Association between pulmonary extravascular water, dead space, and clinical outcome in intubated patients with COVID ARDS

Introduction: The aim of this study was to determine whether there is an association between extravascular lung water index (EVLWi) and physiological respiratory dead space (VDphys/VT) and to determine if these factors are associated with the possibility to being discharged alive on day 28. Method(s): We analyzed a prospective cohort of patients with COVID ARDS supported with invasive mechanical ventilation (IMV) admitted in our ICU who were monitored with volumetric capnography and transpulmonary thermodilution (TPTD). First day TDTP and VDphys/VT were considered. Bohr-Enghoff formula was used to obtain VDphys/ VT. This protocol was approved by the local IRB and informed consent was waived. Result(s): 31 patients with matched TPTD and VDphys/VT during the first 24 h were analyzed in who EVLWi correlated with VDphys/VT (r = 0.599 p = 0.002), however, EVLWi did not associated with PaFi. Patients with EVLWi > 10 ml/kg had higher APACHE II and VDphys/VT. These patients had a lower cumulative incidence to be discharged alive on day 28 with aHR 7.3 [1.4-39.1] p = 0.02 (adjusted by APACHE II and VDphys/VT, Fig. 1A). Remarkably, patients with EVLWi > 10 ml/ kg + VDphys/VT > 57% had worse outcome compared to those who had EVLWi > 10 ml/kg + VDphys/VT < 57% (25% vs 75%, p = 0.032, Fig. 1B). Conclusion(s): In patients with COVID ARDS supported with IMV, VDphys/VT give prognostic data additional to EVLWi.

The efficacy and safety of intravenous imatinib in invasively ventilated patients with COVID-19 related acute respiratory distress syndrome (InventCOVID): a multicentre, randomised, double-blinded, placebocontrolled, phase II clinical study

Background: A central hallmark of ARDS is hypoxemic respiratory failure due to increased pulmonary capillary leakage. The kinase inhibitor imatinib was shown to reverse vascular leak. This study aimed to investigate the effect of intravenous imatinib on pulmonary edema in patients with COVID-19 ARDS. Method(s): This multicentre, randomised, double-blind, placebo-controlled clinical trial (ClinicalTrial.gov identifier NCT04794088) included adult patients admitted to the ICU with moderate or severe COVID-19 ARDS. Patients were randomised 1:1 to receive 200mg intravenous imatinib or placebo twice daily for seven days or until ICU discharge. The change in extravascular lung water index between day 1 and day 4, measured using a PiCCO catheter, was chosen as the primary endpoint. Secondary outcomes included the PaO2/FiO2 ratio, number of ventilator free days, length of ICU admission and 28-day mortality rate. Study drug safety was assessed by daily screening of the patient records for adverse and serious adverse event occurrence and by performing ECGs and targeted clinical laboratory tests to monitor renal, liver and cardiac function. Result(s): Between March 2021 and 2022, 67 predominantly male (58%) patients with a mean age of 63+/-10 years were randomized to receive imatinib or placebo. No adverse events were considered to be related to study drug administration. At the moment of the submission, data cleaning is still ongoing. Conclusion(s): Thus far, intravenous imatinib administration seems safe and feasible in patients with COVID-19 related ARDS.

Effects of changes in veno-venous extracorporeal membrane oxygenation blood flow on the measurement of intrathoracic blood volume and extravascular lung water index: a prospective interventional study.

In severe acute respiratory distress syndrome (ARDS), veno-venous extracorporeal membrane oxygenation (V-V ECMO) has been proposed as a therapeutic strategy to possibly reduce mortality. Transpulmonary thermodilution (TPTD) enables monitoring of the extravascular lung water index (EVLWI) and cardiac preload parameters such as intrathoracic blood volume index (ITBVI) in patients with ARDS, but it is not generally recommended during V-V ECMO. We hypothesized that the amount of extracorporeal blood flow (ECBF) influences the calculation of EVLWI and ITBVI due to recirculation of indicator, which affects the measurement of the mean transit time (MTt), the time between injection and passing of half the indicator, as well as downslope time (DSt), the exponential washout of the indicator. EVLWI and ITBVI were measured in 20 patients with severe ARDS managed with V-V ECMO at ECBF rates from 6 to 4 and 2 l/min with TPTD. MTt and DSt significantly decreased when ECBF was reduced, resulting in a decreased EVLWI (26.1 [22.8-33.8] ml/kg at 6 l/min ECBF vs 22.4 [15.3-31.6] ml/kg at 4 l/min ECBF, p < 0.001; and 13.2 [11.8-18.8] ml/kg at 2 l/min ECBF, p < 0.001) and increased ITBVI (840 [753-1062] ml/m2 at 6 l/min ECBF vs 886 [658-979] ml/m2 at 4 l/min ECBF, p < 0.001; and 955 [817-1140] ml/m2 at 2 l/min ECBF, p < 0.001). In patients with severe ARDS managed with V-V ECMO, increasing ECBF alters the thermodilution curve, resulting in unreliable measurements of EVLWI and ITBVI. German Clinical Trials Register (DRKS00021050). Registered 14/08/2018. https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00021050.

Safety and preliminary efficacy of sequential multiple ascending doses of solnatide to treat pulmonary permeability edema in patients with moderate-to-severe ARDS-a randomized, placebo-controlled, double-blind trial.

BACKGROUND: Acute respiratory distress syndrome (ARDS) is a complex clinical diagnosis with various possible etiologies. One common feature, however, is pulmonary permeability edema, which leads to an increased alveolar diffusion pathway and, subsequently, impaired oxygenation and decarboxylation. A novel inhaled peptide agent (AP301, solnatide) was shown to markedly reduce pulmonary edema in animal models of ARDS and to be safe to administer to healthy humans in a Phase I clinical trial. Here, we present the protocol for a Phase IIB clinical trial investigating the safety and possible future efficacy endpoints in ARDS patients. METHODS: This is a randomized, placebo-controlled, double-blind intervention study. Patients with moderate to severe ARDS in need of mechanical ventilation will be randomized to parallel groups receiving escalating doses of solnatide or placebo, respectively. Before advancing to a higher dose, a data safety monitoring board will investigate the data from previous patients for any indication of patient safety violations. The intervention (application of the investigational drug) takes places twice daily over the course of 7 days, ensued by a follow-up period of another 21 days. DISCUSSION: The patients to be included in this trial will be severely sick and in need of mechanical ventilation. The amount of data to be collected upon screening and during the course of the intervention phase is substantial and the potential timeframe for inclusion of any given patient is short. However, when prepared properly, adherence to this protocol will make for the acquisition of reliable data. Particular diligence needs to be exercised with respect to informed consent, because eligible patients will most likely be comatose and/or deeply sedated at the time of inclusion. TRIAL REGISTRATION: This trial was prospectively registered with the EU Clinical trials register (clinicaltrialsregister.eu). EudraCT Number: 2017-003855-47 .

Transpulmonary thermodilution in patients treated with veno-venous extracorporeal membrane oxygenation.

BACKGROUND: We tested the effect of different blood flow levels in the extracorporeal circuit on the measurements of cardiac stroke volume (SV), global end-diastolic volume index (GEDVI) and extravascular lung water index derived from transpulmonary thermodilution (TPTD) in 20 patients with severe acute respiratory distress syndrome (ARDS) treated with veno-venous extracorporeal membrane oxygenation (ECMO). METHODS: Comparative SV measurements with transesophageal echocardiography and TPTD were performed at least 5 times during the treatment of the patients. The data were interpreted with a Bland-Altman analysis corrected for repeated measurements. The interchangeability between both measurement modalities was calculated and the effects of extracorporeal blood flow on SV measurements with TPTD was analysed with a linear mixed effect model. GEDVI and EVLWI measurements were performed immediately before the termination of the ECMO therapy at a blood flow of 6 l/min, 4 l/min and 2 l/min and after the disconnection of the circuit in 7 patients. RESULTS: 170 pairs of comparative SV measurements were analysed. Average difference between the two modalities (bias) was 0.28 ml with an upper level of agreement of 40 ml and a lower level of agreement of -39 ml within a 95% confidence interval and an overall interchangeability rate between TPTD and Echo of 64%. ECMO blood flow did not influence the mean bias between Echo and TPTD (0.03 ml per l/min of ECMO blood flow; p = 0.992; CI - 6.74 to 6.81). GEDVI measurement was not significantly influenced by the blood flow in the ECMO circuit, whereas EVLWI differed at a blood flow of 6 l/min compared to no ECMO flow (25.9 ± 10.1 vs. 11.0 ± 4.2 ml/kg, p = 0.0035). CONCLUSIONS: Irrespectively of an established ECMO therapy, comparative SV measurements with Echo and TPTD are not interchangeable. Such caveats also apply to the interpretation of EVLWI, especially with a high blood flow in the extracorporeal circulation. In such situations, the clinician should rely on other methods of evaluation of the amount of lung oedema with the haemodynamic situation, vasopressor support and cumulative fluid balance in mind. TRIAL REGISTRATION: German Clinical Trials Register (DRKS00021050). Registered 03/30/2020 https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00017237.