29). No included studies reported statistically significant differences between groups for any of the secondary outcomes. Adverse events, including hypophosphatemia and hypokalemia, were more commonly observed in HVHF-treated patients, although reporting was inconsistent across studies., Conclusions: Insufficient evidence exists of a therapeutic benefit for routine use of HVHF for septic AKI, other than on an experimental basis. Given the logistic challenges related to patient recruitment along with an incomplete understanding of the biologic mechanisms by which HVHF may modify outcomes, further trials should focus on alternative extracorporeal therapies as an adjuvant therapy for septic AKI rather than HVHF.

Circulating inflammatory mediators spilling into the circulation from sites of active inflammation are considered the source of remote tissue injury and associated organ dysfunction in sepsis. Hemofiltration has been proposed as a therapy for sepsis based on its ability to remove circulating inflammatory mediators by sieving or by adsorption, or both. Designing devices and methods for sepsis therapy will require optimization of these two mechanisms. In the present issue of Critical Care Forum, Kellum and Dishart report the relative effects of sieving and adsorption on plasma IL-6 following cecal ligation and puncture in rats. The authors conclude that hemoadsorption is the main mechanism of removal, and discuss some possible implications for filter design but hemoadsorption is well dependant on hemofiltration (the so-called hemofiltration filter adsorption/synergistic effect). It is important to recognize the limitations of conventional systems; Kellum and Dishart have extended our knowledge of hemofiltration filter adsorption, which is quite different from conventional hemoadsorption. If sepsis is a manifestation of a nonlinear dynamic control system out of control, then filtration at modest doses with a large pore filter may succeed as well as high-volume hemofiltration with a conventional cut-off filter. In the present paper, we will explore the strengths and the weaknesses of the 'Kellum and Dishart' study and discussing their findings in the light of the current available literature.