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In vitro studies have thoroughly documented age-dependent impact of storage lesions in packed red blood cells (pRBC) on erythrocyte oxygen carrying capacity. While studies have examined the effect of pRBC age on patient outcome only few data exist on the microcirculation as their primary site of action. In this secondary analysis we examined the relationship between age of pRBC and changes of microcirculatory flow (MCF) in 54 patients based on data from the Basel Bedside assessment Microcirculation Transfusion Limit study (Ba2MiTraL) on effects of pRBC on sublingual MCF. Mean change from pre- to post-transfusion proportion of perfused vessels (∆PPV) was + 8.8% (IQR − 0.5 to 22.5), 5.5% (IQR 0.1 to 10.1), and + 4.7% (IQR − 2.1 to 6.5) after transfusion of fresh (≤ 14 days old), medium (15 to 34 days old), and old (≥ 35 days old) pRBC, respectively. Values for the microcirculatory flow index (MFI) were + 0.22 (IQR − 0.1 to 0.6), + 0.22 (IQR 0.0 to 0.3), and + 0.06 (IQR − 0.1 to 0.3) for the fresh, medium, and old pRBC age groups, respectively. Lower ∆PPV and transfusion of older blood correlated with a higher Sequential Organ Failure Assessment (SOFA) score of patients upon admission to the intensive care unit (ICU) (p = 0.01). However, regression models showed no overall significant correlation between pRBC age and ∆PPV (p = 0.2). Donor or recipient sex had no influence. We detected no significant effect of pRBC on microcirculation. Patients with a higher SOFA score upon ICU admission might experience a negative effect on the ∆PPV after transfusion of older blood.

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Traumatic brain injury (TBI) is increasingly recognised as being responsible for a substantial proportion of the global burden of disease. Neurosurgical interventions are an important aspect of care for patients with TBI, but there is little epidemiological data available on this patient population. We aimed to characterise differences in casemix, management, and mortality of patients receiving emergency neurosurgery for TBI across different levels of human development. Methods: We did a prospective observational cohort study of consecutive patients with TBI undergoing emergency neurosurgery, in a convenience sample of hospitals identified by open invitation, through international and regional scientific societies and meetings, individual contacts, and social media. Patients receiving emergency neurosurgery for TBI in each hospital's 30-day study period were all eligible for inclusion, with the exception of patients undergoing insertion of an intracranial pressure monitor only, ventriculostomy placement only, or a procedure for drainage of a chronic subdural haematoma. The primary outcome was mortality at 14 days postoperatively (or last point of observation if the patient was discharged before this time point). Countries were stratified according to their Human Development Index (HDI)—a composite of life expectancy, education, and income measures—into very high HDI, high HDI, medium HDI, and low HDI tiers. Mixed effects logistic regression was used to examine the effect of HDI on mortality while accounting for and quantifying between-hospital and between-country variation. Findings: Our study included 1635 records from 159 hospitals in 57 countries, collected between Nov 1, 2018, and Jan 31, 2020. 328 (20%) records were from countries in the very high HDI tier, 539 (33%) from countries in the high HDI tier, 614 (38%) from countries in the medium HDI tier, and 154 (9%) from countries in the low HDI tier. The median age was 35 years (IQR 24–51), with the oldest patients in the very high HDI tier (median 54 years, IQR 34–69) and the youngest in the low HDI tier (median 28 years, IQR 20–38). The most common procedures were elevation of a depressed skull fracture in the low HDI tier (69 [45%]), evacuation of a supratentorial extradural haematoma in the medium HDI tier (189 [31%]) and high HDI tier (173 [32%]), and evacuation of a supratentorial acute subdural haematoma in the very high HDI tier (155 [47%]). Median time from injury to surgery was 13 h (IQR 6–32). Overall mortality was 18% (299 of 1635). After adjustment for casemix, the odds of mortality were greater in the medium HDI tier (odds ratio [OR] 2·84, 95% CI 1·55–5·2) and high HDI tier (2·26, 1·23–4·15), but not the low HDI tier (1·66, 0·61–4·46), relative to the very high HDI tier. There was significant between-hospital variation in mortality (median OR 2·04, 95% CI 1·17–2·49). Interpretation: Patients receiving emergency neurosurgery for TBI differed considerably in their admission characteristics and management across human development settings. Level of human development was associated with mortality. Substantial opportunities to improve care globally were identified, including reducing delays to surgery. Between-hospital variation in mortality suggests changes at an institutional level could influence outcome and comparative effectiveness research could identify best practices. Funding: National Institute for Health Research Global Health Research Group.

Aims of the study: Virchow’s triad with stasis, activated coagulation, and endothelial damage is common in SARS-CoV2. Therefore, we sought to retrospectively assess whether the duration of prone position may serve as a risk factor for deep vein thrombosis in critically ill patients. Methods: In this single center retrospective study of a tertiary referral hospital, patients with acute respiratory distress syndrome (ARDS) due to COVID-19 pneumonia admitted to critical care underwent venous ultrasound screening for deep vein thrombosis (DVT). Data on DVT diagnosis, duration of prone positioning, demographic, respiratory, and laboratory parameters were retrospectively collected and compared between DVT and non-DVT patients. Results: 21 patients with ARDS from COVID-19 pneumonia were analyzed. DVT was detected in 11 (52%) patients (76.2% male, median age 64 (58; 68.5) years, median body mass index 31 (27; 33.8) kg/m2). In patients diagnosed with DVT, median prone ventilation had been maintained twice as long as compared to patients without DVT (57 (19; 72) versus 28 (0; 56.3) h, p = 0.227) on ICU day 5 with a trend towards longer prone position time (71 (19; 104) versus 28 (0; 73) h, p = 0.06) on ICU day 7. Conclusions: Prone ventilation and constitutional factors may constitute an additional risk factor for DVT in COVID-19 patients. Since recent studies have shown that therapeutic anticoagulation does not impact the occurrence of thromboembolic events, it may be worthwhile to consider mechanical factors potentially affecting blood flow stasis in this high-risk population. However, due to the limited number of patients, our observations should only be considered as hypothesis-generating. Future studies, sufficiently powered and preferably prospective, will be needed to confirm our hypothesis.

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.

Objectives Current guidelines and expert recommendations stress the need to implement enteral feeds with a higher protein-to-energy ratio to meet protein requirements as recommended while avoiding gastrointestinal side effects and energy overfeeding in ICU patients. Materials and methods Prospective tolerability study in 18 critically ill patients with a high protein formula (high protein-to-energy (HP:E) formula = Fresubin® Intensive; HPG) compared to a contemporary matched conventional therapy group (CTG). The primary outcome was GI intolerance defined as ≥300 ml daily gastric residual volume (GRV), vomiting, or diarrhea on days 1 and 2. Secondary outcomes were the percentage of patients reaching their protein target on day 4 and overall protein intake. Results Groups were comparable regarding demographic characteristics, disease severity, organ failures, mechanical ventilation, and NUTRIC score at baseline. Eighteen patients completed the 4-day feeding period. The number of events of GRV of ≥300 ml/day was equal in both groups (33.3%). The incidence of diarrhea and vomiting was low in the HPG (two patients concerned). EN did not need to be discontinued due to intolerance in any group. Seventy-two percent of patients reached protein targets ≥1.3 g/kgBW/d within 4 days after initiation of enteral feeding, which was superior to the CTG (33%). Post-hoc testing showed group differences of protein intake between HPG and CTG were significant at t = 72 h and t = 96 h. Energy targets were met in both groups. Conclusion The HP:E formula containing 33% whey protein hydrolysate is well tolerated in this tolerability study. Due to the HP:E ratio protein targets can be reached faster. Larger randomized trials are needed to confirm preliminary results. Trial registration ClinicalTrials.gov Identifier: NCT02678325. Registered 2 May 2016.

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.

Background: Supplemental oxygen is the key intervention for severe and critical COVID-19 patients. With the unstable supplies of oxygen in many countries, it is important to define the lowest safe dosage. Methods: In spring 2020, 110 COVID-19 patients were enrolled as part of the Handling Oxygenation Targets in the ICU trial (HOT-ICU). Patients were allocated within 12 h of ICU admission. Oxygen therapy was titrated to a partial pressure of arterial oxygen (PaO2) of 8 kPa (lower oxygenation group) or a PaO2 of 12 kPa (higher oxygenation group) during ICU stay up to 90 days. We report key outcomes at 90 days for the subgroup of COVID-19 patients. Results: At 90 days, 22 of 54 patients (40.7%) in the lower oxygenation group and 23 of 55 patients (41.8%) in the higher oxygenation group had died (adjusted risk ratio: 0.87; 95% confidence interval, 0.58–1.32). The percentage of days alive without life support was significantly higher in the lower oxygenation group (p = 0.03). The numbers of severe ischemic events were low with no difference between the two groups. Proning and inhaled vasodilators were used more frequently, and the positive end-expiratory pressure was higher in the higher oxygenation group. Tests for interactions with the results of the remaining HOT-ICU population were insignificant. Conclusions: Targeting a PaO2 of 8 kPa may be beneficial in ICU patients with COVID-19. These results come with uncertainty due to the low number of patients in this unplanned subgroup analysis, and insignificant tests for interaction with the main HOT-ICU trial. Trial registration number: ClinicalTrials.gov number, NCT03174002. Date of registration: June 2, 2017.

Objectives The association between outcome and kidney injury detected at discharge from the ICU using different biomarkers remains unknown. The objective was to evaluate the association between 1-year survival and kidney injury at ICU discharge. Design Ancillary investigation of a prospective observational study. Setting Twenty-one ICUs with 1-year follow-up. Patients Critically ill patients receiving mechanical ventilation and/or hemodynamic support for at least 24 hours were included. Interventions Serum creatinine, plasma Cystatin C, plasma neutrophil gelatinase-associated lipocalin, urinary neutrophil gelatinase-associated lipocalin, plasma Proenkephalin A 119-159, and estimated glomerular filtration rate (on serum creatinine and plasma Cystatin C) were measured at ICU discharge among ICU survivors. Measurements and main results The association between kidney biomarkers at discharge and mortality was estimated using logistic model with and without adjustment for prognostic factors previously identified in this cohort. Subgroup analyses were performed in patients with discharge serum creatinine less than 1.5-fold baseline at ICU discharge. Among 1,207 ICU survivors included, 231 died during the year following ICU discharge (19.2%). Estimated glomerular filtration rate was significantly lower and kidney injury biomarkers higher at discharge in nonsurvivors. The association between biomarker levels or estimated glomerular filtration rate and mortality remained after adjustment to potential cofounding factors influencing outcome. In patients with low serum creatinine at ICU discharge, 25-47% of patients were classified as subclinical kidney injury depending on the biomarker. The association between kidney biomarkers and mortality remained and mortality was higher than patients without subclinical kidney injury. The majority of patients who developed acute kidney injury during ICU stay had elevated biomarkers of kidney injury at discharge even with apparent recovery based on serum creatinine (i.e., subclinical acute kidney disease). Conclusions Elevated kidney biomarkers measured at ICU discharge are associated with poor 1-year outcome, including in patients with low serum creatinine at ICU discharge.

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 timely administration of balanced vWF (1:1 vWF and FVIII) in addition to platelet transfusion on 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 by adding balanced vWF to platelets will reduce the overall need of transfusion of blood products compared to 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 number of platelet concentrates transfused within the first 48 h after treatment of study medication, quantity of blood loss in the first 48 hours 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 one-year mortality. Patients will be followed after 30 days and 1 year for activities of daily living and mortality assessment. Sample size was calculated to detect a 50% reduction of the number of blood products subsequently transfused within two 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) as well as all national legal and regulatory requirements. Study results will be presented in international conferences and published in a peer-reviewed journal. Trials registration: ClinicalTrials.gov Identifier: NCT04555785 Protocol version: Clinical Study Protocol Version 2, 01.11.2020

Worldwide, the left ventricular assist device Impella® (Abiomed, Danvers, MA, USA) is increasingly implanted in patients with acute cardiogenic shock or undergoing high-risk cardiac interventions. Despite its long history of use, few studies have assessed its safety and possible complications associated with its use. All patients treated with a left-sided Impella® device at the University Hospital of Basel from 1 January 2011 to 31 December 2019 were enrolled. The primary endpoint was the composite rate of mortality and adverse events (bleeding, acute kidney injury, and limb ischemia). Out of 281 included patients, at least one adverse event was present in 262 patients (93%). Rates of in-hospital, 90-day, and one-year mortality were 48%, 47%, and 50%, respectively. BARC type 3 bleeding (62%) and hemolysis (41.6%) were the most common complications. AKI was observed in 50% of all patients. Renal replacement therapy was required in 97 (35%) of all patients. Limb ischemia occurred in 13% of cases. Bleeding and hemolysis are common Impella®-associated complications. Additionally, we found a high rate of AKI. A careful selection of patients receiving microaxial LV support and defining the indication for its use are essential measures to be taken for the benefits to outweigh potential complications.

BackgroundIn vitro studies have thoroughly documented the impact of storage lesions in packed red blood cells (pRBC) on erythrocyte oxygen carrying capacity due to older age of blood products. While studies have examined the effect of pRBC age on patient outcome, only few data exist on the microcirculation, their primary site of action.MethodsIn this secondary analysis, we examined the relationship between the age of pRBC and changes of microcirculatory flow (MCF) in 54 patients. Data from the Basel Bedside assessment Microcirculation Transfusion Limit study (Ba2MiTraL), investigating the effects of one pRBC on the sublingual MCF provided the basis of this study. ResultsMean change from pre-to post-transfusion proportion of perfused vessels (∆PPV) was +8.8% (IQR: -0.5 – 22.5), 5.5% (IQR: 0.1–10.1), and +4.7% (IQR: -2.1 – 6.5) after transfusion of fresh (≤ 14 days old), medium (15 to 34 days old), and old (≥ 35 days old) pRBC, respectively. Values for the microcirculatory flow index (MFI) were +0.22 (IQR: -0.1 – 0.6), +0.22 (IQR: 0.0 – 0.3), and +0.06 (IQR: -0.1 – 0.3) for the fresh, medium, and old pRBC age groups, respectively.Lower ∆PPV and transfusion of older blood were correlated with a higher Sequential Organ Failure Assessment (SOFA) score of patients upon admission to the intensive care unit (ICU) (p=0.01). However, regression models showed no overall significant correlation between pRBC age and ∆PPV (p=0.2). No correlation between donor’s sex or a mismatch between donor and recipient sex was found.ConclusionWe detected no significant correlation between age of pRBC and change in MCF between pre- and post-transfusion among all investigated patients. However, in patients with a higher SOFA score upon ICU admission, there might be a negative effect on the proportion of perfused microcirculatory vessels after transfusion of older blood.

Delirium after surgery and in the intensive care unit (ICU) remains a challenge for patients, families, and caregivers. Over the years, many promising biomarkers have been investigated as potential instruments for risk stratification of delirium. This review aimed to identify and assess the clinical usefulness of candidate serum biomarkers associated with hospital delirium in patients aged 60 years and older. We performed a time-unlimited review of publications indexed in PubMed, Cochrane, Embase, and MEDLINE databases until June 2019 that evaluated baseline and/or longitudinal biomarker measurements in patients suffering from delirium at some point during their hospital stay. A total of 32 studies were included in this review reporting information on 7610 patients. Of these 32 studies, twenty-four studies reported data from surgical patients including four studies in ICU cohorts, five studies reported data from medical patients (1026 patients), and three studies reported data from a mixed cohort (1086 patients), including one study in an ICU cohort. Findings confirm restricted clinical usefulness to predict or diagnose delirium due to limited evidence on which biomarkers can be used and limited availability due to non-routine use. Electronic supplementary material The online version of this article (10.1186/s13613-019-0548-1) contains supplementary material, which is available to authorized users.

BACKGROUND Patients with acute hypoxemic respiratory failure in the intensive care unit (ICU) are treated with supplemental oxygen, but the benefits and harms of different oxygenation targets are unclear. We hypothesized that using a lower target for partial pressure of arterial oxygen (Pao 2) would result in lower mortality than using a higher target. METHODS In this multicenter trial, we randomly assigned 2928 adult patients who had recently been admitted to the ICU (≤12 hours before randomization) and who were receiving at least 10 liters of oxygen per minute in an open system or had a fraction of inspired oxygen of at least 0.50 in a closed system to receive oxygen therapy targeting a Pao 2 of either 60 mm Hg (lower-oxygenation group) or 90 mm Hg (higher-oxygenation group) for a maximum of 90 days. The primary outcome was death within 90 days. RESULTS At 90 days, 618 of 1441 patients (42.9%) in the lower-oxygenation group and 613 of 1447 patients (42.4%) in the higher-oxygenation group had died (adjusted risk ratio, 1.02; 95% confidence interval, 0.94 to 1.11; P=0.64). At 90 days, there was no significant between-group difference in the percentage of days that patients were alive without life support or in the percentage of days they were alive after hospital discharge. The percentages of patients who had new episodes of shock, myocardial ischemia, ischemic stroke, or intestinal ischemia were similar in the two groups (P=0.24). CONCLUSIONS Among adult patients with acute hypoxemic respiratory failure in the ICU, a lower oxygenation target did not result in lower mortality than a higher target at 90 days.

In March 2020, a 64-year-old female with mitral valve insufficiency and persistent atrial fibrillation underwent preoperative noninvasive mapping for developing an ablation strategy. In the computed tomography (CT) scan, typical signs of COVID-19 were described. Since the consecutive polymerase chain reaction (PCR) test was negative, the severely symptomatic patient was planned for urgent surgery. Noninvasive mapping showed that atrial fibrillation was maintained by left atrial structures and pulmonary veins only. On admission day, the preoperative routine COVID-19 PCR test was positive, and after recovery, uneventful mitral valve repair with cryoablation of the left atrium and pulmonary veins was performed. Our case describes the potential benefit of preoperative noninvasive mapping for the development of a surgical ablation strategy, as well as the challenges in managing urgent surgical patients during the COVID-19 pandemic and the corresponding diagnostic relevance of CT.

International audience; Aims: Acute heart failure (AHF) is frequent and life-threatening disease. However, innovative AHF therapies have remained limited, and care is based on experts opinion. Temporal trends and benefits of long-term oral cardiovascular medications on AHF outcomes remain uncertain.Methods and results: This study is registered with PROSPERO (CRD42018099885). A systematic review ranging from 1980 to 2017, searched AHF studies with more than 100 patients that reported death and/or readmission. Primary outcomes were temporal trends, assessed by meta-regression, for 30-day or one-year all-cause death and/or readmission rates. Secondary outcomes were temporal trends of oral cardiovascular therapies and their influence on primary outcomes. Among the 45143 studies screened, 285 were included, representing 15 million AHFs. In the past decades, though mortality and readmission remain high, there was a decline in 30-day all-cause death (OR for a 10-year increment: 0.74 (0.61-0.91); p=0.004) that persisted at one year (OR 0.86 (0.77- 0.96); p=0.007), while 30-day and one-year all-cause readmission rate remained roughly unchanged. Trends of primary outcomes were linear and did not differ among continents. Decline in one-year all-cause death rate correlated with high proportions of oral or beta-blockers, especially when combined with oral renin-angiotensin-aldosterone system inhibitors, but not with diuretics while trends in readmission remained unchanged with these therapies.Conclusions: Though AHF outcomes remain poor, the present study revealed global favorable trends of survival after AHF episodes probably associated with greater use of oral neurohormonal antagonists. The present study urges to implement the combination of oral renin-angiotensin-aldosterone system inhibitors and beta-blockers in patients at risk of AHF. This article is protected by copyright. All rights reserved.

It is currently unclear whether management and outcomes of critically ill patients differ between men and women. We sought to assess the influence of age, sex and diagnoses on the probability of intensive care provision in critically ill cardio- and neurovascular patients in a large nationwide cohort in Switzerland.Retrospective analysis of 450,948 adult patients with neuro- and cardiovascular disease admitted to all hospitals in Switzerland between 01/2012 and 12/2016 using Bayesian modeling.For all diagnoses and populations, median ages at admission were consistently higher for women than for men [75 (64;82) years in women vs. 68 (58;77) years in men, p 0.001]. Overall, women had a lower likelihood to be admitted to an intensive care unit (ICU) than men, despite being more severely ill [odds ratio (OR) 0.78 (0.76-0.79)]. ICU admission probability was lowest in women aged 65 years (OR women:men 0.94 (0.89-0.99), p 0.001). Women 45 years had a similar ICU admission probability as men in the same age category [OR women:men 1.03 (0.94-1.13)], in spite of more severe illness. The odds to die were significantly higher in women than in men per unit increase in Simplified Acute Physiology Score (SAPS) II (OR 1.008 [1.004-1.012]).In the care of the critically ill, our study suggests that women are less likely to receive ICU treatment regardless of disease severity. Underuse of ICU care was most prominent in younger women 45 years. Although our study has several limitations that are imposed by the limited data available from the registries, our findings suggest that current ICU triage algorithms could benefit from careful reassessment. Further, and ideally prospective, studies are needed to confirm our findings.

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7., Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 μg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P

International audience; Rationale: Subclinical acute kidney injury (sub-AKI) refers to patients with low serum creatinine but elevated alternative biomarkers of AKI. Its incidence and outcome in critically ill patients remain, however, largely unknown. Plasma proenkephalin A 119–159 (penKid) has been proposed as a sensitive biomarker of glomerular function.Objectives: In this ancillary study of two cohorts, we explored the incidence and outcome of sub-AKI based on penKid.Methods: A prospective observational study in ICUs was conducted. FROG-ICU (French and European Outcome Registry in ICUs) enrolled 2,087 critically ill patients, and AdrenOSS-1 (Adrenomedullin and Outcome in Severe Sepsis and Septic Shock-1) enrolled 583 septic patients. The primary endpoint was 28-day mortality after ICU admission. Sub-AKI was defined by an admission penKid concentration above the normal range (i.e., >80 pmol/L) in patients not meeting the definition of AKI. A sensitivity analysis was performed among patients with estimated glomerular filtration rate above 60 ml/min/1.73 m2 at ICU admission.Measurements and Main Results: In total, 6.1% (122/2,004) and 6.7% (39/583) of patients from the FROG-ICU and AdrenOSS-1 cohorts met the definition of sub-AKI (11.6% and 17.5% of patients without AKI). In patients without AKI or with high estimated glomerular filtration rate, penKid was associated with higher mortality (adjusted standardized hazard ratio [HR], 1.4 [95% confidence interval, 1.1–1.8]; P = 0.010; and HR, 1.6 [95% confidence interval, 1.3–1.8]; P

BackgroundCritically 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.MethodsPro 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.DiscussionThe Basel Pro BoNo study aims to collect innovative data on the effect of intermittent enteral feeding of critically ill patients on muscle wasting.Trial registrationClinicalTrials.govNCT03587870. Registered on July 16, 2018. Swiss National Clinical Trials Portal SNCTP000003234. Last updated on July 24, 2019.

Study objective Delirium is frequently observed in the postoperative and intensive care unit (ICU) population. Due to the multifactorial origin of delirium and according to international guidelines (e.g., American Geriatrics Society; Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) guideline), there are several but no incontestable options for prevention and symptomatic treatment. The purpose of the Baden PRIDe (Prevention and Reduction of Incidence of postoperative Delirium) trial was to determine whether postoperative cognitive dysfunction and delirium could be prevented by the combination of possible preventive agents such as haloperidol and ketamine. In addition, pre- and postoperative levels of the biomarkers cortisol, neuron specific enolase (NSE) and S100β were measured to investigate their dynamics in delirious and non-delirious patients after surgery. Design The Baden PRIDe Trial was an investigator-initiated, phase IV, two-centre, randomised, placebo-controlled, double-blind clinical trial. Setting Perioperative care. Patients 182 adult patients that underwent elective or emergency surgery under general or combined (i.e., general and regional) anaesthesia. Interventions Pre-anaesthetic, pharmacologic prevention of postoperative brain dysfunction with haloperidol, ketamine, and the combination of both vs. placebo. Measurements Assessment of cognitive performance pre- and postoperatively with the MMSE, the DOS, the Nursing Delirium Screening Scale (Nu-DESC) or the Intensive Care Delirium Screening Checklist (ICDSC) during ICU stay. Main results None of the three study arms – haloperidol, ketamine, or both drugs combined - was significantly superior to placebo for prevention of postoperative brain dysfunction and delirium (P = 0.39). Measured levels of postoperative cortisol were significantly higher in delirious patients. S-100β levels were significantly higher in all postoperative outcome groups (cognitive impairment, delirium, no cognitive decline), whereas postoperative NSE levels declined in all groups. Conclusions The study results offer no possibility for a novel recommendation for prevention of postoperative cognitive decline including delirium. Perioperative S-100β trajectories in patients with cognitive deterioration suggest affection of glial cells in particular. Trial registration ClinicalTrials.gov NCT02433041 ; registered on April 7, 2015.

IntroductionDelirium is frequently observed in the intensive care unit (ICU) population, in particular. Until today, there is no evidence for any reliable pharmacological intervention to treat delirium. The Basel BOMP-AID (BetterOutcome withMelatonin compared toPlaceboAdministered to normalize sleep-wake cycle and treat hypoactiveICUDelirium) randomised trial targets improvement of hypoactive delirium therapy in critically ill patients and will be conducted as a counterpart to the Basel ProDex Study (Study Protocol, BMJ Open, July 2017) on hyperactive and mixed delirium. The aim of the BOMP-AID trial is to assess the superiority of melatonin to placebo for the treatment of hypoactive delirium in the ICU. The study hypothesis is based on the assumption that melatonin administered at night restores a normal circadian rhythm, and that restoration of a normal circadian rhythm will cure delirium.Methods and analysisThe Basel BOMP-AID study is an investigator-initiated, single-centre, randomised controlled clinical trial for the treatment of hypoactive delirium with the once daily oral administration of melatonin 4 mg versus placebo in 190 critically ill patients. The primary outcome measure is delirium duration in 8-hour shifts. Secondary outcome measures include delirium-free days and death at 28 days after study inclusion, number of ventilator days, length of ICU and hospital stay, and sleep quality. Patients will be followed after 3 and 12 months for activities of daily living and mortality assessment. Sample size was calculated to demonstrate superiority of melatonin compared with placebo regarding the duration of delirium. Results will be presented using an intention-to-treat approach.Ethics and disseminationThis 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 International Conference on Harmonisation (ICH) of technical requirements for registration of pharmaceuticals for human use; Good Clinical Practice (GCP) or ISO EN 14155 (as far as applicable), as well as all national legal and regulatory requirements. Study results will be presented in international conferences and published in a peer-reviewed journal.Trial registration numberNCT03438526.Protocol versionClinical Study Protocol Version 3, 10.03.2019.

Purpose Intensive care unit survivors suffer from prolonged impairment, reduced quality of life, and higher mortality rates after discharge compared to the general population. Socioeconomic status may play a partial but important role in mortality and recovery. Therefore, the detection of factors that are responsible for poor long-term outcomes would be beneficial in designing targeted interventions for at-risk populations. Methods For an endpoint analysis, 1834 intensive care unit patients with known French Deprivation Index (FDep) scores were included from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study, which was a prospective, observational, multicenter cohort study performed in 20 French intensive care units in 13 different hospitals. Socioeconomic status was defined by using the FDep score [represented as quintiles when referring to the general French population, as quintiles when referring to the FROG-ICU cohort, or as dichotomized data (which was defined as a FDep ≤ 0 for nondeprived patients)] and by using a detailed social questionnaire that was completed 3 months after discharge. The primary outcome included an all-cause, 1-year mortality after ICU discharge when regarding socioeconomic status. The secondary outcomes included both ICU and hospital lengths of stay, both short- and medium-term mortality, and the quality of life, as assessed during the 1-year follow-up by using the Medical Outcome Survey Short Form-36 (SF-36). The Revised Impact of Event Scale (IES-R) was used to evaluate the symptoms of post-traumatic stress disorder, and the Hospital Anxiety and Depression Scale (HADS) was used to screen for anxiety and depression. Results Of the 1447 patients who were discharged alive from the ICU, 19.2% died over the following year. No association was found between 1-year mortality and socioeconomic status, regardless of whether this association was analyzed in quintiles (p = 0.911 in the quintiles of the general French population; p = 0.589 in the quintiles of the FROG-ICU cohort itself) or as dichotomized data [nondeprived (n = 177; 1-year mortality of 18.2%) versus deprived (n = 97; 1-year mortality of 20.5%; p = 0.304)]. Moreover, no differences were found between the nondeprived and the deprived patients in the ICU and hospital lengths of stay, ICU mortalities, in-hospital mortalities, or 28-day mortalities. The SF-36 was below the score for the normal French population throughout the follow-up period. Socially deprived patients showed significantly lower median scores in the physical function subscale [55, interquartile range (IQR) (28.8–80) vs. 65, IQR (35–90); p = 0.014], the physical role subscale [25, IQR (0–75) vs. 33.3, IQR (0–100); p = 0.022], and the overall physical component scale [47.5, IQR (30–68.8) vs. 54.4, IQR (35–78.8); p = 0.010]. Up to 31.6% of survivors presented symptoms that indicated post-traumatic stress disorder, and up to 31.5% of survivors reported clinically meaningful symptoms of anxiety or depression. Conclusions A lower socioeconomic status was associated with lower self-reported physical component scores in the nondeprived patients. Psychiatric symptoms are frequently reported after an ICU stay, and subsequent interventions should target those fields. Trial registration ClinicalTrials.gov NCT01367093; registered on June 6, 2011. Electronic supplementary material The online version of this article (10.1007/s00134-018-5412-5) contains supplementary material, which is available to authorized users.

Background To determine the preventive and therapeutic effect of dexmedetomidine on intensive care unit (ICU) delirium. Methods The literature search using PubMed and the Cochrane Central Register of Controlled Trials was performed (August 1, 2018) to detect all randomized controlled trials (RCTs) of adult ICU patients receiving dexmedetomidine. Articles were included if they assessed the influence of dexmedetomidine compared to a sedative agent on incidence of ICU delirium or treatment of this syndrome. Accordingly, relevant articles were allocated to the following two groups: (1) articles that assessed the delirium incidence (incidence comparison) or articles that assessed the treatment of delirium (treatment comparison). Incidence of delirium and delirium resolution were the primary outcomes. We combined treatment effects comparing dexmedetomidine versus (1) placebo, (2) standard sedatives, and (3) opioids in random-effects meta-analyses. Risk of bias for each included RCT was assessed following Cochrane standards. Results The literature search resulted in 28 articles (25 articles/4975 patients for the incidence comparison and three articles/166 patients for the treatment comparison). In the incidence comparison, heterogeneity was present in different subgroups. Administration of dexmedetomidine was associated with significantly lower overall incidence of delirium when compared to placebo (RR 0.52; 95% CI 0.39–0.70; I2 = 37%), standard sedatives (RR 0.63; 95% CI 0.46–0.86; I2 = 69%), as well as to opioids (RR 0.61; 95% CI 0.44–0.83; I2 = 0%). Use of dexmedetomidine significantly increased the risks of bradycardia and hypotension. Limited data were available on circulatory insufficiency and mortality. In the treatment comparison, the comparison drugs in the three RCTs were placebo, midazolam, and haloperidol. The resolution of delirium was measured differently in each study. Two out of the three studies indicated clear favorable effects for dexmedetomidine (i.e., compared to placebo and midazolam). The study comparing dexmedetomidine with haloperidol was a pilot study (n = 20) with high variability in the results. Conclusion Findings suggest that dexmedetomidine reduces incidence and duration of ICU delirium. Furthermore, our systematic searches show that there is limited evidence if a delirium shall be treated with dexmedetomidine. Electronic supplementary material The online version of this article (10.1186/s13613-018-0437-z) contains supplementary material, which is available to authorized users.

OBJECTIVES Periodic social events may influence the incidence and course of status epilepticus (SE), likely explained by patients' behavioral changes regarding alcohol intake, sleep, and compliance with antiseizure medication. However, data regarding the association between such events and SE are lacking. The aim of this study was to identify and quantify associations between periodic social events and the incidence, etiology, and outcome of SE. METHODS Adult patients who were admitted to a tertiary academic medical care center with SE from 2005 to 2015 were included. Associations between periodic social events (including birthday, Christmas, New Year's Eve, carnival, national holiday) and the number and etiologies of SE over time were calculated using linear and Poisson regression. Logistic regression was applied to identify associations between time from social events and outcome. RESULTS Four hundred nine patients with a median age of 66 years (interquartile range 52-76) were analyzed. The number of total SE events and SE in patients with known epilepsy peaked within 2 weeks following social events and then decreased with each additional day (incidence rate ratio [IRR]per day 0.99, 95% confidence interval [CI] 0.98-0.99; P

International audience; Purpose: Acute kidney injury (AKI) is associated with the activation of the renin–angiotensin system. Whether angiotensin-converting enzyme inhibitors (ACEi) or angiotensin-receptor blockers (ARB) improve outcome in patients recovering from AKI remains unexplored. The purpose was to investigate the association between prescription of ACEi/ARB at intensive care unit (ICU) discharge and 1-year outcome in patients recovering from AKI.Methods: Association between ACEi/ARB and 1-year mortality rate was explored in 1551 patients discharged from 21 European ICUs in an observational cohort. One-year all-cause mortality after ICU discharge was the primary endpoint. AKI was defined using the kidney disease improvement global outcome definition. Propensity score matching was used to consider the probability to receive ACEi/ARB at ICU discharge and included chronic heart failure, ACEi/ARB on ICU admission, Charlson Comorbidity Index, age, diabetes mellitus, chronic kidney disease, estimated glomerular filtration rate and arterial blood pressure at ICU discharge vasopressors and renal replacement therapy.Results: Overall, 1-year mortality was 28 and 15% in patients with AKI (n = 611, 39%) and without AKI (n = 940), respectively. In patients with AKI, unadjusted, adjusted and propensity-score matched 1-year mortality rates were lower in patients treated with ACEi/ARB at ICU discharge [HR of 0.55 (0.35–0.89), HR of 0.45 (0.27–0.75), and HR of 0.48 (0.27–0.85, p

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.

IntroductionSepsis is the leading cause of acute kidney injury (AKI) in critically ill patients. The Kidney in Sepsis and Septic Shock (Kid-SSS) study evaluated the value of proenkephalin A 119-159 (penkid)-a sensitive biomarker of glomerular function, drawn within 24 hours upon intensive care unit (ICU) admission and analyzed using a chemiluminescence immunoassay-for kidney events in sepsis and septic shock.MethodsThe Kid-SSS study was a substudy of Adrenomedullin and Outcome in Severe Sepsis and Septic Shock (AdrenOSS) (NCT02393781), a prospective, observational, multinational study including 583 patients admitted to the intensive care unit with sepsis or septic shock and a validation cohort of 525 patients from the French and euRopean Outcome reGistry in Intensive Care Units (FROG-ICU) study. The primary endpoint was major adverse kidney events (MAKEs) at day 7, composite of death, renal replacement therapy, and persistent renal dysfunction. The secondary endpoints included AKI, transient AKI, worsening renal function (WRF), and 28-day mortality.ResultsMedian age was 66 years (interquartile range 55-75), and 28-day mortality was 22% (95% confidence interval [CI] 19%-25%). Of the patients, 293 (50.3%) were in shock upon ICU admission. Penkid was significantly elevated in patients with MAKEs, persistent AKI, and WRF (median= 65 [IQR= 45-106] vs. 179 [114-242]; 53 [39-70] vs. 133 [79-196] pmol/l; and 70 [47-121] vs. 174 [93-242] pmol/l, all P< 0.0001), also after adjustment for confounding factors (adjusted odds ratio= 3.3 [95% CI = 1.8-6.0], 3.9 [95% CI = 2.1-7.2], and 3.4 [95% CI = 1.9-6.2], all P&nbsp

International audience; on behalf of the FROG ICU study investigators Acute kidney injury (AKI) is a frequent condition in critically ill patients that affects both short-and long-term outcome [1]. Its early detection remains a challenge, and diagnosis frequently occurs too late with cell damage already present. Implementation of novel biomarkers that reliably identify patients at risk or at an early stage of AKI could offer more efficient management strategies leading to better outcomes. In our investigation, we compared two promising AKI biomarkers: a marker of tubular injury commercialized as a lateral-flow test (NephroCheck®) [2], the product of urinary TIMP-2 (Tissue inhibitor of metalloprotease), and IGFBP 7 (Insulin-like growth factor binding protein; overall TIMP2xIGFBP7), and the filtration marker proenkephalin A 119-159 (penKid). penKid has been recently described as a valuable plasma biomarker of AKI in the acutely ill, including septic patients [3] and patients suffering from acute heart failure [4]. Proenkephalin represents a stable surrogate analyte of labile enkephalins, which are known as endogenous opioids, but also affects kidney function [5]. The aim of our study was to conduct a parallel assessment of the two biomarkers in an intensive care unit (ICU) population from the data of the FROG-ICU study. FROG-ICU has been designed to better understand long-term outcome after ICU discharge as well as risk factors for all-cause and cardiovascular morbidity and associated mortality (FROG-ICU study, ClinicalTrials.gov identifier NCT01367093). It was a large prospective multicenter cohort study with biological (plasma and urine) collection and one-year follow-up of ICU patients. FROG-ICU aims to allow risk stratification of ICU survivors in order to recognize the subset of patients who may benefit from early intervention to allow decreased cardiovascular morbidity and related mortality. The methodology of the FROG-ICU study was published in 2015. From the FROG study including 2087 critically ill patients we randomly selected 200 requiring mechanical ventilation or vasopressor support for more than 24 h with respect to the four categories of the renal Sequential Organ Failure Assessment (SOFA) score (i.e., creatinine level on admission of < 1.2 mg/dL (n = 80), 1.2 to 1.9 mg/dL (n = 40), 2 to 3.4 mg/dL (n = 40), and ≥ 3.5 mg/dL (n = 40)); 78% were male, with a median age of 65 years (interquartile range (IQR) 54–75). In the investigated cohort of a standard population of critically ill, the main cause of ICU admission was septic shock (26%), the median age was 65 years (IQR 54–75), the median SAPS II score was 51 (IQR 41–68), and the ICU mortality was 26%. Other causes of admission include out-of-hospital cardiac arrest (10%), acute respiratory failure (16%), acute neurological disorder (11%), and cardiogenic shock (8%). On ICU admission, the median (and IQR) value of estimated glomerular filtration rate for penKid and TIMP2xIGFBP7 was 47 mL/min (22–88), 85 pmol/L (48–40), and 0.6 UNIT (0.3–2), respectively. AKI was defined using the Kidney Disease Improvement Global Outcome (KDIGO) definition. Accordingly, we used both the variation in serum creatinine during the first 48 h after ICU admission and the maximal value during the 7 days following ICU admission. Admission serum creatinine was used as baseline serum creatinine when the estimated glomerular filtration rate (eGFR) was above 60 ml/min/1.73 m 2 at admission. Otherwise (n = 117, 59% of the study population), baseline serum