Continuous vs Intermittent Meropenem Administration in Critically Ill Patients With Sepsis: The MERCY Randomized Clinical Trial.

Importance: Meropenem is a widely prescribed ß-lactam antibiotic. Meropenem exhibits maximum pharmacodynamic efficacy when given by continuous infusion to deliver constant drug levels above the minimal inhibitory concentration. Compared with intermittent administration, continuous administration of meropenem may improve clinical outcomes. Objective: To determine whether continuous administration of meropenem reduces a composite of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria compared with intermittent administration in critically ill patients with sepsis. Design, Setting, and Participants: A double-blind, randomized clinical trial enrolling critically ill patients with sepsis or septic shock who had been prescribed meropenem by their treating clinicians at 31 intensive care units of 26 hospitals in 4 countries (Croatia, Italy, Kazakhstan, and Russia). Patients were enrolled between June 5, 2018, and August 9, 2022, and the final 90-day follow-up was completed in November 2022. Interventions: Patients were randomized to receive an equal dose of the antibiotic meropenem by either continuous administration (n = 303) or intermittent administration (n = 304). Main Outcomes and Measures: The primary outcome was a composite of all-cause mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. There were 4 secondary outcomes, including days alive and free from antibiotics at day 28, days alive and free from the intensive care unit at day 28, and all-cause mortality at day 90. Seizures, allergic reactions, and mortality were recorded as adverse events. Results: All 607 patients (mean age, 64 [SD, 15] years; 203 were women [33%]) were included in the measurement of the 28-day primary outcome and completed the 90-day mortality follow-up. The majority (369 patients, 61%) had septic shock. The median time from hospital admission to randomization was 9 days (IQR, 3-17 days) and the median duration of meropenem therapy was 11 days (IQR, 6-17 days). Only 1 crossover event was recorded. The primary outcome occurred in 142 patients (47%) in the continuous administration group and in 149 patients (49%) in the intermittent administration group (relative risk, 0.96 [95% CI, 0.81-1.13], P = .60). Of the 4 secondary outcomes, none was statistically significant. No adverse events of seizures or allergic reactions related to the study drug were reported. At 90 days, mortality was 42% both in the continuous administration group (127 of 303 patients) and in the intermittent administration group (127 of 304 patients). Conclusions and Relevance: In critically ill patients with sepsis, compared with intermittent administration, the continuous administration of meropenem did not improve the composite outcome of mortality and emergence of pandrug-resistant or extensively drug-resistant bacteria at day 28. Trial Registration: ClinicalTrials.gov Identifier: NCT03452839.

Diaphragm ultrasound evaluation during weaning from mechanical ventilation in COVID-19 patients: a pragmatic, cross-section, multicenter study.

BACKGROUND: Diaphragmatic dysfunction is a major factor responsible for weaning failure in patients that underwent prolonged invasive mechanical ventilation for acute severe respiratory failure from COVID-19. This study hypothesizes that ultrasound measured diaphragmatic thickening fraction (DTF) could provide corroborating information for weaning COVID-19 patients from mechanical ventilation. METHODS: This was an observational, pragmatic, cross-section, multicenter study in 6 Italian intensive care units. DTF was assessed in COVID-19 patients undergoing weaning from mechanical ventilation from 1st March 2020 to 30th June 2021. Primary aim was to evaluate whether DTF is a predictive factor for weaning failure. RESULTS: Fifty-seven patients were enrolled, 25 patients failed spontaneous breathing trial (44%). Median length of invasive ventilation was 14 days (IQR 7-22). Median DTF within 24 h since the start of weaning was 28% (IQR 22-39%), RASS score (- 2 vs - 2; p = 0.031); Kelly-Matthay score (2 vs 1; p = 0.002); inspiratory oxygen fraction (0.45 vs 0.40; p = 0.033). PaO2/FiO2 ratio was lower (176 vs 241; p = 0.032) and length of intensive care stay was longer (27 vs 16.5 days; p = 0.025) in patients who failed weaning. The generalized linear regression model did not select any variables that could predict weaning failure. DTF was correlated with pH (RR 1.56 × 1027; p = 0.002); Kelly-Matthay score (RR 353; p < 0.001); RASS (RR 2.11; p = 0.003); PaO2/FiO2 ratio (RR 1.03; p = 0.05); SAPS2 (RR 0.71; p = 0.005); hospital and ICU length of stay (RR 1.22 and 0.79, respectively; p < 0.001 and p = 0.004). CONCLUSIONS: DTF in COVID-19 patients was not predictive of weaning failure from mechanical ventilation, and larger studies are needed to evaluate it in clinical practice further. Registered: ClinicalTrial.gov (NCT05019313, 24 August 2021).

Classification and analysis of outcome predictors in non-critically ill COVID-19 patients.

BACKGROUND: Early detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected patients who could develop a severe form of COVID-19 must be considered of great importance to carry out adequate care and optimise the use of limited resources. AIMS: To use several machine learning classification models to analyse a series of non-critically ill COVID-19 patients admitted to a general medicine ward to verify if any clinical variables recorded could predict the clinical outcome. METHODS: We retrospectively analysed non-critically ill patients with COVID-19 admitted to the general ward of the hospital in Pordenone from 1 March 2020 to 30 April 2020. Patients' characteristics were compared based on clinical outcomes. Through several machine learning classification models, some predictors for clinical outcome were detected. RESULTS: In the considered period, we analysed 176 consecutive patients admitted: 119 (67.6%) were discharged, 35 (19.9%) dead and 22 (12.5%) were transferred to intensive care unit. The most accurate models were a random forest model (M2) and a conditional inference tree model (M5) (accuracy = 0.79; 95% confidence interval 0.64-0.90, for both). For M2, glomerular filtration rate and creatinine were the most accurate predictors for the outcome, followed by age and fraction-inspired oxygen. For M5, serum sodium, body temperature and arterial pressure of oxygen and inspiratory fraction of oxygen ratio were the most reliable predictors. CONCLUSIONS: In non-critically ill COVID-19 patients admitted to a medical ward, glomerular filtration rate, creatinine and serum sodium were promising predictors for the clinical outcome. Some factors not determined by COVID-19, such as age or dementia, influence clinical outcomes.

Can Lung Ultrasound Be the Ideal Monitoring Tool to Predict the Clinical Outcome of Mechanically Ventilated COVID-19 Patients? An Observational Study.

BACKGROUND: During the COVID-19 pandemic, lung ultrasound (LUS) has been widely used since it can be performed at the patient's bedside, does not produce ionizing radiation, and is sufficiently accurate. The LUS score allows for quantifying lung involvement; however, its clinical prognostic role is still controversial. METHODS: A retrospective observational study on 103 COVID-19 patients with respiratory failure that were assessed with an LUS score at intensive care unit (ICU) admission and discharge in a tertiary university COVID-19 referral center. RESULTS: The deceased patients had a higher LUS score at admission than the survivors (25.7 vs. 23.5; p-value = 0.02; cut-off value of 25; Odds Ratio (OR) 1.1; Interquartile Range (IQR) 1.0-1.2). The predictive regression model shows that the value of LUSt0 (OR 1.1; IQR 1.0-1.3), age (OR 1.1; IQR 1.0-1.2), sex (OR 0.7; IQR 0.2-3.6), and days in spontaneous breathing (OR 0.2; IQR 0.1-0.5) predict the risk of death for COVID-19 patients (Area under the Curve (AUC) 0.92). Furthermore, the surviving patients showed a significantly lower difference between LUS scores at admission and discharge (mean difference of 1.75, p-value = 0.03). CONCLUSION: Upon entry into the ICU, the LUS score may play a prognostic role in COVID-19 patients with ARDS. Furthermore, employing the LUS score as a monitoring tool allows for evaluating the patients with a higher probability of survival.

Artificial neural network model from a case series of COVID-19 patients: a prognostic analysis.

BACKGROUND AND AIM: There is a need to determine which clinical variables predict the severity of COVID-19. We analyzed a series of critically ill COVID-19 patients to see if any of our dataset's clinical variables were associated with patient outcomes. METHODS: We retrospectively analyzed the data of COVID-19 patients admitted to the ICU of the Hospital in Pordenone from March 11, 2020, to April 17, 2020. Patients' characteristics of survivors and deceased groups were compared. The variables with a different distribution between the two groups were implemented in a generalized linear regression model (LM) and in an Artificial Neural Network (NN) model to verify the "robustness" of the association with mortality. RESULTS: In the considered period, we reviewed the data of 22 consecutive patients: 8 died. The causes of death were a severe respiratory failure (3), multi-organ failure (1), septic shock (1), pulmonary thromboembolism (2), severe hemorrhage (1). Lymphocyte and the platelet count were significantly lower in the group of deceased patients (p-value 0.043 and 0.020, respectively; cut-off values: 660/mm3; 280,000/mm3, respectively). Prothrombin time showed a statistically significant trend (p-value= 0.065; cut-off point: 16.8/sec). The LM model (AIC= 19.032), compared to the NN model (Mean Absolute Error, MAE = 0.02), was substantially alike (MSE 0.159 vs. 0.136). CONCLUSIONS: In the context of critically ill COVID-19 patients admitted to ICU, lymphocytopenia, thrombocytopenia, and lengthening of prothrombin time were strictly correlated with higher mortality. Additional clinical data are needed to be able to validate this prognostic score.

Continuous infusion versus intermittent administration of meropenem in critically ill patients (MERCY): A multicenter randomized double-blind trial. Rationale and design.

OBJECTIVE: Meropenem is a ß-lactam, carbapenem antibacterial agent with antimicrobial activity against gram-negative, gram-positive and anaerobic micro-organisms and is important in the empirical treatment of serious infections in Intensive Care Unit (ICU) patients. Multi-drug resistant gram-negative organisms, coupled with scarcity of new antibiotic classes, forced healthcare community to optimize the therapeutic potential of available antibiotics. Our aim is to investigate the effect of continuous infusion of meropenem against bolus administration, as indicated by a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens in a population of ICU patients. DESIGN: Double blind, double dummy, multicenter randomized controlled trial (1:1 allocation ratio). SETTING: Tertiary and University hospitals. INTERVENTIONS: 600 ICU patients with sepsis or septic shock, needing by clinical judgment antibiotic therapy with meropenem, will be randomized to receive a continuous infusion of meropenem 3 g/24 h or an equal dose divided into three daily boluses (i.e. 1g q8h). MEASUREMENTS: The primary endpoint will be a composite outcome of reducing death and emergence of extensive or pan drug-resistant pathogens. Secondary endpoints will be death from any cause at day 90, antibiotic-free days at day 28, ICU-free days at day 28, cumulative SOFA-free (Sequential Organ Failure Assessment) score from randomization to day 28 and the two, separate, components of the primary endpoint. We expect a primary outcome reduction from 52 to 40% in the continuous infusion group. CONCLUSIONS: The trial will provide evidence for choosing intermittent or continuous infusion of meropenem for critically ill patients with multi-drug resistant gram-negative infections.

Endotracheal intubation to reduce aspiration events in acutely comatose patients: a systematic review.

BACKGROUND: It is customary to believe that a patient with a Glasgow Coma Scale (GCS) score less than or equal to 8 should be intubated to avoid aspiration. We conducted a systematic review to establish if patients with GCS ≤ 8 for trauma or non-traumatic emergencies and treated in the acute care setting (e.g., Emergency Department or Pre-hospital environment) should be intubated to avoid aspiration or aspiration pneumonia/pneumonitis, and consequently, reduce mortality. METHODS: We searched six databases, Pubmed, Embase, Scopus, SpringerLink, Cochrane Library, and Ovid Emcare, from April 15th to October 14th, 2020, for studies involving low GCS score patients of whom the risk of aspiration and related complications was assessed. RESULTS: Thirteen studies were included in the final analysis (7 on non-traumatic population, 4 on trauma population, 1 pediatric and 1 adult mixed case studies). For the non-traumatic cases, two prospective studies and one retrospective study found no difference in aspiration risk between intubated and non-intubated patients. Two retrospective studies reported a reduction in the risk of aspiration in the intubated patient group. For traumatic cases, the study that considered the risk of aspiration did not show any differences between the two groups. A study on adult mixed cases found no difference in the incidence of aspiration among intubated and non-intubated patients. A study on pediatric patients found increased mortality for intubated versus non-intubated non-traumatic patients with a low GCS score. CONCLUSION: Whether intubation results in a reduction in the incidence of aspiration events and whether these are more frequent in patients with low GCS scores are not yet established. The paucity of evidence on this topic makes clinical trials justifiable and necessary. TRIAL REGISTRATION: Prospero registration number: CRD42020136987 .