Early mobilisation in critically ill COVID-19 patients: a subanalysis of the ESICM-initiated UNITE-COVID observational study

Background Early mobilisation (EM) is an intervention that may improve the outcome of critically ill patients. There is limited data on EM in COVID-19 patients and its use during the first pandemic wave. Methods This is a pre-planned subanalysis of the ESICM UNITE-COVID, an international multicenter observational study involving critically ill COVID-19 patients in the ICU between February 15th and May 15th, 2020. We analysed variables associated with the initiation of EM (within 72 h of ICU admission) and explored the impact of EM on mortality, ICU and hospital length of stay, as well as discharge location. Statistical analyses were done using (generalised) linear mixed-effect models and ANOVAs. Results Mobilisation data from 4190 patients from 280 ICUs in 45 countries were analysed. 1114 (26.6%) of these patients received mobilisation within 72 h after ICU admission; 3076 (73.4%) did not. In our analysis of factors associated with EM, mechanical ventilation at admission (OR 0.29; 95% CI 0.25, 0.35; p = 0.001), higher age (OR 0.99; 95% CI 0.98, 1.00; p ≤ 0.001), pre-existing asthma (OR 0.84; 95% CI 0.73, 0.98; p = 0.028), and pre-existing kidney disease (OR 0.84; 95% CI 0.71, 0.99; p = 0.036) were negatively associated with the initiation of EM. EM was associated with a higher chance of being discharged home (OR 1.31; 95% CI 1.08, 1.58; p = 0.007) but was not associated with length of stay in ICU (adj. difference 0.91 days; 95% CI − 0.47, 1.37, p = 0.34) and hospital (adj. difference 1.4 days; 95% CI − 0.62, 2.35, p = 0.24) or mortality (OR 0.88; 95% CI 0.7, 1.09, p = 0.24) when adjusted for covariates. Conclusions Our findings demonstrate that a quarter of COVID-19 patients received EM. There was no association found between EM in COVID-19 patients' ICU and hospital length of stay or mortality. However, EM in COVID-19 patients was associated with increased odds of being discharged home rather than to a care facility. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)

Intestinal Toxic epidermal necrolysis

Toxic epidermal necrolysis (TEN), also known as the Stevens-Johnson Syndrome (SJS), is defined as severe, lifethreatening mucocutaneous reactions, predominantly drug induced, but also associated with infectious diseases. Clinical manifestations consist of erythematous cutaneous lesions, with blister formation and epidermal detachment as a consequence of massive keratinocytes apoptosis. Gastrointestinal involvement by SJS and TEN has been rarely reported. There are many cases with upper esophageal, oropharynx, and anus manifestations, intestinal manifestations are rare and associated with a very high mortality. A 25-year-old man was admitted to our Hospital in April 2015 with diagnosis of TEN, complicated by septic shock and watery diarrhea. Diarrheal symptoms soon started, and an infectious etiology was excluded. Re-epithelialization of the skin started after 3 weeks after admission but diarrheic symptoms persisted. The esophagogastroduodenoscopy (EGDS) showed early hyperemia of duodenum with mucosal edema and bleeding; the same types of lesions were found at the colonoscopy. Histological exams showed no signs of CMV, but granular modifications, compatible with an inflammatory bowel disease. Mesalazine and corticoids was initiated. Few days after, the patient evacuated, in diarrheic episodes, "stripes" of fibrinous material measuring in total more than 2 m. Control colonoscopy showed a colon without haustrations, an erosive mucosa, but no signs of ulcers or pseudo membranes; the ileal mucosa was equally erosive. We also performed capsule endoscopy, to estimate the damage in the small intestine. The structure of the intestinal mucosa appeared to be completely altered, with signs of desquamation and traces of blood, but no evidence of ulcers or active bleeding. During the next 4 months, his skin lesions improved and almost completely recovered, even if some scarring and depigmentation was left. But great daily volumes of watery diarrhea (3 to 5 L/day) persisted along time and brought us to perform a protective colostomy. In conclusion, what we did was primarily supportive treatment: first of all, continuous skin care with antiseptic balneotherapy and Hydrofiber® dressing, intended also to avoid infections; as well as corticoid based eye ointment; fluid and electrolyte replacement depending on necessity; body temperature surveillance; nutritive provision both with parenteral and enteral nutrition. During the 4 months after the first symptoms in addition to gastric feeding we started twice per day a probiotic supplement (Bifidobacterium BB-12, and Lactobacillus). Gradually the volume and the frequency of the diarrhea were reduced and the density increased. the supportive treatment and the treatment of the complications are critical and much more complicated in case of intestinal involvement with diarrhea, and there is still no consensus on a specific protocol of treatment when the gastrointestinal system is involved.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Cerebral perfusion alterations and cognitive decline in critically ill sepsis survivors

Introduction: We investigated the association between cerebral perfusion perturbations in sepsis with possible cognitive decline (CD) after patients’ discharge from the intensive care unit (ICU). Methods: We studied 28 patients with sepsis and Lawton’s Instrumental Activities of Daily Living scale (IADL) scores ≥5 who were discharged from a university ICU institution. We evaluated cerebral circulatory parameters (pulsatility index (PI) and cerebral blood flow index (CBFi) was calculated based on the measured velocity of the middle cerebral artery. Use of the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) test was performed daily, and either the Mini Mental State Examination test (MMSE) or Clock Drawing test was performed at ICU discharge. CD was categorized as persistent coma, positive CAM-ICU test at discharge, MMSE <24, or an abnormal Clock test. Results: Patients had a median pre-ICU IADL score of 6.3 (95% CI 5.9–6.7). Fourteen patients (50%) had CD at discharge. Two were in persistent coma despite sepsis resolution. Information recall was the most affected mental function of the other 12 patients. Only on the first day, patients with CD had higher PI and lower CBFi compared to those without CD (2.2 ± 0.7 vs. 1.4 ± 0.5, p = 0.02; 363 ± 170 vs. 499 ± 133, p = 0.03, respectively). Multivariable analysis revealed delirium, but not PI, as an independent prognostic factor for CD (OR: 29.62, 95%CI 1.91–458.01, p = 0.01). Conclusion: Delirium, but not cerebral perfusion alterations, is an independent risk factor for cognitive impairment in septic patients who were discharged from the ICU.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

the global UNITE-COVID study

Funding Information: AE, FD, GDP, LG, VG, AJ, JK, AL, JM, SNM, MO, MP, MC declare no conflicts of interest. MG reports speaking fees from Baxter and Philips. TDC is supported by Research Foundation Flanders (Grant nr G085920N). MA reports Research Grant from GE, Honoraria from Fisher and Paykel, Pfizer, Orion and Gilead. GC reports grants, personal fees as Speakers’ Bureau Member and Advisory Board Member from Integra and Neuroptics, all outside the submitted work. ACM is supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/V006118/1). SE declares no financial COIs and the following non-financial disclosures: Cochrane editor, American Society of Anesthesiologist data review board member. LF reports research funding from NIHR, Baxter, Ortho-Clinical Diagnostics, Exthera Medical and lecture fees from Baxter, Fresenius, Paion, all outside the submitted work. GG received payment for lectures from Getinge, Draeger Medical, Fisher&Paykel, Biotest, MSD, Gilead and unrestricted research grants from Fisher&Paykel and MSD (all unrelated to the present work). MCMD declares potential conflict of interest with BD. PP declares potential conflicts of interest with Pfizer, MSD and Gilead. SJS reports personal fees from Springer-Verlag, GmbH (Vienna, Austria) for educational commitments grants and non-financial support from ESICM (Bruxelles, Belgium), Fresenius (Germany), Liberate Medical LLC (Crestwood, USA), STIMIT AG (Nidau, Switzerland) Reactive Robotics GmbH (Munich, Germany) as well as from Technical University of Munich, Germany, from national (e.g. DGAI) and international (e.g. ESICM) medical societies (or their congress organizers) in the field of anesthesiology and intensive care, all outside the submitted work; SJS holds stocks in small amounts from Alphabeth Inc., Bayer AG, Rhön-Klinikum AG, and Siemens AG. These did not have any influence on this study. AW reports Honorarium for delivery of educational material for Vygon, GE. JLT declares potential conflict of interest with Getinge. JDW has consulted for Pfizer, MSD (honoraria paid to institution), and is a senior clinical investigator funded by the Research Foundation Flanders (FWO, Ref. 1881020N).Purpose: To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods: Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results: 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%–50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions: ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality.publishersversionpublishe

Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave: the global UNITE-COVID study (Intensive Care Medicine, (2022), 48, 6, (690-705), 10.1007/s00134-022-06705-1)

Publisher Copyright: © 2022 The Author(s).In the original version of this article, the given and family names of Kristina Fuest, Tobias Lahmer, Johannes Herrmann, Patrick Meybohm, Nikolaos Markou, Georgia Vasileiadou were incorrectly structured. The Publisher apologises for this mistake.publishersversionpublishe

Co-infection and ICU-acquired infection in COIVD-19 ICU patients: a secondary analysis of the UNITE-COVID data set

Background: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients.Methods: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method.Results: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO.Conclusions: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids

Clinical and organizational factors associated with mortality during the peak of first COVID-19 wave : the global UNITE-COVID study

Purpose To accommodate the unprecedented number of critically ill patients with pneumonia caused by coronavirus disease 2019 (COVID-19) expansion of the capacity of intensive care unit (ICU) to clinical areas not previously used for critical care was necessary. We describe the global burden of COVID-19 admissions and the clinical and organizational characteristics associated with outcomes in critically ill COVID-19 patients. Methods Multicenter, international, point prevalence study, including adult patients with SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) and a diagnosis of COVID-19 admitted to ICU between February 15th and May 15th, 2020. Results 4994 patients from 280 ICUs in 46 countries were included. Included ICUs increased their total capacity from 4931 to 7630 beds, deploying personnel from other areas. Overall, 1986 (39.8%) patients were admitted to surge capacity beds. Invasive ventilation at admission was present in 2325 (46.5%) patients and was required during ICU stay in 85.8% of patients. 60-day mortality was 33.9% (IQR across units: 20%-50%) and ICU mortality 32.7%. Older age, invasive mechanical ventilation, and acute kidney injury (AKI) were associated with increased mortality. These associations were also confirmed specifically in mechanically ventilated patients. Admission to surge capacity beds was not associated with mortality, even after controlling for other factors. Conclusions ICUs responded to the increase in COVID-19 patients by increasing bed availability and staff, admitting up to 40% of patients in surge capacity beds. Although mortality in this population was high, admission to a surge capacity bed was not associated with increased mortality. Older age, invasive mechanical ventilation, and AKI were identified as the strongest predictors of mortality

Safety and efficacy of eculizumab in anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis (REGAIN): a phase 3, randomised, double-blind, placebo-controlled, multicentre study

Background Complement is likely to have a role in refractory generalised myasthenia gravis, but no approved therapies specifically target this system. Results from a phase 2 study suggested that eculizumab, a terminal complement inhibitor, produced clinically meaningful improvements in patients with anti-acetylcholine receptor antibody-positive refractory generalised myasthenia gravis. We further assessed the efficacy and safety of eculizumab in this patient population in a phase 3 trial. Methods We did a phase 3, randomised, double-blind, placebo-controlled, multicentre study (REGAIN) in 76 hospitals and specialised clinics in 17 countries across North America, Latin America, Europe, and Asia. Eligible patients were aged at least 18 years, with a Myasthenia Gravis-Activities of Daily Living (MG-ADL) score of 6 or more, Myasthenia Gravis Foundation of America (MGFA) class II\ue2\u80\u93IV disease, vaccination against Neisseria meningitides, and previous treatment with at least two immunosuppressive therapies or one immunosuppressive therapy and chronic intravenous immunoglobulin or plasma exchange for 12 months without symptom control. Patients with a history of thymoma or thymic neoplasms, thymectomy within 12 months before screening, or use of intravenous immunoglobulin or plasma exchange within 4 weeks before randomisation, or rituximab within 6 months before screening, were excluded. We randomly assigned participants (1:1) to either intravenous eculizumab or intravenous matched placebo for 26 weeks. Dosing for eculizumab was 900 mg on day 1 and at weeks 1, 2, and 3; 1200 mg at week 4; and 1200 mg given every second week thereafter as maintenance dosing. Randomisation was done centrally with an interactive voice or web-response system with patients stratified to one of four groups based on MGFA disease classification. Where possible, patients were maintained on existing myasthenia gravis therapies and rescue medication was allowed at the study physician's discretion. Patients, investigators, staff, and outcome assessors were masked to treatment assignment. The primary efficacy endpoint was the change from baseline to week 26 in MG-ADL total score measured by worst-rank ANCOVA. The efficacy population set was defined as all patients randomly assigned to treatment groups who received at least one dose of study drug, had a valid baseline MG-ADL assessment, and at least one post-baseline MG-ADL assessment. The safety analyses included all randomly assigned patients who received eculizumab or placebo. This trial is registered with ClinicalTrials.gov, number NCT01997229. Findings Between April 30, 2014, and Feb 19, 2016, we randomly assigned and treated 125 patients, 62 with eculizumab and 63 with placebo. The primary analysis showed no significant difference between eculizumab and placebo (least-squares mean rank 56\uc2\ub76 [SEM 4\uc2\ub75] vs 68\uc2\ub73 [4\uc2\ub75]; rank-based treatment difference \ue2\u88\u9211\uc2\ub77, 95% CI \ue2\u88\u9224\uc2\ub73 to 0\uc2\ub796; p=0\uc2\ub70698). No deaths or cases of meningococcal infection occurred during the study. The most common adverse events in both groups were headache and upper respiratory tract infection (ten [16%] for both events in the eculizumab group and 12 [19%] for both in the placebo group). Myasthenia gravis exacerbations were reported by six (10%) patients in the eculizumab group and 15 (24%) in the placebo group. Six (10%) patients in the eculizumab group and 12 (19%) in the placebo group required rescue therapy. Interpretation The change in the MG-ADL score was not statistically significant between eculizumab and placebo, as measured by the worst-rank analysis. Eculizumab was well tolerated. The use of a worst-rank analytical approach proved to be an important limitation of this study since the secondary and sensitivity analyses results were inconsistent with the primary endpoint result; further research into the role of complement is needed. Funding Alexion Pharmaceuticals