Major adverse cardiovascular events (MACE) in patients with severe COVID-19 registered in the ISARIC WHO clinical characterization protocol: A prospective, multinational, observational study.

PURPOSE: To determine its cumulative incidence, identify the risk factors associated with Major Adverse Cardiovascular Events (MACE) development, and its impact clinical outcomes. MATERIALS AND METHODS: This multinational, multicentre, prospective cohort study from the ISARIC database. We used bivariate and multivariate logistic regressions to explore the risk factors related to MACE development and determine its impact on 28-day and 90-day mortality. RESULTS: 49,479 patients were included. Most were male 63.5% (31,441/49,479) and from high-income countries (84.4% [42,774/49,479]); however, >6000 patients were registered in low-and-middle-income countries. MACE cumulative incidence during their hospital stay was 17.8% (8829/49,479). The main risk factors independently associated with the development of MACE were older age, chronic kidney disease or cardiovascular disease, smoking history, and requirement of vasopressors or invasive mechanical ventilation at admission. The overall 28-day and 90-day mortality were higher among patients who developed MACE than those who did not (63.1% [5573/8829] vs. 35.6% [14,487/40,650] p < 0.001; 69.9% [6169/8829] vs. 37.8% [15,372/40,650] p < 0.001, respectively). After adjusting for confounders, MACE remained independently associated with higher 28-day and 90-day mortality (Odds Ratio [95% CI], 1.36 [1.33-1.39];1.47 [1.43-1.50], respectively). CONCLUSIONS: Patients with severe COVID-19 frequently develop MACE, which is independently associated with worse clinical outcomes.

A protocol of an international validation study to assess the clinical accuracy of the eDIS-ICU delirium screening tool.

BACKGROUND: Delirium is a common, yet underdiagnosed neuropsychiatric complication of intensive care unit (ICU) admission, associated with significant mortality and morbidity. Delirium can be difficult to diagnose, with gold standard assessments by a trained specialist being impractical and rarely performed. To address this, various tools have been developed, enabling bedside clinicians to assess for delirium efficiently and accurately. However, the performance of these tools varies depending on factors including the assessor's training. To address the shortcomings of current tools, electronic tools have been developed. AIMS AND OBJECTIVES: The aims of this validation study are to assess the feasibility, acceptability, and generalisability of a recently developed and pilot-tested electronic delirium screening tool (eDIS-ICU) and compare diagnostic concordance, sensitivity, and specificity between eDIS-ICU, Confusion Assessment Method for the ICU (CAM-ICU), and the Diagnostic and Statistical Manual of Mental Disorders - 5th edition (DSM-V) gold standard in diverse ICU settings. METHODS: Seven hundred participants will be recruited across five sites in three countries. Participants will complete three assessments (eDIS-ICU, CAM-ICU, and DSM-V) twice within one 24-h period. At each time point, assessments will be completed within one hour. Assessments will be administered by three different people at any given time point, with the assessment order and assessor for eDIS-ICU and CAM-ICU randomly allocated. Assessors will be blinded to previous and concurrent assessment results. RESULTS: The primary outcome is comparing diagnostic sensitivity of eDIS-ICU and CAM-ICU against the DSM-V. RELEVANCE TO CLINICAL PRACTICE: This protocol describes a definitive validation study of an electronic diagnostic tool to assess for delirium in the ICU. Delirium remains a common and difficult challenge in the ICU and is linked with multiple neurocognitive sequelae. Various challenges to routine assessment mean many cases are still unrecognised or misdiagnosed. An improved ability for bedside clinicians to screen for delirium accurately and efficiently will support earlier diagnosis, identification of underlying cause(s) and timely treatments, and ultimately improved patient outcomes. CLINICAL TRIAL REGISTRATION NUMBER: This study was prospectively registered on the Australian New Zealand Clinical Trials Registry (ANZCTR) on 8th February 2022 (ACTRN12622000220763).

Effect of flow change on brain injury during an experimental model of differential hypoxaemia in cardiogenic shock supported by extracorporeal membrane oxygenation.

Differential hypoxaemia (DH) is common in patients supported by femoral veno-arterial extracorporeal membrane oxygenation (V-A ECMO) and can cause cerebral hypoxaemia. To date, no models have studied the direct impact of flow on cerebral damage. We investigated the impact of V-A ECMO flow on brain injury in an ovine model of DH. After inducing severe cardiorespiratory failure and providing ECMO support, we randomised six sheep into two groups: low flow (LF) in which ECMO was set at 2.5 L min-1 ensuring that the brain was entirely perfused by the native heart and lungs, and high flow (HF) in which ECMO was set at 4.5 L min-1 ensuring that the brain was at least partially perfused by ECMO. We used invasive (oxygenation tension-PbTO2, and cerebral microdialysis) and non-invasive (near infrared spectroscopy-NIRS) neuromonitoring, and euthanised animals after five hours for histological analysis. Cerebral oxygenation was significantly improved in the HF group as shown by higher PbTO2 levels (+ 215% vs - 58%, p = 0.043) and NIRS (67 ± 5% vs 49 ± 4%, p = 0.003). The HF group showed significantly less severe brain injury than the LF group in terms of neuronal shrinkage, congestion and perivascular oedema (p < 0.0001). Cerebral microdialysis values in the LF group all reached the pathological thresholds, even though no statistical difference was found between the two groups. Differential hypoxaemia can lead to cerebral damage after only a few hours and mandates a thorough neuromonitoring of patients. An increase in ECMO flow was an effective strategy to reduce such damages.

A comprehensive evaluation of hemodynamic energy production and circuit loss using four different ECMO arterial cannulae.

OBJECTIVE: Pulsatile-flow veno-arterial extracorporeal membrane oxygenation (V-A ECMO) has shown encouraging results for microcirculation resuscitation and left ventricle unloading in patients with refractory cardiogenic shock. We aimed to comprehensively assess different V-A ECMO parameters and their contribution to hemodynamic energy production and transfer through the device circuit. METHODS: We used the i-cor® ECMO circuit, which composed of Deltastream DP3 diagonal pump and i-cor® console (Xenios AG), the Hilite 7000 membrane oxygenator (Xenios AG), venous and arterial tubing and a 1 L soft venous pseudo-patient reservoir. Four different arterial cannulae (Biomedicus 15 and 17 Fr, Maquet 15 and 17 Fr) were used. For each cannula, 192 different pulsatile modes were investigated by adjusting flow rate, systole/diastole ratio, pulsatile amplitudes and frequency, yielding 784 unique conditions. A dSpace data acquisition system was used to collect flow and pressure data. RESULTS: Increasing flow rates and pulsatile amplitudes were associated with significantly higher hemodynamic energy production (both p < 0.001), while no significant associations were seen while adjusting systole-to-diastole ratio (p = 0.73) or pulsing frequency (p = 0.99). Arterial cannula represents the highest resistance to hemodynamic energy transfer with 32%-59% of total hemodynamic energy generated being lost within, depending on pulsatile flow settings used. CONCLUSIONS: Herein, we presented the first study to compare hemodynamic energy production with all pulsatile ECLS pump settings and their combinations and widely used yet previously unexamined four different arterial ECMO cannula. Only increased flow rate and amplitude increase hemodynamic energy production as single factors, whilst other factors are relevant when combined.

Iliopsoas haematoma during extracorporeal membrane oxygenation: A registry report from the COVID-19 critical care consortium across 30 countries.

INTRODUCTION: Iliopsoas haematoma (IPH) during extracorporeal membrane oxygenation (ECMO) is a rare bleeding complication that can be fatal due to its progression to abdominal compartment syndrome, but its incidence and risk factors are not well known. We have previously reported an IPH incidence rate of 16% in Japan. Among possible reasons for this high incidence, ethnicity has been hypothesised to play a role. Therefore, we used an international multi-centre cohort registry to test this hypothesis by determining the incidence rate of IPH. METHODS: This study was performed using the COVID-19 Critical Care Consortium database, conducted in 30 countries across five continents between 3 January 2020, and 20 June 2022. RESULTS: Overall, 1102 patients received ECMO for COVID-19-related acute respiratory distress syndrome. Of them, only seven were reported to have IPH, indicating an incidence rate of 0.64%, with comparable rates between the countries. The IPH group tended to have a higher mortality rate (71.4%) than the non-IPH group (51%). CONCLUSIONS: Overall incidence of IPH in the studied COVID-19 ECMO cohort was 0.64%. Most cases were reported from Japan, Belgium, and Italy. In our study, this rare complication did not appear to be confined to Asian patients. Due to the high fatality rate, awareness about the occurrence of IPH should be recognised.

An innovative ovine model of severe cardiopulmonary failure supported by veno-arterial extracorporeal membrane oxygenation.

Refractory cardiogenic shock (CS) often requires veno-arterial extracorporeal membrane oxygenation (VA-ECMO) to sustain end-organ perfusion. Current animal models result in heterogenous cardiac injury and frequent episodes of refractory ventricular fibrillation. Thus, we aimed to develop an innovative, clinically relevant, and titratable model of severe cardiopulmonary failure. Six sheep (60 ± 6 kg) were anaesthetized and mechanically ventilated. VA-ECMO was commenced and CS was induced through intramyocardial injections of ethanol. Then, hypoxemic/hypercapnic pulmonary failure was achieved, through substantial decrease in ventilatory support. Echocardiography was used to compute left ventricular fractional area change (LVFAC) and cardiac Troponin I (cTnI) was quantified. After 5 h, the animals were euthanised and the heart was retrieved for histological evaluations. Ethanol (58 ± 23 mL) successfully induced CS in all animals. cTnI levels increased near 5000-fold. CS was confirmed by a drop in systolic blood pressure to 67 ± 14 mmHg, while lactate increased to 4.7 ± 0.9 mmol/L and LVFAC decreased to 16 ± 7%. Myocardial samples corroborated extensive cellular necrosis and inflammatory infiltrates. In conclusion, we present an innovative ovine model of severe cardiopulmonary failure in animals on VA-ECMO. This model could be essential to further characterize CS and develop future treatments.

Heart failure supported by veno-arterial extracorporeal membrane oxygenation (ECMO): a systematic review of pre-clinical models.

OBJECTIVES: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is increasingly being used to treat patients with refractory severe heart failure. Large animal models are developed to help understand physiology and build translational research projects. In order to better understand those experimental models, we conducted a systematic literature review of animal models combining heart failure and VA-ECMO. STUDIES SELECTION: A systematic review was performed using Medline via PubMed, EMBASE, and Web of Science, from January 1996 to January 2019. Animal models combining experimental acute heart failure and ECMO were included. Clinical studies, abstracts, and studies not employing VA-ECMO were excluded. DATA EXTRACTION: Following variables were extracted, relating to four key features: (1) study design, (2) animals and their peri-experimental care, (3) heart failure models and characteristics, and (4) ECMO characteristics and management. RESULTS: Nineteen models of heart failure and VA-ECMO were included in this review. All were performed in large animals, the majority (n = 13) in pigs. Acute myocardial infarction (n = 11) with left anterior descending coronary ligation (n = 9) was the commonest mean of inducing heart failure. Most models employed peripheral VA-ECMO (n = 14) with limited reporting. CONCLUSION: Among models that combined severe heart failure and VA-ECMO, there is a large heterogeneity in both design and reporting, as well as methods employed for heart failure. There is a need for standardization of reporting and minimum dataset to ensure translational research achieve high-quality standards.

The European Board of Anaesthesiology recommendations for safe medication practice: First update.

These European Board of Anaesthesiology (EBA) recommendations for safe medication practice replace the first edition of the EBA recommendations published in 2011. They were updated because evidence from critical incident reporting systems continues to show that medication errors remain a major safety issue in anaesthesia, intensive care, emergency medicine and pain medicine, and there is an ongoing need for relevant up-to-date clinical guidance for practising anaesthesiologists. The recommendations are based on evidence wherever possible, with a focus on patient safety, and are primarily aimed at anaesthesiologists practising in Europe, although many will be applicable elsewhere. They emphasise the importance of correct labelling practice and the value of incident reporting so that lessons can be learned, risks reduced and a safety culture developed.

Necrosis of the tail of pancreas following proximal splenic artery embolization.

The current case report presents a rare complication of a significant pancreatic tail necrosis following proximal splenic artery embolization in a 32-year-old male patient involved in a motorcycle accident. Proximal angiographic embolization of the splenic injury after trauma is a widely accepted method with excellent success rate; however, possible complications may occur and has been described in the literature. Nevertheless, only a few case reports pertinent to clinically significant pancreatic tail necrosis after the SAE has been reported. Thus, we add a case report to the scarce literature pertinent to this detrimental and rare complication.

Prediction of outcome in traumatic brain injury patients using long-term qEEG features.

Treatment of patients suffering from severe traumatic brain injury (TBI) commonly involves sedation and mechanical ventilation during prolonged stay in the intensive care unit. Continuous EEG is often monitored in these patients to detect epileptic seizures. It has also been suggested that EEG has prognostic value regarding the outcome of the treatment. In this study the ability of 186 qEEG features to predict the outcome of the treatment of TBI patients is assessed. The features are based on the power spectrum of the EEG. The data underlying the study contains long term (over 24 h) recordings from 20 patients treated in the postoperative intensive care unit of the North Estonian Medical Center. 12 qEEG features were found to have predictive value when evaluated by calculating the area under the receiver operating curve constructed from feature probabilities.

The BRAIN TRIAL: a randomised, placebo controlled trial of a Bradykinin B2 receptor antagonist (Anatibant) in patients with traumatic brain injury.

BACKGROUND: Cerebral oedema is associated with significant neurological damage in patients with traumatic brain injury. Bradykinin is an inflammatory mediator that may contribute to cerebral oedema by increasing the permeability of the blood-brain barrier. We evaluated the safety and effectiveness of the non-peptide bradykinin B2 receptor antagonist Anatibant in the treatment of patients with traumatic brain injury. During the course of the trial, funding was withdrawn by the sponsor. METHODS: Adults with traumatic brain injury and a Glasgow Coma Scale score of 12 or less, who had a CT scan showing an intracranial abnormality consistent with trauma, and were within eight hours of their injury were randomly allocated to low, medium or high dose Anatibant or to placebo. Outcomes were Serious Adverse Events (SAE), mortality 15 days following injury and in-hospital morbidity assessed by the Glasgow Coma Scale (GCS), the Disability Rating Scale (DRS) and a modified version of the Oxford Handicap Scale (HIREOS). RESULTS: 228 patients out of a planned sample size of 400 patients were randomised. The risk of experiencing one or more SAEs was 26.4% (43/163) in the combined Anatibant treated group, compared to 19.3% (11/57) in the placebo group (relative risk = 1.37; 95% CI 0.76 to 2.46). All cause mortality in the Anatibant treated group was 19% and in the placebo group 15.8% (relative risk 1.20, 95% CI 0.61 to 2.36). The mean GCS at discharge was 12.48 in the Anatibant treated group and 13.0 in the placebo group. Mean DRS was 11.18 Anatibant versus 9.73 placebo, and mean HIREOS was 3.94 Anatibant versus 3.54 placebo. The differences between the mean levels for GCS, DRS and HIREOS in the Anatibant and placebo groups, when adjusted for baseline GCS, showed a non-significant trend for worse outcomes in all three measures. CONCLUSION: This trial did not reach the planned sample size of 400 patients and consequently, the study power to detect an increase in the risk of serious adverse events was reduced. This trial provides no reliable evidence of benefit or harm and a larger trial would be needed to establish safety and effectiveness. TRIAL REGISTRATION: This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN23625128.

Effect of vitamin B(6) vitamers on platelet aggregation.

The vitamers of vitamin B(6) inhibit platelet aggregation. However, their effect is weak when used separately. After the supplementation of one vitamer, the concentrations of the other ones also increase in plasma due to the interconversion of vitamin B(6) forms. It can be suggested that different vitamers in blood can interact with each other. The aim of this work was to test the effect of different vitamer combinations on platelet aggregation in vitro. Platelet aggregation was induced by ADP, collagen or arachidonic acid and measured photometrically in a Chronolog aggregometer. The inhibition of platelet aggregation by the pairwise combinations of the vitamers was significantly stronger than that of each vitamer separately. The combinations of three and four vitamers were yet more effective, inhibiting platelet aggregation at the concentration of 4 microM. Possible involvement of inhibitory prostaglandins in the effect of vitamin B(6) was studied. The inhibition of platelet aggregation by the vitamers could be prevented by the antagonist of prostacyclin receptors, CAY10441 while the antagonist of prostaglandin D(2) receptors, MK 0524 was ineffective. The results suggest that vitamin B(6) vitamers cause a synergistic inhibitory effect on platelet aggregation at concentrations that can be mediated by the activation of prostacyclin receptors with prostaglandin E(1).

Tracking rhythm in long-term EEG recordings using empirical mode calculation.

A novel algorithm for the detection and tracking of rhythmic patterns in the EEG signal is presented. The algorithm includes the following steps: 1) linear filtering using symmetric impulse response, 2) calculation of the first intrinsic mode of the filter output and 3) calculation of instantaneous frequency and amplitude using the Hilbert transform. The linear filter is adapted according to the instantaneous frequency. The algorithm is shown to perform well in tracking the alpha rhythm (the alpha coma pattern) in critically ill patients sedated with midazolam.

Platelet activity before and after coronary artery bypass grafting.

The normal response of the platelet can be altered either by increased pro-aggregatory stimuli or by diminished anti-aggregatory substances. Increased platelet activation occurs in the cardiovascular disease states of stable angina pectoris and acute coronary syndromes. Also, cardiac surgery involving cardiopulmonary bypass is associated with extensive contact between blood and synthetic surfaces and leads to a strong activation of platelets. Using light transmission aggregometry method, we tested platelet sensitivity to ADP and spontaneous activity in the platelet-rich plasma of patients before and after coronary artery bypass grafting (CABG). The median values of EC50 for ADP were significantly lower at days 3 and 5 after surgery (0.33 and 0.37 microM, respectively) than before surgery (0.65 microM). The medians percentages of spontaneous platelet aggregation were significantly higher after than before surgery (16 and 15% at days 3 and 5 after surgery, respectively, vs. 5% before surgery). Thus, there is a significant increase of spontaneous platelet aggregation and platelet hyperreactivity to ADP in patients after CABG compared with those before surgery.

Intracardiac electrical bioimpedance as a basis for controlling of pacing rate limits.

Intracardiac impedance can provide real-time hemodynamic information to automatically control the lower and upper rate limits of a rate-adaptive pacemaker. It is necessary to overcome a number of technical challenges to accomplish this within the constraints of an implantable device.