RESUMO
Disruption of normal gastrointestinal (GI) function in critical illness is linked to increased morbidity and mortality, and GI dysmotility is frequently observed in patients who are critically ill. Despite its high prevalence, the diagnosis and management of GI motility problems in the intensive care unit remain very challenging, given that critically ill patients often cannot verbalize symptoms and the general lack of understanding of underlying pathophysiology. Common clinical presentations of GI dysmotility issues among critically ill patients include: (1) high gastric residual volumes, acid reflux, and vomiting, (2) abdominal distention, and (3) diarrhea. In this review, we discuss the differential diagnosis for intensive care unit patients with symptoms and signs concerning GI motility issues. There are many myths and longstanding misconceptions about the diagnosis and management of GI dysmotility in critical illness. Here, we uncover these myths and discuss relevant evidence in each subject area, with the goal of re-conceptualizing GI motility disorders in critical care and providing evidence-based recommendations for clinical care.
Assuntos
Estado Terminal , Gastroenteropatias , Humanos , Gastroenteropatias/diagnóstico , Gastroenteropatias/terapia , Motilidade Gastrointestinal , Estômago , Cuidados CríticosRESUMO
BACKGROUND & AIMS: Early reports suggest significant difficulty with enteral feeding in critically ill COVID-19 patients. This study aimed to characterize the prevalence, clinical manifestations, and outcomes of feeding intolerance in critically ill patients with COVID-19. METHODS: We examined 323 adult patients with COVID-19 admitted to the intensive care units (ICUs) of Massachusetts General Hospital between March 11 and June 28, 2020 who received enteral nutrition. Systematic chart review determined prevalence, clinical characteristics, and hospital outcomes (ICU complications, length of stay, and mortality) of feeding intolerance. RESULTS: Feeding intolerance developed in 56% of the patients and most commonly manifested as large gastric residual volumes (83.9%), abdominal distension (67.2%), and vomiting (63.9%). Length of intubation (OR 1.05, 95% CI 1.03-1.08), ≥1 GI symptom on presentation (OR 0.76, 95% CI 0.59-0.97), and severe obesity (OR 0.29, 95% CI 0.13-0.66) were independently associated with development of feeding intolerance. Compared to feed-tolerant patients, patients with incident feeding intolerance were significantly more likely to suffer cardiac, renal, hepatic, and hematologic complications during their hospitalization. Feeding intolerance was similarly associated with poor outcomes including longer ICU stay (median [IQR] 21.5 [14-30] vs. 15 [9-22] days, P < 0.001), overall hospitalization time (median [IQR] 30.5 [19-42] vs. 24 [15-35], P < 0.001) and in-hospital mortality (33.9% vs. 16.1%, P < 0.001). Feeding intolerance was independently associated with an increased risk of death (HR 3.32; 95% CI 1.97-5.6). CONCLUSIONS: Feeding intolerance is a frequently encountered complication in critically ill COVID-19 patients in a large tertiary care experience and is associated with poor outcomes.
Assuntos
COVID-19 , Estado Terminal , Adulto , Humanos , Recém-Nascido , Estado Terminal/terapia , COVID-19/complicações , COVID-19/epidemiologia , COVID-19/terapia , Unidades de Terapia Intensiva , Nutrição Enteral/efeitos adversos , Mortalidade HospitalarRESUMO
We have recently reported that a specific pool of ceramide, located in the plasma membrane, mediated the effects of sublethal doses of the chemotherapeutic compound doxorubicin on enhancing cancer cell migration. We identified neutral sphingomyelinase 2 (nSMase2) as the enzyme responsible to generate this bioactive pool of ceramide. In this work, we explored the role of members of the protein phosphatases 1 family (PP1), and we identified protein phosphatase 1 alpha isoform (PP1 alpha) as the specific PP1 isoform to mediate this phenotype. Using a bioinformatics approach, we build a functional interaction network based on phosphoproteomics data on plasma membrane ceramide. This led to the identification of several ceramide-PP1 alpha downstream substrates. Studies on phospho mutants of ezrin (T567) and Scrib (S1378/S1508) demonstrated that their dephosphorylation is sufficient to enhance cell migration. In summary, we identified a mechanism where reduced doses of doxorubicin result in the dysregulation of cytoskeletal proteins and enhanced cell migration. This mechanism could explain the reported effects of doxorubicin worsening cancer metastasis in animal models.
Assuntos
Ceramidas/fisiologia , Doxorrubicina/farmacologia , Proteína Fosfatase 1/fisiologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Células HeLa , HumanosRESUMO
Chemotherapy has been reported to upregulate sphingomylinases and increase cellular ceramide, often linked to the induction to cell death. In this work, we show that sublethal doses of doxorubicin and vorinostat still increased cellular ceramide, which was located predominantly at the plasma membrane. To interrogate possible functions of this specific pool of ceramide, we used recombinant enzymes to mimic physiological levels of ceramide at the plasma membrane upon chemotherapy treatment. Using mass spectrometry and network analysis, followed by experimental confirmation, the results revealed that this pool of ceramide acutely regulates cell adhesion and cell migration pathways with weak connections to commonly established ceramide functions (eg, cell death). Neutral sphingomyelinase 2 (nSMase2) was identified as responsible for the generation of plasma membrane ceramide upon chemotherapy treatment, and both ceramide at the plasma membrane and nSMase2 were necessary and sufficient to mediate these "side" effects of chemotherapy on cell adhesion and migration. This is the first time a specific pool of ceramide is interrogated for acute signaling functions, and the results define plasma membrane ceramide as an acute signaling effector necessary and sufficient for regulation of cell adhesion and cell migration under chemotherapeutical stress.
Assuntos
Antineoplásicos/farmacologia , Adesão Celular/efeitos dos fármacos , Movimento Celular/efeitos dos fármacos , Ceramidas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Células HeLa , Humanos , Fosforilação/efeitos dos fármacos , Esfingomielina Fosfodiesterase/metabolismoRESUMO
We recently introduced a MαCD-based method to efficiently replace virtually the entire population of plasma membrane outer leaflet phospholipids and sphingolipids of cultured mammalian cells with exogenous lipids (Li et al, (2016) Proc. Natl. Acad. Sci USA 113:14025-14030). Here, we show if the lipid-to- MαCD ratio is too high or low, cells can round up and develop membrane leakiness. We found that this cell damage can be reversed/prevented if cells are allowed to recover from the exchange step by incubation in complete growth medium. After exchange and transfer to complete growth medium cell growth was similar to that of untreated cells. In some cases, cell damage was also prevented by carrying out exchange at close to room temperature (rather than at 37°C). Exchange with lipids that do (sphingomyelin) or do not (unsaturated phosphatidylcholine) support a high level of membrane order in lipid vesicles had the analogous effect on plasma membrane order, confirming exogenous lipid localization in the plasma membrane. Importantly, changes in lipid composition and plasma membrane properties after exchange and recovery persisted for several hours. Thus, it should be possible to use lipid exchange to investigate the effect of plasma membrane lipid composition upon several aspects of membrane structure and function.
Assuntos
Membrana Celular/efeitos dos fármacos , Fosfatidilcolinas/metabolismo , Esfingomielinas/metabolismo , beta-Ciclodextrinas/farmacologia , Animais , Células CHO , Linhagem Celular Tumoral , Membrana Celular/metabolismo , Cricetinae , Cricetulus , Humanos , Gotículas Lipídicas/metabolismo , CoelhosRESUMO
Sphingolipids contribute to the regulation of cell and tissue homeostasis, and disorders of sphingolipid metabolism lead to diseases such as inflammation, stroke, diabetes, and cancer. Sphingolipid metabolic pathways involve an array of enzymes that reside in specific subcellular organelles, resulting in the formation of many diverse sphingolipids with distinct molecular species based on the diversity of the ceramide (Cer) structure. In order to probe compartment-specific metabolism of sphingolipids in this study, we analyzed the Cer and SM species preferentially produced in the inner plasma membrane (PM), Golgi apparatus, ER, mitochondria, nucleus, and cytoplasm by using compartmentally targeted bacterial SMases and ceramidases. The results showed that the length of the acyl chain of Cer becomes longer according to the progress of Cer from synthesis in the ER to the Golgi apparatus, then to the PM. These findings suggest that each organelle shows different properties of SM-derived Cers consistent with its emerging distinct functions in vitro and in vivo.
Assuntos
Ceramidases/metabolismo , Esfingolipídeos/metabolismo , Esfingomielina Fosfodiesterase/metabolismo , Linhagem Celular , Ceramidas/metabolismo , Retículo Endoplasmático/metabolismo , Complexo de Golgi/metabolismo , HumanosRESUMO
In the last 30 years, ceramides have been found to mediate a myriad of biological processes. Ceramides have been recognized as bioactive molecules and their metabolizing enzymes are attractive targets in cancer therapy and other diseases. The molecular mechanism of action of cellular ceramides are still not fully established, with insights into roles through modification of lipid rafts, creation of ceramide platforms, ceramide channels, or through regulation of direct protein effectors such as protein phosphatases and kinases. Recently, the 'Many Ceramides' hypothesis focuses on distinct pools of subcellular ceramides and ceramide species as potential defined bioactive entities. Traditional methods that measure changes in ceramide levels in the whole cell, such as mass spectrometry, fluorescent ceramide analogues, and ceramide antibodies, fail to differentiate specific bioactive species at the subcellular level. However, a few ceramide binding proteins have been reported, and a smaller subgroup within these, have been shown to translocate to ceramide-enriched membranes, revealing these localized pools of bioactive ceramides. In this review we want to discuss and consolidate these works and explore the possibility of defining these binding proteins as new tools are emerging to visualize bioactive ceramides in cells. Our goal is to encourage the scientific community to explore these ceramide partners, to improve techniques to refine the list of these binding partners, making possible the identification of specific domains that recognize and bind ceramides to be used to visualize the 'Many Ceramides' in the cell.