Treatment of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis With Diffuse Alveolar Hemorrhage With Avacopan.

OBJECTIVE: Avacopan, an activated complement factor 5 receptor antagonist, has been approved as adjunct therapy for severe active antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Current evidence supports the management of AAV presenting with diffuse alveolar hemorrhage (DAH) by administering glucocorticoids combined with either rituximab or cyclophosphamide in addition to supportive care. The role of avacopan in patients with DAH as a primary severe disease manifestation of AAV has not been well established. Furthermore, concerns remain regarding timely access to avacopan, the best glucocorticoid tapering regimen, and long-term efficacy and safety of the drug. We sought to identify clinical features and outcomes of patients presenting with DAH secondary to AAV who received avacopan in addition to glucocorticoids and rituximab or cyclophosphamide. METHODS: We performed a retrospective cohort study of all consecutive patients presenting with DAH as part of active severe granulomatosis with polyangiitis or microscopic polyangiitis. Demographic and clinical characteristics were collected at presentation and follow-up. RESULTS: Fifteen patients met inclusion criteria and were observed for a median time of 17 weeks (interquartile range [IQR] 6-37 weeks) after initiation of avacopan. Patients were predominantly female and White, had never smoked, and were a median age of 66 years (IQR 52-72 years) at diagnosis. The majority had newly diagnosed severe AAV with renal involvement. Three patients progressed to respiratory failure. The timing of avacopan introduction and patterns of glucocorticoid tapers varied widely in this cohort. Two serious adverse events related to infection were observed, including one opportunistic infection leading to the patient's death, although neither was directly attributed to avacopan administration. CONCLUSION: We describe the clinical course of patients who presented with the severe AAV disease manifestation of DAH and received avacopan as adjunct therapy. Most patients achieved remission during follow-up, and adverse events, including infection, were observed.

Association of estimated plasma volume with new onset acute kidney injury in hospitalized COVID-19 patients.

PURPOSE: To explore the association of estimated plasma volume (ePV) and plasma volume status (PVS) as surrogates of volume status with new-onset AKI and in-hospital mortality among hospitalized COVID-19 patients. MATERIALS AND METHODS: We performed a retrospective multi-center study on COVID-19-related ARDS patients who were admitted to the Mayo Clinic Enterprise health system. Plasma volume was calculated using the formulae for ePV and PVS, and longitudinal analysis was performed to find the association of ePV and PVS with new-onset AKI during hospitalization as the primary outcome and in-hospital mortality as a secondary outcome. RESULTS: Our analysis included 7616 COVID-19 patients with new-onset AKI occurring in 1365 (17.9%) and a mortality rate of 25.96% among them. A longitudinal multilevel multivariate analysis showed both ePV (OR 1.162; 95% CI 1.048-1.288, p=0.004) and PVS (OR 1.032; 95% CI 1.012-1.050, p=0.001) were independent predictors of new onset AKI. Higher PVS was independently associated with increased in-hospital mortality (OR 1.038, 95% CI 1.007-1.070, p=0.017), but not ePV (OR 0.868, 95% CI 0.740-1.018, p=0.082). CONCLUSION: A higher PVS correlated with a higher incidence of new-onset AKI and worse outcomes in our cohort of hospitalized COVID-19 patients. Further large-scale and prospective studies are needed to understand its utility.

Pneumomediastinum and pneumothorax in coronavirus disease-2019: Description of a case series and a matched cohort study.

Objective: To describe the characteristics of COVID-19 patients with pneumothorax and pneumomediastinum (PTX/PM) and their association with patient outcomes. Patients and methods: Adults admitted to five Mayo Clinic hospitals with COVID-19 between 03/2020-01/2022 were evaluated. PTX/PM was defined by imaging. Descriptive analyses and a matched (age, sex, admission month, COVID-19 severity) cohort comparison was performed. Hospital mortality, length of stay (LOS), and predisposing factors were assessed. Results: Among 6663 patients, 197 had PTX/PM (3 %) (75 PM, 40 PTX, 82 both). The median age was 59, with 71 % males. Exposure to invasive and non-invasive mechanical ventilation and high-flow nasal cannula before PTX/PM were 42 %, 17 %, and 20 %, respectively. Among isolated PTX and PM/PTX patients 70 % and 53.7 % underwent an intervention, respectively, while 96 % of the PM-only group was followed conservatively.A total of 171 patients with PTX/PM were compared to 171 matched controls. PTX/PM patients had more underlying lung disease (40.9 vs. 23.4 %, p < 0.001) and lower median body mass index (BMI) (29.5 vs. 31.3 kg/m2, p = .007) than controls. Among patients with available data, PTX/PM patients had higher median positive end-expiratory and plateau pressures than controls; however, differences were not significant (10 vs. 8 cmH2O; p = 0.38 and 28 vs. 22 cmH2O; p = 0.11, respectively). PTX/PM patients had a higher odds of mortality (adjusted odds ratio [95%CI]: 3.37 [1.61-7.07]) and longer mean LOS (percent change [95%CI]: 39 [9-77]) than controls. Conclusion: In COVID-19 patients with similar severity, PTX/PM patients had more underlying lung disease and lower BMI. They had significantly increased mortality and LOS.

Association of antibiotics with the outcomes in COVID-19 pneumonia patients with elevated PCT levels.

OBJECTIVE: To assess antibiotics impact on outcomes in COVID-19 pneumonia patients with varying procalcitonin (PCT) levels. METHODS: This retrospective cohort study included 3665 COVID-19 pneumonia patients hospitalized at five Mayo Clinic sites (March 2020 to June 2022). PCT levels were measured at admission. Patients' antibiotics use and outcomes were collected via the Society of Critical Care Medicine (SCCM) Viral Infection and Respiratory Illness Universal Study (VIRUS) registry. Patients were stratified into high and low PCT groups based on the first available PCT result. The distinction between high and low PCT was demarcated at both 0.25 ng/ml and 0.50 ng/ml. RESULTS: Our cohort consisted of 3665 patients admitted with COVID-19 pneumonia. The population was predominantly male, Caucasian and non-Hispanic. With the PCT cut-off of 0.25 ng/ml, 2375 (64.8 %) patients had a PCT level <0.25 ng/mL, and 1290 (35.2 %) had PCT ≥0.25 ng/ml. While when the PCT cut off of 0.50 ng/ml was used we observed 2934 (80.05 %) patients with a PCT <0.50 ng/ml while 731(19.94 %) patients had a PCT ≥0.50 ng/ml. Patients with higher PCT levels exhibited significantly higher rates of bacterial infections (0.25 ng/ml cut-off: 4.2 % vs 7.9 %; 0.50 ng/ml cut-off: 4.6 % vs 9.2 %). Antibiotics were used in 66.0 % of the cohort. Regardless of the PCT cutoffs, the antibiotics group showed increased hospital length of stay (LOS), intensive care unit (ICU) admission rate, and mortality. However, early de-escalation (<24 h) of antibiotics correlated with reduced hospital LOS, ICU LOS, and mortality. These results were consistent even after adjusting for confounders. CONCLUSION: Our study shows a substantial number of COVID-19 pneumonia patients received antibiotics despite a low incidence of bacterial infections. Therefore, antibiotics use in COVID pneumonia patients with PCT <0.5 in the absence of clinical evidence of bacterial infection has no beneficial effect.

Are sodium-glucose co-transporter-2 inhibitors associated with improved outcomes in diabetic patients admitted to intensive care units with septic shock?

BACKGROUND: Sodium-glucose cotransporter-2 inhibitors (SGLT2i) have been shown to reduce organ dysfunction in renal and cardiovascular disease. There are limited data on the role of SGLT2i in acute organ dysfunction. We conducted a study to assess the effect of SGLT2i taken prior to intensive care unit (ICU) admission in diabetic patients admitted with septic shock. METHODS: This retrospective cohort study used electronic medical records and included diabetic patients admitted to the ICU with septic shock. We compared diabetic patients on SGLT2i to those who were not on SGLT2i prior to admission. The primary outcome was in-hospital mortality, and secondary outcomes included hospital and ICU length of stay, use of renal replacement therapy, and 28- and 90-day mortality. RESULTS: A total of 98 diabetic patients was included in the study, 36 in the SGLT2i group and 62 in the non-SGLT2i group. The Sequential Organ Failure Assessment and Acute Physiology and Chronic Health Evaluation III scores were similar in the groups. Inpatient mortality was significantly lower in the SGLT2i group (5.6% vs. 27.4%, P=0.008). There was no significant difference in secondary outcomes. CONCLUSIONS: Our study found that diabetic patients on SGLT2i prior to hospitalization who were admitted to the ICU with septic shock had lower inpatient mortality compared to patients not on SGLT2i.

The Association of Asthma and Metabolic Dysfunction With Outcomes of Hospitalized Patients With COVID-19.

BACKGROUND: There have been conflicting results on the association of asthma with the severity of coronavirus disease 2019 (COVID-19). Poor metabolic health has been previously associated with both severe COVID-19 and inflammation in asthma. OBJECTIVES: To examine the association between asthma and COVID-19 outcomes and whether these associations are modified by metabolic syndrome. METHODS: We performed an international, observational cohort study of adult patients hospitalized for COVID-19 from February 2020 through October 2021. The primary outcome was hospital mortality. RESULTS: The study included 27,660 patients from 164 hospitals, 12,114 (44%) female, with a median (interquartile range) age of 63 years (51-75). After adjusting for age, sex, smoking, race, ethnicity, geographic region, and Elixhauser comorbidity index, we found that patients with asthma were not at greater risk of hospital death when compared with patients with no chronic pulmonary disease (controls) (adjusted odds ratio [aOR], 0.97; 95% CI, 0.90-1.04; P = .40). Patients with asthma, when compared with controls, required higher respiratory support identified by the need for supplemental oxygen (aOR, 1.07; 95% CI, 1.01-1.14; P = .02), high-flow nasal cannula or noninvasive mechanical ventilation (aOR, 1.06; 95% CI, 1.00-1.13; P = .04), and invasive mechanical ventilation (aOR, 1.09; 95% CI, 1.03-1.16; P = .003). Metabolic syndrome increased the risk of death in patients with asthma, but the magnitude of observed association was similar to controls in stratified analysis (interaction P value .24). CONCLUSIONS: In this international cohort of hospitalized COVID-19 patients, asthma was not associated with mortality but was associated with increased need for respiratory support. Although metabolic dysfunction was associated with increased risks in COVID-19, these risks were similar for patients with or without asthma.

Alveolar Hemorrhage in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: Results of an International Randomized Controlled Trial (PEXIVAS).

Rationale: Diffuse alveolar hemorrhage (DAH) is a life-threatening manifestation of antineutrophil cytoplasmic antibody-associated vasculitis (AAV). The PEXIVAS (Plasma Exchange and Glucocorticoids in Severe Antineutrophil Cytoplasmic Antibody-Associated Vasculitis) (NCT00987389) trial was the largest in AAV and the first to enroll participants with DAH requiring mechanical ventilation. Objectives: Evaluate characteristics, treatment effects, and outcomes for patients with AAV with and without DAH. Methods: PEXIVAS randomized 704 participants to plasma exchange (PLEX) or no-PLEX and reduced or standard-dose glucocorticoids (GC). DAH status was defined at enrollment as no-DAH, nonsevere, or severe (room air oxygen saturation of ⩽ 85% as measured by pulse oximetry, or use of mechanical ventilation). Measurements and Main Results: At enrollment, 191 (27.1%) participants had DAH (61 severe, including 29 ventilated) and were younger, more frequently relapsing, PR3 (proteinase 3)-ANCA positive, and had lower serum creatinine but were more frequently dialyzed than participants without DAH (n = 513; 72.9%). Among those with DAH, 8/95 (8.4%) receiving PLEX died within 1 year versus 15/96 (15.6%) with no-PLEX (hazard ratio, 0.52; confidence interval [CI], 0.21-1.24), whereas 13/96 (13.5%) receiving reduced GC died versus 10/95 (10.5%) with standard GC (hazard ratio, 1.33; CI, 0.57-3.13). When ventilated, ventilator-free days were similar with PLEX versus no-PLEX (medians, 25; interquartile range [IQR], 22-26 vs. 22-27) and fewer with reduced GC (median, 23; IQR, 20-25) versus standard GC (median, 26; IQR, 25-28). Treatment effects on mortality did not vary by presence or severity of DAH. Overall, 23/191 (12.0%) with DAH died within 1 year versus 34/513 (6.6%) without DAH. End-stage kidney disease and serious infections did not differ by DAH status or treatments. Conclusions: Patients with AAV and DAH differ from those without DAH in multiple ways. Further data are required to confirm or refute a benefit of PLEX or GC dosing on mortality. Original clinical trial registered with www.clinicaltrials.gov (NCT00987389).

Validation of automated data abstraction for SCCM discovery VIRUS COVID-19 registry: practical EHR export pathways (VIRUS-PEEP).

Background: The gold standard for gathering data from electronic health records (EHR) has been manual data extraction; however, this requires vast resources and personnel. Automation of this process reduces resource burdens and expands research opportunities. Objective: This study aimed to determine the feasibility and reliability of automated data extraction in a large registry of adult COVID-19 patients. Materials and methods: This observational study included data from sites participating in the SCCM Discovery VIRUS COVID-19 registry. Important demographic, comorbidity, and outcome variables were chosen for manual and automated extraction for the feasibility dataset. We quantified the degree of agreement with Cohen's kappa statistics for categorical variables. The sensitivity and specificity were also assessed. Correlations for continuous variables were assessed with Pearson's correlation coefficient and Bland-Altman plots. The strength of agreement was defined as almost perfect (0.81-1.00), substantial (0.61-0.80), and moderate (0.41-0.60) based on kappa statistics. Pearson correlations were classified as trivial (0.00-0.30), low (0.30-0.50), moderate (0.50-0.70), high (0.70-0.90), and extremely high (0.90-1.00). Measurements and main results: The cohort included 652 patients from 11 sites. The agreement between manual and automated extraction for categorical variables was almost perfect in 13 (72.2%) variables (Race, Ethnicity, Sex, Coronary Artery Disease, Hypertension, Congestive Heart Failure, Asthma, Diabetes Mellitus, ICU admission rate, IMV rate, HFNC rate, ICU and Hospital Discharge Status), and substantial in five (27.8%) (COPD, CKD, Dyslipidemia/Hyperlipidemia, NIMV, and ECMO rate). The correlations were extremely high in three (42.9%) variables (age, weight, and hospital LOS) and high in four (57.1%) of the continuous variables (Height, Days to ICU admission, ICU LOS, and IMV days). The average sensitivity and specificity for the categorical data were 90.7 and 96.9%. Conclusion and relevance: Our study confirms the feasibility and validity of an automated process to gather data from the EHR.

Clinical features, risk factors, and outcomes of diffuse alveolar hemorrhage in antiphospholipid syndrome: A mixed-method approach combining a multicenter cohort with a systematic literature review.

BACKGROUND: Antiphospholipid syndrome (APS) is a systemic autoimmune disease clinically associated with thrombotic and obstetric events. Additional manifestations have been associated with APS, like diffuse alveolar hemorrhage (DAH). We aimed to summarize all the evidence available to describe the presenting clinical features, their prognostic factors, and short- and long-term outcomes. METHODS: We performed a mixed-method approach combining a multicenter cohort with a systematic literature review (SLR) of patients with incident APS-associated DAH. We described their clinical features, treatments, prognostic factors, and outcomes (relapse, mortality, and requirement of mechanical ventilation [MV]). Kaplan-Meier methods were used to estimate relapse and mortality rates, and Cox and logistic regression models were used to assess the factors associated as appropriate. RESULTS: We included 219 patients with incident APS-associated DAH (61 from Mayo Clinic and 158 from SLR). The median age was 39.5 years, 51% were female, 29% had systemic lupus erythematosus, and 34% presented with catastrophic APS (CAPS). 74% of patients had a history of thrombotic events, and 26% of women had a history of pregnancy morbidity; half of the patients had a history of thrombocytopenia, and a third had valvulopathy. Before DAH, 55% of the patients were anticoagulated. At DAH onset, 65% of patients presented hemoptysis. The relapse rate was 47% at six months and 52% at one year. Triple positivity (HR 4.22, 95% CI 1.14-15.59) was associated with relapse at six months. The estimated mortality at one and five years was 30.3% and 45.8%. Factors associated with mortality were severe thrombocytopenia (< 50 K/µL) (HR 3.10, 95% CI 1.39-6.92), valve vegetations (HR 3.22, 95% CI 1.14-9.07), CAPS (HR 3.80, 95% CI 1.84-7.87), and requirement of MV (HR 2.22, 95% CI 1.03-4.80). Forty-two percent of patients required MV on the incident DAH episode. Patients presenting with severe thrombocytopenia (OR 6.42, 95% CI 1.77-23.30) or CAPS (OR 4.30, 95% CI 1.65-11.16) were more likely to require MV. CONCLUSION: APS-associated DAH is associated with high morbidity and mortality, particularly when presenting with triple positivity, thrombocytopenia, valvular involvement, and CAPS.

Association of plasma volume status with outcomes in hospitalized Covid-19 ARDS patients: A retrospective multicenter observational study.

PURPOSE: To evaluate the association of estimated plasma volume (ePV) and plasma volume status (PVS) on admission with the outcomes in COVID-19-related acute respiratory distress syndrome (ARDS) patients. MATERIALS AND METHODS: We performed a retrospective multi-center study on COVID-19-related ARDS patients who were admitted to the Mayo Clinic Enterprise health system. Plasma volume was calculated using the formulae for ePV and PVS, and these variables were analyzed for correlation with patient outcomes. RESULTS: Our analysis included 1298 patients with sequential organ failure assessment (SOFA) respiratory score ≥ 2 (PaO2/FIO2 ≤300 mmHg) and a mortality rate of 25.96%. A Cox proportional multivariate analysis showed PVS but not ePV as an independent correlation with 90-day mortality after adjusting for the covariates (HR: 1.015, 95% CI: 1.005-1.025, p = 0.002 and HR 1.054, 95% CI 0.958-1.159, p = 0.278 respectively). CONCLUSION: A lower PVS on admission correlated with a greater chance of survival in COVID-19-related ARDS patients. The role of PVS in guiding fluid management should be investigated in future prospective studies.

Amphipathic Liponecrosis Impairs Bacterial Clearance and Causes Infection During Sterile Inflammation.

BACKGROUND & AIMS: Although transient bacteremia is common during dental and endoscopic procedures, infections developing during sterile diseases like acute pancreatitis (AP) can have grave consequences. We examined how impaired bacterial clearance may cause this transition. METHODS: Blood samples from patients with AP, normal controls, and rodents with pancreatitis or those administered different nonesterified fatty acids (NEFAs) were analyzed for albumin-unbound NEFAs, microbiome, and inflammatory cell injury. Macrophage uptake of unbound NEFAs using a novel coumarin tracer were done and the downstream effects-NEFA-membrane phospholipid (phosphatidylcholine) interactions-were studied on isothermal titration calorimetry. RESULTS: Patients with infected AP had higher circulating unsaturated NEFAs; unbound NEFAs, including linoleic acid (LA) and oleic acid (OA); higher bacterial 16S DNA; mitochondrial DNA; altered ß-diversity; enrichment in Pseudomonadales; and increased annexin V-positive myeloid (CD14) and CD3-positive T cells on admission. These, and increased circulating dead inflammatory cells, were also noted in rodents with unbound, unsaturated NEFAs. Isothermal titration calorimetry showed progressively stronger unbound LA interactions with aqueous media, phosphatidylcholine, cardiolipin, and albumin. Unbound NEFAs were taken into protein-free membranes, cells, and mitochondria, inducing voltage-dependent anion channel oligomerization, reducing ATP, and impairing phagocytosis. These were reversed by albumin. In vivo, unbound LA and OA increased bacterial loads and impaired phagocytosis, causing infection. LA and OA were more potent for these amphipathic interactions than the hydrophobic palmitic acid. CONCLUSIONS: Release of stored LA and OA can increase their circulating unbound levels and cause amphipathic liponecrosis of immune cells via uptake by membrane phospholipids. This impairs bacterial clearance and causes infection during sterile inflammation.

Improving the process of ordering outside genomic testing for lung cancer FNA and small biopsy specimens - A multidisciplinary quality improvement project.

Objectives: Lung cancer is an important cause of mortality in the United States. Targeted mutation analysis has the potential to alter mortality in those with non-small-cell lung cancer. As such, the importance of timely tissue turnaround time (TAT) is substantial. We evaluated TAT at Mayo Clinic Arizona and found it to be delayed relative to national standards. Material and Methods: We conducted a series of plan, do, study, and act (PDSA) cycles at a single institution to identify areas for improvement with our lung cancer genomic testing. We assembled a multidisciplinary team and held serial meetings to discuss data from each PDSA cycle. Results: Using PDSA cycles and multidisciplinary discussions, we were able to identify a number of process limitations slowing TAT. We were then able to generate enhanced and timely communication between providers and pathology, educate and enforce the order/requisition workflow, and establish pathology accessioning with lung cancer specimens top priority. Conclusion: We were able to generate and implement a standard operating procedure for genomic testing of lung cancer specimens at our institution, thereby reducing tissue TAT.

Biomarker-Concordant Steroid Administration in Severe Coronavirus Disease-2019.

BACKGROUND: Although corticosteroids have become the standard of care for patients with coronavirus disease-2019 (COVID-19) on supplemental oxygen, there is growing evidence of differential treatment response. This study aimed to evaluate if there was an association between biomarker-concordant corticosteroid treatment and COVID-19 outcomes. METHODS: This registry-based cohort study included adult COVID-19 hospitalized patients between January 2020 and December 2021 from 109 institutions. Patients with available C-reactive protein (CRP) levels within 48 h of admission were evaluated. Those on steroids before admission, stayed in the hospital for <48 h, or were not on oxygen support were excluded. Corticosteroid treatment was biomarker-concordant if given with high baseline CRP ≥150 mg/L or withheld with low CRP (<150 mg/L) and vice-versa was considered discordant (low CRP with steroids, high CRP without steroids). Hospital mortality was the primary outcome. Sensitivity analyses were conducted using varying CRP level thresholds. The model interaction was tested to determine steroid effectiveness with increasing CRP levels. RESULTS: Corticosteroid treatment was biomarker-concordant in 1778 (49%) patients and discordant in 1835 (51%). The concordant group consisted of higher-risk patients than the discordant group. After adjusting for covariates, the odds of in-hospital mortality were significantly lower in the concordant group than the discordant (odds ratio [95% confidence interval (C.I.)] = 0.71 [0.51, 0.98]). Similarly, adjusted mortality difference was significant at the CRP thresholds of 100 and 200 mg/L (odds ratio [95% C.I.] = 0.70 [0.52, 0.95] and 0.57 [0.38, 0.85], respectively), and concordant steroid use was associated with lower need for invasive ventilation for 200 mg/L threshold (odds ratio [95% C.I.] = 0.52 [0.30, 0.91]). In contrast, no outcome benefit was observed at CRP threshold of 50. When the model interaction was tested, steroids were more effective at reducing mortality as CRP levels increased. CONCLUSION: Biomarker-concordant corticosteroid treatment was associated with lower odds of in-hospital mortality in severe COVID-19.

Guidelines for the Management of Adult Acute and Acute-on-Chronic Liver Failure in the ICU: Neurology, Peri-Transplant Medicine, Infectious Disease, and Gastroenterology Considerations.

OBJECTIVES: To develop evidence-based recommendations for clinicians caring for adults with acute liver failure (ALF) or acute on chronic liver failure (ACLF) in the ICU. DESIGN: The guideline panel comprised 27 members with expertise in aspects of care of the critically ill patient with liver failure or methodology. We adhered to the Society of Critical Care Medicine standard operating procedures manual and conflict-of-interest policy. Teleconferences and electronic-based discussion among the panel, as well as within subgroups, served as an integral part of the guideline development. INTERVENTIONS: In part 2 of this guideline, the panel was divided into four subgroups: neurology, peri-transplant, infectious diseases, and gastrointestinal groups. We developed and selected Population, Intervention, Comparison, and Outcomes (PICO) questions according to importance to patients and practicing clinicians. For each PICO question, we conducted a systematic review and meta-analysis where applicable. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation approach. We used the evidence to decision framework to facilitate recommendations formulation as strong or conditional. We followed strict criteria to formulate best practice statements. MEASUREMENTS AND MAIN RESULTS: We report 28 recommendations (from 31 PICO questions) on the management ALF and ACLF in the ICU. Overall, five were strong recommendations, 21 were conditional recommendations, two were best-practice statements, and we were unable to issue a recommendation for five questions due to insufficient evidence. CONCLUSIONS: Multidisciplinary, international experts formulated evidence-based recommendations for the management ALF and ACLF patients in the ICU, acknowledging that most recommendations were based on low quality and indirect evidence.

Development and Validation of an Acute Respiratory Distress Syndrome Prediction Model in Coronavirus Disease 2019: Updated Lung Injury Prediction Score.

OBJECTIVE: To develop and validate an updated lung injury prediction score for coronavirus disease 2019 (COVID-19) (c-LIPS) tailored for predicting acute respiratory distress syndrome (ARDS) in COVID-19. PATIENTS AND METHODS: This was a registry-based cohort study using the Viral Infection and Respiratory Illness Universal Study. Hospitalized adult patients between January 2020 and January 2022 were screened. Patients who qualified for ARDS within the first day of admission were excluded. Development cohort consisted of patients enrolled from participating Mayo Clinic sites. The validation analyses were performed on remaining patients enrolled from more than 120 hospitals in 15 countries. The original lung injury prediction score (LIPS) was calculated and enhanced using reported COVID-19-specific laboratory risk factors, constituting c-LIPS. The main outcome was ARDS development and secondary outcomes included hospital mortality, invasive mechanical ventilation, and progression in WHO ordinal scale. RESULTS: The derivation cohort consisted of 3710 patients, of whom 1041 (28.1%) developed ARDS. The c-LIPS discriminated COVID-19 patients who developed ARDS with an area under the curve (AUC) of 0.79 compared with original LIPS (AUC, 0.74; P<.001) with good calibration accuracy (Hosmer-Lemeshow P=.50). Despite different characteristics of the two cohorts, the c-LIPS's performance was comparable in the validation cohort of 5426 patients (15.9% ARDS), with an AUC of 0.74; and its discriminatory performance was significantly higher than the LIPS (AUC, 0.68; P<.001). The c-LIPS's performance in predicting the requirement for invasive mechanical ventilation in derivation and validation cohorts had an AUC of 0.74 and 0.72, respectively. CONCLUSION: In this large patient sample c-LIPS was successfully tailored to predict ARDS in COVID-19 patients.

Portopulmonary Hypertension in Nontransplanted Patients: Results of the Largest US Single-Institution Registry.

OBJECTIVE: To explore clinical characteristics, risk profiles, and outcomes of patients with portopulmonary hypertension (PoPH) who have contraindications to liver transplant (LT). METHODS: From the largest US single-institution registry of patients with PoPH, we analyzed 160 patients who did not receive LT between 1988 to 2019. Pulmonary arterial hypertension (PAH)-pertinent characteristics, hemodynamic features, treatments, and risk stratification were compared at baseline, first follow-up visit, and censor/death time. RESULTS: Median survival for the entire cohort was 27.5 months from the diagnosis of PoPH. Overall survival was 89%, 77%, 51%, and 38% at 6 months, 1 year, 3 years, and 5 years, respectively. Survival was significantly affected by the severity of liver disease (P<.001). Most patients received PAH-specific therapies (136 [85%]), predominantly monotherapy (123 [77%)]. With treatment, significant improvements were noted in World Health Organization functional class (P=.04), 6-minute walk distance (P<.001), right ventricular function (P<.001), pulmonary vascular resistance (P<.001), and Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management (REVEAL) Lite 2 score (P=.02) univariately. Per European Society of Cardiology risk stratification, no patient met full criteria for low risk at baseline or at follow-up. In a multivariate Cox risk model, 6-minute walk distance, right atrial pressure, pulmonary capillary wedge pressure, bilirubin level, and Model for End-Stage Liver Disease-sodium score of 15 or higher were associated with increased risk of death. CONCLUSION: Patients with PoPH who did not undergo LT had a poor prognosis. This persisted despite use of PAH-specific therapies and significant improvements in hemodynamics, echocardiography parameters of right ventricle function, 6-minute walk distance, and World Health Organization functional class.

Health economic evaluation alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (E-PROSPECT): a cost-effectiveness analysis.

PURPOSE: We sought to compare the cost-effectiveness of probiotics and usual care with usual care without probiotics in mechanically ventilated, intensive care unit patients alongside the Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial (PROSPECT). METHODS: We conducted a health economic evaluation alongside the PROSPECT randomized control trial (October 2013-March 2019). We adopted a public healthcare payer's perspective. Forty-four intensive care units in three countries (Canada/USA/Saudi Arabia) with adult critically ill, mechanically ventilated patients (N = 2,650) were included. Interventions were probiotics (Lactobacillus rhamnosus GG) vs placebo administered enterally twice daily. We collected healthcare resource use and estimated unit costs in 2019 United States dollars (USD) over a time horizon from randomization to hospital discharge/death. We calculated incremental cost-effectiveness ratios (ICERs) comparing probiotics vs usual care. The primary outcome was incremental cost per ventilator-associated pneumonia (VAP) event averted; secondary outcomes were costs per Clostridioides difficile-associated diarrhea (CDAD), antibiotic-associated diarrhea (AAD), and mortality averted. Uncertainty was investigated using nonparametric bootstrapping and sensitivity analyses. RESULTS: Mean (standard deviation [SD]) cost per patient was USD 66,914 (91,098) for patients randomized to probiotics, with a median [interquartile range (IQR)] of USD 42,947 [22,239 to 76,205]. By comparison, for those not receiving probiotics, mean (SD) cost per patient was USD 62,701 (78,676) (median [IQR], USD 41,102 [23,170 to 75,140]; incremental cost, USD 4,213; 95% confidence interval [CI], -2,269 to 10,708). Incremental cost-effectiveness ratios for VAP or AAD events averted, probiotics were dominated by usual care (more expensive, with similar effectiveness). The ICERs were USD 1,473,400 per CDAD event averted (95% CI, undefined) and USD 396,764 per death averted (95% CI, undefined). Cost-effectiveness acceptability curves reveal that probiotics were not cost-effective across wide ranges of plausible willingness-to-pay thresholds. Sensitivity analyses did not change the conclusions. CONCLUSIONS: Probiotics for VAP prevention among critically ill patients were not cost-effective. Study registration data www. CLINICALTRIALS: gov (NCT01782755); registered 4 February 2013.

RéSUMé: OBJECTIF: Nous avons cherché à comparer le rapport coût-efficacité d'un traitement avec probiotiques ajoutés aux soins habituels avec des soins habituels prodigués sans probiotiques chez les patients des soins intensifs sous ventilation mécanique dans le cadre de l'étude PROSPECT (Probiotics to Prevent Severe Pneumonia and Endotracheal Colonization Trial). MéTHODE: Nous avons réalisé une évaluation de l'économie de la santé parallèlement à l'étude randomisée contrôlée PROSPECT (octobre 2013-mars 2019). Nous avons adopté le point de vue d'un payeur public de services de santé. Quarante-quatre unités de soins intensifs dans trois pays (Canada/États-Unis/Arabie saoudite) prenant soin de patients adultes gravement malades sous ventilation mécanique (n = 2650) ont été inclus. Les interventions ont été les suivantes : probiotiques (Lactobacillus rhamnosus GG) vs placebo administrés par voie entérale deux fois par jour. Nous avons recueilli les données concernant l'utilisation des ressources en soins de santé et estimé les coûts unitaires en dollars américains (USD) de 2019 sur un horizon temporel allant de la randomisation au congé de l'hôpital / décès. Nous avons calculé des rapports coût-efficacité différentiels (RCED) en comparant les probiotiques vs les soins habituels. Le critère d'évaluation principal était le coût différentiel par événement évité de pneumonie associée au ventilateur (PAV); les critères d'évaluation secondaires étaient les coûts par diarrhée associée au Clostridioides difficile (DACD), diarrhée associée aux antibiotiques (DAA) et mortalité évitées. L'incertitude a été étudiée à l'aide d'analyses d'amorçage et de sensibilité non paramétriques. RéSULTATS: Le coût moyen (écart type [ÉT]) par patient était de 66 914 (91 098) USD pour les patients randomisés au groupe probiotiques, avec une médiane [écart interquartile (ÉIQ)] de 42 947 USD [22 239 à 76 205]. En comparaison, pour ceux ne recevant pas de probiotiques, le coût moyen (ÉT) par patient était de 62 701 USD (78 676) (médiane [ÉIQ], 41 102 USD [23 170 à 75 140]; coût différentiel, 4213 USD; intervalle de confiance [IC] à 95%, -2269 à 10 708). En matière de rapports coût-efficacité différentiels pour les événements de PAV ou DAA évités, les probiotiques étaient dominés par les soins habituels (plus coûteux, avec une efficacité similaire). Les RCED étaient de 1 473 400 USD par événement de DACD évitée (IC 95 %, non défini) et de 396 764 USD par décès évité (IC 95 %, non défini). Les courbes d'acceptabilité coût-efficacité révèlent que les probiotiques n'étaient pas rentables dans de larges gammes de seuils plausibles de volonté de payer. Les analyses de sensibilité n'ont pas modifié les conclusions. CONCLUSION: Les probiotiques utilisés pour prévenir la PAV chez les patients gravement malades n'étaient pas rentables. Enregistrement de l'étude : www.clinicaltrials.gov (NCT01782755); enregistrée le 4 février 2013.

Pre-hospital Aspirin Use and Patient Outcomes in COVID-19: Results from the International Viral Infection and Respiratory Illness Universal Study (VIRUS).

INTRODUCTION: The goal of this investigation is to assess the association between prehospital use of aspirin (ASA) and patient-centered outcomes in a large global cohort of hospitalized COVID-19 patients. METHODS: This study utilizes data from the Society of Critical Care Medicine Discovery Viral Infection and Respiratory Illness Universal Study (VIRUS) Registry. Adult patients hospitalized from February 15th, 2020, to September 30th, 2021, were included. Multivariable regression analyses were utilized to assess the association between pre-hospital use of ASA and the primary outcome of overall hospital mortality. RESULTS: 21,579 patients were included from 185 hospitals (predominantly US-based, 71.3%), with 4691 (21.7%) receiving pre-hospital ASA. Patients receiving ASA, compared to those without pre-admission ASA use, were generally older (median 70 vs. 59 years), more likely to be male (58.7 vs. 56.0%), caucasian (57.4 vs. 51.6%), and more commonly had higher rates of medical comorbidities. In multivariable analyses, patients receiving pre-hospital ASA had lower mortality (HR: 0.89, 95% CI 0.82-0.97, p=0.01) and reduced hazard for progression to severe disease or death (HR: 0.91, 95% CI 0.84-0.99, p=0.02) and more hospital free days (1.00 days, 95% CI 0.66-1.35, p=0.01) compared to those without pre-hospital ASA use. The overall direction and significance of the results remained the same in sensitivity analysis, after adjusting the multivariable model for time since pandemic. CONCLUSIONS: In this large international cohort, pre-hospital use of ASA was associated with a lower hazard for death in hospitalized patients with COVID-19. Randomized controlled trials may be warranted to assess the utility of pre-hospital use of ASA.

Intensive care unit delirium in patients with severe COVID-19: A prospective observational cohort study.

Background: Delirium is common in patients with severe coronavirus disease-19 (COVID-19). The purpose of our study was to determine whether severe COVID-19 is an independent risk factor for the development of delirium in patients treated in the intensive care unit (ICU). Methods: This prospective observational cohort study involved 162 critically ill patients admitted to a multidisciplinary ICU during 2019 and 2020. A validated screening tool was used to diagnose delirium. Multiple delirium risk factors were collected daily including clinical characteristics, hospital course, lab values, vital signs, surgical exposure, drug exposure, and COVID-19 characteristics. After univariate analysis, a multivariate logistic regression analysis was performed to determine independent risk factors associated with the development of delirium. Results: In our study population, 50 (31%) patients developed delirium. A total of 39 (24.1%) tested positive for COVID-19. Initial analysis showed COVID-19 to be more prevalent in those patients that developed delirium (40% vs. 17%; P = 0.003). Multivariate analysis showed opioid use (odds ratio [OR]: 24 [95% confidence intervals (CI): 16-27]; P ≤ 0.001), benzodiazepine use (OR: 23 [95% CI: 16-63] P = 0.001), and estimated mortality based on acute physiology and chronic health evaluation IV score (OR: 1.04 [95% CI: 1.01-1.07] P = 0.002) to be independently associated with delirium development. COVID-19 (OR: 1.44 [95% CI: 0.13-10.6]; P = 0.7) was not found to be associated with delirium. Conclusion: Delirium is prevalent in critically ill patients admitted to the ICU, including those with COVID-19. However, after adjustment for important covariates, we found in this cohort that COVID-19 was not an independent risk factor for delirium.