RESUMEN

Human factors and non-technical skills (NTS) have been identified as essential contributors to both the propagation and prevention of medical errors in the operating room. Despite extensive study and interventions to nurture and enhance NTS in anesthesiologists, gaps to effective team practice and patient safety remain. Furthermore, the link between added NTS training and clinically significant improved outcomes has not yet been demonstrated. We performed a narrative review to summarize the literature on existing systems and initiatives used to measure and nurture NTS in the clinical operating room setting. Controlled interventions performed to nurture NTS (N.=13) were identified and compared. We comment on the body of current evidence and highlight the achievements and limitations of interventions published thus far. We then propose a novel education and training framework to further develop and enhance non-technical skills in both individual anesthesiologists and operating room teams. We use the cardiac anesthesiology environment as a starting point to illustrate its use, with clinical examples. NTS is a key component of enhancing patient safety. Effective framing of its concepts is central to apply individual characteristics and skills in team environments in the OR and achieve tangible, beneficial patient outcomes.

Asunto(s)

Anestesiólogos , Anestesiología , Humanos , Escolaridad , Corazón , Errores Médicos

RESUMEN

BACKGROUND: The effect of a restrictive versus liberal red-cell transfusion strategy on clinical outcomes in patients undergoing cardiac surgery remains unclear. METHODS: In this multicenter, open-label, noninferiority trial, we randomly assigned 5243 adults undergoing cardiac surgery who had a European System for Cardiac Operative Risk Evaluation (EuroSCORE) I of 6 or more (on a scale from 0 to 47, with higher scores indicating a higher risk of death after cardiac surgery) to a restrictive red-cell transfusion threshold (transfuse if hemoglobin level was <7.5 g per deciliter, starting from induction of anesthesia) or a liberal red-cell transfusion threshold (transfuse if hemoglobin level was <9.5 g per deciliter in the operating room or intensive care unit [ICU] or was <8.5 g per deciliter in the non-ICU ward). The primary composite outcome was death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis by hospital discharge or by day 28, whichever came first. Secondary outcomes included red-cell transfusion and other clinical outcomes. RESULTS: The primary outcome occurred in 11.4% of the patients in the restrictive-threshold group, as compared with 12.5% of those in the liberal-threshold group (absolute risk difference, -1.11 percentage points; 95% confidence interval [CI], -2.93 to 0.72; odds ratio, 0.90; 95% CI, 0.76 to 1.07; P<0.001 for noninferiority). Mortality was 3.0% in the restrictive-threshold group and 3.6% in the liberal-threshold group (odds ratio, 0.85; 95% CI, 0.62 to 1.16). Red-cell transfusion occurred in 52.3% of the patients in the restrictive-threshold group, as compared with 72.6% of those in the liberal-threshold group (odds ratio, 0.41; 95% CI, 0.37 to 0.47). There were no significant between-group differences with regard to the other secondary outcomes. CONCLUSIONS: In patients undergoing cardiac surgery who were at moderate-to-high risk for death, a restrictive strategy regarding red-cell transfusion was noninferior to a liberal strategy with respect to the composite outcome of death from any cause, myocardial infarction, stroke, or new-onset renal failure with dialysis, with less blood transfused. (Funded by the Canadian Institutes of Health Research and others; TRICS III ClinicalTrials.gov number, NCT02042898 .).

Asunto(s)

Procedimientos Quirúrgicos Cardíacos , Transfusión de Eritrocitos/métodos , Adulto , Anciano , Procedimientos Quirúrgicos Cardíacos/efectos adversos , Procedimientos Quirúrgicos Cardíacos/mortalidad , Puente Cardiopulmonar , Femenino , Hemoglobinas/análisis , Mortalidad Hospitalaria , Humanos , Unidades de Cuidados Intensivos , Análisis de Intención de Tratar , Tiempo de Internación , Masculino , Persona de Mediana Edad , Infarto del Miocardio/etiología , Atención Perioperativa , Complicaciones Posoperatorias/etiología , Complicaciones Posoperatorias/mortalidad , Insuficiencia Renal/etiología , Accidente Cerebrovascular/etiología

RESUMEN

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1) are the major incretin hormones that exert insulinotropic and anti-apoptotic actions on pancreatic ß-cells. Insulinotropic actions of the incretins involve modulation of voltage-gated potassium (Kv) channels. In multiple cell types, Kv channel activity has been implicated in cell volume changes accompanying initiation of the apoptotic program. Focusing on Kv2.1, we examined whether regulation of Kv channels in ß-cells contributes to the prosurvival effects of incretins. Overexpression of Kv2.1 in INS-1 ß-cells potentiated apoptosis in response to mitochondrial and ER stress and, conversely, co-stimulation with GIP/GLP-1 uncoupled this potentiation, suppressing apoptosis. In parallel, incretins promoted phosphorylation and acetylation of Kv2.1 via pathways involving protein kinase A (PKA)/mitogen- and stress-activated kinase-1 (MSK-1) and histone acetyltransferase (HAT)/histone deacetylase (HDAC). Further studies demonstrated that acetylation of Kv2.1 was mediated by incretin actions on nuclear/cytoplasmic shuttling of CREB binding protein (CBP) and its interaction with Kv2.1. Regulation of ß-cell survival by GIP and GLP-1 therefore involves post-translational modifications (PTMs) of Kv channels by PKA/MSK-1 and HAT/HDAC. This appears to be the first demonstration of modulation of delayed rectifier Kv channels contributing to the ß-cell prosurvival effects of incretins and of 7-transmembrane G protein-coupled receptor (GPCR)-stimulated export of a nuclear lysine acetyltransferase that regulates cell surface ion channel function.

Asunto(s)

Incretinas/farmacología , Células Secretoras de Insulina/citología , Células Secretoras de Insulina/metabolismo , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Canales de Potasio Shab/metabolismo , Acetilación/efectos de los fármacos , Adulto , Apoptosis/efectos de los fármacos , Proteína de Unión a CREB/metabolismo , Línea Celular , Núcleo Celular/efectos de los fármacos , Núcleo Celular/metabolismo , Supervivencia Celular/efectos de los fármacos , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Endocitosis/efectos de los fármacos , Polipéptido Inhibidor Gástrico/farmacología , Péptido 1 Similar al Glucagón/farmacología , Histona Acetiltransferasas/metabolismo , Histona Desacetilasas/metabolismo , Humanos , Células Secretoras de Insulina/efectos de los fármacos , Células Secretoras de Insulina/enzimología , Fosforilación/efectos de los fármacos , Transporte de Proteínas/efectos de los fármacos , Proteínas Quinasas S6 Ribosómicas 90-kDa/metabolismo , Estaurosporina/farmacología , Tapsigargina/farmacología

RESUMEN

GIP is an important insulinotropic hormone (incretin) that has also been implicated in fat metabolism. There is controversy regarding the actions of GIP on adipocytes. In the current study, the existence of GIP receptors and effects of GIP on lipolysis were studied in differentiated 3T3-L1 cells. GIP receptor messenger RNA was detected by RT-PCR and RNase protection assay. Receptors were detected in binding studies (IC50 26.7 +/- 0.7 nM). GIP stimulated glycerol release with an EC50 of 3.28 +/- 0.63 nM. GIP (10(-9)-10(-7) M) +/- IBMX increased cAMP production by 1180-2246%. The adenylyl cyclase inhibitor MDL 12330A (10(-4) M) inhibited GIP-induced glycerol production by >90%, and reduced cAMP responses to basal. Preincubation of 3T3-L1 cells with insulin inhibited glycerol responses to GIP, and the inhibitory effect of insulin was blocked by the phosphatidylinositol 3'-kinase inhibitor, wortmannin. It is concluded that GIP stimulates glycerol release in 3T3-L1 cells primarily via stimulation of cAMP production, and that insulin antagonizes GIP-induced lipolysis in a wortmannin-sensitive fashion. It is suggested that effects of GIP on fat metabolism in vivo may depend upon the circulating insulin level, and that meal-released GIP may elevate circulating fatty acids, thus optimizing pancreatic beta-cell responsiveness to stimulation by glucose and GIP.

Asunto(s)

Androstadienos/farmacología , Polipéptido Inhibidor Gástrico/farmacología , Antagonistas de Insulina/farmacología , Insulina/farmacología , Lipólisis/efectos de los fármacos , Células 3T3 , Inhibidores de Adenilato Ciclasa , Animales , Diferenciación Celular , AMP Cíclico/biosíntesis , Ratones , ARN Mensajero/metabolismo , Receptores de la Hormona Gastrointestinal/biosíntesis , Receptores de la Hormona Gastrointestinal/genética , Receptores de la Hormona Gastrointestinal/metabolismo , Wortmanina

RESUMEN

The receptors for the two structurally related insulinotropic hormones Glucose-dependent Insulinotropic Polypeptide (GIP) and Glucagon-Like Peptide-1 (GLP-1) share approximately 40% sequence identity and demonstrate complete specificity for their endogenous ligands, while utilizing similar second messenger pathways. In the current study chimeric GIP-GLP-1 receptors were prepared, and the effect of domain-exchange on ligand binding and adenylyl cyclase activation examined. A chimera (CH-2) consisting of the first 132 amino acids of the external N-terminal (NT) domain bound 125I-GIP with high affinity (27.77 +/- 11.85 nM). However, for receptor coupling to cAMP production it was necessary to extend the NT into the first transmembrane (TM-1) region (CH-3: IC50 = 9.04 +/- 1.07 nM; EC50 = 17.1 +/- 3.5 nM). A chimera which included part of TM-3 (CH-4) demonstrated binding and signalling (IC50 = 8.33 +/- 0.14 nM; EC50 = 467.5 +/- 173.6 pM) similar to the wild type receptor (IC50 = 1.33 +/- 0.19 nM; EC50 = 497.9 +/- 211.7 pM). Surprisingly constructs CH-2 and CH-3, while devoid of detectable 125I-GLP-1 binding, were capable of eliciting GLP-1-specific cAMP production (EC50s CH-2 = 81.4 +/- 19.6 nM; CH-3 = 5.99 +/- 0.68 nM) suggesting that receptor activation is not completely dependent on high affinity receptor binding. These data clearly demonstrate that the NT domain of the GIP receptor acts as the ligand-specific binding domain and that the first transmembrane domain is important for receptor activation.

Asunto(s)

Polipéptido Inhibidor Gástrico/farmacología , Glucagón/farmacología , Fragmentos de Péptidos/farmacología , Precursores de Proteínas/farmacología , Receptores de la Hormona Gastrointestinal/química , Receptores de la Hormona Gastrointestinal/metabolismo , Receptores de Glucagón/química , Receptores de Glucagón/metabolismo , Adenilil Ciclasas/metabolismo , Animales , Sitios de Unión , Unión Competitiva , Células CHO , Células COS , Clonación Molecular , Cricetinae , AMP Cíclico/metabolismo , Polipéptido Inhibidor Gástrico/metabolismo , Glucagón/metabolismo , Péptido 1 Similar al Glucagón , Receptor del Péptido 1 Similar al Glucagón , Humanos , Cinética , Modelos Estructurales , Fragmentos de Péptidos/metabolismo , Precursores de Proteínas/metabolismo , Estructura Secundaria de Proteína , Ratas , Receptores de la Hormona Gastrointestinal/biosíntesis , Receptores de Glucagón/biosíntesis , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/química , Proteínas Recombinantes de Fusión/metabolismo , Transducción de Señal , Transfección

RESUMEN

Prostaglandin E2 (PGE2) is an important regulator of systemic hemodynamics and epithelial ion transport. To further investigate the mechanism of PGE2 action, a clone encoding a PGE2 receptor was isolated from a rabbit kidney cortex cDNA library. Expression of the full-length cDNA in COS-1 cells yielded a ligand-binding profile typical for a butaprost-insensitive Gs-coupled E-prostanoid (EP) receptor. Misoprostol-free acid, a receptor-selective PGE analogue, produced concentration-dependent increases in adenosine 3',5'-cyclic monophosphate production. The data are consistent with the receptor being an EP4 subtype. Ribonuclease protection assays demonstrated that this receptor gene is highly expressed in intestine, uterus, and thymus, with lower but significant expression in kidney, whole adrenal, lung, spleen, and stomach. In situ hybridization in kidney revealed intense hybridization to glomeruli and urothelium of the renal pelvis. This prostanoid receptor was also highly expressed in the duodenal epithelium and adrenal cortex. The tissue distribution suggests a functional role for this receptor in mediating glomerular effects of PGE2 and effects on aldosterone secretion, intestinal transport, and immune function.

Asunto(s)

Receptores de Prostaglandina E/genética , Secuencia de Aminoácidos , Animales , Clonación Molecular , Hibridación in Situ , Datos de Secuencia Molecular , Especificidad de Órganos , Conejos , Receptores de Prostaglandina E/metabolismo , Subtipo EP4 de Receptores de Prostaglandina E , Análisis de Secuencia