Identification of two early blood biomarkers ACHE and CLEC12A for improved risk stratification of critically ill COVID-19 patients.

In order to identify biomarkers for earlier prediction of COVID-19 outcome, we collected blood samples from patients with fatal outcomes (non-survivors) and with positive clinical outcomes (survivors) at ICU admission and after seven days. COVID-19 survivors and non-survivors showed significantly different transcript levels for 93 genes in whole blood already at ICU admission as revealed by RNA-Seq. These differences became even more pronounced at day 7, resulting in 290 differentially expressed genes. Many identified genes play a role in the differentiation of hematopoietic cells. For validation, we designed an RT-qPCR assay for C-type lectin domain family 12 member A (CLEC12A) and acetylcholinesterase (ACHE), two transcripts that showed highest potential to discriminate between survivors and non-survivors at both time points. Using our combined RT-qPCR assay we examined 33 samples to accurately predict patient survival with an AUROC curve of 0.931 (95% CI = 0.814-1.000) already at ICU admission. CLEC12A and ACHE showed improved prediction of patient outcomes compared to standard clinical biomarkers including CRP and PCT in combination (AUROC = 0.403, 95% CI = 0.108-0.697) or SOFA score (AUROC = 0.701 95% CI = 0.451-0.951) at day 0. Therefore, analyzing CLEC12A and ACHE gene expression from blood may provide a promising approach for early risk stratification of severely ill COVID-19 patients.

Anesthetic Management during Robotic-Assisted Minimal Invasive Thymectomy Using the Da Vinci System: A Single Center Experience.

Background: Robotic-assisted surgery is gaining more adaption in different surgical specialties. The number of patients undergoing robotic-assisted thymectomy is continuously increasing. Such procedures are accompanied by new challenges for anesthesiologists. We are presenting our primary anesthesiologic experience in such patients. Methods: This is a retrospective single center study, evaluating 28 patients who presented with thymoma or myasthenia gravis (MG) and undergone minimal invasive robotic-assisted thoracic thymectomy between 01/2020−01/2022. We present our fast-track anesthesia management as a component of the enhanced recovery program and its primary results. Results: Mean patient's age was 46.8 ± 18.1 years, and the mean height was 173.1 ± 9.3 cm. Two-thirds of patients were female (n = 18, 64.3%). The preoperative mean forced expiratory volume in the first second (FEV1) was 3.8 ± 0.7 L, forced vital capacity (FVC) was 4.7 ± 1.1 L, and the FEV1/FVC ratio was 80.4 ± 5.3%. After the creation of capnomediastinum, central venous pressure and airway pressure have been significantly increased from the baseline values (16.5 ± 4.9 mmHg versus 13.4 ± 5.1 mmHg, p < 0.001 and 23.4 ± 4.4 cmH2O versus 19.3 ± 3.9 cmH2O, p < 0.001, respectively). Most patients (n = 21, 75%) developed transient arrhythmias episodes with hypotension. All patients were extubated at the end of surgery and discharged awake to the recovery room. The first 16 (57.1%) patients were admitted to the intensive care unit and the last 12 patients were only observed in intermediate care. Postoperatively, one patient developed atelectasis and was treated with non-invasive ventilation therapy. Pneumonia or reintubation was not observed. Finally, no significant difference was observed between MG and thymoma patients regarding analgesics consumption or incidence of complications. Conclusions: Robotic-assisted surgery is a rapidly growing technology with increased adoption in different specialties. Fast-track anesthesia is an important factor in an enhanced recovery program and the anesthetist should be familiar with challenges in this kind of operation to achieve optimal results. So far, our anesthetic management of patients undergoing robotic-assisted thymectomy reports safe and feasible procedures.

Differential Regulation of CD45 Expression on Granulocytes, Lymphocytes, and Monocytes in COVID-19.

CD45 is a transmembrane glycoprotein and protein tyrosine phosphatase expressed on the surface of all nucleated hematopoietic cells. While there is increasing evidence demonstrating the involvement of CD45 in immune system regulation, no information on CD45 expression in inflammation and sepsis is currently available. Therefore, we determined the CD45 surface expression on granulocytes, lymphocytes, and monocytes in patients with COVID-19 and healthy volunteers in both absence and presence of lipopolysaccharide (LPS). Following approval by the local ethics committee, whole blood samples were obtained from patients with COVID-19 infection on day 1 of hospital admission and healthy volunteers. Samples were incubated in absence and presence of LPS and CD45 was measured in granulocytes, lymphocytes, and monocytes using flow cytometry. In comparison with healthy individuals, COVID-19 patients showed an increased CD45 expression on the surface of granulocytes (+35%, p < 0.02) and lymphocytes (+39%, p < 0.0001), but a reduced CD45 expression on monocytes (−35%, p < 0.0001). LPS incubation of whole blood from healthy individuals increased the CD45 expression on granulocytes (+430%, p < 0.0001), lymphocytes (+32%, p = 0.0012), and monocytes (+36%, p = 0.0005), respectively. LPS incubation of whole blood samples from COVID-19 patients increased the CD45 expression on granulocytes and monocytes, and decreased the CD45 expression on lymphocytes. In conclusion, CD45 expression on leucocytes is altered: (1) in COVID-19 patients, and (2) in in vitro endotoxemia in a complex cell-specific way, thus representing a new immunoregulatory mechanism.

Impaired ketogenesis ties metabolism to T cell dysfunction in COVID-19.

Anorexia and fasting are host adaptations to acute infection, and induce a metabolic switch towards ketogenesis and the production of ketone bodies, including ß-hydroxybutyrate (BHB)1-6. However, whether ketogenesis metabolically influences the immune response in pulmonary infections remains unclear. Here we show that the production of BHB is impaired in individuals with SARS-CoV-2-induced acute respiratory distress syndrome (ARDS) but not in those with  influenza-induced ARDS. We found that BHB promotes both the survival of and the production of interferon-γ by CD4+ T cells. Applying a metabolic-tracing analysis, we established that BHB provides an alternative carbon source to fuel oxidative phosphorylation (OXPHOS) and the production of bioenergetic amino acids and glutathione, which is important for maintaining the redox balance. T cells from patients with SARS-CoV-2-induced ARDS were exhausted and skewed towards glycolysis, but could be metabolically reprogrammed by BHB to perform OXPHOS, thereby increasing their functionality. Finally, we show in mice that a ketogenic diet and the delivery of BHB as a ketone ester drink restores CD4+ T cell metabolism and function in severe respiratory infections, ultimately reducing the mortality of mice infected with SARS-CoV-2. Altogether, our data reveal that BHB is an alternative source of carbon that promotes T cell responses in pulmonary viral infections, and highlight impaired ketogenesis as a potential confounding factor in severe COVID-19.

Effects of acetazolamide on pulmonary artery pressure and prevention of high-altitude pulmonary edema after rapid active ascent to 4,559 m.

Acetazolamide prevents acute mountain sickness (AMS) by inhibition of carbonic anhydrase. Since it also reduces acute hypoxic pulmonary vasoconstriction (HPV), it may also prevent high-altitude pulmonary edema (HAPE) by lowering pulmonary artery pressure. We tested this hypothesis in a randomized, placebo-controlled, double-blind study. Thirteen healthy, nonacclimatized lowlanders with a history of HAPE ascended (<22 h) from 1,130 to 4,559 m with one overnight stay at 3,611 m. Medications were started 48 h before ascent (acetazolamide: n = 7, 250 mg 3 times/day; placebo: n = 6, 3 times/day). HAPE was diagnosed by chest radiography and pulmonary artery pressure by measurement of right ventricular to atrial pressure gradient (RVPG) by transthoracic echocardiography. AMS was evaluated with the Lake Louise Score (LLS) and AMS-C score. The incidence of HAPE was 43% versus 67% (acetazolamide vs. placebo, P = 0.39). Ascent to altitude increased RVPG from 20 ± 5 to 43 ± 10 mmHg (P < 0.001) without a group difference (P = 0.68). Arterial Po2 fell to 36 ± 9 mmHg (P < 0.001) and was 8.5 mmHg higher with acetazolamide at high altitude (P = 0.025). At high altitude, the LLS and AMS-C score remained lower in those taking acetazolamide (both P < 0.05). Although acetazolamide reduced HAPE incidence by 35%, this effect was not statistically significant, and was considerably less than reductions of about 70%-100% with prophylactic dexamethasone, tadalafil, and nifedipine performed with the same ascent profile at the same location. We could not demonstrate a reduction in RVPG compared with placebo treatment despite reductions in AMS severity and better arterial oxygenation. Limited by small sample size, our data do not support recommending acetazolamide for the prevention of HAPE in mountaineers ascending rapidly to over 4,500 m.NEW & NOTEWORTHY This randomized, placebo-controlled, double-blind study is the first to investigate whether acetazolamide, which reduces acute mountain sickness (AMS), inhibits short-term hypoxic pulmonary vasoconstriction, and also prevents high-altitude pulmonary edema (HAPE) in a fast-climbing ascent to 4,559 m. We found no statistically significant reduction in HAPE incidence or differences in hypoxic pulmonary artery pressures compared with placebo despite reductions in AMS and greater ventilation-induced arterial oxygenation. Our data do not support recommending acetazolamide for HAPE prevention.

Risk factors for postoperative delirium in patients undergoing lower extremity joint arthroplasty: a retrospective population-based cohort study.

BACKGROUND: With an ageing population, the demand for joint arthroplasties and the burden of postoperative delirium is likely to increase. Given the lack of large-scale data, we investigated associations between perioperative risk factors and postoperative delirium in arthroplasty surgery. METHODS: This retrospective population-based cohort study, utilized national claims data from the all-payer Premier Healthcare database containing detailed billing information from >25% nationwide hospitalizations. Patients undergoing elective total hip/knee arthroplasty surgery (2006-2016) were included.The primary outcome was postoperative delirium, while potential risk factors included age, gender, race, insurance type, and modifiable exposures including anesthesia type, opioid prescription dose (low/medium/high), benzodiazepines, meperidine, non-benzodiazepine hypnotics, ketamine, corticosteroids, and gabapentinoids. RESULTS: Among 1 694 795 patients' postoperative delirium was seen in 2.6% (14 785/564 226) of hip and 2.9% (32 384/1 130 569) of knee arthroplasties. Multivariable models revealed that the utilization of long acting (OR 2.10 CI 1.82 to 2.42), combined long/short acting benzodiazepines (OR 1.74 CI 1.56 to 1.94), and gabapentinoids (OR 1.26 CI 1.16 to 1.36) was associated with increased odds of postoperative delirium. Lower odds of postoperative delirium were seen for neuraxial versus general anesthesia (OR 0.81 CI 0.70 to 0.93) and with the utilization of non-steroidal anti-inflammatory drugs (OR 0.85 CI 0.79 to 0.91) as well as cyclooxygenase-2 inhibitors (OR 0.82 CI 0.77 to 0.89). Age-stratified analysis revealed lower odds with high versus low opioid dose (OR 0.86 CI 0.76 to 0.98) in patients >65 years. Findings were consistent between hip and knee arthroplasties. CONCLUSIONS: In this large national cohort, we identified various modifiable risk factors (including anesthesia type and pharmaceutical agents) for postoperative delirium, demonstrating possible prevention pathways.

Effectiveness of intravenous acetaminophen for postoperative pain management in hip and knee arthroplasties: a population-based study.

BACKGROUND AND OBJECTIVES: The significance of intravenous over oral acetaminophen (APAP) as part of multimodal analgesic protocols is contested, particularly when considering its relatively high price and use in a surgical cohort such as total hip or knee arthroplasty (THA/TKA), which generally tolerates oral medications. This study aims to elucidate APAP's effectiveness in a large, population-based patient sample. METHODS: 1 039 647 THA/TKA procedures were sampled from the Premier Healthcare claims database 2011-2016. APAP use was categorized by intravenous/oral and use on the day of surgery, postoperative day 1 and thereafter. Outcomes were opioid utilization (in oral morphine equivalents), length and cost of hospitalization, and opioid-related adverse effects (respiratory, gastrointestinal, and naloxone use as a proxy). Mixed-effects models measured the associations between intravenous/oral APAP use and outcomes. Percent (%) change and 95% CIs are reported. RESULTS: Overall, 23.6% (n=245 454) of patients received intravenous APAP; of these, 56.3% (n=138 180) received just one dose on the day of surgery. After adjustment for relevant covariates, particularly use of >1 dose of intravenous APAP (compared with no use) on postoperative day 1 was associated with -6.0% (CI -7.2% to -4.7%) reduced opioid utilization; this was -10.7% (CI -11.4% to -9.9%) for use of > 1 dose oral APAP on postoperative day 1. Further comparisons regarding other outcomes also favored oral (over intravenous) APAP. CONCLUSIONS: These results do not support the routine use of intravenous APAP in patients undergoing lower joint arthroplasty, especially since oral APAP shows more beneficial outcome patterns.

Prolonged antibiotic prophylaxis after thoracoabdominal esophagectomy does not reduce the risk of pneumonia in the first 30 days: a retrospective before-and-after analysis.

PURPOSE: Thoracoabdominal esophageal resection for malignant disease is frequently associated with pulmonary infection. Whether prolonged antibiotic prophylaxis beyond a single perioperative dose is advantageous in preventing pulmonary infection after thoracoabdominal esophagectomy remains unclear. METHODS: In this retrospective before-and-after analysis, 173 patients between January 2009 and December 2014 from a prospectively maintained database were included. We evaluated the effect of a 5-day postoperative course of moxifloxacin, which is a frequently used antimicrobial agent for pneumonia, on the incidence of pulmonary infection and mortality after thoracoabdominal esophagectomy. RESULTS: 104 patients received only perioperative antimicrobial prophylaxis (control group) and 69 additionally received a 5-day postoperative antibiotic therapy with moxifloxacin (prolonged-course). 22 (12.7%) of all patients developed pneumonia within the first 30 days after surgery. No statistically significant differences were seen between the prolonged group and control group in terms of pneumonia after 7 (p = 0.169) or 30 days (p = 0.133), detected bacterial species (all p > 0.291) and 30-day mortality (5.8 vs 10.6%, p = 0.274). CONCLUSION: A preemptive 5-day postoperative course of moxifloxacin does not reduce the incidence of pulmonary infection and does not improve mortality after thoracoabdominal esophagectomy.

Inhaled Budesonide Does Not Affect Hypoxic Pulmonary Vasoconstriction at 4559 Meters of Altitude.

Berger, Marc Moritz, Franziska Macholz, Peter Schmidt, Sebastian Fried, Tabea Perz, Daniel Dankl, Josef Niebauer, Peter Bärtsch, Heimo Mairbäurl, and Mahdi Sareban. Inhaled budesonide does not affect hypoxic pulmonary vasoconstriction at 4559 meters of altitude. High Alt Med Biol 19:52-59, 2018.-Oral intake of the corticosteroid dexamethasone has been shown to lower pulmonary artery pressure (PAP) and to prevent high-altitude pulmonary edema. This study tested whether inhalation of the corticosteroid budesonide attenuates PAP and right ventricular (RV) function after rapid ascent to 4559 m. In this prospective, randomized, double-blind, and placebo-controlled trial, 50 subjects were randomized into three groups to receive budesonide at 200 or 800 µg twice/day (n = 16 and 17, respectively) or placebo (n = 17). Inhalation was started 1 day before ascending from 1130 to 4559 m within 20 hours. Systolic PAP (SPAP) and RV function were assessed by transthoracic echocardiography at low altitude (423 m) and after 7, 20, 32, and 44 hours at 4559 m. Ascent to high altitude increased SPAP about 1.7-fold (p < 0.001), whereas RV function was preserved. There was no difference in SPAP and RV function between groups at low and high altitude (all p values >0.10). Capillary partial pressure of oxygen (PO2) and carbon dioxide as well as the alveolar to arterial PO2 difference were decreased at high altitude but not affected by budesonide. Prophylactic inhalation of budesonide does not attenuate high-altitude-induced pulmonary vasoconstriction and RV function after rapid ascent to 4559 m.