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 as a Decision Marker for Early Discharge of Patients with COVID-19 Symptoms in the Emergency Department.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (The Covid-19 pandemic) strains health care capacity. Better risk stratification, with discharge of patients with a predicted mild disease trajectory, can ease this burden. Elevated blood-soluble urokinase plasminogen activator receptor (suPAR) has previously been shown to be associated with risk of intubation in confirmed COVID-19 patients. OBJECTIVE: To evaluate whether point-of-care measures of suPAR in patients presenting to the emergency department (ED) with symptoms of COVID-19 can identify patients that can be safely discharged. METHODS: Observational cohort study including all patients in the ED with symptoms of COVID-19 from March 19 to April 3, 2020. SuPAR was measured at first presentation. Review of electronic patient records 14 days after admission was used to assess disease trajectory. Primary endpoints were mild, moderate, severe, or very severe trajectory. The predictive value of suPAR, National Early Warning Score (NEWS), C-reactive protein (CRP), and duration of symptoms was calculated using receiver operating characteristics (ROC). RESULTS: Of 386 patients, 171 (44%) had a mild disease trajectory, 79 (20%) a moderate, 63 (16%) a severe, and 73 (19%) a very severe disease trajectory. Low suPAR was a strong marker of mild disease trajectory. Results suggest a cut-off for discharge for suPAR < 2.0 ng/mL if suPAR is used as a single parameter, and <3.0 ng/mL when combined with NEWS ≤ 4 and CRP < 10 mg/L. CONCLUSION: suPAR is a potential biomarker for triage and safe early discharge of patients with COVID-19 symptoms in the ED. suPAR can be used even before SARS-CoV-2 status is known.

COVID-19 mortality among selective serotonin reuptake inhibitor users-results from a nationwide cohort.

OBJECTIVE: To examine differences in mortality and/or severe acute respiratory syndrome between selective serotonin reuptake inhibitor- (SSRI) users and non-SSRI users up to 60 days after a positive SARS-CoV-2 real-time reverse transcription PCR test. METHODS: Retrospective cohort study including all Danish residents above the age of eighteen with a positive SARS-CoV-2 PCR test from 26 February, 2020 to 5 October, 2021. The follow-up period was 60 days. The primary outcome was all-cause mortality, and the secondary outcome was severe acute respiratory syndrome. Exposure of interest was SSRI use. Differences between SSRI users and non-users were examined with Cox regression. RESULTS: Altogether, 286,447 SARS-CoV-2 positive individuals were identified, and 7113 met the criteria for SSRI use. SSRI users had a mean age of 50.4 years, and 34% were males. Non-SSRI users had a mean age of 41.4 years, and 50% were males. Similar vaccination frequency was observed among the two groups. Sertraline was the most commonly used SSRI, followed by citalopram and escitalopram. We found 255 deaths among SSRI users (3.6%) and 2872 deaths among non-SSRI users (1.0%). SSRI use was significantly associated with increased mortality, with a hazard ratio of 1.32 (95% confidence interval, 1.16 -1.50; p 0.015), even when adjusting for age, sex, vaccination status, and comorbidities. DISCUSSION: We found significantly higher mortality when comparing SSRI users to non-SSRI users within 60 days after a positive SARS-CoV-2 PCR test. Even when considering possible residual confounding, a positive effect of SSRI intake seems highly unlikely. Our study therefore speaks against the hypothesis of repurposing SSRI drugs for COVID-19 treatment.

suPAR Cut-Offs for Risk Stratification in Patients With Symptoms of COVID-19.

OBJECTIVES: Elevated soluble urokinase Plasminogen Activator Receptor (suPAR) is a biomarker associated with adverse outcomes. We aimed to investigate the associations between plasma suPAR levels (testing the cut-offs ⩽4, 4-6, and ⩾6 ng/mL) with risk of 14-day mortality, and with the risk of mechanical ventilation in patients that tested positive for SARS-CoV-2. METHODS: Observational cohort study of patients presenting with symptoms of COVID-19 at Department of Emergency Medicine, Amager and Hvidovre Hospital, Denmark from March 19th, 2020 to April 3rd, 2020. Plasma suPAR was measured using suPARnostic technologies. Patients were followed for development of mechanical ventilation and mortality for 14 days. Validation of our findings were carried out in a similar sized COVID-19 patient cohort from Mikkeli Central Hospital, Finland. RESULTS: Among 386 patients with symptoms of COVID-19, the median (interquartile range) age was 64 years (46-77), 57% were women, median suPAR was 4.0 ng/mL (2.7-5.9). In total, 35 patients (9.1%) died during the 14 days follow-up. Patients with suPAR ⩽4 ng/mL (N = 196; 50.8%) had a low risk of mortality (N = 2; 1.0%; negative predictive value of 99.0%, specificity 55.3%, sensitivity 95.2%, positive predictive value 17.4%). Among patients with suPAR ⩾6 ng/mL (N = 92; 23.8%), 16 died (17.4%). About 99 patients (25.6%) tested positive for SARS CoV-2 and of those 12 (12.1%) developed need for mechanical ventilation. None of the SARS-CoV-2 positive patients with suPAR ⩽4 ng/mL (N = 28; 38.8%) needed mechanical ventilation or died. The Mikkeli Central Hospital validation cohort confirmed our findings concerning suPAR cut-offs for risk of development of mechanical ventilation and mortality. CONCLUSIONS: Patients with symptoms of COVID-19 and suPAR ⩽4 or ⩾6 ng/mL had low or high risk, respectively, concerning the need for mechanical ventilation or mortality. We suggest cut-offs for identification of risk groups in patients presenting to the ED with symptoms of or confirmed COVID-19.

Rarity of invasiveness in right-sided infective endocarditis.

OBJECTIVE: The rarity of invasiveness of right-sided infective endocarditis (IE) compared with left-sided has not been well recognized and evaluated. Thus, we compared invasiveness of right- versus left-sided IE in surgically treated patients. PATIENTS AND METHODS: From January 2002 to January 2015, 1292 patients underwent surgery for active IE, 138 right-sided and 1224 left-sided. Among patients with right-sided IE, 131 had tricuspid and 7 pulmonary valve IE; 12% had prosthetic valve endocarditis. Endocarditis-related invasiveness was based on echocardiographic and operative findings. RESULTS: Invasive disease was rare on the right side, occurring in 1 patient (0.72%; 95% confidence interval 0.02%-4.0%); rather, it was limited to valve cusps/leaflets or was superficial. In contrast, IE was invasive in 408 of 633 patients with aortic valve (AV) IE (65%), 113 of 369 with mitral valve (MV) IE (31%), and 148 of 222 with AV and MV IE (67%). Staphylococcus aureus was a more predominant organism in right-sided than left-sided IE (right 40%, AV 19%, MV 29%), yet invasion was observed almost exclusively on the left side of the heart, which was more common and more severe with AV than MV IE and more common with prosthetic valve endocarditis than native valve IE. CONCLUSIONS: Rarity of right-sided invasion even when caused by S aureus suggests that invasion and development of cavities/"abscesses" in patients with IE may be driven more by chamber pressure than organism, along with other reported host-microbial interactions. The lesser invasiveness of MV compared with AV IE suggests a similar mechanism: decompression of MV annulus invasion site(s) toward the left atrium.

suPAR is associated with risk of future acute surgery and post-operative mortality in acutely admitted medical patients.

BACKGROUND: Acutely admitted medical patients are often fragile and in risk of future surgery. The biomarker soluble urokinase plasminogen activator receptor (suPAR) is a predictor of readmission and mortality in the acute care setting. We aimed to investigate if suPAR also predicts acute surgery, which is associated with higher mortality than elective surgery, and if it predicts post-operative mortality. METHODS: A retrospective registry-based cohort study of 17,312 patients admitted to an acute medical unit in Denmark, from 18 November 2013 until 30 September 2015. The first admission with available suPAR was defined as the index admission, and patients were followed via national registries until 1 January 2016. The risk of acute surgery during the entire follow-up period as well as the 90-day post-operative mortality risk was modeled by Cox regression analyses adjusted for sex, age, C-reactive protein, and Charlson Comorbidity Index (Charlson Score). RESULTS: Acute surgery was carried out on 2404 patients (13.9%) after a median of 45 days (interquartile range 5-186) following the index admission. Patients receiving acute surgery had higher baseline suPAR compared with patients receiving elective- or no surgery (p < 0.0001). The hazard ratio (HR) for acute surgery was 1.50 (95% confidence interval (CI): 1.42-1.59) for every doubling of the suPAR level in the adjusted Cox regression analysis. Death within 90 days occurred in 439 (18.3%) patients receiving acute surgery, and the adjusted HR for post-operative mortality was 1.73 (95% CI: 1.52-1.95). DISCUSSION: Elevated levels of suPAR in acutely admitted medical patients were independently associated with increased risk of future acute surgery as well as with 90-day post-operative mortality. TRIAL REGISTRATION: This retrospective registry-based cohort study was approved by the Danish Health and Medicines authority (reference no. 3-3013-1061/1). All processing of personal data followed national guidelines, and the project was approved by the Danish Data Protection Agency (reference no. HVH-2014-018, 02767).

Readmittance rates within seven days are preferable in quality measuring of emergency departments.

INTRODUCTION: The objective of this article was to qualify and test the recommendations of a national Danish report. We conducted an investigation on the readmittance rate as well as reasons for readmittance in a patient cohort defined through the process of internal audit at the Emergency Department at Zealand University Hospital, Køge, Denmark. METHODS: A retrospective, descriptive study of admitted patients in November 2014, including a total of 1,440 patients. Data and parameters were obtained from electronic patient records. RESULTS: A total of 162 patients were readmitted within 30 days from their initial admission (11% of the cohort). Of this group, 139 (86%) readmittances were unpreventable or planned. Readmissions caused by missed diagnosis or insufficient treatment accounted for 8% and 6%, respectively. The median time until readmission in these cases were two and four and a half days, respectively. The median time to readmission for the unpreventable readmissions ranged from 13 to 18.5 days. CONCLUSION: In terms of patient safety, our data support a seven-day observation period for readmission rates when measuring or monitoring quality of care in emergency departments. FUNDING: none. TRIAL REGISTRATION: none.

Lung recruitment maneuver depresses central hemodynamics in patients following cardiac surgery.

OBJECTIVE: To assess the impact of the lung recruitment maneuver on circulation following cardiac surgery. DESIGN AND SETTING: Prospective randomized cross-over study at the Departments of Anesthesia and Thoracic Surgery, Copenhagen University Hospital. PATIENTS: Ten adult undergoing coronary artery bypass surgery. INTERVENTIONS: Patients were randomized to two durations of lung recruitment maneuvers (40 cmH2O airway pressure for 10 s and 20 s or vice versa after 5 min) administered immediately after surgery. MEASUREMENTS AND RESULTS: Transesophageal echocardiography (left ventricular short axis view), pulse contour cardiac output, and arterial blood pressure were monitored continuously. Systemic and pulmonary arterial blood gases were sampled before and after each lung recruitment maneuver to calculate the intrapulmonary shunt. Left ventricular end-diastolic areas decreased significantly during both the 10-s and the 20-s lung recruitment maneuvers. Cardiac output was 5.6+/-0.8 l/min at baseline, decreasing by 3.0+/-1.1 l/min and 3.6+/-1.2 l/min during lung recruitment maneuvers of 10 and 20 s, respectively. Shunt decreased from 20+/-5% to 15+/-6% after the first lung recruitment maneuver and from 15+/-6% to 12+/-5% after the second. CONCLUSIONS: Lung recruitment maneuvers markedly reduced cardiac output and left ventricular end-diastolic areas in hemodynamically stable patients following cardiac surgery.

Fifteen years' clinical experience with the CarboMedics prosthetic heart valve.

BACKGROUND AND AIM OF THE STUDY: The CarboMedics bileaflet prosthetic heart valve was first implanted as part of a prospective clinical study at the authors' institution in November 1987. The patient cohort included was part of a multicenter trial set up by the manufacturer for an FDA application. The present report details findings over a 15-year period, with a continuous follow up on this patient cohort. METHODS: Between November 1987 and August 1990, 132 patients (68 males, 64 females; median age 56 years; range: 12-74 years) received a CarboMedics heart valve prosthesis. All patients were included in the study, whether surgery was elective or emergency, first time or reoperation. There were 69 aortic, 49 mitral and 12 double (aortic and mitral) valve replacements. Two patients had isolated tricuspid valve replacement. Concomitant surgery was performed in 15 patients. Anticoagulation with warfarin was started on postoperative day 1. After discharge, patients were examined regularly as outpatients for up to five years. Subsequent follow up was obtained prospectively by questionnaires to the patients' general practitioners and with telephone calls to the patients. Actuarial estimates of survival and freedom from morbid events were calculated using the Kaplan-Meier method; 95% confidence limits for the distribution function were calculated according to the Greenwood formula. RESULTS: Complete follow up information was available on 94% of the patients; total follow up was 1,270.3 patient-years (pt-yr). Actuarial survival at 15 years was 51+/-4.9% overall; 56+/-6.2% for single aortic, 51+/-8.0% for single mitral, and 30+/-15.9% for double valve replacements. Actuarial rates of freedom from complications were: valve thrombosis 100%, embolism 89+/-3.3%, and all anticoagulant-related bleeding 76+/-4.5%. The linearized rates per 100 pt-yr were: embolism 0.94 (aortic 0.74, mitral 1.25); anticoagulant-related bleeding 2.28; paravalvular leakage overall 0.24 (aortic 0.29); prosthetic valve endocarditis overall 0.24 (aortic 0.29, mitral 0.21). There was no hemolysis, prosthetic valve dysfunction, or structural deterioration. CONCLUSION: Over a 15-year time frame, the CarboMedics prosthetic heart valve has proven to be a highly reliable device with no structural failures and a low incidence of valve-related complications.

Fourteen years' experience with the CarboMedics valve in young adults with aortic valve disease.

BACKGROUND AND AIM OF THE STUDY: Homografts and the Ross procedure are recommended by many surgeons for aortic valve replacement (AVR) in young adults. The study aim was to monitor patient outcome over a 14-year period after implanting mechanical CarboMedics prosthetic heart valves in young adults with aortic valve disease. METHODS: Between November 1987 and December 2000, 55 patients (42 males, 13 females; median age 33 years; range 15-40 years) each received a CarboMedics valve in the aortic position. All patients were included on a consecutive and non-selected basis. Concomitant surgery was performed in five patients. Anticoagulation was commenced on postoperative day 1. After discharge, patients were followed up by their cardiologist or general practitioner using questionnaires and telephone calls. Actuarial estimates of survival and freedom from morbid events were calculated using the Kaplan-Meier method. RESULTS: No patient died during surgery. Complete follow up data were available for all patients; total follow up was 404 patient-years (pt-yr). The 30-day mortality rate was zero. Actuarial survival at 14 years was 90 +/- 4.9%, and actuarial freedom from all valve-related events 92 +/- 3.7%. No valve thrombosis or major bleeding events were identified. Linearized rates per 100 pt-yr were: embolism 0.25; paravalvular leakage 0.25; prosthetic endocarditis 0.25; and reoperation 0.50. There was no hemolysis, prosthetic valve dysfunction, or structural deterioration. CONCLUSION: Over a 14-year period, implantation of the CarboMedics prosthetic heart valve has proven to be an excellent solution for AVR in young adults with aortic valve disease.