Mark Alan Tidswell

IMPORTANCE: The relationship between endotoxin activity, organ failure, and mortality is not well understood. OBJECTIVE: To test whether the combination of endotoxin activity and organ failure identifies patients at higher risk of death from sepsis and determine the relationship to previously described sepsis phenotypes. DESIGN, SETTING, AND PARTICIPANTS: Prospective observational study in four ICUs enrolling critically ill patients with septic shock. MAIN OUTCOMES AND MEASURES: Endotoxin activity assay (EAA) results, Sequential Organ Failure Assessment (SOFA), and multiple organ dysfunction (MODS) and 28-day mortality. RESULTS: We enrolled 90 patients aged 25–95 years and set an EAA cutoff of greater than or equal to 0.6 together with SOFA greater than 11 or MODS greater than 9 to define endotoxic septic shock (ESS). At baseline mean EAA was 0.64 (sd = 0.19), whereas mean SOFA and MODS were 10.3 (sd 3.2) and 5.8 (sd 3.1), respectively. EAA greater than or equal to 0.6 and SOFA greater than 11 were present in 20 patients (23.3%) and these patients had 60% mortality. EAA greater than or equal to 0.6 and SOFA less than or equal to 11 occurred in 31 (36.0%) with mortality 12.9%. Of the 35 remaining patients with EAA less than 0.6, 29 (33.7%) had SOFA less than or equal to 11 and 5 of them (17.2%) died. Only six patients (7.0%) had EAA less than 0.6 and SOFA greater than 11 and none died (p < 0.001). All patients with MODS greater than 9 also had EAA greater than or equal to 0.6 (12 patients) with 75% mortality. EAA greater than or equal to 0.6 with MODS less than or equal to 9 occurred in 39 patients with 17.9% mortality (p < 0.001). ESS (EAA ≥ 0.6 together with SOFA > 11 or MODS > 9) occurred in 21 patients and they had significantly higher mortality (57.1% vs. 15.9%, p < 0.001) compared with non-ESS, with a relative risk for death of 3.58 (95% CI, 1.86–6.91). Among ESS patients, 7 (33.3%) had δ phenotype, whereas only 4 (5.8%) had δ among non-ESS (p = 0.001). CONCLUSIONS AND RELEVANCE: ESS compromises patients with the highest mortality rate from sepsis. Such patients are most appropriate for trials testing anti-endotoxin therapy for improving survival.

RATIONALE: The optimal treatment for early hypoxemic respiratory failure is unclear, and both high-flow nasal cannula and non-invasive ventilation are used. Determining clinically relevant outcomes for evaluating non-invasive respiratory support modalities remains a challenge. OBJECTIVES: To compare the effectiveness of initial treatment with high-flow nasal cannula versus non-invasive ventilation for acute hypoxemic respiratory failure. METHODS: We conducted a retrospective cohort study of patients with acute hypoxemic respiratory failure treated with high-flow nasal cannula or non-invasive ventilation within 24 hours of Emergency Department arrival (1/2018-12/2022). We matched patients 1:1 using a propensity score for odds of receiving non-invasive ventilation. The primary outcome was major adverse pulmonary events (28-day mortality, ventilator-free days, non-invasive respiratory support hours) calculated using a Win Ratio. MEASUREMENTS AND MAIN RESULTS: 1,265 patients met inclusion criteria. 795 (62.8%) received high-flow oxygen and 470 (37.2%) received non-invasive ventilation. We propensity score matched 736/1,265 (58.2%) patients. There was no difference between non-invasive ventilation vs high-flow nasal cannula in 28-day mortality (17.7% vs 23.1%, p=0.08) or ventilator-free days (median [Interquartile Range]: 28 [25, 28] vs 28 [13, 28], p=0.50), but patients on non-invasive ventilation required treatment for fewer hours (median 7 vs 13, p< 0.001). Win Ratio for composite major adverse pulmonary events favored non-invasive ventilation (1.26, 95%CI 1.06-1.49, p< 0.001). CONCLUSIONS: In this observational study of patients with acute hypoxemic respiratory failure, initial treatment with non-invasive ventilation was superior to high-flow nasal cannula for major pulmonary adverse events. Evaluation of composite outcomes is important in the assessment of respiratory support modalities.

The coronavirus disease 2019 (COVID19) pandemic had caused more than 500,000 deaths in the United States. Although it mainly manifests with respiratory symptoms, postmortem examination reveals that it is more of a systemic disease affecting mutliple body organs. Postmortem needle core biopsies from multiple organs were obtained from 9 patients who died at our institution in the months of April and May of 2020 due to a confirmed SARS-CoV-2 infection by RT-PCR testing of nasopharyngeal swabs. The core biopsies from body organs included lungs (8), liver (7), kidneys (5), heart (2), spleen (2), and brain (2). Histopathological examination was performed in conjunction with a set of special and immunohistochemical stains. Electron microscopy examination was also done in 4 cases. The cohort consisted of 6 males and 3 females with a mean age of 70.4 years (range: 68–79). The majority had comorbidities (8/9) and presented with respiratory symptoms (9/9). The most significant postmortem findings were mainly in the lungs, including alveolar hemorrhage, hyaline membranes, fibrin thrombi, intraalveolar macrophages, type-2 pneumocyte hyperplasia, and interstitial myofibroblast reaction and collagen deposition. Immunohistochemical stains showed predominance of T-lymphocytes with a mixture of CD4 and CD8 positive cells. Examination of liver showed minimal to marked microvesicular and macrovesicular steatosis and centrilobular congestion and necrosis. Tissue from kidneys revealed mild to severe acute tubular injury. Microglial activation and Alzheimer type-II astrocytosis were noted in brain, and mild white pulp depletion was seen in the spleen. Electron microscopy showed the presence of foreign bodies suspicious for viral particles ranging in size from 52.6 to 97.9 nm in 2/4 cases. Our findings based on postmortem core needle biopsies confirm the observation that most severely affected patients have significant pulmonary pathology. However, other organs show findings that may lead to a better understanding of this disease. Postmortem examination will continue to be an invaluable tool for studying the pathologic manifestations of COVID-19.

Acute upper airway obstruction is a medical emergency and can be caused by many serious conditions such as a foreign body occluding the airway, intrinsic swelling (as in anaphylaxis), or extrinsic compression. Thyromegaly has rarely been reported as a source of airway compromise. We present a patient whose thyromegaly is presumed to have been induced by lithium and was massive enough to cause severe airway compromise.

The human innate immune system initiates inflammation in response to bacterial molecules, particularly Gram-negative bacterial endotoxin. The steps by which endotoxin exposure leads to systemic inflammation include binding to Toll-like receptor-4 that specifically recognizes endotoxin and subsequently triggers cellular and molecular inflammatory responses. Severe sepsis is a systemic inflammatory response to infection that induces organ dysfunction and threatens a person's survival. Severe sepsis is frequently associated with increased blood levels of endotoxin. It is a significant medical problem that effects approximately 700,000 patients every year in the USA, resulting in 250,000 deaths. Eritoran tetrasodium is a nonpathogenic analog of bacterial endotoxin that antagonizes inflammatory signaling by the immune receptor Toll-like receptor-4. Eritoran is being evaluated for the treatment of patients with severe sepsis.

Endotoxin is a potent stimulus of proinflammatory response and systemic coagulation in patients with severe sepsis. Endotoxin is a component of Gram-negative bacteria that triggers an innate immune response through Toll-like receptor 4 signaling pathways in myeloid cells. We evaluated safety and tolerability of two dose regimens of eritoran tetrasodium (E5564), a synthetic Toll-like receptor 4 antagonist, and explored whether it decreases 28-day mortality rate in subjects with severe sepsis. Prospective, randomized, double-blind, placebo-controlled, multicenter, ascending-dose phase II trial. Adult intensive care units in the United States and Canada. Three hundred adults within 12 hrs of recognition of severe sepsis, with Acute Physiology and Chronic Health Evaluation (APACHE) II-predicted risk of mortality between 20% and 80%. Intravenous eritoran tetrasodium (total dose of either 45 mg or 105 mg) or placebo administered every 12 hrs for 6 days. Prevalence of adverse events was similar among subjects treated with 45 mg or 105 mg of eritoran tetrasodium or with placebo. For modified intent-to-treat subjects, 28-day all-cause mortality rates were 26.6% (eritoran tetrasodium 105 mg), 32.0% (eritoran tetrasodium 45 mg), and 33.3% in the placebo group. Mortality rate in the eritoran tetrasodium 105-mg group was not significantly different from placebo (p = .335). In prespecified subgroups, subjects at highest risk of mortality by APACHE II score quartile had a trend toward lower mortality rate in the eritoran tetrasodium 105-mg group (33.3% vs. 56.3% placebo group, p = .105). A trend toward a higher mortality rate was observed in subjects in the lowest APACHE II score quartile for the eritoran 105-mg group (12.0% vs. 0.0% placebo group, p = .083). Eritoran tetrasodium treatment appears well tolerated. The observed trend toward a lower mortality rate at the 105-mg dose, in subjects with severe sepsis and high predicted risk of mortality, should be further investigated.