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Current Opinion in Critical Care Aug 2023Critical illness imposes a severe insult on the body, with various stressors triggering pronounced cell damage. This compromises cellular function, leading to a high... (Review)
Review
PURPOSE OF REVIEW
Critical illness imposes a severe insult on the body, with various stressors triggering pronounced cell damage. This compromises cellular function, leading to a high risk of multiple organ failure. Autophagy can remove damaged molecules and organelles but appears insufficiently activated during critical illness. This review discusses insight into the role of autophagy in critical illness and the involvement of artificial feeding in insufficient autophagy activation in critical illness.
RECENT FINDINGS
Animal studies manipulating autophagy have shown its protective effects against kidney, lung, liver, and intestinal injury after several critical insults. Autophagy activation also protected peripheral, respiratory, and cardiac muscle function, despite aggravated muscle atrophy. Its role in acute brain injury is more equivocal. Animal and patient studies showed that artificial feeding suppressed autophagy activation in critical illness, particularly with high protein/amino acid doses. Feeding-suppressed autophagy may explain short and long-term harm by early enhanced calorie/protein feeding in large randomized controlled trials.
SUMMARY
Insufficient autophagy during critical illness is at least partly explained by feeding-induced suppression. This may explain why early enhanced nutrition failed to benefit critically ill patients or even induced harm. Safe, specific activation of autophagy avoiding prolonged starvation opens perspectives for improving outcomes of critical illness.
Topics: Animals; Humans; Critical Illness; Autophagy; Nutritional Support; Nutritional Status; Liver
PubMed: 37306474
DOI: 10.1097/MCC.0000000000001056 -
JAMA Network Open Aug 2023The Sepsis Prediction Model (SPM) is a proprietary decision support tool created by Epic Systems; it generates a predicting sepsis score (PSS). The model has not...
IMPORTANCE
The Sepsis Prediction Model (SPM) is a proprietary decision support tool created by Epic Systems; it generates a predicting sepsis score (PSS). The model has not undergone validation against existing sepsis prediction tools, such as Systemic Inflammatory Response Syndrome (SIRS), Sequential Organ Failure Assessment (SOFA), or quick Sepsis-Related Organ Failure Asessement (qSOFA).
OBJECTIVE
To assess the validity and timeliness of the SPM compared with SIRS, qSOFA, and SOFA.
DESIGN, SETTING, AND PARTICIPANTS
This retrospective cohort study included all adults admitted to 5 acute care hospitals in a single US health system between June 5, 2019, and December 31, 2020. Data analysis was conducted from March 2021 to February 2023.
MAIN OUTCOMES AND MEASURES
A sepsis event was defined as receipt of 4 or more days of antimicrobials, blood cultures collected within ±48 hours of initial antimicrobial, and at least 1 organ dysfunction as defined by the organ dysfunction criteria optimized for the electronic health record (eSOFA). Time zero was defined as 15 minutes prior to qualifying antimicrobial or blood culture order.
RESULTS
Of 60 507 total admissions, 1663 (2.7%) met sepsis criteria, with 1324 electronic health record-confirmed sepsis (699 [52.8%] male patients; 298 [22.5%] Black patients; 46 [3.5%] Hispanic/Latinx patients; 945 [71.4%] White patients), 339 COVID-19 sepsis (183 [54.0%] male patients; 98 [28.9%] Black patients; 36 [10.6%] Hispanic/Latinx patients; and 189 [55.8%] White patients), and 58 844 (97.3%; 26 632 [45.2%] male patients; 12 698 [21.6%] Black patients; 3367 [5.7%] Hispanic/Latinx patients; 40 491 White patients) did not meet sepsis criteria. The median (IQR) age was 63 (51 to 73) years for electronic health record-confirmed sepsis, 69 (60 to 77) years for COVID-19 sepsis, and 60 (42 to 72) years for nonsepsis admissions. Within the vendor recommended threshold PSS range of 5 to 8, PSS of 8 or greater had the highest balanced accuracy for classifying a sepsis admission at 0.79 (95% CI, 0.78 to 0.80). Change in SOFA score of 2 or more had the highest sensitivity, at 0.97 (95% CI, 0.97 to 0.98). At a PSS of 8 or greater, median (IQR) time to score positivity from time zero was 68.00 (6.75 to 605.75) minutes. For SIRS, qSOFA, and SOFA, median (IQR) time to score positivity was 7.00 (-105.00 to 08.00) minutes, 74.00 (-22.25 to 599.25) minutes, and 28.00 (-108.50 to 134.00) minutes, respectively.
CONCLUSIONS AND RELEVANCE
In this cohort study of hospital admissions, balanced accuracy of the SPM outperformed other models at higher threshold PSS; however, application of the SPM in a clinical setting was limited by poor timeliness as a sepsis screening tool as compared to SIRS and SOFA.
Topics: Adult; Humans; Male; Middle Aged; Aged; Female; Systemic Inflammatory Response Syndrome; Cohort Studies; Multiple Organ Failure; Organ Dysfunction Scores; Retrospective Studies; COVID-19; Sepsis
PubMed: 37624600
DOI: 10.1001/jamanetworkopen.2023.29729 -
Cell Death & Disease Jul 2023Sepsis involves endothelial cell (EC) dysfunction, which contributes to multiple organ failure. To improve therapeutic prospects, elucidating molecular mechanisms of...
Sepsis involves endothelial cell (EC) dysfunction, which contributes to multiple organ failure. To improve therapeutic prospects, elucidating molecular mechanisms of vascular dysfunction is of the essence. ATP-citrate lyase (ACLY) directs glucose metabolic fluxes to de novo lipogenesis by generating acetyl-Co-enzyme A (acetyl-CoA), which facilitates transcriptional priming via protein acetylation. It is well illustrated that ACLY participates in promoting cancer metastasis and fatty liver diseases. Its biological functions in ECs during sepsis remain unclear. We found that plasma levels of ACLY were increased in septic patients and were positively correlated with interleukin (IL)-6, soluble E-selectin (sE-selectin), soluble vascular cell adhesion molecule 1 (sVCAM-1), and lactate levels. ACLY inhibition significantly ameliorated lipopolysaccharide challenge-induced EC proinflammatory response in vitro and organ injury in vivo. The metabolomic analysis revealed that ACLY blockade fostered ECs a quiescent status by reducing the levels of glycolytic and lipogenic metabolites. Mechanistically, ACLY promoted forkhead box O1 (FoxO1) and histone H3 acetylation, thereby increasing the transcription of c-Myc (MYC) to facilitate the expression of proinflammatory and gluco-lipogenic genes. Our findings revealed that ACLY promoted EC gluco-lipogenic metabolism and proinflammatory response through acetylation-mediated MYC transcription, suggesting ACLY as the potential therapeutic target for treating sepsis-associated EC dysfunction and organ injury.
Topics: Humans; Lipogenesis; ATP Citrate (pro-S)-Lyase; Inflammation; Adenosine Triphosphate
PubMed: 37414769
DOI: 10.1038/s41419-023-05932-8 -
Seminars in Liver Disease Nov 2023Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute... (Review)
Review
Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute decompensation in liver function with associated multiorgan failure and high short-term mortality. Current evidence points to ACLF being reversible, particularly in those at the lower end of the severity spectrum. However, there are no specific treatments for ACLF, and overall outcomes remain poor. Expedited liver transplantation as a treatment option is limited by organ shortage and a lack of priority allocation for this indication. Other options are therefore urgently needed, and our improved understanding of the condition has led to significant efforts to develop novel therapies. In conclusion, this review aims to summarize the current understanding of the pathophysiological processes involved in the onset, progression, and recovery of ACLF and discuss novel therapies under development.
Topics: Humans; Acute-On-Chronic Liver Failure; Liver Cirrhosis; Liver Transplantation; Multiple Organ Failure; Syndrome; Prognosis
PubMed: 38101419
DOI: 10.1055/s-0043-1776773 -
International Immunopharmacology Nov 2023Neutrophils release neutrophil extracellular traps (NETs) to trap pathogenic microorganisms. NETs are involved in the inflammatory response and bacterial killing and... (Review)
Review
Neutrophils release neutrophil extracellular traps (NETs) to trap pathogenic microorganisms. NETs are involved in the inflammatory response and bacterial killing and clearance. However, their excessive activation can lead to an inflammatory storm in the body, which may damage tissues and cause organ dysfunction. Organ dysfunction is the main pathophysiological cause of sepsis and also a cause of the high mortality rate in sepsis. Acute lung injury caused by sepsis accounts for the highest proportion of organ damage in sepsis. NET formation can lead to the development of sepsis because by promoting the release of interleukin-1 beta, interleukin-8, and tumor necrosis factor-alpha, thereby accelerating acute lung injury. In this review, we describe the critical role of NETs in sepsis-associated acute lung injury and review the current knowledge and novel therapeutic approaches.
Topics: Humans; Extracellular Traps; Multiple Organ Failure; Neutrophils; Acute Lung Injury; Sepsis
PubMed: 37688916
DOI: 10.1016/j.intimp.2023.110436 -
Frontiers in Immunology 2023Sepsis represents a global health concern, and patients with severe sepsis are at risk of experiencing MODS (multiple organ dysfunction syndrome), which is associated... (Review)
Review
Sepsis represents a global health concern, and patients with severe sepsis are at risk of experiencing MODS (multiple organ dysfunction syndrome), which is associated with elevated mortality rates and a poorer prognosis. The development of sepsis involves hyperactive inflammation, immune disorder, and disrupted microcirculation. It is crucial to identify targets within these processes to develop therapeutic interventions. One such potential target is Panx1 (pannexin-1), a widely expressed transmembrane protein that facilitates the passage of molecules smaller than 1 KDa, such as ATP. Accumulating evidence has implicated the involvement of Panx1 in sepsis-associated MODS. It attracts immune cells via the purinergic signaling pathway, mediates immune responses via the Panx1-IL-33 axis, promotes immune cell apoptosis, regulates blood flow by modulating VSMCs' and vascular endothelial cells' tension, and disrupts microcirculation by elevating endothelial permeability and promoting microthrombosis. At the level of organs, Panx1 contributes to inflammatory injury in multiple organs. Panx1 primarily exacerbates injury and hinders recovery, making it a potential target for sepsis-induced MODS. While no drugs have been developed explicitly against Panx1, some compounds that inhibit Panx1 hemichannels have been used extensively in experiments. However, given that Panx1's role may vary during different phases of sepsis, more investigations are required before interventions against Panx1 can be applied in clinical. Overall, Panx1 may be a promising target for sepsis-induced MODS. Nevertheless, further research is needed to understand its complex role in different stages of sepsis fully and to develop suitable pharmaceutical interventions for clinical use.
Topics: Humans; Endothelial Cells; Multiple Organ Failure; Apoptosis; Inflammation; Membrane Proteins
PubMed: 37711629
DOI: 10.3389/fimmu.2023.1217366 -
Journal of Personalized Medicine Nov 2023This article looks at the challenges of sedoanalgesia for sepsis patients, and argues for a personalised approach. Sedation is a necessary part of treatment for patients... (Review)
Review
This article looks at the challenges of sedoanalgesia for sepsis patients, and argues for a personalised approach. Sedation is a necessary part of treatment for patients in intensive care to reduce stress and anxiety and improve long-term prognoses. Sepsis patients present particular difficulties as they are at increased risk of a wide range of complications, such as multiple organ failure, neurological dysfunction, septic shock, ARDS, abdominal compartment syndrome, vasoplegic syndrome, and myocardial dysfunction. The development of any one of these complications can cause the patient's rapid deterioration, and each has distinct implications in terms of appropriate and safe forms of sedation. In this way, the present article reviews the sedative and analgesic drugs commonly used in the ICU and, placing special emphasis on their strategic administration in sepsis patients, develops a set of proposals for sedoanalgesia aimed at improving outcomes for this group of patients. These proposals represent a move away from simplistic approaches like avoiding benzodiazepines to more "objective-guided sedation" that accounts for a patient's principal pathology, as well as any comorbidities, and takes full advantage of the therapeutic arsenal currently available to achieve personalised, patient-centred treatment goals.
PubMed: 38138868
DOI: 10.3390/jpm13121641 -
Critical Care Medicine Dec 2023To determine if angiotensin II is associated with improved outcomes as measured by 30- and 90-day mortality as well as other secondary outcomes such as organ dysfunction...
OBJECTIVES
To determine if angiotensin II is associated with improved outcomes as measured by 30- and 90-day mortality as well as other secondary outcomes such as organ dysfunction and adverse events.
DESIGN
Retrospective, matched analysis of patients receiving angiotensin II compared with both historical and concurrent controls receiving equivalent doses of nonangiotensin II vasopressors.
SETTING
Multiple ICUs in a large, university-based hospital.
PATIENTS
Eight hundred thirteen adult patients with shock admitted to an ICU and requiring vasopressor support.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
Angiotensin II use had no association with the primary outcome of 30-day mortality (60% vs 56%; p = 0.292). The secondary outcome of 90-day mortality was also similar (65% vs 63%; p = 0.440) as were changes in Sequential Organ Failure Assessment scores over a 5-day monitoring period after enrollment. Angiotensin II was not associated with increased rates of kidney replacement therapy (odds ratio [OR], 1.39; 95% CI, 0.88-2.19; p = 0.158) or receipt of mechanical ventilation (OR, 1.50; 95% CI, 0.41-5.51; p = 0.539) after enrollment, and the rate of thrombotic events was similar between angiotensin II and control patients (OR, 1.02; 95% CI, 0.71-1.48; p = 0.912).
CONCLUSIONS
In patients with severe shock, angiotensin II was not associated with improved mortality or organ dysfunction and was not associated with an increased rate of adverse events.
Topics: Adult; Humans; Angiotensin II; Multiple Organ Failure; Retrospective Studies; Shock; Vasoconstrictor Agents
PubMed: 37378469
DOI: 10.1097/CCM.0000000000005975 -
Biochemical Pharmacology Mar 2024Adipose organ, historically known as specialized lipid-handling tissue serving as the long-term fat depot, is now appreciated as the largest endocrine organ composed of... (Review)
Review
Adipose organ, historically known as specialized lipid-handling tissue serving as the long-term fat depot, is now appreciated as the largest endocrine organ composed of two main compartments, i.e., subcutaneous and visceral adipose tissue (AT), madding up white and beige/brown adipocytes. Adipose organ dysfunction manifested as maldistribution of the compartments, hypertrophic, hypoxic, inflamed, and insulin-resistant AT, contributes to the development of type 2 diabetes (T2D). Here, we highlight the role of nitric oxide (NO·) in AT (dys)function in relation to developing T2D. The key aspects determining lipid and glucose homeostasis in AT depend on the physiological levels of the NO· produced via endothelial NO· synthases (eNOS). In addition to decreased NO· bioavailability (via decreased expression/activity of eNOS or scavenging NO·), excessive NO· produced by inducible NOS (iNOS) in response to hypoxia and AT inflammation may be a critical interfering factor diverting NO· signaling to the formation of reactive oxygen and nitrogen species, resulting in AT and whole-body metabolic dysfunction. Pharmacological approaches boosting AT-NO· availability at physiological levels (by increasing NO· production and its stability), as well as suppression of iNOS-NO· synthesis, are potential candidates for developing NO·-based therapeutics in T2D.
Topics: Humans; Nitric Oxide; Diabetes Mellitus, Type 2; Multiple Organ Failure; Obesity; Hypoxia; Lipids
PubMed: 38325496
DOI: 10.1016/j.bcp.2024.116043 -
Gene Aug 2023In addition to oxidative damage, sepsis can cause multiple organ dysfunction and poses a life-threatening threat. In addition to severe tissue damage, hypotension, and...
In addition to oxidative damage, sepsis can cause multiple organ dysfunction and poses a life-threatening threat. In addition to severe tissue damage, hypotension, and multiple organ failure, sepsis can cause high morbidity and mortality. It is the lungs that are most vulnerable in abdominal sepsis, with impaired oxygen and nutrient exchange occurring in the pulmonary microcirculation. However, the etiology of sepsis and the link between sepsis and lung injury has not been elucidated. In this work, by exploring the data from the GEO and CTD database, a gene association study was conducted to determine whether sepsis-induced lung injury is caused by BPA. Further analysis demonstrated that MMP9, CEBPA, CYP1B1, CTSD, FKBP5, DGAT2, HP, TIMP2, ARG1 and MGST1 may play an important role in sepsis-induced lung injury. Finally, the single-cell RNA sequence demonstrated that CEBPA is mainly enriched in lung epithelial cells and epithelial cells, whereas CYP1B1 is closely related to basal cells, macrophages, and interstitial cells. In order to maintain lung function, epithelial and alveolar macrophages as well as other lung cells are important. When the lung epithelium is activated for a prolonged period of time, barrier function may be compromised and tissue damage may result, aggravating the lung injury. By using the animal model, we successfully simulated the model of sepsis lung injury. The HE staining demonstrated the rats with BPA-treated septic lung injury showed more alveolar structure to be disordered, pulmonary interstitial edema to be evident, and red blood cells as well as inflammatory cells. For PCR assay, the results demonstrated that the expression level of CEBPA is higher in the lung samples with sepsis compared with the normal samples of the lung. In order to evaluate the expression level of CEBPA and CYP1B1 in lung tissue, we then performed the PCR assay. For CYP1B1, the results demonstrated that the expression level of CYP1B1 in lung samples with sepsis is lower than in normal lung samples. In total, BPA may be a potential contributing factor to sepsis-induced lung injury.
Topics: Rats; Animals; Acute Lung Injury; Lung; Macrophages; Sepsis
PubMed: 37343733
DOI: 10.1016/j.gene.2023.147575