ST-Elevation Myocardial Infarction Among Septic Shock and Coronary Interventions: A National Emergency Database Study.

OBJECTIVE: To study coronary interventions and mortality among patients with ST-elevated myocardial infarction (STEMI) who were admitted with septic shock. METHODS: Data from the national emergency department sample (NEDS) that constitutes 20% sample of hospital-owned emergency departments in the United States was analyzed for the septic shock related visits from 2016 to 2018. Septic shock was defined by the ICD codes. RESULTS: Out of 1 375 507 adult septic shock patients, 521 300 had a primary diagnosis of septic shock (mean age 67.41±15.67 years, 51.1% females) in the national emergency database for the years 2016 to 2018. Of these patients, 2768 (0.53%) had STEMI recorded during the hospitalization. Mortality rates for STEMI patients were higher than patients without STEMI (52.3% vs 23.5%). Mortality rates improved with PCI among STEMI patients (43.8% vs 56.2%). Coronary angiography was performed among 16% of patients of which percutaneous coronary intervention (PCI) rates were 7.7% among patients with STEMI septic shock. PCI numerically improved mortality, however, had no significant difference than patients without PCI on multivariate logistic regression and univariate logistic regression post coarsened exact matching of baseline characteristics among STEMI patients. Among the predictors, STEMI was a significant predictor of mortality in septic shock patients (OR 2.87, 95% CI 2.37-3.49; P<.001). Age, peripheral vascular disease, were predominant predictors of mortality in STEMI with septic shock subgroup (P <.001). Pneumonia was the predominant underlying infection among STEMI (36.4%) and without STEMI group (29.5%). CONCLUSION: STEMI complicating septic shock worsens mortality. PCI and coronary angiography numerically improved mortality, however, had no significant difference from patients without PCI. More research will be needed to improve mortality in such a critically ill subgroup of patients.

Renin and Survival in Patients Given Angiotensin II for Catecholamine-Resistant Vasodilatory Shock. A Clinical Trial.

Rationale: Exogenous angiotensin II increases mean arterial pressure in patients with catecholamine-resistant vasodilatory shock (CRVS). We hypothesized that renin concentrations may identify patients most likely to benefit from such therapy.Objectives: To test the kinetic changes in renin concentrations and their prognostic value in patients with CRVS.Methods: We analyzed serum samples from patients enrolled in the ATHOS-3 (Angiotensin II for the Treatment of High-Output Shock) trial for renin, angiotensin I, and angiotensin II concentrations before the start of administration of angiotensin II or placebo and after 3 hours.Measurements and Main Results: Baseline serum renin concentration (normal range, 2.13-58.78 pg/ml) was above the upper limits of normal in 194 of 255 (76%) study patients with a median renin concentration of 172.7 pg/ml (interquartile range [IQR], 60.7 to 440.6 pg/ml), approximately threefold higher than the upper limit of normal. Renin concentrations correlated positively with angiotensin I/II ratios (r = 0.39; P < 0.001). At 3 hours after initiation of angiotensin II therapy, there was a 54.3% reduction (IQR, 37.9% to 66.5% reduction) in renin concentration compared with a 14.1% reduction (IQR, 37.6% reduction to 5.1% increase) with placebo (P < 0.0001). In patients with renin concentrations above the study population median, angiotensin II significantly reduced 28-day mortality to 28 of 55 (50.9%) patients compared with 51 of 73 patients (69.9%) treated with placebo (unstratified hazard ratio, 0.56; 95% confidence interval, 0.35 to 0.88; P = 0.012) (P = 0.048 for the interaction).Conclusions: The serum renin concentration is markedly elevated in CRVS and may identify patients for whom treatment with angiotensin II has a beneficial effect on clinical outcomes.Clinical trial registered with www.clinicaltrials.gov (NCT02338843).

Angiotensin II for the Treatment of Vasodilatory Shock.

BACKGROUND: Vasodilatory shock that does not respond to high-dose vasopressors is associated with high mortality. We investigated the effectiveness of angiotensin II for the treatment of patients with this condition. METHODS: We randomly assigned patients with vasodilatory shock who were receiving more than 0.2 µg of norepinephrine per kilogram of body weight per minute or the equivalent dose of another vasopressor to receive infusions of either angiotensin II or placebo. The primary end point was a response with respect to mean arterial pressure at hour 3 after the start of infusion, with response defined as an increase from baseline of at least 10 mm Hg or an increase to at least 75 mm Hg, without an increase in the dose of background vasopressors. RESULTS: A total of 344 patients were assigned to one of the two regimens; 321 received a study intervention (163 received angiotensin II, and 158 received placebo) and were included in the analysis. The primary end point was reached by more patients in the angiotensin II group (114 of 163 patients, 69.9%) than in the placebo group (37 of 158 patients, 23.4%) (odds ratio, 7.95; 95% confidence interval [CI], 4.76 to 13.3; P<0.001). At 48 hours, the mean improvement in the cardiovascular Sequential Organ Failure Assessment (SOFA) score (scores range from 0 to 4, with higher scores indicating more severe dysfunction) was greater in the angiotensin II group than in the placebo group (-1.75 vs. -1.28, P=0.01). Serious adverse events were reported in 60.7% of the patients in the angiotensin II group and in 67.1% in the placebo group. Death by day 28 occurred in 75 of 163 patients (46%) in the angiotensin II group and in 85 of 158 patients (54%) in the placebo group (hazard ratio, 0.78; 95% CI, 0.57 to 1.07; P=0.12). CONCLUSIONS: Angiotensin II effectively increased blood pressure in patients with vasodilatory shock that did not respond to high doses of conventional vasopressors. (Funded by La Jolla Pharmaceutical Company; ATHOS-3 ClinicalTrials.gov number, NCT02338843 .).

Angiotensin I and angiotensin II concentrations and their ratio in catecholamine-resistant vasodilatory shock.

BACKGROUND: In patients with vasodilatory shock, plasma concentrations of angiotensin I (ANG I) and II (ANG II) and their ratio may reflect differences in the response to severe vasodilation, provide novel insights into its biology, and predict clinical outcomes. The objective of these protocol prespecified and subsequent post hoc analyses was to assess the epidemiology and outcome associations of plasma ANG I and ANG II levels and their ratio in patients with catecholamine-resistant vasodilatory shock (CRVS) enrolled in the Angiotensin II for the Treatment of High-Output Shock (ATHOS-3) study. METHODS: We measured ANG I and ANG II levels at baseline, calculated their ratio, and compared these results to values from healthy volunteers (controls). We dichotomized patients according to the median ANG I/II ratio (1.63) and compared demographics, clinical characteristics, and clinical outcomes. We constructed a Cox proportional hazards model to test the independent association of ANG I, ANG II, and their ratio with clinical outcomes. RESULTS: Median baseline ANG I level (253 pg/mL [interquartile range (IQR) 72.30-676.00 pg/mL] vs 42 pg/mL [IQR 30.46-87.34 pg/mL] in controls; P <  0.0001) and median ANG I/II ratio (1.63 [IQR 0.98-5.25] vs 0.4 [IQR 0.28-0.64] in controls; P <  0.0001) were elevated, whereas median ANG II levels were similar (84 pg/mL [IQR 23.85-299.50 pg/mL] vs 97 pg/mL [IQR 35.27-181.01 pg/mL] in controls; P = 0.9895). At baseline, patients with a ratio above the median (≥1.63) had higher ANG I levels (P <  0.0001), lower ANG II levels (P <  0.0001), higher albumin concentrations (P = 0.007), and greater incidence of recent (within 1 week) exposure to angiotensin-converting enzyme inhibitors (P <  0.00001), and they received a higher norepinephrine-equivalent dose (P = 0.003). In the placebo group, a baseline ANG I/II ratio <1.63 was associated with improved survival (hazard ratio 0.56; 95% confidence interval 0.36-0.88; P = 0.01) on unadjusted analyses. CONCLUSIONS: Patients with CRVS have elevated ANG I levels and ANG I/II ratios compared with healthy controls. In such patients, a high ANG I/II ratio is associated with greater norepinephrine requirements and is an independent predictor of mortality, thus providing a biological rationale for interventions aimed at its correction. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02338843. Registered 14 January 2015.

Angiotensin II for the treatment of distributive shock in the intensive care unit: A US cost-effectiveness analysis.

BACKGROUND: Patients with distributive shock who are unresponsive to traditional vasopressors are commonly considered to have severe distributive shock and are at high mortality risk. Here, we assess the cost-effectiveness of adding angiotensin II to the standard of care (SOC) for severe distributive shock in the US critical care setting from a US payer perspective. METHODS: Short-term mortality outcomes were based on 28-day survival rates from the ATHOS-3 study. Long-term outcomes were extrapolated to lifetime survival using individually estimated life expectancies for survivors. Resource use and adverse event costs were drawn from the published literature. Health outcomes evaluated were lives saved, life-years gained, and quality-adjusted life-years (QALYs) gained using utility estimates for the US adult population weighted for sepsis mortality. Deterministic and probabilistic sensitivity analyses assessed uncertainty around results. We analyzed patients with severe distributive shock from the ATHOS-3 clinical trial. RESULTS: The addition of angiotensin II to the SOC saved .08 lives at Day 28 compared to SOC alone. The cost per life saved was estimated to be $108,884. The addition of angiotensin II to the SOC was projected to result in a gain of .96 life-years and .66 QALYs. This resulted in an incremental cost-effectiveness ratio of $12,843 per QALY. The probability of angiotensin II being cost-effective at a threshold of $50,000 per QALY was 86 percent. CONCLUSIONS: For treatment of severe distributive shock, angiotensin II is cost-effective at acceptable thresholds.

Monitoring the corrected QT in the acute care setting: A comparison of the 12­lead ECG and bedside monitor.

INTRODUCTION: Prolongation of the QT interval is a well-recognized complication associated with many commonly used medications. Emergency Department monitoring of the corrected QT (QTc) both before and after medication administration is typically performed using the 12­lead electrocardiogram (ECG). The purpose of this study is to compare the QTc reported on the 12­lead ECG to that reported by single brand of bedside monitor. METHODS: A convenience sample of emergency department patients over the age of 18 undergoing bedside monitoring and who had an ECG ordered by their treating physician were enrolled. These patients underwent simultaneous ECG and monitor QTc calculation. The primary outcome of interest was the correlation between the monitor and ECG QTc. Secondary outcomes included ability of each method to identify patients with a QTc >500ms and the ability of each method to identify patients with a QTc <450ms. RESULTS: A total of 125 patients had simultaneous ECG and monitor QTc measurements recorded. There was moderate correlation between the monitor and ECG QTc (Pearson's correlation coefficient=0.55). The median difference between the ECG QTc and the monitor QTc (ECG QTc minus monitor QTc) was -7ms (IQR -23 to 11ms). CONCLUSION: We found that there was moderate correlation between the QTc reported on the 12 lead ECG and that reported by the bedside monitor. This correlation is not strong enough to support the use of the bedside monitor as a substitute for the 12­lead ECG when evaluating a patient's QTc.

Coin-Shaped Opacities in the Stomach.

On day 7 after hospital admission, a patient with end-stage kidney disease prescribed sevelamer, hydrocodone-acetaminophen, hydromorphone, and chewable lanthanum tablets developed intermittent apneic episodes, bilateral rhonchi, and responsiveness to verbal commands only with deep painful stimulus; a chest radiograph showed 4 radio-opaque coin-shaped opacities in the stomach. What is the diagnosis and what would you do next?

Rosuvastatin for sepsis-associated acute respiratory distress syndrome.

BACKGROUND: In the acute respiratory distress syndrome (ARDS), inflammation in the lungs and other organs can cause life-threatening organ failure. Inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) can modulate inflammatory responses. Previous observational studies suggested that statins improved clinical outcomes in patients with sepsis. We hypothesized that rosuvastatin therapy would improve clinical outcomes in critically ill patients with sepsis-associated ARDS. METHODS: We conducted a multicenter trial in which patients with sepsis-associated ARDS were randomly assigned to receive either enteral rosuvastatin or placebo in a double-blind manner. The primary outcome was mortality before hospital discharge home or until study day 60 if the patient was still in a health care facility. Secondary outcomes included the number of ventilator-free days (days that patients were alive and breathing spontaneously) to day 28 and organ-failure-free days to day 14. RESULTS: The study was stopped because of futility after 745 of an estimated 1000 patients had been enrolled. There was no significant difference between study groups in 60-day in-hospital mortality (28.5% with rosuvastatin and 24.9% with placebo, P=0.21) or in mean (±SD) ventilator-free days (15.1±10.8 with rosuvastatin and 15.1±11.0 with placebo, P=0.96). The groups were well matched with respect to demographic and key physiological variables. Rosuvastatin therapy, as compared with placebo, was associated with fewer days free of renal failure to day 14 (10.1±5.3 vs. 11.0±4.7, P=0.01) and fewer days free of hepatic failure to day 14 (10.8±5.0 vs. 11.8±4.3, P=0.003). Rosuvastatin was not associated with an increased incidence of serum creatine kinase levels that were more than 10 times the upper limit of the normal range. CONCLUSIONS: Rosuvastatin therapy did not improve clinical outcomes in patients with sepsis-associated ARDS and may have contributed to hepatic and renal organ dysfunction. (Funded by the National Heart, Lung, and Blood Institute and the Investigator-Sponsored Study Program of AstraZeneca; ClinicalTrials.gov number, NCT00979121.).

A pilot clinical trial of recombinant human angiotensin-converting enzyme 2 in acute respiratory distress syndrome.

BACKGROUND: Renin-angiotensin system (RAS) signaling and angiotensin-converting enzyme 2 (ACE2) have been implicated in the pathogenesis of acute respiratory distress syndrome (ARDS). We postulated that repleting ACE2 using GSK2586881, a recombinant form of human angiotensin-converting enzyme 2 (rhACE2), could attenuate acute lung injury. METHODS: We conducted a two-part phase II trial comprising an open-label intrapatient dose escalation and a randomized, double-blind, placebo-controlled phase in ten intensive care units in North America. Patients were between the ages of 18 and 80 years, had an American-European Consensus Criteria consensus diagnosis of ARDS, and had been mechanically ventilated for less than 72 h. In part A, open-label GSK2586881 was administered at doses from 0.1 mg/kg to 0.8 mg/kg to assess safety, pharmacokinetics, and pharmacodynamics. Following review of data from part A, a randomized, double-blind, placebo-controlled investigation of twice-daily doses of GSK2586881 (0.4 mg/kg) for 3 days was conducted (part B). Biomarkers, physiological assessments, and clinical endpoints were collected over the dosing period and during follow-up. RESULTS: Dose escalation in part A was well-tolerated without clinically significant hemodynamic changes. Part B was terminated after 39 of the planned 60 patients following a planned futility analysis. Angiotensin II levels decreased rapidly following infusion of GSK2586881, whereas angiotensin-(1-7) and angiotensin-(1-5) levels increased and remained elevated for 48 h. Surfactant protein D concentrations were increased, whereas there was a trend for a decrease in interleukin-6 concentrations in rhACE2-treated subjects compared with placebo. No significant differences were noted in ratio of partial pressure of arterial oxygen to fraction of inspired oxygen, oxygenation index, or Sequential Organ Failure Assessment score. CONCLUSIONS: GSK2586881 was well-tolerated in patients with ARDS, and the rapid modulation of RAS peptides suggests target engagement, although the study was not powered to detect changes in acute physiology or clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01597635 . Registered on 26 January 2012.

Treatment of drug-induced seizures.

Seizures are a common complication of drug intoxication, and up to 9% of status epilepticus cases are caused by a drug or poison. While the specific drugs associated with drug-induced seizures may vary by geography and change over time, common reported causes include antidepressants, stimulants and antihistamines. Seizures occur generally as a result of inadequate inhibitory influences (e.g., gamma aminobutyric acid, GABA) or excessive excitatory stimulation (e.g. glutamate) although many other neurotransmitters play a role. Most drug-induced seizures are self-limited. However, status epilepticus occurs in up to 10% of cases. Prolonged or recurrent seizures can lead to serious complications and require vigorous supportive care and anticonvulsant drugs. Benzodiazepines are generally accepted as the first line anticonvulsant therapy for drug-induced seizures. If benzodiazepines fail to halt seizures promptly, second line drugs include barbiturates and propofol. If isoniazid poisoning is a possibility, pyridoxine is given. Continuous infusion of one or more anticonvulsants may be required in refractory status epilepticus. There is no role for phenytoin in the treatment of drug-induced seizures. The potential role of ketamine and levetiracetam is promising but not established.

An observational case series of dabigatran and rivaroxaban exposures reported to a poison control system.

OBJECTIVE: Characterize clinical presentations and outcomes of dabigatran and rivaroxaban exposures reported to a poison control system. METHODS: Data for cases of dabigatran and rivaroxaban exposures called into the California Poison Control System from January 2011 to July 2013 were collected. Data collected included patient demographics, type of exposure, medication, dosage, vital signs, laboratory values, interventions, outcomes, and disposition. Exclusion criteria included confirmed nonexposures or miscoded cases. RESULTS: A total of 56 cases were identified, with 7 excluded, leaving 37 dabigatran and 12 rivaroxaban cases. Children age 12 years or less accounted for 5 dabigatran and 2 rivaroxaban cases. Bleeding was reported in 15 dabigatran cases. There were 4 cases of acute self-harm overdose with dabigatran ranging from 1800 to 3900 mg. Mild bleeding was reported in only one of these overdose cases. There were 2 fatal hemorrhages in dabigatran cases, both in chronic therapeutic dosing. Bleeding was reported in 5 rivaroxaban cases, all in patients with chronic exposure; no deaths were reported. There were no adverse outcomes in pediatric patients. Coagulation parameters did not correlate well with bleeding. CONCLUSIONS: In our series, the greatest risk of adverse events was in patients chronically taking these agents, irrespective of excess dosing. Acute self-harm ingestions and accidental pediatric ingestions had few adverse effects, although massive overdose can lead to abnormal coagulation studies. It does not appear that single low-dose ingestions of either medication will lead to clinically significant bleeding. It may be possible to manage some pediatric exposures and most accidental ingestions with observation.

Hypoxemic Respiratory Failure and Coccidioidomycosis-Associated Acute Respiratory Distress Syndrome.

Background: Severe coccidioidomycosis presenting with respiratory failure is an uncommon manifestation of disease. Current knowledge of this condition is limited to case reports and small case series. Methods: A retrospective multicenter review of patients with coccidioidomycosis-associated acute respiratory distress syndrome (CA-ARDS) was conducted. It assessed clinical and laboratory variables at the time of presentation, reviewed the treatment course, and compared this cohort with a national database of patients with noncoccidioidomycosis ARDS. Survivors and nonsurvivors of coccidioidomycosis were also compared to determine prognostic factors. Results: In this study, CA-ARDS (n = 54) was most common in males, those of Hispanic ethnicity, and those with concurrent diabetes mellitus. As compared with the PETAL network database (Prevention and Early Treatment of Acute Lung Injury; n = 1006), patients with coccidioidomycosis were younger, had fewer comorbid conditions, and were less acidemic. The 90-day mortality was 15.4% for patients with coccidioidomycosis, as opposed to 42.6% (P < .0001) for patients with noncoccidioidomycosis ARDS. Patients with coccidioidomycosis who died, as compared with those who survived, were older, had higher APACHE II scores (Acute Physiology and Chronic Health Evaluation), and did not receive corticosteroid therapy. Conclusions: CA-ARDS is an uncommon but morbid manifestation of infection. When compared with a national database, the overall mortality appears favorable vs other causes of ARDS. Patients with CA-ARDS had a low overall mortality but required prolonged antifungal therapy. The utility of corticosteroids in this condition remains unconfirmed.

Using the ROX Index to Predict Treatment Outcome for High-Flow Nasal Cannula and/or Noninvasive Ventilation in Patients With COPD Exacerbations.

BACKGROUND: The ratio of oxygen saturation index (ROX index; or SpO2 /FIO2 /breathing frequency) has been shown to predict risk of intubation after high-flow nasal cannula (HFNC) support among adults with acute hypoxemic respiratory failure primarily due to pneumonia. However, its predictive value for other subtypes of respiratory failure is unknown. This study investigated whether the ROX index predicts liberation from HFNC or noninvasive ventilation (NIV), intubation with mechanical ventilation, or death in adults admitted for respiratory failure due to an exacerbation of COPD. METHODS: We performed a retrospective study of 260 adults hospitalized with a COPD exacerbation and treated with HFNC and/or NIV (continuous or bi-level). ROX index scores were collected at treatment initiation and predefined time intervals throughout HFNC and/or NIV treatment or until the subject was intubated or died. A ROX index score of ≥ 4.88 was applied to the cohort to determine if the same score would perform similarly in this different cohort. Accuracy of the ROX index was determined by calculating the area under the receiver operator curve. RESULTS: A total of 47 subjects (18%) required invasive mechanical ventilation or died while on HFNC/NIV. The ROX index at treatment initiation, 1 h, and 6 h demonstrated the best prediction accuracy for avoidance of invasive mechanical ventilation or death (area under the receiver operator curve 0.73 [95% CI 0.66-0.80], 0.72 [95% CI 0.65-0.79], and 0.72 [95% CI 0.63-0.82], respectively). The optimal cutoff value for sensitivity (Sn) and specificity (Sp) was a ROX index score > 6.88 (sensitivity 62%, specificity 57%). CONCLUSIONS: The ROX index applied to adults with COPD exacerbations treated with HFNC and/or NIV required higher scores to achieve similar prediction of low risk of treatment failure when compared to subjects with hypoxemic respiratory failure/pneumonia. ROX scores < 4.88 did not accurately predict intubation or death.

Serum Troponin I Assessments in 5- to 30-Year-Olds After BNT162b2 Vaccination.

INTRODUCTION: Rare myocarditis and pericarditis cases have occurred in coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccine recipients. Troponin levels, a potential marker of myocardial injury, were assessed in healthy participants before and after BNT162b2 vaccination. METHODS: Vaccine-experienced 12- to 30-year-olds in phase 3 crossover C4591031 Substudy B (NCT04955626) who had two or three prior BNT162b2 30-µg doses were randomized to receive BNT162b2 30 µg followed by placebo, or placebo followed by BNT162b2 30 µg, 1 month apart. A participant subset, previously unvaccinated against COVID-19, in the phase 3 C4591007 study (NCT04816643) received up to three vaccinations (BNT162b2 10 µg or placebo [5- to 11-year-olds]) or open-label BNT162b2 30 µg (12- to 15-year-olds). Blood samples collected pre-vaccination, 4 days post-vaccination, and 1-month post-vaccination (C4591031 Substudy B only) were analyzed. Frequencies of elevated troponin I levels (male, > 35 ng/l; female, > 17 ng/l) were assessed. RESULTS: Percentages of 12- to 30-year-olds (n = 1485) in C4591031 Substudy B with elevated troponin levels following BNT162b2 or placebo receipt were 0.5% and 0.8% before vaccination, 0.7% and 1.0% at day 4, and 0.7% and 0.5% at 1 month, respectively. In Study C4591007 (n = 1265), elevated troponin I levels were observed in 0.2, 0.4, and 0.2% of 5- to 11-year-old BNT162b2 recipients at baseline and 4 days post-dose 2 and 3, respectively; corresponding values in 12- to 15-year-olds were 0.4, 0.4, and 0.7%. No 5- to 11-year-old placebo recipients had elevated troponin levels. No myocarditis or pericarditis cases or deaths were reported. CONCLUSIONS: Among 5- to < 30-year-olds in both studies, troponin levels were rarely elevated (≤ 1.0%) and similar before and post-vaccination; troponin levels were also similar between BNT162b2 and placebo in 12- to 30-year-old and 5- to 11-year-old recipients in the respective studies. No myocarditis or pericarditis cases were reported. These findings did not provide evidence that BNT162b2 causes troponin elevations. No utility of routine measurement of troponin levels in asymptomatic BNT162b2 recipients was identified.

Effect of low-osmolality intravenous contrast on serum osmolal gap in adults.

BACKGROUND: Contrast media used today is considered "low-osmolality." No study has evaluated the effect of intravenous contrast media on the measurement of the osmolal gap in adult patients. OBJECTIVE: To determine if "low-osmolality" intravenous contrast media administered to adult patients undergoing computed tomography (CT) of the abdomen and pelvis affects the osmolal gap. METHODS: We performed a prospective pilot study in the Emergency Department of a university-affiliated tertiary care center. Patients were enrolled if they were age ≥18 years and <60 years and the treatment team had ordered an abdomen and pelvis CT with intravenous (i.v.) contrast procedure and a serum basic metabolic panel (BMP) that included serum glucose, blood urea nitrogen, and sodium. Once enrolled, a serum osmolality and serum ethanol level was ordered and obtained on the same blood draw as the BMP before the CT. Patients were excluded if they had detectable ethanol on laboratory screen, if they were suspected to have ingested methanol, ethylene glycol, isopropanol, mannitol, or underwent CT with i.v. contrast within the prior 24 h. Paired samples were compared using the Wilcoxon signed-rank test. RESULTS: Of the 100 patients screened, 18 patients were lost due to withdrawal of consent or missing data. The median of the osmolal gap pre-CT was 8.18 with an interquartile range of 4.76-11.15. The median of the osmolal gap post-CT was 11.23 with an interquartile range of 7.29-14.83. The difference in the osmolal gap was a median of 2.34 (p = 0.0003) with an interquartile range of -1.32-5.97. CONCLUSION: Although the effect in our study was small, clinicians should be aware of the ability of contrast media to increase the osmolal gap.

A ten-year retrospective California Poison Control System experience with possible amatoxin mushroom calls.

INTRODUCTION: Mushrooms containing amatoxin are found worldwide and represent a challenging poisoning for the clinician and consulting poison center. This study evaluates the experience of a large poison system with possible amatoxin-containing mushroom ingestion calls. METHODS: A 10-year retrospective review of the California Poison Control System database was performed for amatoxin mushroom ingestion calls resulting in hospitalization. Cases found were abstracted and data statistically analyzed for association with a composite endpoint of death, liver transplant, and/or the need for dialysis. RESULTS: Amatoxin-containing mushroom calls are infrequent with the vast majority (98.4 percent) coming from Northern California during the rainier first and fourth quarters (October through March) of the year. Elevated initial aminotransferase activities and international normalized ratios were predictive of the composite negative outcome. The mortality plus liver transplant and hemodialysis composite rate was 8.2 percent, consistent with current literature. CONCLUSION: The California Poison Control System has relatively few amatoxin-containing mushroom ingestion calls that result in hospitalization but those that are reported mostly occur in Northern California. Treatment bias towards the sickest patients may explain the association of intravenous fluid use or treatment with acetylcysteine or silibinin with meeting the composite outcome. The initial presence of elevated hepatic aminotransferase activity and international normalized ratios are poor prognostic indicators and are likely reflective of late presentation, an advanced toxic phase of amatoxin poisoning, and/or delays in time to obtain poison center consultation.

ZLN005 improves the protective effect of mitochondrial function on alveolar epithelial cell aging by upregulating PGC-1α.

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal pulmonary interstitial disease that usually occurs in the elderly. The senescence of alveolar epithelial cells (AECs) is an important mechanism of IPF. The AECs of patients with IPF have lower expression of peroxisome proliferator-activated receptor-γ coactivator-1 alpha (PGC-1α), which has been shown to play an important role in maintaining mitochondrial morphology and energy metabolism. This study sought to explore the mechanism by which ZLN005 improves mitochondrial function by upregulating PGC-1α to protect AECs from aging. Methods: Western blot was used to detect the expression of PGC-1α, mitochondrial synthesis protein nuclear respiratory factor-1 (NRF-1), and p21WAF1 in the lung tissue of the IPF patients and the mice with bleomycin (BLM)-induced pulmonary fibrosis. A549 cells and mice AEC2 cells were treated with hydrogen peroxide (H2O2) to construct cell senescence models. Cell senescence was detected by senescence-associated beta-galactosidase staining. The mitochondrial respiratory function was measured, including the adenosine triphosphate (ATP) generation, reactive oxygen species (ROS) level, changes in cell membrane potential, and energy metabolism. Using lentivirus as a vector and using gene editing technology to over express (upPGC-1α) and knockdown PGC-1α (shPGC-1α) in the A549 cells. The PGC-1α agonist ZLN005 was used to pretreat the A549 and shPGC-1α A549 cells, and cell aging and mitochondrial respiratory function were observed. Results: The Western blot and immunofluorescence assays showed that the expression of PGC-1α and NRF-1 was decreased in the lung tissues of the IPF patients and BLM-induced mice pulmonary fibrosis model, while the expression of p21WAF1 was increased. The results of the immunofluorescence and mitochondrial function experiments also indicated that the expression of PGC-1α and mitochondrial synthesis protein NRF-1 were decreased in the senescent cells. Further, the mitochondrial morphology was abnormal and the mitochondrial function was impaired. PGC-1α was involved in the AEC senescence by regulating mitochondrial morphology and function. Treatment with the agonist of PGC-1α (i.e., ZLN005) blocked the H2O2-induced cell senescence by enhancing the expression of PGC-1α. Conclusions: These results provide preliminary insights into the potential clinical application of ZLN005 as a novel therapeutic agent for the treatment of IPF.

Angiotensin II treatment is associated with improved oxygenation in ARDS patients with refractory vasodilatory shock.

BACKGROUND: The physiological effects of renin-angiotensin system modulation in acute respiratory distress syndrome (ARDS) remain controversial and have not been investigated in randomized trials. We sought to determine whether angiotensin-II treatment is associated with improved oxygenation in shock-associated ARDS. METHODS: Post-hoc subgroup analysis of the Angiotensin Therapy for High Output Shock (ATHOS-3) trial. We studied patients who met modified Berlin ARDS criteria at enrollment. The primary outcome was PaO2/FiO2-ratio (P:F) at 48-h adjusted for baseline P:F. Secondary outcomes included oxygenation index, ventilatory ratio, PEEP, minute-ventilation, hemodynamic measures, patients alive and ventilator-free by day-7, and mortality. RESULTS: Of 81 ARDS patients, 34 (42%) and 47 (58%) were randomized to angiotensin-II or placebo, respectively. In angiotensin-II patients, mean P:F increased from 155 mmHg (SD: 69) at baseline to 265 mmHg (SD: 160) at hour-48 compared with no change with placebo (148 mmHg (SD: 63) at baseline versus 164 mmHg (SD: 74) at hour-48)(baseline-adjusted difference: + 98.4 mmHg [95%CI 35.2-161.5], p = 0.0028). Similarly, oxygenation index decreased by - 6.0 cmH2O/mmHg at hour-48 with angiotensin-II versus - 0.4 cmH2O/mmHg with placebo (baseline-adjusted difference: -4.8 cmH2O/mmHg, [95%CI - 8.6 to - 1.1], p = 0.0273). There was no difference in PEEP, minute ventilation, or ventilatory ratio. Twenty-two (64.7%) angiotensin-II patients had sustained hemodynamic response to treatment at hour-3 versus 17 (36.2%) placebo patients (absolute risk-difference: 28.5% [95%CI 6.5-47.0%], p = 0.0120). At day-7, 7/34 (20.6%) angiotensin-II patients were alive and ventilator-free versus 5/47(10.6%) placebo patients. Day-28 mortality was 55.9% in the angiotensin-II group versus 68.1% in the placebo group. CONCLUSIONS: In post-hoc analysis of the ATHOS-3 trial, angiotensin-II was associated with improved oxygenation versus placebo among patients with ARDS and catecholamine-refractory vasodilatory shock. These findings provide a physiologic rationale for trials of angiotensin-II as treatment for ARDS with vasodilatory shock. TRIAL REGISTRATION: ClinicalTrials.Gov Identifier: NCT02338843 (Registered January 14th 2015).

Safety, Tolerability, and Pharmacokinetics of Single and Multiple Ascending Intravenous Infusions of PF-07304814 (Lufotrelvir) in Participants Hospitalized With COVID-19.

Background: An urgent need remains for antiviral therapies to treat patients hospitalized with COVID-19. PF-07304814-the prodrug (lufotrelvir) and its active moiety (PF-00835231)-is a potent inhibitor of the SARS-CoV-2 3CL protease. Method: Eligible participants were 18 to 79 years old and hospitalized with confirmed COVID-19. This first-in-human phase 1b study was designed with 2 groups: single ascending dose (SAD) and multiple ascending dose (MAD). Participants could receive local standard-of-care therapy. In SAD, participants were randomized to receive a 24-hour infusion of lufotrelvir/placebo. In MAD, participants were randomized to receive a 120-hour infusion of lufotrelvir/placebo. The primary endpoint was to assess the safety and tolerability of lufotrelvir. The secondary endpoint was to evaluate the pharmacokinetics of lufotrelvir and PF-00835231. Results: In SAD, participants were randomized to receive 250 mg lufotrelvir (n = 2), 500 mg lufotrelvir (n = 2), or placebo (n = 4) by continuous 24-hour infusion. In MAD, participants were randomized to receive 250 mg lufotrelvir (n = 7), 500 mg lufotrelvir (n = 6), or placebo (n = 4) by continuous 120-hour infusion. No adverse events or serious adverse events were considered related to lufotrelvir. At doses of 250 and 500 mg, concentrations for the prodrug lufotrelvir and active moiety PF-00835231 increased in a dose-related manner. Unbound concentrations of the lufotrelvir active metabolite reached steady state approximately 2- and 4-fold that of in vitro EC90 following 250- and 500-mg doses, respectively. Conclusions: These safety and pharmacokinetic findings support the continued evaluation of lufotrelvir in clinical studies. Clinical Trials Registration. ClinicalTrials.gov NCT04535167.

A Least Absolute Shrinkage and Selection Operator-Derived Predictive Model for Postoperative Respiratory Failure in a Heterogeneous Adult Elective Surgery Patient Population.

BACKGROUND: Postoperative respiratory failure (PRF) is associated with increased hospital charges and worse patient outcomes. Reliable prediction models can help to guide postoperative planning to optimize care, to guide resource allocation, and to foster shared decision-making with patients. RESEARCH QUESTION: Can a predictive model be developed to accurately identify patients at high risk of PRF? STUDY DESIGN AND METHODS: In this single-site proof-of-concept study, we used structured query language to extract, transform, and load electronic health record data from 23,999 consecutive adult patients admitted for elective surgery (2014-2021). Our primary outcome was PRF, defined as mechanical ventilation after surgery of > 48 h. Predictors of interest included demographics, comorbidities, and intraoperative factors. We used logistic regression to build a predictive model and the least absolute shrinkage and selection operator procedure to select variables and to estimate model coefficients. We evaluated model performance using optimism-corrected area under the receiver operating curve and area under the precision-recall curve and calculated sensitivity, specificity, positive and negative predictive values, and Brier scores. RESULTS: Two hundred twenty-five patients (0.94%) demonstrated PRF. The 18-variable predictive model included: operations on the cardiovascular, nervous, digestive, urinary, or musculoskeletal system; surgical specialty orthopedic (nonspine); Medicare or Medicaid (as the primary payer); race unknown; American Society of Anesthesiologists class ≥ III; BMI of 30 to 34.9 kg/m2; anesthesia duration (per hour); net fluid at end of the operation (per liter); median intraoperative FIO2, end title CO2, heart rate, and tidal volume; and intraoperative vasopressor medications. The optimism-corrected area under the receiver operating curve was 0.835 (95% CI,0.808-0.862) and the area under the precision-recall curve was 0.156 (95% CI, 0.105-0.203). INTERPRETATION: This single-center proof-of-concept study demonstrated that a structured query language extract, transform, and load process, based on readily available patient and intraoperative variables, can be used to develop a prediction model for PRF. This PRF prediction model is scalable for multicenter research. Clinical applications include decision support to guide postoperative level of care admission and treatment decisions.