Causes, Consequences, and Treatments of Sleep and Circadian Disruption in the ICU: An Official American Thoracic Society Research Statement.

Background: Sleep and circadian disruption (SCD) is common and severe in the ICU. On the basis of rigorous evidence in non-ICU populations and emerging evidence in ICU populations, SCD is likely to have a profound negative impact on patient outcomes. Thus, it is urgent that we establish research priorities to advance understanding of ICU SCD. Methods: We convened a multidisciplinary group with relevant expertise to participate in an American Thoracic Society Workshop. Workshop objectives included identifying ICU SCD subtopics of interest, key knowledge gaps, and research priorities. Members attended remote sessions from March to November 2021. Recorded presentations were prepared and viewed by members before Workshop sessions. Workshop discussion focused on key gaps and related research priorities. The priorities listed herein were selected on the basis of rank as established by a series of anonymous surveys. Results: We identified the following research priorities: establish an ICU SCD definition, further develop rigorous and feasible ICU SCD measures, test associations between ICU SCD domains and outcomes, promote the inclusion of mechanistic and patient-centered outcomes within large clinical studies, leverage implementation science strategies to maximize intervention fidelity and sustainability, and collaborate among investigators to harmonize methods and promote multisite investigation. Conclusions: ICU SCD is a complex and compelling potential target for improving ICU outcomes. Given the influence on all other research priorities, further development of rigorous, feasible ICU SCD measurement is a key next step in advancing the field.

Metabolic networks in a porcine model of trauma and hemorrhagic shock demonstrate different control mechanism with carbohydrate pre-feed.

BACKGROUND: Treatment with oral carbohydrate prior to trauma and hemorrhage confers a survival benefit in small animal models. The impact of fed states on survival in traumatically injured humans is unknown. This work uses regulatory networks to examine the effect of carbohydrate pre-feeding on metabolic response to polytrauma and hemorrhagic shock in a clinically-relevant large animal model. METHODS: Male Yorkshire pigs were fasted overnight (n = 64). Pre-fed animals (n = 32) received an oral bolus of Karo\textregistered\syrup before sedation. All animals underwent a standardized trauma, hemorrhage, and resuscitation protocol. Serum samples were obtained at set timepoints. Proton NMR was used to identify and quantify serum metabolites. Metabolic regulatory networks were constructed from metabolite concentrations and rates of change in those concentrations to identify controlled nodes and controlling nodes of the network. RESULTS: Oral carbohydrate pre-treatment was not associated with survival benefit. Six metabolites were identified as controlled nodes in both groups: adenosine, cytidine, glycerol, hypoxanthine, lactate, and uridine. Distinct groups of controlling nodes were associated with controlled nodes; however, the composition of these groups depended on feeding status. CONCLUSIONS: A common metabolic output, typically associated with injury and hypoxia, results from trauma and hemorrhagic shock. However, this output is directed by different metabolic inputs depending upon the feeding status of the subject. Nodes of the network that are related to mortality can potentially be manipulated for therapeutic effect; however, these nodes differ depending upon feeding status.

Anoxia inhibits biofilm development and modulates antibiotic activity.

BACKGROUND: Many infections involve bacterial biofilms that are notoriously antibiotic resistant. Unfortunately, the mechanism for this resistance is unclear. We tested the effect of oxygen concentration on development of Staphylococcus aureus biofilms, and on the ability of gentamicin and vancomycin to inhibit biofilm development. MATERIALS AND METHODS: To mimic catheter-associated biofilms, silastic coupons were inoculated with 10(7)S aureus and incubated either aerobically (∼21% O2) or anaerobically (10% CO2, 5% H2, 85% N2) for 16 h at 37°C with varying concentrations of gentamicin and vancomycin. Viable colony-forming units were quantified from sonicated biofilms, and the crystal violet assay quantified biofilm biomass. Metabolomic profiles probed biochemical differences between aerobic and anaerobic biofilms. RESULTS: Control biofilms (no antibiotic) cultivated aerobically contained 8.1-8.6 log10S aureus. Anaerobiasis inhibited biofilm development, quantified by viable bacterial numbers and biomass (P < 0.05). Bactericidal concentrations of gentamicin inhibited biofilm development in normoxia but not anoxia, likely because bacterial uptake of gentamicin is oxygen dependent. The inhibitory effect of vancomycin was more uniform aerobically and anaerobically, although at high bactericidal concentrations, vancomycin effectiveness was decreased under anoxia. There were notable differences in the metabolomic profiles of biofilms cultivated under normoxia versus anoxia. CONCLUSIONS: Compared with aerobic incubation, anaerobiasis resulted in decreased biofilm development, and metabolomics is a promising tool to identify key compounds involved in biofilm formation. The effectiveness of a specific antibiotic depended on its mode of action, as well as on the oxygen concentration in the environment.

Urinary 1H-NMR metabolomics can distinguish pancreatitis patients from healthy controls.

CONTEXT: The characterization of the urinary metabolome may yield biomarkers indicative of pancreatitis. OBJECTIVES: We establish a non-invasive technique to compare urinary metabolic profiles in patients with acute and chronic pancreatitis to healthy controls. METHODS: Urine was obtained from healthy controls (HC, n=5), inpatients with mild acute pancreatitis (AP, n=5), and outpatients with chronic pancreatitis (CP, n=5). Proton nuclear magnetic resonance spectra were obtained for each sample. Metabolites were identified and quantified in each spectrum; resulting concentrations were normalized to account for differences in dilution among samples. Kruskal-Wallis test, post-hoc Mann-Whitney U tests, and principal component analysis were performed to identify metabolites that discriminate healthy controls, acute pancreatitis, and chronic pancreatitis. RESULTS: Sixty metabolites were identified and quantified; five were found to differ significantly (P<0.05) among the three groups. Of these, citrate and adenosine remained significant after validation by random permutation. Principal component analysis demonstrated that healthy control urine samples can be differentiated from patients with chronic pancreatitis or acute pancreatitis; chronic pancreatitis patients could not be distinguished from acute pancreatitis patients. CONCLUSIONS: This metabolomic investigation demonstrates that this non-invasive technique offers insight into the metabolic states of pancreatitis. Although the identified metabolites cannot conclusively be defined as biomarkers of disease, future studies will validate our findings in larger patient cohorts.

Extracorporeal Membrane Oxygenation Patient Outcomes Following Restrictive Blood Transfusion Protocol.

OBJECTIVES: To investigate the effect of a restrictive blood product utilization protocol on blood product utilization and clinical outcomes. DESIGN: We retrospectively reviewed all adult extracorporeal membrane oxygenation (ECMO) patients from January 2019 to December 2021. The restrictive protocol, implemented in March 2020, was defined as transfusion of blood products for a hemoglobin level less than 7, platelet levels less than 50, and/or fibrinogen levels less than 100. Subgroup analysis was performed based on the mode of ECMO received: venoarterial ECMO, venovenous ECMO, and ECMO support following extracorporeal cardiopulmonary resuscitation (ECPR). SETTING: M Health Fairview University of Minnesota Medical Center. PATIENTS: The study included 507 patients. INTERVENTIONS: One hundred fifty-one patients (29.9%) were placed on venoarterial ECMO, 70 (13.8%) on venovenous ECMO, and 286 (56.4%) on ECPR. MEASUREMENTS AND MAIN RESULTS: For patients on venoarterial ECMO (48 [71.6%] vs. 52 [63.4%]; p = 0.374), venovenous ECMO (23 [63.9%] vs. 15 [45.5%]; p = 0.195), and ECPR (54 [50.0%] vs. 69 [39.2%]; p = 0.097), there were no significant differences in survival on ECMO. The last recorded mean hemoglobin value was also significantly decreased for venoarterial ECMO (8.10 [7.80-8.50] vs. 7.50 [7.15-8.25]; p = 0.001) and ECPR (8.20 [7.90-8.60] vs. 7.55 [7.10-8.88]; p < 0.001) following implementation of the restrictive transfusion protocol. CONCLUSIONS: These data suggest that a restrictive transfusion protocol is noninferior to ECMO patient survival. Additional, prospective randomized trials are required for further investigation of the safety of a restrictive transfusion protocol.

Comparison of Outcomes and Process of Care for Patients Treated at Hospitals Dedicated for COVID-19 Care vs Other Hospitals.

Importance: Early in the SARS-CoV-2 pandemic, the M Health Fairview Hospital System established dedicated hospitals for establishing cohorts and caring for patients with COVID-19, yet the association between treatment at COVID-19-dedicated hospitals and mortality and complications is not known. Objective: To analyze the mortality rate and complications associated with treatment at the COVID-19-dedicated hospitals. Design, Setting, and Participants: This retrospective cohort study evaluated data prospectively collected from March 1, 2020, through June 30, 2021, from 11 hospitals in Minnesota, including 2 hospitals created solely to care for patients with COVID-19. Data obtained included demographic characteristics, treatments, and outcomes of interest for all patients with a confirmed COVID-19 infection admitted to this hospital system during the study period. Exposures: Patients were grouped based on whether they received treatment from 1 of the 2 COVID-19-dedicated hospitals compared with the remainder of the hospitals within the hospital system. Main Outcomes and Measures: Multivariate analyses, including risk-adjusted logistic regression and propensity score matching, were performed to evaluate the primary outcome of in-hospital mortality and secondary outcomes, including complications and use of COVID-specific therapeutics. Results: There were 5504 patients with COVID-19 admitted during the study period (median age, 62.5 [IQR, 45.0-75.6] years; 2854 women [51.9%]). Of these, 2077 patients (37.7%) (median age, 63.4 [IQR, 50.7-76.1] years; 1080 men [52.0%]) were treated at 1 of the 2 COVID-19-dedicated hospitals compared with 3427 (62.3%; median age, 62.0 [40.0-75.1] years; 1857 women (54.2%) treated at other hospitals. The mortality rate was 11.6% (n = 241) at the dedicated hospitals compared with 8.0% (n = 274) at the other hospitals (P < .001). However, risk-adjusted in-hospital mortality was significantly lower for patients in the COVID-19-dedicated hospitals in both the unmatched group (n = 2077; odds ratio [OR], 0.75; 95% CI, 0.59-0.95) and the propensity score-matched group (n = 1317; OR, 0.78; 95% CI, 0.58-0.99). The rate of overall complications in the propensity score-matched group was significantly lower (OR, 0.81; 95% CI, 0.66-0.99) and the use of COVID-19-specific therapeutics including deep vein thrombosis prophylaxis (83.9% vs 56.9%; P < .001), high-dose corticosteroids (56.1% vs 22.2%; P < .001), remdesivir (61.5% vs 44.5%; P < .001), and tocilizumab (7.9% vs 2.0; P < .001) was significantly higher. Conclusions and Relevance: In this cohort study, COVID-19-dedicated hospitals had multiple benefits, including providing high-volume repetitive treatment and isolating patients with the infection. This experience suggests improved in-hospital mortality for patients treated at dedicated hospitals owing to improved processes of care and supports the use of establishing cohorts for future pandemics.

Outcomes of Patients Undergoing Interfacility Extracorporeal Membrane Oxygenation Transfer Based on Cannulation Location and Mode of Transport.

As the use of extracorporeal membrane oxygenation (ECMO) expands, so has the need for interfacility transfer to ECMO centers. However, the impact of these transfers has not been fully studied. This study evaluates complications and inhospital mortality in adult patients treated with venovenous (V-V) ECMO based on institutional location of cannulation and mode of transport. DESIGN: Retrospective cohort study. SETTING: Large midwestern ECMO center. PATIENTS: Adult patients receiving VV-ECMO. INTERVENTIONS: Need for transfer to ECMO center following VV-ECMO cannulation. MEASUREMENTS AND MAIN RESULTS: The study included 102 adult patients, 57% of which were cannulated at an outside institution prior to transfer. Of these, 60% were transported by ground, and the remainder were transported by air. Risk-adjusted logistic regression did not reveal any significant increase in odds for any complication or inhospital mortality between the groups based on location of cannulation or mode of transport. CONCLUSIONS: This study supports the practice of interfacility ECMO transfer with no difference in outcomes or inhospital mortality based on institutional location of cannulation or mode of transport.

Enhancing cosinor analysis of circadian phase markers using the gamma distribution.

The cosinor model, in which a cosine curve is fitted to periodic data within a regression model, is a frequently used method for describing patterns of cyclical activity such as circadian rhythms. For circadian variables of interest (eg, melatonin and heart rate) that do not take on negative values, the assumption of normally distributed residuals required by the general linear model, which is most commonly used for cosinor analysis, may not be appropriate. Alternatively, a generalized linear model with the gamma distribution (GZLM-gamma) is specifically defined to accommodate non-negative outcomes. Herein, we demonstrate the improved fit and gains of efficiency in detection of circadian rhythm afforded by using the GZLM-gamma in cosinor models of heart rate, actigraphic activity, and urinary 6-sulfatoxymelatonin. Notably, this improved detection of circadian rhythm allows retention of additional patients for downstream analyses, further improving study power.

Evaluation of Minnesota Score in the Allocation of Venovenous Extracorporeal Membrane Oxygenation During Resource Scarcity.

Background: In this study, we evaluate the previously reported novel Minnesota Score for association with in-hospital mortality and allocation of venovenous extracorporeal membrane oxygenation in patients with acute respiratory distress syndrome with or without SARS-CoV-2 pneumonia. Methods: This was a retrospective cohort study across four extracorporeal membrane oxygenation centers in Minnesota. Logistic regression was used to assess the relationship between the scores and in-hospital mortality, duration of ECMO cannulation, and discharge disposition. Priority groups were established statistically by maximizing the sum of sensitivity and specificity and compared to the previous qualitatively established priority groups. Results: Of 124 patients included in the study, 38% were treated for COVID-19 acute respiratory distress syndrome. The median age was 48 years, and 73% were male. The in-hospital mortality rate was 38%. The Minnesota Score was significantly associated with in-hospital mortality only (OR 1.13, p=0.02). Statistically determined cut points were similar to qualitative cut points. SARS-CoV-2 status did not change the findings. Conclusions: In our patient cohort, the Minnesota Score is associated with increased mortality. With further validation, proposed priority groups could be utilized for allocation of ECMO in times of increasing scarcity.

Increasing Mortality in Venovenous Extracorporeal Membrane Oxygenation for COVID-19-Associated Acute Respiratory Distress Syndrome.

OBJECTIVES: Determine the factors associated with mortality in venovenous extracorporeal membrane oxygenation (V-V ECMO) patients with COVID-19 infection and provide an updated report of clinical outcomes for patients treated with V-V ECMO for COVID-19 in Minnesota. DESIGN: Multicenter prospective observational study. SETTING: The four adult Extracorporeal Life Support Organization-certified Centers of Excellence in Minnesota. PATIENTS: A total of 100 patients treated with V-V ECMO for COVID-19-associated acute respiratory distress syndrome (ARDS) from March 2020 to May 2021. INTERVENTIONS: Not applicable. MEASUREMENTS AND MAIN RESULTS: The primary outcome was 60-day survival for patients treated with V-V ECMO for COVID-19. Outcomes of patients treated from November 2020 to May 2021(cohort 2) were compared with data from a previous cohort of patients, collected from March 2020 to October 2020 (cohort 1). The data from both cohorts were merged into a single dataset (Combined Cohort). Survival on V-V ECMO due to COVID-19-associated ARDS significantly decreased after October 2020 (63% vs 41%; p = 0.026). The median interval from hospital admission to V-V ECMO cannulation was significantly associated with 60-day mortality (10 d [6-14 d] in nonsurvivors vs 7 d [4-9 d] in survivors; p = 0.001) in the Combined Cohort and was also significantly longer in cohort 2 than cohort 1 (10 d [7-14 d] vs 6 d [4-10 d]; p < 0.001). In the Combined Cohort, the 60-day survival for patients who did not receive steroids was 86% (n = 12) versus 45% (n = 39) for patients who received at least one dose of steroids (p = 0.005). CONCLUSIONS: There was a significant increase in mortality for patients treated with V-V ECMO for COVID-19-associated ARDS in cohort 2 compared with cohort 1. Further research is required to determine the cause of the worsening trend in mortality.

Perioperative Coagulation Changes in Total Pancreatectomy and Islet Autotransplantation.

OBJECTIVES: Thrombotic complications after total pancreatectomy with islet autotransplantation (TPIAT) are common. However, the systemic changes to coagulation in the perioperative period have not been well studied. Our objective was to evaluate the derangements in coagulation in the perioperative period for this procedure. METHODS: This was a prospective observational study of patients undergoing elective TPIAT for chronic pancreatitis. Multiple methods of evaluating coagulation, including 2 viscoelastic assays and standard laboratory assays were obtained at defined intraoperative and postoperative intervals. RESULTS: Fifteen patients were enrolled. Laboratory values demonstrated initial intraoperative hypercoagulability before significant systemic anticoagulation after islet infusion with heparin. Hypercoagulability is again seen at postoperative days 3 and 7. Subgroup analysis did not identify any major coagulation parameters associated with portal vein thrombosis formation. CONCLUSIONS: Apart from the immediate period after islet cell and heparin infusion, patients undergoing TPIAT are generally hypercoagulable leading to a high rate of thrombotic complications. Portal vein thrombosis development had minimal association with systemic derangements in coagulation as it is likely driven by localized inflammation at the time of islet cell infusion. This study may provide the groundwork for future studies to identify improvements in thrombotic complications.

Light Levels in ICU Patient Rooms: Dimming of Daytime Light in Occupied Rooms.

One-third of patients report disruption of sleep by overnight light. Importantly, light causes both immediate sleep disturbance and influences circadian function, a fundamental process underpinning high-quality sleep. Short bursts of light at night and/or lack of bright daytime light disrupt circadian alignment, leading to sleep deficiency. To improve understanding of 24-hour light patterns, we conducted a longitudinal study of light levels in intensive care unit (ICU) rooms. Over 450 room-days, we observed high variability, dim daytime light, and active dimming of natural sunlight in occupied rooms. Such noncircadian light patterns have multifactorial influences on sleep and are a key target for sleep improvement in the ICU.

The Use of Venovenous Extracorporeal Membrane Oxygenation in COVID-19 Infection: One Region's Comprehensive Experience.

Severe acute respiratory distress syndrome (ARDS) unresponsive to conventional intensive care unit (ICU) management is an accepted indication for venovenous extracorporeal membrane oxygenation (V-V ECMO) support. The frequency with which patients with coronavirus disease 2019 (COVID-19) pneumonia are selected for V-V ECMO has not been described. This was a cohort study including all patients placed on either V-V ECMO or venoarteriovenous ECMO at the four adult ECMO Centers of Excellence. Primary outcomes evaluated were survival to decannulation from the ECMO circuit, survival to discharge, and 60-day survival. Secondary outcomes were hospital length of stay (LOS), ICU LOS, length of ECMO cannulation, and length of intubation. During the study period, which corresponded to the first surge in COVID-19 hospitalizations in Minnesota, 35 patients with ARDS were selected for V-V ECMO support out of 1,849 adult ICU patients with COVID-19 infection in the state (1.9% incidence; 95% CI, 1.3-2.6%). This represents 46 (95% CI, 34-61) expected V-V ECMO patients per 100,000 confirmed positive cases of COVID-19. Twenty-six of the 35 patients (74.3%) supported with V-V ECMO survived to 60-day post-ECMO decannulation. Recent studies have demonstrated ongoing success rescuing patients with severe ARDS in COVID-19 infection. Our data add to the support of ECMO and the consideration for encouraging cooperation among regional ECMO centers to ensure access to this highest level of care. Finally, by evaluating all the patients of a single region, we estimate overall need for this resource intensive intervention based on the overall number of COVID-19 cases and ICU admissions.

Risk Factors of Mortality for Patients Receiving Venovenous Extracorporeal Membrane Oxygenation for COVID-19 Acute Respiratory Distress Syndrome.

Background: Venovenous extracorporeal membrane oxygenation (VV-ECMO) for select adults with severe acute respiratory distress syndrome (ARDS) cause by coronavirus disease 2019 (COVID-19) infection is a guideline-supported therapy with associated hospital survival of 62%-74%, similar to expected survival with VV-ECMO for other indications. However, ECMO is a resource-heavy intervention, and these patients often require long ECMO runs and prolonged intensive care unit (ICU) care. Identifying factors associated with mortality in VV-ECMO patients with COVID-19 infection can inform the evaluation of ECMO candidates as well as prognostication for those patients on prolonged VV-ECMO. Patients and Methods: This was a retrospective cohort study that included all patients who received either VV- or venoarteriovenous (VAV)-ECMO at one of four ECMO Centers of Excellence in the state of Minnesota between March 1, 2020 and November 1, 2020. The primary outcome was 60-day survival. Secondary outcomes were hospital complications, infectious complications, and complications from ECMO. Results: There were 46 patients who met criteria during this study period and 30 survived to 60-day follow-up (65.2%). Prior to cannulation, older patient age (55.5 in non-survivors vs. 49.1 years in survivors; p = 0.03), lower P/F ratio (62.1 vs. 76.2; p = 0.04), and higher sequential organ failure assessment (SOFA) score (8.1 vs. 6.6; p = 0.02) were identified as risk factors for mortality. After ECMO cannulation, increased mortality was associated with increased number of antibiotic days (25.9 vs. 14.5; p = 0.04), increased number of transfusions (23.9 vs. 9.9; p = 0.03), elevated white blood cell (WBC) count at post-ECMO days one through three, elevated D-dimer at post-ECMO day 21-27, and decreased platelet count from post-ECMO days 14 and onward using univariable analysis. Conclusions: Multiple markers of infection including leukocytosis, thrombocytopenia, and increased antibiotic days are associated with increased mortality in patients placed on VV-ECMO for COVID-19 infection and subsequent ARDS. Knowledge of these factors may assist with determining appropriate candidates for this limited resource as well as direct goals of care in prolonged ECMO courses.

Characterizing COVID-19 clinical phenotypes and associated comorbidities and complication profiles.

PURPOSE: Heterogeneity has been observed in outcomes of hospitalized patients with coronavirus disease 2019 (COVID-19). Identification of clinical phenotypes may facilitate tailored therapy and improve outcomes. The purpose of this study is to identify specific clinical phenotypes across COVID-19 patients and compare admission characteristics and outcomes. METHODS: This is a retrospective analysis of COVID-19 patients from March 7, 2020 to August 25, 2020 at 14 U.S. hospitals. Ensemble clustering was performed on 33 variables collected within 72 hours of admission. Principal component analysis was performed to visualize variable contributions to clustering. Multinomial regression models were fit to compare patient comorbidities across phenotypes. Multivariable models were fit to estimate associations between phenotype and in-hospital complications and clinical outcomes. RESULTS: The database included 1,022 hospitalized patients with COVID-19. Three clinical phenotypes were identified (I, II, III), with 236 [23.1%] patients in phenotype I, 613 [60%] patients in phenotype II, and 173 [16.9%] patients in phenotype III. Patients with respiratory comorbidities were most commonly phenotype III (p = 0.002), while patients with hematologic, renal, and cardiac (all p<0.001) comorbidities were most commonly phenotype I. Adjusted odds of respiratory, renal, hepatic, metabolic (all p<0.001), and hematological (p = 0.02) complications were highest for phenotype I. Phenotypes I and II were associated with 7.30-fold (HR:7.30, 95% CI:(3.11-17.17), p<0.001) and 2.57-fold (HR:2.57, 95% CI:(1.10-6.00), p = 0.03) increases in hazard of death relative to phenotype III. CONCLUSION: We identified three clinical COVID-19 phenotypes, reflecting patient populations with different comorbidities, complications, and clinical outcomes. Future research is needed to determine the utility of these phenotypes in clinical practice and trial design.

Liver metabolomic changes identify biochemical pathways in hemorrhagic shock.

BACKGROUND: Despite ongoing advances in treatment, thousands of patients still die annually from complications due to hemorrhagic shock, a condition causing dramatic physiologic and metabolic changes as cells switch to anaerobic metabolism in response to oxygen deprivation. As the shift from aerobic to anaerobic metabolism occurs in the peripheral tissues during shock, the liver must increase production of endogenous glucose as well as process excess lactate produced in the periphery. This places the liver at the center of metabolic regulation in the body during hemorrhagic shock. Therefore, we hypothesized that liver tissue from pigs during an in vivo model of hemorrhagic shock (n = 6) would reflect resultant metabolic changes. MATERIALS AND METHODS: The in vivo model of shock consisted of 45 min of shock followed by 8 h of hypotensive resuscitation (80 mmHg) and subsequent normotensive resuscitation (90 mmHg) ending 48 h after the shock period. Control groups of pigs (n = 3) (1) shock with no resuscitation, and (2) only anesthesia and instrumentation, also were included. Metabolic changes within the liver after shock and during resuscitation were investigated using both proton ((1)H) and phosphorous ((31)P) nuclear magnetic resonance (NMR) spectroscopy. RESULTS: Concentrations of glycerylphosphorylcholine (GPC) and glycerylphosphorylethanolamine (GPE) were significantly lower at 8 h after shock, with recovery to baseline by 23 and 48 h after shock. Uridine diphosphate-glucose (UDP-glucose), and phosphoenolpyruvate (PEP) were elevated 23 h after shock. CONCLUSIONS: These results indicate that (1)H and (31)P NMR spectroscopy can be used to identify differences in liver metabolites in an in vivo model of hemorrhagic shock, indicating that metabolomic analysis can be used to elucidate biochemical events occurring during this complex disease process.

Metabolomics Pilot Study Identifies Desynchronization of 24-H Rhythms and Distinct Intra-patient Variability Patterns in Critical Illness: A Preliminary Report.

Background: Synchronized circadian rhythms play a key role in coordinating physiologic health. Desynchronized circadian rhythms may predispose individuals to disease or be indicative of underlying disease. Intensive care unit (ICU) patients likely experience desynchronized circadian rhythms due to disruptive environmental conditions in the ICU and underlying pathophysiology. This observational pilot study was undertaken to determine if 24-h rhythms are altered in ICU patients relative to healthy controls by profiling 24-h rhythms in vital signs and plasma metabolites. Methods: We monitored daily rhythms in 5 healthy controls and 5 ICU patients for 24 h. Heart rate and blood pressure were measured every 30 min, temperature was measured every hour, and blood was sampled for mass spectrometry-based plasma metabolomics every 4 h. Bedside sound levels were measured every minute. Twenty-four hours rhythms were evaluated in vitals and putatively identified plasma metabolites individually and in each group using the cosinor method. Results: ICU patient rooms were significantly louder than healthy controls' rooms and average noise levels were above EPA recommendations. Healthy controls generally had significant 24-h rhythms individually and as a group. While a few ICU patients had significant 24-h rhythms in isolated variables, no significant rhythms were identified in ICU patients as a group, except in cortisol. This indicates a lack of coherence in phases and amplitudes among ICU patients. Finally, principal component analysis of metabolic profiles showed surprising patterns in plasma sample clustering. Each ICU patient's samples were clearly discernable in individual clusters, separate from a single cluster of healthy controls. Conclusions: In this pilot study, ICU patients' 24-h rhythms show significant desynchronization compared to healthy controls. Clustering of plasma metabolic profiles suggests that metabolomics could be used to track individual patients' clinical courses longitudinally. Our results show global disordering of metabolism and the circadian system in ICU patients which should be characterized further in order to determine implications for patient care.

Characterizing COVID-19 Clinical Phenotypes and Associated Comorbidities and Complication Profiles.

BACKGROUND: There is limited understanding of heterogeneity in outcomes across hospitalized patients with coronavirus disease 2019 (COVID-19). Identification of distinct clinical phenotypes may facilitate tailored therapy and improve outcomes. OBJECTIVE: Identify specific clinical phenotypes across COVID-19 patients and compare admission characteristics and outcomes. DESIGN, SETTINGS, AND PARTICIPANTS: Retrospective analysis of 1,022 COVID-19 patient admissions from 14 Midwest U.S. hospitals between March 7, 2020 and August 25, 2020. METHODS: Ensemble clustering was performed on a set of 33 vitals and labs variables collected within 72 hours of admission. K-means based consensus clustering was used to identify three clinical phenotypes. Principal component analysis was performed on the average covariance matrix of all imputed datasets to visualize clustering and variable relationships. Multinomial regression models were fit to further compare patient comorbidities across phenotype classification. Multivariable models were fit to estimate the association between phenotype and in-hospital complications and clinical outcomes. Main outcomes and measures: Phenotype classification (I, II, III), patient characteristics associated with phenotype assignment, in-hospital complications, and clinical outcomes including ICU admission, need for mechanical ventilation, hospital length of stay, and mortality. RESULTS: The database included 1,022 patients requiring hospital admission with COVID-19 (median age, 62.1 [IQR: 45.9-75.8] years; 481 [48.6%] male, 412 [40.3%] required ICU admission, 437 [46.7%] were white). Three clinical phenotypes were identified (I, II, III); 236 [23.1%] patients had phenotype I, 613 [60%] patients had phenotype II, and 173 [16.9%] patients had phenotype III. When grouping comorbidities by organ system, patients with respiratory comorbidities were most commonly characterized by phenotype III (p=0.002), while patients with hematologic (p<0.001), renal (p<0.001), and cardiac (p<0.001) comorbidities were most commonly characterized by phenotype I. The adjusted odds of respiratory (p<0.001), renal (p<0.001), and metabolic (p<0.001) complications were highest for patients with phenotype I, followed by phenotype II. Patients with phenotype I had a far greater odds of hepatic (p<0.001) and hematological (p=0.02) complications than the other two phenotypes. Phenotypes I and II were associated with 7.30-fold (HR: 7.30, 95% CI: (3.11-17.17), p<0.001) and 2.57-fold (HR: 2.57, 95% CI: (1.10-6.00), p=0.03) increases in the hazard of death, respectively, when compared to phenotype III. CONCLUSION: In this retrospective analysis of patients with COVID-19, three clinical phenotypes were identified. Future research is urgently needed to determine the utility of these phenotypes in clinical practice and trial design.

Correction: Chronic Alcohol Ingestion Increases Mortality and Organ Injury in a Murine Model of Septic Peritonitis.

[This corrects the article DOI: 10.1371/journal.pone.0062792.].