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Rationale: Bacterial lung microbiota are correlated with lung inflammation and acute respiratory distress syndrome (ARDS) and altered in severe coronavirus disease (COVID-19). However, the association between lung microbiota (including fungi) and resolution of ARDS in COVID-19 remains unclear. We hypothesized that increased lung bacterial and fungal burdens are related to nonresolving ARDS and mortality in COVID-19. Objectives: To determine the relation between lung microbiota and clinical outcomes of COVID-19-related ARDS. Methods: This observational cohort study enrolled mechanically ventilated patients with COVID-19. All patients had ARDS and underwent bronchoscopy with BAL. Lung microbiota were profiled using 16S rRNA gene sequencing and quantitative PCR targeting the 16S and 18S rRNA genes. Key features of lung microbiota (bacterial and fungal burden, α-diversity, and community composition) served as predictors. Our primary outcome was successful extubation adjudicated 60 days after intubation, analyzed using a competing risk regression model with mortality as competing risk. Measurements and Main Results: BAL samples of 114 unique patients with COVID-19 were analyzed. Patients with increased lung bacterial and fungal burden were less likely to be extubated (subdistribution hazard ratio, 0.64 [95% confidence interval, 0.42-0.97]; P = 0.034 and 0.59 [95% confidence interval, 0.42-0.83]; P = 0.0027 per log10 increase in bacterial and fungal burden, respectively) and had higher mortality (bacterial burden, P = 0.012; fungal burden, P = 0.0498). Lung microbiota composition was associated with successful extubation (P = 0.0045). Proinflammatory cytokines (e.g., tumor necrosis factor-α) were associated with the microbial burdens. Conclusions: Bacterial and fungal lung microbiota are related to nonresolving ARDS in COVID-19 and represent an important contributor to heterogeneity in COVID-19-related ARDS.

Background Concerns have been expressed regarding a possible association between arterial hyperoxia and adverse outcomes in critically ill patients. Oxygen status is commonly monitored noninvasively by peripheral saturation monitoring (SpO2). However, the risk of hyperoxia above specific SpO2 levels in critically ill patients is unknown. The purpose of this study was to determine a threshold value of SpO2 above which the prevalence of arterial hyperoxia distinctly increases. Methods This is a cross-sectional study in adult mechanically ventilated intensive care patients in a tertiary referral center. In 100 patients, we collected 200 arterial blood gases (ABG) and simultaneously registered SpO2 levels, as well as hemodynamic and ventilation parameters and vasoactive medication. Patients under therapeutic hypothermia were excluded. Results The risk of arterial hyperoxia, defined as PaO2 > 100 mm Hg or > 125 mm Hg, was negligible when SpO2 was ≤ 95% or ≤ 96%, respectively. The majority (89% and 54%, respectively for PaO2 > 100 mm Hg and 125 mm Hg) of ICU patients with SpO2 of 100% had arterial hyperoxia. The relation between SpO2 and PaO2 was not clearly affected by hemodynamic or other clinical variables (pH, pCO2, body temperature, recent blood transfusion). Conclusion In critically ill patients, the prevalence of arterial hyperoxia increases when SpO2 is > 95%. Above this saturation level, supplemental oxygen should be administered with caution in patients potentially susceptible to adverse effects of hyperoxia.

INTRODUCTION: Neutrophilic granulocytes express cluster of differentiation 64 (CD64) antigen upon activation. CD64 can be used as a marker of bacterial infection and sepsis. The goal of this study was to determine whether CD64 is a useful biomarker for critically ill patients and analyze longitudinal measurements with regard to outcome and sepsis severity. METHODS: In this prospective observational study, CD64 analysis was performed daily until discharge from ICU or death. Demographics, clinical, laboratory data, and outcome defined as 28-day survival were recorded. Patients were included when admitted to the ICU with sepsis, severe sepsis, or septic shock and within 24 h from start of antibiotic treatment. RESULTS: Hundred and fifty-five consecutive patients were enrolled. At baseline, a difference in CD64 of 2.26 (1.33-4.47) vs. 1.49 (0.89-2.24) (P = 0.004) was seen between patients with a positive culture and negative culture. CD64 at day 1 was higher with patients with septic shock when compared with sepsis (P = 0.012). No difference of CD64 between survivors and nonsurvivors was seen. CONCLUSION: This study demonstrated that CD64 discriminates between critically ill patients with culture positive and negative sepsis and correlates with severity of disease. However, CD64 index is not a good predictor for 28-day mortality in the critically ill patient.

Echinocandins, such as anidulafungin, are the first-line treatment for candidemia or invasive candidiasis in critically ill patients. There are conflicting data on the pharmacokinetic properties of anidulafungin in intensive care unit (ICU) patients. Adult ICU patients (from 3 hospitals) receiving anidulafungin for suspected or proven fungal infections were included in the present study. Patients were considered evaluable if a pharmacokinetic curve for day 3 could be completed. Twenty-three of 36 patients (7 female and 16 male) were evaluable. The median (range) age and body weight were 66 (28 to 88) years and 76 (50 to 115) kg, respectively. Pharmacokinetic sampling on day 3 ( n = 23) resulted in a median anidulafungin area under the concentration-time curve from 0 to 24 h (AUC 0–24 ) of 72.1 (interquartile range [IQR], 61.3 to 94.0) mg · h · liter −1 , a median daily trough concentration ( C 24 ) of 2.2 (IQR, 1.9 to 2.9) mg/liter, a median maximum concentration of drug in serum ( C max ) of 5.3 (IQR, 4.1 to 6.0) mg/liter, a median volume of distribution ( V ) of 46.0 (IQR, 32.2 to 60.2) liters, and a median clearance (CL) of 1.4 (IQR, 1.1 to 1.6) liters · h −1 . Pharmacokinetic sampling on day 7 ( n = 13) resulted in a median AUC 0–24 of 82.7 (IQR, 73.0 to 129.5) mg · h · liter −1 , a median minimum concentration of drug in serum ( C min ) of 2.8 (IQR, 2.2 to 4.2) mg/liter, a median C max of 5.9 (IQR, 4.6 to 8.0) mg/liter, a median V of 39.7 (IQR, 32.2 to 54.4) liters, and a median CL of 1.2 (IQR, 0.8 to 1.4) liters · h −1 . The geometric mean ratio for the AUC day7 /AUC day3 term was 1.13 (90% confidence interval [CI], 1.03 to 1.25). The exposure in the ICU patient population was in accordance with previous reports on anidulafungin pharmacokinetics in ICU patients but was lower than that for healthy volunteers or other patient populations. Larger cohorts of patients or pooled data analyses are necessary to retrieve relevant covariates. (This study has been registered at ClinicalTrials.gov under identifier NCT01438216.)

Hospitalized patients often receive oxygen supplementation, which can lead to a supraphysiological oxygen tension (hyperoxia). Hyperoxia can have hemodynamic effects, including an increase in systemic vascular resistance. This increase suggests hyperoxia-induced vasoconstriction, yet reported direct effects of hyperoxia on vessel tone have been inconsistent. Furthermore, hyperoxia-induced changes in vessel diameter have not been studied in mice, currently the most used mammal model of disease. In this study we set out to develop a pressure-myograph model using isolated vessels from mice for investigation of pathways involved in hyperoxic vasoconstriction. Isolated conduit and resistance arteries (femoral artery and gracilis arteriole, respectively) from C57BL/6 mice were exposed to normoxia (PO2 of 80 mmHg) and three levels of hyperoxia (PO2 of 215, 375 and 665 mmHg) in a no-flow pressure myograph setup. Under the different PO2 levels, dose-response agonist induced endothelium-dependent vasodilation (acetylcholine, arachidonic acid), endothelium-independent vasodilation (s-nitroprusside), as well as vasoconstriction (norepinephrine, prostaglandin F2α) were examined. The investigated arteries did not respond to oxygen by a change in vascular tone. In the dose-response studies, maximal responses and EC50 values to any of the aforementioned agonists were not affected by hyperoxia either. We conclude that arteries and arterioles from healthy mice are not intrinsically sensitive to hyperoxic conditions. The present ex-vivo model is therefore not suitable for further research into mechanisms of hyperoxic vasoconstriction.

Introduction Cluster of Differentiation 64 (CD64) antigen is a membrane glycoprotein expressed on monocytes and macrophages. It is the high affinity neutrophil FcgRI receptor which is weakly expressed by neutrophils at physiological levels, but strongly upregulated within 4-6 hours by the pleiotropic cytokines such as Interferon-γ (IFN-γ) and Granulocyte Colony Stimulating Factor (G-CSF) which are produced in sepsis [1]. CD64 can be used as a diagnostic marker of bacterial infection and sepsis using flow cytometry. Objectives The primary goal of this study was to determine whether CD64 is a useful biomarker for sepsis in adult critically ill patients. Secondly, since longitudinal data of CD64 expression are limited in the critically ill patient, a further goal was to clarify longitudinal expression patterns of CD64 on neutrophils with regard to outcome and sepsis severity. Methods A prospective observational study between August 2011 and March 2013 in 155 consecutive patients who were admitted with sepsis, severe sepsis or septic shock was performed in a mixed medical-surgical ICU in a university hospital in the Netherlands. CD64 analysis were performed daily until discharge from ICU or death. Demographics, clinical, laboratory data and outcome defined as 28-day survival were recorded. They were included within 24 hours from start of antibiotic treatment. Results Hundred-and-fifty-five consecutive patients were enrolled. Patients with a sepsis (1.53; 1.00-2.77) showed a lower CD64 index than patients with a severe sepsis and septic shock (2.66;1.36-4.49) p = 0.004. Furthermore a peak value on day two and subsequently a steady decline in all three groups was seen, independent of outcome. A significant difference in CD64 at baseline of 2.65 [1.37-4.47] versus 1.74 [0.97-3.16] (p = 0.002) was seen between patients with a positive culture and negative culture at admission, respectively. This difference persisted until two days after inclusion. CD64 index was associated with severity in organ failure (SOFA-score). The higher the SOFA score, the higher the CD64 index measured at the same day. Analysis showed no significant difference during the first 14 days with regard to CD64 index for 28-day mortality between survivors versus non-survivors, although, towards the end, non-survivors are showing higher levels. Conclusions This prospective study demonstrated that CD64 expression could be of diagnostic support, in addition to current tests in discriminating between critically ill patients with culture positive- and negative sepsis. Furthermore, CD64 expression correlates with severity of disease expressed as the daily SOFA-score, however, CD64 index was not a good predictor for 28-day mortality in the critically ill patient.

Background and objective Mild therapeutic hypothermia (MTH) is used to limit neurological injury and improve survival after cardiac arrest (CA) and cardiopulmonary resuscitation, but the optimal mode of cooling is controversial. We therefore compared the effectiveness of MTH using invasive intravascular or non-invasive surface cooling with temperature feedback control. Methods This retrospective study in post-CA patients studied the effects of intravascular cooling (CoolGard, Zoll, n=97), applied on the intensive care unit (ICU) in one university hospital compared with those of surface cooling (Medi-Therm, Gaymar, n=76) applied in another university hospital. Results Time to reach target temperature and cooling speeds did not differ between groups. During the maintenance phase, mean core temperature was 33.1 degrees C (range 32.7-33.7 degrees C) versus 32.5 degrees C (range 31.7-33.4 degrees C) at targets of 33.0 and 32.5 degrees C in intravascularly versus surface cooled patients, respectively. The variation coefficient for temperature during maintenance was higher in the surface than the intravascular cooling group (mean 0.85% vs 0.35%, p

Hyperoxia is frequently encountered in the intensive care unit (ICU) and during surgical procedures such as coronary artery bypass surgery (CABG). Higher oxygen concentrations intuitively provide a salutary oxygen reserve, but hyperoxia can induce adverse effects such as systemic vasoconstriction, reduction of cardiac output, increased microcirculatory heterogeneity and increased reactive oxygen species production. Previous studies in patients undergoing CABG surgery suggest reduced myocardial damage when avoiding extreme perioperative hyperoxia (>400 mmHg). Here, we compare moderate hyperoxia to near-physiological values.