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The World Health Organization defines overweight and obesity as the condition where excess or abnormal fat accumulation increases risks to health. The prevalence of obesity is increasing worldwide and is around 20% in ICU patients. Adipose tissue is highly metabolically active, and especially visceral adipose tissue has a deleterious adipocyte secretory profile resulting in insulin resistance and a chronic low-grade inflammatory and procoagulant state. Obesity is strongly linked with chronic diseases such as type 2 diabetes, hypertension, cardiovascular diseases, dyslipidemia, non-alcoholic fatty liver disease, chronic kidney disease, obstructive sleep apnea and hypoventilation syndrome, mood disorders and physical disabilities. In hospitalized and ICU patients and in patients with chronic illnesses, a J-shaped relationship between BMI and mortality has been demonstrated, with overweight and moderate obesity being protective compared with a normal BMI or more severe obesity (the still debated and incompletely understood “obesity paradox”). Despite this protective effect regarding mortality, in the setting of critical illness morbidity is adversely affected with increased risk of respiratory and cardiovascular complications, requiring adapted management. Obesity is associated with increased risk of AKI and infection, may require adapted drug dosing and nutrition and is associated with diagnostic and logistic challenges. In addition, negative attitudes toward obese patients (the social stigma of obesity) affect both health care workers and patients.

Sepsis-related mortality roughly doubles when acute kidney injury (AKI) occurs and end-stage renal disease is more common in sepsis-associated AKI survivors. So far, no licensed treatment for the prevention of AKI is available, however the data on alkaline phosphatase (AP) is promising and might change this. Sepsis-associated AKI is believed to be the result of inflammation and hypoxia combined. Systemic inflammation started by recognition of 'pathogen-associated molecular patterns' (PAMPs) such as lipopolysaccharide (LPS) which binds to Toll-like receptor 4 and leads to the production of inflammatory mediators. Due to this inflammatory process renal microcirculation gets impaired leading to hypoxia resulting in cell damage or cell death. In the process of cell damage so called 'danger-associated molecular patterns' (DAMPs) are released resulting in a sustained inflammatory effect. Apart from the systemic inflammation DAMPs and PAMPs also interact with receptors in the proximal tubule of the kidney causing a local inflammatory response leading to leukocyte infiltration and tubular lesions, combined with renal cell apoptosis and ultimately to AKI. In the longer-term, inflammation-mediated inadequate repair mechanism may lead to fibrosis and development of chronic kidney disease. AP is an endogenous enzyme that dephosphorylates and thereby detoxifies several compounds, including LPS. A small phase 2 clinical trial in sepsis patients showed that urinary excretion of tubular injury markers was attenuated and creatinine clearance improved in sepsis patients treated with AP. This renal protective effect was confirmed in a second small clinical phase 2 trial in sepsis patients with AKI. Subsequently, a large trial in sepsis patients with AKI was conducted using a human recombinant AP. In 301 patients no improvement of kidney function within 7 days after enrolment was observed, but kidney function was significantly better on day 21 and day 28 and all-cause 28-day mortality was significantly lower (14.4% in AP group versus 26.7% in the placebo group). Possible explanations of this lack of short-term kidney function improvement are discussed and potential effects of AP on renal repair mechanisms, including inflammation-mediated induction of fibrosis, that may explain the beneficial longer-term effects of AP are proposed.

Background/objectivesObesity appears to be an independent risk factor for ICU admission and a severe disease course in COVID-19 patients. An aberrant inflammatory response and impaired respiratory function have been suggested as underlying mechanisms. We investigated whether obesity is associated with differences in inflammatory, respiratory, and clinical outcome parameters in critically ill COVID-19 patients.Subjects/methodsSixty-seven COVID-19 ICU patients were divided into obese (BMI ≥ 30 kg/m2, n = 18, 72% class I obesity, 28% class II obesity) and non-obese (BMI < 30 kg/m2, n = 49) groups. Concentrations of circulating interleukin (IL)-6, IL-8, IL-10, tumor necrosis factor alpha (TNF-α), interferon gamma (IFN-γ), interferon gamma-induced protein (IP)-10, monocyte chemoattractant protein (MCP)-1, and IL-1 receptor antagonist (RA) were determined from ICU admission until 10 days afterward, and routine laboratory and clinical parameters were collected.ResultsBMI was 32.6 [31.2–34.5] and 26.0 [24.4–27.7] kg/m2 in the obese and non-obese group, respectively. Apart from temperature, which was significantly lower in obese patients (38.1 [36.9–38.9] vs. 38.7 [38.0 −39.5] °C, p = 0.02), there were no between-group differences on ICU admission. Plasma cytokine concentrations declined over time (p < 0.05 for all), but no differences between obese and non-obese patients were observed. Also, BMI did not correlate with the cytokine response (IL-6 r = 0.09, p = 0.61, TNF-α r = 0.03, p = 0.99, IP-10 r = 0.28, p = 0.11). The kinetics of clinical inflammatory parameters and respiratory mechanics were also similar in both groups. Finally, no differences in time on ventilator, ICU length of stay or 40-day mortality between obese and non-obese patients were apparent.ConclusionsIn COVID-19 patients requiring mechanical ventilation in the ICU, a higher BMI is not related to a different immunological response, unfavorable respiratory mechanics, or impaired outcome.

Cementless tibial fixation in total knee replacement (TKR) has potential for improved fixation and ease of revision. Achieving primary stability in cementless TKR is critical to the performance of the components. Excessive micromotion may prevent osseointegration at the bone–implant interface. Computational finite element (FE) studies have been used to predict micromotion at the interface, but analysis of an entire activity cycle is computational expensive, prohibiting large numbers of analyses. Surrogate modeling methods can be used to train a numerical model to predict the response of an FE model. These models are computationally efficient and are suitable for high-volume or iterative analyses requiring probabilistic, statistical or optimization methods. The objective of this work was to train a surrogate model capable of predicting micromotion over the entire bone–implant interface. A proximal tibial bone with mapped material properties was virtually implanted with a tibial tray. A FE model, with six-degree-of-freedom loads sampled from telemetric patients during walking, was used to generate training data for the surrogate model. The linear response surrogate model was evaluated for six full gait cycles; the average and peak micromotion across the interface, and the percentage of bone–implant interface surface area experiencing micromotions less than 50 and greater than 150µm were calculated both as a function of the activity cycle and as the composite peak micromotion throughout the cycle. Differences in root-mean-square (RMS) micromotion between FE and surrogate models were less than 14µm. FE analysis time for a complete gait cycle was 15h, compared to 30s for the surrogate model. Surrogate models have significant potential to rapidly predict micromotion over the entire bone–implant interface, allowing greater range in loading conditions to be explored than is possible through conventional methods.

Background In immunocompromised patients with acute hypoxemic respiratory failure (ARF), initial management aims primarily to avoid invasive mechanical ventilation (IMV). Methods To assess the impact of initial management on IMV and mortality rates, we performed a multinational observational prospective cohort study in 16 countries (68 centers). Results A total of 1611 patients were enrolled (hematological malignancies 51.9%, solid tumors 35.2%, systemic diseases 17.3%, and solid organ transplantation 8.8%). The main ARF etiologies were bacterial (29.5%), viral (15.4%), and fungal infections (14.7%), or undetermined (13.2%). On admission, 915 (56.8%) patients were not intubated. They received standard oxygen ( N  = 496, 53.9%), high-flow oxygen (HFNC, N  = 187, 20.3%), noninvasive ventilation (NIV, N  = 153, 17.2%), and NIV + HFNC ( N  = 79, 8.6%). Factors associated with IMV included age (hazard ratio = 0.92/year, 95% CI 0.86–0.99), day-1 SOFA (1.09/point, 1.06–1.13), day-1 PaO 2 /FiO 2 (1.47, 1.05–2.07), ARF etiology ( Pneumocystis jirovecii pneumonia (2.11, 1.42–3.14), invasive pulmonary aspergillosis (1.85, 1.21–2.85), and undetermined cause (1.46, 1.09–1.98). After propensity score matching, HFNC, but not NIV, had an effect on IMV rate (HR = 0.77, 95% CI 0.59–1.00, p  = 0.05). ICU, hospital, and day-90 mortality rates were 32.4, 44.1, and 56.4%, respectively. Factors independently associated with hospital mortality included age (odds ratio = 1.18/year, 1.09–1.27), direct admission to the ICU (0.69, 0.54–0.87), day-1 SOFA excluding respiratory score (1.12/point, 1.08–1.16), PaO 2 /FiO 2  < 100 (1.60, 1.03–2.48), and undetermined ARF etiology (1.43, 1.04–1.97). Initial oxygenation strategy did not affect mortality; however, IMV was associated with mortality, the odds ratio depending on IMV conditions: NIV + HFNC failure (2.31, 1.09–4.91), first-line IMV (2.55, 1.94–3.29), NIV failure (3.65, 2.05–6.53), standard oxygen failure (4.16, 2.91–5.93), and HFNC failure (5.54, 3.27–9.38). Conclusion HFNC has an effect on intubation but not on mortality rates. Failure to identify ARF etiology is associated with higher rates of both intubation and mortality. This suggests that in addition to selecting the appropriate oxygenation device, clinicians should strive to identify the etiology of ARF.

Background A subset of critically ill COVID-19 patients develop a hyperinflammatory state. Anakinra, a recombinant interleukin-1 receptor antagonist, is known to be effective in several hyperinflammatory diseases. We investigated the effects of anakinra on inflammatory parameters and clinical outcomes in critically ill, mechanically ventilated COVID-19 patients with clinical features of hyperinflammation. Methods In this prospective cohort study, 21 critically ill COVID-19 patients treated with anakinra were compared to a group of standard care. Serial data of clinical inflammatory parameters and concentrations of multiple circulating cytokines were determined and aligned on start day of anakinra in the treatment group, and median start day of anakinra in the control group. Analysis was performed for day − 10 to + 10 relative to alignment day. Clinical outcomes were analyzed during 28 days. Additionally, three sensitivity analyses were performed: (1) using propensity score-matched groups, (2) selecting patients who did not receive corticosteroids, and (3) using a subset of the control group aimed to match the criteria (fever, elevated ferritin) for starting anakinra treatment. Results Baseline patient characteristics and clinical parameters on ICU admission were similar between groups. As a consequence of bias by indication, plasma levels of aspartate aminotransferase (ASAT) ( p  = 0.0002), ferritin ( p  = 0.009), and temperature ( p  = 0.001) were significantly higher in the anakinra group on alignment day. Following treatment, no relevant differences in kinetics of circulating cytokines were observed between both groups. Decreases of clinical parameters, including temperature ( p  = 0.03), white blood cell counts ( p  = 0.02), and plasma levels of ferritin ( p  = 0.003), procalcitonin ( p  = 0.001), creatinine ( p  = 0.01), and bilirubin ( p  = 0.007), were more pronounced in the anakinra group. No differences in duration of mechanical ventilation or ICU length of stay were observed between groups. Sensitivity analyses confirmed these results. Conclusions Anakinra is effective in reducing clinical signs of hyperinflammation in critically ill COVID-19 patients. A randomized controlled trial is warranted to draw conclusion about the effects of anakinra on clinical outcomes.

On initial presentation, differentiation between early-stage coronavirus disease 2019 (COVID-19) and classical bacterial community-acquired pneumonia can be challenging. Furthermore, COVID-19 patients may develop a hyperinflammatory phase later in their disease process, which is particularly difficult to distinguish from a secondary bacterial infection. As a consequence, 72% of COVID-19 patients receive empirical antibiotic therapy during hospital stay [1]. Antibiotic overuse undoubtedly leads to an exacerbation of another—slowly progressive—pandemic: antimicrobial resistance [2].Procalcitonin (PCT) has proven useful in the early diagnosis of lower respiratory tract infections of bacterial origin [3]. Furthermore, in the ICU setting, serial measurement of PCT can safely guide the withdrawal of antibiotic therapy [4].In patients with COVID-19, C-reactive protein (CRP) is usually increased on presentation while PCT is often low [5]. PCT appears to increase in COVID patients with severe disease and/or in those presenting with secondary bacterial infections [6]. Longitudinal data on both biomarkers in COVID-19 infections are currently lacking. Also, it is unclear to what extent PCT and CRP predict the occurrence of secondary infections in these patients.

Keywords: HLA-DR, mHLA-DR, COVID, COVID-19, SARS-CoV-2, Monocytes, Immune suppression

There may be sex-based disparities in intensive care unit (ICU) management and outcomes. We compared baseline variables, interventions, and outcomes of immunocompromised critically ill men and women. We performed a post hoc analysis of the Efraim study, a prospective multinational cohort study of immunocompromised adults with acute hypoxemic respiratory failure admitted to one of 68 ICU in 16 countries between November 2015 and July 2016. We compared in unadjusted and adjusted analyses baseline variables, ICU interventions, and outcomes between men and women. We included 1536 immunocompromised adults (922 men, 614 women) in this study. Women and men had similar age, BMI, and diagnoses leading to immunosuppression; hematopoietic cell transplant was more common in men. On the first ICU day, SOFA score was higher in men vs. women (7 [IQR 4–10] vs 6 [4–10]), p = 0.0005). The use of ICU supportive interventions, including mechanical ventilation, vasopressors, renal replacement, bronchoalveolar lavage, and ARDS adjuncts, were similar between men and women; as were mortality in ICU, in hospital, and at 90 days. After adjustment, female sex (sub-hazard ratio 1.19, 95 % CI 1.05–1.36, p = 0.007), SOFA score on ICU day 1 (sHR 1.16, 95 % CI 1.12–1.19, p < 0.001) and chronic kidney disease (sHR 0.74, 95 % CI 0.59–0.93, p = 0.009) were associated with mechanical ventilation. Age, performance status and SOFA score on ICU day 1 were associated with hospital mortality. In this post hoc analysis of immunocompromised adult ICU patients with hypoxemic respiratory failure, women and men received similar ICU interventions, and had similar outcomes. •We performed a post hoc analysis of Efraim, a prospective multinational cohort study of immunocompromised adults with AHRF•We compared baseline variables, interventions, and outcomes of critically ill men and women•Men and women received similar ICU supportive interventions and had similar outcomes•After adjustment, female sex, SOFA score on ICU day 1, and chronic kidney disease were associated with MV•Age, performance status and SOFA score on ICU day 1 were associated with hospital mortality

Background It is unclear whether influenza infection and associated co-infection are associated with patient-important outcomes in critically ill immunocompromised patients with acute respiratory failure. Methods Preplanned secondary analysis of EFRAIM, a prospective cohort study of 68 hospitals in 16 countries. We included 1611 patients aged 18 years or older with non-AIDS-related immunocompromise, who were admitted to the ICU with acute hypoxemic respiratory failure. The main exposure of interest was influenza infection status. The primary outcome of interest was all-cause hospital mortality, and secondary outcomes ICU length of stay (LOS) and 90-day mortality. Results Influenza infection status was categorized into four groups: patients with influenza alone ( n  = 95, 5.8%), patients with influenza plus pulmonary co-infection ( n  = 58, 3.6%), patients with non-influenza pulmonary infection ( n  = 820, 50.9%), and patients without pulmonary infection ( n  = 638, 39.6%). Influenza infection status was associated with a requirement for intubation and with LOS in ICU ( P  < 0.001). Patients with influenza plus co-infection had the highest rates of intubation and longest ICU LOS. On crude analysis, influenza infection status was associated with ICU mortality ( P  < 0.001) but not hospital mortality ( P  = 0.09). Patients with influenza plus co-infection and patients with non-influenza infection alone had similar ICU mortality (41% and 37% respectively) that was higher than patients with influenza alone or those without infection (33% and 26% respectively). A propensity score-matched analysis did not show a difference in hospital mortality attributable to influenza infection (OR = 1.01, 95%CI 0.90–1.13, P  = 0.85). Age, severity scores, ARDS, and performance status were all associated with ICU, hospital, and 90-day mortality. Conclusions Category of infectious etiology of respiratory failure (influenza, non-influenza, influenza plus co-infection, and non-infectious) was associated with ICU but not hospital mortality. In a propensity score-matched analysis, influenza infection was not associated with the primary outcome of hospital mortality. Overall, influenza infection alone may not be an independent risk factor for hospital mortality in immunosuppressed patients.