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Journal of intensive care medicine 37(7), 970-978 (2022). doi:10.1177/08850666211052460, Published by Wiley-Blackwell, [Erscheinungsort nicht ermittelbar]

Early death in sepsis occurs frequently; however, specific causes are largely unknown. An autopsy can contribute to ascertain causes of death. The objective of the study was to determine discrepancies in clinical diagnosis and postmortem findings in septic intensive care unit (ICU) patients deceased within 48 h after ICU admission. All septic ICU patients who deceased within 48 h after ICU admission were identified and included. Four intensivists determined the clinical cause of death by medical record review. An autopsy was performed within 24 h of death. Clinical diagnosis and postmortem findings were compared and classified as autopsy-identified missed clinical diagnoses and autopsy-refuted diagnoses. Class I and II missed major diagnoses using the Goldman criteria were scored. Between 2012 and 2017, 1107 septic patients were admitted to ICU. Of these, 344 patients (31%) died, of which 97 patients (28%) deceased within 48 h. In 32 (33%) early deceased patients, an autopsy was agreed. There were 26 autopsy-identified missed clinical diagnoses found, mostly myocardial infarction (n = 4) and pneumonia (n = 4). In four patients (13%), a class I discrepancy was found. In fourteen patients (42%), a class II discrepancy was found. In conclusion, an autopsy is an important diagnostic tool that can identify definite causes of death. These diagnoses deviate from diagnoses established during admission in early deceased sepsis patients.

Background: The majority of patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are admitted to the Intensive Care Unit (ICU) for mechanical ventilation. The role of multi-organ failure during ICU admission as driver for outcome remains to be investigated yet.Design and setting: Prospective cohort of mechanically ventilated critically ill with SARS-CoV-2 infection.Participants and methods: 94 participants of the MaastrICCht cohort (21% women) had a median length of stay of 16 days (maximum of 77). After division into survivors (n = 59) and non-survivors (n = 35), we analysed 1555 serial SOFA scores using linear mixed-effects models.Results: Survivors improved one SOFA score point more per 5 days (95% CI: 4-8) than non-survivors. Adjustment for age, sex, and chronic lung, renal and liver disease, body-mass index, diabetes mellitus, cardiovascular risk fac-tors, and Acute Physiology and Chronic Health Evaluation II score did not change this result. This association was stronger for women than men (P-interaction = 0.043).Conclusions: The decrease in SOFA score associated with survival suggests multi-organ failure involvement dur -ing mechanical ventilation in patients with SARS-CoV-2. Surviving women appeared to improve faster than sur-viving men. Serial SOFA scores may unravel an unfavourable trajectory and guide decisions in mechanically ventilated patients with SARS-CoV-2.(c) 2020 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background Postoperative outcome prediction in elderly is based on preoperative physical status but its predictive value is uncertain. The goal was to evaluate the value of risk assessment performed perioperatively in predicting outcome in case of admission to an intensive care unit (ICU). Methods A total of 108 postsurgical patients were retrospectively selected from a prospectively recorded database of 144 elderly septic patients (>70 years) admitted to the ICU department after elective or emergency abdominal surgery between 2012 and 2017. Perioperative risk assessment scores including Portsmouth Physiological and Operative Severity Score for the enumeration of Mortality (P-POSSUM) and American Society of Anaesthesiologists Physical Status classification (ASA) were determined. Acute Physiology and Chronic Health Evaluation IV (APACHE IV) was obtained at ICU admission. Results In-hospital mortality was 48.9% in elderly requiring ICU admission after elective surgery (n = 45), compared to 49.2% after emergency surgery (n = 63). APACHE IV significantly predicted in-hospital mortality after complicated elective surgery [area under the curve 0.935 (p p = 0.002) and 0.736 (p = 0.006), respectively). Conclusions Perioperative risk assessment reflecting premorbid physical status of elderly loses its value when complications occur requiring unplanned ICU admission. Risks in elderly should be re-assessed based on current clinical condition prior to ICU admission, because outcome prediction is more reliable then.

BACKGROUND: Low skeletal muscle mass on intensive care unit admission is related to increased mortality. It is however unknown whether this association is influenced by co-morbidities that are associated with skeletal muscle loss. The aim of this study was to investigate whether sarcopenia is an independent risk factor for hospital mortality in critical illness in the presence of co-morbidities associated with muscle wasting.METHODS: Data of 155 patients with abdominal sepsis were retrospectively analyzed. Skeletal muscle area was assessed using CT-scans at the level of vertebra L3. Demographic and clinical data were retrieved from electronic patient files. Sarcopenia was defined as a muscle area index below the 5th percentile of the general population. Uni- and multivariable analyses were performed to assess the association between sarcopenia and hospital mortality, correcting for age and comorbidities.RESULTS: The prevalence of sarcopenia was higher in patients that did not survive until hospital discharge. However, it appeared that this relation was confounded by the presence of chronic renal insufficiency and cancer. These were independent risk factors for hospital mortality, whereas sarcopenia was not.CONCLUSION: In critically ill patients with abdominal sepsis, muscle wasting associated co-morbidities rather than sarcopenia were risk factors for hospital mortality.

Background: There is a demand for a non-invasive bedside method to diagnose Acute Respiratory Distress Syndrome (ARDS). Octane was discovered and validated as the most important breath biomarker for diagnosis of ARDS using gas-chromatography and mass-spectrometry (GC-MS). However, GC-MS is unsuitable as a point-of-care (POC) test in the intensive care unit (ICU). Therefore, we determined if a newly developed POC breath test can reliably detect octane in exhaled breath of invasively ventilated ICU patients. Methods: Two developmental steps were taken to design a POC breath test that relies on gas-chromatography using air as carrier gas with a photoionization detector. Calibration measurements were performed with a laboratory prototype in healthy subjects. Subsequently, invasively ventilated patients were included for validation and assessment of repeatability. After evolving to a POC breath test, this device was validated in a second group of invasively ventilated patients. Octane concentration was based on the area under the curve, which was extracted from the chromatogram and compared to known values from calibration measurements. Results: Five healthy subjects and 53 invasively ventilated patients were included. Calibration showed a linear relation (R2 = 1.0) between the octane concentration and the quantified octane peak in the low parts per billion (ppb) range. For the POC breath test the repeatability was excellent (R2 = 0.98, ICC = 0.97 (95% CI 0.94–0.99)). Conclusion: This is the first study to show that a POC breath test can rapidly and reliably detect octane, with excellent repeatability, at clinically relevant levels of low ppb in exhaled breath of ventilated ICU patients. This opens possibilities for targeted exhaled breath analysis to be used as a bedside test and makes it a potential diagnostic tool for the early detection of ARDS.

Objectives: Changes in muscle mass and quality are important targets for nutritional intervention in critical illness. Effects of such interventions may be assessed using sequential computed tomography (CT) scans. However, fluid and lipid infiltration potentially affects muscle area measurements. The aim of this study was to evaluate changes in muscle mass and quality in critical illness with special emphasis on the influence of edema on this assessment. Methods: Changes in skeletal muscle area index (SMI) and radiation attenuation (RA) at the level of vertebra L3 were analyzed using sequential CT scans of 77 patients with abdominal sepsis. Additionally, the relation between these changes and disease severity using the maximum Sequential Organ Failure Assessment (SOFA) score and change in edema were studied. Results: SMI declined on average 0.35%/d (1.22%; P = 0.013). However, SMI increased in 41.6% of the study population. Increasing edema formation was significantly associated with increased SMI and with a higher SOFA score. Muscle RA decreased during critical illness, but was not significantly associated with changes in SMI or changes in edema. Conclusion: In critically ill patients, edema affects skeletal muscle area measurements, which leads to an overestimation of skeletal muscle area. A higher SOFA score was associated with edema formation. Because both edema and fat infiltration may affect muscle RA, the separate effects of these on muscle quality are difficult to distinguish. When using abdominal CT scans to changes in muscle mass and quality in critically ill patients, researchers must be aware and careful with the interpretation of the results. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Background Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin Definition. Diagnosis is subjective and often late. Untargeted metabolomics analysis of exhaled breath with gas chromatography and mass spectrometry (GC-MS) showed that the breath concentration of octane has a high diagnostic accuracy for ARDS. To facilitate rapid bedside measurement of this biomarker, a point-of-care (POC) breath test was developed. A prototype already showed good reproducibility and repeatability for the detection of octane. In this study we aim to measure octane in exhaled breath of invasively ventilated intensive care unit (ICU) patients and validate the diagnostic accuracy of the breath test for the early diagnosis of ARDS. Methods This is a multicentre observational cohort study in patients admitted to the ICU receiving invasive ventilation for at least 24 hours. At least 500 patients in two academic hospitals in The Netherlands will be included. ARDS patients will be compared to patients without ARDS. ARDS diagnosis will be based on the Berlin Definition. Two diagnostic assessments will be performed during the first 72 hours of invasive ventilation, including breath sampling, arterial blood gas analysis and lung ultrasound (LUS). In patients fulfilling the criteria for ARDS, three additional breath samples will be taken to assess resolution. The primary endpoint is the diagnostic accuracy for ARDS, defined by the area under the receiver operating characteristics curve (AUROCC) of octane concentration in exhaled breath. Secondary endpoints are the association between exhaled breath octane and ARDS adjusted for confounders, and the added diagnostic accuracy of the breath test on top of the Lung Injury Prediction Score (LIPS). Discussion This is the first study that validates a metabolic biomarker of ARDS in an adequate sample size. The major novelty is the use of a POC breath test that has been specifically developed for the purpose of diagnosing ARDS. Strengths are; assessment in the early phase, in patients at risk for ARDS, longitudinal sampling and an expert panel to reliably diagnose ARDS. This study will provide a decisive answer on the question if exhaled breath metabolomics can be used to diagnose ARDS. Trial registration The trial is registered at trialregister.nl (ID: NL8226) with the tag "DARTS".

Background: There is a demand for a non-invasive bedside method to diagnose Acute Respiratory Distress Syndrome (ARDS). Octane was discovered and validated as the most important breath biomarker for diagnosis of ARDS using gas-chromatography and mass-spectrometry (GC-MS). However, GC-MS is unsuitable as a point-of-care (POC) test in the intensive care unit (ICU). Therefore, we determined if a newly developed POC breath test can reliably detect octane in exhaled breath of invasively ventilated ICU patients. Methods: Two developmental steps were taken to design a POC breath test that relies on gas-chromatography using air as carrier gas with a photoionization detector. Calibration measurements were performed with a laboratory prototype in healthy subjects. Subsequently, invasively ventilated patients were included for validation and assessment of repeatability. After evolving to a POC breath test, this device was validated in a second group of invasively ventilated patients. Octane concentration was based on the area under the curve, which was extracted from the chromatogram and compared to known values from calibration measurements. Results: Five healthy subjects and 53 invasively ventilated patients were included. Calibration showed a linear relation (R2 = 1.0) between the octane concentration and the quantified octane peak in the low parts per billion (ppb) range. For the POC breath test the repeatability was excellent (R2 = 0.98, ICC = 0.97 (95% CI 0.94–0.99)). Conclusion: This is the first study to show that a POC breath test can rapidly and reliably detect octane, with excellent repeatability, at clinically relevant levels of low ppb in exhaled breath of ventilated ICU patients. This opens possibilities for targeted exhaled breath analysis to be used as a bedside test and makes it a potential diagnostic tool for the early detection of ARDS.

Objectives To determine the appropriateness of empiric antibiotic therapy and the possible benefit of adding short-course gentamicin in septic shock patients with abdominal, urogenital, or an unknown focus. Secondary objectives were the effect of gentamicin addition on shock reversal and the incidence of a fungal infection. Methods Microbiological cultures, antibiotic treatment, and antibiotic resistance patterns of the cultured microorganisms were recorded during the first 5 days of admission. Inappropriate antibiotic therapy was defined as a prescription within the first 24 h that did not cover cultured bacteria during the first 5 days of admission and was determined in the overall group and in patients receiving adjunctive gentamicin (combination therapy) versus patients receiving monotherapy. Binomial logistic regression analysis was used to investigate the association of gentamicin addition with shock reversal. Results Of 203 septic shock patients, with abdominal (n = 143), urogenital (n = 27) or unknown (n = 33) focus, 115 patients received monotherapy, and 88 patients received combination therapy. Inappropriate therapy occurred in 29 patients (14%), more frequently in monotherapy (17%) versus combination therapy (10%). Combination therapy would have been effective in 55% of patients with inappropriate monotherapy. We found no association between gentamicin addition and shock reversal (p = .223). A fungal infection was present in 22 patients (11%). Conclusion Inappropriate empirical antibiotic therapy occurs in 17% of septic shock patients receiving monotherapy. In 55% of these patients, additional gentamicin would have resulted in appropriate therapy. When clinical course is unfavourable, lowering the threshold for administering adjunctive aminoglycoside and antifungal therapy should be considered.

Rationale: Recent studies showed that biological subphenotypes in acute respiratory distress syndrome (ARDS) provide prognostic enrichment and show potential for predictive enrichment. Objectives: To determine whether these subphenotypes and their prognostic and potential for predictive enrichment could be extended to other patients in the ICU, irrespective of fulfilling the definition of ARDS. Methods: This is a secondary analysis of a prospective observational study of adult patients admitted to the ICU. We tested the prognostic enrichment of both cluster-derived and latentclass analysis (LCA)-derived biological ARDS subphenotypes by evaluating the association with clinical outcome (ICU-day, 30-day mortality, and ventilator-free days) using logistic regression and Cox regression analysis. We performed a principal component analysis to compare blood leukocyte gene expression profiles between subphenotypes and the presence of ARDS. Measurements and Main Results: We included 2,499 mechanically ventilated patients (674 with and 1,825 without ARDS). The cluster-derived "reactive"subphenotype was, independently of ARDS, significantly associated with a higher probability of ICU mortality, higher 30-day mortality, and a lower probability of successful extubation while alive compared with the "uninflamed"subphenotype. The blood leukocyte gene expression profiles of individual subphenotypes were similar for patients with and without ARDS. LCA-derived subphenotypes also showed similar profiles. Conclusions: The prognostic and potential for predictive enrichment of biological ARDS subphenotypes may be extended to mechanically ventilated critically ill patients without ARDS. Using the concept of biological subphenotypes for splitting cohorts of critically ill patients could add to improving future precision-based trial strategies and lead to identifying treatable traits for all critically ill patients.

Background The incidence of pulmonary thromboembolism is high in SARS-CoV-2 patients admitted to the Intensive Care. Elevated biomarkers of coagulation (fibrinogen and D-dimer) and inflammation (c-reactive protein (CRP) and ferritin) are associated with poor outcome in SARS-CoV-2. Whether the time-course of fibrinogen, D-dimer, CRP and ferritin is associated with the occurrence of pulmonary thromboembolism in SARS-CoV-2 patients is unknown. We hypothesise that patients on mechanical ventilation with SARS-CoV-2 infection and clinical pulmonary thromboembolism have lower concentrations of fibrinogen and higher D-dimer, CRP, and ferritin concentrations over time compared to patients without a clinical pulmonary thromboembolism. Methods In a prospective study, fibrinogen, D-dimer, CRP and ferritin were measured daily. Clinical suspected pulmonary thromboembolism was either confirmed or excluded based on computed tomography pulmonary angiography (CTPA) or by transthoracic ultrasound (TTU) (i.e., right-sided cardiac thrombus). In addition, patients who received therapy with recombinant tissue plasminogen activator were included when clinical instability in suspected pulmonary thromboembolism did not allow CTPA. Serial data were analysed using a mixed-effects linear regression model, and models were adjusted for known risk factors (age, sex, APACHE-II score, body mass index), biomarkers of coagulation and inflammation, and anticoagulants. Results Thirty-one patients were considered to suffer from pulmonary thromboembolism ((positive CTPA (n = 27), TTU positive (n = 1), therapy with recombinant tissue plasminogen activator (n = 3)), and eight patients with negative CTPA were included. After adjustment for known risk factors and anticoagulants, patients with, compared to those without, clinical pulmonary thromboembolism had lower average fibrinogen concentration of − 0.9 g/L (95% CI: − 1.6 – − 0.1) and lower average ferritin concentration of − 1045 μg/L (95% CI: − 1983 – − 106) over time. D-dimer and CRP average concentration did not significantly differ, 561 μg/L (− 6212–7334) and 27 mg/L (− 32–86) respectively. Ferritin lost statistical significance, both in sensitivity analysis and after adjustment for fibrinogen and D-dimer. Conclusion Lower average concentrations of fibrinogen over time were associated with the presence of clinical pulmonary thromboembolism in patients at the Intensive Care, whereas D-dimer, CRP and ferritin were not. Lower concentrations over time may indicate the consumption of fibrinogen related to thrombus formation in the pulmonary vessels.

Biological subphenotypes have been identified in acute respiratory distress syndrome (ARDS) based on two parsimonious models: the “uninflamed” and “reactive” subphenotype (cluster‐model) and “hypo‐inflammatory” and “hyper‐inflammatory” (latent class analysis (LCA) model). The distinction between the subphenotypes is mainly driven by inflammatory and coagulation markers in plasma. However, systemic inflammation is not specific for ARDS and it is unknown whether these subphenotypes also reflect differences in the alveolar compartment. Alveolar inflammation and dysbiosis of the lung microbiome have shown to be important mediators in the development of lung injury. This study aimed to determine whether the “reactive” or “hyper‐inflammatory” biological subphenotype also had higher concentrations of inflammatory mediators and enrichment of gut‐associated bacteria in the lung. Levels of alveolar inflammatory mediators myeloperoxidase (MPO), surfactant protein D (SPD), interleukin (IL)‐1b, IL‐6, IL‐10, IL‐8, interferon gamma (IFN‐ƴ), and tumor necrosis factor‐alpha (TNFα) were determined in the mini‐BAL fluid. Key features of the lung microbiome were measured: bacterial burden (16S rRNA gene copies/ml), community diversity (Shannon Diversity Index), and community composition. No statistically significant differences between the “uninflamed” and “reactive” ARDS subphenotypes were found in a selected set of alveolar inflammatory mediators and key features of the lung microbiome. LCA‐derived subphenotypes and stratification based on cause of ARDS (direct vs. indirect) showed similar profiles, suggesting that current subphenotypes may not reflect the alveolar host response. It is important for future research to elucidate the pulmonary biology within each subphenotype properly, which is arguably a target for intervention., Preliminary results suggest that biological subphenotypes of ARDS may not reflect differences in alveolar inflammation and key features of the lung microbiome.

Background Sepsis is a global health care problem with a high mortality. Early death seems common; however, data are sparse. The objective of the present study was to report causes and influencing factors of early death in sepsis and septic shock. Methods All septic ICU patients were included from 2012 to 2017. Early death was predefined as occurring within 48 h. Causes and factors leading up to death were reported by a panel of four intensivists, independently reviewing the medical files. Following factors were assessed: (1) delay in ICU admission; (2) futile ICU treatment; (3) missed diagnosis or inadequate treatment on the ICU. Fleiss kappa was used to assess inter-observer agreement. Results 1107 septic patients (APACHE II score 25 +/- 8) were included. 344 patients died of which 97 (28%) within 48 h. In 33% an autopsy was performed. Primary causes of early death were multiple organ failure, mesenteric ischaemia and death after cardio-pulmonary resuscitation (CPR). Delay in ICU admission was scored in 32% of early deaths with slight agreement (kappa = 0.180), futile ICU treatment in 29% with moderate agreement (kappa = 0.415) and missed diagnosis or treatment in 7% of cases with slight agreement (kappa = 0.122). Conclusions Early death after ICU admission in sepsis is common and primarily caused by multiple organ failure, mesenteric ischaemia and death after unsuccessful CPR. Influencing factors were delay in ICU admission and futile ICU admission. Fleiss kappa indicates substantial variability in clinical judgement between intensivists, strengthening the necessity for shared decision making.

Rationale Acute respiratory distress syndrome (ARDS) is currently diagnosed by the Berlin definition, which does not include a direct measure of pulmonary oedema, endothelial permeability or pulmonary inflammation. We hypothesised that biomarkers of these processes have good diagnostic accuracy for ARDS. Methods Medline and Scopus were searched for original diagnostic studies using minimally invasive testing. Primary outcome was the diagnostic accuracy per test and was categorised by control group. The methodological quality was assessed with QUADAS-2 tool. Biomarkers that had an area under the receiver operating characteristic curve (AUROCC) of >0.75 and were studied with minimal bias against an unselected control group were considered to be promising. Results Forty-four articles were included. The median AUROCC for all evaluated tests was 0.80 (25th to 75th percentile: 0.72–0.88). The type of control group influenced the diagnostic accuracy (p=0.0095). Higher risk of bias was associated with higher diagnostic accuracy (AUROCC 0.75 for low-bias, 0.77 for intermediate-bias and 0.84 for high-bias studies; p=0.0023). Club cell protein 16 and soluble receptor for advanced glycation end-products in plasma and two panels with biomarkers of oxidative stress in breath showed good diagnostic accuracy in low-bias studies that compared ARDS patients to an unselected intensive care unit (ICU) population. Conclusion This systematic review revealed only four diagnostic tests fulfilling stringent criteria for a promising biomarker in a low-bias setting. For implementation into the clinical setting, prospective studies in a general unselected ICU population with good methodological quality are needed., Accuracy of diagnosis of acute respiratory distress syndrome (ARDS) is associated with risk of bias. There is a lack of validated diagnostic tests in an unbiased setting, emphasising the need for quality driven diagnostic research in ARDS. https://bit.ly/2GfPAvf

International guidelines do not recommend a specific probe for assessment of lung aeration using lung ultrasound (LUS). The aim of this study was to assess the concordance between linear and sector array probes of a handheld ultrasound device in assessment of lung aeration in invasively ventilated intensive care unit patients. This study included intensive care unit patients who were expected to be ventilated for longer than 24 h. A 12-region LUS exam was performed with a linear and a sector array probe. In each image, the LUS aeration score and number of B-lines were determined. Adding the LUS aeration scores of all regions resulted in a global LUS aeration score. Agreement between the two probes was calculated using intra-class correlation coefficients (ICCs). A total of 30 LUS exams were performed in 19 patients, resulting in a total of 328 pairs of images. Twenty-nine pairs of images were excluded from analysis because the images from the linear probe could not be scored. ICCs calculated for the remaining images revealed good concordance the LUS aeration scores for individual images (ICC = 0.73, 95% confidence interval 0.67-0.78), number of B-lines (ICC = 0.79, 95% confidence interval 0.72-0.83) and global LUS aeration score (ICC = 0.74, 95% confidence interval 0.52-0.87). In conclusion, there is good concordance between linear and sector array probes of a handheld ultrasound device in assessment of lung aeration patterns in mechanically ventilated intensive care unit patients. However, in roughly 10% of the images acquired using the linear probe, the aeration pattern could not be scored. (E-mail: m.r. smit@amsterdamumc.nl) (C) 2020 World Federation for Ultrasound in Medicine & Biology. All rights reserved.

Background The risk of pulmonary embolism (PE) in patients with Coronavirus Disease 2019 (COVID-19) is recognized. The prevalence of PE in patients with respiratory deterioration at the Emergency Department (ED), the regular ward, and the Intensive Care Unit (ICU) are not well-established. Objectives We aimed to investigate how often PE was present in individuals with COVID-19 and respiratory deterioration in different settings, and whether or not disease severity as measured by CT-severity score (CTSS) was related to the occurrence of PE. Patients/methods Between April 6th and May 3rd, we enrolled 60 consecutive adult patients with confirmed COVID-19 from the ED, regular ward and ICU who met the pre-specified criteria for respiratory deterioration. Results A total of 24 (24/60: 40% (95% CI: 28–54%)) patients were diagnosed with PE, of whom 6 were in the ED (6/23: 26% (95% CI: 10–46%)), 8 in the regular ward (8/24: 33% (95% CI: 16–55%)), and 10 in the ICU (10/13: 77% (95% CI: 46–95%)). CTSS (per unit) was not associated with the occurrence of PE (age and sex-adjusted OR 1.06 (95%CI 0.98–1.15)). Conclusion The number of PE diagnosis among patients with COVID-19 and respiratory deterioration was high; 26% in the ED, 33% in the regular ward and 77% in the ICU respectively. In our cohort CTSS was not associated with the occurrence of PE. Based on the high number of patients diagnosed with PE among those scanned we recommend a low threshold for performing computed tomography angiography in patients with COVID-19 and respiratory deterioration., Highlights • The high prevalence of pulmonary embolism in COVID-19 is not limited to the ICU • Respiratory deterioration in COVID-19 patients should prompt a low threshold CTPA • Regular thromboprophylaxis may be insufficient to prevent PE in COVID-19 patients

BackgroundThe course of the disease in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in mechanically ventilated patients is unknown. To unravel the clinical heterogeneity of the SARS-CoV-2 infection in these patients, we designed the prospective observational Maastricht Intensive Care COVID cohort;MaastrICCht. We incorporated serial measurements that harbour aetiological, diagnostic and predictive information. The study aims to investigate the heterogeneity of the natural course of critically ill patients with SARS-CoV-2 infection.Study populationMechanically ventilated patients admitted to the Intensive Care with SARS- CoV-2 infection.Main messageWe will collect clinical variables, vital parameters, laboratory variables, mechanical ventilator settings, chest electrical impedance tomography, electrocardiograms, echocardiography as well as other imaging modalities to assess heterogeneity of the natural course of SARS-CoV-2 infection in critically ill patients. TheMaastrICChtcohort is, also designed to foster various other studies and registries and intends to create an open-source database for investigators. Therefore, a major part of the data collection is aligned with an existing national Intensive Care data registry and two international COVID-19 data collection initiatives. Additionally, we create a flexible design, so that additional measures can be added during the ongoing study based on new knowledge obtained from the rapidly growing body of evidence.ConclusionThe spread of the COVID-19 pandemic requires the swift implementation of observational research to unravel heterogeneity of the natural course of the disease of SARS- CoV-2 infection in mechanically ventilated patients. Our design is expected to enhance aetiological, diagnostic and prognostic understanding of the disease. This paper describes the design of theMaastrICChtcohort.Strengths and limitations of this studySerial measurements that characterize the disease course of SARS-CoV-2 infection in mechanically ventilated patientsData collection and analysis according to a predefined protocolFlexible, evolving design enabling the study of multiple aspects of SARS-CoV-2 infection in mechanically ventilated patientsSingle centre, including only ICU patients

Background: Clear definitions for septic shock assist clinicians regarding recognition, treatment and standardized reporting of characteristics and outcome of this entity. Sepsis-3 definition of septic shock incorporates a new criterion, a lactate level >2mmol/L. Differences in epidemiology and outcome of septic shock based upon both definitions were studied in an intensive care (ICU) population of septic patients. Methods: We analyzed a prospectively collected cohort of data in the ICU of the Maastricht University Medical Centre. 632 septic patients were included. ICU mortality was compared between the patient group fulfilling Sepsis-3 definition for septic shock and those that met Sepsis-2 definition. Furthermore, association between lactate levels and ICU mortality was studied. Results: Of 632 septic patients, 482 (76.3%) had septic shock according to Sepsis-2 and 300 patients (48.4%) according to Sepsis-3 definition, respectively. Patients meeting Sepsis-3 definition had a higher mortality than patients meeting Sepsis-2 definition (38.9 vs. 34.0%). Serum lactate levels between 2 and 4 mmol/L (25.0 vs. 26.2%, OR 0.94 (0.5-1.5)) and between 4 and 6 mmol/L (23.8 vs. 26.2%, OR 0.88 (0.4-1.7)) compared to levels

Volatile organic compounds in breath can reflect host and pathogen metabolism and might be used to diagnose pneumonia. We hypothesized that rats with Streptococcus pneumoniae ( SP) or Pseudomonas aeruginosa ( PA) pneumonia can be discriminated from uninfected controls by thermal desorption-gas chromatography-mass-spectrometry (TD-GC-MS) and selected ion flow tube-mass spectrometry (SIFT-MS) of exhaled breath. Male adult rats ( n = 50) received an intratracheal inoculation of 1) 200 µl saline, or 2) 1 × 107 colony-forming units of SP or 3) 1 × 107 CFU of PA. Twenty-four hours later the rats were anaesthetized, tracheotomized, and mechanically ventilated. Exhaled breath was analyzed via TD-GC-MS and SIFT-MS. Area under the receiver operating characteristic curves (AUROCCs) and correct classification rate (CCRs) were calculated after leave-one-out cross-validation of sparse partial least squares-discriminant analysis. Analysis of GC-MS data showed an AUROCC (95% confidence interval) of 0.85 (0.73–0.96) and CCR of 94.6% for infected versus noninfected animals, AUROCC of 0.98 (0.94–1) and CCR of 99.9% for SP versus PA, 0.92 (0.83–1.00), CCR of 98.1% for SP versus controls and 0.97 (0.92–1.00), and CCR of 99.9% for PA versus controls. For these comparisons the SIFT-MS data showed AUROCCs of 0.54, 0.89, 0.63, and 0.79, respectively. Exhaled breath analysis discriminated between respiratory infection and no infection but with even better accuracy between specific pathogens. Future clinical studies should not only focus on the presence of respiratory infection but also on the discrimination between specific pathogens.

Volatile organic compounds (VOCs) in breath can reflect host and pathogen metabolism and might be used to diagnose pneumonia (Oort J Breath Res 2018). We hypothesized that rats with Streptococcus pneumoniae (SP) or Pseudomonas aeruginosa (PA) pneumonia can be discriminated from uninfected controls by gas-chromatography mass-spectrometry (GC-MS) of exhaled breath. Male adult rats (N = 50) received an intra-tracheal inoculation of 1) 200µL saline, 2) 1x107 colony forming units (cfu) of SP or 3) 1x107 cfu of PA. 24 hours later the rats were anaesthetized, tracheotomized and mechanically ventilated. Exhaled breath was analyzed via GC-MS. Area under the receiver operating characteristic curve (AUROCC) was calculated after leave-one-out cross-validation of sparse partial least squares discriminant analysis (sPLS-DA). The AUROCC was 0.85 (95%-CI: 0.73-0.96) for infected vs. non-infected animals. The AUROCC was 0.98 (95%-CI: 0.94-1) for SP vs. PA, 0.92 (95%-CI: 0.83-1) for SP vs. controls and 0.97 (95%-CI: 0.92-1) for PA vs. controls. Exhaled breath analysis discriminated with good accuracy between respiratory infection and no infection, but with much better accuracy between the specific pathogens. Clinical studies should focus more on the discrimination between specific pathogens, instead of the general presence of respiratory infection.

Diagnostic strategies currently used for pneumonia are time-consuming, lack accuracy and suffer from large inter-observer variability. Exhaled breath contains thousands of volatile organic compounds (VOCs), which include products of host and pathogen metabolism. In this systematic review we investigated the use of so-called 'breathomics' for diagnosing pneumonia. A Medline search yielded 18 manuscripts reporting on animal and human studies using organic and inorganic molecules in exhaled breath, that all could be used to answer whether analysis of VOC profiles could potentially improve the diagnostic process of pneumonia. Papers were categorised based on their specific aims; the exclusion of pneumonia; the detection of specific respiratory pathogens; and whether targeted or untargeted VOC analysis was used. Ten studies reported on the association between VOCs and presence of pneumonia. Eight studies demonstrated a difference in exhaled VOCs between pneumonia and controls; in the individual studies this discrimination was based on unique sets of VOCs. Eight studies reported on the accuracy of a breath test for a specific respiratory pathogen: five of these concerned preclinical studies in animals. All studies were valued as having a high risk of bias, except for one study that used an external validation cohort. The findings in the identified studies are promising. However, as yet no breath test has been shown to have sufficient diagnostic accuracy for pneumonia. We are in need of studies that further translate the knowledge from discovery studies to clinical practice.

Background Exhaled breath analysis is an emerging technology in respiratory disease and infection. Electronic nose devices (e-nose) are small and portable with a potential for point of care application. Ventilator-associated pneumonia (VAP) is a common nosocomial infection occurring in the intensive care unit (ICU). The current best diagnostic approach is based on clinical criteria combined with bronchoalveolar lavage (BAL) and subsequent bacterial culture analysis. BAL is invasive, laborious and time consuming. Exhaled breath analysis by e-nose is non-invasive, easy to perform and could reduce diagnostic time. Aim of this study was to explore whether an e-nose can be used as a non-invasive in vivo diagnostic tool for VAP. Methods Seventy-two patients met the clinical diagnostic criteria of VAP and underwent BAL. In thirty-three patients BAL analysis confirmed the diagnosis of VAP [BAL+(VAP+)], in thirty-nine patients the diagnosis was rejected [BAL−]. Before BAL was performed, exhaled breath was sampled from the expiratory limb of the ventilator into sterile Tedlar bags and subsequently analysed by an e-nose with metal oxide sensors (DiagNose, C-it, Zutphen, The Netherlands). From further fifty-three patients without clinical suspicion of VAP or signs of respiratory disease exhaled breath was collected to serve as a control group [control(VAP−]). The e-nose data from exhaled breath were analysed using logistic regression. Results The ROC curve comparing [BAL+(VAP+)] and [control(VAP−)] patients had an area under the curve (AUC) of 0.82 (95% CI 0.73–0.9). The sensitivity was 88% with a specificity of 66%. The comparison of [BAL+(VAP+)] and [BAL−] patients revealed an AUC of 0.69; 95% CI 0.57–0.81) with a sensitivity of 76% with a specificity of 56%. Conclusion E-nose lacked sensitivity and specificity in the diagnosis of VAP in the present study for current clinical application. Further investigation into this field is warranted to explore the diagnostic possibilities of this promising new technique.

The incidence of ventilator-associated pneumonia (VAP) before and after the introduction of selective oral decontamination (SOD) only and selective digestive tract decontamination (SDD) in a general intensive care population was examined. SOD as standard of care was introduced in December 2010 and SDD, including SOD, in January 2012 for all patients with an expected length of intensive care unit (ICU) stay of at least 48 h. The diagnosis of VAP was based on clinical criteria and quantitative cultures of bronchoalveolar lavage fluid. A total of 4945 mechanically ventilated patients accounting for 37 554 ventilator days in the period from 2005 to 2013 were analyzed. The incidence of VAP per 1000 ventilator days declined significantly from 4.38 +/- 1.64 before to 1.64 +/- 0.43 after introduction of SOD/SDD (p = 0.007). Implementation of SOD/SDD as standard of care in ICUs may thus be effective in preventing VAP.

Background: The clinical picture of ventilator-associated pneumonia (VAP) can be mimicked by other infectious and non-infectious diseases. The aim of this study was to determine the alternative diagnoses and to develop a diagnostic flow chart for patients suspected of having VAP not meeting the diagnostic broncho-alveolar lavage (BAL) criteria. Methods: Adult intensive care patients with a clinical suspicion of VAP and negative BAL results were included. The clinical suspicion of VAP was based on the combination of clinical, radiological, and microbiological criteria. BAL was considered positive if cell differentiation revealed >= 2% cells with intracellular organisms and/or quantitative culture results of >= 10(4) cfu/ml. The most likely alternative diagnosis of fever and pulmonary densities was retrospectively determined by two authors independently. Results: In all, 110 of 207 patients with suspected VAP did not meet the diagnostic BAL criteria and required further diagnostic evaluation. In 67 patients an alternative diagnosis for fever could be found. In 51 patients an alternative diagnosis of both fever and pulmonary densities could be established. In almost 40% of patients no alternative diagnosis could be provided. Non-bacterial pneumonia was diagnosed in 10 patients with Herpes simplex virus 1 (HSV-1) as the most common pathogen. In eight patients non-infectious pneumonitis was diagnosed. Conclusion: Due to the wide range of alternative diagnoses and applied tests the diagnostic work-up proved to be necessarily individualized and guided by repeated clinical assessment. The most frequently found alternative diagnoses were viral pneumonia and non-infectious pneumonitis.

Acanthamoeba polyphaga mimivirus (APMV) belongs to the amoebae-associated microorganisms. Antibodies to APMV have been found in patients with pneumonia suggesting a potential role as a respiratory pathogen. In addition, positive serology for APMV was associated with an increased duration of mechanical ventilation and intensive care unit stay in patients with ventilator-associated pneumonia. The aim of the present study was to assess the presence of APMV in bronchoalveolar lavage fluid samples of critically ill patients suspected of ventilator-associated pneumonia. The study was conducted in the intensive care unit of the Maastricht University Medical Centre. All consecutive bronchoalveolar lavage fluid samples obtained between January 2005 and October 2009 from patients suspected of ventilator-associated pneumonia were eligible for inclusion. All samples were analyzed by real-time PCR targeting the APMV. A total of 260 bronchoalveolar lavage fluid samples from 214 patients (139 male, 75 female) were included. Bacterial ventilator-associated pneumonia was confirmed microbiologically in 105 out of 260 (40%) suspected episodes of ventilator-associated pneumonia (86 patients). The presence of APMV DNA could not be demonstrated in the bacterial ventilator-associated pneumonia positive or in the bacterial ventilator-associated pneumonia negative bronchoalveolar lavage fluid samples. Although suspected, APMV appeared not to be present in critically ill patients suspected of ventilator-associated pneumonia, and APMV does not seem to be a frequent cause of ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) is a nosocomial infection occurring in the intensive care unit (ICU). The diagnostic standard is based on clinical criteria and bronchoalveolar lavage (BAL). Exhaled breath analysis is a promising non-invasive method for rapid diagnosis of diseases and contains volatile organic compounds (VOCs) that can differentiate diseased from healthy individuals. The aim of this study was to determine whether analysis of VOCs in exhaled breath can be used as a non-invasive monitoring tool for VAP. One hundred critically ill patients with clinical suspicion of VAP underwent BAL. Before BAL, exhaled air samples were collected and analysed by gas chromatography time-of-flight mass spectrometry (GC-tof-MS). The clinical suspicion of VAP was confirmed by BAL diagnostic criteria in 32 patients [VAP(+)] and rejected in 68 patients [VAP(−)]. Multivariate statistical comparison of VOC profiles between VAP(+) and VAP(−) revealed a subset of 12 VOCs that correctly discriminated between those two patient groups with a sensitivity and specificity of 75.8% ± 13.5% and 73.0% ± 11.8%, respectively. These results suggest that detection of VAP in ICU patients is possible by examining exhaled breath, enabling a simple, safe and non-invasive approach that could diminish diagnostic burden of VAP.

Ventilator-associated pneumonia (VAP) is a hospital-acquired infection occurring in the intensive care unit (ICU). The current diagnostic standard is bronchoalveolar lavage (BAL). However, this method is invasive and time-consuming. Analysis of volatile organic compounds (VOCs) in exhaled breath is a non-invasive method that is able to diagnose many pulmonary diseases including COPD and asthma. The aim of this study was to assess the diagnostic potential of exhaled breath to diagnose VAP in ventilated critically ill patients in the ICU. A total of 100 ventilated critically ill patients who were clinically suspected of VAP were included. Using BAL microbial analysis, the clinical suspicion of VAP was confirmed in 32 patients (VAP+) and rejected in 68 patients (VAP-). Prior to the BAL procedure, an exhaled air sample was collected from each patient. The exhaled air samples were measured for the total amount of VOCs by gas chromatography – time of flight – mass spectrometry (GC- tof -MS), and subsequently analysed by multivariate statistics to extract the compounds with the most discriminative power. Statistical comparison revealed that 12 VOCs could correctly classify VAP+ and VAP- with an accuracy of 74.2% ± 4.3 and a sensitivity and specificity of 75.8% ± 5 and 73.0% ± 4.3 respectively. These results suggest that it is possible to determine the presence of VAP in ICU patients by exhaled breath. Such a quick and non-invasive diagnosis of VAP will reduce the disease burden of these patients by earlier diagnosis, but will also reduce the necessity for BAL in the ICU.

It has been questioned if Candida pneumonia exists as a clinical entity. Only histopathology can establish the definite diagnosis. Less invasive diagnostic strategies lack specificity and have been insufficiently validated. Scarcity of this pathomechanism and nonspecific clinical presentation make validation and the development of a clinical algorithm difficult. In the present study, we analyze whether Candida pneumonia exists in our critical care population. We used a bronchoalveolar lavage (BAL) specimen database that we have built in a structural diagnostic approach to ventilator-associated pneumonia for more than a decade consisting of 832 samples. Microbiological data were linked to clinical information and available autopsy data. We searched for critically ill patients with respiratory failure with no other microbiological or clinical explanation than exclusive presence of Candida species in BAL fluid. Five cases could be identified with Candida as the likely cause of pneumonia.