Hemojuvelin mediated hepcidin induction requires both bone morphogenetic protein type I receptors ALK2 and ALK3.

Hemojuvelin (HJV) is a GPI-anchored protein of the repulsive guidance molecule (RGM) family acting as a bone morphogenetic protein (BMP) co-receptor to induce the hepatic iron regulatory protein hepcidin. Hepcidin causes ubiquitination and degradation of the sole known iron exporter ferroportin thereby limiting iron availability. The detailed signaling mechanism of HJV in vivo has yet to be investigated. In the current manuscript, we used an established model of adeno-associated virus (AAV) mediated liver-specific overexpression of HJV in murine models of hepatocyte-specific deficiency of the BMP type I receptors Alk2 or Alk3. In control mice, HJV overexpression increased hepatic Hamp mRNA levels, soluble HJV (sHJV), splenic iron content (SIC), as well as pSMAD1/5/8 levels. In contrast, in Alk2fl/fl;Alb-Cre and Alk3fl/fl;Alb-Cre mice, which present with moderate and severe iron overload, respectively, the administration of AAV-HJV induced HJV and sHJV. However, it did not rescue the iron overload phenotypes of those mice. Serum iron levels were induced in Alk2fl/fl;Alb-Cre mice following HJV overexpression. In PBS-injected Alk3fl/fl;Alb-Cre mice serum iron levels and the expression of duodenal ferroportin remained high, whereas Hamp mRNA levels were decreased to 1-5% of the levels detected in controls. This was reduced even further by AAV-HJV overexpression. SIC remained low in mice with hepatocyte-specific Alk2 or Alk3 deficiency, reflecting disturbed iron homeostasis with high serum iron levels and transferrin saturation and an inability to induce hepcidin by HJV overexpression. The data indicate that ALK2 and ALK3 are both required in vivo for the HJV-mediated induction of hepcidin.

Volatile versus propofol sedation after cardiac valve surgery: a single-center prospective randomized controlled trial.

BACKGROUND: Optimal intensive care of patients undergoing valve surgery is a complex balancing act between sedation for monitoring and timely postoperative awakening. It remains unclear, if these requirements can be fulfilled by volatile sedations in intensive care medicine in an efficient manner. Therefore, this study aimed to assess the time to extubation and secondary the workload required. METHODS: We conducted a prospective randomized single-center trial at a tertiary university hospital to evaluate the postoperative management of open valve surgery patients. The study was randomized with regard to the use of volatile sedation compared to propofol sedation. Sedation was discontinued 60 min after admission for critical postoperative monitoring. RESULTS: We observed a significantly earlier extubation (91 ± 39 min vs. 167 ± 77 min; p < 0.001), eye-opening (86 ± 28 min vs. 151 ± 71 min; p < 0.001) and command compliance (93 ± 38 min vs. 164 ± 75 min; p < 0.001) using volatile sedation, which in turn was associated with a significantly increased workload of a median of 9:56 min (± 4:16 min) set-up time. We did not observe any differences in complications. Cardiopulmonary bypass time did not differ between the groups 101 (IQR 81; 113) versus 112 (IQR 79; 136) minutes p = 0.36. CONCLUSIONS: Using volatile sedation is associated with few minutes additional workload in assembling and enables a significantly accelerated evaluation of vulnerable patient groups. Volatile sedation has considerable advantages and emerges as a safe sedation technique in our vulnerable study population. TRIAL REGISTRATION: Clinical trials registration (NCT04958668) was completed on 1 July 2021.

The value of artificial intelligence for the treatment of mechanically ventilated intensive care unit patients: An early health technology assessment.

PURPOSE: The health and economic consequences of artificial intelligence (AI) systems for mechanically ventilated intensive care unit patients often remain unstudied. Early health technology assessments (HTA) can examine the potential impact of AI systems by using available data and simulations. Therefore, we developed a generic health-economic model suitable for early HTA of AI systems for mechanically ventilated patients. MATERIALS AND METHODS: Our generic health-economic model simulates mechanically ventilated patients from their hospitalisation until their death. The model simulates two scenarios, care as usual and care with the AI system, and compares these scenarios to estimate their cost-effectiveness. RESULTS: The generic health-economic model we developed is suitable for estimating the cost-effectiveness of various AI systems. By varying input parameters and assumptions, the model can examine the cost-effectiveness of AI systems across a wide range of different clinical settings. CONCLUSIONS: Using the proposed generic health-economic model, investors and innovators can easily assess whether implementing a certain AI system is likely to be cost-effective before an exact clinical impact is determined. The results of the early HTA can aid investors and innovators in deployment of AI systems by supporting development decisions, informing value-based pricing, clinical trial design, and selection of target patient groups.

Adjusting Current Hemoglobin Thresholds: A Way to Improve Outcome in Women Undergoing Major Surgery.

Background/Objective: In the perioperative setting, a suboptimal total hemoglobin (Hb) mass puts women and men at an unreasonable disadvantage. Anemia is an independent risk factor for transfusion, postoperative complications, and mortality. The Hb cut-off value for women was set at <12.0 g/dL by the World Health Organization (WHO) and has been rigorously debated for decades. The aim of this study was to elucidate the risk for postoperative complications in female patients with Hb levels < 12.0, 12.0-12.9, and ≥13.0 g/dL. Material and Methods: Single-center retrospective analysis of female patients undergoing major surgery. Results: In total, 6,516 patients ≥18 years of age had major surgery between 2018 and 2019 and 2,446 female patients were included in analysis. Mean age was 67.4 ± 16.6, 66.4 ± 15.6, and 64.5 ± 15.5 years in female patients with preoperative Hb levels <12.0, 12.0-12.9 and ≥13.0 g/dL, respectively. The transfusion rate of red blood cells (RBCs) was significantly higher in female patients with Hb <12.0 g/dL (53%) and with Hb 12.0-12.9 g/dL (31%) compared to female patients ≥13.0 g/dL (22%). Rates of pneumonia, acute kidney injury, and sepsis were significantly higher in patients with Hb <12.0 and 12.0-12.9 g/dL compared to patients with Hb ≥13.0 g/dL. Total length of hospital stay was significantly longer in female patients with Hb <12.0 g/dL than patients with Hb 12.0-12.9 g/dL and Hb ≥13.0 g/dL (10 days vs. 8 days). Conclusion: Taken together, our data show that Hb values below 12.9 g/dL are associated with increased probability of RBC transfusions and increased risk of postoperative complications. In addition, our results indicate that postoperative outcomes for women might be optimized by increasing cut-off values for anemia. The call to revise the anemia threshold for women by the WHO can no longer be disregarded.

Preoperative hemoglobin thresholds for survival equity in women and men.

Anemia affects humans throughout life, and is linked to higher morbidity and mortality. Unclear is whether hemoglobin values are equivalent between women and men. This study evaluates the association of preoperative hemoglobin levels with in-hospital mortality and estimates thresholds for survival equity between men and women. All adult patients undergoing surgery between 2010 and 2019 from 14 German hospitals were included in the study. Thresholds for survival equity were determined with generalized additive models. In total, 842,130 patients with a median in-hospital follow-up time of 7 days were analyzed. During follow-up 20,370 deaths occurred. Preoperative hemoglobin stratified in-hospital mortality (log-rank test p < 0.001) and was associated with mortality independently of demographic risk, surgical risk and health status. For each 1 g/dL reduction in preoperative hemoglobin, the odds of mortality increased by a factor of 1.22 (95% CI 1.21-1.23, p < 0.001). A preoperative hemoglobin threshold of 10.5 g/dL reflected equivalent risk for both male and female patients. Hemoglobin levels below 10.5 g/dL had higher risk of mortality for women than for men. The findings from this study aid evidence-based thresholds, inform anemia management and promote equitable care, thus enhancing patient outcomes.

Management and Outcome of Women with Placenta Accreta Spectrum and Treatment with Uterine Artery Embolization.

BACKGROUND: Placenta accreta spectrum (PAS) disorders are a continuum of placental pathologies with increased risk for hemorrhage, blood transfusion and maternal morbidity. Uterine artery embolization (UAE) is a safe approach to the standardization of complex PAS cases. The aim of this study is to analyze anemia and transfusion rate, outcome and anesthesiological management of women who underwent caesarean delivery with subsequent UAE for the management of PAS. MATERIAL AND METHODS: This retrospective observational study included all pregnant women admitted to the University Hospital Frankfurt between January 2012 and September 2023, with a diagnosis of PAS who underwent a two-step surgical approach for delivery and placenta removal. Primary procedure included cesarean delivery with subsequent UAE, secondary procedure included placenta removal after a minim of five weeks via curettage or HE. Maternal characteristics, anesthesiological management, complications, anemia rate, blood loss and administration of blood products were analyzed. RESULTS: In total, 17 women with PAS were included in this study. Of these, 5.9% had placenta increta and 94.1% had placenta percreta. Median blood loss was 300 (200-600) mL during primary procedure and 3600 (450-5500) mL during secondary procedure. In total, 11.8% and 62.5% of women received red blood cell transfusion during the primary and secondary procedures, respectively. After primary procedure, postpartum anemia rate was 76.5%. The HE rate was 64.7%. Regional anesthesia was used in 88.2% during primary procedure. CONCLUSION: The embolization of the uterine artery for women diagnosed with PAS is safe. Anemia management and the implementation of blood conservation strategies are crucial in women undergoing UAE for the management of PAS.

Current concepts in postpartum anemia management.

PURPOSE OF REVIEW: Postpartum anemia (PPA) is common in women after childbirth and affects about 50-80% of all women worldwide. Iron deficiency (ID) is the main cause for anemia and constitutes a potentially preventable condition with great impact on the mother's physical and mental condition after delivery. In most cases, PPA is associated with antenatal ID and peripartum blood losses. Numerous published studies confirmed the positive effect of PPA diagnosis and treatment. RECENT FINDINGS: Iron deficiency as well as iron deficiency anemia (IDA) are common in the postpartum period and represent significant health problems in women of reproductive age. SUMMARY: Important movements towards early detection and therapy of postpartum anemia have been observed. However, postpartum anemia management is not implemented on a large scale as many healthcare professionals are not aware of the most recent findings in the field. Diagnosis and therapy of PPA, particularly iron supplementation in ID and IDA, has proven to be highly effective with a tremendous effect on women's wellbeing and outcome.

Current concepts in the use of cell salvage in obstetrics.

PURPOSE OF REVIEW: The worldwide leading cause of maternal death is severe maternal hemorrhage. Maternal hemorrhage can be profound leading to an entire loss of blood volume. In the past two decades, Patient Blood Management has evolved to improve patient's care and safety. In surgeries with increased blood loss exceeding 500 ml, the use of cell salvage is strongly recommended in order to preserve the patient's own blood volume and to minimize the need for allogeneic red blood cell (RBC) transfusion. In this review, recent evidence and controversies of the use of cell salvage in obstetrics are discussed. RECENT FINDINGS: Numerous medical societies as well as national and international guidelines recommend the use of cell salvage during maternal hemorrhage. SUMMARY: Intraoperative cell salvage is a strategy to maintain the patient's own blood volume and decrease the need for allogeneic RBC transfusion. Historically, cell salvage has been avoided in the obstetric population due to concerns of iatrogenic amniotic fluid embolism (AFE) or induction of maternal alloimmunization. However, no definite case of AFE has been reported so far. Cell salvage is strongly recommended and cost-effective in patients with predictably high rates of blood loss and RBC transfusion, such as women with placenta accreta spectrum disorder. However, in order to ensure sufficient practical experience in a multiprofessional obstetric setting, liberal use of cell salvage appears advisable.

Red blood cell transfusion in patients undergoing elective primary glioblastoma resection.

BACKGROUND: Red blood cell (RBC) transfusion in patients undergoing major elective cranial surgery is associated with increased postoperative morbidity and mortality. This study aims to identify the clinical outcome of transfused glioblastoma patients undergoing primary surgical tumor resection and identify risk factors for RBC transfusion. MATERIAL AND METHODS: Between 2009 and 2019, 406 patients underwent elective primary glioblastoma resection. For multivariate analysis to assess risk factors for RBC transfusion, logistic regression was conducted. The impact of RBC transfusion on overall survival was assessed using Kaplan-Meier analysis. RESULTS: In total, 36 (8.9%) patients received RBC transfusion. Preoperative anemia rate was significantly higher in transfused patients compared to patients without RBC transfusion (33.3 vs 6.5%; p<0.0001). Postoperative complications as well as hospital length of stay (LOS) (p<0.0001) were significantly increased in transfused patients compared to non-transfused patients. After multivariate analysis, risk factors for RBC transfusion were preoperative anemia (p<0.0001), intraoperative blood loss (p<0.0001), female gender (p=0.0056) and radiation (p=0.0064). Kaplan-Meier curves revealed that RBC transfusion and being elderly (age ≥75 years) were relevant for overall survival. DISCUSSION: RBC transfusion is associated with increased postoperative morbidity and mortality in patients undergoing elective primary glioblastoma resection. Preoperative anemia and intraoperative blood loss are major risk factors for RBC transfusion. Preoperative anemia management and blood conservation strategies are crucial in patients undergoing elective primary glioblastoma resection.

Anaemia and red blood cell transfusion in women with placenta accreta spectrum: an analysis of 38,060 cases.

Placenta accreta spectrum (PAS) has become a significant life-threatening issue due to its increased incidence and associated morbidity and mortality. Pregnancy is often associated with states of anaemia, and severe maternal haemorrhage represents a major risk factor for red blood cell (RBC) transfusion. The present study retrospectively analyzed the prevalence of anaemia, transfusion requirements and outcome in women with PAS. Using data from the German Statistical Office pregnant patients with deliveries hospitalized between January 2012 and December 2021 were included. Primary outcome was the prevalence of anemia and administration of RBCs. Secondary outcome were complications in women with PAS who received RBC transfusion. In total 6,493,606 pregnant women were analyzed, of which 38,060 (0.59%) were diagnosed with PAS. The rate of anaemia during pregnancy (60.36 vs. 23.25%; p < 0.0001), postpartum haemorrhage (47.08 vs. 4.41%; p < 0.0001) and RBC transfusion rate (14.68% vs. 0.72%; p < 0.0001) were higher in women with PAS compared to women without PAS. Women with PAS who had bleeding and transfusion experienced significantly more peripartum complications than those who did not. A multiple logistic regression revealed that the probability for RBC transfusion in all pregnant women was positively associated with anaemia (OR 21.96 (95% CI 21.36-22.58)). In women with PAS, RBC transfusion was positively associated with the presence of renal failure (OR 11.27 (95% CI 9.35-13.57)) and congestive heart failure (OR 6.02 (95% CI (5.2-7.07)). Early anaemia management prior to delivery as well as blood conservation strategies are crucial in women diagnosed with PAS.

Mechanical ventilation as a major driver of COVID-19 hospitalization costs: a costing study in a German setting.

BACKGROUND: While COVID-19 hospitalization costs are essential for policymakers to make informed health care resource decisions, little is known about these costs in western Europe. The aim of the current study is to analyze these costs for a German setting, track the development of these costs over time and analyze the daily costs. METHODS: Administrative costing data was analyzed for 598 non-Intensive Care Unit (ICU) patients and 510 ICU patients diagnosed with COVID-19 at the Frankfurt University hospital. Descriptive statistics of total per patient hospitalization costs were obtained and assessed over time. Propensity scores were estimated for length of stay (LOS) at the general ward and mechanical ventilation (MV) duration, using covariate balancing propensity score for continuous treatment. Costs for each additional day in the general ward and each additional day in the ICU with and without MV were estimated by regressing the total hospitalization costs on the LOS and the presence or absence of several treatments using generalized linear models, while controlling for patient characteristics, comorbidities, and complications. RESULTS: Median total per patient hospitalization costs were €3,010 (Q1 - Q3: €2,224-€5,273), €5,887 (Q1 - Q3: €3,054-€10,879) and €21,536 (Q1 - Q3: €7,504-€43,480), respectively, for non-ICU patients, non-MV and MV ICU patients. Total per patient hospitalization costs for non-ICU patients showed a slight increase over time, while total per patient hospitalization costs for ICU patients decreased over time. Each additional day in the general ward for non-ICU COVID-19 patients costed €463.66 (SE: 15.89). Costs for each additional day in the general ward and ICU without and with mechanical ventilation for ICU patients were estimated at €414.20 (SE: 22.17), €927.45 (SE: 45.52) and €2,224.84 (SE: 70.24). CONCLUSIONS: This is, to our knowledge, the first study examining the costs of COVID-19 hospitalizations in Germany. Estimated costs were overall in agreement with costs found in literature for non-COVID-19 patients, except for higher estimated costs for mechanical ventilation. These estimated costs can potentially improve the precision of COVID-19 cost effectiveness studies in Germany and will thereby allow health care policymakers to provide better informed health care resource decisions in the future.

Use of cell salvage in obstetrics in Germany: analysis of national database of 305 610 cases with peripartum haemorrhage.

BACKGROUND: One of the leading causes of maternal death worldwide is severe obstetric haemorrhage after childbirth. Use of intraoperative cell salvage is strongly recommended by international guidelines on patient blood management. Recent data provide strong evidence that use of cell salvage in obstetrics is effective and safe in women with postpartum haemorrhage resulting in fewer transfusion-related adverse events and shorter hospital stay. We retrospectively analysed the use of cell salvage in bleeding women during delivery for a period of 10 yr in German hospitals. METHODS: Data from the German Federal Statistical Office were used that covers all in-hospital birth deliveries from 2011 to 2020. Prevalence of peripartum haemorrhage (pre-, intra-, and post-partum haemorrhage), comorbidities, peripartum complications, administration of blood products, and use of cell salvage were analysed. RESULTS: Of 6 356 046 deliveries in Germany, 305 610 women (4.8%) suffered from peripartum haemorrhage. Of all women with peripartum haemorrhage, postpartum haemorrhage was the main cause for major obstetric haemorrhage (92.33%). Cell salvage was used in only 228 (0.07%) of all women with peripartum haemorrhage (cell salvage group). In women undergoing Caesarean delivery with postpartum haemorrhage, cell salvage was used in only 216 out of 70 450 women (0.31%). CONCLUSION: Cell salvage during peripartum haemorrhage is rarely used in Germany. There is tremendous potential for the increased use of cell salvage in peripartum haemorrhage nationwide.

Extract from the 2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery - Patient Blood Management.

The 2022 Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery of the European Society of Cardiology are an update on the previous guidelines reported in 2014. The revised guidelines provide standardized perioperative cardiovascular management of surgical patients and emphasis on risk assessment of the patient combined with the inherent risk of the surgical procedure. One of the novelties in these guidelines is the Patient Blood Management programme, which is based on a three pillar concept: preoperative hemoglobin optimization, minimize iatrogenic blood loss and bleeding, and harness tolerance to anemia in an effort to improve patient outcome. In this review, we highlight the three pillars of Patient Blood Management and recommendations made by the 2022 ESC Guidelines on cardiovascular assessment and management of patients undergoing non-cardiac surgery.

Anemia, red blood cell transfusion and administration of blood products in obstetrics: a nationwide analysis of more than 6 million cases from 2011-2020.

BACKGROUND: The prevalence of anemia is high, especially in obstetrics. There is large evidence, that anemia during pregnancy is associated with increased maternal morbidity and mortality. Anemia and peripartum hemorrhage remain the main causes for transfusion of red blood cells (RBC). Patient Blood Management (PBM) reduces the need for RBC transfusion significantly. The present study retrospectively analyzed the impact and prevalence of anemia and RBC transfusion on pregnant women. MATERIALS AND METHODS: Data were retrieved from the German Statistical Office on pregnant women who delivered in hospital between January 1st 2011 and December 31st 2020. The prevalence of anemia, peripartum hemorrhage, comorbidities, administration of blood products and complications were analyzed. RESULTS: A total of 6,356,046 pregnant women were analyzed of whom 78,257 (1.23%) received RBC transfusion (RBC transfusion group) and 6,277,789 (98.77%) did not receive RBC transfusion (non-RBC transfusion group). In all women analyzed anemia rate was 23.74%. The rates of anemia during pregnancy (70.39 vs 23.15%; p<0.0001), postpartum hemorrhage (41.42 vs 4.35%; p<0.0001), hospital length of stay (127.5 vs 87.08 hours; p<0.0001) and single complications were higher in women with RBC transfusion compared to women without RBC transfusion. DISCUSSION: The prevalence of anemia and the increased risk for RBC transfusion show that there is great potential for effective implementation of PBM in obstetrics. The treatment of anemia during pregnancy and reduction of RBC transfusions will decrease maternal morbidity and mortality.

User Perceptions of Avatar-Based Patient Monitoring for Intensive Care Units: An International Exploratory Sequential Mixed-Methods Study.

Visual Patient Avatar ICU is an innovative approach to patient monitoring, enhancing the user's situation awareness in intensive care settings. It dynamically displays the patient's current vital signs using changes in color, shape, and animation. The technology can also indicate patient-inserted devices, such as arterial lines, central lines, and urinary catheters, along with their insertion locations. We conducted an international, multi-center study using a sequential qualitative-quantitative design to evaluate users' perception of Visual Patient Avatar ICU among physicians and nurses. Twenty-five nurses and twenty-five physicians from the ICU participated in the structured interviews. Forty of them completed the online survey. Overall, ICU professionals expressed a positive outlook on Visual Patient Avatar ICU. They described Visual Patient Avatar ICU as a simple and intuitive tool that improved information retention and facilitated problem identification. However, a subset of participants expressed concerns about potential information overload and a sense of incompleteness due to missing exact numerical values. These findings provide valuable insights into user perceptions of Visual Patient Avatar ICU and encourage further technology development before clinical implementation.

Using Visual Patient to Show Vital Sign Predictions, a Computer-Based Mixed Quantitative and Qualitative Simulation Study.

BACKGROUND: Machine learning can analyze vast amounts of data and make predictions for events in the future. Our group created machine learning models for vital sign predictions. To transport the information of these predictions without numbers and numerical values and make them easily usable for human caregivers, we aimed to integrate them into the Philips Visual-Patient-avatar, an avatar-based visualization of patient monitoring. METHODS: We conducted a computer-based simulation study with 70 participants in 3 European university hospitals. We validated the vital sign prediction visualizations by testing their identification by anesthesiologists and intensivists. Each prediction visualization consisted of a condition (e.g., low blood pressure) and an urgency (a visual indication of the timespan in which the condition is expected to occur). To obtain qualitative user feedback, we also conducted standardized interviews and derived statements that participants later rated in an online survey. RESULTS: The mixed logistic regression model showed 77.9% (95% CI 73.2-82.0%) correct identification of prediction visualizations (i.e., condition and urgency both correctly identified) and 93.8% (95% CI 93.7-93.8%) for conditions only (i.e., without considering urgencies). A total of 49 out of 70 participants completed the online survey. The online survey participants agreed that the prediction visualizations were fun to use (32/49, 65.3%), and that they could imagine working with them in the future (30/49, 61.2%). They also agreed that identifying the urgencies was difficult (32/49, 65.3%). CONCLUSIONS: This study found that care providers correctly identified >90% of the conditions (i.e., without considering urgencies). The accuracy of identification decreased when considering urgencies in addition to conditions. Therefore, in future development of the technology, we will focus on either only displaying conditions (without urgencies) or improving the visualizations of urgency to enhance usability for human users.

EVIDENCE FROM FATAL COVID-19 FOR TARGETING THE BRADYKININ METABOLISM-A SINGLE-CENTER COHORT STUDY.

ABSTRACT: Background: Severe progression of COVID-19 to critical illness, with pulmonary failure, multiple organ failure, and death, is driven by systemic inflammatory responses with overproduction of inflammatory cytokines. In the past years, the potential role of bradykinin, leading to inappropriate immune responses in the pathogenesis of COVID-19, has been raised in a so-called bradykinin storm. However, clinical investigations of bradykinin, its metabolite des-Arg 9 -bradykinin, or substance P, are rare or completely lacking during intensive care of COVID-19 patients. A prospective prolonged cohort study was conducted, including 44 COVID-19 patients (09/2020-02/2021, prevalent wildtype SARS-CoV-2) from the intensive care unit. Plasma levels of bradykinin, des-Arg 9 -bradykinin, and substance P were measured daily by ELISA in survivors (n = 21) and nonsurvivors (n = 23) of COVID-19 from admission until discharge or death. Results: We found significantly higher plasma levels of des-Arg 9 -bradykinin in survivors and nonsurvivors of COVID-19 compared with healthy controls. In addition, plasma des-Arg 9 -bradykinin levels were higher ( P < 0.001, effect size = 0.79) in nonsurvivors compared with survivors of COVID-19 and correlated significantly with disease worsening, and clinical parameters of inflammation, like leukocyte count, IL-6 or lactate dehydrogenase, and outcome. Consequently, compared with healthy controls, bradykinin and substance P plasma levels were significantly reduced in survivors and nonsurvivors of COVID-19. Furthermore, plasma substance P levels were significantly reduced ( P < 0.001, effect size = 0.7) in nonsurvivors compared with survivors of COVID-19, whereas plasma bradykinin levels did not significantly differ between survivors and nonsurvivors of COVID-19. Conclusion: Our data demonstrates that des-Arg 9 -bradykinin is significantly elevated in COVID-19 intensive care unit patients and is associated with disease severity, clinical inflammatory parameters, and survival. These results indicate that des-Arg 9 -bradykinin, not bradykinin, is one of the pivotal peptides of concern for the lethal COVID-19 aggravation and outcome. Further investigations are necessary to evaluate whether des-Arg 9 -bradykinin exhibits potent blood biomarker properties in COVID-19 and offer new treatment approaches.