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Contains fulltext : 287661.pdf (Publisher’s version ) (Closed access) BACKGROUND: Vilobelimab, an anti-C5a monoclonal antibody, was shown to be safe in a phase 2 trial of invasively mechanically ventilated patients with COVID-19. Here, we aimed to determine whether vilobelimab in addition to standard of care improves survival outcomes in this patient population. METHODS: This randomised, double-blind, placebo-controlled, multicentre phase 3 trial was performed at 46 hospitals in the Netherlands, Germany, France, Belgium, Russia, Brazil, Peru, Mexico, and South Africa. Participants aged 18 years or older who were receiving invasive mechanical ventilation, but not more than 48 h after intubation at time of first infusion, had a PaO(2)/FiO(2) ratio of 60-200 mm Hg, and a confirmed SARS-CoV-2 infection with any variant in the past 14 days were eligible for this study. Eligible patients were randomly assigned (1:1) to receive standard of care and vilobelimab at a dose of 800 mg intravenously for a maximum of six doses (days 1, 2, 4, 8, 15, and 22) or standard of care and a matching placebo using permuted block randomisation. Treatment was not continued after hospital discharge. Participants, caregivers, and assessors were masked to group assignment. The primary outcome was defined as all-cause mortality at 28 days in the full analysis set (defined as all randomly assigned participants regardless of whether a patient started treatment, excluding patients randomly assigned in error) and measured using Kaplan-Meier analysis. Safety analyses included all patients who had received at least one infusion of either vilobelimab or placebo. This study is registered with ClinicalTrials.gov, NCT04333420. FINDINGS: From Oct 1, 2020, to Oct 4, 2021, we included 368 patients in the ITT analysis (full analysis set; 177 in the vilobelimab group and 191 in the placebo group). One patient in the vilobelimab group was excluded from the primary analysis due to random assignment in error without treatment. At least one dose of study treatment was given to 364 (99%) patients (safety analysis set). 54 patients (31%) of 177 in the vilobelimab group and 77 patients (40%) of 191 in the placebo group died in the first 28 days. The all-cause mortality rate at 28 days was 32% (95% CI 25-39) in the vilobelimab group and 42% (35-49) in the placebo group (hazard ratio 0·73, 95% CI 0·50-1·06; p=0·094). In the predefined analysis without site-stratification, vilobelimab significantly reduced all-cause mortality at 28 days (HR 0·67, 95% CI 0·48-0·96; p=0·027). The most common TEAEs were acute kidney injury (35 [20%] of 175 in the vilobelimab group vs 40 [21%] of 189 in the placebo), pneumonia (38 [22%] vs 26 [14%]), and septic shock (24 [14%] vs 31 [16%]). Serious treatment-emergent adverse events were reported in 103 (59%) of 175 patients in the vilobelimab group versus 120 (63%) of 189 in the placebo group. INTERPRETATION: In addition to standard of care, vilobelimab improves survival of invasive mechanically ventilated patients with COVID-19 and leads to a significant decrease in mortality. Vilobelimab could be considered as an additional therapy for patients in this setting and further research is needed on the role of vilobelimab and C5a in other acute respiratory distress syndrome-causing viral infections. FUNDING: InflaRx and the German Federal Government.

Background The prediction of in-hospital mortality for ICU patients with COVID-19 is fundamental to treatment and resource allocation. The main purpose was to develop an easily implemented score for such prediction. Methods This was an observational, multicenter, development, and validation study on a national critical care dataset of COVID-19 patients. A systematic literature review was performed to determine variables possibly important for COVID-19 mortality prediction. Using a logistic multivariable model with a LASSO penalty, we developed the Rapid Evaluation of Coronavirus Illness Severity (RECOILS) score and compared its performance against published scores. Results Our development (validation) cohort consisted of 1480 (937) adult patients from 14 (11) Dutch ICUs admitted between March 2020 and April 2021. Median age was 65 (65) years, 31% (26%) died in hospital, 74% (72%) were males, average length of ICU stay was 7.83 (10.25) days and average length of hospital stay was 15.90 (19.92) days. Age, platelets, PaO2/FiO2 ratio, pH, blood urea nitrogen, temperature, PaCO2, Glasgow Coma Scale (GCS) score measured within +/−24 h of ICU admission were used to develop the score. The AUROC of RECOILS score was 0.75 (CI 0.71–0.78) which was higher than that of any previously reported predictive scores (0.68 [CI 0.64–0.71], 0.61 [CI 0.58–0.66], 0.67 [CI 0.63–0.70], 0.70 [CI 0.67–0.74] for ISARIC 4C Mortality Score, SOFA, SAPS-III, and age, respectively). Conclusions Using a large dataset from multiple Dutch ICUs, we developed a predictive score for mortality of COVID-19 patients admitted to ICU, which outperformed other predictive scores reported so far., Acta Anaesthesiologica Scandinavica, 66 (1), ISSN:0001-5172, ISSN:1399-6576

There is a need for reliable predictors in patients with moderate to severe traumatic brain injury to assist clinical decision making. We assess the ability of early continuous EEG monitoring at the intensive care unit (ICU) in patients with traumatic brain injury (TBI) to predict long term clinical outcome and evaluate its complementary value to current clinical standards. We performed continuous EEG measurements in patients with moderate to severe TBI during the first week of ICU admission. We assessed the Extended Glasgow Outcome Scale (GOSE) at 12 months, dichotomized into poor (GOSE 1–3) and good (GOSE 4–8) outcome. We extracted EEG spectral features, brain symmetry index, coherence, aperiodic exponent of the power spectrum, long range temporal correlations, and broken detailed balance. A random forest classifier using feature selection was trained to predict poor clinical outcome based on EEG features at 12, 24, 48, 72 and 96 h after trauma. We compared our predictor with the IMPACT score, the best available predictor, based on clinical, radiological and laboratory findings. In addition we created a combined model using EEG as well as the clinical, radiological and laboratory findings. We included hundred-seven patients. The best prediction model using EEG parameters was found at 72 h after trauma with an AUC of 0.82 (0.69–0.92), specificity of 0.83 (0.67–0.99) and sensitivity of 0.74 (0.63–0.93). The IMPACT score predicted poor outcome with an AUC of 0.81 (0.62–0.93), sensitivity of 0.86 (0.74–0.96) and specificity of 0.70 (0.43–0.83). A model using EEG and clinical, radiological and laboratory parameters resulted in a better prediction of poor outcome (p < 0.001) with an AUC of 0.89 (0.72–0.99), sensitivity of 0.83 (0.62–0.93) and specificity of 0.85 (0.75–1.00). EEG features have potential use for predicting clinical outcome and decision making in patients with moderate to severe TBI and provide complementary information to current clinical standards.

Background SARS-CoV-2 induces endothelial damage and activates the complement system. In severe COVID-19 patients, complement split factor C5a is highly elevated leading to inflammation that contributes to multiorgan failure. The anti-C5a monoclonal antibody, Vilobelimab (Vilo), which preserves the membrane attack complex (MAC), was investigated in an adaptively designed, randomized double-blind, placebo (P)-controlled Phase 3 international multicenter study for survival in critically ill COVID-19 patients (pts). Methods COVID-19 pneumonia pts (N=368; Vilo n=177, P n=191), mechanically ventilated within 48 hrs before treatment, received up to 6, 800 mg infusions of Vilo or P on top of standard of care. The primary and main secondary endpoints were 28-day (d) and 60-d all-cause mortality. Results Pts enrolled in the study were on corticosteroids (97%) and anti-coagulants (98%) as standard of care. A smaller proportion (20%) were either continuing or had taken immunomodulators such as tocilizumab and baricitinib prior to receiving Vilo. The 28-d all-cause mortality was 31.7% with Vilo vs 41.6% with P (Kaplan-Meier estimates; Cox regression site-stratified, HR 0.73; 95% CI:0.50-1.06; P=0.094), representing a 23.8% relative mortality reduction. In predefined primary outcome analysis without site stratification, however, Vilo significantly reduced mortality at 28 (HR 0.67; 95% CI:0.48-0.96; P=0.027) and 60 days (HR 0.67; 95% CI:0.48-0.92; P=0.016). Vilo also significantly reduced 28-d mortality in more severe pts with baseline WHO ordinal scale score of 7 (n=237, HR 0.62; 95% CI:0.40-0.95; P=0.028), severe ARDS/PaO2/FiO2 ≤ 100 mmHg (n=98, HR 0.55; 95% CI:0.30-0.98; P=0.044) and eGFR < 60 mL/min/1.73m2 (n=108, HR 0.55; 95% CI:0.31-0.96; P=0.036). Treatment-emergent AEs were 90.9% Vilo vs 91.0% P. Infections were comparable: Vilo 62.9%, P 59.3%. Infection incidence per 100 Pt days were equal. No meningococcal infections were reported. Serious AEs were 58.9% Vilo, 63.5% P. Conclusion Vilo significantly reduced mortality at 28 and 60 days in critically ill COVID-19 pts with no increase in infections suggesting the importance of targeting C5a while preserving MAC. Vilo targets inflammation which may represent an approach to treat sepsis and ARDS caused by other respiratory viruses. Disclosures Alexander Vlaar, MD, PhD, InflaRx GmbH: Advisor/Consultant Maria Habel, PhD, InflaRx GmbH: Stocks/Bonds Claus Thielert, PhD, InflaRx GmbH: Stocks/Bonds James Dickinson, MSc, InflaRx GmbH: Stocks/Bonds simon Rückinger, PhD, InflaRx GmbH: Advisor/Consultant Robert Zerbib, MSc, InflaRx GmbH: Stocks/Bonds Dorothee Neukirchen, PhD, InflaRx GmbH: Stocks/Bonds Korinna Pilz, MD, MSc, InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds Renfeng Guo, MD, InflaRx GmbH: Board Member|InflaRx GmbH: CSO|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds Diederik van de Beek, MD, PhD, InflaRx GmbH: Advisor/Consultant Niels Riedemann, MD, PhD, InflaRx GmbH: Board Member|InflaRx GmbH: CEO|InflaRx GmbH: Ownership Interest|InflaRx GmbH: Stocks/Bonds.

Funder: European Society of Intensive Care Medicine; doi: http://dx.doi.org/10.13039/501100013347, BACKGROUND: The COVID-19 pandemic presented major challenges for critical care facilities worldwide. Infections which develop alongside or subsequent to viral pneumonitis are a challenge under sporadic and pandemic conditions; however, data have suggested that patterns of these differ between COVID-19 and other viral pneumonitides. This secondary analysis aimed to explore patterns of co-infection and intensive care unit-acquired infections (ICU-AI) and the relationship to use of corticosteroids in a large, international cohort of critically ill COVID-19 patients. METHODS: This is a multicenter, international, observational study, including adult patients with PCR-confirmed COVID-19 diagnosis admitted to ICUs at the peak of wave one of COVID-19 (February 15th to May 15th, 2020). Data collected included investigator-assessed co-infection at ICU admission, infection acquired in ICU, infection with multi-drug resistant organisms (MDRO) and antibiotic use. Frequencies were compared by Pearson's Chi-squared and continuous variables by Mann-Whitney U test. Propensity score matching for variables associated with ICU-acquired infection was undertaken using R library MatchIT using the "full" matching method. RESULTS: Data were available from 4994 patients. Bacterial co-infection at admission was detected in 716 patients (14%), whilst 85% of patients received antibiotics at that stage. ICU-AI developed in 2715 (54%). The most common ICU-AI was bacterial pneumonia (44% of infections), whilst 9% of patients developed fungal pneumonia; 25% of infections involved MDRO. Patients developing infections in ICU had greater antimicrobial exposure than those without such infections. Incident density (ICU-AI per 1000 ICU days) was in considerable excess of reports from pre-pandemic surveillance. Corticosteroid use was heterogenous between ICUs. In univariate analysis, 58% of patients receiving corticosteroids and 43% of those not receiving steroids developed ICU-AI. Adjusting for potential confounders in the propensity-matched cohort, 71% of patients receiving corticosteroids developed ICU-AI vs 52% of those not receiving corticosteroids. Duration of corticosteroid therapy was also associated with development of ICU-AI and infection with an MDRO. CONCLUSIONS: In patients with severe COVID-19 in the first wave, co-infection at admission to ICU was relatively rare but antibiotic use was in substantial excess to that indication. ICU-AI were common and were significantly associated with use of corticosteroids. Trial registration ClinicalTrials.gov: NCT04836065 (retrospectively registered April 8th 2021)., European Society of Intensive Care Medicine ACM is supported by a Clinician Scientist Fellowship from the Medical Research Council (MR/V006118/1)

Background For mechanically ventilated critically ill COVID-19 patients, prone positioning has quickly become an important treatment strategy, however, prone positioning is labor intensive and comes with potential adverse effects. Therefore, identifying which critically ill intubated COVID-19 patients will benefit may help allocate labor resources. Methods From the multi-center Dutch Data Warehouse of COVID-19 ICU patients from 25 hospitals, we selected all 3619 episodes of prone positioning in 1142 invasively mechanically ventilated patients. We excluded episodes longer than 24 h. Berlin ARDS criteria were not formally documented. We used supervised machine learning algorithms Logistic Regression, Random Forest, Naive Bayes, K-Nearest Neighbors, Support Vector Machine and Extreme Gradient Boosting on readily available and clinically relevant features to predict success of prone positioning after 4 h (window of 1 to 7 h) based on various possible outcomes. These outcomes were defined as improvements of at least 10% in PaO2/FiO2 ratio, ventilatory ratio, respiratory system compliance, or mechanical power. Separate models were created for each of these outcomes. Re-supination within 4 h after pronation was labeled as failure. We also developed models using a 20 mmHg improvement cut-off for PaO2/FiO2 ratio and using a combined outcome parameter. For all models, we evaluated feature importance expressed as contribution to predictive performance based on their relative ranking. Results The median duration of prone episodes was 17 h (11–20, median and IQR, N = 2632). Despite extensive modeling using a plethora of machine learning techniques and a large number of potentially clinically relevant features, discrimination between responders and non-responders remained poor with an area under the receiver operator characteristic curve of 0.62 for PaO2/FiO2 ratio using Logistic Regression, Random Forest and XGBoost. Feature importance was inconsistent between models for different outcomes. Notably, not even being a previous responder to prone positioning, or PEEP-levels before prone positioning, provided any meaningful contribution to predicting a successful next proning episode. Conclusions In mechanically ventilated COVID-19 patients, predicting the success of prone positioning using clinically relevant and readily available parameters from electronic health records is currently not feasible. Given the current evidence base, a liberal approach to proning in all patients with severe COVID-19 ARDS is therefore justified and in particular regardless of previous results of proning.

What is known and objective The safety and efficacy of different antifungal agents in the prophylaxis of invasive fungal infection in patients with haematological disorders are known. We comment on the poor bioavailability of posaconazole suspension to suggest that it is not useful in critically ill COVID patients. Comment The increased mortality and high incidence of COVID-associated pulmonary aspergillosis (CAPA) might justify administration of off-label posaconazole for preventing CAPA, being the only drug officially registered for prophylaxis of fungal infections. We decided to initiate off-label posaconazole prophylaxis in COVID-19 patients, who were mechanically ventilated and exposed to high-dose steroids for progressive pulmonary disease or ARDS. We found that posaconazole suspension was inadequate. Very low trough levels were observed after administration, and the dose adjustments necessary for the therapeutic drug monitoring (TDM) of the drug in our critically ill ICU patients were not useful. What is new and conclusion Posaconazole suspension should not be used to prevent CAPA in COVID-19 patients on high-dose steroid therapy.

Background The decision to attempt or refrain from resuscitation is preferably based on prognostic factors for outcome and subsequently communicated with patients. Both patients and physicians consider good communication important, however little is known about patient involvement in and understanding of cardiopulmonary resuscitation (CPR) directives. Aim To determine the prevalence of Do Not Resuscitate (DNR)-orders, to describe recollection of CPR-directive conversations and factors associated with patient recollection and understanding. Methods This was a two-week nationwide multicentre cross-sectional observational study using a study-specific survey. The study population consisted of patients admitted to non-monitored wards in 13 hospitals. Data were collected from the electronic medical record (EMR) concerning CPR-directive, comorbidity and at-home medication. Patients reported their perception and expectations about CPR-counselling through a questionnaire. Results A total of 1136 patients completed the questionnaire. Patients’ CPR-directives were documented in the EMR as follows: 63.7% full code, 27.5% DNR and in 8.8% no directive was documented. DNR was most often documented for patients >80 years (66.4%) and in patients using >10 medications (45.3%). Overall, 55.8% of patients recalled having had a conversation about their CPR-directive and 48.1% patients reported the same CPR-directive as the EMR. Most patients had a good experience with the CPR-directive conversation in general (66.1%), as well as its timing (84%) and location (94%) specifically. Conclusions The average DNR-prevalence is 27.5%. Correct understanding of their CPR-directive is lowest in patients aged ≥80 years and multimorbid patients. CPR-directive counselling should focus more on patient involvement and their correct understanding.

Background: Identification of distinct clinical phenotypes in critically ill COVID-19 patients could improve understanding of the disease heterogeneity and enable prognostic and predictive enrichment facilitating more personalized treatment. However, previous attempts did not take into account temporal dynamics of the disease. By including the dimension of time, we aim to gain further insights into the heterogeneity of COVID-19.Methods: We used highly granular data from 3202 adult critically ill COVID patients in the multicenter Dutch Data Warehouse that were admitted to one of 25 Dutch ICUs between February 2020 and March 2021. Parameters including demographics, clinical observations, medications, laboratory values, vital signs, and data from life support devices were selected based on relevance and availability. Twenty-one consecutive datasets were created that each covered 24 hours of ICU data for each day of ICU treatment up until day 21. After aggregation and multiple imputation of the temporal data, clinical phenotypes in each dataset were identified by performing multiple cluster analyses. Clinical phenotypes were identified by aggregating values from all patients per cluster. Both evolution of the clinical phenotypes over time and patient allocation to these clusters over time were tracked.Results: The final patient cohort consisted of 2438 critically ill COVID-19 patients with a registered ICU mortality outcome. Forty-one parameters were chosen for the cluster analysis. On admission, both a mild and a more severe clinical phenotype were found. After day 4, the severe phenotype split into an intermediate and a severe phenotype for 11 consecutive days. Heterogeneity between phenotypes appears to be strongly driven by inflammation and dead space ventilation. During the 21-day period only 8.2% and 4.6% of patients in the initial mild and severe clusters remained assigned to the same phenotype respectively. The clinical phenotype half-life was between 5 and 6 days for the mild and severe phenotypes, and about 3 days for the medium severe phenotype.Conclusions: Patients typically do not remain in the same cluster throughout intensive care treatment. This may have important implications for prognostic or predictive enrichment. Prominent dissimilarities between clinical phenotypes are predominantly driven by inflammation and dead space ventilation.

Introduction Determining the optimal timing for extubation can be challenging in the intensive care. In this study, we aim to identify predictors for extubation failure in critically ill patients with COVID-19. Methods We used highly granular data from 3464 adult critically ill COVID patients in the multicenter Dutch Data Warehouse, including demographics, clinical observations, medications, fluid balance, laboratory values, vital signs, and data from life support devices. All intubated patients with at least one extubation attempt were eligible for analysis. Transferred patients, patients admitted for less than 24 h, and patients still admitted at the time of data extraction were excluded. Potential predictors were selected by a team of intensive care physicians. The primary and secondary outcomes were extubation without reintubation or death within the next 7 days and within 48 h, respectively. We trained and validated multiple machine learning algorithms using fivefold nested cross-validation. Predictor importance was estimated using Shapley additive explanations, while cutoff values for the relative probability of failed extubation were estimated through partial dependence plots. Results A total of 883 patients were included in the model derivation. The reintubation rate was 13.4% within 48 h and 18.9% at day 7, with a mortality rate of 0.6% and 1.0% respectively. The grandient-boost model performed best (area under the curve of 0.70) and was used to calculate predictor importance. Ventilatory characteristics and settings were the most important predictors. More specifically, a controlled mode duration longer than 4 days, a last fraction of inspired oxygen higher than 35%, a mean tidal volume per kg ideal body weight above 8 ml/kg in the day before extubation, and a shorter duration in assisted mode ( Conclusion The most important predictors for extubation failure in critically ill COVID-19 patients include ventilatory settings, inflammatory parameters, neurological status, and body mass index. These predictors should therefore be routinely captured in electronic health records.

Background The Coronavirus disease 2019 (COVID-19) pandemic has underlined the urgent need for reliable, multicenter, and full-admission intensive care data to advance our understanding of the course of the disease and investigate potential treatment strategies. In this study, we present the Dutch Data Warehouse (DDW), the first multicenter electronic health record (EHR) database with full-admission data from critically ill COVID-19 patients. Methods A nation-wide data sharing collaboration was launched at the beginning of the pandemic in March 2020. All hospitals in the Netherlands were asked to participate and share pseudonymized EHR data from adult critically ill COVID-19 patients. Data included patient demographics, clinical observations, administered medication, laboratory determinations, and data from vital sign monitors and life support devices. Data sharing agreements were signed with participating hospitals before any data transfers took place. Data were extracted from the local EHRs with prespecified queries and combined into a staging dataset through an extract–transform–load (ETL) pipeline. In the consecutive processing pipeline, data were mapped to a common concept vocabulary and enriched with derived concepts. Data validation was a continuous process throughout the project. All participating hospitals have access to the DDW. Within legal and ethical boundaries, data are available to clinicians and researchers. Results Out of the 81 intensive care units in the Netherlands, 66 participated in the collaboration, 47 have signed the data sharing agreement, and 35 have shared their data. Data from 25 hospitals have passed through the ETL and processing pipeline. Currently, 3464 patients are included in the DDW, both from wave 1 and wave 2 in the Netherlands. More than 200 million clinical data points are available. Overall ICU mortality was 24.4%. Respiratory and hemodynamic parameters were most frequently measured throughout a patient's stay. For each patient, all administered medication and their daily fluid balance were available. Missing data are reported for each descriptive. Conclusions In this study, we show that EHR data from critically ill COVID-19 patients may be lawfully collected and can be combined into a data warehouse. These initiatives are indispensable to advance medical data science in the field of intensive care medicine.

Supplemental Digital Content is available in the text., OBJECTIVES: As coronavirus disease 2019 is a novel disease, treatment strategies continue to be debated. This provides the intensive care community with a unique opportunity as the population of coronavirus disease 2019 patients requiring invasive mechanical ventilation is relatively homogeneous compared with other ICU populations. We hypothesize that the novelty of coronavirus disease 2019 and the uncertainty over its similarity with noncoronavirus disease 2019 acute respiratory distress syndrome resulted in substantial practice variation between hospitals during the first and second waves of coronavirus disease 2019 patients. DESIGN: Multicenter retrospective cohort study. SETTING: Twenty-five hospitals in the Netherlands from February 2020 to July 2020, and 14 hospitals from August 2020 to December 2020. PATIENTS: One thousand two hundred ninety-four critically ill intubated adult ICU patients with coronavirus disease 2019 were selected from the Dutch Data Warehouse. Patients intubated for less than 24 hours, transferred patients, and patients still admitted at the time of data extraction were excluded. MEASUREMENTS AND MAIN RESULTS: We aimed to estimate between-ICU practice variation in selected ventilation parameters (positive end-expiratory pressure, Fio2, set respiratory rate, tidal volume, minute volume, and percentage of time spent in a prone position) on days 1, 2, 3, and 7 of intubation, adjusted for patient characteristics as well as severity of illness based on Pao2/Fio2 ratio, pH, ventilatory ratio, and dynamic respiratory system compliance during controlled ventilation. Using multilevel linear mixed-effects modeling, we found significant (p ≤ 0.001) variation between ICUs in all ventilation parameters on days 1, 2, 3, and 7 of intubation for both waves. CONCLUSIONS: This is the first study to clearly demonstrate significant practice variation between ICUs related to mechanical ventilation parameters that are under direct control by intensivists. Their effect on clinical outcomes for both coronavirus disease 2019 and other critically ill mechanically ventilated patients could have widespread implications for the practice of intensive care medicine and should be investigated further by causal inference models and clinical trials.

Background Sepsis is one of the most frequent reasons for acute intensive care unit (ICU) admission of very old patients and mortality rates are high. However, the impact of pre-existing physical and cognitive function on long-term outcome of ICU patients ≥ 80 years old (very old intensive care patients (VIPs)) with sepsis is unclear. Objective To investigate both the short- and long-term mortality of VIPs admitted with sepsis and assess the relation of mortality with pre-existing physical and cognitive function. Design Prospective cohort study. Setting 241 ICUs from 22 European countries in a six-month period between May 2018 and May 2019. Subjects Acutely admitted ICU patients aged ≥80 years with sequential organ failure assessment (SOFA) score ≥ 2. Methods Sepsis was defined according to the sepsis 3.0 criteria. Patients with sepsis as an admission diagnosis were compared with other acutely admitted patients. In addition to patients’ characteristics, disease severity, information about comorbidity and polypharmacy and pre-existing physical and cognitive function were collected. Results Out of 3,596 acutely admitted VIPs with SOFA score ≥ 2, a group of 532 patients with sepsis were compared to other admissions. Predictors for 6-month mortality were age (per 5 years): Hazard ratio (HR, 1.16 (95% confidence interval (CI), 1.09–1.25, P 4): HR, 1.34 (95% CI, 1.18–1.51, P Conclusions There is substantial long-term mortality in VIPs admitted with sepsis. Frailty, age and disease severity were identified as predictors of long-term mortality in VIPs admitted with sepsis.

The decision to attempt or refrain from resuscitation is preferably based on prognostic factors for outcome and subsequently communicated with patients. Both patients and physicians consider good communication important, however little is known about patient involvement in and understanding of cardiopulmonary resuscitation (CPR) directives.To determine the prevalence of Do Not Resuscitate (DNR)-orders, to describe recollection of CPR-directive conversations and factors associated with patient recollection and understanding.This was a two-week nationwide multicentre cross-sectional observational study using a study-specific survey. The study population consisted of patients admitted to non-monitored wards in 13 hospitals. Data were collected from the electronic medical record (EMR) concerning CPR-directive, comorbidity and at-home medication. Patients reported their perception and expectations about CPR-counselling through a questionnaire.A total of 1136 patients completed the questionnaire. Patients' CPR-directives were documented in the EMR as follows: 63.7% full code, 27.5% DNR and in 8.8% no directive was documented. DNR was most often documented for patients80 years (66.4%) and in patients using10 medications (45.3%). Overall, 55.8% of patients recalled having had a conversation about their CPR-directive and 48.1% patients reported the same CPR-directive as the EMR. Most patients had a good experience with the CPR-directive conversation in general (66.1%), as well as its timing (84%) and location (94%) specifically.The average DNR-prevalence is 27.5%. Correct understanding of their CPR-directive is lowest in patients aged ≥80 years and multimorbid patients. CPR-directive counselling should focus more on patient involvement and their correct understanding.

Summary Objective Acute respiratory distress syndrome (ARDS) frequently complicates critical illness. We hypothesized that an infusion of recombinant human activated protein C (rh-APC), a natural anticoagulant, would attenuate pulmonary coagulopathy and injury. Methods In this sub study of a multicenter open-label randomized controlled trial of patients with ARDS, we compared an intravenous (i.v.) infusion of rh-APC (24 mcg kg−1 h−1 for 96 h) with placebo. Patients with sepsis or septic shock were excluded. Results In 27 patients serial non-directed bronchoalveolar lavage fluid (NBLF) samples were obtained: 16 patients were treated with rh-APC and 11 patients with placebo. The rh-APC infusion was associated with higher APC levels in plasma during the infusion period of 4 days (P = 0.001), as well as higher APC levels in NBLF up to day 5 after the start of the infusion (P = 0.028). An infusion of rh-APC was associated with lower levels of thrombin–antithrombin complexes (P = 0.009) and soluble tissue factor (P = 0.011) in NBLF, compared with treatment with placebo. An infusion of rh-APC affected fibrinolysis, as plasminogen activator activity levels in NBLF were higher in the patients treated with rh-APC (P = 0.01), presumably as a result of lower NBLF levels of plasminogen activator inhibitor 1, (P = 0.01). The rh-APC infusion decreased the lung injury score (P = 0.005) and simplified the acute physiology score (P = 0.013) on day 5, when compared with baseline. The rh-APC infusion was not associated with bleeding complications. Conclusion An infusion of rh-APC in patients with ARDS attenuates pulmonary coagulopathy and injury.

To evaluate the effect of hemodynamic management guided by upper limits of cardiac filling volumes or pressures on durations of mechanical ventilation and lengths of stay in critically ill patients with shock.Prospective, randomized, clinical trial.Mixed intensive care unit of a large teaching hospital and mixed intensive care unit of a tertiary care, academic medical center.A total 120 septic (n = 72) and nonseptic (n = 48) shock patients, randomized (after stratification) to transpulmonary thermodilution (n = 60) or pulmonary artery catheter (n = 60) between February 2007 and July 2009.Hemodynamic management was guided by algorithms including upper limits for fluid resuscitation of extravascular lung water (10 mL/kg) and global end-diastolic volume index (850 mL/m) in the transpulmonary thermodilution group and pulmonary artery occlusion pressure (18-20 mm Hg) in the pulmonary artery catheter group for 72 hrs after enrollment.Primary outcomes were ventilator-free days and lengths of stay in the intensive care unit and the hospital. Secondary outcomes included organ failures and mortality. Cardiac comorbidity was more frequent in nonseptic than in septic shock. Ventilator-free days, lengths of stay, organ failures, and 28-day mortality (overall 33.3%) were similar between monitoring groups. Transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with more days on mechanical ventilation and longer intensive care unit and hospital lengths of stay in nonseptic (p = .001) but not in septic shock. In both conditions, fewer patients met the upper limit of volume than of pressure criteria at baseline and transpulmonary thermodilution (vs. pulmonary artery catheter) monitoring was associated with a more positive fluid balance at 24 hrs.Hemodynamic management guided by transpulmonary thermodilution vs. pulmonary artery catheter in shock did not affect ventilator-free days, lengths of stay, organ failures, and mortality of critically ill patients. Use of the a transpulmonary thermodilution algorithm resulted in more days on mechanical ventilation and intensive care unit length of stay compared with the pulmonary artery catheter algorithm in nonseptic shock but not in septic shock. This may relate to cardiac comorbidity and a more positive fluid balance with use of transpulmonary thermodilution in nonseptic shock.

BACKGROUND: There is an association between blood transfusion and pulmonary complications in cardiac surgery. Mediators of increased pulmonary vascular leakage after transfusion are unknown. We hypothesized that factors may include antibodies or bioactive lipids, which have been implicated in transfusion-related acute lung injury. STUDY DESIGN AND METHODS: We performed a prospective cohort study in two university hospital intensive care units in the Netherlands. Pulmonary vascular permeability was measured in cardiac surgery patients after receiving no, restrictive (one or two transfusions), or multiple (five or more transfusions) transfusions (n = 20 per group). The pulmonary leak index (PLI), using Ga-67-labeled transferrin, was determined within 3 hours postoperatively. Blood products were screened for bioactive lipid accumulation and the presence of antibodies. RESULTS: The PLI was elevated in all groups after cardiac surgery. Transfused patients had a higher PLI compared to nontransfused patients (33 x 10(-3) +/- 20 x 10(-3) vs. 23 x 10(-3) +/- 11 x 10(-3)/min, p

Disturbed alveolar fibrin turnover is a characteristic feature of pneumonia. Inhibitors of coagulation could exert lung-protective effects via anticoagulant (inhibiting fibrin deposition) and possibly anti-inflammatory pathways, but could also affect host defense. In this randomized controlled in vivo laboratory study, rats were challenged intratracheally with Pseudomonas aeruginosa, inducing pneumonia, and randomized to local treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin, or danaparoid. Induction of P. aeruginosa pneumonia resulted in activation of pulmonary coagulation and inhibition of pulmonary fibrinolysis, as reflected by increased pulmonary levels of thrombin-AT complexes and fibrin degradation products and decreased pulmonary levels plasminogen activator activity. Pseudomonas aeruginosa pneumonia was accompanied by systemic coagulopathy, since systemic levels of thrombin-AT complexes increased, and systemic levels of plasminogen activator activity decreased. Although rh-APC and plasma-derived AT potently limited pulmonary coagulopathy, neither heparin nor danaparoid affected net pulmonary fibrin turnover. Recombinant human APC also displayed systemic anticoagulant effects. Neither bacterial clearance nor pulmonary inflammation was affected by anticoagulant therapy. Nebulization of rh-APC or plasma-derived AT attenuated pulmonary coagulopathy, but not bacterial clearance or inflammation, in a rat model of P. aeruginosa pneumonia.

BACKGROUND: Pulmonary coagulopathy may contribute to an adverse outcome in lung injury. We assessed the effects of local anticoagulant therapy on bronchoalveolar and systemic haemostasis in a rat model of endotoxemia-induced lung injury.METHODS: Male Sprague-Dawley rats were intravenously challenged with lipopolysaccharide (LPS) and treated with nebulized normal saline (placebo), recombinant human-activated protein C (APC), plasma-derived antithrombin (AT), heparin, or danaparoid.RESULTS: Intravenous administration of LPS resulted in lung injury associated with elevated bronchoalveolar levels of thrombin-antithrombin complex (TATc), 6.9 +/- 0.8 ng/mL (placebo) versus 0.5 +/- 0.2 ng/mL (healthy control) (p < 0.01), and elevated bronchoalveolar levels of fibrin degradation products (FDP), 555 +/- 74 ng/mL versus 27 +/- 12 ng/mL (p < 0.01). Nebulized APC, AT, and danaparoid all significantly limited the rise of bronchoalveolar levels of TATc, 2.4 +/- 0.7 ng/mL), 1.5 +/- 0.2, 3.8 +/- 0.7, and 3.2 +/- 0.9 ng/mL, respectively (all p < 0.01 vs. placebo), and fibrin degradation products, 243 +/- 77, 113 +/- 20, 317 +/- 74, and 300 +/- 42 ng/mL (all p < 0.01 vs. placebo). Heparin and danaparoid also significantly affected systemic coagulopathy. However, pulmonary inflammatory responses [neutrophil influx into the lungs, bronchoalveolar levels of myeloperoxidase, and bronchoalveolar levels of tumor necrosis factor (TNF), interleukin (IL)-6 and CINC-3], and histopathology of lungs were not affected by nebulization of anticoagulants.CONCLUSIONS: In conclusion, local treatment with APC, AT, heparin, or danaparoid attenuate pulmonary coagulopathy, but not inflammation, in rats with endotoxemia-induced lung injury.

OBJECTIVE: Pulmonary hypertension is a characteristic feature of acute respiratory distress syndrome (ARDS) and contributes to mortality. Administration of sildenafil in ambulatory patients with pulmonary hypertension improves oxygenation and ameliorates pulmonary hypertension. Our aim was to determine whether sildenafil is beneficial for patients with ARDS. DESIGN: Prospective, open-label, multicenter, interventional cohort study. SETTING: Medical-surgical ICU of two university hospitals. PATIENTS: Ten consecutive patients meeting the NAECC criteria for ARDS. INTERVENTIONS: A single dose of 50 mg sildenafil citrate administered via a nasogastric tube. MAIN RESULTS: Administration of sildenafil in patients with ARDS decreased mean pulmonary arterial pressure from 25 to 22 mmHg (P = 0.022) and pulmonary artery occlusion pressure from 16 to 13 mmHg (P = 0.049). Systemic mean arterial pressures were markedly decreased from 81 to 75 mmHg (P = 0.005). Sildenafil did not improve pulmonary arterial oxygen tension, but resulted in a further increase in the shunt fraction. CONCLUSION: Although sildenafil reduced pulmonary arterial pressures during ARDS, the increased shunt fraction and decreased arterial oxygenation render it unsuitable for the treatment of patients with ARDS

SummaryThe crosstalk between coagulation and inflammation and the propensity for microthromboembolic disease during sepsis calls for anticoagulant measures to prevent tissue hypoxygenation and to attenuate organ damage and dysfunction. Only one anticoagulant, recombinant human activated protein C (aPC, drotrecogin-α) has a proven survival benefit when used as an adjunctive therapy for human sepsis, partly because of its anti-inflammatory effect. However, heparin (-like compounds) may exert similar beneficial anti-inflammatory actions as aPC, in spite of the relatively narrow therapeutic window for anticoagulation. This narrative review is based on a Medline search of relevant basic and clinical studies published in English and discusses the potential role of heparin in modulating inflammatory responses in the treatment of animal models and human sepsis and its harmful sequelae. In any case, the results of a metaanalysis based on animal data suggest a potentially life-saving effect of heparin (-like compounds) in the treatment of sepsis.Therefore, a prospective randomized clinical trial is called upon to study effects in human sepsis.

In medical emergencies, supplemental oxygen is often administrated routinely. Most paramedics and physicians believe that high concentrations of oxygen are life-saving 1. Over the last century, however, a plethora of studies point to possible detrimental effects of hyperoxia induced by supplemental oxygen in a variety of medical emergencies. This viewpoint provides a historical overview and questions the safety of routine high-dose oxygen administration and is based on pathophysiology and (pre)clinical findings in various medical emergencies.

Background Cardiac surgery is frequently complicated by an acute vascular lung injury and this may be mediated, at least in part, by the (soluble) receptor for advanced glycation end products (sRAGE). Methods In two university hospital intensive care units, circulating sRAGE was measured together with the 68Gallium-transferrin pulmonary leak index (PLI), a measure of pulmonary vascular permeabiliy, in 60 consecutive cardiac surgery patients stratified by the amount of blood transfusion, within 3 hours of admission to the intensive care. Results Cardiac surgery resulted in elevated plasma sRAGE levels compared to baseline (315 ± 181 vs 110 ± 55 pg/ml, P = 0.001). In 37 patients the PLI was elevated 50% above normal. The PLI correlated with sRAGE (r2 = 0.11, P = 0.018). Plasma sRAGE discriminated well between those with an elevated PLI and those with a normal PLI (area under the operator curve 0.75; P = 0.035; 95% CI 0.55-0.95), with 91% sensitivity but low specificity of 36% at a cutoff value of 200 pg/mL. Blood transfusion did not influence sRAGE levels. Conclusions sRAGE is elevated in plasma after cardiac surgery and indicates increased pulmonary vascular permeability. The level of sRAGE is not affected by transfusion.

To the Editor: We read with great interest the article by Kilgannon and coworkers1 demonstrating a dose-dependent linear relationship between supranormal oxygen tension after resuscitation from cardiac arrest and in-hospital death. This observation is important and merits further …

Introduction: Blood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but cause-and-effect relations remain unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulation occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI). Methods: We performed a case control study in a mixed medical-surgical intensive care unit of a university hospital in the Netherlands. Cardiac surgery patients (n = 45) were grouped as follows: those who received no transfusion, those who received a restrictive transfusion (one two units of blood) or those who received multiple transfusions (at least five units of blood). Nondirected bronchoalveolar lavage fluid (BALF) and blood were obtained within 3 hours postoperatively. Normal distributed data were analyzed using analysis of variance and Dunnett’s post hoc test. Nonparametric data were analyzed using the Kruskal-Wallis and Mann-Whitney U tests. Results: Restrictive transfusion increased BALF levels of interleukin (IL)-1b and D-dimer compared to nontransfused controls (P < 0.05 for all), and IL-1b levels were further enhanced by multiple transfusions (P

Presenting symptoms include cervical masses (76%), nasal dysfunction (73%), tinnitus and deafness (62%), headache (35%), and weight loss (7%). 4 On physical examination, cervical masses (75%) and cerebral nerve palsy (20%) are often found. 4

A 49-year-old woman with a history of adult-onset Still's disease (AOSD) presented with fever, general malaise and a rash. Laboratory blood testing revealed an extremely high level of serum ferritin, essentially restricting the differential diagnosis to either haemophagocytic syndrome as a complication of AOSD, or a flare-up of the latter. Haemophagocytosis as a complication of AOSD was diagnosed in our patient. After treatment with prednisone, she fully recovered and the serum ferritin returned to a normal level. Haemophagocytic syndrome is a rare but potentially life-threatening complication of lymphoproliferative and autoimmune diseases, as well as of viral infections. It is characterised by high fever, hepatosplenomegaly, cytopenia and extremely high levels of serum ferritin. Activation of macrophages and histiocytes induces phagocytosis of erythrocytes in the bone marrow and other parts of the reticuloendothelial system. The fact that haemophagocytic syndrome and AOSD are often described together, and coincide with extremely elevated serum ferritin levels characteristic to both entities, suggests a related pathogenesis.

The aim of the study is to evaluate the effects of red blood cell (RBC) transfusions on pulmonary parameters in critically ill, non-bleeding patients. Retrospective chart analysis was performed on critically ill patients without overt bleeding in the intensive care unit (ICU) of a university hospital. In 83 patients in a 5-month period, who had received at least 1 RBC unit and stayed at least 24 h in the ICU, 199 transfusions of median 2 RBCs per transfusion (n = 504) were studied. Pulmonary parameters were retrieved during the period between 24 h before the start of transfusion and 24-48 h after transfusion. Outcome was assessed. The P(a)O(2)/F(I)O(2) dose-dependently decreased from 250 +/- 105 at baseline to 240 +/- 102 mmHg at 24 h after RBC transfusion (P = 0.003), irrespective of acute lung injury at baseline and RBC storage time. The lung injury score (LIS) also increased dose-dependently, whereas, at 48 h, oxygenation and LIS largely returned to baseline. For every seven RBCs transfused, the LIS transiently increased by 1 unit. There were no changes in haemodynamics, lung mechanics or chest radiography. The total number of RBCs given in the ICU did not directly contribute to ICU and 1-year mortality prediction. Transfusion of RBCs decreases oxygenation thereby increasing the LIS, dose-dependently and transiently, in a heterogeneous population of critically ill, non-bleeding patients, independent of prior cardiorespiratory status and RBC storage time. The effects are subtle, may go unseen and unreported and may represent subclinical transfusion-related acute lung injury. They do not adversely affect outcome, even at 1-year follow-up.

Background: Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) frequently necessitate mechanical ventilation in the intensive care unit. The syndromes have a high mortality rate and there is at present no treatment specifically directed at the underlying pathogenesis. Central in the pathophysiology of ALI/ARDS is alveolocapillary inflammation leading to permeability edema. As a result of the crosstalk between inflammation and coagulation, activation of proinflammatory and procoagulant/antifibrinolytic pathways contributes to disruption of the endothelial barrier. Protein C (PC) plays a central role in maintaining the equilibrium between coagulation and inflammation. Additionally, natural anticoagulants, such as PC, are depleted, both in blood as well as in the lung. Therefore, the PC system is of interest as a therapeutic target in patients with ALI/ARDS. Method: This review is based on a Medline search of relevant basic and clinical studies. Objective: It discusses the potential role of activated PC in modulating the proinflammatory/procoagulant state for enhancing endothelial barrier function in animal models and human ALI/ARDS

Objectives To study risk factors, including the level of cross-clamping and ischemia/reperfusion, for lung vascular injury after aortic surgery. Design Single-center prospective observational study. Patients and Methods Twenty-seven consecutive and mechanically ventilated patients were included within 3 h after elective aortic surgery, i.e., surgery on the thoracoabdominal aorta supported by left atrial to femoral bypass (n = 3), surgery on the suprarenal aorta (n = 5), surgery on the infrarenal aorta (n = 15), and reconstructions of the celiac and mesenteric arteries (n = 4). The 67Gallium (Ga)-transferrin pulmonary leak index (PLI) served as a measure of lung vascular injury. Results The PLI was elevated (≥14.1 × 10−3/min) in 74% of all patients and more so in patients undergoing suprarenal aortic surgery or reconstruction of celiac and mesenteric arteries than in the patients undergoing the other types of surgery (P = 0.006). Clamping of the celiac and/or mesenteric arteries during surgery (n = 6) resulted in an almost 4 times higher PLI compared with not clamping these arteries (P = 0.001). In general linear models, the elevated PLI was particularly associated with suprarenal and celiac/mesenteric artery surgery, independently of aortic camping time and transfusion of blood products, even though the PLI directly correlated with aortic clamping time and number of red blood cell concentrates transfused (P = 0.031 or less). Conclusions This study suggests that hepatosplanchnic rather than lower body/leg ischemia/reperfusion is a major risk factor for pulmonary vascular injury, associated with aortic surgery and independent of clamping time and transfusion of blood products.

Early stent occlusion after myocardial infarction is associated with increased morbidity and mortality, and antiplatelet drugs are applied to prevent these complications. We report on 3 patients with gastrointestinal bleeding or who were scheduled for emergency surgery and who received donor platelet transfusion early in the course after stenting. These patients had symptomatic coronary artery stenoses and were treated with antiplatelet therapy. Stent occlusion was diagnosed 6 to 17 hours after donor platelet transfusion, suggested by electrocardiographic and, in 1 patient, angiographic findings. One patient died of intractable bleeding from the gastrointestinal tract. Our observations emphasize the risks involved in platelet transfusion, and support withholding such therapy, unless vitally indicated, in patients who have undergone recent bare-metal coronary artery stent implantation.

The crosstalk between coagulation and inflammation and the propensity for microthromboembolic disease during sepsis calls for anticoagulant measures to prevent tissue hypoxygenation and to attenuate organ damage and dysfunction. Only one anticoagulant, recombinant human activated protein C (aPC, drotrecogin-alpha) has a proven survival benefit when used as an adjunctive therapy for human sepsis, partly because of its anti-inflammatory effect. However, heparin (-like compounds) may exert similar beneficial anti-inflammatory actions as aPC, in spite of the relatively narrow therapeutic window for anticoagulation. This narrative review is based on a Medline search of relevant basic and clinical studies published in English and discusses the potential role of heparin in modulating inflammatory responses in the treatment of animal models and human sepsis and its harmful sequelae. In any case, the results of a meta-analysis based on animal data suggest a potentially life-saving effect of heparin (-like compounds) in the treatment of sepsis. Therefore, a prospective randomized clinical trial is called upon to study effects in human sepsis.

Objectives Poor survival of patients with a haematological malignancy admitted to the intensive care unit (ICU) prompts for proper admission triage and prediction of ICU treatment failure and long-term mortality. We therefore tried to find predictors of the latter outcomes. Methods A retrospective analysis of charts and a prospective follow-up study were done, of haemato-oncological patients, admitted to our ICU in a 7-year period with a follow-up until 2 yr thereafter. Clinical parameters during the first four consecutive days were taken to calculate the simplified acute physiology (SAPS II) and the sequential organ failure assessment (SOFA) scores, of proven predictive value in general ICU populations. Results From a total of 58 patients (n = 47 with acute myelogenous leukaemia or non-Hodgkin lymphoma), admitted into ICU mostly because of respiratory insufficiency, sepsis, shock or combinations, 36 patients had died during their stay in the ICU. Of ICU survivors (n = 22), 20 patients died during follow-up so that the 1-year survival rate was only 12%. The SAPS II and particularly the SOFA scores were of high predictive value for ICU and long-term mortality. Conclusions Patients with life-threatening complications of haematological malignancy admitted to ICU ran a high risk for death in the ICU and on the long-term, and the risk can be well predicted by SOFA. The latter may help us to decide on intensive care in individual cases, in order to avoid potentially futile care for patients with a SOFA score of 15 or higher.

Blood transfusion is associated with increased morbidity and mortality in cardiac surgery patients, but the cause and effect relation remains unknown. We hypothesized that blood transfusion is associated with changes in pulmonary and systemic inflammation and coagulopathy, occurring in patients who do not meet the clinical diagnosis of transfusion-related acute lung injury (TRALI).

Introduction Disturbed alveolar fibrin turnover is a cardinal feature of severe pneumonia. Clinical studies suggest that natural inhibitors of coagulation exert lung-protective effects via anticoagulant and possibly also anti-inflammatory pathways. Intravenous infusion of the natural anticoagulants increases the risk of bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized anticoagulants on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia. Methods In this randomized controlled in vivo laboratory study rats were challenged intratracheally with S. pneumoniae, inducing pneumonia, and randomized to treatment with normal saline (placebo), recombinant human activated protein C (rh-APC), plasma-derived antithrombin (AT), heparin or danaparoid, by means of nebulization. Results S. pneumoniae infection increased pulmonary levels of thrombin-antithrombin complexes and fibrin degradation products. All nebulized anticoagulants significantly limited pulmonary coagulopathy. None of the agents except danaparoid resulted in changes in systemic coagulopathy. Treatment with plasma-derived AT reduced outgrowth of S. pneumoniae and histopathologic damage in lungs. In vitro experiments confirmed outgrowth was reduced in bronchoalveolar lavage fluid (BALF) from rats treated with plasma-derived AT compared with placebo. Neutralizing of cationic components in BALF diminished the inhibitory effects on bacterial outgrowth of BALF, suggesting a role for cationic antimicrobial proteins. Conclusions Nebulization of anticoagulants attenuates pulmonary coagulopathy during S. pneumoniae pneumonia in rats while only danaparoid affects systemic coagulation. Nebulized plasma-derived AT reduces bacterial outgrowth and exerts significant lung-protective effects.

RATIONALE: Alveolar fibrin deposition is intrinsic to pneumonia and acute lung injury. Activation of coagulation during pulmonary inflammation is primarily mediated by the tissue factor–factor VIIa pathway. Tissue factor levels in the lungs increase during pulmonary inflammation due to disruption of endothelial–epithelial barrier and expression of tissue factor on alveolar macrophages. Intravenous infusion of the natural anticoagulants activated protein C (APC) or antithrombin (AT) has been shown to have lung–protective effects in critically ill patients, but increases the risk of severe bleeding. Local administration may allow for higher treatment dosages and increased local efficacy while at the same time reducing the risk of bleeding. We evaluated the effect of nebulized tissue factor pathway inhibitor (TFPI), APC or AT on pulmonary coagulopathy and inflammation in a rat model of Streptococcus pneumoniae pneumonia. DESIGN: Randomized controlled in vivo study in a rat model of S. pneumoniae pneumonia. Twenty–eight male Sprague–Dawley rats were challenged intratracheally with S. pneumoniae (serotype 3, 106 colony forming units), inducing pneumonia. Rats were randomized to nebulization with TFPI, APC, AT or normal saline. RESULTS: Rats infected with S. pneumoniae had increased pulmonary and systemic levels of thrombin–antithrombin complexes (TATc) and fibrin degradation products (FDP), indicating increased coagulation. Simultaneously, pulmonary plasminogen activator inhibitor 1 (PAI–1) activity was increased and plasminogen activator activity (PAA) was reduced, indicating inhibition of endogenous fibrinolysis. Treatment with any nebulized natural anticoagulant significantly attenuated the rise in bronchoalveolar TATc (3.5 ± 0.9 ng/mL (TFPI), 3.6 ± 0.6 ng/mL (APC) and 4.6 ± 0.6 ng/mL (AT) versus 9.1 ± 0.75 ng/mL in saline treated rats, P CONCLUSIONS: Nebulization of natural anticoagulants attenuates pulmonary coagulopathy during S. pneumoniae pneumonia. While APC and TFPI leaves local inflammation and host defense unaltered, AT exerts significant lung–protective effects in pneumococcal pneumonia in rats.