Convalescent Plasma for Covid-19-Induced ARDS in Mechanically Ventilated Patients.

BACKGROUND: Passive immunization with plasma collected from convalescent patients has been regularly used to treat coronavirus disease 2019 (Covid-19). Minimal data are available regarding the use of convalescent plasma in patients with Covid-19-induced acute respiratory distress syndrome (ARDS). METHODS: In this open-label trial, we randomly assigned adult patients with Covid-19-induced ARDS who had been receiving invasive mechanical ventilation for less than 5 days in a 1:1 ratio to receive either convalescent plasma with a neutralizing antibody titer of at least 1:320 or standard care alone. Randomization was stratified according to the time from tracheal intubation to inclusion. The primary outcome was death by day 28. RESULTS: A total of 475 patients underwent randomization from September 2020 through March 2022. Overall, 237 patients were assigned to receive convalescent plasma and 238 to receive standard care. Owing to a shortage of convalescent plasma, a neutralizing antibody titer of 1:160 was administered to 17.7% of the patients in the convalescent-plasma group. Glucocorticoids were administered to 466 patients (98.1%). At day 28, mortality was 35.4% in the convalescent-plasma group and 45.0% in the standard-care group (P = 0.03). In a prespecified analysis, this effect was observed mainly in patients who underwent randomization 48 hours or less after the initiation of invasive mechanical ventilation. Serious adverse events did not differ substantially between the two groups. CONCLUSIONS: The administration of plasma collected from convalescent donors with a neutralizing antibody titer of at least 1:160 to patients with Covid-19-induced ARDS within 5 days after the initiation of invasive mechanical ventilation significantly reduced mortality at day 28. This effect was mainly observed in patients who underwent randomization 48 hours or less after ventilation initiation. (Funded by the Belgian Health Care Knowledge Center; ClinicalTrials.gov number, NCT04558476.).

Safety, efficacy, and pharmacokinetics of gremubamab (MEDI3902), an anti-Pseudomonas aeruginosa bispecific human monoclonal antibody, in P. aeruginosa-colonised, mechanically ventilated intensive care unit patients: a randomised controlled trial.

BACKGROUND: Ventilator-associated pneumonia caused by Pseudomonas aeruginosa (PA) in hospitalised patients is associated with high mortality. The effectiveness of the bivalent, bispecific mAb MEDI3902 (gremubamab) in preventing PA nosocomial pneumonia was assessed in PA-colonised mechanically ventilated subjects. METHODS: EVADE (NCT02696902) was a phase 2, randomised, parallel-group, double-blind, placebo-controlled study in Europe, Turkey, Israel, and the USA. Subjects ≥ 18 years old, mechanically ventilated, tracheally colonised with PA, and without new-onset pneumonia, were randomised (1:1:1) to MEDI3902 500, 1500 mg (single intravenous dose), or placebo. The primary efficacy endpoint was the incidence of nosocomial PA pneumonia through 21 days post-dose in MEDI3902 1500 mg versus placebo, determined by an independent adjudication committee. RESULTS: Even if the initial sample size was not reached because of low recruitment, 188 subjects were randomised (MEDI3902 500/1500 mg: n = 16/87; placebo: n = 85) between 13 April 2016 and 17 October 2019. Out of these, 184 were dosed (MEDI3902 500/1500 mg: n = 16/85; placebo: n = 83), comprising the modified intent-to-treat set. Enrolment in the 500 mg arm was discontinued due to pharmacokinetic data demonstrating low MEDI3902 serum concentrations. Subsequently, enrolled subjects were randomised (1:1) to MEDI3902 1500 mg or placebo. PA pneumonia was confirmed in 22.4% (n = 19/85) of MEDI3902 1500 mg recipients and in 18.1% (n = 15/83) of placebo recipients (relative risk reduction [RRR]: - 23.7%; 80% confidence interval [CI] - 83.8%, 16.8%; p = 0.49). At 21 days post-1500 mg dose, the mean (standard deviation) serum MEDI3902 concentration was 9.46 (7.91) µg/mL, with 80.6% (n = 58/72) subjects achieving concentrations > 1.7 µg/mL, a level associated with improved outcome in animal models. Treatment-emergent adverse event incidence was similar between groups. CONCLUSIONS: The bivalent, bispecific monoclonal antibody MEDI3902 (gremubamab) did not reduce PA nosocomial pneumonia incidence in PA-colonised mechanically ventilated subjects. Trial registration Registered on Clinicaltrials.gov ( NCT02696902 ) on 11th February 2016 and on EudraCT ( 2015-001706-34 ) on 7th March 2016.

Early hyperlactatemia predicts pancreatic fistula after surgery.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a major complication after pancreatic surgery and results from an impaired healing of the pancreatic enteric anastomosis. Whether perioperative hemodynamic fluid management aiming to provide an adequate tissue perfusion could influence the occurrence of POPF is unknown. Serum lactate level is a well-recognized marker of decreased tissue perfusion and is known to be associated with higher morbidity and mortality in various postoperative settings. We aimed to determine in a retrospective high-volume center's cohort whether postoperative hyperlactatemia could predict POPF occurrence. METHOD: We conducted a retrospective analysis of 96 consecutive patients admitted in the intensive care unit (ICU) after pancreaticoduodenectomy or distal pancreatectomy. Univariate analysis was conducted to compare lactate levels at 6 h between patients evolving with versus without POPF. A logistic regression model was developed and included potential confounding factors. RESULTS: POPF occurred in 28 patients (29 %). Serum lactate level 6 h after admission was significantly higher in the POPF group (2.8 mmol/L [95 % confidence interval (CI): 2.1-3.5] versus 1.8 mmol/L [95 % CI: 1.8-2.4], p-value = 0.04) whereas it did not differ at ICU admission or at 12 h. Despite similar cumulative fluid balance, fluid intake and vasopressor use, hyperlactatemia > 2.5 mmol/L (Odds ratio (OR): 3.58; 95 % CI: 1.22-10.48; p-value = 0.020) and red blood cells transfusion (OR: 1.24; 95 % CI: 1.03-1.49; p-value = 0.022) were found to be independent predictive factors of POPF occurrence. CONCLUSION: In patients undergoing partial pancreatectomy, hyperlactatemia measured 6 h after ICU admission is a predictive factor for the occurrence of POPF. Inflammatory changes after surgery may account for this observation and should be further evaluated.

Predictive value of the heart rate reserve in patients with permanent atrial fibrillation treated according to a strict rate-control strategy.

AIMS: Atrial fibrillation (AF) patients treated according to a rate-control strategy seem to have excellent outcomes as long as their ventricular response is kept low. However, the stringency of the rate control to adopt with pharmacologic agents is not clearly defined. In particular, the clinical importance of preserving a heart rate (HR) reserve (HRR) during exercise has not yet been investigated. METHODS AND RESULTS: We prospectively analysed the HR response profiles during exercise of 202 patients with permanent AF for whom a strict rate-control strategy was the preferred treatment option. Patients were asked to perform an exercise test on a cycle ergometer until exhaustion. The HRR was defined as the difference between the HR at peak exercise and the resting HR before exercise, divided by the resting HR. Patients were followed-up for at least 24 months or until death or hospitalization for heart failure. The mean resting HR was 80 ± 16 b.p.m. After a median follow-up period of 3 ± 1 years, 31 patients (15.3%) of our initial population (80% male, age 72 ± 12 years) presented either a hospitalization for heart failure (n = 13, 6.4%) or a death (n = 18, 8.9%). Using a univariate analysis, we found that these events correlated with a lower exercise capacity [hazard ratio, HR 0.98, 95% confidence interval, CI (0.96; 0.99), P < 0.001] and a lower HRR [HR 0.30, 95% CI (0.15; 0.60), P < 0.001]. Using a multivariate analysis, both the exercise capacity [HR 0.98, 95% CI (0.97; 0.99), P = 0.008] and the HRR [HR 0.42, 95% CI (0.20-0.87), P = 0.02] remained significantly associated with the outcome. In particular, 4-year survival free from hospitalization for heart failure was better in patients with a preserved HRR (HRR >40%, P < 0.001). No correlation was found between the treatment category (i.e. beta-blockers, calcium channel antagonist, and digoxin) and the HRR. CONCLUSION: An impaired HRR in patients with permanent AF treated according to a strict rate-control strategy is associated with an increased risk of hospitalization for heart failure.

Case Report: Late Reactivation of Herpes B Virus After a Monkey Bite: A Case of Severe Meningoencephalitis.

Macacine alphaherpesvirus 1, also known as herpes B virus (BV), is an alphaherpesvirus endemic to several macaque species, capable of causing zoonotic infections in humans, with high mortality rates. Evidence of reactivation in humans has rarely been reported. Here we depict a case of BV reactivation after 54 years, leading to severe meningoencephalitis. This case supports the use of antiviral prophylaxis in patients surviving a confirmed BV central nervous system infection. We sequenced DNA from BV obtained from the patient's cerebrospinal fluid. Phylogenetic analysis showed significant divergence in the clustering of this particular BV strain compared with other known BVs. Therefore, additional efforts are needed to obtain a broader sequence landscape from BVs circulating in monkeys.

Prospective evaluation of the efficacy, safety, and optimal biomarker enrichment strategy for nangibotide, a TREM-1 inhibitor, in patients with septic shock (ASTONISH): a double-blind, randomised, controlled, phase 2b trial.

BACKGROUND: Activation of the triggering receptor expressed on myeloid cells-1 (TREM-1) pathway is associated with septic shock outcomes. Data suggest that modulation of this pathway in patients with activated TREM-1 might improve survival. Soluble TREM-1 (sTREM-1), a potential mechanism-based biomarker, might facilitate enrichment of patient selection in clinical trials of nangibotide, a TREM-1 modulator. In this phase 2b trial, we aimed to confirm the hypothesis that TREM1 inhibition might improve outcomes in patients with septic shock. METHODS: This double-blind, randomised, placebo-controlled, phase 2b trial assessed the efficacy and safety of two different doses of nangibotide compared with placebo, and aimed to identify the optimum treatment population, in patients across 42 hospitals with medical, surgical, or mixed intensive care units (ICUs) in seven countries. Non-COVID-19 patients (18-85 years) meeting the standard definition of septic shock, with documented or suspected infection (lung, abdominal, or urinary [in patients ≥65 years]), were eligible within 24 h of vasopressor initiation for the treatment of septic shock. Patients were randomly assigned in a 1:1:1 ratio to intravenous nangibotide 0·3 mg/kg per h (low-dose group), nangibotide 1·0 mg/kg per h (high-dose group), or matched placebo, using a computer-generated block randomisation scheme (block size 3). Patients and investigators were masked to treatment allocation. Patients were grouped according to sTREM-1 concentrations at baseline (established from sepsis observational studies and from phase 2a change to data) into high sTREM-1 (≥ 400 pg/mL). The primary outcome was the mean difference in total Sequential Organ Failure Assessment (SOFA) score from baseline to day 5 in the low-dose and high-dose groups compared with placebo, measured in the predefined high sTREM-1 (≥ 400 pg/mL) population and in the overall modified intention-to-treat population. Secondary endpoints included all-cause 28-day mortality, safety, pharmacokinetics, and evaluation of the relationship between TREM-1 activation and treatment response. This study is registered with EudraCT, 2018-004827-36, and Clinicaltrials.gov, NCT04055909. FINDINGS: Between Nov 14, 2019, and April 11, 2022, of 402 patients screened, 355 were included in the main analysis (116 in the placebo group, 118 in the low-dose group, and 121 in the high-dose group). In the preliminary high sTREM-1 population (total 253 [71%] of 355; placebo 75 [65%] of 116; low-dose 90 [76%] of 118; high-dose 88 [73%] of 121), the mean difference in SOFA score from baseline to day 5 was 0·21 (95% CI -1·45 to 1·87, p=0·80) in the low-dose group and 1·39 (-0·28 to 3·06, p=0·104) in the high-dose group versus placebo. In the overall population, the difference in SOFA score from baseline to day 5 between the placebo group and low-dose group was 0·20 (-1·09 to 1·50; p=0·76),and between the placebo group and the high-dose group was 1·06 (-0·23 to 2·35, p=0·108). In the predefined high sTREM-1 cutoff population, 23 (31%) patients in the placebo group, 35 (39%) in the low-dose group, and 25 (28%) in the high-dose group had died by day 28. In the overall population, 29 (25%) patients in the placebo, 38 (32%) in the low-dose, and 30 (25%) in the high-dose group had died by day 28. The number of treatment-emergent adverse events (111 [96%] patients in the placebo group, 113 [96%] in the low-dose group, and 115 [95%] in the high-dose group) and serious treatment-emergent adverse events (28 [24%], 26 [22%], and 31 [26%]) was similar between all three groups. High-dose nangibotide led to a clinically relevant improvement in SOFA score (of two points or more) from baseline to day 5 over placebo in those with higher cutoff concentrations (≥532 pg/mL) of sTREM-1 at baseline. Low dose nangibotide displayed a similar pattern with lower magnitude of effect across all cutoff values. INTERPRETATION: This trial did not achieve the primary outcome of improvement in SOFA score at the predefined sTREM-1 value. Future studies are needed to confirm the benefit of nangibotide at higher concentrations of TREM-1 activation. FUNDING: Inotrem.

Pharmacokinetic profiles of intravenous versus subcutaneous administration of low molecular weight heparin for thromboprophylaxis in critically ill patients: A randomized controlled trial.

BACKGROUND: Low molecular weight heparins (LMWH) are recommended for thromboprophylaxis in ICU patients but often fail to reach adequate peak anti-Xa activity. OBJECTIVE: To compare the pharmacokinetic profiles of intravenous (IV) versus subcutaneous (SC) route of administration of LMWH. METHOD: This was a prospective, monocentric, randomized trial. Patients were randomized to the IV route of administration with a 4-h infusion of nadroparin 3800 IU or to the SC route of administration. Randomization was stratified according to the need for vasopressor or not. Anti-Xa activity was measured at baseline, and at 1, 2, 4, 6, 8, 12 and 24 h after the administration was started. RESULTS: Sixty patients were included, of whom 30 were randomized to the IV group and 30 to the SC route. Pharmacokinetic profiles were significantly different. Mean peak anti-Xa activity was 0.38 IU/ml in the IV group vs 0.20 IU/ml in the SC group (p < 0.001). Trough values and AUC (0-24 h) were similar in both groups. Pharmacokinetic profiles were similar whether patients received vasopressors or not. CONCLUSIONS: The IV route of administration with a 4-h infusion lead to a significantly higher peak anti-Xa activity without affecting trough value or the AUC (0-24 h). Whether the IV administration of LMWH might improve the efficacy of thromboprophylaxis requires further research. REGISTRATION: ClinicalTrials.gov, NCT04982055, retrospectively registered 08 July 2021, https://clinicaltrials.gov/ct2/show/NCT04982055?cond=NCT04982055&draw=2&rank=1.

Effect of anti-interleukin drugs in patients with COVID-19 and signs of cytokine release syndrome (COV-AID): a factorial, randomised, controlled trial.

BACKGROUND: Infections with SARS-CoV-2 continue to cause significant morbidity and mortality. Interleukin (IL)-1 and IL-6 blockade have been proposed as therapeutic strategies in COVID-19, but study outcomes have been conflicting. We sought to study whether blockade of the IL-6 or IL-1 pathway shortened the time to clinical improvement in patients with COVID-19, hypoxic respiratory failure, and signs of systemic cytokine release syndrome. METHODS: We did a prospective, multicentre, open-label, randomised, controlled trial, in hospitalised patients with COVID-19, hypoxia, and signs of a cytokine release syndrome across 16 hospitals in Belgium. Eligible patients had a proven diagnosis of COVID-19 with symptoms between 6 and 16 days, a ratio of the partial pressure of oxygen to the fraction of inspired oxygen (PaO2:FiO2) of less than 350 mm Hg on room air or less than 280 mm Hg on supplemental oxygen, and signs of a cytokine release syndrome in their serum (either a single ferritin measurement of more than 2000 µg/L and immediately requiring high flow oxygen or mechanical ventilation, or a ferritin concentration of more than 1000 µg/L, which had been increasing over the previous 24 h, or lymphopenia below 800/mL with two of the following criteria: an increasing ferritin concentration of more than 700 µg/L, an increasing lactate dehydrogenase concentration of more than 300 international units per L, an increasing C-reactive protein concentration of more than 70 mg/L, or an increasing D-dimers concentration of more than 1000 ng/mL). The COV-AID trial has a 2 × 2 factorial design to evaluate IL-1 blockade versus no IL-1 blockade and IL-6 blockade versus no IL-6 blockade. Patients were randomly assigned by means of permuted block randomisation with varying block size and stratification by centre. In a first randomisation, patients were assigned to receive subcutaneous anakinra once daily (100 mg) for 28 days or until discharge, or to receive no IL-1 blockade (1:2). In a second randomisation step, patients were allocated to receive a single dose of siltuximab (11 mg/kg) intravenously, or a single dose of tocilizumab (8 mg/kg) intravenously, or to receive no IL-6 blockade (1:1:1). The primary outcome was the time to clinical improvement, defined as time from randomisation to an increase of at least two points on a 6-category ordinal scale or to discharge from hospital alive. The primary and supportive efficacy endpoints were assessed in the intention-to-treat population. Safety was assessed in the safety population. This study is registered online with ClinicalTrials.gov (NCT04330638) and EudraCT (2020-001500-41) and is complete. FINDINGS: Between April 4, and Dec 6, 2020, 342 patients were randomly assigned to IL-1 blockade (n=112) or no IL-1 blockade (n=230) and simultaneously randomly assigned to IL-6 blockade (n=227; 114 for tocilizumab and 113 for siltuximab) or no IL-6 blockade (n=115). Most patients were male (265 [77%] of 342), median age was 65 years (IQR 54-73), and median Systematic Organ Failure Assessment (SOFA) score at randomisation was 3 (2-4). All 342 patients were included in the primary intention-to-treat analysis. The estimated median time to clinical improvement was 12 days (95% CI 10-16) in the IL-1 blockade group versus 12 days (10-15) in the no IL-1 blockade group (hazard ratio [HR] 0·94 [95% CI 0·73-1·21]). For the IL-6 blockade group, the estimated median time to clinical improvement was 11 days (95% CI 10-16) versus 12 days (11-16) in the no IL-6 blockade group (HR 1·00 [0·78-1·29]). 55 patients died during the study, but no evidence for differences in mortality between treatment groups was found. The incidence of serious adverse events and serious infections was similar across study groups. INTERPRETATION: Drugs targeting IL-1 or IL-6 did not shorten the time to clinical improvement in this sample of patients with COVID-19, hypoxic respiratory failure, low SOFA score, and low baseline mortality risk. FUNDING: Belgian Health Care Knowledge Center and VIB Grand Challenges program.

Cardiogenic Shock in a Hemodialyzed Patient on Flecainide: Treatment with Intravenous Fat Emulsion, Extracorporeal Cardiac Life Support, and CytoSorb® Hemoadsorption.

A 67-year-old woman with a history of end-stage renal disease on hemodialysis received a therapeutic dose (150 mg daily) of flecainide for three weeks. She was admitted to the Emergency Department for malaise and dizziness, and the electrocardiogram revealed ventricular tachycardia treated by amiodarone. Hemodynamic condition remained stable, and the toxicity of flecainide was initially not suspected until she developed within 8 hours a cardiogenic shock requiring vasopressors. The patient then received sodium bicarbonate (300 mmol) and dobutamine but experienced cardiac arrest two hours later. The administration of intravenous fat emulsion (IFE) was associated with return of spontaneous circulation, but there was a relapse of cardiovascular shock at the end of IFE infusion. The patient was placed on extracorporeal cardiac life support (ECLS), continuous hemofiltration, and hemoadsorption using the CytoSorb® cartridge. Serial determinations of serum flecainide concentration were obtained during the course of hemoadsorption, with a terminal half-life of 3.7 h during the first four hours and a global plasma clearance of 40.3 ml/min over the first 22 hours. The weaning of ECLS was possible on day 7. Intravenous fat emulsion infusion was followed by a significant increase in serum flecainide concentration. In addition, while conventional techniques of extrarenal epuration usually appear as poorly effective for flecainide removal, a mean plasma clearance of 40.3 ml/min was observed using the hemoadsorption technique based on CytoSorb® cartridge. However, the impact on the clinical course was probably extremely modest in comparison with ECLS.

Acute ventricular wall thickening: sepsis, thrombotic microangiopathy, or myocarditis?

Background. Acute myocardial oedema has been documented in experimental models of ischemia-reperfusion injury or sepsis and is usually investigated by magnetic resonance imaging. Purpose. We describe a case of acute ventricular wall thickening documented by echocardiography in a patient developing sepsis and thrombotic microangiopathy. Case Description. A 40-year-old woman, with a history of mixed connective tissue disease, was admitted with laryngeal oedema and fever. She developed Streptococcus pneumoniae septicaemia and subsequent laboratory abnormalities were consistent with a thrombotic microangiopathy. Echocardiography revealed an impressive diffuse thickening of the whole myocardium (interventricular septum 18 mm; posterior wall 16 mm) with diffuse hypokinesia and markedly reduced left ventricular ejection fraction (31%). There was also a moderate pericardial effusion. Echocardiography was normal two months before. The patient died from acute heart failure. Macroscopic and microscopic examination of the heart suggested that the ventricular wall thickening was induced by oedematous changes, together with an excess of inflammatory cells. Conclusion. Acute ventricular wall thickening that corresponded to myocardial oedema as a first hypothesis was observed at echocardiography during the course of septicaemia complicated by thrombotic microangiopathy.

Severe rhabdomyolysis associated with simvastatin and role of ciprofloxacin and amlodipine coadministration.

Simvastatin is among the most commonly used prescription medications for cholesterol reduction and the most common statin-related adverse drug reaction is skeletal muscle toxicity. Multiple factors have been shown to influence simvastatin-induced myopathy. In addition to age, gender, ethnicity, genetic predisposition, and dose, drug-drug interactions play a major role. This is particularly true for drugs that are extensively metabolized by cytochrome P450 (CYP)3A4. We describe a particularly severe case of rhabdomyolysis after the introduction of ciprofloxacin, a weak CYP3A4 inhibitor, in a patient who previously tolerated the simvastatin-amlodipine combination.

Asymptomatic late migration of an atrial pacemaker lead into the right lung.

This report illustrates an unusual case of asymptomatic late cardiac perforation by an atrial pacemaker lead into the right lung. In the present case, the lead was explanted by simple manual traction through the device pocket without any complications.

Extensive Spinal Cord Injury following Staphylococcus aureus Septicemia and Meningitis.

Bacterial meningitis is rarely complicated by spinal cord involvement in adults. We report a case of Staphylococcus aureus septicemia complicated by meningitis and extensive spinal cord injury, leading to ascending brain stem necrosis and death. This complication was investigated by magnetic resonance imaging which demonstrated intramedullary hyperintensity on T2-weighted images and by multimodality evoked potentials. Postmortem microscopic examination confirmed that the extensive spinal cord injury was of ischemic origin, caused by diffuse leptomeningitis and endarteritis.