Ongoing exposure to endocrine disrupting phthalates and alternative plasticizers in neonatal intensive care unit patients.

Due to endocrine disrupting effects, di-(2-ethylhexyl) phthalate (DEHP), a plasticizer used to soften plastic medical devices, was restricted in the EU Medical Devices Regulation (EU MDR 2017/745) and gradually replaced by alternative plasticizers. Neonates hospitalized in the neonatal intensive care unit (NICU) are vulnerable to toxic effects of plasticizers. From June 2020 to August 2022, urine samples (n = 1070) were repeatedly collected from premature neonates (n = 132, 4-10 samples per patient) born at <31 weeks gestational age and/or <1500 g birth weight in the Antwerp University Hospital, Belgium. Term control neonates (n = 21, 1 sample per patient) were included from the maternity ward. Phthalate and alternative plasticizers' metabolites were analyzed using liquid-chromatography coupled to tandem mass spectrometry. Phthalate metabolites were detected in almost all urine samples. Metabolites of alternative plasticizers, di-(2-ethylhexyl)-adipate (DEHA), di-(2-ethylhexyl)-terephthalate (DEHT) and cyclohexane-1,2-dicarboxylic-di-isononyl-ester (DINCH), had detection frequencies ranging 30-95 %. Urinary phthalate metabolite concentrations were significantly higher in premature compared to control neonates (p = 0.023). NICU exposure to respiratory support devices and blood products showed increased phthalate metabolite concentrations (p < 0.001). Phthalate exposure increased from birth until four weeks postnatally. The estimated phthalate intake exceeded animal-derived no-effect-levels (DNEL) in 10 % of samples, with maximum values reaching 24 times the DNEL. 29 % of premature neonates had at least once an estimated phthalate intake above the DNEL. Preterm neonates are still exposed to phthalates during NICU stay, despite the EU Medical Devices Regulation. NICU exposure to alternative plasticizers is increasing, though currently not regulated, with insufficient knowledge on their hazard profile.

Clinical and molecular epidemiological features of critically ill patients with invasive group A Streptococcus infections: a Belgian multicenter case-series.

BACKGROUND: Recent alerts have highlighted an increase in group A streptococcal (GAS) infections since 2022 in Europe and the United States. Streptococcus pyogenes can cause limited skin or mucosal disease, but can also present as severe invasive disease necessitating critical care. We performed a multicenter retrospective study of patients with GAS infections recently admitted to Belgian intensive care units (ICUs) since January 2022. We describe patient characteristics and investigate the molecular epidemiology of the S. pyogenes strains involved. RESULTS: Between January 2022 and May 2023, a total of 86 cases (56 adults, 30 children) with GAS disease were admitted to critical care in the university hospitals of Leuven, Antwerp and Liège. We noted a strikingly high incidence of severe community-acquired pneumonia (sCAP) (45% of adults, 77% of children) complicated with empyema in 45% and 83% of adult and pediatric cases, respectively. Two-thirds of patients with S. pyogenes pneumonia had viral co-infection, with influenza (13 adults, 5 children) predominating. Other disease presentations included necrotizing fasciitis (23% of adults), other severe skin/soft tissue infections (16% of adults, 13% of children) and ear/nose/throat infections (13% of adults, 13% of children). Cardiogenic shock was frequent (36% of adults, 20% of children). Fifty-six patients (65%) had toxic shock syndrome. Organ support requirements were high and included invasive mechanical ventilation (77% of adults, 50% of children), renal replacement therapy (29% of adults, 3% of children) and extracorporeal membrane oxygenation (20% of adults, 7% of children). Mortality was 21% in adults and 3% in children. Genomic analysis of S. pyogenes strains from 55 out of 86 patients showed a predominance of emm1 strains (73%), with a replacement of the M1global lineage by the toxigenic M1UK lineage (83% of emm1 strains were M1UK). CONCLUSIONS: The recent rise of severe GAS infections (2022-23) is associated with introduction of the M1UK lineage in Belgium, but other factors may be at play-including intense circulation of respiratory viruses and potentially an immune debt after the COVID pandemic. Importantly, critical care physicians should include S. pyogenes as causative pathogen in the differential diagnosis of sCAP.

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.).

The impact of a summative national prescribing assessment and curriculum type on the development of the prescribing competence of junior doctors.

PURPOSE: The primary aim of this study was to investigate the effect of including the Dutch National Pharmacotherapy Assessment (DNPA) in the medical curriculum on the level and development of prescribing knowledge and skills of junior doctors. The secondary aim was to evaluate the relationship between the curriculum type and the prescribing competence of junior doctors. METHODS: We re-analysed the data of a longitudinal study conducted in 2016 involving recently graduated junior doctors from 11 medical schools across the Netherlands and Belgium. Participants completed three assessments during the first year after graduation (around graduation (+ / - 4 weeks), and 6 months, and 1 year after graduation), each of which contained 35 multiple choice questions (MCQs) assessing knowledge and three clinical case scenarios assessing skills. Only one medical school used the DNPA in its medical curriculum; the other medical schools used conventional means to assess prescribing knowledge and skills. Five medical schools were classified as providing solely theoretical clinical pharmacology and therapeutics (CPT) education; the others provided both theoretical and practical CPT education (mixed curriculum). RESULTS: Of the 1584 invited junior doctors, 556 (35.1%) participated, 326 (58.6%) completed the MCQs and 325 (58.5%) the clinical case scenarios in all three assessments. Junior doctors whose medical curriculum included the DNPA had higher knowledge scores than other junior doctors (76.7% [SD 12.5] vs. 67.8% [SD 12.6], 81.8% [SD 11.1] vs. 76.1% [SD 11.1], 77.0% [12.1] vs. 70.6% [SD 14.0], p < 0.05 for all three assessments, respectively). There was no difference in skills scores at the moment of graduation (p = 0.110), but after 6 and 12 months junior doctors whose medical curriculum included the DNPA had higher skills scores (both p < 0.001). Junior doctors educated with a mixed curriculum had significantly higher scores for both knowledge and skills than did junior doctors educated with a theoretical curriculum (p < 0.05 in all assessments). CONCLUSION: Our findings suggest that the inclusion of the knowledge focused DNPA in the medical curriculum improves the prescribing knowledge, but not the skills, of junior doctors at the moment of graduation. However, after 6 and 12 months, both the knowledge and skills were higher in the junior doctors whose medical curriculum included the DNPA. A curriculum that provides both theoretical and practical education seems to improve both prescribing knowledge and skills relative to a solely theoretical curriculum.

Ferroptosis and pyroptosis signatures in critical COVID-19 patients.

Critical COVID-19 patients admitted to the intensive care unit (ICU) frequently suffer from severe multiple organ dysfunction with underlying widespread cell death. Ferroptosis and pyroptosis are two detrimental forms of regulated cell death that could constitute new therapeutic targets. We enrolled 120 critical COVID-19 patients in a two-center prospective cohort study to monitor systemic markers of ferroptosis, iron dyshomeostasis, pyroptosis, pneumocyte cell death and cell damage on the first three consecutive days after ICU admission. Plasma of 20 post-operative ICU patients (PO) and 39 healthy controls (HC) without organ failure served as controls. Subsets of COVID-19 patients displayed increases in individual biomarkers compared to controls. Unsupervised clustering was used to discern latent clusters of COVID-19 patients based on biomarker profiles. Pyroptosis-related interleukin-18 accompanied by high pneumocyte cell death was independently associated with higher odds at mechanical ventilation, while the subgroup with high interleuking-1 beta (but limited pneumocyte cell death) displayed reduced odds at mechanical ventilation and lower mortality hazard. Meanwhile, iron dyshomeostasis with a tendency towards higher ferroptosis marker malondialdehyde had no association with outcome, except for the small subset of patients with very high catalytic iron independently associated with reduced survival. Forty percent of patients did not have a clear signature of the cell death mechanisms studied in this cohort. Moreover, repeated moderate levels of soluble receptor of advanced glycation end products and growth differentiation factor 15 during the first three days after ICU admission are independently associated with adverse clinical outcome compared to sustained lower levels. Altogether, the data point towards distinct subgroups in this cohort of critical COVID-19 patients with different systemic signatures of pyroptosis, iron dyshomeostasis, ferroptosis or pneumocyte cell death markers that have different outcomes in ICU. The distinct groups may allow 'personalized' treatment allocation in critical COVID-19 based on systemic biomarker profiles.

Hair as an alternative matrix to assess exposure of premature neonates to phthalate and alternative plasticizers in the neonatal intensive care unit.

Due to adverse health effects, di-(2-ethylhexyl) phthalate (DEHP), a plasticizer used to soften plastic medical devices (PMDs), was restricted, and gradually replaced by alternative plasticizers (APs). Up to this date, urine was the sole matrix studied for plasticizer exposure in neonates hospitalized in the neonatal intensive care unit (NICU), a population highly vulnerable to toxic effects of plasticizers. The primary aim of this study was to assess simultaneous measurement of phthalate and AP metabolites in neonatal scalp hair. In addition, we aimed to use this matrix to investigate exposure of premature neonates to plasticizers during their stay in the NICU. Hair samples in this study were collected from premature neonates and their mothers included in a prospective birth cohort study in a tertiary NICU at the Antwerp University Hospital (UZA), Belgium. Samples from premature neonates (n = 45) and their mothers (n = 107) as well as from control neonates (n = 24) and mothers (n = 29) were analyzed using liquid-chromatography coupled to tandem mass spectrometry. This is the first study reporting metabolites of phthalate and alternative plasticizers in neonatal hair samples as biomarkers for exposure to these plasticizers. Results showed that hair sampled from premature neonates after a NICU stay contained significantly higher metabolite concentrations of both phthalates (DEHP, DiBP, and DnBP; 9.0-2500, 9.3-2200, and 24.7-5300 ng/g), and alternative plasticizers (DEHA, DEHT, and TOTM; 38.8-3400, 127.5-5700, and 10.8-8700 ng/g) - when compared to healthy control neonates. Besides, DEHP and DEHT metabolite concentrations were significantly higher than in hair sampled from adult populations. In addition, prolonged NICU exposure to non-invasive respiratory support devices and gastric tubes was correlated with increased concentrations in hair samples, indicating accumulation of plasticizers in this alternative matrix. In conclusion, our data indicate that preterm neonates are still highly exposed to phthalate and alternative plasticizers during NICU stay, despite the EU Medical Devices Regulation.

Risk Factors Associated with Severe RSV Infection in Infants: What Is the Role of Viral Co-Infections?

The respiratory syncytial virus (RSV) represents the leading cause of viral lower respiratory tract infections (LRTI) in children worldwide and is associated with significant morbidity and mortality rates. The clinical picture of an RSV infection differs substantially between patients, and the role of viral co-infections is poorly investigated. During two consecutive winter seasons from October 2018 until February 2020, we prospectively included children up to 2 years old presenting with an acute LRTI, both ambulatory and hospitalized. We collected clinical data and tested nasopharyngeal secretions for a panel of 16 different respiratory viruses with multiplex RT-qPCR. Disease severity was assessed with traditional clinical parameters and scoring systems. A total of 120 patients were included, of which 91.7% were RSV positive; 42.5% of RSV-positive patients had a co-infection with at least one other respiratory virus. We found that patients suffering from a single RSV infection had higher pediatric intensive care unit (PICU) admission rates (OR = 5.9, 95% CI = 1.53 to 22.74), longer duration of hospitalization (IRR = 1.25, 95% CI = 1.03 to 1.52), and a higher Bronchiolitis Risk of Admission Score (BRAS) (IRR = 1.31, 95% CI = 1.02 to 1.70) compared to patients with RSV co-infections. No significant difference was found in saturation on admission, O2 need, or ReSViNET-score. In our cohort, patients with a single RSV infection had increased disease severity compared to patients with RSV co-infections. This suggests that the presence of viral co-infections might influence the course of RSV bronchiolitis, but heterogeneity and small sample size in our study prevents us from drawing strong conclusions. IMPORTANCE RSV is worldwide the leading cause of serious airway infections. Up to 90% of children will be infected by the age of 2. RSV symptoms are mostly mild and typically mimic a common cold in older children and adolescents, but younger children can develop severe lower respiratory tract disease, and currently it is unclear why certain children develop severe disease while others do not. In this study, we found that children with a single RSV infection had a higher disease severity compared to patients with viral co-infections, suggesting that the presence of a viral co-infection could influence the course of an RSV bronchiolitis. As preventive and therapeutic options for RSV-associated disease are currently limited, this finding could potentially guide physicians to decide which patients might benefit from current or future treatment options early in the course of disease, and therefore, warrants further investigation.

The effects of differing anticoagulant regimes on blood quality after cell salvage in coronary artery bypass grafting (CABG): a pilot study.

BACKGROUND: Cell salvage reduces allogenic blood transfusion requirements in surgery. We present a pilot study exploring the impact of anticoagulant choice, citrate or heparin, on the quality of cell salvaged blood in adults undergoing coronary artery bypass grafting (CABG). MATERIALS AND METHODS: Elective on pump CABG patients were randomly allocated to citrate or heparin anticoagulation. We measured red blood cell characteristics and inflammation in both the blood collection reservoir and the washed red blood cell concentrate. Postoperatively, the level of biomarkers and the coagulation profile in the peripheral blood as well as the transfusion requirements of allogenic blood products were studied. RESULTS: Thirty eight patients were included, 19 in the citrate group and 19 in the heparin group. Baseline characteristics were similar. In the washed red blood cell concentrate, Mean Hb (g/dl) and Ht (%) were lower in the citrate group [Hb: 18.1 g/dL (SD 1.3) vs. 21.1 (1.6), p < 0.001; Ht: 59.9% (54.7-60.9) vs. 63.7% (62.3-64.8); p < 0.001]; Mean corpuscular volume (MCV, µm 3) was higher [99.1fL (9.4) vs. 88 (4.2), p < 0.001] and mean corpuscular hemoglobin concentration (MCHC, g/dl) lower in the citrate group [31.9 g/dl (29.6-32.4) vs. 33.6 (33.1-34.0) p < 0.001]. Thrombocyte count (1000/µl) was higher in the citrate group [31.0 (26.0-77.0) vs. 13.0 (10.0-39.0); p = 0.006]. There were no differences in the requirement for allogenic blood products' transfusion (intraoperatively and postoperatively) or in the coagulation parameters after washed red blood cell concentrate infusion. Higher IL-10 was found in the citrate group in the blood collection reservoir, higher neutrophil-derived myeloperoxidase (MPO) in the heparin group after washed red blood cell concentrate infusion. CONCLUSION: Though red blood cells in washed red blood cell concentrate were more swollen and diluted in the citrate group with more residual thrombocytes, published quality guidelines were met in both groups. Our pilot study suggests that differences in inflammatory markers in the blood collection reservoir and after infusion of washed red blood cell concentrate indicate a possible pro-inflammatory effect of heparin compared to citrate. A larger study is warranted to confirm these results and their possible clinical consequences. Trial registration ClinicalTrials.gov : NCT02674906. Registered 5 February 2016.

Inactivation of SARS-CoV-2 and Other Enveloped and Non-Enveloped Viruses with Non-Thermal Plasma for Hospital Disinfection.

As recently highlighted by the SARS-CoV-2 pandemic, viruses have become an increasing burden for health, global economy, and environment. The control of transmission by contact with contaminated materials represents a major challenge, particularly in hospital environments. However, the current disinfection methods in hospital settings suffer from numerous drawbacks. As a result, several medical supplies that cannot be properly disinfected are not reused, leading to severe shortages and increasing amounts of waste, thus prompting the search for alternative solutions. In this work, we report that non-thermal plasma (NTP) can effectively inactivate SARS-CoV-2 from non-porous and porous materials commonly found in healthcare facilities. We demonstrated that 5 min treatment with a dielectric barrier discharge NTP can inactivate 100% of SARS-CoV-2 (Wuhan and Omicron strains) from plastic material. Using porcine respiratory coronavirus (surrogate for SARS-CoV-2) and coxsackievirus B3 (highly resistant non-enveloped virus), we tested the NTP virucidal activity on hospital materials and obtained complete inactivation after 5 and 10 min, respectively. We hypothesize that the produced reactive species and local acidification contribute to the overall virucidal effect of NTP. Our results demonstrate the potential of dielectric barrier discharge NTPs for the rapid, efficient, and low-cost disinfection of healthcare materials.

The Relationship Between Esophageal Pressure and Diaphragm Thickening Fraction in Spontaneously Breathing Sedated Children: A Feasibility Study.

OBJECTIVES: Diaphragm ultrasound is a novel alternative to esophageal pressure measurements in the evaluation of diaphragm function and activity, but data about its reliability in a pediatric setting are lacking. We aimed to compare the esophageal pressure swing (∆P es , gold standard) with the diaphragmatic thickening fraction (DTF) as a measure of inspiratory effort in sedated children. Additionally, we studied the effect of positive end-expiratory pressure (PEEP) on the end-expiratory thickness of the diaphragm (DT ee ). DESIGN: Prospective open-label non-randomized interventional physiological cohort study. SETTING: Operating room in tertiary academic hospital. PATIENTS: Children 28 days to 13 years old scheduled for elective surgery with general anesthesia, spontaneously breathing through a laryngeal mask airway, were eligible for inclusion. Exclusion criteria were disorders or previous surgery of the diaphragm, anticipated difficult airway or acute cardiopulmonary disease. All measurements were performed prior to surgery. INTERVENTIONS: Patients were subjected to different levels of respiratory load, PEEP and anesthetic depth in a total of seven respiratory conditions. MEASUREMENTS AND MAIN RESULTS: The esophageal pressure and diaphragm thickening fraction were simultaneously recorded for five breaths at each respiratory condition. The relation between ∆P es and DTF was studied in a mixed model. We analyzed 407 breaths in 13 patients. Both DTF ( p = 0.03) and ∆Pes ( p = 0.002) could detect respiratory activity, and ∆P es and DTF were associated across respiratory conditions ( p < 0.001; R2 = 31%). With increasing inspiratory load, ∆P es increased significantly, while DTF did not ( p = 0.08). Additionally, DT ee did not differ significantly between 10, 5, and 0 cm H 2 O PEEP ( p = 0.08). CONCLUSIONS: In spontaneously breathing sedated children and across different respiratory conditions, DTF could differentiate minimal or no inspiratory effort from substantial inspiratory effort and was associated with ∆P es . Increased efforts resulted in higher ∆P es but not larger DTF.

Unapparent systemic effects of regional anticoagulation with citrate in continuous renal replacement therapy: a narrative review.

The use of citrate, through reversible binding of calcium, has become the preferred choice for anticoagulation in continuous renal replacement therapy in the critically ill patient. Though generally considered as very efficacious in acute kidney injury, this type of anticoagulation can cause acid-base disorders as well as citrate accumulation and overload, phenomena which have been well described. The purpose of this narrative review is to provide an overview of some other, non-anticoagulation effects of citrate chelation during its use as anticoagulant. We highlight the effects seen on the calcium balance and hormonal status, phosphate and magnesium balance, as well as oxidative stress resulting from these unapparent effects. As most of these data on these non-anticoagulation effects have been obtained in small observational studies, new and larger studies documenting both short- and long-term effects should be undertaken. Subsequent future guidelines for citrate-based continuous renal replacement therapy should take not only the metabolic but also these unapparent effects into account.

Minimizing Lung Injury During Laparoscopy in Head-Down Tilt: A Physiological Cohort Study.

BACKGROUND: Increased intra-abdominal pressure during laparoscopy induces atelectasis. Positive end-expiratory pressure (PEEP) can alleviate atelectasis but may cause hyperinflation. Cyclic opening of collapsed alveoli and hyperinflation can lead to ventilator-induced lung injury and postoperative pulmonary complications. We aimed to study the effect of PEEP on atelectasis, lung stress, and hyperinflation during laparoscopy in the head-down (Trendelenburg) position. METHODS: An open-label, repeated-measures, interventional, physiological cohort trial was designed. All participants were recruited from a single tertiary Belgian university hospital. Twenty-three nonobese patients scheduled for laparoscopy in the Trendelenburg position were recruited.We applied a decremental PEEP protocol: 15 (high), 10 and 5 (low) cm H 2 O. Atelectasis was studied with the lung ultrasound score, the end-expiratory transpulmonary pressure, the arterial oxygen partial pressure to fraction of inspired oxygen concentration (P ao2 /Fi o2 ) ratio, and the dynamic respiratory system compliance. Global hyperinflation was evaluated by dead space volume, and regional ventilation was evaluated by lung ultrasound. Lung stress was estimated using the transpulmonary driving pressure and dynamic compliance. Data are reported as medians (25th-75th percentile). RESULTS: At 15, 10, and 5 cm H 2 O PEEP, the respective measurements were: lung ultrasound scores (%) 11 (0-22), 27 (11-39), and 53 (42-61) ( P < .001); end-expiratory transpulmonary pressures (cm H 2 O) 0.9 (-0.6 to 1.7), -0.3 (-2.0 to 0.7), and -1.9 (-4.6 to -0.9) ( P < .001); P ao2 /Fi o2 ratios (mm Hg) 471 (435-538), 458 (410-537), and 431 (358-492) ( P < .001); dynamic respiratory system compliances (mL/cm H 2 O) 32 (26-36), 30 (25-34), and 27 (22-30) ( P < .001); driving pressures (cm H 2 O) 8.2 (7.5-9.5), 9.3 (8.5-11.1), and 11.0 (10.3-12.2) ( P < .001); and alveolar dead space ventilation fractions (%) 10 (9-12), 10 (9-12), and 9 (8-12) ( P = .23). The lung ultrasound score was similar between apical and basal lung regions at each PEEP level ( P = .76, .37, and .76, respectively). CONCLUSIONS: Higher PEEP levels during laparoscopy in the head-down position facilitate lung-protective ventilation. Atelectasis and lung stress are reduced in the absence of global alveolar hyperinflation.

Neonatal exposure to phthalate and alternative plasticizers via parenteral nutrition.

Di-(2-ethylhexyl) phthalate (DEHP), a plasticizer used to soften plastic medical devices (PMDs), was restricted in PMDs due to adverse health effects, being gradually replaced by alternative plasticizers (APs). Parenteral nutrition (PN), essential in the care for premature neonates in the neonatal intensive care unit, is stored in plastic storage bags and administered intravenously through plastic infusion circuits. We investigated to which extent PN contributes to current phthalate and AP exposure in premature neonates. First, we showed that DEHP and several APs are present in relevant amounts in PMDs used for neonatal PN administration. Secondly, ex vivo experiments mimicking clinical PN administration showed that lipid emulsions contained significant concentrations of DEHP and several APs (ATBC, TOTM, DEHT & DEHA), while hardly any plasticizers were detected in non-lipid solutions. ATBC leached from infusion circuits, while lipid emulsions were the major source for DEHP, TOTM, DEHT, and DEHA. PN administration resulted in estimated daily exposures of 13.9 µg/kg/d DEHP and 95.7 µg/kg/d ATBC in premature neonates, below their respective reference doses. Our data indicate that premature neonates requiring PN are still exposed to DEHP, as well as to a range of APs, making it a target for reduction of harmful plasticizer exposure.

Fluid Management, Intra-Abdominal Hypertension and the Abdominal Compartment Syndrome: A Narrative Review.

BACKGROUND: General pathophysiological mechanisms regarding associations between fluid administration and intra-abdominal hypertension (IAH) are evident, but specific effects of type, amount, and timing of fluids are less clear. OBJECTIVES: This review aims to summarize current knowledge on associations between fluid administration and intra-abdominal pressure (IAP) and fluid management in patients at risk of intra-abdominal hypertension and abdominal compartment syndrome (ACS). METHODS: We performed a structured literature search from 1950 until May 2021 to identify evidence of associations between fluid management and intra-abdominal pressure not limited to any specific study or patient population. Findings were summarized based on the following information: general concepts of fluid management, physiology of fluid movement in patients with intra-abdominal hypertension, and data on associations between fluid administration and IAH. RESULTS: We identified three randomized controlled trials (RCTs), 38 prospective observational studies, 29 retrospective studies, 18 case reports in adults, two observational studies and 10 case reports in children, and three animal studies that addressed associations between fluid administration and IAH. Associations between fluid resuscitation and IAH were confirmed in most studies. Fluid resuscitation contributes to the development of IAH. However, patients with IAH receive more fluids to manage the effect of IAH on other organ systems, thereby causing a vicious cycle. Timing and approach to de-resuscitation are of utmost importance, but clear indicators to guide this decision-making process are lacking. In selected cases, only surgical decompression of the abdomen can stop deterioration and prevent further morbidity and mortality. CONCLUSIONS: Current evidence confirms an association between fluid resuscitation and secondary IAH, but optimal fluid management strategies for patients with IAH remain controversial.

Anti-C5a antibody (vilobelimab) therapy for critically ill, invasively mechanically ventilated patients with COVID-19 (PANAMO): a multicentre, double-blind, randomised, placebo-controlled, phase 3 trial.

BACKGROUND: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. METHODS: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO2/FiO2 ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420. FINDINGS: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. INTERPRETATION: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government.

Do we become better prescribers after graduation: A 1-year international follow-up study among junior doctors.

AIM: The aim of this study was to investigate how the prescribing knowledge and skills of junior doctors in the Netherlands and Belgium develop in the year after graduation. We also analysed differences in knowledge and skills between surgical and nonsurgical junior doctors. METHODS: This international, multicentre (n = 11), longitudinal study analysed the learning curves of junior doctors working in various specialties via three validated assessments at about the time of graduation, and 6 months and 1 year after graduation. Each assessment contained 35 multiple choice questions (MCQs) on medication safety (passing grade ≥85%) and three clinical scenarios. RESULTS: In total, 556 junior doctors participated, 326 (58.6%) of whom completed the MCQs and 325 (58.5%) the clinical case scenarios of all three assessments. Mean prescribing knowledge was stable in the year after graduation, with 69% (SD 13) correctly answering questions at assessment 1 and 71% (SD 14) at assessment 3, whereas prescribing skills decreased: 63% of treatment plans were considered adequate at assessment 1 but only 40% at assessment 3 (P < .001). While nonsurgical doctors had similar learning curves for knowledge and skills as surgical doctors (P = .53 and P = .56 respectively), their overall level was higher at all three assessments (all P < .05). CONCLUSION: These results show that junior doctors' prescribing knowledge and skills did not improve while they were working in clinical practice. Moreover, their level was under the predefined passing grade. As this might adversely affect patient safety, educational interventions should be introduced to improve the prescribing competence of junior doctors.

Identification of Potential Urinary Metabolite Biomarkers of Pseudomonas aeruginosa Ventilator-Associated Pneumonia.

Introduction: Ventilator-associated pneumonia (VAP) caused by Pseudomonas aeruginosa is a major cause of morbidity and mortality in hospital intensive care units (ICU). Rapid identification of P. aeruginosa-derived markers in easily accessible patients' samples can enable an early detection of P. aeruginosa VAP (VAP-PA), thereby stewarding antibiotic use and improving clinical outcomes. Methods: Metabolites were analysed using liquid chromatography-mass spectrometry (LC-MS) in prospectively collected urine samples from mechanically ventilated patients admitted to the Antwerp University Hospital ICU. Patients were followed from the start of mechanical ventilation (n = 100 patients) till the time of clinical diagnosis of VAP (n = 13). Patients (n = 8) in whom diagnosis of VAP was further confirmed by culturing respiratory samples and urine samples were studied for semi-quantitative metabolomics. Results: We first show that multivariate analyses highly discriminated VAP-PA from VAP-non-PA as well as from the pre-infection groups (R 2 = .97 and .98, respectively). A further univariate analysis identified 58 metabolites that were significantly elevated or uniquely present in VAP-PA compared to the VAP-non-PA and pre-infection groups (P < .05). These comprised both a known metabolite of histidine as well as a novel nicotine metabolite. Most interestingly, we identified 3 metabolites that were not only highly upregulated for, but were also highly specific to, VAP-PA, as these metabolites were completely absent in all pre-infection timepoints and in VAP-non-PA group. Conclusions: Considerable differences exist between urine metabolites in VAP-PA compared to VAP due to other bacterial aetiologies as well to non-VAP (pre-infection) timepoints. The unique urinary metabolic biomarkers we describe here, if further validated, could serve as highly specific diagnostic biomarkers of VAP-PA.

Flow-controlled ventilation in moderate acute respiratory distress syndrome due to COVID-19: an open-label repeated-measures controlled trial.

BACKGROUND: Flow-controlled ventilation (FCV), a novel mode of mechanical ventilation characterised by constant flow during active expiration, may result in more efficient alveolar gas exchange, better lung recruitment and might be useful in limiting ventilator-induced lung injury. However, data regarding FCV in mechanically ventilated patients with acute lung injury or acute respiratory distress syndrome (ARDS) are scarce. OBJECTIVES: We hypothesised that the use of FCV is feasible and would improve oxygenation in moderate COVID-19 ARDS compared to conventional ventilation. DESIGN: Open-label repeated-measures controlled trial. SETTING: From February to April 2021, patients with moderate COVID-19 ARDS were recruited in a tertiary referral intensive care unit. PATIENTS: Patients with moderate ARDS (PaO2/FIO2 ratio 100-200 mmHg, SpO2 88-94% and PaO2 60-80 mmHg) were considered eligible. Exclusion criteria were: extremes of age (< 18 years, > 80 years), obesity (body mass index > 40 kg/m2), prone positioning at the time of intervention, mechanical ventilation for more than 10 days and extracorporeal membrane oxygenation. Eleven patients were recruited. INTERVENTION: Participants were ventilated in FCV mode for 30 min, and subsequently in volume-control mode (VCV) for 30 min. MAIN OUTCOME MEASURES: Feasibility of FCV to maintain oxygenation was assessed by the PaO2/FiO2 ratio (mmHg) as a primary outcome parameter. Secondary outcomes included ventilator parameters, PaCO2 and haemodynamic data. All adverse events were recorded. RESULTS: FCV was feasible in all patients and no adverse events were observed. There was no difference in the PaO2/FIO2 ratio after 30 min of ventilation in FCV mode (169 mmHg) compared to 30 min of ventilation in VCV mode subsequently (168 mmHg, 95% CI of pseudo-medians (- 10.5, 3.6), p = 0.56). The tidal volumes (p < 0.01) and minute ventilation were lower during FCV (p = 0.01) while PaCO2 was similar at the end of the 30-min ventilation periods (p = 0.31). Mean arterial pressure during FCV was comparable to baseline. CONCLUSIONS: Thirty minutes of FCV in patients with moderate COVID-19 ARDS receiving neuromuscular blocking agents resulted in similar oxygenation, compared to VCV. FCV was feasible and did not result in adverse events. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT04894214.

The effects of antibiotic cycling and mixing on acquisition of antibiotic resistant bacteria in the ICU: A post-hoc individual patient analysis of a prospective cluster-randomized crossover study.

BACKGROUND: Repeated rotation of empiric antibiotic treatment strategies is hypothesized to reduce antibiotic resistance. Clinical rotation studies failed to change unit-wide prevalence of antibiotic resistant bacteria (ARB) carriage, including an international cluster-randomized crossover study. Unit-wide effects may differ from individual effects due to "ecological fallacy". This post-hoc analysis of a cluster-randomized crossover study assesses differences between cycling and mixing rotation strategies in acquisition of carriage with Gram-negative ARB in individual patients. METHODS: This was a controlled cluster-randomized crossover study in 7 ICUs in 5 European countries. Clinical cultures taken as routine care were used for endpoint assessment. Patients with a first negative culture and at least one culture collected in total were included. Community acquisitions (2 days of admission or less) were excluded. Primary outcome was ICU-acquisition of Enterobacterales species with reduced susceptibility to: third- or fourth generation cephalosporins or piperacillin-tazobactam, and Acinetobacter species and Pseudomonas aeruginosa with reduced susceptibility for piperacillin-tazobactam or carbapenems. Cycling (altering first-line empiric therapy for Gram-negative bacteria, every other 6-weeks), to mixing (changing antibiotic type every empiric antibiotic course). Rotated antibiotics were third- or fourth generation cephalosporins, piperacillin-tazobactam and carbapenems. RESULTS: For this analysis 1,613 admissions were eligible (855 and 758 during cycling and mixing, respectively), with 16,437 microbiological cultures obtained. Incidences of acquisition with ARB during ICU-stay were 7.3% (n = 62) and 5.1% (n = 39) during cycling and mixing, respectively (p-value 0.13), after a mean of 17.7 (median 15) and 20.8 (median 13) days. Adjusted odds ratio for acquisition of ARB carriage during mixing was 0.62 (95% CI 0.38 to 1.00). Acquired carriage with ARB were Enterobacterales species (n = 61), Pseudomonas aeruginosa (n = 38) and Acinetobacter species (n = 20), with no statistically significant differences between interventions. CONCLUSIONS: There was no statistically significant difference in individual patients' risk of acquiring carriage with Gram-negative ARB during cycling and mixing. These findings substantiate the absence of difference between cycling and mixing on the epidemiology of Gram-negative ARB in ICU. TRIAL REGISTRATION: This trial is registered with ClinicalTrials.gov, registered 10 January 2011, NCT01293071.