RESUMO
BACKGROUND: During a continuous femoral nerve block, the influence of catheter tip position relative to the femoral nerve on infusion characteristics remains unknown. METHODS: We inserted bilateral femoral perineural catheters in volunteers (ultrasound-guided, needle in-plane). Subjects' dominant side was randomized to have the catheter tip placed either anterior or posterior to the femoral nerve. The contralateral limb received the alternative position. Ropivacaine 0.1% was administered through both catheters concurrently for 6 hours (4 mL/h). Outcome measures included the maximum voluntary isometric contraction (MVIC) of the quadriceps femoris muscle and tolerance to cutaneous electrical current over to the distal quadriceps tendon. Measurements were performed at hour 0 (baseline), and on the hour until hour 9, as well as hour 22. The primary end point was the MVIC of the quadriceps at hour 6. RESULTS: As a percentage of the baseline measurement, quadriceps MVIC for limbs with anterior (n = 16) and posterior (n = 16) catheter tip placement did not differ to a statistically significant degree at hour 6 (mean [SD] 29% [26] vs 30% [28], respectively; 95% confidence interval: -22% to 20%; P = 0.931), or at any other time point. However, the maximum tolerance to cutaneous electrical current was higher in limbs with anterior compared with posterior catheter tip placement at hour 6 (20 [23] mA vs 6 [4] mA, respectively; 95% confidence interval: 1-27 mA; P = 0.035), as well as at hours 1, 7, 8, and 9 (P < 0.04). CONCLUSIONS: This study documents the significant (70%-80%) quadriceps femoris weakness induced by a continuous femoral nerve block infusion at a relatively low dose of ropivacaine (4 mg/h) delivered through a perineural catheter located both anterior and posterior to the femoral nerve. In contrast, an anterior placement increases cutaneous sensory block compared with a posterior insertion, without a concurrent relative increase in motor block.
Assuntos
Nervo Femoral/fisiologia , Debilidade Muscular/etiologia , Bloqueio Nervoso/efeitos adversos , Pele/inervação , Adulto , Cateterismo , Feminino , Humanos , Masculino , Estudos Prospectivos , Adulto JovemRESUMO
BACKGROUND: Patients who misuse alcohol are at increased risk for surgical complications. Four weeks of preoperative abstinence decreases the risk of complications, but practical approaches for early preoperative identification of alcohol misuse are needed. OBJECTIVE: To evaluate whether results of alcohol screening with the Alcohol Use Disorders Identification Test - Consumption (AUDIT-C) questionnaire-up to a year before surgery-were associated with the risk of postoperative complications. DESIGN: This is a cohort study. SETTING AND PARTICIPANTS: Male Veterans Affairs (VA) patients were eligible if they had major noncardiac surgery assessed by the VA's Surgical Quality Improvement Program (VASQIP) in fiscal years 2004-2006, and completed the AUDIT-C alcohol screening questionnaire (0-12 points) on a mailed survey within 1 year before surgery. MAIN OUTCOME MEASURE: One or more postoperative complication(s) within 30 days of surgery based on VASQIP nurse medical record reviews. RESULTS: Among 9,176 eligible men, 16.3% screened positive for alcohol misuse with AUDIT-C scores ≥ 5, and 7.8% had postoperative complications. Patients with AUDIT-C scores ≥ 5 were at significantly increased risk for postoperative complications, compared to patients who drank less. In analyses adjusted for age, smoking, and days from screening to surgery, the estimated prevalence of postoperative complications increased from 5.6% (95% CI 4.8-6.6%) in patients with AUDIT-C scores 1-4, to 7.9% (6.3-9.7%) in patients with AUDIT-Cs 5-8, 9.7% (6.6-14.1%) in patients with AUDIT-Cs 9-10 and 14.0% (8.9-21.3%) in patients with AUDIT-Cs 11-12. In fully-adjusted analyses that included preoperative covariates potentially in the causal pathway between alcohol misuse and complications, the estimated prevalence of postoperative complications increased significantly from 4.8% (4.1-5.7%) in patients with AUDIT-C scores 1-4, to 6.9% (5.5-8.7%) in patients with AUDIT-Cs 5-8 and 7.5% (5.0-11.3%) among those with AUDIT-Cs 9-10. CONCLUSIONS: AUDIT-C scores of 5 or more up to a year before surgery were associated with increased postoperative complications.
Assuntos
Alcoolismo/complicações , Alcoolismo/epidemiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , United States Department of Veterans Affairs , Veteranos , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Humanos , Masculino , Pessoa de Meia-Idade , Cuidados Pré-Operatórios/métodos , Fatores de Risco , Inquéritos e Questionários , Estados Unidos/epidemiologia , Adulto JovemRESUMO
Opioid receptors play an important role in both behavioral and homeostatic functions. We herein report tetrahydroquinoline derivatives as opioid receptor antagonists. SAR studies led to the identification of the potent antagonist 2v, endowed with 1.58nM (K(i)) functional activity against the µ opioid receptor. DMPK data suggest that novel tetrahydroquinoline analogs may be advantageous in peripheral applications.
Assuntos
Antagonistas de Entorpecentes , Quinolinas/química , Quinolinas/farmacologia , Receptores Opioides/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Quinolinas/farmacocinética , Ratos , Ratos Long-Evans , Relação Estrutura-AtividadeRESUMO
We are presenting the first ultra-high pressure LC (UHPLC) method for rapid quantitative measurement of vitamin A, E (alpha- and gamma-tocopherol), beta-carotene and CoQ(10) from human serum. The chromatography was performed on Shield RP(18) UHPLC column with UV detection. The method was validated based on linearity, accuracy, matrix effects study, precision and stability. The calibration was linear over the following range: 0.09-10.0 for retinol and gamma-tocopherol, 0.05-5 for beta-carotene, 0.9-100 for alpha-tocopherol and 0.14-15 mg/L for CoQ(10). The limit of detection and quantitation for retinol, gamma-tocopherol, beta-carotene, alpha-tocopherol and CoQ(10) were as follows 0.07/0.024, 0.018/0.06, 0.004/0.12, 0.078/0.261, 0.008/0.028 mg/L. The recoveries were above 85%. The inter- and intra-assay precision was below 10%. Reference intervals were established for children and adults. Because of its low cost, extremely short analysis time (2 min) and excellent chromatographic reproducibility this UHPLC method can easily be adopted for high-throughput clinical and pharmacokinetics studies.
Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Gorduras/química , Espectrofotometria Ultravioleta/métodos , Ubiquinona/análogos & derivados , Vitaminas/sangue , Calibragem , Padrões de Referência , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Solubilidade , Ubiquinona/sangueRESUMO
BACKGROUND: Patients of ASA physical status 1, 2, and 3 undergoing elective surgery do not have underlying conditions that are a constant threat to life, and hence should not be expected to be at significant risk for death on the day of surgery. METHODS: We analyzed 815,077 ASA physical status 1, 2, and 3 elective surgery patients in the Department of Veterans Affairs National Surgical Quality Improvement Program database to identify patients who died on the day of surgery. We then attempted to identify factors predictive of unexpected death and to identify potential areas for improvement in care. A subset of the cases underwent individual chart review as well to identify areas for improvement in anesthesia care. RESULTS: Of the total patients, 0.08% died on the day of surgery. The strongest predictive factor by multiple variable regression was the type of surgery, with aortic surgery resulting in an odds ratio of 13.67, (95% CI 9.76-19.17). Other factors predictive of death were identified by multiple variable regressions and included low albumin, existence of dyspnea, and elevated bilirubin or creatinine. Chart reviews of 88 of the deaths found that opportunities for improved anesthesia care were present in 13 of the 88. We estimated that a death that might have been prevented by improved anesthesia care occurred in approximately 1/13,900 cases. Myocardial infarction and hemorrhage were frequently identified factors. An unexpected factor was that the period between the conclusion of surgery and the final transfer of care in recovery was a time when many of the deaths occurred. CONCLUSIONS: We conclude that, although patient and surgical factors lead to the vast majority of deaths on the day of surgery, there are identifiable areas for reducing the incidence of such deaths by improvements in anesthesia care.
Assuntos
Hospitais de Veteranos , Complicações Pós-Operatórias/mortalidade , Centro Cirúrgico Hospitalar , Procedimentos Cirúrgicos Operatórios/mortalidade , Feminino , Hospitais de Veteranos/normas , Humanos , Modelos Logísticos , Masculino , Valor Preditivo dos Testes , Cuidados Pré-Operatórios , Estudos Prospectivos , Garantia da Qualidade dos Cuidados de Saúde , Centro Cirúrgico Hospitalar/normas , Estados Unidos , United States Department of Veterans AffairsRESUMO
OBJECTIVES: To evaluate whether the use of epidural steroid injections (ESIs) is associated with decreased subsequent opioid use in patients in the Department of Veteran's Affairs (VA) and to determine whether treatment with multiple injections are associated with decreased opioid use and lumbar surgery after ESIs. DESIGN: VA patients undergoing ESIs during the study period for specific low back pain (LBP) diagnoses were identified, and lumbar surgery and opioid use were examined for 6 months before and after ESI. SETTING: National VA administrative data. PARTICIPANTS: U.S. veterans (retrospective data analysis). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Opioid use and lumbar surgery after ESIs. RESULTS: During the 2-year study period, 13,741 different VA patients underwent an ESI for LBP. The majority of patients were using opioids before their ESIs (64%), as were the majority after their ESIs (67%). Of patients not on opioids before the ESIs, 38% were prescribed opioids afterward, whereas only 16% of people on opioids before the ESIs stopped using opioids afterward. Patients who received more than 3 injections were more likely than patients receiving fewer injections to start taking opioids after ESIs (19% vs 13%, P<.001) and to undergo lumbar surgery after ESIs (8.7% vs 6.3%, P=.003). CONCLUSIONS: Opioid use did not decrease in the 6 months after ESIs. In this population, patients who received multiple injections were more likely to start taking opioids and to undergo lumbar surgery within the 6 months after treatment with ESIs. These findings are concerning because our data suggest that ESIs are not reducing opioid use in this VA population.
Assuntos
Corticosteroides/uso terapêutico , Analgésicos Opioides/uso terapêutico , Injeções Epidurais/estatística & dados numéricos , Dor Lombar/terapia , Vértebras Lombares/cirurgia , Uso de Medicamentos/estatística & dados numéricos , Feminino , Humanos , Dor Lombar/etiologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Doenças da Coluna Vertebral/diagnóstico , Doenças da Coluna Vertebral/terapia , Estados Unidos , VeteranosRESUMO
A high-throughput analytical method was developed for the measurement of asymmetric dimethylarginine (ADMA) and L-arginine (ARG) from plasma using LC/MS/MS. The sample preparation was simple and only required microfiltration prior to analysis. ADMA and ARG were assayed using mixed-mode ion-exchange chromatography which allowed for the retention of the un-derivatized compounds. The need for chromatographic separation of ADMA from symmetric dimethylarginine (SDMA) was avoided by using an ADMA specific product ion. As a result, the analytical method only required a total run time of 2 min. The method was validated by linearity, with r2>or=0.995 for both compounds, and accuracy, with no more than 7% deviation from the theoretical value. The estimated limit of detection and limit of quantification were suitable for clinical evaluations. The mean values of plasma ADMA and ARG taken from healthy volunteers (n=15) were 0.66+/-0.12 and 87+/-35 microM, respectively; the mean molar ratio of ARG to ADMA was 142+/-81.
Assuntos
Arginina/análogos & derivados , Arginina/sangue , Cromatografia por Troca Iônica/métodos , Espectrometria de Massas em Tandem/métodos , Humanos , Reprodutibilidade dos TestesRESUMO
BACKGROUND: The Veterans Health Administration's (VHA's) National Center for Patient Safety developed a cognitive aid to help anesthesiologists manage rare, high-mortality adverse events. METHODS: Six months after the aids were sent to VHA facilities with anesthesia machines, anesthesia providers were surveyed about their knowledge and use of the aid. RESULTS: Seven percent of respondents had used the cognitive aid in an emergency ("emergent users"). Most (87%) of respondents were aware of the aid. Half used it only as a reference ("reference users"), 30% were nonusers, and 13% of respondents were unaware of the aid. User groups did not differ regarding exposure to emergencies. All emergent users reported that it helped during an emergency, and 93% reported that it was well designed and easy to use. Emergent users were more likely than other groups to have first found out about it through formal orientation (53%; p < .001). Nonusers (46%) and reference users (38%) were more likely than emergent users (30%) and those who never saw it (5%) to have first found out about it through informal communication with a colleague (p = < 0.001). The majority of those who never saw the aid first became aware of it through this survey (71%; p < .001). The aid was used most commonly for difficult airway. DISCUSSION: A cognitive aid for use in rare emergencies proved clinically useful to anesthesia providers.
Assuntos
Anestesiologia/métodos , Árvores de Decisões , Guias de Prática Clínica como Assunto , Gestão da Segurança/métodos , Administração Hospitalar/métodos , Humanos , Garantia da Qualidade dos Cuidados de Saúde/métodos , Fatores de Tempo , Estados Unidos , United States Department of Veterans AffairsRESUMO
The high expression of MCH in the hypothalamus with the lean hypophagic phenotype coupled with increased resting metabolic rate and resistance to high fat diet-induced obesity of MCH KO mice has spurred considerable efforts to develop small molecule MCHR1 antagonists. Starting from a lead thienopyrimidinone series, structure-activity studies at the 3- and 6-positions of the thienopyrimidinone core afforded potent and selective MCHR1 antagonists with representative examples having suitable pharmacokinetic properties. Based on structure-activity relationships, a structural model for MCHR1 was constructed to explain the binding mode of these antagonists. In general, a good correlation was observed between pKas and activity in the right-hand side of the template, with Asp123 playing an important role in the enhancement of binding affinity. A representative example when evaluated chronically in diet-induced obese mice resulted in good weight loss effects. These antagonists provide a viable lead series in the discovery of new therapies for the treatment of obesity.
Assuntos
Fármacos Antiobesidade/síntese química , Pirimidinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Tiofenos/síntese química , Administração Oral , Animais , Fármacos Antiobesidade/química , Fármacos Antiobesidade/farmacologia , Disponibilidade Biológica , Células CHO , Cricetinae , Cricetulus , Canal de Potássio ERG1 , Canais de Potássio Éter-A-Go-Go/efeitos dos fármacos , Canais de Potássio Éter-A-Go-Go/fisiologia , Genes Reporter , Meia-Vida , Humanos , Camundongos , Camundongos Obesos , Modelos Moleculares , Pirimidinas/química , Pirimidinas/farmacologia , Ratos , Relação Estrutura-Atividade , Tiofenos/química , Tiofenos/farmacologiaRESUMO
Genetic manipulation studies in mice at both the MCH receptor 1 (MCHR1) as well as the MCH peptide levels have implicated MCHR1 as a key player in energy homeostasis. The phenotype exhibited by these studies, that is, increased metabolic rate, resistance to high fat diet, and subsequent weight loss, has spurred considerable efforts to develop antagonists of MCHR1. In continuation of efforts directed toward this goal, the present work capitalizes on the putative binding mode of an MCH antagonist, resulting in the identification of several novel chemotypes that are potent and selective MCHR1 antagonists. In addition, the favorable pharmacokinetics of representative examples has allowed for the evaluation of an MCHR1 antagonist in a high fat diet-induced obese rodent model of obesity. The tolerability of the right-hand side of the template for diverse chemotypes accompanied by favorable effects on weight loss enhances the attractiveness of this template in the pursuit toward development of effective anti-obesity agents.
Assuntos
Fármacos Antiobesidade/síntese química , Pirimidinas/síntese química , Receptores de Somatostatina/antagonistas & inibidores , Tiofenos/síntese química , Animais , Fármacos Antiobesidade/farmacocinética , Fármacos Antiobesidade/farmacologia , Sítios de Ligação , Células CHO , Cricetinae , Cricetulus , Camundongos , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Ratos , Receptores de Somatostatina/química , Relação Estrutura-Atividade , Tiofenos/farmacocinética , Tiofenos/farmacologiaRESUMO
BACKGROUND: Prophylactic antibiotics (PA) given within 60 minutes before surgical incision decrease risk of subsequent surgical site infection. Nationwide quality improvement initiatives have focused on improving the proportion of patients who receive timely prophylactic antibiotics. STUDY DESIGN: This is a cohort study of major surgical procedures performed in 108 Veterans Affairs hospitals between January and December 2005. Using data from the External Peer Review Program and the National Surgical Quality Improvement Program, we examined factors associated with timely PA administration. Univariate and multivariable analyses were performed. RESULTS: There were 8,137 major surgical procedures: cardiac (2,664), hip and knee arthroplasty (3,603), colon (1,142), arterial vascular (606), and hysterectomy (122). Timely PA occurred in 76.2% of patients, 18.2% received them too early, and 5.4% received them too late. Early administration accounted for 79% of untimely PA. Differences in timeliness were seen by procedure type (68% to 87%; p < 0.0001), admission status (67% to 80%; p < 0.0001), and antibiotic class (65% to 89%; p < 0.0001). PA administration occurred in the operating room for 63.5% of patients. When PA administration occurred in the operating room, they were timely in 89% of patients, compared with 54% of patients where administration was outside the operating room (odds ratio, 7.74; 95% CI = 6.49 to 9.22). CONCLUSIONS: Early PA administration accounted for the majority of inappropriately timed PA. Efforts to improve performance on this measure should focus on administering antibiotics in the operating room.
Assuntos
Antibioticoprofilaxia/normas , Procedimentos Cirúrgicos Operatórios , Infecção da Ferida Cirúrgica/prevenção & controle , Antibioticoprofilaxia/estatística & dados numéricos , Feminino , Hospitais de Veteranos , Humanos , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Garantia da Qualidade dos Cuidados de Saúde , Estados Unidos , Vancomicina/administração & dosagemRESUMO
A series of 2'-alkylthio-2-(anilinomethyl)imidazolines were prepared to examine the effect of the alkyl group size, sulfur oxidation state, and phenyl ring substitution on ligand binding and agonism of alpha-adrenergic receptor subtypes alpha1a, alpha1b, alpha1d, alpha2a, and alpha2c. Binding at all receptor subtypes decreased for compounds in the sulfone oxidation state as compared to their sulfide analogues. While sulfides were generally potent, nonselective agonists, sulfones exhibited alpha1a subtype selectivity in a cell-based functional assay. Sulfone (32) was 250-7000-fold selective for alpha1a vs all other subtypes.
Assuntos
Agonistas alfa-Adrenérgicos/síntese química , Imidazóis/síntese química , Receptores Adrenérgicos alfa 1/efeitos dos fármacos , Sulfonas/síntese química , Agonistas alfa-Adrenérgicos/química , Agonistas alfa-Adrenérgicos/farmacologia , Cálcio/metabolismo , Linhagem Celular , AMP Cíclico/biossíntese , Fibroblastos/metabolismo , Humanos , Imidazóis/química , Imidazóis/farmacologia , Sulfonas/química , Sulfonas/farmacologiaRESUMO
Opioid analgesics with both micro and delta opioid receptor activation represent a new approach to the treatment of severe pain with an improved safety profile. Compounds with this profile may exhibit strong analgesic properties due to micro agonism, with a reduced side effect profile resulting from delta agonism. Replacing the p-diethylamide of the known potent delta opioid receptor selective agonist BW373U86 with a m-diethylamide resulted in a compound with agonist activity at both the micro and delta opioid receptors. Modifying the amide to an N-methyl-N-phenylamide increased agonist potency at both receptors. A series of 3-(alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-alkyl-N-arylbenzamides have been made to explore the structure-activity relationship (SAR) around the N-methyl-N-phenylamide. Several potent agonists of both the micro and delta opioid receptors have been identified, including (+)-3-((alphaR)-alpha-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-hydroxybenzyl)-N-(4-fluorophenyl)-N-methylbenzamide (23), which has EC50 values of 0.67 and 1.1 nM at the micro (guinea pig ileum assay) and delta (mouse vas deferens assay) opioid receptors, respectively.
Assuntos
Benzamidas/síntese química , Piperazinas/síntese química , Receptores Opioides delta/agonistas , Receptores Opioides mu/agonistas , Animais , Benzamidas/química , Benzamidas/farmacologia , Cobaias , Íleo/efeitos dos fármacos , Íleo/fisiologia , Técnicas In Vitro , Masculino , Camundongos , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Piperazinas/química , Piperazinas/farmacologia , Estereoisomerismo , Relação Estrutura-Atividade , Ducto Deferente/efeitos dos fármacos , Ducto Deferente/fisiologiaRESUMO
BACKGROUND: Historically, the anterolateral interscalene block--deposition of local anesthetic adjacent to the brachial plexus roots/trunks--has been used for surgical procedures involving the shoulder. The resulting block frequently failed to provide surgical anesthesia of the hand and forearm, even though the brachial plexus at this level included all of the axons of the upper-extremity terminal nerves. However, it remains unknown whether deposition of local anesthetic adjacent to the seventh cervical root or inferior trunk results in anesthesia of the hand and forearm. METHODS: Using ultrasound guidance and a needle-in-plane posterior approach, a Tuohy needle was positioned with the tip located between the deepest and next-deepest visualized brachial plexus root/trunk, followed by injection of mepivacaine (1.5%). Grip strength and the tolerance to cutaneous electrical current in 5 terminal nerve distributions were measured at baseline and then every 5 minutes following injection for a total of 30 minutes. The primary end point was the proportion of cases in which the interscalene nerve block resulted in a decrease in grip strength of at least 90% and hand and forearm anesthesia (tolerance to >50 mA of current in all 5 terminal nerve distributions) within 30 minutes. The primary hypothesis was that a single-injection interscalene brachial plexus block produces a similar rate of anesthesia of the hand and forearm to the published success rate of 95% for other brachial plexus block approaches. RESULTS: Of 55 subjects with blocks placed per protocol, all had a successful block of the shoulder as defined by inability to abduct at the shoulder joint. Thirty-three subjects had measurements at 30 minutes following local anesthetic deposition, and only 5 (15%) of these subjects had a surgical block of the hand and forearm (P < 0.0001; 95% confidence interval, 6%-33%). We therefore reject the hypothesis that the interscalene block as performed in this study provides equivalent anesthesia to the hand and forearm compared with other brachial plexus block techniques. Block failures of the hand and forearm were due to inadequate cutaneous anesthesia of the ulnar (n = 27; 82%), median (n = 26; 78%), or radial (n = 22; 67%) distributions; the medial forearm (n = 25; 76%); and/or the lateral forearm (n = 14; 42%). Failure to achieve at least a 90% reduction in grip strength occurred in 16 subjects (48%). CONCLUSIONS: This study did not find evidence to support the hypothesis that local anesthetic injected adjacent to the deepest brachial plexus roots/trunks reliably results in surgical anesthesia of the hand and forearm.
Assuntos
Plexo Braquial/diagnóstico por imagem , Antebraço/cirurgia , Mãos/cirurgia , Bloqueio Nervoso/métodos , Ultrassonografia de Intervenção/métodos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: Both AUDIT-C alcohol screening scores up to a year before surgery and clinical documentation of drinking over 2 drinks per day immediately prior to surgery ("documented drinking >2d/d") are associated with increased postoperative complications and health care utilization. The purpose of this study was to evaluate whether documented drinking >2d/d contributed additional information about postoperative risk beyond past-year AUDIT-C screening results. METHOD: Male Veterans Affairs (VA) patients who had a non-emergent, non-cardiac, major surgery assessed by the VA's Surgical Quality Improvement Program 10/2003-9/2006 and completed the AUDIT-C by mailed survey in the prior year were eligible for this study. Linear or logistic regression models compared 30-day postoperative complication(s), return to operating room (OR), hospital length of stay (LOS), and intensive care unit (ICU) days across eight groups defined by past-year AUDIT-C score and clinically documented drinking >2d/d, with AUDIT-C scores 1-4 and no documented drinking >2d/d as the referent, after adjusting for important covariates. RESULTS: Overall 8811 patients met inclusion criteria. Among patients with documented drinking >2d/d immediately prior to surgery, postoperative risk varied widely depending on past-year AUDIT-C score; scores ≥5 were associated with increased risk of complication(s), and scores ≥9 with increased hospital LOS and ICU days. Among patients without documentation of drinking >2d/d, increasing AUDIT-C scores were not associated with these outcomes. CONCLUSIONS: Clinical documentation of drinking >2d/d immediately prior to surgery contributed additional information about postoperative risk beyond past-year AUDIT-C score. However, among patients with documented drinking >2d/d, postoperative risk varied widely depending on the AUDIT-C score.
Assuntos
Consumo de Bebidas Alcoólicas/efeitos adversos , Consumo de Bebidas Alcoólicas/epidemiologia , Programas de Rastreamento/métodos , Complicações Pós-Operatórias/diagnóstico , Complicações Pós-Operatórias/epidemiologia , Veteranos , Idoso , Alcoolismo/epidemiologia , Inquéritos Epidemiológicos/métodos , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Fatores de TempoRESUMO
The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.
Assuntos
Diabetes Mellitus Tipo 2/tratamento farmacológico , Descoberta de Drogas , Hipoglicemiantes/química , Hipoglicemiantes/farmacologia , Metilaminas/química , Metilaminas/farmacologia , Transportadores de Ânions Orgânicos Dependentes de Sódio/antagonistas & inibidores , Simportadores/antagonistas & inibidores , Tiazepinas/química , Tiazepinas/farmacologia , Animais , Ácidos e Sais Biliares/metabolismo , Cães , Estabilidade de Medicamentos , Células HEK293 , Humanos , Hipoglicemiantes/metabolismo , Hipoglicemiantes/uso terapêutico , Masculino , Metilaminas/metabolismo , Metilaminas/uso terapêutico , Camundongos , Ratos , Solubilidade , Tiazepinas/metabolismo , Tiazepinas/uso terapêuticoRESUMO
BACKGROUND: Alcohol screening scores ≥5 on the Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) up to a year before surgery have been associated with postoperative complications, but the association with postoperative health care use is unknown. This study evaluated whether AUDIT-C scores in the year before surgery were associated with postoperative hospital length of stay, total ICU days, return to the operating room, and hospital readmission. STUDY DESIGN: This cohort study included male Veterans Affairs patients who completed the AUDIT-C on mailed surveys (October 2003 through September 2006) and were hospitalized for nonemergent noncardiac major operations in the following year. Postoperative health care use was evaluated across 4 AUDIT-C risk groups (scores 0, 1 to 4, 5 to 8, and 9 to 12) using linear or logistic regression models adjusted for sociodemographics, smoking status, surgical category, relative value unit, and time from AUDIT-C to surgery. Patients with AUDIT-C scores indicating low-risk drinking (scores 1 to 4) were the referent group. RESULTS: Adjusted analyses revealed that among eligible surgical patients (n = 5,171), those with the highest AUDIT-C scores (ie, 9 to 12) had longer postoperative hospital length of stay (5.8 [95% CI, 5.0-6.7] vs 5.0 [95% CI, 4.7-5.3] days), more ICU days (4.5 [95% CI, 3.2-5.8] vs 2.8 [95% CI, 2.6-3.1] days), and increased probability of return to the operating room (10% [95% CI, 6-13%] vs 5% [95% CI, 4-6%]) in the 30 days after surgery, but not increased hospital readmission within 30 days postdischarge, relative to the low-risk group. CONCLUSIONS: AUDIT-C screening results could be used to identify patients at risk for increased postoperative health care use who might benefit from preoperative alcohol interventions.
Assuntos
Consumo de Bebidas Alcoólicas , Alcoolismo/diagnóstico , Cuidados Pós-Operatórios/estatística & dados numéricos , Idoso , Estudos de Coortes , Humanos , Unidades de Terapia Intensiva/estatística & dados numéricos , Tempo de Internação , Masculino , Pessoa de Meia-Idade , Readmissão do Paciente , Período Pós-Operatório , Análise de Regressão , Reoperação , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Patients who screen positive for alcohol misuse on the Alcohol Use Disorder Identification Test Consumption Questionnaire (AUDIT-C ≥5 points) have significantly increased postoperative complications. Severe alcohol misuse (AUDIT-C ≥9 points) is associated with increased postoperative health care use; however, little is known about the prevalence of alcohol misuse in demographic and clinical subgroups of surgical patients. METHODS: The prevalence of alcohol misuse was evaluated among 10,284 patients (9,771 men and 513 women) who underwent major noncardiac surgery in Veterans Affairs (VA) hospitals during the fiscal years 2004 to 2006 and completed the AUDIT-C. Sex-stratified analyses evaluated prevalence rates of alcohol misuse (AUDIT-C ≥5) and severe misuse (AUDIT-C ≥9) across demographic and clinical subgroups. RESULTS: Overall, 1,607 (16%) men and 24 (5%) women screened positive for alcohol misuse (AUDIT-C ≥5) in the year before operation, with 4% and 2% screening positive for severe misuse (AUDIT-C ≥9), respectively. Alcohol misuse was more common among men who were <60 years of age, divorced or separated, current smokers, or American Stoke Association class 1 or 2, and those with cirrhosis/hepatitis or substance use disorders. Among patients with alcohol misuse, 36% of men and 58% of women were American Society of Anesthesiologists class 1 or 2, and most did not have diagnoses that were commonly associated with alcohol misuse. CONCLUSION: Alcohol misuse is relatively common in male surgical patients. Moreover, surgical patients undergoing operation who screen positive for alcohol misuse are often relatively healthy, without health problems that might alert providers to their alcohol misuse in the absence of screening.