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COVID-19-associated respiratory failure offers the unprecedented opportunity to evaluate the differential host response to a uniform pathogenic insult. Understanding whether there are distinct subphenotypes of severe COVID-19 may offer insight into its pathophysiology. Sequential Organ Failure Assessment (SOFA) score is an objective and comprehensive measurement that measures dysfunction severity of six organ systems, i.e., cardiovascular, central nervous system, coagulation, liver, renal, and respiration. Our aim was to identify and characterize distinct subphenotypes of COVID-19 critical illness defined by the post-intubation trajectory of SOFA score. Intubated COVID-19 patients at two hospitals in New York city were leveraged as development and validation cohorts. Patients were grouped into mild, intermediate, and severe strata by their baseline post-intubation SOFA. Hierarchical agglomerative clustering was performed within each stratum to detect subphenotypes based on similarities amongst SOFA score trajectories evaluated by Dynamic Time Warping. Distinct worsening and recovering subphenotypes were identified within each stratum, which had distinct 7-day post-intubation SOFA progression trends. Patients in the worsening suphenotypes had a higher mortality than those in the recovering subphenotypes within each stratum (mild stratum, 29.7% vs. 10.3%, p = 0.033; intermediate stratum, 29.3% vs. 8.0%, p = 0.002; severe stratum, 53.7% vs. 22.2%, p

Vascular injury is a menacing element of acute respiratory distress syndrome (ARDS) pathogenesis. To better understand the role of vascular injury in COVID-19 ARDS, we used lung autopsy immunohistochemistry and blood proteomics from COVID-19 subjects at distinct timepoints in disease pathogenesis, including a hospitalized cohort at risk of ARDS development (“at risk”, N=59), an intensive care unit cohort with ARDS (“ARDS”, N=31), and a cohort recovering from ARDS (“recovery”, N=12). COVID-19 ARDS lung autopsy tissue revealed an association between vascular injury and platelet-rich microthrombi. This link guided the derivation of a protein signature in the at risk cohort characterized by lower expression of vascular proteins in subjects who died, an early signal of vascular limitation termed the maladaptive vascular response. These findings were replicated in COVID-19 ARDS subjects, as well as when bacterial and influenza ARDS patients (N=29) were considered, hinting at a common final pathway of vascular injury that is more disease (ARDS) then cause (COVID-19) specific, and may be related to vascular cell death. Among recovery subjects, our vascular signature identified patients with good functional recovery one year later. This vascular injury signature could be used to identify ARDS patients most likely to benefit from vascular targeted therapies.

BackgroundAlthough acute respiratory distress syndrome (ARDS) is associated with high mortality, its direct causal link with death is unclear. Clarifying this link is important to justify costly research on prevention of ARDS.ObjectiveTo estimate the attributable mortality, if any, of ARDS.DesignFirst, we performed a systematic review and meta-analysis of observational studies reporting mortality of critically ill patients with and without ARDS matched for underlying risk factor. Next, we conducted a survival analysis of prospectively collected patient-level data from subjects enrolled in three intensive care unit (ICU) cohorts to estimate the attributable mortality of critically ill septic patients with and without ARDS using a novel causal inference method.ResultsIn the meta-analysis, 44 studies (47 cohorts) involving 56 081 critically ill patients were included. Mortality was higher in patients with versus without ARDS (risk ratio 2.48, 95% CI 1.86 to 3.30; pConclusionsARDS has a direct causal link with mortality. Our findings provide information about the extent to which continued funding of ARDS prevention trials has potential to impart survival benefit.PROSPERO Registration NumberCRD42017078313

RationaleCOVID-19-associated respiratory failure offers the unprecedented opportunity to evaluate the differential host response to a uniform pathogenic insult. Prior studies of Acute Respiratory Distress Syndrome (ARDS) have identified subphenotypes with differential outcomes. Understanding whether there are distinct subphenotypes of severe COVID-19 may offer insight into its pathophysiology.ObjectivesTo identify and characterize distinct subphenotypes of COVID-19 critical illness defined by the post-intubation trajectory of Sequential Organ Failure Assessment (SOFA) score.MethodsIntubated COVID-19 patients at two hospitals in New York city were leveraged as development and validation cohorts. Patients were grouped into mild, intermediate, and severe strata by their baseline post-intubation SOFA. Hierarchical agglomerative clustering was performed within each stratum to detect subphenotypes based on similarities amongst SOFA score trajectories evaluated by Dynamic Time Warping. Statistical tests defined trajectory subphenotype predictive markers.Measurements and Main ResultsDistinct worsening and recovering subphenotypes were identified within each stratum, which had distinct 7-day post-intubation SOFA progression trends. Patients in the worsening suphenotypes had a higher mortality than those in the recovering subphenotypes within each stratum (mild stratum, 29.7% vs. 10.3%, p=0.033; intermediate stratum, 29.3% vs. 8.0%, p=0.002; severe stratum, 53.7% vs. 22.2%, pConclusionsThere are clear worsening and recovering subphenotypes of COVID-19 respiratory failure after intubation, which are more predictive of outcomes than baseline severity of illness. Organ dysfunction trajectory may be well suited as a surrogate for research in COVID-19 respiratory failure.At a Glance CommentaryScientific Knowledge on the SubjectCOVID-19 associated respiratory failure leads to a significant risk of morbidity and mortality. It is clear that there is heterogeneity in the viral-induced host response leading to differential outcomes, even amongst those treated with mechanical ventilation. There are many studies of COVID-19 disease which use intubation status as an outcome or an inclusion criterion. However, there is less understanding of the post intubation course in COVID-19.What This Study Adds to the FieldWe have developed and validated a novel subphenotyping model based on post-intubation organ dysfunction trajectory in COVID-19 patients. Specifically, we identified clear worsening and recovering organ dysfunction trajectory subphenotypes, which are more predictive of outcomes than illness severity at baseline. Dynamic inflammatory markers and ventilator variables rather than baseline severity of illness, demographics and comorbidities differentiate the worsening and recovering subphenotypes. Trajectory subphenotypes offer a potential road map for understanding the evolution of critical illness in COVID-19.

Background: The main clinical manifestations of coronavirus disease 2019 (COVID-19) onset are respiratory symptoms, including cough, sputum and dyspnea. However, a significant proportion of patients initially manifested extra-respiratory symptoms, such as fever, myalgia and diarrhea. Here we compared the different characteristics and outcomes between the patients with respiratory symptoms and extra-respiratory symptoms at illness onset.Methods: The patients admitted to the respiratory departments from eight hospitals out of Wuhan with nucleic acid-positive of severe acute respiratory syndrome coronavirus (SARS-CoV-2) were recruited. Epidemiological information, clinical manifestations, laboratory findings, and radiological characteristics, treatment regimens and outcomes data were recorded and analyzed.Results: The median age of the recruited 541 subjects was 43 years (IQR, 33-55). Of the 541 subjects, 404 (74.5%) subjects had initial symptom that were respiratory, while 137 (25.5%) subjects had extra-respiratory symptoms. Respiratory COVID-19 subjects had more secondary bacterial infections (pp = 0.01) dyspnea (OR = 4.91, p < 0.001) and secondary bacterial infection (OR = 19.8, p < 0.001) were independently associated with development of ARDS among COVID-19 patients.Conclusion: we identify COVID-19 subjects with dyspnea at disease onset have worse prognosis. We also demonstrate age and secondary bacterial infections to be independently associated with ARDS development in subjects with COVID-19.

Necroptosis is a genetically regulated form of necrotic cell death that has emerged as an important pathway in human disease. The necroptosis pathway is induced by a variety of signals, including death receptor ligands, and regulated by receptor-interacting protein kinases 1 and 3 (RIPK1 and RIPK3) and mixed-lineage kinase domain–like pseudokinase (MLKL), which form a regulatory necrosome complex. RIPK3-mediated phosphorylation of MLKL executes necroptosis. Recent studies, using animal models of tissue injury, have revealed that RIPK3 and MLKL are key effectors of injury propagation. This Review explores the functional roles of RIPK3 and MLKL as crucial pathogenic determinants and markers of disease progression and severity in experimental models of human disease, including acute and chronic pulmonary diseases; renal, hepatic, cardiovascular, and neurodegenerative diseases; cancer; and critical illness.

BACKGROUND. In sepsis, there may be dysregulation in programed cell death pathways, typified by apoptosis and necroptosis. Programmed cell death pathways may contribute to variability in the immune response. TRAIL is a potent inducer of apoptosis. Receptor-interacting serine/threonine protein kinase-3 (RIPK3) is integral to the execution of necroptosis. We explored whether plasma TRAIL levels were associated with in-hospital mortality, organ dysfunction, and septic shock. We also explored the relationship between TRAIL and RIPK3. METHODS. We performed an observational study of critically ill adults admitted to intensive care units at 3 academic medical centers across 2 continents, using 1 as derivation and the other 2 as validation cohorts. Levels of TRAIL were measured in the plasma of 570 subjects by ELISA. RESULTS. In all cohorts, lower (

The relationship between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness remains unclear. We examined the association between neuromuscular blocking agents and ICU-acquired weakness, critical illness polyneuropathy, and critical illness myopathy.PubMed, EMBASE, Web of Science, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health Literature, and bibliographies of included studies were searched from database inception until September 24, 2015.Randomized controlled trials and prospective observational studies examining the association between neuromuscular blocking agents and ICU-acquired weakness, critical illness polyneuropathy, or critical illness myopathy.One author screened titles/abstracts. Two authors independently reviewed full text and extracted data from included studies. Meta-analysis was performed using the DerSimonian-Laird random effects model (OpenMetaAnalyst 10.10 for OS.X). We assessed reporting bias with funnel plots and heterogeneity with the I statistic.Of 2,170 titles/abstracts screened, 99 full texts were selected for review, yielding one randomized controlled trial and 18 prospective observational studies, for a total of 2,254 patients. The randomized controlled trial did not show an association between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness (odds ratio, 1.21; 95% CI, 0.67-2.19), but pooled data from all included studies suggested a modest association (odds ratio, 1.25; 95% CI, 1.06-1.48; I = 16%). Funnel plots suggested reporting bias, and sensitivity analyses showed a disproportionate contribution from critical illness polyneuropathy/critical illness myopathy and severe sepsis/septic shock studies.This meta-analysis suggests a modest association between neuromuscular blocking agents and neuromuscular dysfunction acquired in critical illness; limitations include studies with a high risk of bias and a disproportionate contribution from studies examining patients for critical illness polyneuropathy/critical illness myopathy and those with severe sepsis/septic shock.

BackgroundAcute respiratory distress syndrome (ARDS) is heterogeneous. As an indication of the heterogeneity of ARDS, there are patients whose syndrome improves rapidly (i.e., within 24 hours), others whose hypoxemia improves gradually and still others whose severe hypoxemia persists for several days. The latter group of patients with persistent severe ARDS poses challenges to clinicians. We attempted to assess the baseline characteristics and outcomes of persistent severe ARDS and to identify which variables are useful to predict it.MethodsA secondary analysis of patient-level data from the ALTA, EDEN and SAILS ARDSNet clinical trials was conducted. We defined persistent severe ARDS as a partial pressure of arterial oxygen to fraction of inspired oxygen ratio (PaO2:FiO2) of equal to or less than 100 mmHg on the second study day following enrollment. Regularized logistic regression with an L1 penalty [Least Absolute Shrinkage and Selection Operator (LASSO)] techniques were used to identify predictive variables of persistent severe ARDS.ResultsOf the 1531 individuals with ARDS alive on the second study day after enrollment, 232 (15%) had persistent severe ARDS. Of the latter, 100 (43%) individuals had mild or moderate hypoxemia at baseline. Usage of vasopressors was greater [144/232 (62%) versus 623/1299 (48%); pConclusionsPatients with persistent severe ARDS have distinct baseline characteristics and poor prognosis. Identifying such patients at enrollment may be useful for the prognostic enrichment of trials.

Hypocalcaemia is a rare complication of calcium channel blocker overdose, having been reported only once previously (J Toxicol Clin Toxicol, 1992, 30, 309). In this article, we report a case of a 37-year-old woman who developed hypocalcaemia after a verapamil overdose, review the literature and propose a mechanism for this rare finding.

Neuromuscular blocking agents (NMBAs), or “paralytics,” often are deployed in the sickest patients in the intensive care unit (ICU) when usual care fails. Despite the publication of guidelines on the use of NMBAs in the ICU in 2002, clinicians have needed more direction to determine which patients would benefit from NMBAs and which patients would be harmed. Recently, new evidence has shown that paralytics hold more promise when used in carefully selected lung injury patients for brief periods of time. When used in early acute respiratory distress syndrome (ARDS), NMBAs assist to establish a lung protective strategy, which leads to improved oxygenation, decreased pulmonary and systemic inflammation, and potentially improved mortality. It also is increasingly recognized that NMBAs can cause harm, particularly critical illness polyneuromyopathy (CIPM), when used for prolonged periods or in septic shock. In this review, we address several practical considerations for clinicians who use NMBAs in their practice. Ultimately, we conclude that NMBAs should be considered a lung protective adjuvant in early ARDS and that clinicians should consider using an alternative NMBA to the aminosteroids in septic shock with less severe lung injury pending further studies.

A 44-year-old African-American woman was admitted with four months of intermittent “shock-like” sensations in her chest radiating to both arms; she developed left arm weakness just prior to admission. A cervical spine magnetic resonance imaging (MRI) demonstrated intramedullary enhancement from C1 to T1 (Fig. 1 Panel a). Figure 1. Cervical spine magnetic resonance imaging (MRI) of a 44-year-old African-American woman. Panel a: MRI with gadolinium contrast 3 weeks prior to admission. Panel b: MRI with gadolinium contrast after 8 weeks of corticosteroid therapy. Neurologic examination showed 4/5 strength of left wrist flexors and extensors, decreased bilateral light touch and pinprick sensation from C5 to T5, and hyperalgesia bilaterally from T1 to T3. Chest x-ray showed hilar adenopathy. Serum angiotensin converting enzyme level was 191 U/L (normal 9–67). Lumbar puncture was remarkable for a protein of 54 mg/dl (normal 15–45) and glucose of 30 mg/dl (normal 45–80; serum glucose 106). Transbronchial biopsy showed non-caseating granulomas. Sarcoidosis is an idiopathic inflammatory disease characterized by non-caseating granulomas affecting any organ. Neurologic involvement occurs in 5–17 % of sarcoidosis patients, with 0.43 % having spinal cord involvement.1 The most common cerebrospinal fluid findings are elevated protein and hypoglycorrhachia, presumably a manifestation of chronic meningeal inflammation.2 Owing to the invasive nature of spinal cord biopsy, neurosarcoidosis is often diagnosed with extraneural tissue and the appropriate clinical syndrome.3,4 Treatment generally includes immunosuppressive agents. This patient’s neurological deficits and radiographic abnormalities improved with corticosteroids (Fig. ​(Fig.11 Panel b).

I was surprised that Wittenberg did not mention the use of ultrasound in anaesthesia and critical care.1 Ever since the National Institute for Health and Care Excellence advocated the use of ultrasound for central venous access in 2002, every anaesthetic department has been obliged to purchase an …