Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Prolonged and severe CNS depression and truncal ataxia in an accidental pediatric perampanel ingestion

Background: Perampanel exerts antiepileptic effects by reducing neuronal excitation via noncompetitive antagonism of the postsynaptic ionotropic-AMPA-glutamate receptors. Clinical effects in overdose are limited and only mild effects have been reported in adults. Methods: This is a single patient chart review. Results: A previously healthy 2-year-old 15-kg female presented after witnessed ingestion of 30mg of perampanel (2mg/kg).Within 10 minutes of ingestion, the child became ataxic and was unable to walk. She presented to the ED, 30 minutes post-ingestion and had normal VS but was minimally responsive. She was emergently intubated due to profound CNS depression. After transfer to a tertiary care facility, vitals were as follows: 36.5 °C, HR 117, BP 113/73, RR 20(vent), and 100% on 40% FiO2. She required no sedation and ABG showed 7.24/56/65. Serum laboratory results were otherwise unremarkable. UDS immunoassay and GC-MS were both negative. She remained hemodynamically stable and remained intubated for 72 hours with gradual improvement in mental status. After extubation, patient still exhibited truncal ataxia and did not return to her neurologic baseline until 96 hours post-ingestion. Serum perampanel level was 870 ng/mL (ref \u3c 20 ng/mL). Discussion: To date, there are no reported pediatric ingestions of perampanel. Adult toxicity describes mild neurologic symptoms. In this case, our patient exhibited profound CNS depression requiring mechanical ventilation for a prolonged period. At this time, we suggest all pediatric exposures be referred to the ED. Conclusion: This is the first reported confirmed case of perampanel overdose in a child. Pediatric toxicity may result in profound CNS depression requiring prolonged mechanical ventilatory support

Atrioesophageal fistula: A risk of atrial fibrillation ablation

Learning Objectives: Atrial-Fibrillation (AFib) affects 3-6 million Americans. Preferred management is rate-control with anticoagulation. Rhythm-control can be used for symptomatic AFib with some support for atrial ablation as a safe alternative, especially to avoid antiarrhythmic adverse effects. There is an observed 3% complication rate associated with ablation. The most severe complication, Atrioesophageal Fistula (AEF), occurs in less than 0.1% of patients. Despite the rare occurrence, it carries a high rate of mortality. Methods: 52-year-old male with history of AFib on rivaroxaban and metoprolol, now 3 weeks post radiofrequency ablation, presented with ripping chest pain. He was febrile and tachycardic with leukocytosis. CT angiography was negative for concern of aortic dissection. He had a seizure in the ED prompting antibiotic treatment of suspected CNS infection. Blood cultures grew S. mitis, S. salvarius and Neisseria species. Subsequent development of left extremity weakness prompted CNS imaging which revealed multiple acute infarcts. He was transferred to a tertiary center for escalation of care. On ICU arrival, repeat CT head confirmed embolic infarcts with new hemorrhage. Review of outside CT chest showed extra-esophageal gas posterior to the left atrium concerning for AEF. Cardiothoracic surgery performed CT esophogram confirming gas but no signs of AEF. Endoscopy did not reveal esophageal perforation. TEE ruled out endocarditis, but found a small ASD. AEF was thought unlikely and an IVC filter was placed. Later while eating, the patient had acute loss of consciousness requiring intubation. CT head without contrast showed new embolic infarcts and hemorrhages. Given recurrence of fever and bacteremia, CT body was performed showing air in the left atrium supporting previously suspected AEF. Neurologically devastated and a poor surgical candidate, he was made comfort care and passed. Results: Patients developing AEF usually present 2-60 days after ablation. Most common symptoms are fever, neurological deficits, bleeding and chest pain. Fistulas are often one-way causing embolism more often than bleed. CT is the test of choice but only 75% sensitive initially and 85% on repeat. Endoscopy and TEE are relatively contraindicated. Surgery is the preferred treatment with 34% mortality versus 64% with stenting and almost 100% with medical management. AEF are extremely difficult to confirm and often herald death, but with high suspicion and rapid intervention meaningful survival is possible

Atrioesophageal fistula: A risk of atrial fibrillation ablation

Learning Objectives: Atrial-Fibrillation (AFib) affects 3-6 million Americans. Preferred management is rate-control with anticoagulation. Rhythm-control can be used for symptomatic AFib with some support for atrial ablation as a safe alternative, especially to avoid antiarrhythmic adverse effects. There is an observed 3% complication rate associated with ablation. The most severe complication, Atrioesophageal Fistula (AEF), occurs in less than 0.1% of patients. Despite the rare occurrence, it carries a high rate of mortality. Methods: 52-year-old male with history of AFib on rivaroxaban and metoprolol, now 3 weeks post radiofrequency ablation, presented with ripping chest pain. He was febrile and tachycardic with leukocytosis. CT angiography was negative for concern of aortic dissection. He had a seizure in the ED prompting antibiotic treatment of suspected CNS infection. Blood cultures grew S. mitis, S. salvarius and Neisseria species. Subsequent development of left extremity weakness prompted CNS imaging which revealed multiple acute infarcts. He was transferred to a tertiary center for escalation of care. On ICU arrival, repeat CT head confirmed embolic infarcts with new hemorrhage. Review of outside CT chest showed extra-esophageal gas posterior to the left atrium concerning for AEF. Cardiothoracic surgery performed CT esophogram confirming gas but no signs of AEF. Endoscopy did not reveal esophageal perforation. TEE ruled out endocarditis, but found a small ASD. AEF was thought unlikely and an IVC filter was placed. Later while eating, the patient had acute loss of consciousness requiring intubation. CT head without contrast showed new embolic infarcts and hemorrhages. Given recurrence of fever and bacteremia, CT body was performed showing air in the left atrium supporting previously suspected AEF. Neurologically devastated and a poor surgical candidate, he was made comfort care and passed. Results: Patients developing AEF usually present 2-60 days after ablation. Most common symptoms are fever, neurological deficits, bleeding and chest pain. Fistulas are often one-way causing embolism more often than bleed. CT is the test of choice but only 75% sensitive initially and 85% on repeat. Endoscopy and TEE are relatively contraindicated. Surgery is the preferred treatment with 34% mortality versus 64% with stenting and almost 100% with medical management. AEF are extremely difficult to confirm and often herald death, but with high suspicion and rapid intervention meaningful survival is possible

Atrioesophageal fistula: A risk of atrial fibrillation ablation

Learning Objectives: Atrial-Fibrillation (AFib) affects 3-6 million Americans. Preferred management is rate-control with anticoagulation. Rhythm-control can be used for symptomatic AFib with some support for atrial ablation as a safe alternative, especially to avoid antiarrhythmic adverse effects. There is an observed 3% complication rate associated with ablation. The most severe complication, Atrioesophageal Fistula (AEF), occurs in less than 0.1% of patients. Despite the rare occurrence, it carries a high rate of mortality. Methods: 52-year-old male with history of AFib on rivaroxaban and metoprolol, now 3 weeks post radiofrequency ablation, presented with ripping chest pain. He was febrile and tachycardic with leukocytosis. CT angiography was negative for concern of aortic dissection. He had a seizure in the ED prompting antibiotic treatment of suspected CNS infection. Blood cultures grew S. mitis, S. salvarius and Neisseria species. Subsequent development of left extremity weakness prompted CNS imaging which revealed multiple acute infarcts. He was transferred to a tertiary center for escalation of care. On ICU arrival, repeat CT head confirmed embolic infarcts with new hemorrhage. Review of outside CT chest showed extra-esophageal gas posterior to the left atrium concerning for AEF. Cardiothoracic surgery performed CT esophogram confirming gas but no signs of AEF. Endoscopy did not reveal esophageal perforation. TEE ruled out endocarditis, but found a small ASD. AEF was thought unlikely and an IVC filter was placed. Later while eating, the patient had acute loss of consciousness requiring intubation. CT head without contrast showed new embolic infarcts and hemorrhages. Given recurrence of fever and bacteremia, CT body was performed showing air in the left atrium supporting previously suspected AEF. Neurologically devastated and a poor surgical candidate, he was made comfort care and passed. Results: Patients developing AEF usually present 2-60 days after ablation. Most common symptoms are fever, neurological deficits, bleeding and chest pain. Fistulas are often one-way causing embolism more often than bleed. CT is the test of choice but only 75% sensitive initially and 85% on repeat. Endoscopy and TEE are relatively contraindicated. Surgery is the preferred treatment with 34% mortality versus 64% with stenting and almost 100% with medical management. AEF are extremely difficult to confirm and often herald death, but with high suspicion and rapid intervention meaningful survival is possible

Emergency Department Triage Blood Glucose Levels: Outcomes Implications in Patients with Severe Sepsis and Septic Shock

Background: Patients with severe sepsis and septic shock often present with a variety of organ dysfunctions including metabolic derangements. The appropriate metabolic stress response in sepsis includes release of glucose leading to stress-hyperglycemia and is commonly seen in these Emergency Department (ED) patients. Many studies focus on metabolic glucose abnormalities and its effect on outcomes at the time of Intensive Care Unit (ICU) admission. Hyperglycemia present on ICU admission has been associated with adverse outcomes irrespective of the presence or absence of diabetes mellitus. Methods: We analyzed our ED quality sepsis database in concern to triage glucose levels and associated 30 day mortality from August 2015 to October 2016 to determine adjustments in active glucose monitoring in the ED. Results: We identified 683 patients with severe sepsis (N=399) and septic shock (N=284). Average glucose levels at the 1stED laboratory evaluation was 172 mg/ dL (SD=149). Patients with septic shock had on average lower glucose levels (170 mg/dL) than patients with severe sepsis (174 mg/dL). Sepsis survivors had higher triage glucose (176 mg/dL, N=525) than non-survivors (159 mg/dL, N=157). When stratifying patients by glucose levels, we found that patients with glucose levels less than 70 mg/dL at ED triage had the highest mortality. The incidence of glucose of ≤ 70 mg/ dL was 7% (N=49) for all patients with severe sepsis and septic shock combined. The mortality in this group was 44% (21/49) which was significantly (p=0.001) higher than mortality in patients with higher glucose levels (136/634, 21%). In patients with glucose levels of ≥ 180 mg/dL the mortality was not different (35/177, 26%, p=0.9) when compared to patients with glucose levels ranging from 70-180 mg/dL. Conclusion: Glucose monitoring for patients with sepsis in the ED aids recognition of correctable metabolic derangements early in management. In the ED, the metabolic-stress response to sepsis is commonly stress-hyperglycemia, but hypoglycemia can also occur in the early phases of sepsis. Hypoglycemia at ED triage has a higher than expected mortality and needs to be recognized and treated accordingly

Sepsis-3 the Dysregulated Host Response and Cytokine Changes

RATIONALE: New Sepsis-3 definitions have been published, stating that sepsis is a “life-threatening organ dysfunction caused by a dysregulated host response to infection”. The Sepsis-3 authors identified that “Limitations of previous definitions included an excessive focus on inflammation and inadequate specificity and sensitivity of the systemic inflammatory response syndrome (SIRS) criteria.” With the new definitions it was proposed that identification of septic patients with a dysregulated host response is aided by the use of a quick SOFA (qSOFA) score and not by the use of SIRS criteria. qSOFA score is considered abnormal when 2 of 3 criteria are met. These criteria include sytolic blood pressure \u3c 100mmHg, respiratory rate \u3e 24 and mental status changes. We re-examined an established data-base for patients with vasopressor dependent septic shock comparing SIRS criteria to qSOFA criteria in concern to available measured cytokine markers as indicator of a dysregulated host response. If qSOFA indicates an abnormal host response, prominent cytokine markers such as IL-1RA, IL-1α, IL-6, IL-8, IL-10 and TNF-α should show similar trends as SIRS criteria. METHODS: Re-examination of established IRB approved research data base for patients with vasopressor dependent septic shock with measured multiplex cytokine markers (Milliplex HCYTMAG-60K-PX29) as indicator of a dysregulated host response to infection in concern to SIRS criteria and newly established qSOFA score. RESULTS: For 174 patients data was re-examined. At the time of enrollment within 24 hours following shock onset the average qSOFA score was 1.47 and average SIRS criteria 2.06. Table 1 shows measured cytokine values in regard to number of either SIRS criteria or qSOFA score. The average values of measured cytokine markers increased with increasing number of SIRS criteria for IL-1RA, IL-1a, IL-6, IL-8, IL-10 and TNF-a. Similar cytokine increases in relation to the number of qSOFA score was only seen for IL-8, IL-10 and TNF-a.∗Average values shown as ng/mL (Table presented). CONCLUSION. In patients with vasopressor dependent shock increasing SIRS criteria are related to increases in measured circulating cytokine markers of inflammation. Circulating cytokine markers as indicator for an abnormal host response to infection do not increase with increasing qSOFA scores similar to the SIRS criteria and therefore may not be indicative of all aspects of this dysregulated host response

On-Tissue Localization of Ceramides and Other Sphingolipids by MALDI Mass Spectrometry Imaging

A novel MALDI-FTICR imaging mass spectrometry (MALDI-IMS) workflow is described for on-tissue detection, spatial localization, and structural confirmation of low abundance bioactive ceramides and other sphingolipids. Increasingly, altered or elevated levels of sphingolipids, sphingolipid metabolites, and sphingolipid metabolizing enzymes have been associated with a variety of disorders such as diabetes, obesity, lysosomal storage disorders, and cancer. Ceramide, which serves as a metabolic hub in sphingolipid metabolism, has been linked to cancer signaling pathways and to metabolic regulation with involvement in autophagy, cell-cycle arrest, senescence, and apoptosis. Using kidney tissues from a new Farber disease mouse model in which ceramides of all acyl chain lengths and other sphingolipid metabolites accumulate in tissues, specific ceramides and sphingomyelins were identified by on-tissue isolation and fragmentation, coupled with an on-tissue digestion by ceramidase or sphingomyelinase. Multiple glycosphingolipid species were also detected. The newly generated library of sphingolipid ions was then applied to MALDI-IMS of human lung cancer tissues. Multiple tumor specific ceramide and sphingomyelin species were detected and confirmed by on-tissue enzyme digests and structural confirmation. High-resolution MALDI-IMS in combination with novel on-tissue ceramidase and sphingomyelinase enzyme digestions makes it now possible to rapidly visualize the distribution of bioactive ceramides and sphingomyelin in tissues