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 .

[Pregnancy and Irreversible Loss of Brain Functions - Case Report]. / Intensivtherapie bei Schwangerer mit irreversiblem Hirnfunktionsausfall.

A 29-year-old woman suffered major traumatic brain injury caused by a car accident. As diagnostic measures had revealed an early pregnancy (9th week), treatment on the intensive care unit was continued for 5 months, after unfavourable cerebral prognosis was followed by an irreversible loss of brain function in the 10th week of pregnancy. After assisted vaginal delivery of a healthy child in the 31th week of pregnancy on the critical care unit, organ procurement took place according to the presumed will of the patient. The article presents the details of the critical care therapy and discusses the supportive medical measures. Those measures served primarily to uphold the pregnancy und support the healthy development and delivery of the fetus and only in second instance the organ preservation aiming on organ donation. Necessary measures included maintenance of vital functions, hemostasis of electrolytes, nutrition, treatment of infection, prevention of adverse effects on the fetus, substitution of hormones and vitamins as well as the preparation of a planned or an unplanned delivery.

[Ethical, Psychosocial and Legal Aspects of the Treatment of Pregnant Patients with Brain Death]. / Ethische, psychosoziale und rechtliche Aspekte der Behandlung hirntoter Schwangerer.

The therapy of brain-dead pregnant women is an extreme example not only of the possibilities in current critical care, but also of resulting ethical, social and legal controversies, an area not familiar to most clinicians. Based on the case of a patient with fatal traumatic brain injury, a previously unknown early pregnancy and stated will to donate organs, we will discuss several aspects using published case reports: therapeutic goals, especially palliative care vs. continuation; implications of brain death diagnosis; considerations on legal care; involvement of relatives, especially the child's father; dynamics within the care team; and finally the issue of putative organ donation. This complex case once more depicts that even facing such highly unfavourable framework and seemingly irreconcilable factors, pregnancy can prevail. The researched facts and considerations in this article are intended to give an overview of potential dilemmas and might serve as a starting point in similar situations.

Point of care diagnostic of hypercoagulability and platelet function in COVID-19 induced acute respiratory distress syndrome: a retrospective observational study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) associated coagulopathy (CAC) leads to thromboembolic events in a high number of critically ill COVID-19 patients. However, specific diagnostic or therapeutic algorithms for CAC have not been established. In the current study, we analyzed coagulation abnormalities with point-of-care testing (POCT) and their relation to hemostatic complications in patients suffering from COVID-19 induced Acute Respiratory Distress Syndrome (ARDS). Our hypothesis was that specific diagnostic patterns can be identified in patients with COVID-19 induced ARDS at risk of thromboembolic complications utilizing POCT. METHODS: This is a single-center, retrospective observational study. Longitudinal data from 247 rotational thromboelastometries (Rotem®) and 165 impedance aggregometries (Multiplate®) were analysed in 18 patients consecutively admitted to the ICU with a COVID-19 induced ARDS between March 12th to June 30th, 2020. RESULTS: Median age was 61 years (IQR: 51-69). Median PaO2/FiO2 on admission was 122 mmHg (IQR: 87-189), indicating moderate to severe ARDS. Any form of hemostatic complication occurred in 78 % of the patients with deep vein/arm thrombosis in 39 %, pulmonary embolism in 22 %, and major bleeding in 17 %. In Rotem® elevated A10 and maximum clot firmness (MCF) indicated higher clot strength. The delta between EXTEM A10 minus FIBTEM A10 (ΔA10) > 30 mm, depicting the sole platelet-part of clot firmness, was associated with a higher risk of thromboembolic events (OD: 3.7; 95 %CI 1.3-10.3; p = 0.02). Multiplate® aggregometry showed hypoactive platelet function. There was no correlation between single Rotem® and Multiplate® parameters at intensive care unit (ICU) admission and thromboembolic or bleeding complications. CONCLUSIONS: Rotem® and Multiplate® results indicate hypercoagulability and hypoactive platelet dysfunction in COVID-19 induced ARDS but were all in all poorly related to hemostatic complications..

Acquired platelet GPVI receptor dysfunction in critically ill patients with sepsis.

Glycoprotein VI (GPVI), the platelet immunoreceptor tyrosine activating motif (ITAM) receptor for collagen, plays a striking role on vascular integrity in animal models of inflammation and sepsis. Understanding ITAM-receptor signaling defects in humans suffering from sepsis may improve our understanding of the pathophysiology, especially during disease onset. In a pilot study, platelets from 15 patients with sepsis were assessed consecutively at day of admission, day 5 to 7, and the day of intensive care unit (ICU) discharge and subjected to comprehensive analyses by flow cytometry, aggregometry, and immunoblotting. Platelet function was markedly reduced in all patients. The defect was most prominent after GPVI stimulation with collagen-related peptide. In 14 of 15 patients, GPVI dysfunction was already present at time of ICU admission, considerably before the critical drop in platelet counts. Sepsis platelets failed to transduce the GPVI-mediated signal to trigger tyrosine phosphorylation of Syk kinase or LAT. GPVI deficiency was partially inducible in platelets of healthy donors through coincubation in whole blood, but not in plasma from patients with sepsis. Platelet aggregation upon GPVI stimulation increased only in those patients whose condition ameliorated. As blunted GPVI signaling occurred early at sepsis onset, this defect could be exploited as an indicator for early sepsis diagnosis, which needs to be confirmed in prospective studies.

Dual-room twin-CT scanner in multiple trauma care: first results after implementation in a level one trauma centre.

PURPOSE: The trauma centre of the Wuerzburg University Hospital has integrated a pioneering dual-room twin-CT scanner in a multiple trauma pathway. For concurrent treatment of two trauma patients, two carbon CT examination and intervention tables are positioned head to head with one sliding CT-Gantry in the middle. The focus of this study is the process of trauma care with the time to CT (tCT) and the time to operation (tOR) as quality indicator. METHODS: All patients with suspected multiple trauma, who required emergency surgery and who were initially diagnosed by the CT trauma protocol between 05/2018 and 12/2018 were included. Data relating to time spans (tCT and tOR), severity of injury and outcome was obtained. RESULTS: 110 of the 589 screened trauma patients had surgery immediately after finishing primary assessment in the ER. The ISS was 17 (9-34) (median and interquartile range, IQR). tCT was 15 (11-19) minutes (median and IQR) and tOR was 96.5 (75-119) minutes (median and IQR). In the first 30 days, seven patients died (6.4%) including two within the first 24 h (2%). There were two ICU days (1-6) (median and IQR) and one (0-1) (median and IQR) ventilator day. CONCLUSION: The twin-CT technology is a fascinating tool to organize high-quality trauma care for two multiple trauma patients simultaneously.

Effects of inhaled nitric oxide in COVID-19-induced ARDS - Is it worthwhile?

BACKGROUND: Changes in pulmonary hemodynamics and ventilation/perfusion were proposed as hallmarks of Coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). Inhaled nitric oxide (iNO) may overcome these issues and improve arterial oxygenation. METHODS: We retrospectively analyzed arterial oxygenation and pulmonary vasoreactivity in seven COVID-19 ARDS patients receiving 20 ppm iNO for 15-30 minutes. RESULTS: The inhalation of NO significantly improved oxygenation. All patients with severe ARDS had higher partial pressures of oxygen and reduced pulmonary vascular resistance. Significant changes in pulmonary shunting were not observed. CONCLUSION: Overall, iNO could provide immediate help and delay respiratory deterioration in COVID-19-induced moderate to severe ARDS.

Biodistribution and serologic response in SARS-CoV-2 induced ARDS: A cohort study.

BACKGROUND: The viral load and tissue distribution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remain important questions. The current study investigated SARS-CoV-2 viral load, biodistribution and anti-SARS-CoV-2 antibody formation in patients suffering from severe corona virus disease 2019 (COVID-19) induced acute respiratory distress syndrome (ARDS). METHODS: This is a retrospective single-center study in 23 patients with COVID-19-induced ARDS. Data were collected within routine intensive care. SARS-CoV-2 viral load was assessed via reverse transcription quantitative polymerase chain reaction (RT-qPCR). Overall, 478 virology samples were taken. Anti-SARS-CoV-2-Spike-receptor binding domain (RBD) antibody detection of blood samples was performed with an enzyme-linked immunosorbent assay. RESULTS: Most patients (91%) suffered from severe ARDS during ICU treatment with a 30-day mortality of 30%. None of the patients received antiviral treatment. Tracheal aspirates tested positive for SARS-CoV-2 in 100% of the cases, oropharyngeal swabs only in 77%. Blood samples were positive in 26% of the patients. No difference of viral load was found in tracheal or blood samples with regard to 30-day survival or disease severity. SARS-CoV-2 was never found in dialysate. Serologic testing revealed significantly lower concentrations of SARS-CoV-2 neutralizing IgM and IgA antibodies in survivors compared to non-survivors (p = 0.009). CONCLUSIONS: COVID-19 induced ARDS is accompanied by a high viral load of SARS-CoV-2 in tracheal aspirates, which remained detectable in the majority throughout intensive care treatment. Remarkably, SARS-CoV-2 RNA was never detected in dialysate even in patients with RNAemia. Viral load or the buildup of neutralizing antibodies was not associated with 30-day survival or disease severity.

COVID-19 Induced Acute Respiratory Distress Syndrome-A Multicenter Observational Study.

Background: Proportions of patients dying from the coronavirus disease-19 (COVID-19) vary between different countries. We report the characteristics; clinical course and outcome of patients requiring intensive care due to COVID-19 induced acute respiratory distress syndrome (ARDS). Methods: This is a retrospective, observational multicentre study in five German secondary or tertiary care hospitals. All patients consecutively admitted to the intensive care unit (ICU) in any of the participating hospitals between March 12 and May 4, 2020 with a COVID-19 induced ARDS were included. Results: A total of 106 ICU patients were treated for COVID-19 induced ARDS, whereas severe ARDS was present in the majority of cases. Survival of ICU treatment was 65.0%. Median duration of ICU treatment was 11 days; median duration of mechanical ventilation was 9 days. The majority of ICU treated patients (75.5%) did not receive any antiviral or anti-inflammatory therapies. Venovenous (vv) ECMO was utilized in 16.3%. ICU triage with population-level decision making was not necessary at any time. Univariate analysis associated older age, diabetes mellitus or a higher SOFA score on admission with non-survival during ICU stay. Conclusions: A high level of care adhering to standard ARDS treatments lead to a good outcome in critically ill COVID-19 patients.

Redistribution of pulmonary ventilation after lung surgery detected with electrical impedance tomography.

BACKGROUND: Regional ventilation of the lung can be visualized by pulmonary electrical impedance tomography (EIT). The aim of this study was to examine the post-operative redistribution of regional ventilation after lung surgery dependent on the side of surgery and its association with forced vital capacity. METHODS: In this prospective, observational cohort study 13 patients undergoing right and 13 patients undergoing left-sided open or video-thoracoscopic procedures have been investigated. Pre-operative measurements with EIT and spirometry were compared with data obtained 3 days post-operation. The center of ventilation (COV) within a 32 × 32 pixel matrix was calculated from EIT data. The transverse axis coordinate of COV, COVx (left/right), was modified to COVx' (ipsilateral/contralateral). Thus, COVx' shows a negative change if ventilation shifts contralateral independent of the side of surgery. This enabled testing with two-way ANOVA for repeated measurements (side, time). RESULTS: The perioperative shift of COVx' was dependent on the side of surgery (P = .007). Ventilation shifted away from the side of surgery after the right-sided surgery (COVx'-1.97 pixel matrix points, P < .001), but not after the left-sided surgery (COVx'-0.61, P = .425). The forced vital capacity (%predicted) decreased from 94 (83-109)% (median [quartiles]; [left-sided]) and 89 (80-97)% (right-sided surgery) to 61 (59-66)% and 62 (40-72)% (P < .05), respectively. The perioperative changes in forced vital capacity (%predicted) were weakly associated with the shift of COVx'. CONCLUSION: Only after right-sided lung surgery, EIT showed reduced ventilation on the side of surgery while vital capacity was markedly reduced in both groups.

Vaginal delivery in the 30+4 weeks of pregnancy and organ donation after brain death in early pregnancy.

A 28-year-old woman suffered a traffic accident resulting in severe head injuries with deleterious prognosis. Diagnostics further revealed a hitherto unknown pregnancy, at suspected week 9. Based on the patient's wish to donate organs, brain death protocol confirmed irreversible loss of brain function. Yet, vital pregnancy rendered organ transplantation impossible. Multiple ethical and legal issues arose, from invalidation of established legal care after brain death to the delivery of a healthy child after trauma and long-term critical care. After medicolegal and ethical counselling, pregnancy was sustained, and the goal of organ donation postponed. Critical care focused on foetal homeostasis. At 30+4 weeks, a viable girl was born via assisted vaginal delivery. Postpartal organ donation resulted in heart, kidney and pancreas transplantation. The case emphasises the medical, legal and ethical challenges to combine two apparently diametrical goals: the successful full-term pregnancy and the fulfilment of a patient's wish to donate organs.

Perioperative redistribution of regional ventilation and pulmonary function: a prospective observational study in two cohorts of patients at risk for postoperative pulmonary complications.

BACKGROUND: Postoperative pulmonary complications (PPCs) increase morbidity and mortality of surgical patients, duration of hospital stay and costs. Postoperative atelectasis of dorsal lung regions as a common PPC has been described before, but its clinical relevance is insufficiently examined. Pulmonary electrical impedance tomography (EIT) enables the bedside visualization of regional ventilation in real-time within a transversal section of the lung. Dorsal atelectasis or effusions might cause a ventral redistribution of ventilation. We hypothesized the existence of ventral redistribution in spontaneously breathing patients during their recovery from abdominal and peripheral surgery and that vital capacity is reduced if regional ventilation shifts to ventral lung regions. METHODS: This prospective observational study included 69 adult patients undergoing elective surgery with an expected intermediate or high risk for PPCs. Patients undergoing abdominal and peripheral surgery were recruited to obtain groups of equal size. Patients received general anesthesia with and without additional regional anesthesia. On the preoperative, the first and the third postoperative day, EIT was performed at rest and during spirometry (forced breathing). The center of ventilation in dorso-ventral direction (COVy) was calculated. RESULTS: Both groups received intraoperative low tidal volume ventilation. Postoperative ventral redistribution of ventilation (forced breathing COVy; preoperative: 16.5 (16.0-17.3); first day: 17.8 (16.9-18.2), p < 0.004; third day: 17.4 (16.2-18.2), p = 0.020) and decreased forced vital capacity in percentage of predicted values (FVC%predicted) (median: 93, 58, 64%, respectively) persisted after abdominal surgery. In addition, dorsal to ventral shift was associated with a decrease of the FVC%predicted on the third postoperative day (r = - 0.66; p < 0.001). A redistribution of pulmonary ventilation was not observed after peripheral surgery. FVC%predicted was only decreased on the first postoperative day (median FVC%predicted on the preoperative, first and third day: 85, 81 and 88%, respectively). In ten patients occurred pulmonary complications after abdominal surgery also in two patients after peripheral surgery. CONCLUSIONS: After abdominal surgery ventral redistribution of ventilation persisted up to the third postoperative day and was associated with decreased vital capacity. The peripheral surgery group showed only minor changes in vital capacity, suggesting a role of the location of surgery for postoperative redistribution of pulmonary ventilation. TRIAL REGISTRATION: This prospective observational single centre study was submitted to registration prior to patient enrollment at ClinicalTrials.gov (NCT02419196, Date of registration: December 1, 2014). Registration was finalized at April 17, 2015.

Liberal transfusion strategy to prevent mortality and anaemia-associated, ischaemic events in elderly non-cardiac surgical patients - the study design of the LIBERAL-Trial.

BACKGROUND: Perioperative anaemia leads to impaired oxygen supply with a risk of vital organ ischaemia. In healthy and fit individuals, anaemia can be compensated by several mechanisms. Elderly patients, however, have less compensatory mechanisms because of multiple co-morbidities and age-related decline of functional reserves. The purpose of the study is to evaluate whether elderly surgical patients may benefit from a liberal red blood cell (RBC) transfusion strategy compared to a restrictive transfusion strategy. METHODS: The LIBERAL Trial is a prospective, randomized, multicentre, controlled clinical phase IV trial randomising 2470 elderly (≥ 70 years) patients undergoing intermediate- or high-risk non-cardiac surgery. Registered patients will be randomised only if Haemoglobin (Hb) reaches ≤9 g/dl during surgery or within 3 days after surgery either to the LIBERAL group (transfusion of a single RBC unit when Hb ≤ 9 g/dl with a target range for the post-transfusion Hb level of 9-10.5 g/dl) or the RESTRICTIVE group (transfusion of a single RBC unit when Hb ≤ 7.5 g/dl with a target range for the post-transfusion Hb level of 7.5-9 g/dl). The intervention per patient will be followed until hospital discharge or up to 30 days after surgery, whichever occurs first. The primary efficacy outcome is defined as a composite of all-cause mortality, acute myocardial infarction, acute ischaemic stroke, acute kidney injury (stage III), acute mesenteric ischaemia and acute peripheral vascular ischaemia within 90 days after surgery. Infections requiring iv antibiotics with re-hospitalisation are assessed as important secondary endpoint. The primary endpoint will be analysed by logistic regression adjusting for age, cancer surgery (y/n), type of surgery (intermediate- or high-risk), and incorporating centres as random effect. DISCUSSION: The LIBERAL-Trial will evaluate whether a liberal transfusion strategy reduces the occurrence of major adverse events after non-cardiac surgery in the geriatric population compared to a restrictive strategy within 90 days after surgery. TRIAL REGISTRATION: ClinicalTrials.gov (identifier: NCT03369210 ).

Weaning from prolonged veno-venous extracorporeal membrane oxygenation (ECMO) after transfer to a specialized center: a retrospective study.

Veno-venous extracorporeal membrane oxygenation (vvECMO) is increasingly used as rescue therapy in severe respiratory failure. In patients with pre-existent lung diseases or persistent lung injury weaning from vvECMO can be challenging. This study sought to investigate outcomes of patients transferred to a specialized ECMO center after prolonged ECMO therapy. We performed a retrospective analysis of all patients admitted to our medical intensive care unit (ICU) between 01/2013 and 12/2016 who were transferred from an external ICU after > 8 days on vvECMO. 12 patients on ECMO for > 8 days were identified. Prior to transfer, patients underwent ECMO therapy for 18 ± 9.5 days. Total time on ECMO was 60 ± 46.6 days. 11/12 patients could be successfully weaned from ECMO, 7/12 in the first 28 days after transfer (8 ± 8.8 ECMO-free days at day 28). In 7 patients, ECMO could be terminated after at least partial lung recovery, in 4 patients after salvage lung transplant. No patient died or needed re-initiation of ECMO therapy at day 28. In summary, weaning from vvECMO was feasible even after prolonged ECMO courses and salvage lung transplant could be avoided in most cases. Patients may benefit from transfer to a specialized ECMO center.

Percutaneous Mechanical Circulation Support Combined with Extracorporeal Membrane Oxygenation (oxyRVAD) in Secondary Right Heart Failure.

Right heart failure (RHF) because of pulmonary hypertension (PH) is a frequently encountered clinical problem with high mortality. The last resort, if pharmacological therapy fails, is mechanical circulatory support. There is a lack of percutaneous systems to support the right ventricle (RV). Venoarterial extracorporeal membrane oxygenation is widely used as a bailout in acute RHF in non-left ventricular assist device patients. Venoarterial extracorporeal membrane oxygenation does not unload the left ventricle and may cause failure of the left ventricle if used for a longer period of time. We report the long-term use of an ECMO-based percutaneous right ventricular assist system (oxyRVAD) capable to deliver up to 6 L/min of blood flow with a returning cannula placed in the main pulmonary artery used in RHF originating from PH with poor oxygenation. We present a series of four patients on oxyRVAD (mean treatment duration 15 ± 7.6 days). Patients benefited from the system clinically; however, two patients eventually died while on oxyRVAD. Nevertheless, we provide a proof-of-concept of this system in PH patients, which is feasible and might provide a useful "bridge-to-recovery" or "bridge-to-transplant" option in the management of patients with severe RHF because of PH.

Double Peripheral Venous and Arterial Cannulation for Extracorporeal Membrane Oxygenation in Combined Septic and Cardiogenic Shock.

BACKGROUND The use of venoarterial extracorporeal membrane oxygenation (va-ECMO) via peripheral cannulation for septic shock is limited by blood flow and increased afterload for the left ventricle. CASE REPORT A 15-year-old girl with acute myelogenous leukemia, suffering from severe septic and cardiogenic shock, was treated by venoarterial extracorporeal membrane oxygenation (va-ECMO). Sufficient extracorporeal blood flow matching the required oxygen demand could only be achieved by peripheral cannulation of both femoral arteries. Venous drainage was performed with a bicaval cannula inserted via the left V. femoralis. To accomplish left ventricular unloading, an additional drainage cannula was placed in the left atrium via percutaneous atrioseptostomy (va-va-ECMO). Cardiac function recovered and the girl was weaned from the ECMO on day 6. Successful allogenic stem cell transplantation took place 2 months later. CONCLUSIONS In patients with vasoplegic septic shock and impaired cardiac contractility, double peripheral venoarterial extracorporeal membrane oxygenation (va-va-ECMO) with transseptal left atrial venting can by a lifesaving option.