Early Extubation following Cardiac Surgery in a Veterans Population

Background: Early tracheal extubation is an important component of the "fast track" cardiac surgery pathway. Factors associated with time to extubation in the Department of Veterans Affairs (DVA) population are unknown. The authors determined associations of preoperative risk and intraoperative clinical process variables with time to extubation in this population.

Methods: Three hundred four consecutive patients undergoing coronary artery bypass graft, valve surgery, or both on a fast track clinical pathway between October 1, 1993 and September 30, 1995 at a university-affiliated DVA medical center were studied retrospectively. After univariate screening of a battery of preoperative risk and intraoperative clinical process variables, stepwise logistic regression was used to determine associations with tracheal extubation 10 h (late) after surgery. Postoperative lengths of stay, complications, and 30-day and 6-month mortality rates were compared between the two groups.

Results: One hundred forty-six patients (48.3%) were extubated early; one patient required emergent reintubation (0.7%). Of the preoperative risk variables considered, only age (odds ratio, 1.80 per 10-yr increment) and preoperative intra-aortic balloon pump (odds ratio, 7.88) were multivariately associated with time to extubation (model R) ("late" association is indicated by an odds ratio >1.00; "early" association is indicated by an odds ratio <1.00). Entry of these risk variables into a second regression model, followed by univariately significant intraoperative clinical process variables, yielded the following associations (model R-P): age (odds ratio, 1.86 per 10-yr increment), sufentanil dose (odds ratio, 1.54 per 1-[micro sign]g/kg increment), major inotrope use (odds ratio, 5.73), platelet transfusion (odds ratio, 10.03), use of an arterial graft (odds ratio, 0.32), and fentanyl dose (odds ratio, 1.45 per 10-[micro sign]g/kg increment). Time of arrival in the intensive care unit after surgery was also significant (odds ratio, 1.42 per 1-h increment). Intraoperative clinical process variables added significantly to model performance (P < 0.001 by the likelihood ratio test).     

Control of refractory status epilepticus precipitated by anticonvulsant withdrawal using left vagal nerve stimulation: a case report

OBJECTIVE: To describe a case of left vagal nerve stimulation (VNS) resulting in immediate cessation of status epilepticus (SE) with good neurological outcome. CASE DESCRIPTION: A 30-year-old man with medically intractable seizures including episodes of SE was successfully treated using left VNS. After requiring discontinuation of phenytoin, valproic acid, carbamazepine, and topiramate because of severe allergic reactions resembling Stevens-Johnson syndrome, the patient required pentobarbital coma along with phenobarbital, tiagabine, and levetiracetam for seizure frequency reduction. He underwent left vagal nerve stimulator placement after nearly 9 days of barbiturate-induced coma, with stimulation initiated in the operating room. On the following day, electroencephalography revealed resolution of previously observed periodic lateral epileptiform discharges and the patient was free of seizures. Prestimulation seizure frequency was recorded at 59 times a day, with some seizures enduring 45 minutes despite barbiturate coma. Poststimulation, the patient has been free of seizures for 19 days and is presently taking only levetiracetam and phenobarbital, from which he continues to be successfully weaned without seizures. He is awake, alert, and can recall events leading up to his seizures, with good long-term memory and residual left upper extremity and lower extremity weakness. CONCLUSION: This case illustrates the role of left vagal stimulation in the treatment of SE and otherwise medically intractable seizures caused by allergic reactions. To our knowledge, this is the first case in the world literature for adults reporting cessation of SE after VNS. Another case with a similar improvement has been reported in the pediatric population.     

A Pre-Hospital Patient Education Program Improves Outcomes of Bariatric Surgery

Background

We designed an assessment and education program which was delivered to patients prior to first outpatient appointment for bariatric surgery. We hypothesised that this program would streamline care and would lead to improved weight loss following bariatric surgery.

Methods

The program incorporates a structured general practitioners (GP) review, a patient information evening and an on-line learning package. It was introduced in September 2012. Patient flow through the program was recorded. Outcomes of the new program were compared with contemporaneously treated patients who did not undertake the pre-hospital program.

Results

All 636 patients on the waiting list for first appointment at the Alfred Health bariatric surgery clinic were invited to participate. There were 400 patients ultimately removed from the waiting list for first appointment. Of the remaining 236 patients, 229 consented to participate in the new program. The mean BMI was 47.8?±?9.2. The fail to attend first appointment rate dropped from 12 to 2.1 %. At 12 months post-bariatric surgery, patients who undertook the new program (n?=?82) had a mean excess weight loss (EWL) of 41.1?±?20.3 % where as those treated on the standard pathway (n?=?61) had a mean EWL 32?±?18.0 % (p?=?0.012).

Conclusions

The introduction of a pre-hospital education program has led to an improvement in attendance rates and early weight loss post-bariatric surgery.

     

George Peters Award: How does breast-specific gamma imaging affect the management of patients with newly diagnosed breast cancer?

Background

We sought to determine the number of patients with known breast cancer who were found to have an additional, mammographically occult lesion detected on breast-specific gamma imaging (BSGI).

Methods

An institutional review board-approved review of all patients who underwent BSGI at Beth Israel Medical Center from 2006 to 2008 was performed.

Results

A total of 82 patients underwent BSGI for newly diagnosed breast cancer. Of these, 18 had an additional abnormality, and 17 were biopsied. There were 4 cases of invasive ductal carcinoma, 1 invasive lobular carcinoma, 1 ductal carcinoma in situ, 1 lobular carcinoma in situ, 2 papillomas, and 8 benign biopsies. One patient proceeded directly to mastectomy and an area of ductal carcinoma in situ was found, corresponding to the BSGI.

Conclusions

In our study group, 22% of patients had a surgical change in management based on BSGI findings. BSGI detected additional carcinoma in 9%. BSGI plays an important role in the clinical management of patients with known breast cancer.     

Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in Mice

OBJECTIVE

Oxyntomodulin (OXM) is a glucagon-like peptide 1 (GLP-1) receptor (GLP1R)/glucagon receptor (GCGR) dual agonist peptide that reduces body weight in obese subjects through increased energy expenditure and decreased energy intake. The metabolic effects of OXM have been attributed primarily to GLP1R agonism. We examined whether a long acting GLP1R/GCGR dual agonist peptide exerts metabolic effects in diet-induced obese mice that are distinct from those obtained with a GLP1R-selective agonist.

RESEARCH DESIGN AND METHODS

We developed a protease-resistant dual GLP1R/GCGR agonist, DualAG, and a corresponding GLP1R-selective agonist, GLPAG, matched for GLP1R agonist potency and pharmacokinetics. The metabolic effects of these two peptides with respect to weight loss, caloric reduction, glucose control, and lipid lowering, were compared upon chronic dosing in diet-induced obese (DIO) mice. Acute studies in DIO mice revealed metabolic pathways that were modulated independent of weight loss. Studies in Glp1r^−/− and Gcgr^−/− mice enabled delineation of the contribution of GLP1R versus GCGR activation to the pharmacology of DualAG.

RESULTS

Peptide DualAG exhibits superior weight loss, lipid-lowering activity, and antihyperglycemic efficacy comparable to GLPAG. Improvements in plasma metabolic parameters including insulin, leptin, and adiponectin were more pronounced upon chronic treatment with DualAG than with GLPAG. Dual receptor agonism also increased fatty acid oxidation and reduced hepatic steatosis in DIO mice. The antiobesity effects of DualAG require activation of both GLP1R and GCGR.

CONCLUSIONS

Sustained GLP1R/GCGR dual agonism reverses obesity in DIO mice and is a novel therapeutic approach to the treatment of obesity.Obesity is an important risk factor for type 2 diabetes, and ∼90% of patients with type 2 diabetes are overweight or obese (1). Among new therapies for type 2 diabetes, peptidyl mimetics of the gut-derived incretin hormone glucagon-like peptide 1 (GLP-1) stimulate insulin biosynthesis and secretion in a glucose-dependent manner (2,3) and cause modest weight loss in type 2 diabetic patients. The glucose-lowering and antiobesity effects of incretin-based therapies for type 2 diabetes have prompted evaluation of the therapeutic potential of other glucagon-family peptides, in particular oxyntomodulin (OXM). The OXM peptide is generated by post-translational processing of preproglucagon in the gut and is secreted postprandially from l-cells of the jejuno-ileum together with other preproglucagon-derived peptides including GLP-1 (4,5). In rodents, OXM reduces food intake and body weight, increases energy expenditure, and improves glucose metabolism (6–8). A 4-week clinical study in obese subjects demonstrated that repeated subcutaneous administration of OXM was well tolerated and caused significant weight loss with a concomitant reduction in food intake (9). An increase in activity-related energy expenditure was also noted in a separate study involving short-term treatment with the peptide (10).OXM activates both, the GLP-1 receptor (GLP1R) and glucagon receptor (GCGR) in vitro, albeit with 10- to 100-fold reduced potency compared with the cognate ligands GLP-1 and glucagon, respectively (11–13). It has been proposed that OXM modulates glucose and energy homeostasis solely by GLP1R agonism, because its acute metabolic effects in rodents are abolished by coadministration of the GLP1R antagonist exendin(9–39) and are not observed in Glp1r^−/− mice (7,8,14,15). Other aspects of OXM pharmacology, however, such as protective effects on murine islets and inhibition of gastric acid secretion appear to be independent of GLP1R signaling (14). In addition, pharmacological activation of GCGR by glucagon, a master regulator of fasting metabolism (16), decreases food intake in rodents and humans (17–19), suggesting a potential role for GCGR signaling in the pharmacology of OXM. Because both OXM and GLP-1 are labile in vivo (T_1/2 ∼12 min and 2–3 min, respectively) (20,21) and are substrates for the cell surface protease dipeptidyl peptidase 4 (DPP-4) (22), we developed two long-acting DPP-4–resistant OXM analogs as pharmacological agents to better investigate the differential pharmacology and therapeutic potential of dual GLP1R/GCGR agonism versus GLP1R-selective agonism. Peptide DualAG exhibits in vitro GLP1R and GCGR agonist potency comparable to that of native OXM and is conjugated to cholesterol via a Cys sidechain at the C-terminus for improved pharmacokinetics. Peptide GLPAG differs from DualAG by only one residue (Gln³→Glu) and is an equipotent GLP1R agonist, but has no significant GCGR agonist or antagonist activity in vitro. The objective of this study was to leverage the matched GLP1R agonist potencies and pharmacokinetics of peptides DualAG and GLPAG in comparing the metabolic effects and therapeutic potential of a dual GLP1R/GCGR agonist with a GLP1R-selective agonist in a mouse model of obesity.     

Effects of Gastric Band Adjustments on Intraluminal Pressure

Background

Understanding of the effects of adjustments to laparoscopic adjustable gastric band (LAGB) volume is limited. Changes in intraluminal pressure may be important and explain patients reporting a tighter LAGB after saline is removed and an identical volume replaced.

Methods

Using high-resolution manometry, changes in the basal intraluminal pressure at the level of the LAGB in response to sequential, small alterations in LAGB volume were recorded. All fluid was removed from the LAGB and replaced, pressures and motility were reassessed.

Results

Sixteen patients (four males, age 45.4?±?13.2 years) participated. A linear increase (r ²?=?0.87?±?0.12) in intraluminal pressure was observed after a threshold volume was reached. The threshold volume varied considerably (1.0 to 5.8 ml). The gradient of the linear increase was 21.2?±?8.7 mmHg/ml. The mean basal intraluminal pressure at the level of the LAGB was initially 19.1?±?8.9 mmHg and increased to 37.0?±?20.4 mmHg (p?=?0.001) after removing and replacing the same volume of saline. There was an increase in distal esophageal peristaltic pressure (123.5?±?34.7 vs. 157.4?±?52.6 mmHg, p?=?0.003) and a decrease in the proportion of normal swallows (0.85?±?0.22 vs. 0.53?±?0.47, p?=?0.02). Nine patients also developed adverse symptoms.

Conclusions

Intraluminal pressure at the level of the LAGB is an objective measure of the restriction produced by LAGBs. The addition of fluid to the LAGB results in a linear increase in intraluminal pressure once a threshold volume is reached. The removal and replacement of the same volume of saline from the LAGB may temporarily increase intraluminal pressure.     

Transforming growth factor-beta regulation of the insulin-like growth factor binding protein-4 protease system in cultured human osteoblasts.

IGFBP-4 is an inhibitor of IGF-I in bone. We show that TGF-beta regulates IGFBP-4 and enhances IGF-I-stimulated growth of cultured human bone cells through increased expression of an IGFBP-4 protease, PAPP-A. This effect of TGF-beta on IGF-I bioavailability may promote local bone formation. Insulin-like growth factor binding protein (IGFBP-4) proteolysis is implicated in the regulation of local insulin-like growth factor (IGF)-I bioavailability during bone remodeling. The IGFBP-4 protease secreted by normal adult human osteoblastic (hOB) cells in culture is a novel metalloproteinase, pregnancy-associated plasma protein-A (PAPP-A). We have recently identified an inhibitor of PAPP-A, the precursor form of major basic protein (proMBP). Very little is known about the molecular regulation of this IGFBP-4 protease system. In the present study, we determined the effect of transforming growth factor (TGF)-beta and IGF-II, the two most abundant growth factors in human bone, on PAPP-A and proMBP expression in primary cultures of hOB cells. Treatment with TGF-beta resulted in time- and dose-dependent increases in PAPP-A mRNA expression, with a maximal 12-fold increase after 24 h of stimulation with 10 ng/ml TGF-beta. Increased PAPP-A levels in hOB cell-conditioned medium paralleled PAPP-A gene expression. In addition, TGF-beta completely suppressed proMBP expression. Treatment of hOB cells with IGF-II had no effect on PAPP-A or proMBP gene expression. However, IGFBP-4 proteolysis in cell-free assay was dependent on IGF-II, and there was increased IGF-II-dependent IGFBP-4 protease activity in conditioned medium from hOB cells that were treated with TGF-beta. IGF-I stimulation of hOB cell proliferation was markedly enhanced by pretreatment with TGF-beta and [Leu27]IGF-II, and this enhancement was prevented with protease-resistant IGFBP-4. In summary, TGF-beta regulates IGFBP-4 proteolysis in hOB cells through increased expression of the protease, PAPP-A, and decreased expression of the inhibitor, proMBP. However, functional activation of the IGFBP-4 protease system is dependent on IGF-II, which acts at a post-translational level. These data support a model whereby local TGF-beta and IGF-II in the bone microenvironment coordinately amplify IGF-I bioavailability through controlled IGFBP-4 proteolysis, which may be a means to promote bone formation.     

Improving quality of care in cardiac surgery: evaluating risk factors, processes of care, structures of care, and outcomes

The 1985 release of hospital report cards by the Health Care Financing Administration awakened the public's awareness of variations in outcomes following patient treatment. In 1972, the Department of Veterans Affairs initiated an oversight process for all VA-based cardiac surgery programs. In response to Public Law 99-166, the Continuous Improvement in Cardiac Surgery Program (CICSP) national database was developed in 1987. This CICSP effort reported variations in outcomes across VA cardiac programs. In 1997, the CICSP expanded (CICSP-X) to identify the interrelationships of risk factors with processes and structures of care, as well as clinical outcomes. Based on VA findings to date, these quality improvement endeavors appear to have positively affected short-term and longer-term cardiac surgical outcomes. To advance a new patient-focused paradigm for continuous improvement in cardiac surgical care quality for all US citizens, an integrated data-driven reporting approach with broad-based participation should be implemented to optimally improve patient care.     

Peripheral quantitative computed tomography in children and adolescents: the 2007 ISCD Pediatric Official Positions

Peripheral quantitative computed tomography (pQCT) has mainly been used as a research tool in children. To evaluate the clinical utility of pQCT and formulate recommendations for its use in children, the International Society of Clinical Densitometry (ISCD) convened a task force to review the literature and propose areas of consensus and future research. The types of pQCT technology available, the clinical application of pQCT for bone health assessment in children, the important elements to be included in a pQCT report, and quality control monitoring techniques were evaluated. The review revealed a lack of standardization of pQCT techniques, and a paucity of data regarding differences between pQCT manufacturers, models and software versions and their impact in pediatric assessment. Measurement sites varied across studies. Adequate reference data, a critical element for interpretation of pQCT results, were entirely lacking, although some comparative data on healthy children were available. The elements of the pQCT clinical report and quality control procedures are similar to those recommended for dual-energy X-ray absorptiometry. Future research is needed to establish evidence-based criteria for the selection of the measurement site, scan acquisition and analysis parameters, and outcome measures. Reference data that sufficiently characterize the normal range of variability in the population also need to be established.     

Smaller Hip Circumference is Associated with Dyslipidemia and the Metabolic Syndrome in Obese Women

BACKGROUND: There is great need for simple anthropometric measures that predict risk. The authors explored the relationship between body composition measures and features of the metabolic syndrome (MtS) in women aged between 20 and 50 years with class I obesity. METHODS:This is a cross-sectional study of 49 obese (BMI 30-35) women recruited into a weight management randomized trial. An analysis was conducted of the baseline weight, anthropometric measures, skin-fold thickness, bioelectrical impedance, whole body dual-energy x-ray absorptiometry (DEXA), and their relationships with the features of the MtS. RESULTS: All women but one (n=48) had a population risk waist circumference of >88 cm. 16 of the 49 (33%) fulfilled the criteria of the metabolic syndrome. Simple anthropometric measures provided the strongest correlations with the presence of the MtS. Cut-off values were selected using receiver operator characteristics. Waist circumference of >100 cm and hip circumference <115cm was associated with odds ratios of 5.2 (95% CI, 1.4-20) and 12.3 (95% CI, 3.0-51) respectively for the MtS. Regional DEXA analysis showed that lower leg fat mass rather than fat-free mass was associated with the MtS. The dyslipidemia of the MtS was associated with a lower leg fat mass, while higher HbAlc levels and HOMA, an indirect measure of insulin resistance, were seen with increased trunk fat. Percentage fat as measured by skin-fold thickness and bioelectrical impedance were not related to any features. Women with the metabolic syndrome were found to have lower bone mineral content as measured by DEXA. CONCLUSION: Weight distribution is highly predictive of metabolic risk. Smaller hip and larger waist circumference provided independent effect. BMI adjusted anthropometric measures may be of value.