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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.

Mild therapeutic hypothermia (MTH) is being used to improve neurological outcome and survival in patients successfully resuscitated after cardiac arrest. The impact on coagulation may be difficult to assess since most coagulation parameters are measured at 37°C and not at actual body core temperature. Therefore we investigated the effects of MTH both at body core (target) temperature of 32°C and at 37°C.Patients admitted at the ICU after cardiac arrest treated with MTH. Baseline blood samples, measured at 37°C were taken directly at arrival. The second and third samples were drawn within 1h and 24h after reaching target temperature and were measured at 32°C and 37°C. A final sample was drawn when the patient returned to normotemperature (measured at 37°C). Clotting time (CT) and maximum clotting formation (MCF) were measured with thromboelastometry.Upon reaching target temperature (32°C) Extem and Intem CT were increased compared to baseline with 57s (49-75) to 65s (59-72) and 165s (144-183) to 193s (167-212) respectively (median with IQR; P0.05), with a further significant increase after 24h of hypothermia with 68s (57-80) and 221s (196-266). Samples analyzed at 32°C showed a significant longer CT of 12s in Extem and 33s in Intem compared to 37°C. MCF was not affected by MTH or adjustment of temperature.The mild effect of MTH on coagulation parameters remains unidentified when measured at 37°C. Although measurements at 32°C differ from those at 37°C, this does not appear to be of clinical relevance as all values were still within the reference range.

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.

Resumen Todavia hay confusion acerca de la toma de decisiones al final de la vida y la eutanasia, tanto en el extranjero como en los Paises Bajos. La eutanasia no tiene ningun papel en las unidades de medicina intensiva, en general, simplemente porque no se cumplen las condiciones necesarias para llevarse a cabo. Aun asi sigue prestandose a confusion, meramente por la presuncion de que la situacion en los Paises Bajos es diferente debido a la legislacion de la eutanasia. El uso de terminologia confusa como «eutanasia pasiva», «eutanasia voluntaria» o «eutanasia involuntaria» genera confusion entre los medicos y la poblacion general, y por ello deben evitarse. Las decisiones al final de la vida forman, de hecho, parte del trabajo diario de los intensivistas. Para determinar la futilidad de los objetivos terapeuticos, son importantes la experiencia medica previa, recoger toda la informacion necesaria y conocer las limitaciones de un tratamiento medico, pero tambien tener en cuenta las voluntades y los deseos del paciente. Una vez determinado que el objetivo de sobrevivir a la unidad de medicina intensiva con una calidad de vida aceptable para el paciente esta mas alla de su alcance, el objetivo del tratamiento deberia ser la optimizacion y permision del proceso de la muerte. Retirar u omitir el tratamiento futil de soporte vital en un paciente que lo solicita no es eutanasia.

Todavía hay confusión acerca de la toma de decisiones al final de la vida y la eutanasia, tanto en el extranjero como en los Países Bajos. La eutanasia no tiene ningún papel en las unidades de medicina intensiva, en general, simplemente porque no se cumplen las condiciones necesarias para llevarse a cabo. Aun así sigue prestándose a confusión, meramente por la presunción de que la situación en los Países Bajos es diferente debido a la legislación de la eutanasia. El uso de terminología confusa como "eutanasia pasiva", "eutanasia voluntaria" o "eutanasia involuntaria" genera confusión entre los médicos y la población general, y por ello deben evitarse. Las decisiones al final de la vida forman, de hecho, parte del trabajo diario de los intensivistas. Para determinar la futilidad de los objetivos terapéuticos, son importantes la experiencia médica previa, recoger toda la información necesaria y conocer las limitaciones de un tratamiento médico, pero también tener en cuenta las voluntades y los deseos del paciente. Una vez determinado que el objetivo de sobrevivir a la unidad de medicina intensiva con una calidad de vida aceptable para el paciente está más allá de su alcance, el objetivo del tratamiento debería ser la optimización y permisión del proceso de la muerte. Retirar u omitir el tratamiento fútil de soporte vital en un paciente que lo solicita no es eutanasia. Abroad, but also in The Netherlands, there are many misunderstandings concerning end of life decisions and euthanasia. In general, euthanasia does not play any role in the intensive care units, simply because it does not fulfill the conditions to carry it out. However, there is still confusion, merely due to the assumption that the Dutch situation is different because of their legislation on euthanasia. The use of the unclear terminology such as "passive euthanasia", "voluntary euthanasia" or "involuntary euthanasia" contributes to the confusion of lay people and physicians, and should therefore be avoided. End of life decisions in intensive care patients are in fact a structural part of work of intensivists. Collecting all necessary information including the wishes and will of the patient, medical expertise and acknowledging limitations of medical treatment will help to determine futility of treatment goals. Once it is determined that surviving the intensive care unit with a quality of life acceptable for the patient is beyond reach, the goal of treatment should be improved and the dying process optimized. Stopping a treatment modality at the request of a will-competent patient or because of futility is not euthanasia.

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.

Oxidative stress is an important part of a wide range of pathologies and therefore an interesting parameter to determine. However, the detection of reactive oxygen species (ROS), is not straightforward. Sample heterogeneity, delayed analysis and sample preparation, reduces specificity and sensitivity due to probe activation by light, air, probe leakage from cells or cellular activation by sample manipulation. Hence, samples should be processed minimally and analysed immediately if possible. Since clinical research can be subject to uncontrollable timetables and only few departments have access to a dedicated laboratory, the quantification of ROS is challenging.

Background and objective The haemodynamics of crystalloid and colloid fluid loading may depend on underlying disease, i.e. sepsis versus non-sepsis. Design and setting A single-centre, single-blinded, randomized clinical trial was carried out on 24 critically ill sepsis and 24 non-sepsis patients with clinical hypovolaemia, assigned to loading with normal saline, gelatin 4%, hydroxyethyl starch 6% or albumin 5% in a 90-min (delta) central venous pressure (CVP)-guided fluid loading protocol. Transpulmonary thermodilution was done each 30 min, yielding, among others, global end-diastolic volume and cardiac indices (GEDVI, CI). Results Sepsis patients had hyperdynamic hypotension in spite of myocardial depression and dilatation, and greater inotropic/vasopressor requirements than non-sepsis patients. Independent of underlying disease, CVP and GEDVI increased more after colloid than saline loading (P