Hyperoxemia and hypoxemia impair cellular oxygenation: a study in healthy volunteers.

INTRODUCTION: Administration of oxygen therapy is common, yet there is a lack of knowledge on its ability to prevent cellular hypoxia as well as on its potential toxicity. Consequently, the optimal oxygenation targets in clinical practice remain unresolved. The novel PpIX technique measures the mitochondrial oxygen tension in the skin (mitoPO2) which allows for non-invasive investigation on the effect of hypoxemia and hyperoxemia on cellular oxygen availability. RESULTS: During hypoxemia, SpO2 was 80 (77-83)% and PaO2 45(38-50) mmHg for 15 min. MitoPO2 decreased from 42(35-51) at baseline to 6(4.3-9)mmHg (p < 0.001), despite 16(12-16)% increase in cardiac output which maintained global oxygen delivery (DO2). During hyperoxic breathing, an FiO2 of 40% decreased mitoPO2 to 20 (9-27) mmHg. Cardiac output was unaltered during hyperoxia, but perfused De Backer density was reduced by one-third (p < 0.01). A PaO2 < 100 mmHg and > 200 mmHg were both associated with a reduction in mitoPO2. CONCLUSIONS: Hypoxemia decreases mitoPO2 profoundly, despite complete compensation of global oxygen delivery. In addition, hyperoxemia also decreases mitoPO2, accompanied by a reduction in microcirculatory perfusion. These results suggest that mitoPO2 can be used to titrate oxygen support.

Anti-inflammatory therapies are associated with delayed onset of anemia and reduction in transfusion requirements in critically ill patients: results from two studies.

BACKGROUND: Anemia is a hallmark of critical illness, which is largely inflammatory driven. We hypothesized that the use of anti-inflammatory agents limits the development of anemia and reduces the need for red blood cell (RBC) transfusions in patients with a hyper-inflammatory condition due to COVID-19. METHODS: An observational cohort (n = 772) and a validation cohort (a subset of REMAP-CAP, n = 119) of critically ill patients with hypoxemic respiratory failure due to COVID-19 were analyzed, who either received no treatment, received steroids or received steroids plus IL-6 blocking agents. The trajectory of hemoglobin (Hb) decline and the need for RBC transfusions were compared using descriptive statistics as well as multivariate modeling. RESULTS: In both cohorts, Hb level was higher in the treated groups compared to the untreated group at all time points. In the observational cohort, incidence and number of transfused patients were lower in the group receiving the combination treatment compared to the untreated groups. In a multivariate analysis controlling for baseline Hb imbalance and mechanical ventilation, receipt of steroids remained associated with a slower decline in Hb level and the combination treatment remained associated with a slower decline of Hb and with less transfusions. Results remained the same in the validation cohort. CONCLUSION: Immunomodulatory treatment was associated with a slower decline in Hb level in critically ill patients with COVID-19 and with less transfusion. Findings point toward inflammation as an important cause for the occurrence of anemia in the critically ill.

Transforming research to improve therapies for trauma in the twenty-first century.

Improvements have been made in optimizing initial care of trauma patients, both in prehospital systems as well as in the emergency department, and these have also favorably affected longer term outcomes. However, as specific treatments for bleeding are largely lacking, many patients continue to die from hemorrhage. Also, major knowledge gaps remain on the impact of tissue injury on the host immune and coagulation response, which hampers the development of interventions to treat or prevent organ failure, thrombosis, infections or other complications of trauma. Thereby, trauma remains a challenge for intensivists. This review describes the most pressing research questions in trauma, as well as new approaches to trauma research, with the aim to bring improved therapies to the bedside within the twenty-first century.

Micronutrient Status of Critically Ill Patients with COVID-19 Pneumonia.

Micronutrient deficiencies can develop in critically ill patients, arising from factors such as decreased intake, increased losses, drug interactions, and hypermetabolism. These deficiencies may compromise important immune functions, with potential implications for patient outcomes. Alternatively, micronutrient blood levels may become low due to inflammation-driven redistribution rather than consumption. This explorative pilot study investigates blood micronutrient concentrations during the first three weeks of ICU stay in critically ill COVID-19 patients and evaluates the impact of additional micronutrient administration. Moreover, associations between inflammation, disease severity, and micronutrient status were explored. We measured weekly concentrations of vitamins A, B6, D, and E; iron; zinc; copper; selenium; and CRP as a marker of inflammation state and the SOFA score indicating disease severity in 20 critically ill COVID-19 patients during three weeks of ICU stay. Half of the patients received additional (intravenous) micronutrient administration. Data were analyzed with linear mixed models and Pearson's correlation coefficient. High deficiency rates of vitamins A, B6, and D; zinc; and selenium (50-100%) were found at ICU admission, along with low iron status. After three weeks, vitamins B6 and D deficiencies persisted, and iron status remained low. Plasma levels of vitamins A and E, zinc, and selenium improved. No significant differences in micronutrient levels were found between patient groups. Negative correlations were identified between the CRP level and levels of vitamins A and E, iron, transferrin, zinc, and selenium. SOFA scores negatively correlated with vitamin D and selenium levels. Our findings reveal high micronutrient deficiency rates at ICU admission. Additional micronutrient administration did not enhance levels or expedite their increase. Spontaneous increases in vitamins A and E, zinc, and selenium levels were associated with inflammation resolution, suggesting that observed low levels may be attributed, at least in part, to redistribution rather than true deficiencies.

Contemporary management of major haemorrhage in critical care.

Haemorrhagic shock is frequent in critical care settings and responsible for a high mortality rate due to multiple organ dysfunction and coagulopathy. The management of critically ill patients with bleeding and shock is complex, and treatment of these patients must be rapid and definitive. The administration of large volumes of blood components leads to major physiological alterations which must be mitigated during and after bleeding. Early recognition of bleeding and coagulopathy, understanding the underlying pathophysiology related to specific disease states, and the development of individualised management protocols are important for optimal outcomes. This review describes the contemporary understanding of the pathophysiology of various types of coagulopathic bleeding; the diagnosis and management of critically ill bleeding patients, including major haemorrhage protocols and post-transfusion management; and finally highlights recent areas of opportunity to better understand optimal management strategies for managing bleeding in the intensive care unit (ICU).

Transfusion of female blood in a rat model is associated with red blood cells entrapment in organs.

Transfusion of red blood cells (RBCs) has been associated with adverse outcomes. Mechanisms may be related to donor sex and biological age of RBC. This study hypothesized that receipt of female blood is associated with decreased post-transfusion recovery (PTR) and a concomitant increased organ entrapment in rats, related to young age of donor RBCs. Donor rats underwent bloodletting to stimulate production of new, young RBCs, followed by Percoll fractionation for further enrichment of young RBCs based on their low density. Control donors did not undergo these procedures. Male rats received either a (biotinylated) standard RBC product or a product enriched for young RBCs, derived from either male or female donors. Controls received saline. Organs and blood samples were harvested after 24 hours. This study found no difference in PTR between groups, although only the group receiving young RBCs from females failed to reach a PTR of 75%. Receipt of both standard RBCs and young RBCs from females was associated with increased entrapment of donor RBCs in the lung, liver, and spleen compared to receiving blood from male donors. Soluble ICAM-1 and markers of hemolysis were higher in recipients of female blood compared to control. In conclusion, transfusing RBCs from female donors, but not from male donors, is associated with trapping of donor RBCs in organs, accompanied by endothelial activation and hemolysis.

The diagnostic accuracy of lung ultrasound to determine PiCCO-derived extravascular lung water in invasively ventilated patients with COVID-19 ARDS.

BACKGROUND: Lung ultrasound (LUS) can detect pulmonary edema and it is under consideration to be added to updated acute respiratory distress syndrome (ARDS) criteria. However, it remains uncertain whether different LUS scores can be used to quantify pulmonary edema in patient with ARDS. OBJECTIVES: This study examined the diagnostic accuracy of four LUS scores with the extravascular lung water index (EVLWi) assessed by transpulmonary thermodilution in patients with moderate-to-severe COVID-19 ARDS. METHODS: In this predefined secondary analysis of a multicenter randomized-controlled trial (InventCOVID), patients were enrolled within 48 hours after intubation and underwent LUS and EVLWi measurement on the first and fourth day after enrolment. EVLWi and ∆EVLWi were used as reference standards. Two 12-region scores (global LUS and LUS-ARDS), an 8-region anterior-lateral score and a 4-region B-line score were used as index tests. Pearson correlation was performed and the area under the receiver operating characteristics curve (AUROCC) for severe pulmonary edema (EVLWi > 15 mL/kg) was calculated. RESULTS: 26 out of 30 patients (87%) had complete LUS and EVLWi measurements at time point 1 and 24 out of 29 patients (83%) at time point 2. The global LUS (r = 0.54), LUS-ARDS (r = 0.58) and anterior-lateral score (r = 0.54) correlated significantly with EVLWi, while the B-line score did not (r = 0.32). ∆global LUS (r = 0.49) and ∆anterior-lateral LUS (r = 0.52) correlated significantly with ∆EVLWi. AUROCC for EVLWi > 15 ml/kg was 0.73 for the global LUS, 0.79 for the anterior-lateral and 0.85 for the LUS-ARDS score. CONCLUSIONS: Overall, LUS demonstrated an acceptable diagnostic accuracy for detection of pulmonary edema in moderate-to-severe COVID-19 ARDS when compared with PICCO. For identifying patients at risk of severe pulmonary edema, an extended score considering pleural morphology may be of added value. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT04794088, registered on 11 March 2021. European Clinical Trials Database number 2020-005447-23.

Exploring NT-proBNP, syndecan-1, and cytokines as biomarkers for transfusion-associated circulatory overload in a critically ill patient population receiving a single-unit red blood cell transfusion.

BACKGROUND: Transfusion-associated circulatory overload (TACO) is an often underdiagnosed pulmonary transfusion complication. A biomarker could aid with the diagnosis. To date, B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) seem the most promising biomarkers in the general hospital population. The aim was to evaluate NT-proBNP as a biomarker for TACO in a critically ill patient population and explore syndecan-1 and cytokines as other potential biomarkers. STUDY DESIGN AND METHODS: A retrospective study was performed using samples and clinical data collected during a prospective observational study. Adult patients admitted to the intensive care and transfused with a single red blood cell unit were included. TACO cases were retrospectively identified using a case definition based on the current TACO definition. The primary biomarker was NT-proBNP, also we measured syndecan-1 IL-6, IL-8, and IL-10. All markers were measured directly before transfusion, 1 and 24 h after transfusion. RESULTS: Our cohort included 64 patients, 12 of which were identified as TACO patients. TACO patients had a lower PaO2 /FiO2 ratio and were more often ventilated following transfusion compared to non-TACO patients. There was no significant difference in NT-proBNP between pre- and post-transfusion levels nor between TACO and non-TACO patients. Syndecan-1 was significantly elevated in TACO patients both pre- and post-transfusion compared to non-TACO patients. DISCUSSION: NT-proBNP was not associated with TACO in this critically ill patient population. Interestingly, levels of syndecan-1 were increased in TACO patients at baseline. More research is needed to clarify this association and its possibilities as a biomarker to predict patients at risk for TACO.

The Effects of Heparan Sulfate Infusion on Endothelial and Organ Injury in a Rat Pneumosepsis Model.

Septic shock is characterized by endothelial dysfunction, leading to tissue edema and organ failure. Heparan sulfate (HS) is essential for vascular barrier integrity, possibly via albumin as a carrier. We hypothesized that supplementing fluid resuscitation with HS would improve endothelial barrier function, thereby reducing organ edema and injury in a rat pneumosepsis model. Following intratracheal inoculation with Streptococcus pneumoniae, Sprague Dawley rats were randomized to resuscitation with a fixed volume of either Ringer's Lactate (RL, standard of care), RL supplemented with 7 mg/kg HS, 5% human albumin, or 5% human albumin supplemented with 7 mg/kg HS (n = 11 per group). Controls were sham inoculated animals. Five hours after the start of resuscitation, animals were sacrificed. To assess endothelial permeability, 70 kD FITC-labelled dextran was administered before sacrifice. Blood samples were taken to assess markers of endothelial and organ injury. Organs were harvested to quantify pulmonary FITC-dextran leakage, organ edema, and for histology. Inoculation resulted in sepsis, with increased lactate levels, pulmonary FITC-dextran leakage, pulmonary edema, and pulmonary histologic injury scores compared to healthy controls. RL supplemented with HS did not reduce median pulmonary FITC-dextran leakage compared to RL alone (95.1 CI [62.0-105.3] vs. 87.1 CI [68.9-139.3] µg/mL, p = 0.76). Similarly, albumin supplemented with HS did not reduce pulmonary FITC-dextran leakage compared to albumin (120.0 [93.8-141.2] vs. 116.2 [61.7 vs. 160.8] µg/mL, p = 0.86). No differences were found in organ injury between groups. Heparan sulfate, as an add-on therapy to RL or albumin resuscitation, did not reduce organ or endothelial injury in a rat pneumosepsis model. Higher doses of heparan sulfate may decrease organ and endothelial injury induced by shock.

The effects of resuscitation with different plasma products on endothelial permeability and organ injury in a rat pneumosepsis model.

BACKGROUND: Endothelial injury and permeability are a hallmark of sepsis. Initial resuscitation of septic patients with crystalloids is associated with aggravation of endothelial permeability, which may be related either to low protein content or to volume. We investigated whether initial resuscitation with different types of plasma or albumin decreases endothelial dysfunction and organ injury in a pneumosepsis rat model compared to the same volume of crystalloids. STUDY DESIGN AND METHODS: Sprague-Dawley rats were intratracheally inoculated with Streptococcus pneumoniae. Twenty-four hours after inoculation, animals were randomized to 2 control groups and 5 intervention groups (n = 11 per group) to receive resuscitation with a fixed volume (8 mL/kg for 1 h) of either Ringer's Lactate, 5% human albumin, fresh frozen plasma derived from syngeneic donor rats (rFFP), human-derived plasma (hFFP) or human-derived solvent detergent plasma (SDP). Controls were non-resuscitated (n = 11) and healthy animals. Animals were sacrificed 5 h after start of resuscitation (T = 5). Pulmonary FITC-dextran leakage as a reflection of endothelial permeability was used as the primary outcome. RESULTS: Inoculation with S. Pneumoniae resulted in sepsis, increased median lactate levels (1.6-2.8 mM, p < 0.01), pulmonary FITC-dextran leakage (52-134 µg mL-1, p < 0.05) and lung injury scores (0.7-6.9, p < 0.001) compared to healthy controls. Compared to animals receiving no resuscitation, animals resuscitated with rFFP had reduced pulmonary FITC leakage (134 vs 58 µg/mL, p = 0.011). However, there were no differences in any other markers of organ or endothelial injury. Resuscitation using different human plasma products or 5% albumin showed no differences in any outcome. CONCLUSIONS: Resuscitation with plasma did not reduce endothelial and organ injury when compared to an equal resuscitation volume of crystalloids. Rat-derived FFP may decrease pulmonary leakage induced by shock.

Optimal Dosing and Timing of High-Dose Corticosteroid Therapy in Hospitalized Patients With COVID-19: Study Protocol for a Retrospective Observational Multicenter Study (SELECT).

BACKGROUND: In hospitalized patients with COVID-19, the dosing and timing of corticosteroids vary widely. Low-dose dexamethasone therapy reduces mortality in patients requiring respiratory support, but it remains unclear how to treat patients when this therapy fails. In critically ill patients, high-dose corticosteroids are often administered as salvage late in the disease course, whereas earlier administration may be more beneficial in preventing disease progression. Previous research has revealed that increased levels of various biomarkers are associated with mortality, and whole blood transcriptome sequencing has the ability to identify host factors predisposing to critical illness in patients with COVID-19. OBJECTIVE: Our goal is to determine the most optimal dosing and timing of corticosteroid therapy and to provide a basis for personalized corticosteroid treatment regimens to reduce morbidity and mortality in hospitalized patients with COVID-19. METHODS: This is a retrospective, observational, multicenter study that includes adult patients who were hospitalized due to COVID-19 in the Netherlands. We will use the differences in therapeutic strategies between hospitals (per protocol high-dose corticosteroids or not) over time to determine whether high-dose corticosteroids have an effect on the following outcome measures: mechanical ventilation or high-flow nasal cannula therapy, in-hospital mortality, and 28-day survival. We will also explore biomarker profiles in serum and bronchoalveolar lavage fluid and use whole blood transcriptome analysis to determine factors that influence the relationship between high-dose corticosteroids and outcome. Existing databases that contain routinely collected electronic data during ward and intensive care admissions, as well as existing biobanks, will be used. We will apply longitudinal modeling appropriate for each data structure to answer the research questions at hand. RESULTS: As of April 2023, data have been collected for a total of 1500 patients, with data collection anticipated to be completed by December 2023. We expect the first results to be available in early 2024. CONCLUSIONS: This study protocol presents a strategy to investigate the effect of high-dose corticosteroids throughout the entire clinical course of hospitalized patients with COVID-19, from hospital admission to the ward or intensive care unit until hospital discharge. Moreover, our exploration of biomarker and gene expression profiles for targeted corticosteroid therapy represents a first step towards personalized COVID-19 corticosteroid treatment. TRIAL REGISTRATION: ClinicalTrials.gov NCT05403359; https://clinicaltrials.gov/ct2/show/NCT05403359. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/48183.

ESICM guidelines on acute respiratory distress syndrome: definition, phenotyping and respiratory support strategies.

The aim of these guidelines is to update the 2017 clinical practice guideline (CPG) of the European Society of Intensive Care Medicine (ESICM). The scope of this CPG is limited to adult patients and to non-pharmacological respiratory support strategies across different aspects of acute respiratory distress syndrome (ARDS), including ARDS due to coronavirus disease 2019 (COVID-19). These guidelines were formulated by an international panel of clinical experts, one methodologist and patients' representatives on behalf of the ESICM. The review was conducted in compliance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement recommendations. We followed the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and grade recommendations and the quality of reporting of each study based on the EQUATOR (Enhancing the QUAlity and Transparency Of health Research) network guidelines. The CPG addressed 21 questions and formulates 21 recommendations on the following domains: (1) definition; (2) phenotyping, and respiratory support strategies including (3) high-flow nasal cannula oxygen (HFNO); (4) non-invasive ventilation (NIV); (5) tidal volume setting; (6) positive end-expiratory pressure (PEEP) and recruitment maneuvers (RM); (7) prone positioning; (8) neuromuscular blockade, and (9) extracorporeal life support (ECLS). In addition, the CPG includes expert opinion on clinical practice and identifies the areas of future research.

Mild induced hypothermia and coagulation and platelet function in patients with septic shock: Secondary outcome of a randomized trial.

Coagulation abnormalities and microthrombi contribute to septic shock, but the impact of body temperature regulation on coagulation in patients with sepsis is unknown. We tested the hypothesis that mild induced hypothermia reduces coagulation and platelet aggregation in patients with septic shock. Secondary analysis of randomized controlled trial. Adult patients with septic shock who required mechanical ventilation from eight intensive care units in Denmark were randomly assigned to mild induced hypothermia for 24 h or routine thermal management. Viscoelastography and platelet aggregation were assessed at trial inclusion, after 12 h of thermal management, and 24 h after inclusion. A total of 326 patients were randomized to mild induced hypothermia (n = 163) or routine thermal management (n = 163). Mild induced hypothermia slightly prolonged activated partial thromboplastin time and thrombus initiation time (R time 8.0 min [interquartile range, IQR 6.6-11.1] vs. 7.2 min [IQR 5.8-9.2]; p = .004) and marginally inhibited thrombus propagation (angle 68° [IQR 59-73] vs. 71° [IQR 63-75]; p = .014). The effect was also present after 24 h. Clot strength remained unaffected (MA 71 mm [IQR 66-76] with mild induced hypothermia vs. 72 mm (65-77) with routine thermal management, p = .9). The proportion of patients with hyperfibrinolysis was not affected (0.7% vs. 3.3%; p = .19), but the proportion of patients with no fibrinolysis was high in the mild hypothermia group (8.8% vs. 40.4%; p < .001). The mild induced hypothermia group had lower platelet aggregation: ASPI 85U (IQR 50-113) versus 109U (IQR 74-148, p < .001), ADP 61U (IQR 40-83) versus 79 U (IQR 54-101, p < .001), TRAP 108 (IQR 83-154) versus 119 (IQR 94-146, p = .042) and COL 50U (IQR 34-66) versus 67U (IQR 46-92, p < .001). In patients with septic shock, mild induced hypothermia slightly impaired clot initiation, but did not change clot strength. Platelet aggregation was slightly impaired. The effect of mild induced hypothermia on viscoelastography and platelet aggregation was however not in a range that would have clinical implications. We did observe a substantial reduction in fibrinolysis.

Research priorities for therapeutic plasma exchange in critically ill patients.

Therapeutic plasma exchange (TPE) is a therapeutic intervention that separates plasma from blood cells to remove pathological factors or to replenish deficient factors. The use of TPE is increasing over the last decades. However, despite a good theoretical rationale and biological plausibility for TPE as a therapy for numerous diseases or syndromes associated with critical illness, TPE in the intensive care unit (ICU) setting has not been studied extensively. A group of eighteen experts around the globe from different clinical backgrounds used a modified Delphi method to phrase key research questions related to "TPE in the critically ill patient". These questions focused on: (1) the pathophysiological role of the removal and replacement process, (2) optimal timing of treatment, (3) dosing and treatment regimes, (4) risk-benefit assumptions and (5) novel indications in need of exploration. For all five topics, the current understanding as well as gaps in knowledge and future directions were assessed. The content should stimulate future research in the field and novel clinical applications.

A Systematic Review of Viscoelastic Testing in Patients with Subarachnoid Hemorrhage.

OBJECTIVE: Bleeding and thromboembolic complications frequently occur after subarachnoid hemorrhage (SAH) and substantially contribute to poor outcome. Viscoelastic testing could be used for detection of coagulopathies after SAH. This review summarizes literature on the usefulness of viscoelastic testing to detect coagulopathy in patients with SAH and explores whether viscoelastic parameters are associated with SAH-related complications and clinical outcome. METHODS: PubMed, Embase, and Google Scholar were systematically searched on August 18, 2022. Two authors independently selected studies that reported viscoelastic testing in patients with SAH and assessed the quality of studies using the Newcastle-Ottawa Scale or a previously reported framework for quality assessment. Data were meta-analyzed if methodologically possible. RESULTS: The search yielded 19 studies (1160 patients with SAH). Pooling of data including all relevant studies was not possible for any of the outcome measurements because of methodological differences. Thirteen of 19 studies evaluated the association of coagulation profiles and SAH, of which 11 studies showed a hypercoagulable profile. Rebleeding was associated with platelet dysfunction, deep venous thrombosis was associated with faster clot initiation, and both delayed cerebral ischemia and poor outcome were associated with increased clot strength. CONCLUSIONS: This explorative review shows that patients with SAH frequently have a hypercoagulable profile. Thromboelastography (TEG) and rotational thromboelastometry (ROTEM) parameters are associated with rebleeding, delayed cerebral ischemia, deep venous thrombosis, and poor clinical outcome after SAH; however, more research on the subject is needed. Future studies should focus on determining the optimal time frame and cutoff values for TEG or ROTEM to predict these complications.