Publications by authors named "Janneke Horn"

184 Publications

Dutch multicentre, prospective follow-up, cohort study comparing the neurological and neuropsychological sequelae of hospitalised non-ICU- and ICU-treated COVID-19 survivors: a study protocol.

BMJ Open 2021 10 7;11(10):e054901. Epub 2021 Oct 7.

Department of Psychiatry and Neuropsychology, Maastricht University Faculty of Health Medicine and Life Sciences, Maastricht, The Netherlands

Introduction: Owing to the novelty of COVID-19, there are still large knowledge gaps concerning its effect on the brain and the resulting impact on peoples' lives. This large-scale prospective follow-up study investigates COVID-19-associated brain damage, neuropsychological dysfunction and long-term impact on the well-being of patients and their close ones. It is hypothesised that structural brain damage and cognitive dysfunction primarily occur in severely ill patients, as compared with moderately ill patients. Cognitive complaints, emotional distress and impact on well-being are hypothesised to be less dependent on illness severity.

Methods And Analysis: For this multicentre study, 200 patients with COVID-19 (100 intensive care unit (ICU) patients and 100 non-ICU patients) formerly hospitalised in one of the six recruiting hospitals during the first European infection wave (ie, March to June 2020) and their close ones will be recruited. At minimally 6 months posthospital discharge, patients will perform a set of neuropsychological tests and are subjected to a 3T MRI scan. Patients and close ones will fill out a set of questionnaires, also at minimally 6 months posthospital discharge and again another 6 months thereafter. Data related to COVID-19 hospitalisation will be extracted from the patients' medical records. MRI abnormalities will ultimately be related to neuropsychological test performance and questionnaire outcomes.

Ethics And Dissemination: Ethics approval was granted by the medical research ethics committee of Maastricht University Medical Centre and Maastricht University (NL75102.068.20). The project is sponsored by The Brain Foundation Netherlands. Findings will be presented at national and international conferences, as well as published in peer-reviewed scientific journals.

Trial Registration Number: NCT04745611.
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http://dx.doi.org/10.1136/bmjopen-2021-054901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8507410PMC
October 2021

Reply to Scarpino et al., SSEP amplitude for prognostication in post-anoxic coma: A further step towards standardization.

Resuscitation 2021 10 23;167:432. Epub 2021 Aug 23.

Department of Intensive Care, Amsterdam UMC and University of Amsterdam, the Netherlands; Amsterdam Neuroscience, Amsterdam, the Netherlands.

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http://dx.doi.org/10.1016/j.resuscitation.2021.08.030DOI Listing
October 2021

Serum markers of brain injury can predict good neurological outcome after out-of-hospital cardiac arrest.

Intensive Care Med 2021 Sep 21;47(9):984-994. Epub 2021 Aug 21.

Department of Clinical Sciences Lund, Neurology, Skåne University Hospital, Lund University, Getingevägen 4, 222 41, Lund, Sweden.

Purpose: The majority of unconscious patients after cardiac arrest (CA) do not fulfill guideline criteria for a likely poor outcome, their prognosis is considered "indeterminate". We compared brain injury markers in blood for prediction of good outcome and for identifying false positive predictions of poor outcome as recommended by guidelines.

Methods: Retrospective analysis of prospectively collected serum samples at 24, 48 and 72 h post arrest within the Target Temperature Management after out-of-hospital cardiac arrest (TTM)-trial. Clinically available markers neuron-specific enolase (NSE) and S100B, and novel markers neurofilament light chain (NFL), total tau, ubiquitin carboxy-terminal hydrolase L1 (UCH-L1) and glial fibrillary acidic protein (GFAP) were analysed. Normal levels with a priori cutoffs specified by reference laboratories or defined from literature were used to predict good outcome (no to moderate disability, Cerebral Performance Category scale 1-2) at 6 months.

Results: Seven hundred and seventeen patients were included. Normal NFL, tau and GFAP had the highest sensitivities (97.2-98% of poor outcome patients had abnormal serum levels) and NPV (normal levels predicted good outcome in 87-95% of patients). Normal S100B and NSE predicted good outcome with NPV 76-82.2%. Normal NSE correctly identified 67/190 (35.3%) patients with good outcome among those classified as "indeterminate outcome" by guidelines. Five patients with single pathological prognostic findings despite normal biomarkers had good outcome.

Conclusion: Low levels of brain injury markers in blood are associated with good neurological outcome after CA. Incorporating biomarkers into neuroprognostication may help prevent premature withdrawal of life-sustaining therapy.
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http://dx.doi.org/10.1007/s00134-021-06481-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8421280PMC
September 2021

The circulatory small non-coding RNA landscape in community-acquired pneumonia on intensive care unit admission.

J Cell Mol Med 2021 08 17;25(16):7621-7630. Epub 2021 Jul 17.

Center for Experimental Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, The Netherlands.

Community-acquired pneumonia (CAP) is a major cause of sepsis. Despite several clinical trials targeting components of the inflammatory response, no specific treatment other than antimicrobial therapy has been approved. This argued for a deeper understanding of sepsis immunopathology, in particular factors that can modulate the host response. Small non-coding RNA, for example, micro (mi)RNA, have been established as important modifiers of cellular phenotypes. Notably, miRNAs are not exclusive to the intracellular milieu but have also been detected extracellular in the circulation with functional consequences. Here, we sought to determine shifts in circulatory small RNA levels of critically ill patients with CAP-associated sepsis and to determine the influence of clinical severity and causal pathogens on small RNA levels. Blood plasma was collected from 13 critically ill patients with sepsis caused by CAP on intensive care unit admission and from 5 non-infectious control participants. Plasma small RNA-sequencing identified significantly altered levels of primarily mature miRNAs in CAP relative to controls. Pathways analysis of high or low abundance miRNA identified various over-represented cellular biological pathways. Analysis of small RNA levels against common clinical severity and inflammatory parameters indices showed direct and indirect correlations. Additionally, variance of plasma small RNA levels in CAP patients may be explained, at least in part, by differences in causal pathogens. Small nuclear RNA levels were specifically altered in CAP due to Influenza infection in contrast to Streptococcus pneumoniae infection. Pathway analysis of plasma miRNA signatures unique to Influenza or Streptococcus pneumoniae infections showed enrichment for specific proteoglycan, cell cycle, and immunometabolic pathways.
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http://dx.doi.org/10.1111/jcmm.16406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8358855PMC
August 2021

Prognostication in postanoxic coma: Not too early, not too late.

Resuscitation 2021 11 14;168:237. Epub 2021 Jul 14.

Clinical Neurophysiology (CNPH), TechMed Centre, University of Twente, the Netherlands; Department of Neurology, Rijnstate Hospital, Arnhem, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.resuscitation.2021.06.025DOI Listing
November 2021

Practice of adjunctive treatments in critically ill COVID-19 patients-rational for the multicenter observational PRoAcT-COVID study in The Netherlands.

Ann Transl Med 2021 May;9(9):813

Department of Intensive Care, Amsterdam UMC, location 'AMC', Amsterdam, The Netherlands.

Background: Patients with coronavirus disease 2019 (COVID-19) may need hospitalization for supplemental oxygen, and some need intensive care unit (ICU) admission for escalation of care. Practice of adjunctive and supportive treatments remain uncertain and may vary widely between countries, within countries between hospitals, and possibly even within ICUs. We aim to investigate practice of adjunctive and supportive treatments, and their associations with outcome, in critically ill COVID-19 patients.

Methods: The 'PRactice of Adjunctive Treatments in Intensive Care Unit Patients with Coronavirus Disease 2019' (PRoAcT-COVID) study is a national, observational study to be undertaken in a large set of ICUs in The Netherlands. The PRoAcT-COVID includes consecutive ICU patients, admitted because of COVID-19 to one of the participating ICUs during a 3-month period. Daily follow-up lasts 28 days. The primary endpoint is a combination of adjunctive treatments, including types of oxygen support, ventilation, rescue therapies for hypoxemia refractory to supplementary oxygen or during invasive ventilation, other adjunctive and supportive treatments, and experimental therapies. We will also collect tracheostomy rate, duration of invasive ventilation and ventilator-free days and alive at day 28 (VFD-28), ICU and hospital length of stay, and the mortality rates in the ICU, hospital and at day 90.

Discussion: The PRoAcT-COVID study is an observational study combining high density treatment data with relevant clinical outcomes. Information on treatment practices, and their associations with outcomes in COVID-19 patients in highly and urgently needed. The results of the PRoAcT-COVID study will be rapidly available, and circulated through online presentations, such as webinars and electronic conferences, and publications in peer-reviewed journals-findings will also be presented at a dedicated website. At request, and after agreement of the PRoAcT-COVID steering committee, source data will be made available through local, regional and national anonymized datasets.

Trial Registration: The PRoAcT-COVID study is registered at clinicaltrials.gov (study identifier NCT04719182).
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http://dx.doi.org/10.21037/atm-21-764DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246237PMC
May 2021

EEG registration after cardiac arrest: On the way to plug and play?

Resuscitation 2021 08 12;165:182-183. Epub 2021 Jul 12.

Dept of Clinical Neurophysiology, Amsterdam Neurosciences, Amsterdam University Medical Centers, Amsterdam, The Netherlands.

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http://dx.doi.org/10.1016/j.resuscitation.2021.06.014DOI Listing
August 2021

Assessment of Lung Reaeration at 2 Levels of Positive End-expiratory Pressure in Patients With Early and Late COVID-19-related Acute Respiratory Distress Syndrome.

J Thorac Imaging 2021 Sep;36(5):286-293

Departments of Intensive Care.

Purpose: Patients with novel coronavirus disease (COVID-19) frequently develop acute respiratory distress syndrome (ARDS) and need invasive ventilation. The potential to reaerate consolidated lung tissue in COVID-19-related ARDS is heavily debated. This study assessed the potential to reaerate lung consolidations in patients with COVID-19-related ARDS under invasive ventilation.

Materials And Methods: This was a retrospective analysis of patients with COVID-19-related ARDS who underwent chest computed tomography (CT) at low positive end-expiratory pressure (PEEP) and after a recruitment maneuver at high PEEP of 20 cm H2O. Lung reaeration, volume, and weight were calculated using both CT scans. CT scans were performed after intubation and start of ventilation (early CT), or after several days of intensive care unit admission (late CT).

Results: Twenty-eight patients were analyzed. The median percentages of reaerated and nonaerated lung tissue were 19% [interquartile range, IQR: 10 to 33] and 11% [IQR: 4 to 15] for patients with early and late CT scans, respectively (P=0.049). End-expiratory lung volume showed a median increase of 663 mL [IQR: 483 to 865] and 574 mL [IQR: 292 to 670] after recruitment for patients with early and late CT scans, respectively (P=0.43). The median decrease in lung weight attributed to nonaerated lung tissue was 229 g [IQR: 165 to 376] and 171 g [IQR: 81 to 229] after recruitment for patients with early and late CT scans, respectively (P=0.16).

Conclusions: The majority of patients with COVID-19-related ARDS undergoing invasive ventilation had substantial reaeration of lung consolidations after recruitment and ventilation at high PEEP. Higher PEEP can be considered in patients with reaerated lung consolidations when accompanied by improvement in compliance and gas exchange.
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http://dx.doi.org/10.1097/RTI.0000000000000600DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386391PMC
September 2021

Induced normothermia ameliorates the procoagulant host response in human endotoxaemia.

Br J Anaesth 2021 Jun 23;126(6):1111-1118. Epub 2021 Apr 23.

Laboratory of Experimental Intensive Care and Anaesthesiology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Intensive Care Medicine, OLVG Hospital, Amsterdam, the Netherlands.

Background: Dysregulation of coagulation occurs commonly in sepsis, ranging from mild coagulopathy with decreased platelets to disseminated intravascular coagulation (DIC). We investigated the effect of induced normothermia on coagulation during lipopolysaccharide (LPS)-induced endotoxaemia in healthy volunteers.

Methods: Twelve volunteers received an infusion of bacterial lipopolysaccharide (Escherichia coli; 2 ng kg) and were assigned to either induced normothermia or control. Induced normothermia to maintain core temperature at 37°C consisted of external surface cooling, cold i.v. fluids, and medication to reduce shivering (buspirone, clonidine, and magnesium sulphate). The primary outcome was the DIC score (International Society on Thrombosis and Haemostasis guideline). Prothrombin time (PT), activated partial thromboplastin time (aPTT), D-dimer, plasma von Willebrand factor (vWf), and rotational thromboelastometry (ROTEM) were measured before and 1, 3, 6, and 8 h after LPS infusion. Differences between groups were tested with a mixed effects model.

Results: In control subjects, lipopolysaccharide caused a fever, transiently decreased platelet levels and lowered activated partial thromboplastin time, while prolonging prothrombin time and increasing D-Dimer and vWf levels. Normothermia prevented the DIC-score exceeding 4, which occurred in 50% of control subjects. Normothermia also reduced the fall in platelet count by 67x10 L([95%CI:27-107]; p=0.002), aPTT (mean difference:3s [95%CI:1-5]; p=0.005) and lowered vWf levels by 89% ([95%CI:6-172]; p=0.03), compared to the fever group. ROTEM measurements were unaffected by lipopolysaccharide.

Conclusion: In human endotoxaemia, induced normothermia decreases markers of endothelial activation and DIC. Maintaining normothermia may reduce coagulopathy in hyperinflammatory states.
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http://dx.doi.org/10.1016/j.bja.2021.02.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8258978PMC
June 2021

SSEP amplitudes add information for prognostication in postanoxic coma.

Resuscitation 2021 06 10;163:172-175. Epub 2021 Apr 10.

Department of Intensive Care, Amsterdam UMC and University of Amsterdam, The Netherlands; Amsterdam Neuroscience, Amsterdam, The Netherlands.

Objective: To investigate whether somatosensory evoked potential (SSEP) amplitude adds information for prediction of poor outcome in postanoxic coma.

Methods: In this retrospective cohort study we included adult patients admitted after cardiac arrest between January 2010 and June 2018 who remained in coma and had SSEP recorded for prognostication. Outcome was dichotomized in poor (Cerebral Performance Category (CPC) 4-5) and good (CPC 1-3) at ICU discharge. Sensitivity of bilaterally absent N20 potential was calculated. In case the N20 potential was not bilaterally absent, the amplitude contralateral to stimulation side (baseline-N20, N20-P25, and maximum) was determined. At a specificity of 100%, SEPP amplitude sensitivities were determined for poor outcome.

Results: SSEP recordings were performed in 197 patients of whom 57 had bilaterally absent N20 potentials. From 140 patients, 16 (11%) had a good outcome. The sensitivity for poor outcome of bilaterally absent N20 was 31%. At a specificity of 100%, contralateral amplitude thresholds were 0.34 μV (baseline-N20), 0.99 μV (N20-P25) and 1.0 μV (maximum), corresponding to a sensitivity for poor outcome of 38%, 44% and 40%. Combination of bilaterally absent N20 and a N20-P25 threshold below 0.99 μV yielded a sensitivity of 62%.

Conclusions: Our results confirm that very low cortical SSEP amplitudes are highly predictive of poor outcome in patients with postanoxic coma. Adding 'N20-P25 threshold amplitude' to the 'bilaterally absent N20' criterion, increased sensitivity substantially.
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http://dx.doi.org/10.1016/j.resuscitation.2021.03.033DOI Listing
June 2021

Ventilation management in acute respiratory failure related to COVID-19 versus ARDS from another origin - a descriptive narrative review.

Expert Rev Respir Med 2021 08 13;15(8):1013-1023. Epub 2021 Apr 13.

Department of Intensive Care, Amsterdam University Medical Centers, location 'AMC', Amsterdam, The Netherlands.

Introduction: It is uncertain whether ventilation in patients with acute respiratory failure related to coronavirus disease 2019 (COVID-19) differs from that in patients with acute respiratory distress syndrome (ARDS) from another origin.

Areas Covered: We undertook two literature searches in PubMed to identify observational studies reporting on ventilation management--one in patients with acute respiratory failure related to COVID-19, and one in patients with ARDS from another origin. The searches identified 14 studies in patients with acute respiratory failure related to COVID-19, and 8 studies in patients with ARDS from another origin.

Expert Opinion: In patients with acute respiratory failure related to COVID-19, ventilation management seems to be similar to that of patients with ARDS from another origin. The future lies in studies focused on personalized treatment of ARDS of all origins, including COVID-19.
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http://dx.doi.org/10.1080/17476348.2021.1913060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054495PMC
August 2021

Ultra-early tranexamic acid after subarachnoid haemorrhage (ULTRA): a randomised controlled trial.

Lancet 2021 01 23;397(10269):112-118. Epub 2020 Dec 23.

Department of Radiology and Nuclear Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Background: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months.

Methods: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812.

Findings: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups.

Interpretation: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale.

Funding: Fonds NutsOhra.
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http://dx.doi.org/10.1016/S0140-6736(20)32518-6DOI Listing
January 2021

The effects of tidal volume size and driving pressure levels on pulmonary complement activation: an observational study in critically ill patients.

Intensive Care Med Exp 2020 Dec 18;8(Suppl 1):74. Epub 2020 Dec 18.

Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Mechanical ventilation can induce or even worsen lung injury, at least in part via overdistension caused by too large volumes or too high pressures. The complement system has been suggested to play a causative role in ventilator-induced lung injury.

Aims And Methods: This was a single-center prospective study investigating associations between pulmonary levels of complement activation products and two ventilator settings, tidal volume (V) and driving pressure (ΔP), in critically ill patients under invasive ventilation. A miniature bronchoalveolar lavage (BAL) was performed for determination of pulmonary levels of C5a, C3b/c, and C4b/c. The primary endpoint was the correlation between BAL fluid (BALF) levels of C5a and V and ΔP. Levels of complement activation products were also compared between patients with and without ARDS or with and without pneumonia.

Results: Seventy-two patients were included. Median time from start of invasive ventilation till BAL was 27 [19 to 34] hours. Median V and ΔP before BAL were 6.7 [IQR 6.1 to 7.6] ml/kg predicted bodyweight (PBW) and 15 [IQR 11 to 18] cm HO, respectively. BALF levels of C5a, C3b/c and C4b/c were neither different between patients with or without ARDS, nor between patients with or without pneumonia. BALF levels of C5a, and also C3b/c and C4b/c, did not correlate with V and ΔP. Median BALF levels of C5a, C3b/c, and C4b/c, and the effects of V and ΔP on those levels, were not different between patients with or without ARDS, and in patients with or without pneumonia.

Conclusion: In this cohort of critically ill patients under invasive ventilation, pulmonary levels of complement activation products were independent of the size of V and the level of ΔP. The associations were not different for patients with ARDS or with pneumonia. Pulmonary complement activation does not seem to play a major role in VILI, and not even in lung injury per se, in critically ill patients under invasive ventilation.
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http://dx.doi.org/10.1186/s40635-020-00356-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746430PMC
December 2020

The predictive validity for mortality of the driving pressure and the mechanical power of ventilation.

Intensive Care Med Exp 2020 Dec 18;8(Suppl 1):60. Epub 2020 Dec 18.

Department of Intensive Care, University of Amsterdam, Amsterdam University Medical Centers, Location "Academic Medical Center", Meibergdreeg 9, 1105 AZ, Amsterdam, The Netherlands.

Background: Outcome prediction in critically ill patients under invasive ventilation remains extremely challenging. The driving pressure (ΔP) and the mechanical power of ventilation (MP) are associated with patient-centered outcomes like mortality and duration of ventilation. The objective of this study was to assess the predictive validity for mortality of the ΔP and the MP at 24 h after start of invasive ventilation.

Methods: This is a post hoc analysis of an observational study in intensive care unit patients, restricted to critically ill patients receiving invasive ventilation for at least 24 h. The two exposures of interest were the modified ΔP and the MP at 24 h after start of invasive ventilation. The primary outcome was 90-day mortality; secondary outcomes were ICU and hospital mortality. The predictive validity was measured as incremental 90-day mortality beyond that predicted by the Acute Physiology, Age and Chronic Health Evaluation (APACHE) IV score and the Simplified Acute Physiology Score (SAPS) II.

Results: The analysis included 839 patients with a 90-day mortality of 42%. The median modified ΔP at 24 h was 15 [interquartile range 12 to 19] cm HO; the median MP at 24 h was 206 [interquartile range 145 to 298] 10 J/min/kg predicted body weight (PBW). Both parameters were associated with 90-day mortality (odds ratio (OR) for 1 cm HO increase in the modified ΔP, 1.05 [95% confidence interval (CI) 1.03 to 1.08]; P < 0.001; OR for 100 10 J/min/kg PBW increase in the MP, 1.20 [95% CI 1.09 to 1.33]; P < 0.001). Area under the ROC for 90-day mortality of the modified ΔP and the MP were 0.70 [95% CI 0.66 to 0.74] and 0.69 [95% CI 0.65 to 0.73], which was neither different from that of the APACHE IV score nor that of the SAPS II.

Conclusions: In adult patients under invasive ventilation, the modified ΔP and the MP at 24 h are associated with 90 day mortality. Neither the modified ΔP nor the MP at 24 h has predictive validity beyond the APACHE IV score and the SAPS II.
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http://dx.doi.org/10.1186/s40635-020-00346-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7746416PMC
December 2020

The leukocyte non-coding RNA landscape in critically ill patients with sepsis.

Elife 2020 12 11;9. Epub 2020 Dec 11.

Amsterdam UMC, University of Amsterdam, Center for Experimental Molecular Medicine, Amsterdam Infection & Immunity, Amsterdam, Netherlands.

The extent of non-coding RNA alterations in patients with sepsis and their relationship to clinical characteristics, soluble mediators of the host response to infection, as well as an advocated in vivo model of acute systemic inflammation is unknown. Here we obtained whole blood from 156 patients with sepsis and 82 healthy subjects among whom eight were challenged with lipopolysaccharide in a clinically controlled setting (human endotoxemia). Via next-generation microarray analysis of leukocyte RNA we found that long non-coding RNA and, to a lesser extent, small non-coding RNA were significantly altered in sepsis relative to health. Long non-coding RNA expression, but not small non-coding RNA, was largely recapitulated in human endotoxemia. Integrating RNA profiles and plasma protein levels revealed known as well as previously unobserved pathways, including non-sensory olfactory receptor activity. We provide a benchmark dissection of the blood leukocyte 'regulome' that can facilitate prioritization of future functional studies.
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http://dx.doi.org/10.7554/eLife.58597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7775110PMC
December 2020

PRactice of VENTilation in Patients with Novel Coronavirus Disease (PRoVENT-COVID): rationale and protocol for a national multicenter observational study in The Netherlands.

Ann Transl Med 2020 Oct;8(19):1251

Department of Intensive Care, Amsterdam UMC location AMC, The Netherlands.

Background: The coronavirus disease 2019 (COVID-19) pandemic is rapidly expanding across the world, with more than 100,000 new cases each day as of end-June 2020. Healthcare workers are struggling to provide the best care for COVID-19 patients. Approaches for invasive ventilation vary widely between and within countries and new insights are acquired rapidly. We aim to investigate invasive ventilation practices and outcome in COVID-19 patients in the Netherlands.

Methods: PRoVENT-COVID ('study of PRactice of VENTilation in COVID-19') is an investigator-initiated national, multicenter observational study to be undertaken in intensive care units (ICUs) in The Netherlands. Consecutive COVID-19 patients aged 18 years or older, who are receiving invasive ventilation in the participating ICUs, are to be enrolled during a 10-week period, with a daily follow-up of 7 days. The primary outcome is ventilatory management (including tidal volume expressed as mL/kg predicted body weight and positive end-expiratory pressure expressed as cmHO) during the first 3 days of ventilation. Secondary outcomes include other ventilatory variables, use of rescue therapies for refractory hypoxemia such as prone positioning and extracorporeal membrane oxygenation, use of sedatives, vasopressors and inotropes; daily cumulative fluid balances; acute kidney injury; ventilator-free days and alive at day 28 (VFD-28), duration of ICU and hospital stay, and ICU, hospital and 90-day mortality.

Discussion: PRoVENT-COVID will be the largest observational study to date, with high density ventilatory data and major outcomes. There is urgent need for a better understanding of ventilation practices, and the effects of ventilator settings on outcomes in COVID-19 patients. The results of PRoVENT-COVID will be rapidly disseminated through electronic presentations, such as webinars and electronic conferences, and publications in international peer-reviewed journals. Access to source data will be made available through local, regional and national anonymized datasets on request, and after agreement of the PRoVENT-COVID steering committee.

Trial Registration: PRoVENT-COVID is registered at clinicaltrials.gov (identifier NCT04346342).
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http://dx.doi.org/10.21037/atm-20-5107DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7607125PMC
October 2020

Ventilation management and clinical outcomes in invasively ventilated patients with COVID-19 (PRoVENT-COVID): a national, multicentre, observational cohort study.

Lancet Respir Med 2021 02 23;9(2):139-148. Epub 2020 Oct 23.

Department of Intensive Care, Amsterdam University Medical Centers location Academic Medical Center, Amsterdam, Netherlands; ACHIEVE, Centre of Applied Research, Amsterdam University of Applied Sciences, Faculty of Health, Amsterdam, Netherlands.

Background: Little is known about the practice of ventilation management in patients with COVID-19. We aimed to describe the practice of ventilation management and to establish outcomes in invasively ventilated patients with COVID-19 in a single country during the first month of the outbreak.

Methods: PRoVENT-COVID is a national, multicentre, retrospective observational study done at 18 intensive care units (ICUs) in the Netherlands. Consecutive patients aged at least 18 years were eligible for participation if they had received invasive ventilation for COVID-19 at a participating ICU during the first month of the national outbreak in the Netherlands. The primary outcome was a combination of ventilator variables and parameters over the first 4 calendar days of ventilation: tidal volume, positive end-expiratory pressure (PEEP), respiratory system compliance, and driving pressure. Secondary outcomes included the use of adjunctive treatments for refractory hypoxaemia and ICU complications. Patient-centred outcomes were ventilator-free days at day 28, duration of ventilation, duration of ICU and hospital stay, and mortality. PRoVENT-COVID is registered at ClinicalTrials.gov (NCT04346342).

Findings: Between March 1 and April 1, 2020, 553 patients were included in the study. Median tidal volume was 6·3 mL/kg predicted bodyweight (IQR 5·7-7·1), PEEP was 14·0 cm HO (IQR 11·0-15·0), and driving pressure was 14·0 cm HO (11·2-16·0). Median respiratory system compliance was 31·9 mL/cm HO (26·0-39·9). Of the adjunctive treatments for refractory hypoxaemia, prone positioning was most often used in the first 4 days of ventilation (283 [53%] of 530 patients). The median number of ventilator-free days at day 28 was 0 (IQR 0-15); 186 (35%) of 530 patients had died by day 28. Predictors of 28-day mortality were gender, age, tidal volume, respiratory system compliance, arterial pH, and heart rate on the first day of invasive ventilation.

Interpretation: In patients with COVID-19 who were invasively ventilated during the first month of the outbreak in the Netherlands, lung-protective ventilation with low tidal volume and low driving pressure was broadly applied and prone positioning was often used. The applied PEEP varied widely, despite an invariably low respiratory system compliance. The findings of this national study provide a basis for new hypotheses and sample size calculations for future trials of invasive ventilation for COVID-19. These data could also help in the interpretation of findings from other studies of ventilation practice and outcomes in invasively ventilated patients with COVID-19.

Funding: Amsterdam University Medical Centers, location Academic Medical Center.
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http://dx.doi.org/10.1016/S2213-2600(20)30459-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7584441PMC
February 2021

Anti-C5a antibody IFX-1 (vilobelimab) treatment versus best supportive care for patients with severe COVID-19 (PANAMO): an exploratory, open-label, phase 2 randomised controlled trial.

Lancet Rheumatol 2020 Dec 28;2(12):e764-e773. Epub 2020 Sep 28.

Department of Neurology, Amsterdam Neuroscience, University of Amsterdam, Amsterdam UMC, Amsterdam, Netherlands.

Background: Severe COVID-19 is characterised by inflammation and coagulation in the presence of complement system activation. We aimed to explore the potential benefit and safety of selectively blocking the anaphylatoxin and complement protein C5a with the monoclonal antibody IFX-1 (vilobelimab), in patients with severe COVID-19.

Methods: We did an exploratory, open-label, randomised phase 2 trial (part of the adaptive phase 2/3 PANAMO trial) of intravenous IFX-1 in adults with severe COVID-19 at three academic hospitals in the Netherlands. Eligibility criteria were age 18 years or older; severe pneumonia with pulmonary infiltrates consistent with pneumonia, a clinical history of severe shortness of breath within the past 14 days, or a need for non-invasive or invasive ventilation; severe disease defined as a ratio of partial pressure of arterial oxygen to fractional concentration of oxygen in inspired air (PaO/FiO) between 100 mm Hg and 250 mm Hg in the supine position; and severe acute respiratory syndrome coronavirus 2 infection confirmed by RT-PCR. Patients were randomly assigned 1:1 to receive IFX-1 (up to seven doses of 800 mg intravenously) plus best supportive care (IFX-1 group) or best supportive care only (control group). The primary outcome was the percentage change in PaO/FiO in the supine position between baseline and day 5. Mortality at 28 days and treatment-emergent and serious adverse events were key secondary outcomes. The primary analysis was done in the intention-to-treat population and safety analyses were done in all patients according to treatment received. This trial is registered at ClinicalTrials.gov (NCT04333420).

Findings: Between March 31 and April 24, 2020, 30 patients were enrolled and randomly assigned to the IFX-1 group (n=15) or the control group (n=15). During the study it became clear that several patients could not be assessed regularly in the supine position because of severe hypoxaemia. It was therefore decided to focus on all PaO/FiO assessments (irrespective of position). At day 5 after randomisation, the mean PaO/FiO (irrespective of position) was 158 mm Hg (SD 63; range 84-265) in the IFX-1 group and 189 mm Hg (89; 71-329) in the control group. Analyses of the least squares mean relative change in PaO/FiO at day 5 showed no differences between treatment groups (17% change in the IFX-1 group 41% in the control group; difference -24% [95% CI -58 to 9], p=0·15. Kaplan-Meier estimates of mortality by 28 days were 13% (95% CI 0-31) for the IFX-1 group and 27% (4-49) for the control group (adjusted hazard ratio for death 0·65 [95% CI 0·10-4·14]). The frequency of serious adverse events were similar between groups (nine [60%] in the IFX-1 group seven [47%] in the control group) and no deaths were considered related to treatment assignment. However, a smaller proportion of patients had pulmonary embolisms classed as serious in the IFX-1 group (two [13%]) than in the control group (six [40%]). Infections classed as serious were reported in three (20%) patients in the IFX-1 group versus five (33%) patients in the control group.

Interpretation: In this small exploratory phase 2 part of the PANAMO trial, C5a inhibition with IFX-1 appears to be safe in patients with severe COVID-19. The secondary outcome results in favour of IFX-1 are preliminary because the study was not powered on these endpoints, but they support the investigation of C5a inhibition with IFX-1 in a phase 3 trial using 28-day mortality as the primary endpoint.

Funding: InflaRx.
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http://dx.doi.org/10.1016/S2665-9913(20)30341-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7521913PMC
December 2020

Long-Term Mortality Among ICU Patients With Stroke Compared With Other Critically Ill Patients.

Crit Care Med 2020 10;48(10):e876-e883

National Intensive Care Evaluation Foundation, Amsterdam University Medical Center, Amsterdam, The Netherlands.

Objectives: Assessment of all-cause mortality of intracerebral hemorrhage and ischemic stroke patients admitted to the ICU and comparison to the mortality of other critically ill ICU patients classified into six other diagnostic subgroups and the general Dutch population.

Design: Observational cohort study.

Setting: All ICUs participating in the Dutch National Intensive Care Evaluation database.

Patients: All adult patients admitted to these ICUs between 2010 and 2015; patients were followed until February 2017.

Interventions: None.

Measurements And Main Results: Of all 370,386 included ICU patients, 7,046 (1.9%) were stroke patients, 4,072 with ischemic stroke, and 2,974 with intracerebral hemorrhage. Short-term mortality in ICU-admitted stroke patients was high with 30 days mortality of 31% in ischemic stroke and 42% in intracerebral hemorrhage. In the longer term, the survival curve gradient among ischemic stroke and intracerebral hemorrhage patients stabilized. The gradual alteration of mortality risk after ICU admission was assessed using left-truncation with increasing minimum survival period. ICU-admitted stroke patients who survive the first 30 days after suffering from a stroke had a favorable subsequent survival compared with other diseases necessitating ICU admission such as patients admitted due to sepsis or severe community-acquired pneumonia. After having survived the first 3 months after ICU admission, multivariable Cox regression analyses showed that case-mix adjusted hazard ratios during the follow-up period of up to 3 years were lower in ischemic stroke compared with sepsis (adjusted hazard ratio, 1.21; 95% CI, 1.06-1.36) and severe community-acquired pneumonia (adjusted hazard ratio, 1.57; 95% CI, 1.39-1.77) and in intracerebral hemorrhage patients compared with these groups (adjusted hazard ratio, 1.14; 95% CI, 0.98-1.33 and adjusted hazard ratio, 1.49; 95% CI, 1.28-1.73).

Conclusions: Stroke patients who need intensive care treatment have a high short-term mortality risk, but this alters favorably with increasing duration of survival time after ICU admission in patients with both ischemic stroke and intracerebral hemorrhage, especially compared with other populations of critically ill patients such as sepsis or severe community-acquired pneumonia patients.
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http://dx.doi.org/10.1097/CCM.0000000000004492DOI Listing
October 2020

The circular RNA landscape in specific peripheral blood mononuclear cells of critically ill patients with sepsis.

Crit Care 2020 07 13;24(1):423. Epub 2020 Jul 13.

Center for Experimental Molecular Medicine, Amsterdam University Medical Centers, location Academic Medical Center, University of Amsterdam, Room G2-105, Meibergdreef 9, 1105 AZ, Amsterdam, the Netherlands.

Background: Dysregulation of the host immune response is a pathognomonic feature of sepsis. Abnormal physiological conditions are understood to shift efficient linear splicing of protein-coding RNA towards non-canonical splicing, characterized by the accumulation of non-coding circularized (circ)RNA. CircRNAs remain unexplored in specific peripheral blood mononuclear cells (PBMCs) during sepsis. We here sought to identify and characterize circRNA expression in specific PBMCs of patients with sepsis due to community-acquired pneumonia (CAP) relative to healthy subjects.

Methods: The study comprised a discovery cohort of six critically ill patients diagnosed with sepsis due to community-acquired pneumonia and four (age, gender matched) healthy subjects. PBMCs were isolated, and fluorescence-activated cell sorting was used to purify CD14+ monocytes, CD4+, CD8+ T cells, and CD19+ B cells for RNA sequencing. CD14+ monocytes from independent six healthy volunteers were purified, and total RNA was treated with or without RNase R.

Results: RNA sequencing of sorted CD14+ monocytes, CD4+, CD8+ T cells, and CD19+ B cells from CAP patients and healthy subjects identified various circRNAs with predominantly cell-specific expression patterns. CircRNAs were expressed to a larger extent in monocytes than in CD4+, CD8+ T cells, or B cells. Cells from CAP patients produced significantly higher levels of circRNA as compared to healthy subjects. Considering adjusted p values, circVCAN (chr5:83519349-83522309) and circCHD2 (chr15:93000512-93014909) levels in monocytes were significantly altered in sepsis. Functional inference per cell-type uncovered pathways mainly attuned to cell proliferation and cytokine production. In addition, our data does not support a role for these circRNAs in microRNA sequestration. Quantitative PCR analysis in purified monocytes from an independent group of healthy volunteers confirmed the existence of circVCAN and circCHD2.

Conclusions: We provide a benchmark map of circRNA expression dynamics in specific immune cell subsets of sepsis patients secondary to CAP. CircRNAs were more abundant in immune cells of sepsis patients relative to healthy subjects. Further studies evaluating circRNA expression in larger cohorts of sepsis patients are warranted.
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http://dx.doi.org/10.1186/s13054-020-03146-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7359566PMC
July 2020

EEG reactivity testing for prediction of good outcome in patients after cardiac arrest.

Neurology 2020 08 10;95(6):e653-e661. Epub 2020 Jul 10.

From the Departments of Neurology/Clinical Neurophysiology (M.M.A., A.-F.v.R.) and Intensive Care (J. Horn, M.J.S.), Amsterdam Neuroscience, and Laboratory for Experimental Intensive Care and Anesthesiology (J. Horn, M.J.S.), Amsterdam UMC, University of Amsterdam; Department of Neurology (J. Hofmeijer, H.M.K.), Rijnstate Hospital, Arnhem; Clinical Neurophysiology (J. Hofmeijer, M.J.A.M.v.P.), MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede; Department of Intensive Care (C.W.E.H., C.R.v.K.) and Department of Intensive Care Medicine and Neurology, Donders Institute for Brain, Cognition, and Behaviour (H.M.K.), Radboud University Medical Center, Nijmegen; Department of Clinical Neurophysiology (M.J.A.M.v.P.), Medisch Spectrum Twente, Enschede, the Netherlands; Nuffield Department of Medicine (M.J.S.), University of Oxford, UK; and Mahidol-Oxford Tropical Medicine Research Unit (MORU) (M.J.S.), Mahidol University, Bangkok, Thailand.

Objective: To determine the additional value of EEG reactivity (EEG-R) testing to EEG background pattern for prediction of good outcome in adult patients after cardiac arrest (CA).

Methods: In this post hoc analysis of a prospective cohort study, EEG-R was tested twice a day, using a strict protocol. Good outcome was defined as a Cerebral Performance Category score of 1-2 within 6 months. The additional value of EEG-R per EEG background pattern was evaluated using the diagnostic odds ratio (DOR). Prognostic value (sensitivity and specificity) of EEG-R was investigated in relation to time after CA, sedative medication, different stimuli, and repeated testing.

Results: Between 12 and 24 hours after CA, data of 108 patients were available. Patients with a continuous (n = 64) or discontinuous (n = 19) normal voltage background pattern with reactivity were 3 and 8 times more likely to have a good outcome than without reactivity (continuous: DOR, 3.4; 95% confidence interval [CI], 0.97-12.0; = 0.06; discontinuous: DOR, 8.0; 95% CI, 1.0-63.97; = 0.0499). EEG-R was not observed in other background patterns within 24 hours after CA. In 119 patients with a normal voltage EEG background pattern, continuous or discontinuous, any time after CA, prognostic value was highest in sedated patients (sensitivity 81.3%, specificity 59.5%), irrespective of time after CA. EEG-R induced by handclapping and sternal rubbing, especially when combined, had highest prognostic value. Repeated EEG-R testing increased prognostic value.

Conclusion: EEG-R has additional value for prediction of good outcome in patients with discontinuous normal voltage EEG background pattern and possibly with continuous normal voltage. The best stimuli were clapping and sternal rubbing.
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http://dx.doi.org/10.1212/WNL.0000000000009991DOI Listing
August 2020

Performance of a guideline-recommended algorithm for prognostication of poor neurological outcome after cardiac arrest.

Intensive Care Med 2020 10 3;46(10):1852-1862. Epub 2020 Jun 3.

Department of Clinical Sciences Lund, Neurology, Skåne University Hospital, Lund University, Getingevägen 4, 222 41, Lund, Sweden.

Purpose: To assess the performance of a 4-step algorithm for neurological prognostication after cardiac arrest recommended by the European Resuscitation Council (ERC) and the European Society of Intensive Care Medicine (ESICM).

Methods: Retrospective descriptive analysis with data from the Target Temperature Management (TTM) Trial. Associations between predicted and actual neurological outcome were investigated for each step of the algorithm with results from clinical neurological examinations, neuroradiology (CT or MRI), neurophysiology (EEG and SSEP) and serum neuron-specific enolase. Patients examined with Glasgow Coma Scale Motor Score (GCS-M) on day 4 (72-96 h) post-arrest and available 6-month outcome were included. Poor outcome was defined as Cerebral Performance Category 3-5. Variations of the ERC/ESICM algorithm were explored within the same cohort.

Results: The ERC/ESICM algorithm identified poor outcome patients with 38.7% sensitivity (95% CI 33.1-44.7) and 100% specificity (95% CI 98.8-100) in a cohort of 585 patients. An alternative cut-off for serum neuron-specific enolase, an alternative EEG-classification and variations of the GCS-M had minor effects on the sensitivity without causing false positive predictions. The highest overall sensitivity, 42.5% (95% CI 36.7-48.5), was achieved when prognosticating patients irrespective of GCS-M score, with 100% specificity (95% CI 98.8-100) remaining.

Conclusion: The ERC/ESICM algorithm and all exploratory multimodal variations thereof investigated in this study predicted poor outcome without false positive predictions and with sensitivities 34.6-42.5%. Our results should be validated prospectively, preferably in patients where withdrawal of life-sustaining therapy is uncommon to exclude any confounding from self-fulfilling prophecies.
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http://dx.doi.org/10.1007/s00134-020-06080-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527324PMC
October 2020

Serum GFAP and UCH-L1 for the prediction of neurological outcome in comatose cardiac arrest patients.

Resuscitation 2020 09 21;154:61-68. Epub 2020 May 21.

Department of Clinical Sciences Lund, Anaesthesia and Intensive Care, Lund University, Helsingborg Hospital, Lund, Sweden.

Objective: Neurological outcome prediction is crucial early after cardiac arrest. Serum biomarkers released from brain cells after hypoxic-ischaemic injury may aid in outcome prediction. The only serum biomarker presently recommended in the European Resuscitation Council prognostication guidelines is neuron-specific enolase (NSE), but NSE has limitations. In this study, we therefore analyzed the outcome predictive accuracy of the serum biomarkers glial fibrillary acidic protein (GFAP) and ubiquitin C-terminal hydrolase-L1 (UCH-L1) in patients after cardiac arrest.

Methods: Serum GFAP and UCH-L1 were collected at 24, 48 and 72 h after cardiac arrest. The primary outcome was neurological function at 6-month follow-up assessed by the cerebral performance category scale (CPC), dichotomized into good (CPC1-2) and poor (CPC3-5). Prognostic accuracies were tested with receiver-operating characteristics by calculating the area under the receiver-operating curve (AUROC) and compared to the AUROC of NSE.

Results: 717 patients were included in the study. GFAP and UCH-L1 discriminated between good and poor neurological outcome at all time-points when used alone (AUROC GFAP 0.88-0.89; UCH-L1 0.85-0.87) or in combination (AUROC 0.90-0.91). The combined model was superior to GFAP and UCH-L1 separately and NSE (AUROC 0.75-0.85) at all time-points. At specificities ≥95%, the combined model predicted poor outcome with a higher sensitivity than NSE at 24 h and with similar sensitivities at 48 and 72 h.

Conclusion: GFAP and UCH-L1 predicted poor neurological outcome with high accuracy. Their combination may be of special interest for early prognostication after cardiac arrest where it performed significantly better than the currently recommended biomarker NSE.
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http://dx.doi.org/10.1016/j.resuscitation.2020.05.016DOI Listing
September 2020

Steps to recovery: body weight-supported treadmill training for critically ill patients: a randomized controlled trial.

Trials 2020 May 15;21(1):409. Epub 2020 May 15.

Department of Rehabilitation, Amsterdam Movement Sciences, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, Amsterdam, Netherlands.

Background: Early mobilization has been proven effective for patients in intensive care units (ICUs) to improve functional recovery. However, early mobilization of critically ill, often mechanically ventilated, patients is cumbersome because of the attachment to tubes, drains, monitoring devices and muscle weakness. A mobile treadmill with bodyweight support may help to initiate mobilization earlier and more effectively. The aim of this study is to assess the effectiveness of weight-supported treadmill training in critically ill patients during and after ICU stay on time to independent functional ambulation.

Methods: In this randomized controlled trial, a custom-built bedside body weight-supported treadmill will be used and evaluated. Patients are included if they have been mechanically ventilated for at least 48 hours, are able to follow instructions, have quadriceps muscle strength of Medical Research Council sum-score 2 (MRC 2) or higher, can sit unsupported and meet the safety criteria for physical exercise. Exclusion criteria are language barriers, no prior walking ability, contraindications for physiotherapy or a neurological condition as reason for ICU admission. We aim to include 88 patients and randomize them into either the intervention or the control group. The intervention group will receive usual care plus bodyweight-supported treadmill training (BWSTT) daily. The BWSSTT consists of walking on a mobile treadmill while supported by a harness. The control group will receive usual care physiotherapy treatment daily consisting of progressive activities such as bed-cycling and active functional training exercises. In both groups, we will aim for a total of 40 minutes of physiotherapy treatment time every day in one or two sessions, as tolerated by the patient. The primary outcome is time to functional ambulation as measured in days, secondary outcomes include walking distance, muscle strength, status of functional mobility and symptoms of post-traumatic stress. All measurements will be done by assessors who are blinded to the intervention on the regular wards until hospital discharge.

Discussion: This will be the first study comparing the effects of BWSTT and conventional physiotherapy for critically ill patients during and after ICU stay. The results of this study contribute to a better understanding of the effectiveness of early physiotherapy interventions for critically ill patients.

Trial Registration: Dutch Trial Register (NTR) ID: NL6766. Registered at 1 December 2017.
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http://dx.doi.org/10.1186/s13063-020-04333-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7227333PMC
May 2020

Copeptin as a marker of outcome after cardiac arrest: a sub-study of the TTM trial.

Crit Care 2020 04 28;24(1):185. Epub 2020 Apr 28.

Department of Clinical Sciences Lund, Anesthesia & Intensive care, Lund University, Helsingborg Hospital, Helsingborg, Sweden.

Background: Arginine vasopressin has complex actions in critically ill patients, involving vasoregulatory status, plasma volume, and cortisol levels. Copeptin, a surrogate marker for arginine vasopressin, has shown promising prognostic features in small observational studies and is used clinically for early rule out of acute coronary syndrome. The objective of this study was to explore the association between early measurements of copeptin, circulatory status, and short-term survival after out-of-hospital cardiac arrest.

Methods: Serial blood samples were collected at 24, 48, and 72 h as part of the target temperature management at 33 °C versus 36 °C after cardiac arrest trial, an international multicenter randomized trial where unconscious survivors after out-of-hospital cardiac arrest were allocated to an intervention of 33 or 36 °C for 24 h. Primary outcome was 30-day survival with secondary endpoints circulatory cause of death and cardiovascular deterioration composite; in addition, we examined the correlation with extended the cardiovascular sequential organ failure assessment (eCvSOFA) score.

Results: Six hundred ninety patients were included in the analyses, of whom 203 (30.3%) developed cardiovascular deterioration within 24 h, and 273 (39.6%) died within 30 days. Copeptin measured at 24 h was found to be independently associated with 30-day survival, hazard ratio 1.17 [1.06-1.28], p = 0.001; circulatory cause of death, odds ratio 1.03 [1.01-1.04], p = 0.001; and cardiovascular deterioration composite, odds ratio of 1.05 [1.02-1.08], p < 0.001. Copeptin at 24 h was correlated with eCvSOFA score with rho 0.19 [0.12-0.27], p < 0.001.

Conclusion: Copeptin is an independent marker of severity of the post cardiac arrest syndrome, partially related to circulatory failure.

Trial Registration: Clinical Trials, NCT01020916. Registered November 26, 2009.
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http://dx.doi.org/10.1186/s13054-020-02904-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7189642PMC
April 2020

Transesophageal Versus Surface Electromyography of the Diaphragm in Ventilated Subjects.

Respir Care 2020 Sep 31;65(9):1309-1314. Epub 2020 Mar 31.

Department of Intensive Care, Amsterdam UMC, University of Amsterdam, Amsterdam, the Netherlands.

Background: Detection of diaphragmatic muscle activity during invasive ventilation may provide valuable information about patient-ventilator interactions. Transesophageal electromyography of the diaphragm ([Formula: see text]) is used in neurally adjusted ventilatory assist. This technique is invasive and can only be applied with one specific ventilator. Surface electromyography of the diaphragm ([Formula: see text]) is noninvasive and can potentially be applied with all types of ventilators. The primary objective of our study was to compare the ability of diaphragm activity detection between [Formula: see text] and [Formula: see text].

Methods: In this single-center pilot study, [Formula: see text] and [Formula: see text] recordings were obtained simultaneously for 15 min in adult subjects in the ICU who were invasively ventilated. The number of breathing efforts detected by [Formula: see text] and [Formula: see text] were determined. The percentage of detected breathing efforts by [Formula: see text] compared with [Formula: see text] was calculated. Temporal and signal strength relations on optimum recordings of 10 breaths per subject were also compared. The Spearman correlation coefficient was used to determine the correlation between [Formula: see text] and [Formula: see text]. Agreement was calculated by using Bland-Altman statistics.

Results: Fifteen subjects were included. The [Formula: see text] detected 3,675 breathing efforts, of which 3,162 (86.0%) were also detected by [Formula: see text]. A statistically significant temporal correlation (r = 0.95, < .001) was found between [Formula: see text] and [Formula: see text] in stable recordings. The mean difference in the time intervals between both techniques was 10.1 ms, with limits of agreement from -410 to 430 ms.

Conclusions: Analysis of our results showed that [Formula: see text] was not reliable for breathing effort detection in subjects who were invasively ventilated compared with [Formula: see text]. In stable recordings, however, [Formula: see text] and [Formula: see text] had excellent temporal correlation and good agreement. With optimization of signal stability, [Formula: see text] may become a useful monitoring tool.
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http://dx.doi.org/10.4187/respcare.07094DOI Listing
September 2020

Nebulized Heparin in Burn Patients with Inhalation Trauma-Safety and Feasibility.

J Clin Med 2020 Mar 25;9(4). Epub 2020 Mar 25.

Laboratory of Experimental Intensive Care and Anesthesiology (L·E·I·C·A), Amsterdam University Medical Centers, 1105 AZ Amsterdam, The Netherlands.

Background: Pulmonary hypercoagulopathy is intrinsic to inhalation trauma. Nebulized heparin could theoretically be beneficial in patients with inhalation injury, but current data are conflicting. We aimed to investigate the safety, feasibility, and effectiveness of nebulized heparin.

Methods: International multicenter, double-blind, placebo-controlled randomized clinical trial in specialized burn care centers. Adult patients with inhalation trauma received nebulizations of unfractionated heparin (25,000 international unit (IU), 5 mL) or placebo (0.9% NaCl, 5 mL) every four hours for 14 days or until extubation. The primary outcome was the number of ventilator-free days at day 28 post-admission. Here, we report on the secondary outcomes related to safety and feasibility.

Results: The study was prematurely stopped after inclusion of 13 patients (heparin = 7, placebo = 6) due to low recruitment and high costs associated with the trial medication. Therefore, no analyses on effectiveness were performed. In the heparin group, serious respiratory problems occurred due to saturation of the expiratory filter following nebulizations. In total, 129 out of 427 scheduled nebulizations were withheld in the heparin group (in 3 patients) and 45 out of 299 scheduled nebulizations were withheld in the placebo group (in 2 patients). Blood-stained sputum or expected increased bleeding risks were the most frequent reasons to withhold nebulizations.

Conclusion: In this prematurely stopped trial, we encountered important safety and feasibility issues related to frequent heparin nebulizations in burn patients with inhalation trauma. This should be taken into account when heparin nebulizations are considered in these patients.
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http://dx.doi.org/10.3390/jcm9040894DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7230289PMC
March 2020

Potential of Parameters of Iron Metabolism for the Diagnosis of Anemia of Inflammation in the Critically Ill.

Transfus Med Hemother 2020 Feb 3;47(1):61-67. Epub 2019 May 3.

Department of Intensive Care Medicine, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands.

Background: Anemia of inflammation (AI) is the most common cause of anemia in the critically ill, but its diagnosis is a challenge. New therapies specific to AI are in development, and they require accurate detection of AI. This study explores the potential of parameters of iron metabolism for the diagnosis of AI during an ICU stay.

Methods: In a nested case-control study, 30 patients developing AI were matched to 60 controls. The iron parameters were determined in plasma samples during an ICU stay. Receiver operating characteristic curves were used to determine the iron parameter threshold with the highest sensitivity and specificity to predict AI. Likelihood ratios as well as positive and negative predictive values were calculated as well.

Results: The sensitivity of iron parameters for diagnosing AI ranges between 62 and 76%, and the specificity between 57 and 72%. Iron and transferrin show the greatest area under the curve. Iron shows the highest sensitivity, and transferrin and transferrin saturation display the highest specificity. Hepcidin and ferritin show the lowest specificity. At an actual anemia prevalence of 53%, the diagnostic accuracy of iron, transferrin, and transferrin saturation was fair, with a positive predictive value between 71 and 73%. Combining iron, transferrin, transferrin saturation, hepcidin, and/or ferritin levels did not increase the accuracy of the AI diagnosis.

Conclusions: In this explorative study on the use of different parameters of iron metabolism for diagnosing AI during an ICU stay, low levels of commonly measured markers such as plasma iron, transferrin, and transferrin saturation have the highest sensitivity and specificity and outperform ferritin and hepcidin.
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http://dx.doi.org/10.1159/000497123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7036579PMC
February 2020

Microbiological profile of nosocomial infections following cardiac arrest: Insights from the targeted temperature management (TTM) trial.

Resuscitation 2020 03 4;148:227-233. Epub 2020 Feb 4.

Department of Intensive Care, Academic Medical Centre, Amsterdam, The Netherlands; Laboratory of Experimental Intensive Care and Anesthesiology, Amsterdam, The Netherlands. Electronic address:

Aims: Infectious complications frequently occur in intensive care unit patients admitted after out-of-hospital cardiac arrest. There is debate on the effects of temperature management on the incidence of infections, as well as on the efficacy and choice of antibiotic prophylaxis. In this substudy of the targeted temperature management (TTM) trial, we describe the microbiological profile of infectious complications in patients with cardiac arrest and examined the impact of TTM at 33 °C compared to TTM at 36 °C. Furthermore we aimed to determine the association between antibiotic prophylaxis and the incidence of infections.

Methods: This is a posthoc analysis of the TTM cohort. Microbiological data was retrospectively collected for the first 14-days of ICU-admission. Logistic regression was used to determine the relationship between antibiotic prophylaxis and pneumonia adjusted for mortality.

Results: Of 696 patients included in this analysis, 158 (23%) developed pneumonia and 28 (4%) had bacteremia with a clinically relevant pathogen. Staphylococcus aureus was the most common pathogen isolated in patients with pneumonia (23%) and in patients with bacteremia (24%). Gram-negative pathogens were most common overall. TTM did not have an impact on the microbiological profile. The use of antibiotic prophylaxis was significantly associated with a reduced risk of infection (OR 0.59, 95%CI 0.43-0.79, p = 0.0005). This association remained significant after correcting for confounders (OR 0.64, 95%CI 0.46-0.90; p = 0.01). The association is not present in a model after correction for clustering within centers (aOR 0.55, 95%CI 0.20-1.47, p = 0.22). Adjustment for mortality did not influence the outcome.

Conclusion: Gram-negative pathogens are the most common causes of nosocomial infections following cardiac arrest. TTM does not impact the microbiological profile. It remains unclear whether patients in ICUs using antibiotic prophylaxis have a reduced risk of pneumonia and bacteremia that is unrelated to center effects.
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http://dx.doi.org/10.1016/j.resuscitation.2019.11.033DOI Listing
March 2020
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