Nivolumab-Induced Cytokine Release Syndrome: A Case Report and Literature Review.

BACKGROUND CRS (cytokine release syndrome) is a massive activation of the inflammatory system characterized by a supra-physiological rate of inflammatory cytokines. The interleukin 6 cytokine plays a central role in CRS. The main clinical sign of CRS is fever, but CRS can lead to multiple organ failure in severe cases. CRS is usually described in sepsis, more recently in SARS COV-2 infection, and in chimeric antigen receptor T-cell therapy. However, it can also be associated with immune checkpoint inhibitors (ICIs), which is infrequently described. ICI have growing indications and can lead to CRS by causing an uncontrolled activation of the immune system. There are currently no treatment guidelines for ICI-induced CRS. CASE REPORT We report a rare case of grade 3 CRS induced by nivolumab associated with 5-fluorouracil and oxaliplatin for gastric cancer. The patient was 65-year-old man with an adenocarcinoma of the cardia. CRS developed during the tenth course of treatment and was characterized by fever, hypotension requiring vasopressors, hypoxemia, acute kidney injury, and thrombopenia. The patient was transferred quickly to the Intensive Care Unit. He was treated for suspected sepsis, but it was ruled out after multiple laboratory examinations. There was rapid resolution after infusion of hydrocortisone. CONCLUSIONS The use of ICIs is expanding. Nivolumab-induced CRS is rarely described but can be severe and lead to multiple organ dysfunction; therefore, intensive care practitioners should be informed about this adverse effect. More studies are needed to better understand this condition and establish treatment guidelines.

Interventions to improve appropriateness of laboratory testing in the intensive care unit: a narrative review.

Healthcare expenses are increasing, as is the utilization of laboratory resources. Despite this, between 20% and 40% of requested tests are deemed inappropriate. Improper use of laboratory resources leads to unwanted consequences such as hospital-acquired anemia, infections, increased costs, staff workload and patient stress and discomfort. The most unfavorable consequences result from unnecessary follow-up tests and treatments (overuse) and missed or delayed diagnoses (underuse). In this context, several interventions have been carried out to improve the appropriateness of laboratory testing. To date, there have been few published assessments of interventions specific to the intensive care unit. We reviewed the literature for interventions implemented in the ICU to improve the appropriateness of laboratory testing. We searched literature from 2008 to 2023 in PubMed, Embase, Scopus, and Google Scholar databases between April and June 2023. Five intervention categories were identified: education and guidance (E&G), audit and feedback, gatekeeping, computerized physician order entry (including reshaping of ordering panels), and multifaceted interventions (MFI). We included a sixth category exploring the potential role of artificial intelligence and machine learning (AI/ML)-based assisting tools in such interventions. E&G-based interventions and MFI are the most frequently used approaches. MFI is the most effective type of intervention, and shows the strongest persistence of effect over time. AI/ML-based tools may offer valuable assistance to the improvement of appropriate laboratory testing in the near future. Patient safety outcomes are not impaired by interventions to reduce inappropriate testing. The literature focuses mainly on reducing overuse of laboratory tests, with only one intervention mentioning underuse. We highlight an overall poor quality of methodological design and reporting and argue for standardization of intervention methods. Collaboration between clinicians and laboratory staff is key to improve appropriate laboratory utilization. This article offers practical guidance for optimizing the effectiveness of an intervention protocol designed to limit inappropriate use of laboratory resources.

Efficacy and safety of rezafungin and caspofungin in candidaemia and invasive candidiasis: pooled data from two prospective randomised controlled trials.

BACKGROUND: Rezafungin, a new US Food and Drug Administration-approved, long-acting echinocandin to treat candidaemia and invasive candidiasis, was efficacious with a similar safety profile to caspofungin in clinical trials. We conducted pooled analyses of the phase 2 STRIVE and phase 3 ReSTORE rezafungin trials. METHODS: ReSTORE was a multicentre, double-blind, double-dummy, randomised phase 3 trial conducted at 66 tertiary care centres in 15 countries. STRIVE was a multicentre, double-blind, double-dummy, randomised phase 2 trial conducted at 44 centres in 10 countries. Adults (≥18 years) with candidaemia or invasive candidiasis were treated with once-a-week intravenous rezafungin (400 mg and 200 mg) or once-a-day intravenous caspofungin (70 mg and 50 mg). Efficacy was evaluated in a pooled modified intent-to-treat (mITT) population. Primary efficacy endpoint was day 30 all-cause mortality (tested for non-inferiority with a pre-specified margin of 20%). Secondary efficacy endpoint was mycological response. Safety was also evaluated. The STRIVE and ReSTORE trials are registered with ClinicalTrials.gov, NCT02734862 and NCT03667690, and both studies are complete. FINDINGS: ReSTORE was conducted from Oct 12, 2018, to Oct 11, 2021, and STRIVE from July 26, 2016, to April 18, 2019. The mITT population, pooling the data from the two trials, comprised 139 patients for rezafungin and 155 patients for caspofungin. Day 30 all-cause mortality rates were comparable between groups (19% [26 of 139] for the rezafungin group and 19% [30 of 155] for the caspofungin group) and the upper bound of the 95% CI for the weighted treatment difference was below 10% (-1·5% [95% CI -10·7 to 7·7]). Mycological eradication occurred by day 5 in 102 (73%) of 139 rezafungin patients and 100 (65%) of 155 caspofungin patients (weighted treatment difference 10·0% [95% CI -0·3 to 20·4]). Safety profiles were similar across groups. INTERPRETATION: Rezafungin was non-inferior to caspofungin for all-cause mortality, with a potential early treatment benefit, possibly reflecting rezafungin's front-loaded dosing regimen. These findings are of clinical importance in fighting active and aggressive infections and reducing the morbidity and mortality caused by candidaemia and invasive candidiasis. FUNDING: Melinta Therapeutics and Cidara Therapeutics.

Adsorptive therapies in sepsis and inflammation: description of the various adsorptive techniques and their failure to improve outcomes.

Blood purification as an adjunctive therapy has been studied for several decades. In this review, we will focus on the most recent studies, particularly on adsorption techniques. These include hemofilters with adsorptive membranes, both endotoxin-specific and non-specific. In addition, we will discuss sorbents that target endotoxins, as well as devices that non-selectively capture viruses and bacteria. For each technique, we will also explore the reasons why blood purification methods have thus far failed to improve survival. Conventionally, reasons for the lack of success in blood purification techniques have been attributed to the need for better patient stratification through bedside measurements of interleukins and endotoxins. The choice of assay is also crucial, with endotoxin activity assays being preferable to other forms of limulus amoebocyte lysate assays. Another critical factor is timing, as administering blood purification at the wrong moment can potentially harm the patient. Mechanistic studies are still lacking for most devices, leaving us to treat patients blindly, except in endotoxin cases. In the context of viruses, especially COVID-19, we require a deeper understanding of the complexities involved in viral replication, as this could significantly impact the efficacy of blood purification techniques. The failures highlighted for each device should be viewed as potential areas for improvement. Despite the challenges, we remain hopeful that these techniques will eventually succeed and prove beneficial in the future.

Effective Treatment of Acute Tricyclic Antidepressant Poisoning with Cardiogenic Shock and Severe Rhabdomyolysis Using ECMO and CytoSorb® Adsorber.

BACKGROUND Tricyclic antidepressant (TCA) drugs are a common cause of fatal poisoning because of their cardiotoxic and arrhythmogenic effects. Classic supportive management includes sodium bicarbonate, gastrointestinal chelating agents, and vasopressors. Recently, intravenous lipid emulsion (supported by a low evidence level) has also been used. CASE REPORT We report the case of a 55-year-old woman admitted to our Intensive Care Unit (ICU) with acute imipramine self-poisoning. She arrived at the emergency department 7 hours after imipramine ingestion; she had severe rhabdomyolysis upon admission, with creatine phosphokinase levels at about 52 500 IU/L (normal, <200 IU/L). She quickly developed cardiogenic shock and malign arrhythmia requiring veno-arterial extra corporeal membrane oxygenation (VA-ECMO). Continuous renal replacement therapy (CRRT) with CytoSorb® (CytoSorbents, Monmouth Junction, New York, United Sates of America) was started 19 hours after admission. We performed serial blood measurements of imipramine and its active metabolite desipramine as well as viewing the levels on the CRRT-circuit monitor. Cardiac function improved and ECMO was explanted after 4 days. She also had severe acute respiratory distress syndrome, which resolved spontaneously. The neurologic outcome was favorable despite early myoclonus. The patient regained consciousness on the fifth day. Her clinical evolution was marked by acute ischemia of the lower left limb due to the arterial ECMO cannula. CONCLUSIONS These measurements document the efficacy of the CytoSorb® adsorber in removing a lipophilic drug from a patient's bloodstream. To our knowledge, this is the first published case of CytoSorb® extracorporeal blood purification therapy for acute TCA poisoning.

Sedation for adult ICU patients: A narrative review including a retrospective study of our own data.

The optimization of patients' treatment in the intensive care unit (ICU) needs a lot of information and literature analysis. Many changes have been made in the last years to help evaluate sedated patients by scores to help take care of them. Patients were completely sedated and had continuous intravenous analgesia and neuromuscular blockades. These three drug classes were the main drugs used for intubated patients in the ICU. During these last 20 years, ICU management went from fully sedated to awake, calm, and nonagitated patients, using less sedatives and choosing other drugs to decrease the risks of delirium during or after the ICU stay. Thus, the usefulness of these three drug classes has been challenged. The analgesic drugs used were primarily opioids but the use of other drugs instead is increasing to lessen or wean the use of opioids. In severe acute respiratory distress syndrome patients, neuromuscular blocking agents have been used frequently to block spontaneous respiration for 48 hours or more; however, this has recently been abolished. Optimizing a patient's comfort during hemodynamic or respiratory extracorporeal support is essential to reduce toxicity and secondary complications.