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The ongoing coronavirus disease (COVID-19) pandemic has been unprecedented on many levels, not least of which are the challenges in understanding the pathophysiology of these new critically ill patients. One widely reported phenomenon is that of a profoundly hypoxemic patient with minimal to no dyspnea out of proportion to the extent of radiographic abnormality and change in lung compliance. This apparently unique presentation, sometimes called "happy hypoxemia or hypoxia" but better described as "silent hypoxemia," has led to the speculation of underlying pathophysiological differences between COVID-19 lung injury and acute respiratory distress syndrome (ARDS) from other causes. We explore three proposed distinctive features of COVID-19 that likely bear on the genesis of silent hypoxemia, including differences in lung compliance, pulmonary vascular responses to hypoxia, and nervous system sensing and response to hypoxemia. In the context of known principles of respiratory physiology and neurobiology, we discuss whether these particular findings are due to direct viral effects or, equally plausible, are within the spectrum of typical ARDS pathophysiology and the wide range of hypoxic ventilatory and pulmonary vascular responses and dyspnea perception in healthy people. Comparisons between lung injury patterns in COVID-19 and other causes of ARDS are clouded by the extent and severity of this pandemic, which may underlie the description of "new" phenotypes, although our ability to confirm these phenotypes by more invasive and longitudinal studies is limited. However, given the uncertainty about anything unique in the pathophysiology of COVID-19 lung injury, there are no compelling pathophysiological reasons at present to support a therapeutic approach for these patients that is different from the proven standards of care in ARDS.

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.

Throughout the current pandemic, much has been written on the relationship between hypoxemia and the presence of respiratory symptoms in acute COVID-19 lung disease. Now that we are faced with a large population of patients suffering from the sequelae of acute COVID-19 infection whom we hope to

Background: The stress of high altitude alters vascular permeability, which may be related to structural changes in the endothelial glycocalyx. We aimed to study these changes by measuring plasma c...

Acute respiratory distress syndrome (ARDS) is a rapidly developing non-cardiogenic pulmonary edema caused by pulmonary and systemic infections or sterile tissue injuries that evoke a severe lung-damaging host inflammatory response. The lung loses its normal gas exchange efficiency with disruption of the tight permeability characteristics of the alveolar capillary barrier. Interstitial and subsequent alveolar edema lead to alveolar collapse/de-recruitment, reduced lung compliance and greater pulmonary vascular resistance, often with marked regional heterogeneity in severity. Regional heightened stress applied to surrounding normal or less injured lung from edematous and collapsed regions along with associated barotrauma, volutrauma and atelectrauma with mechanical or extreme spontaneous ventilatory efforts further propagate injury in a vicious cycle called ventilator induced lung injury. Resulting arterial hypoxemia and hypercapnia arise from the creation of regions of shunt and low ventilation-perfusion (VA/Q) ratios, in addition to creation of high VA/Q and dead space areas by blood flow obstruction with thrombosis and/or high ventilating pressures. The pathophysiology of ARDS is discussed in this article and focuses on changes in the lung parenchyma and vasculature that reduce compliance, increase vascular resistance and compromise maintenance of dry normally compliant alveolar space by active alveolar fluid clearance and passive lymphatic fluid clearance from the lung interstitium. The COVID-19 pandemic that has emerged with the novel coronavirus, SARS-CoV-2, has generated a new form of severe acute lung injury that resembles ARDS in many of its features, but has different characteristics in its earliest stages leading to more profound hypoxemia and loss of dyspnea perception with less radiologically evident lung injury, not described before in ARDS. Understanding the pathophysiological features of ARDS and COVID-19 lung injury is critical to the best use of supportive therapies such as low tidal volume ventilation, supplemental oxygen concentrations, positive end-expiratory pressure (PEEP), permissive hypercapnia, prone positioning and neuromuscular blockade.

BACKGROUND: Systemic arterial gas embolism (SAGE) is a rare yet serious and underrecognized complication of bronchoscopic procedures. A recent case of presumed SAGE after transbronchial needle aspiration prompted a systematic literature review of SAGE after biopsy procedures during flexible bronchoscopy. METHODS: We performed a systematic database search for case reports and case series pertaining to SAGE after bronchoscopic lung biopsy; reports or series involving only bronchoscopic laser therapy or argon plasma coagulation (APC) were excluded. Patient data were extracted directly from published reports. RESULTS: A total of 29 unique patient reports were assessed for patient demographics, specifics of the procedure, clinical manifestations, diagnostic findings, and clinical outcomes. Cases of SAGE occurred after multiple types of bronchoscopic biopsy and under both positive and negative pressure ventilation. The most common clinical findings were neurologic, followed by cardiac manifestations; temporal patterns included acute onset of cardiac or neurologic emergencies immediately after biopsy, or delayed awakening post-procedure. There was a high mortality rate among cases (28%), with residual neurologic deficits also common (24%). DISCUSSION: SAGE is an underrecognized but severe adverse effect of bronchoscopic lung biopsy, which often presents with acute coronary or cerebral ischemia or delayed awakening from sedation. It is important for all physicians who perform bronchoscopic biopsies to be aware of the clinical manifestations and therapeutic management of SAGE in order to mitigate morbidity and mortality among patients undergoing these procedures.

The creation of dedicated sepsis guidelines and their broad dissemination over the past 2 decades have contributed to significant improvements in sepsis care. These successes have spurred the creation of bundled care mandates by major healthcare payers, such as the Center for Medicare and Medicaid Services. However, despite the likely benefits of guideline-directed sepsis bundles, mandated treatments in sepsis may lead to unintended consequences as the standard of care in sepsis improves. In particular, the heterogeneous spectrum of presentation and disease severity in sepsis, as well as the complexity surrounding the benefits of specific interventions in sepsis, argues for an individualized and titrated approach to interventions: an approach generally not afforded by care mandates. In this review, we review the risks and benefits of mandated care for sepsis, with particular emphasis on the potential adverse consequences of common bundle components such as early empiric antibiotics, weight-based fluid administration, and serum lactate monitoring. Unlike guideline-directed care, mandated care in sepsis precludes providers from tailoring treatments to heterogeneous clinical scenarios and may lead to unintended harms for individual patients.

Prognostication in sepsis is limited by disease heterogeneity, and measures to risk-stratify patients in the proximal phases of care lack simplicity and accuracy. Hyperlactatemia and vasopressor dependence are easily identifiable risk factors for poor outcomes. This study compares incidence and hospital outcomes in sepsis based on initial serum lactate level and vasopressor use in the emergency department (ED). In a retrospective analysis of a prospectively identified dual-center ED registry, patients with sepsis were categorized by ED vasopressor use and initial serum lactate level. Vasopressor-dependent patients were categorized as dysoxic shock (lactate >4.0 mmol/L) and vasoplegic shock (≤4.0 mmol/L). Patients not requiring vasopressors were categorized as cryptic shock major (lactate >4.0 mmol/L), cryptic shock minor (>2.0 and ≤4.0 mmol/L), and sepsis without lactate elevation (≤2.0 mmol/L). Of 446 patients included, 4.9% (n = 22) presented in dysoxic shock, 11.7% (n = 52) in vasoplegic shock, 12.1% (n = 54) in cryptic shock major, 30.9% (n = 138) in cryptic shock minor, and 40.4% (n = 180) in sepsis without lactate elevation. Group mortality rates at 28 days were 50.0, 21.1, 18.5, 12.3, and 7.2%, respectively. After adjusting for potential confounders, odds ratios for mortality at 28 days were 15.1 for dysoxic shock, 3.6 for vasoplegic shock, 3.8 for cryptic shock major, and 1.9 for cryptic shock minor, when compared to sepsis without lactate elevation. Lactate elevation is associated with increased mortality in both vasopressor dependent and normotensive infected patients presenting to the emergency department (ED). Cryptic shock mortality (normotension + lactate >4 mmol/L) is equivalent to vasoplegic shock mortality (vasopressor requirement + lactate

Patients suffering from chronic mountain sickness (CMS) have excessive erythrocytosis. Low level cobalt toxicity as a likely contributor has been demonstrated in some subjects. We performed a randomized, placebo controlled clinical trial in Cerro de Pasco, Peru (4380 m), where 84 participants with a hematocrit (HCT) >= 65% and CMS score > 6, were assigned to four treatment groups of placebo, acetazolamide (ACZ, which stimulates respiration), N-acetylcysteine (NAC, an antioxidant that chelates cobalt) and combination of ACZ and NAC for 6 weeks. The primary outcome was change in hematocrit and secondary outcomes were changes in PaO2, PaCO2, CMS score, and serum and urine cobalt concentrations. The mean ( SD) hematocrit, CMS score and serum cobalt concentrations were 69 +/- 4%, 9.8 +/- 2.4 and 0.24 +/- 0.15 mu g/l, respectively for the 66 participants. The ACZ arm had a relative reduction in HCT of 6.6% vs. 2.7% (p = 0.048) and the CMS score fell by 34.9% vs. 14.8% (p = 0.014) compared to placebo, while the reduction in PaCO2 was 10.5% vs. an increase of 0.6% = 0.003), with a relative increase in PaO2 of 13.6% vs. 3.0%. NAC reduced CMS score compared to placebo (relative reduction of 34.0% vs. 14.8%, p = 0.017), while changes in other parameters failed to reach statistical significance. The combination of ACZ and NAC was no better than ACZ alone. No changes in serum and urine cobalt concentrations were seen within any treatment arms. ACZ reduced polycythemia and CMS score, while NAC improved CMS score without significantly lowering hematocrit. Only a small proportion of subjects had cobalt toxicity, which may relate to the closing of contaminated water sources and several other environmental protection measures.

Introduction: Lactate clearance has been implicated as a predictor of mortality among emergency department (ED) patients with severe sepsis or septic shock. We aimed to validate prior studies showing that lactate clearance during the ED stay is associated with decreased mortality. Methods: Retrospective dual-centered cross-sectional study using patients identified in the Yale-New Haven Hospital Emergency Medicine sepsis registry with severe sepsis or septic shock who had initial lactate levels measured in the ED and upon arrival (

Nitric oxide (NO) is a potent vasodilator in terrestrial vertebrates, but whether vascular endothelial-derived NO plays a role in vascular regulation in fish remains controversial. To explore this issue, a study was made of spiny dogfish sharks (Squalus acanthias) in normoxia and acute hypoxia (60 min exposure to seawater equilibrated with 3% oxygen) with various agents known to alter NO metabolism or availability. In normoxia, nitroprusside (a NO donor) reduced blood pressure by 20%, establishing that vascular smooth muscle responds to NO. L-arginine, the substrate for NO synthase, had no hemodynamic effect. Acetylcholine, which stimulates endothelial NO and prostaglandin production in mammals, reduced blood pressure, but also caused marked bradycardia. L-NAME, an inhibitor of all NO synthases, caused a small 10% rise in blood pressure, but cell-free hemoglobin (a potent NO scavenger and hypertensive agent in mammals) had no effect. Acute hypoxia caused a 15% fall in blood pressure, which was blocked by L-NAME and cell-free hemoglobin. Serum nitrite, a marker of NO production, rose with hypoxia, but not with L-NAME. Results suggest that NO is not an endothelial-derived vasodilator in the normoxic elasmobranch. The hypertensive effect of L-NAME may represent inhibition of NO production in the CNS and nerves regulating blood pressure. In acute hypoxia, there is a rapid up-regulation of vascular NO production that appears to be responsible for hypoxic vasodilation.