Objectives: To assess the effect of anticoagulation with bivalirudin administered intravenously on gas-exchange in patients with COVID-19 and respiratory failure using invasive mechanical ventilation. Trial design: This is a single centre parallel group, superiority, randomized (1:1 allocation ratio) controlled trial. Participants: All patients admitted to the Hamad Medical Corporation -ICU in Qatar for COVID-19 associated respiratory distress and in need of mechanical ventilation are screened for eligibility. Inclusion criteria: all adult patients admitted to the ICU who test positive for COVID-19 by PCR-test and in need for mechanical ventilation are eligible for inclusion. Upon crossing the limit of D-dimers (1.2 mg/L) these patients are routinely treated with an increased dose of anticoagulant according to our local protocol. This will be the start of randomization. Exclusion criteria: pregnancy, allergic to the drug, inherited coagulation abnormalities, no informed consent. Intervention and comparator: The intervention group will receive the anticoagulant bivalirudin intravenously with a target aPTT of 45-70 sec for three days while the control group will stay on the standard treatment with low-molecular-weight heparins /unfractionated heparin subcutaneously (see scheme in Additional file 1). All other treatment will be unchanged and left to the attending physicians. Main outcomes: As a surrogate parameter for clinical improvement and primary outcome we will use the PaO2/FiO2 (P/F) ratio. Randomisation: After inclusion, the patients will be randomized using a closed envelope method into the conventional treatment group, which uses the standard strategy and the experimental group which receives anticoagulation treatment with bivalirudin using an allocation ratio of 1:1. Blinding (masking): Due to logistical and safety reasons (assessment of aPTT to titrate the study drug) only the data-analyst will be blinded to the groups. Numbers to be randomised (sample size): We performed a sample size calculation and assumed the data for P/F ratio (according to literature) is normally distributed and used the mean which would be: 160 and SD is 80. We expect the treatment will improve this by 30%. In order to reach a power of 80% we would need 44 patients per group (in total 88 patients). Taking approximately 10% of dropout into account we will include 100 patients (50 in each group). Trial Status: The local registration number is MRC-05-082 with the protocol version number 2. The date of approval is 18th June 2020. Recruitment started on 28^th June and is expected to end in November 2020. Trial registration: The protocol is registered before starting subject recruitment under the title: “Anticoagulation in patients suffering from COVID-19 disease. The ANTI-CO Trial” in ClinicalTrials.org with the registration number: NCT04445935. Registered on 24 June 2020. Full protocol: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 2). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

Awake prone position (APP) has been reported to improve oxygenation in patients with COVID-19 disease and to reduce the requirement for invasive mechanical ventilation for patients requiring support with high flow nasal cannula. There is conflicting data for patients requiring lower-level oxygen support. Does APP reduce escalation of oxygen support in COVID-19 patients requiring supplementary oxygen?The primary outcome was defined as an escalation of oxygen support from simple supplementary oxygen (NP, HM, NRB) to NIV (CPAP or BiPAP), HFNC or IMV; OR from NIV (CPAP or BiPAP) or HFNC to IMV by day30. Two center, prospective, non-blind, randomised controlled trial. Patients with confirmed or suspected COVID-19 pneumonia requiring ≥ 5 liters/min oxygen to maintain saturations ≥ 94 % were randomised to either APP or control group. The APP group received a 3-h APP session three times per day for three days. Between 9 May and July 13, 2021, 89 adults were screened and 61 enrolled, 31 to awake prone position and 30 controls. There was no difference in the primary outcome, 7 (22.6 %) patients randomised to APP and 9 (30.0 %) controls required escalation of oxygen support (OR 0.68 (0.22–2.14), P = 0.51). There were no differences in any secondary outcomes, in APP did not improve oxygenation. In COVID-19 patients, the use of APP did not prevent escalation of oxygen support from supplementary to invasive or non-invasive ventilation or improve patient respiratory physiology. NCT04853979 (clinicaltrials.gov).

Weaning is the process of successfully liberating the patient from mechanical ventilation. The majority of patients will separate from the ventilator after a successful spontaneous breathing trial (SBT). In a minority of patients, weaning can be challenging and prolonged. Finding the cause of weaning difficulty is crucial to minimize the rates of extubation failure and prolonged ventilation. Diaphragm dysfunction (DD) has been described as a separate entity responsible for weaning failure with an incidence of 23–80%. It has also been associated with difficult weaning, prolonged intensive care unit (ICU) stay and mechanical ventilation, and increased ICU and hospital mortality. Sepsis, shock, and ventilator induced diaphragm dysfunction are important risk factors of DD. Diaphragm dysfunction has several mechanisms. Disuse atrophy and microstructural changes of the diaphragm have been described as the two cardinal pathophysiologic features. Establishing the diagnosis of DD can be complex in critically ill patients. Bilateral anterior magnetic phrenic stimulation is widely considered as the gold standard but is only available in large research centers with limited availability. Ultrasonography of the diaphragm is a promising tool given its wide availability, affordability, and non-invasive nature. Ultrasound is operator dependent, however and it does not provide continuous monitoring capabilities. The diaphragm thickening fraction (DTF) can be calculated from measuring the end-expiratory and end-inspiratory diaphragm thickness at the bedside. It correlates well with transdiaphragmatic pressure. Electromyography of the diaphragm may overcome the limitation of ultrasound by offering a continuous assessment of the diaphragmatic electrical activity, but it requires the placement of a specialized nasogastric tube. Management of DD is better approached by implementing a preventive and a curative strategy. From animal studies, allowing for spontaneous breathing on mechanical ventilation may prevent the problem. The degree of the recommended patient effort and ventilator assistance to achieve optimal balance between diaphragmatic loading and unloading are yet to be defined. Monitoring DTF while finding the optimal ventilator support level can be useful in this context. Another modality to prevent DD is diaphragm pacing applied through a transvenous phrenic nerve pacing system. Animal studies in pigs showed that this modality resulted in less diaphragm atrophy when pacing was synchronized with ventilation. There is an ongoing study to assess the role of diaphragm pacing to recondition and strengthen the diaphragm in difficult to wean mechanically ventilated patients (Clinicaltrials.gov NCT03107949). Once diaphragm dysfunction is established, no specific treatments exist at this time. Other causes of weaning failure like cardiac dysfunction have to be excluded and treated. Improving respiratory load and respiratory muscle weakness imbalance is also crucial. While it appears to improve inspiratory muscle strength parameters, inspiratory muscle training has not consistently shown improvements in weaning success. Levosemindan showed some benefit in improving diaphragm contractility and efficiency in healthy volunteers but was later found to increase likelihood of weaning failure in septic patients. Anabolic steroids were not found to be effective in treating diaphragm dysfunction in several studies. More evidence is needed before recommending non-invasive ventilation post-extubation in all DD patients.

This systematic review and meta-analysis aimed to evaluate clinical outcomes associated with different systemic heparin protocols (conservative v standard intensity) during extracorporeal membrane oxygenation (ECMO) support. Included studies comprised both venovenous and venoarterial ECMO modalities. A systematic review and meta-analysis were conducted per Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. The PubMed, Cochrane Library, and Scopus databases were searched through November 15, 2024, for studies comparing conservative anticoagulation (no or low-target activated partial thromboplastin time [aPTT] of 40-60 seconds, anticoagulation monitoring) with standard anticoagulation (standard heparin target aPTT of 60-80 seconds). Studies were conducted in intensive care units across multiple international centers. Eight studies (601 patients; 280 in the conservative group and 321 in the standard group) were included in the meta-analysis. Conservative (no or low-target aPTT of 40-60 seconds, anticoagulation monitoring) versus standard anticoagulation (standard heparin target aPTT of 60-80 seconds). Primary outcomes included mortality, major bleeding, and thrombosis; secondary outcomes were stroke, limb ischemia, and circuit thrombosis. Random-effects models assessed outcomes, with heterogeneity evaluated using the Q test and I² statistic. A total of 698 studies were identified (PubMed, 461; Cochrane Library, 94; Scopus, 143). After removal of duplicates, 358 records were screened, and 245 studies were excluded. Twenty-seven studies underwent full-text review, with 13 meeting the inclusion criteria. Eight studies (601 patients; 280 in the conservative group and 321 in the standard group) were included in the meta-analysis. Mortality was similar between the conservative group (131 of 280 patients [46.8%]) and the standard group (159 of 321 [49.5%]) (odds ratio [OR], 1.04 [95% confidence interval (CI), 0.53-2.05]; I² = 64%). Thrombotic events were assessed in 4 studies (26 of 123 in the conservative group [21.1%] v 47 of 178 in the standard group [26.4%]; OR, 0.60 [95% CI, 0.33-1.09]; I² = 0%). Stroke (5 of 127 v 5 of 178), limb ischemia (10 of 87 v 20 of 147), and circuit thrombosis (15 of 141 v 15 of 191) did not differ between groups. However, major bleeding significantly favored conservative strategies (7 studies; 74 of 251 [29.5%] v 157 of 297 [52.9%]; OR, 0.40 [95% CI, 0.18-0.91]; p = 0.03; I² = 72%). The findings of this systematic review and meta-analysis indicate a potential association between conservative anticoagulation strategies during ECMO and reduced bleeding events without increased mortality or thrombotic complications, including stroke, limb ischemia, and circuit thrombosis. Given the low event rates, wide CIs, and absence of a formal power calculation, these null findings should not be interpreted as evidence of equivalence.