Effects of Etomidate on Postintubation Hypotension, Inflammatory Markers, and Mortality in Critically Ill Patients with COVID-19: An International, Multicenter, Retrospective Study.

OBJECTIVE: To evaluate the association of etomidate with postintubation hypotension, inflammation, and mortality in critically ill patients with COVID-19. DESIGN: International, multicenter, retrospective study. PARTICIPANTS: Critically ill patients hospitalized specifically for COVID-19 from three major academic institutions in the US and Europe. MAIN OUTCOME AND MEASURES: Patients were allocated into the etomidate (ET) group or another induction agent (OA) group. The primary outcome was postintubation hypotension. Secondary outcomes included postintubation inflammatory status, in-hospital mortality, and mortality at 30 days. RESULTS: 171 patients with a median age of 68 (IQR 58-73) years were included (ET, n = 98; OA, n = 73). Etomidate was associated with lower postintubation mean arterial pressure [74.33 (64-85) mm Hg versus 81.84 (69.75-94.25) mm Hg, p = 0.005] compared to other agents. No statistically significant differences were generally observed in inflammatory markers between the two groups at 7- and 14-days after admission to the intensive care unit. In-hospital mortality [77 (79%) versus 41 (56%), p = 0.003] and mortality at 30-days [78 (80%) versus 43 (59%), p = 0.006] were higher in the ET group. In multivariate logistic regression analysis, only etomidate (p = 0.009) and postintubation mean arterial pressure (p < 0.001) had a statistically significant effect on mortality, in contrast to stress-dose steroids (p = 0.301), after adjusting for creatinine (p = 0.695), blood urea nitrogen (p = 0.153), age (p = 0.055), oxygen saturation of hemoglobin (SpO2) (p = 0.941), and fraction of inspired oxygen (FiO2) (p = 0.712). CONCLUSIONS: Administration of a single-bolus dose of etomidate in critically ill patients with COVID-19 is associated with lower postintubation mean arterial pressure and higher in-hospital and 30-day mortality compared to other induction agents.

Association of vasopressors with mortality in critically ill patients with COVID-19: a systematic review and meta-analysis

Exogenous catecholamines may have pronounced side effects and affect physiological cascades. The aim of this study was to investigate the effect of vasopressors on mortality of critically ill patients with coronavirus disease 2019 (COVID-19). A systematic search of PubMed, Scopus, and ClinicalTrials.gov was conducted for relevant articles until December 2022. Eligibility criteria were randomized controlled and non-randomized trials. The primary outcome was in-hospital and 30-day mortality. The quality of studies was assessed using the Methodological Index for Non-Randomized Studies (MINORS) tool, while paired meta-analysis was used to estimate the pooled risk ratios (RR) along with their 95% Confidence Interval (95% CI). Analyses of 22 studies (n = 8034) revealed that vasopressor use is associated with mortality compared to no vasopressor therapy [RR (95%CI): 4.30 (3.21, 5.75);p < 0.001]. In-hospital and 30-day mortality are significantly higher in patients who receive vasopressors [RR (95%CI): 4.60 (2.47, 8.55);p < 0.001 and RR (95%CI): 2.97 (1.72, 5.14);p < 0.001, respectively]. Also, analyses of data from 10 studies (n = 3519) revealed that vasopressor use is associated with acute kidney injury [RR (95%CI): 3.17 (2.21, 4.54);p < 0.001]. In conclusion, current use of vasopressors in critically ill patients with COVID-19 may be associated with higher in-hospital mortality, 30-day mortality, and incidence rate of acute kidney injury. Further research is required to estimate the correlation of specific vasopressor characteristics (type, timing, dose, combination) with adverse effects and mortality in this population. Graphical Supplementary Information The online version contains supplementary material available at 10.1007/s44254-023-00013-7.

High-flow nasal oxygen versus conventional oxygen therapy in patients with COVID-19 pneumonia and mild hypoxaemia: a randomised controlled trial.

RATIONALE: In patients with COVID-19 pneumonia and mild hypoxaemia, the clinical benefit of high-flow nasal oxygen (HFNO) remains unclear. We aimed to examine whether HFNO compared with conventional oxygen therapy (COT) could prevent escalation of respiratory support in this patient population. METHODS: In this multicentre, randomised, parallel-group, open-label trial, patients with COVID-19 pneumonia and peripheral oxygen saturation (SpO2) ≤92% who required oxygen therapy were randomised to HFNO or COT. The primary outcome was the rate of escalation of respiratory support (ie, continuous positive airway pressure, non-invasive ventilation or invasive mechanical ventilation) within 28 days. Among secondary outcomes, clinical recovery was defined as the improvement in oxygenation (SpO2 ≥96% with fractional inspired oxygen (FiO2) ≤30% or partial pressure of arterial carbon dioxide/FiO2 ratio >300 mm Hg). RESULTS: Among 364 randomised patients, 55 (30.3%) of 181 patients assigned to HFNO and 70 (38.6%) of 181 patients assigned to COT underwent escalation of respiratory support, with no significant difference between groups (absolute risk difference -8.2% (95% CI -18% to +1.4%); RR 0.79 (95% CI 0.59 to 1.05); p=0.09). There was no significant difference in clinical recovery (69.1% vs 60.8%; absolute risk difference 8.2% (95% CI -1.5% to +18.0%), RR 1.14 (95% CI 0.98 to 1.32)), intensive care unit admission (7.7% vs 11.0%, absolute risk difference -3.3% (95% CI -9.3% to +2.6%)), and in hospital length of stay (11 (IQR 8-17) vs 11 (IQR 7-20) days, absolute risk difference -1.0% (95% CI -3.1% to +1.1%)). CONCLUSIONS: Among patients with COVID-19 pneumonia and mild hypoxaemia, the use of HFNO did not significantly reduce the likelihood of escalation of respiratory support. TRIAL REGISTRATION NUMBER: NCT04655638.

Remdesivir-induced Bradycardia is not Associated with Worse Outcome in Patients with COVID-19: A Retrospective Analysis.

BACKGROUND: COVID-19, is primarily a respiratory illness but is known to cause extrapulmonary manifestations, especially on the cardiovascular system. Bradycardia is commonly reported in COVID-19 patients despite no prior history of occurrence, and many studies have shown an association with increased mortality. Multiple case reports have been published showcasing remdesivir potentially causing bradycardia. Our aim was to investigate the incidence of bradycardia in patients receiving remdesivir and examine the association with disease severity and survival outcomes. METHODS: A retrospective study was performed including 160 COVID-19 patients receiving remdesivir for 5 days. Patients' demographics, comorbidities, medication, vital signs, laboratory tests and outcome were recorded. Bradycardia was defined as a heart rate < 60 beats/min and severe bradycardia < 50 beats/min. RESULTS: One hundred eighteen (73.8%) patients experienced at least one episode of bradycardia during hospitalisation. Bradycardia was present in 12 (7.5%) patients before treatment with remdesivir. The rate of bradycardia increased up to the 6th day of hospitalisation (40.6%) and subsequently diminished and normalised within 5 days after the last remdesivir dose (5% at Day 10). Severe bradycardia was observed in 13 (7.5%) patients. No difference was observed in ICU admission between groups (bradycardia vs no bradycardia). When we stratified patients according to the outcome of hospitalisation, no significant difference was observed in the occurrence of bradycardia between groups (alive vs dead) [p = 0.853]. CONCLUSIONS: Treatment with remdesivir may be associated with new-onset bradycardia in hospitalised patients with COVID-19. However, bradycardia is transient and is not associated with ICU admission and mortality.

Soluble Urokinase Plasminogen Activator Receptor and Venous Thromboembolism in COVID-19.

Background Venous thromboembolism (VTE) contributes significantly to COVID-19 morbidity and mortality. The urokinase receptor system is involved in the regulation of coagulation. Levels of soluble urokinase plasminogen activator receptor (suPAR) reflect hyperinflammation and are strongly predictive of outcomes in COVID-19. Whether suPAR levels identify patients with COVID-19 at risk for VTE is unclear. Methods and Results We leveraged a multinational observational study of patients hospitalized for COVID-19 with suPAR and D-dimer levels measured on admission. In 1960 patients (mean age, 58 years; 57% men; 20% Black race), we assessed the association between suPAR and incident VTE (defined as pulmonary embolism or deep vein thrombosis) using logistic regression and Fine-Gray modeling, accounting for the competing risk of death. VTE occurred in 163 (8%) patients and was associated with higher suPAR and D-dimer levels. There was a positive association between suPAR and D-dimer (ß=7.34; P=0.002). Adjusted for clinical covariables, including D-dimer, the odds of VTE were 168% higher comparing the third with first suPAR tertiles (adjusted odds ratio, 2.68 [95% CI, 1.51-4.75]; P<0.001). Findings were consistent when stratified by D-dimer levels and in survival analysis accounting for death as a competing risk. On the basis of predicted probabilities from random forest, a decision tree found the combined D-dimer <1 mg/L and suPAR <11 ng/mL cutoffs, identifying 41% of patients with only 3.6% VTE probability. Conclusions Higher suPAR was associated with incident VTE independently of D-dimer in patients hospitalized for COVID-19. Combining suPAR and D-dimer identified patients at low VTE risk. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

Watch Out for Burnout in COVID-19: A Greek Health Care Personnel Study.

The aim of the current study was to examine the mental well-being of healthcare personnel (HCP) working in COVID-19 units in Greece and to calculate the prevalence of burnout (BO) amongst them. A questionnaire based on the Maslach Burnout Inventory for Medical Personnel was utilized between February 21st, 2021 and March 5th, 2021. A total of 190 HCP responded to the questionnaire, of which 73.7% were nurses and midwives. The mean age of the participants was 38.3 (8.4) years. Overall, 71.6% of the participants had a high BO score, while 20.5% had a moderate and 7.9% had a low BO score. Night shifts in COVID-19 wards and job dissatisfaction were significantly associated with a high BO score (P = .03 and P < .0001, respectively). The majority of HCP working in COVID-19 wards in Greece is experiencing high levels of overall BO and emotional exhaustion.

Circulating suPAR associates with severity and in-hospital progression of COVID-19.

BACKGROUND: COVID-19 disease progression is characterized by hyperinflammation and risk stratification may aid in early aggressive treatment and advanced planning. The aim of this study was to assess whether suPAR and other markers measured at hospital admission can predict the severity of COVID-19. METHODS: The primary outcome measure in this international, multi-centre, prospective, observational study with adult patients hospitalized primarily for COVID-19 was the association of WHO Clinical Progression Scale (WHO-CPS) with suPAR, ferritin, CRP, albumin, LDH, eGFR, age, procalcitonin, and interleukin-6. Admission plasma suPAR levels were determined using the suPARnostic® ELISA and suPARnostic® Turbilatex assays. RESULTS: Seven hundred and sixty-seven patients, 440 (57.4%) males and 327 (42.6%) females, were included with a median age of 64 years. Log-suPAR levels significantly correlated with WHO-CPS score, with each doubling of suPAR increasing the score by one point (p < .001). All the other markers were also correlated with WHO-CPS score. Admission suPAR levels were significantly lower in survivors (7.10 vs. 9.63, 95% CI 1.47-3.59, p < .001). A linear model (SALGA) including suPAR, serum albumin, serum lactate dehydrogenase, eGFR, and age can best estimate the WHO-CPS score and survival. Combining all five parameters in the SALGA model can improve the accuracy of discrimination with an AUC of 0.80 (95% CI: 0.759-0.836). CONCLUSIONS: suPAR levels significantly correlated with WHO-CPS score, with each doubling of suPAR increasing the score by one point. The SALGA model may serve as a quick tool for predicting disease severity and survival at admission.

Inflammation, Hyperglycemia, and Adverse Outcomes in Individuals With Diabetes Mellitus Hospitalized for COVID-19.

OBJECTIVE: Diabetes mellitus (DM) is a major risk factor for severe coronavirus disease 2019 (COVID-19) for reasons that are unclear. RESEARCH DESIGN AND METHODS: We leveraged the International Study of Inflammation in COVID-19 (ISIC), a multicenter observational study of 2,044 patients hospitalized with COVID-19, to characterize the impact of DM on in-hospital outcomes and assess the contribution of inflammation and hyperglycemia to the risk attributed to DM. We measured biomarkers of inflammation collected at hospital admission and collected glucose levels and insulin data throughout hospitalization. The primary outcome was the composite of in-hospital death, need for mechanical ventilation, and need for renal replacement therapy. RESULTS: Among participants (mean age 60 years, 58.2% males), those with DM (n = 686, 33.5%) had a significantly higher cumulative incidence of the primary outcome (37.8% vs. 28.6%) and higher levels of inflammatory biomarkers than those without DM. Among biomarkers, DM was only associated with higher soluble urokinase plasminogen activator receptor (suPAR) levels in multivariable analysis. Adjusting for suPAR levels abrogated the association between DM and the primary outcome (adjusted odds ratio 1.23 [95% CI 0.78, 1.37]). In mediation analysis, we estimated the proportion of the effect of DM on the primary outcome mediated by suPAR at 84.2%. Hyperglycemia and higher insulin doses were independent predictors of the primary outcome, with effect sizes unaffected by adjusting for suPAR levels. CONCLUSIONS: Our findings suggest that the association between DM and outcomes in COVID-19 is largely mediated by hyperinflammation as assessed by suPAR levels, while the impact of hyperglycemia is independent of inflammation.

Angiotensin-Converting Enzyme Inhibitors, Angiotensin II Receptor Blockers, and Outcomes in Patients Hospitalized for COVID-19.

Background Use of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers (ACEi/ARB) is thought to affect COVID-19 through modulating levels of angiotensin-converting enzyme 2, the cell entry receptor for SARS-CoV2. We sought to assess the association between ACEi/ARB, biomarkers of inflammation, and outcomes in patients hospitalized for COVID-19. Methods and Results We leveraged the ISIC (International Study of Inflammation in COVID-19), identified patients admitted for symptomatic COVID-19 between February 1, 2020 and June 1, 2021 for COVID-19, and examined the association between in-hospital ACEi/ARB use and all-cause death, need for ventilation, and need for dialysis. We estimated the causal effect of ACEi/ARB on the composite outcomes using marginal structural models accounting for serial blood pressure and serum creatinine measures. Of 2044 patients in ISIC, 1686 patients met inclusion criteria, of whom 398 (23.6%) patients who were previously on ACEi/ARB received at least 1 dose during their hospitalization for COVID-19. There were 215 deaths, 407 patients requiring mechanical ventilation, and 124 patients who required dialysis during their hospitalization. Prior ACEi/ARB use was associated with lower levels of soluble urokinase plasminogen activator receptor and C-reactive protein. In multivariable analysis, in-hospital ACEi/ARB use was associated with a lower risk of the composite outcome of in-hospital death, mechanical ventilation, or dialysis (adjusted hazard ratio 0.49, 95% CI [0.36-0.65]). Conclusions In patients hospitalized for COVID-19, ACEi/ARB use was associated with lower levels of inflammation and lower risk of in-hospital outcomes. Clinical trials will define the role of ACEi/ARB in the treatment of COVID-19. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT04818866.

Sinus bradycardia is associated with poor outcome in critically ill patients with COVID-19 due to the B.1.1.7 Lineage.

The progress of COVID-19 from moderate to severe may be precipitous, while the characteristics of the disease are heterogenous. The aim of this study was to describe the development of sinus bradycardia in critically ill patients with COVID-19 and its association with outcome in outbreak due to the SARS-CoV-2 B.1.1.7 Lineage. We leveraged the multi-center SuPAR in Adult Patients With COVID-19 (SPARCOL) study and identified patients who required admission to intensive care unit (ICU). Inclusion criteria were: (a) adult (≥18 years old) patients hospitalized primarily for COVID-19; (b) a confirmed SARS-CoV-2 infection diagnosed through reverse transcriptase polymerase chain reaction test of nasopharyngeal or oropharyngeal samples; and (c) at least one blood sample collected at admission and stored for suPAR, hs-CRP, and ferritin testing. All patients had continuous heart rate monitoring during hospitalization. In total, 81 patients were included. Of them, 17 (21 %) and 64 (79 %) were intubated and admitted to the ICU during the first and second wave, respectively. Two (12 %) and 62 (97 %) developed bradycardia before ICU admission, respectively (p < 0.001). Patients with bradycardia had increased suPAR (p < 0.001) and hs-CRP level (p < 0.001). Infusion of isoprenaline and/or noradrenaline was necessary to maintain an adequate rate and peripheral perfusion in all patients. Mortality was significantly higher in patients with bradycardia (p < 0.001). In conclusion, bradycardia was associated with poor outcome. As B.1.1.7 variant strain is spreading more rapidly in many countries, our findings help in the identification of patients who may require early admission to ICU.

Video Laryngoscopy Improves Intubation Times With Level C Personal Protective Equipment in Novice Physicians: A Randomized Cross-Over Manikin Study.

BACKGROUND: The use of video laryngoscopes by novice physicians may improve first-pass success rates compared with direct laryngoscopy. OBJECTIVE: The aim of the present study was to assess whether time to intubation, number of laryngoscopy attempts, and first-pass success rate during laryngoscopy with the video laryngoscope or conventional Macintosh laryngoscope are affected by personal protective equipment (PPE) donning. METHODS: Seventy inexperienced physicians were randomly assigned to video laryngoscope or Macintosh groups and were instructed to perform intubation with both devices on a manikin, using PPE or a standard uniform. The primary outcomes were insertion time, number of laryngoscopy attempts, and first-pass success rates for each device with or without donning PPE. RESULTS: In the Macintosh group, significantly less time was needed for the first successful intubation without PPE vs. with PPE (12.17 ± 3.69 s vs. 24.07 ± 5.09 s, respectively; p < 0.0001). On the other hand, such difference was not observed in the video laryngoscope group (14.99 ± 3.01 s vs. 14.01 ± 3.35 s, respectively; p = 0.07). With PPE, the first-pass success rate was significantly higher in the video laryngoscope group [41 (58.6%) vs. 66 (94.3%), p < 0.001]. The use of the video laryngoscope resulted in a significant decrease in insertion time compared with the Macintosh blade (14.01 ± 3.35 s vs. 24.07 ± 5.09 s, respectively; p < 0.0001). CONCLUSION: First-pass success and insertion time with the video laryngoscope were not affected by PPE donning. However, both were negatively affected with the Macintosh laryngoscope.

A Critical Appraisal of the Effects of Anesthetics on Immune-system Modulation in Critically Ill Patients With COVID-19.

PURPOSE: The aim of the present article was to briefly summarize current knowledge about the immunomodulatory effects of general anesthetics and the possible clinical effects of this immunomodulation in patients with COVID-19. METHODS: The PubMed, Scopus, and Google Scholar databases were comprehensively searched for relevant studies. FINDINGS: The novel coronavirus causes a wide spectrum of clinical manifestations, with a large absolute number of patients experiencing severe pneumonia and rapid progression to acute respiratory distress syndrome and multiple organ failure. In these patients, the equilibrium of the inflammatory response is a major determinant of survival. The impact of anesthetics on immune-system modulation may vary and includes both pro-inflammatory and anti-inflammatory effects. IMPLICATIONS: Inhibition of the development of severe inflammation and/or the enhancement of inflammation resolution by anesthetics may limit organ damage and improve outcomes in patients with COVID-19.

Soluble Urokinase Receptor (SuPAR) in COVID-19-Related AKI.

BACKGROUND: AKI commonly occurs in patients with coronavirus disease 2019 (COVID-19). Its pathogenesis is poorly understood. The urokinase receptor system is a key regulator of the intersection between inflammation, immunity, and coagulation, and soluble urokinase plasminogen activator receptor (suPAR) has been identified as an immunologic risk factor for AKI. Whether suPAR is associated with COVID-19-related AKI is unknown. METHODS: In a multinational observational study of adult patients hospitalized for COVID-19, we measured suPAR levels in plasma samples from 352 adult patients that had been collected within 48 hours of admission. We examined the association between suPAR levels and incident in-hospital AKI. RESULTS: Of the 352 patients (57.4% were male, 13.9% were black, and mean age was 61 years), 91 (25.9%) developed AKI during their hospitalization, of whom 25 (27.4%) required dialysis. The median suPAR level was 5.61 ng/ml. AKI incidence rose with increasing suPAR tertiles, from a 6.0% incidence in patients with suPAR <4.60 ng/ml (first tertile) to a 45.8% incidence of AKI in patients with suPAR levels >6.86 ng/ml (third tertile). None of the patients with suPAR <4.60 ng/ml required dialysis during their hospitalization. In multivariable analysis, the highest suPAR tertile was associated with a 9.15-fold increase in the odds of AKI (95% confidence interval [95% CI], 3.64 to 22.93) and a 22.86-fold increase in the odds of requiring dialysis (95% CI, 2.77 to 188.75). The association was independent of inflammatory markers and persisted across subgroups. CONCLUSIONS: Admission suPAR levels in patients hospitalized for COVID-19 are predictive of in-hospital AKI and the need for dialysis. SuPAR may be a key component of the pathophysiology of AKI in COVID-19.

Soluble Urokinase Plasminogen Activator Receptor: A Biomarker for Predicting Complications and Critical Care Admission of COVID-19 Patients.

The novel coronavirus infection has spread worldwide, causing a wide spectrum of clinical manifestations. Most patients develop moderate clinical illness, but a substantial number will experience severe pneumonia, which may rapidly progress to acute respiratory distress syndrome and multiple organ failure. In this population, soluble urokinase plasminogen activator receptor (suPAR) could serve as a quick triage test and independent marker of clinical severity, hospital and intensive care unit admission, complications, and mortality.