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Abstract Introduction von Willebrand Factor (vWF) is a key protein mediating platelet adhesion on the surface of damaged endothelia. To the best of our knowledge, no trial exists that investigated the effect of platelet transfusion in combination with the administration of balanced vWF in severe blood loss, despite being widely used in clinical practice. The Basel Will-Plate study will investigate the impact of the timely administration of balanced vWF (1:1 vWF and FVIII) in addition to platelet transfusion on the need for blood and coagulation factor transfusion in patients admitted to the intensive care unit (ICU) who suffer from severe bleeding. The study hypothesis is based on the assumption that adding balanced vWF to platelets will reduce the overall need for transfusion of blood products compared to the transfusion of platelets alone. Methods and analysis The Will-Plate study is an investigator-initiated, single-centre, double-blinded randomised controlled clinical trial in 120 critically ill patients needing platelet transfusion. The primary outcome measure will be the number of fresh frozen plasma (FFP) and red blood cell (RBC) transfusions according to groups. Secondary outcome measures include the number of platelet concentrates transfused within the first 48 h after treatment of study medication, quantity of blood loss in the first 48 h after treatment with the study medication, length of stay in ICU and hospital, number of revision surgeries for haemorrhage control, ICU mortality, hospital mortality, 30-day mortality and 1-year mortality. Patients will be followed after 30 days and 1 year for activities of daily living and mortality assessment. The sample size was calculated to detect a 50% reduction in the number of blood products subsequently transfused within 2 days in patients with Wilate® compared to placebo. Ethics and dissemination This study has been approved by the Ethics Committee of Northwestern and Central Switzerland and will be conducted in compliance with the protocol, the current version of the Declaration of Helsinki, the ICH-GCP or ISO EN 14155 (as far as applicable) and all national legal and regulatory requirements. The study results will be presented at international conferences and published in a peer-reviewed journal. Trials registration ClinicalTrials.gov NCT04555785. Protocol version: Clinical Study Protocol Version 2, 01.11.2020. Registered on Sept. 21, 2020.

Abstract Background Timely management of acute myocardial infarction (AMI) and acute stroke has undergone impressive progress during the last decade. However, it is currently unknown whether both sexes have profited equally from improved strategies. We sought to analyze sex-specific temporal trends in intensive care unit (ICU) admission and mortality in younger patients presenting with AMI or stroke in Switzerland. Methods Retrospective analysis of temporal trends in 16,954 younger patients aged 18 to ≤ 52 years with AMI or acute stroke admitted to Swiss ICUs between 01/2008 and 12/2019. Results Over a period of 12 years, ICU admissions for AMI decreased more in women than in men (− 6.4% in women versus − 4.5% in men, p

Abstract Background We report a case of sudden, lethal metabolic acidosis in a 70-year-old man on long-term nucleoside reverse transcriptase inhibitor (NRTI) -based antiretroviral therapy (ART) who had developed atypical necrotizing fasciitis 1 month after kidney transplantation. Case presentation The HIV infection of the patient was treated for the last four months with an integrase strand inhibitor (dolutegravir 50 mg/d) plus a NRTI backbone including lamivudine (150 mg/d) and abacavir (600 mg/d). In this renal transplant patient we hypothesize that the co-existence of sepsis, renal failure and an accumulation of lamivudine led to the development of fatal metabolic acidosis and hyperlactatemia. Although lamivudine is only rarely associated with hyperlactatemia, there is evidence that overdose may be a risk factor for developing it. In our patient the lamivudine concentration two days after stopping and during hemodiafiltration was more than 50 times higher than therapeutic target trough concentrations. Likely reasons for this were renal impairment and concurrent treatment with trimethoprim, known to inhibit the renal elimination of lamivudine. Conclusions NRTIs could trigger the development of hyperlactatemia in septic patients. The use of NRTI sparing regimens might be considered in the presence of this critical condition.

Abstract Background Capnocytophaga canimorsus is a Gram-negative capnophilic rod and part of dogs/cats’ normal oral flora. It can be transmitted by bites, scratches, or even by contact of saliva with injured skin. Asplenic patients and patients with alcohol abuse are at particular risk for fulminant C. canimorsus sepsis. However, also immunocompetent patients can have a severe or even fatal infection. This is the first case of a severe C. canimorsus infection in an immunocompromised host complicated by acute renal cortical necrosis with a “reverse rim sign” in contrast-enhanced computed tomography on hospital admission. Case presentation We report the case of a 44-year functionally asplenic patient after an allogeneic stem cell transplantation, who presented with septic shock after a minor dog bite injury 4 days prior. Because of abdominal complaints, epigastric pain with local peritonism, and radiological gallbladder wall thickening, an abdominal focus was suspected after the initial work-up. The patient underwent emergent open cholecystectomy, but the clinical suspicion of abdominal infection was not confirmed. Septic shock was further complicated by cardiomyopathy and disseminated intravascular coagulation. As a causative pathogen, C. canimorsus could be isolated. The clinical course was complicated by permanent hemodialysis and extensive acral necrosis requiring amputation of several fingers and both thighs. Conclusion We present a severe case of a C. canimorsus infection in a functionally asplenic patient after a minor dog bite. The clinical course was complicated by septic shock, disseminated intravascular coagulation, and the need for multiple amputations. In addition, the rare form of acute renal failure - bilateral acute renal cortical necrosis – was visible as “reverse rim sign” on computed tomography scan. This case is an example of the potential disastrous consequences when omitting pre-emptive antibiotic therapy in wounds inflicted by cats and dogs, particularly in asplenic patients.

Abstract Background Critically ill patients rapidly develop muscle wasting resulting in sarcopenia, long-term disability and higher mortality. Bolus nutrition (30–60 min period), whilst having a similar incidence of aspiration as continuous feeding, seems to provide metabolic benefits through increased muscle protein synthesis due to higher leucine peaks. To date, clinical evidence on achievement of nutritional goals and influence of bolus nutrition on skeletal muscle metabolism in ICU patients is lacking. The aim of the Pro BoNo study (Protein Bolus Nutrition) is to compare intermittent and continuous enteral feeding with a specific high-protein formula. We hypothesise that target quantity of protein is reached earlier (within 36 h) by an intermittent feeding protocol with a favourable influence on muscle protein synthesis. Methods Pro BoNo is a prospective randomised controlled study aiming to compare the impact of intermittent and continuous enteral feeding on preventing muscle wasting in 60 critically ill patients recruited during the first 48 h after ICU admission. The primary outcome measure is the time until the daily protein target (≥ 1.5 g protein/kg bodyweight/24 h) is achieved. Secondary outcome measures include tolerance of enteral feeding and evolution of glucose, urea and IGF-1. Ultrasound and muscle biopsy of the quadriceps will be performed. Discussion The Basel Pro BoNo study aims to collect innovative data on the effect of intermittent enteral feeding of critically ill patients on muscle wasting. Trial registration ClinicalTrials.gov NCT03587870 . Registered on July 16, 2018. Swiss National Clinical Trials Portal SNCTP000003234. Last updated on July 24, 2019.

Abstract Background The pathophysiology of pulmonary edema is generally considered to result from elevated pulmonary capillary hydrostatic pressure due to increased left atrial pressure in consequence of a failing left ventricle. Case presentation We present a case of pulmonary edema secondary to severe hypalbuminemia under excessive respiratory drive in a 29-year-old Caucasian woman in respiratory distress with detected bilateral central pulmonary embolism. Conclusion In conjunction with severe hypalbuminemia, even the negative intrathoracic pressure swings of respiratory distress may cause pulmonary edema. Detrimental consequences of non-invasive ventilation due to uncontrolled tidal volume and pressure swings need to be considered when treating patients in hypoxemic respiratory failure with low serum albumin.

Abstract Background Adrenomedullin (ADM) regulates vascular tone and endothelial permeability during sepsis. Levels of circulating biologically active ADM (bio-ADM) show an inverse relationship with blood pressure and a direct relationship with vasopressor requirement. In the present prospective observational multinational Adrenomedullin and Outcome in Sepsis and Septic Shock 1 (, AdrenOSS-1) study, we assessed relationships between circulating bio-ADM during the initial intensive care unit (ICU) stay and short-term outcome in order to eventually design a biomarker-guided randomized controlled trial. Methods AdrenOSS-1 was a prospective observational multinational study. The primary outcome was 28-day mortality. Secondary outcomes included organ failure as defined by Sequential Organ Failure Assessment (SOFA) score, organ support with focus on vasopressor/inotropic use, and need for renal replacement therapy. AdrenOSS-1 included 583 patients admitted to the ICU with sepsis or septic shock. Results Circulating bio-ADM levels were measured upon admission and at day 2. Median bio-ADM concentration upon admission was 80.5 pg/ml [IQR 41.5–148.1 pg/ml]. Initial SOFA score was 7 [IQR 5–10], and 28-day mortality was 22%. We found marked associations between bio-ADM upon admission and 28-day mortality (unadjusted standardized HR 2.3 [CI 1.9–2.9]; adjusted HR 1.6 [CI 1.1–2.5]) and between bio-ADM levels and SOFA score (p < 0.0001). Need of vasopressor/inotrope, renal replacement therapy, and positive fluid balance were more prevalent in patients with a bio-ADM > 70 pg/ml upon admission than in those with bio-ADM ≤ 70 pg/ml. In patients with bio-ADM > 70 pg/ml upon admission, decrease in bio-ADM below 70 pg/ml at day 2 was associated with recovery of organ function at day 7 and better 28-day outcome (9.5% mortality). By contrast, persistently elevated bio-ADM at day 2 was associated with prolonged organ dysfunction and high 28-day mortality (38.1% mortality, HR 4.9, 95% CI 2.5–9.8). Conclusions AdrenOSS-1 shows that early levels and rapid changes in bio-ADM estimate short-term outcome in sepsis and septic shock. These data are the backbone of the design of the biomarker-guided AdrenOSS-2 trial. Trial registration ClinicalTrials.gov, NCT02393781. Registered on March 19, 2015.

Abstract Background All forms of shock, particularly septic shock, that involve insufficient blood supply to tissues to meet metabolic demands are main causes of morbidity and mortality worldwide and develop in one third of patients admitted to the intensive care unit (ICU). This alarmingly high incidence underlines the importance of further research in this field. Uncertainty remains about the undeceiving parameters for guidance of fluid resuscitation to avoid acute kidney injury (AKI) and renal replacement therapy. However, there are consequences of fluid overload (e.g. organ oedema and high interstitial pressures). This proposed study aims to establish a new framework of parameters for the guidance of fluid resuscitation in shock therapy focusing on the first 72 h, amending the currently used parameters (i.e. cardiac output, heart rate, blood pressure, central venous pressure) with an array of additional measurements including assessment of total body water (TBW), renal vascular resistance (renal resistive index (RRI)), intra-abdominal pressure (IAP) and microcirculatory blood flow (MBF). Methods This observational cohort study includes patients in shock presenting to the ICU. In addition to routine parameters (i.e. cardiac output, heart rate, blood pressure, central venous pressure) for volume resuscitation, MBF will be recorded using sublingual incident dark field microscopy, IAP, RRI seen in duplex-sonography and TBW will be estimated using bio-impedance analysis for correlation and eventually signalling of AKI and need for renal replacement therapy. Follow-up measurements will be taken at set intervals up to 72 h post admittance. To investigate the association between the newly investigated parameters and the occurrence of an AKI, we will compare the difference between measurements taken after admittance to the ICU and baseline values in patients with and without AKI using a two-sample t test. A linear regression model will be constructed to investigate the first and secondary outcome. Results Between January 2016 and August 2017, a total of 33 patients were recruited. The final results are expected in the second half of 2018. Conclusions The VoluKid study will investigate a new approach to assess volaemia and parameters indicating AKI in patients in shock who undergo volume resuscitation in the ICU. Trial registration The study was registered at ClinicalTrials.gov (Identifier: NCT02666404) on January 18, 2016, and at the Swiss National Clinical Trial Portal (SNCPT; Identifier: SNCTP000001693) on February 13, 2016.

Abstract Background Delirium is a neurobehavioural syndrome that frequently develops in the postoperative setting. The incidence of elderly patients who develop delirium during hospital stay ranges from 10-80%. Delirium was first described more than half a century ago in the cardiac surgery population, where it was already discovered as a state that might be accompanied by serious complications such as prolonged ICU and hospital stay, reduced quality of life and increased mortality. Furthermore, the duration of delirium is associated with worse long-term cognitive function in the general ICU population. This long-term experience with delirium suggests a high socioeconomic burden and has been a focus of many studies. Due to the multifactorial origin of delirium, we have several but no incontestable options for prevention and symptomatic treatment. Overall, delirium represents a high burden not only for patient and family members, but also for the medical care team that aims to prevent postoperative delirium to avoid serious consequences associated with it. The purpose of this study is to determine whether postoperative delirium can be prevented by the combination of established preventive agents. In addition, measured levels of pre- and postoperative cortisol, neuron specific enolase (NSE) and S-100β will be used to investigate dynamics of these parameters in delirious and non-delirious patients after surgery. Methods/design The Baden PRIDe Trial is an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial for the prevention of delirium with haloperidol, ketamine, and the combination of both vs. placebo in 200 patients scheduled for surgery. We would like to investigate superiority of one of the three treatment arms (i.e., haloperidol, ketamine, combined treatment) to placebo. Discussion There is limited but promising evidence that haloperidol and ketamine can be used to prevent delirium. Clinical care for patients might improve as the results of this study may lead to better algorithms for the prevention of delirium. Trial registration ClinicalTrials.gov, NCT02433041. Registered on 7 April 2015. Swiss National Clinical Trial Portal, SNCTP000001628. Registered on 9 December 2015.