Growth hormone secretagogue MK-677: no clinical effect on AD progression in a randomized trial.

BACKGROUND: In animals, insulin-like growth factor-1 (IGF-1) increases clearance of beta-amyloid, a pathologic hallmark of Alzheimer disease (AD), from the CNS. Serum IGF-1 level decreases with age, and shows a further decrease in AD. We examined whether the growth hormone secretagogue MK-677 (ibutamoren mesylate), a potent inducer of IGF-1 secretion, slows the rate of progression of symptoms in patients with AD. METHODS: A double-blind, multicenter study was conducted in which 563 patients with mild to moderate AD were randomized to receive MK-677 25 mg or placebo daily for 12 months. Efficacy measures were mean change from baseline at month 12 on the Clinician's Interview Based Impression of Change with caregiver input (CIBIC-plus), the cognitive subscale of the Alzheimer's Disease Assessment Scale (ADAS-Cog), Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL), and the Clinical Dementia Rating-sum of boxes (CDR-sob). RESULTS: A total of 416 patients completed treatment and assessments at 12 months. Administration of MK-677 25 mg resulted in a 60.1% increase in serum IGF-1 levels at 6 weeks and a 72.9% increase at 12 months. In mixed-effects models that included treatment, time (month), randomization strata (baseline MMSE score < or =20 vs >20), and interaction of treatment-by-time, there were no significant differences between the treatment groups on the CIBIC-plus or the mean change from baseline scores on the ADAS-Cog, ADCS-ADL, or CDR-sob scores over 12 months. CONCLUSION: Despite evidence of target engagement as indicated by an increase in serum insulin-like growth factor-1, the human growth hormone secretagogue MK-677 25 mg was ineffective at slowing the rate of progression of Alzheimer disease.

Rofecoxib: no effect on Alzheimer's disease in a 1-year, randomized, blinded, controlled study.

BACKGROUND: Inflammatory mechanisms have been implicated in the pathogenesis of Alzheimer's disease (AD) and may be mediated via the cyclo-oxygenase-2 enzyme. This study sought to evaluate the effect of rofecoxib, a nonsteroidal anti-inflammatory drug that selectively inhibits cyclo-oxygenase-2, in slowing the progression of dementia in patients with established AD. METHODS: A double-blinded, multicenter trial was conducted in which 692 patients with mild or moderate AD aged 50 years or older were randomly assigned to receive 25 mg rofecoxib or placebo daily for 12 months. The key efficacy measures were mean change from baseline at month 12 on the cognitive subscale of the AD Assessment Scale (ADAS-cog) and score on the Clinician's Interview Based Impression of Change with caregiver input (CIBIC+). RESULTS: Four hundred eighty-one patients (70%) completed assessments and remained on treatment at 12 months. No significant differences between treatments were found on the mean change from baseline error score for the ADAS-cog (rofecoxib = 4.84; placebo = 5.44; difference = -0.60) or mean score on the CIBIC+ (rofecoxib = 4.90; placebo = 4.87; difference = 0.03) over 12 months. This result persisted after adjusting for severity of dementia at baseline, presence of the APOE-epsilon4 allele, and donepezil use. Secondary analyses did not reveal any significant differences on any other measures. CONCLUSION: The failure of selective cyclo-oxygenase-2 inhibition to slow the progression of AD may indicate either that the disease process is too advanced to modify in patients with established dementia or that cyclo-oxygenase-2 does not play a significant role in the pathogenesis of the disorder.

Pharmacokinetic profile and tolerability of indinavir-ritonavir combinations in healthy volunteers.

This was a randomized, double-blind, placebo-controlled parallel study in human immunodeficiency virus type 1 (HIV-1)-uninfected healthy subjects to investigate the pharmacokinetic interaction between indinavir (IDV) and ritonavir (RTV). Subjects were allocated to treatment groups of IDV given with RTV in the following milligram doses twice daily: 800 mg of IDV-100 mg of RTV (800-100 mg), 800-200, 800-400, and 400-400 mg, placebo of IDV with RTV doses of 100, 200, and 400 mg, and placebo of both IDV and RTV. Doses of both drugs were administered for 14 days with a low-fat meal and one dose on day 15 with a high-fat meal. Blood was obtained for drug concentration measurements on days 14 and 15. Seventy-three volunteers enrolled in the study: 29 men and 44 women. Fifty-three volunteers completed the study. When compared to standard historical data for 800 mg of IDV every 8 h (q8h), the IDV area under the concentration-time curve for 24 h (AUC(24)) of IDV-RTV regimens 400-400, 800-100, and 800-200 mg were at least 1.4, 2.3, and 3.3 times higher, respectively, regardless of meal. The concentrations at the end of the dosing interval were 10 to 25 times higher than that observed in the standard regimen of 800 mg of IDV q8h for IDV-RTV 800-100 and 800-200 mg regimens, respectively. RTV at 200 mg maximally enhanced the IDV profile. Improved tolerability was associated with IDV-RTV 800-100 mg versus IDV-RTV 800-200, 800-400, and 400-400 mg q12h. The advantages of IDV-RTV twice daily over 800 mg of IDV q8h include no food restrictions and twice-daily dosing. Also, the regimens achieve levels of IDV that may be helpful in suppressing strains of HIV-1 that have reduced susceptibility to IDV or other protease inhibitors.

Indinavir did not increase the short-term risk of adverse cardiovascular events relative to nucleoside reverse transcriptase inhibitor therapy in four phase III clinical trials.

A retrospective person-time analysis of the randomized and non-randomized extension phases of four phase III trials was performed to assess the incidence of adverse cardiovascular events in 2680 HIV-infected patients receiving indinavir or nucleoside reverse transcriptase inhibitor therapy, or both. The observed rate of cardiovascular events was not increased in patients receiving indinavir-based regimens compared with therapy without a protease inhibitor. Extrapolation of these findings is limited by the brief length of therapy and the small number of cases.

Randomized, double-blind trial comparing indinavir alone, zidovudine alone and indinavir plus zidovudine in antiretroviral therapy-naive HIV-infected individuals with CD4 cell counts between 50 and 250/mm3.

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p<0. 0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.

Effect of patient position on the incidence of vasovagal response to venous cannulation.

BACKGROUND: This study was undertaken to determine the effect of patient position on the incidence of vasovagal responses to venous cannulation in ambulatory surgery patients. METHODS: Three hundred surgical outpatients, aged 18 to 40 years, were randomly assigned by week to the sitting or recumbent position. Blood pressure and heart rate were recorded during and for 6 minutes following venous cannulation. An observer recorded signs and symptoms suggestive of a vasovagal response. RESULTS: A vasovagal reaction occurred in 12.6% of sitting patients and 2.1% of recumbent patients. Two sitting patients, 1.3%, experienced frank syncope. Symptomatic patients were more likely (39.1%) than asymptomatic patients (8.3%) to have a history of fainting. In symptomatic patients who were sitting, mean arterial pressure fell from 90.4 mm Hg (SD, 10.6) at baseline to 64.4 mm Hg (SD, 14.3) during cannulation. Similarly, heart rate fell from 76.6 beats per minute (SD, 15.6) at baseline to 59.0 beats per minute (SD, 11.7) after cannulation. CONCLUSIONS: The vasovagal response during venous cannulation occurs more frequently in the sitting patient who has a history of fainting and is associated with a significant decline in blood pressure and heart rate.

Three-dimensional transesophageal echocardiography for depiction of regional left-ventricular performance: initial results and future directions.

To assess the potential of a prototype transesophageal echocardiography probe for evaluating left-ventricular wall motion in three dimensions, we acquired images under anesthesia in 15 patients who had akinesia or dyskinesia and 8 patients who had normal function demonstrated on preoperative ventriculography. Short-axis, oblique transgastric scans were obtained in 16 of the patients and four-chamber, long-axis oblique scans were obtained in 12 patients, with five patients (22%) yielding good-quality scans of both types. Off-line, we outlined the endocardial borders manually and used the outlines to make computer-generated three-dimensional models of the endocardial surfaces, color-tiled according to regional ejection fraction. Compared with contrast ventriculograms, the regional ejection fraction histograms derived from these models showed 86% concordance for detecting dyssynergy. However, the concordance between the ventriculograms and the color-tiled models in localizing the dyssynergy was only 67% overall. Uncertainty in rotational alignment between the reconstructions and the ventriculograms appeared to contribute to misreading the location of dyssynergy. In addition, the apical region appeared to have been missed in 8 (50%) of the short-axis scans, whereas it was visualized in all long-axis scans. We conclude that three-dimensional analysis of the location, extent, and degree of left-ventricular dyssynergy is feasible from transesophageal echocardiograms and could have wide application in the study of regional ventricular function. However, improvements are necessary to enable the transducer to scan the cardiac apex more reliably from the short-axis viewpoint and to have a means for spatially orienting the images with respect to an external frame of reference.

Vaso-vagal reactions in an ambulatory surgery center.

This prospective study was undertaken to determine the incidence and factors predisposing to vaso-vagal reactions during venous cannulation in an ambulatory surgery population. In 141 ambulatory surgery patients, signs and symptoms of a reaction together with mean arterial pressure and heart rate were recorded at 1-min intervals during and for 6 min after venous cannulation. Overall, 10.6% of patients were symptomatic (95% confidence interval [CI] 6%-17%). The incidence was 16.6% (95% CI 8.4%-24.9%) in patients < or = 40 yr and 33.3% (95% CI 6.7%-60.0%) with a prior fainting history. Young age, duration or number of attempts at venous cannulation, and fainting history were independently associated with increased risk of a reaction (P < 0.03-0.004 by multiple repression analysis). Minimum mean arterial pressure was less in symptomatic patients than in those who were asymptomatic (58 mm Hg +/- 11.3 SD versus 82 mm Hg +/- 14.3 SD, P < 0.0001). We conclude that reactions occur commonly, particularly in the young or in patients with a history of fainting. Reactions are typically associated with significant hypotension that may require treatment.

Methodology for three-dimensional reconstruction of the left ventricle from transesophageal echocardiograms.

A technique is presented for three-dimensional (3-D) reconstruction of the left-ventricular endocardial surface from multiplanar transesophageal echocardiograms, using both commercial software and investigator written Fortran programs for Intel 80286 and 80386 microcomputers. The approach provides quantitative global and regional cardiac performance measures and allows viewing the endocardial surface, at end-diastole and end-systole, from chosen perspectives. Anatomical landmarks are incorporated to aid in orientation. For regional calculation, the surface is divided into equal angular elements with each conceptually connected to the left-ventricular end-diastole centroid, forming a pyramidal volume element. This angular division automatically normalizes for heart size. The fractional change of these elements over the cardiac cycle provides a regional ejection fraction measure which is color-coded on the reconstructed endocardial surface. Composite perspective views, regional ejection fraction histograms and calculations of global end-diastolic, end-systolic, and stroke volumes, are all performed by the method.

Comparison of desflurane with propofol in outpatients undergoing peripheral orthopedic surgery.

This study was undertaken to compare desflurane with propofol anesthesia in outpatients undergoing peripheral orthopedic surgery. Data were combined from two institutions participating in a multicenter study. Ninety-one patients, ASA physical status I or II, were each randomly assigned to one of four groups. After administration of fentanyl (2 micrograms/kg) and d-tubocurarine (3 mg), intravenous propofol was administered to induce anesthesia in groups I and II and desflurane in groups III and IV. Maintenance was provided by desflurane/N2O in groups I and III, propofol/N2O in group II, and desflurane/O2 in group IV. Emergence and recovery variables, psychometric test results, and side effects were recorded by observers unaware of the experimental treatment. Patients in group II experienced less nausea than other groups (P = 0.002) despite this group having required more intraoperative fentanyl supplementation than groups III and IV (P = 0.01). Time to emergence, discharge, and psychometric test results were similar in all groups. Desflurane appears to be comparable with propofol as an outpatient anesthetic, facilitating rapid recovery and discharge home.

Electroencephalography during surgery with cardiopulmonary bypass and hypothermia.

After more than 30 yr of use, electroencephalographic (EEG) monitoring during cardiopulmonary bypass has not gained wide clinical acceptance. To assess its utility to predict central nervous system injury, two-channel recordings were made from 78 patients undergoing cardiopulmonary bypass and anesthetized with fentanyl/diazepam/enflurane. The perfusion regimen included the use of high pump flow, a bubble oxygenator, and no arterial tubing filter. Target values were 28-32 degrees C for the minimum rectal temperature, 60-80 mmHg for mean arterial pressure, and 20-25% for hematocrit. Eight descriptors of the Fourier power spectra of the EEG were calculated off-line, and outcome comparisons were made with the results from neuropsychological tests. Among 58 patients yielding complete data of acceptable quality, a statistically significant reduction in total power was observed from prebypass to postbypass, accompanied by an increase in the fractional power in the theta and beta frequency bands and in the spectral edge frequency. The shifts in total and theta power were weakly associated with short-term but not with long-term changes in neuropsychological scores. Nearly 40% of the patients' EEGs were corrupted with electrical noise at some time during bypass. In 15 patients selected for having high-quality recordings and no neuropsychological deficit, an extensive statistical analysis failed to reveal any consistent variation in the EEG descriptors with hypothermia. Under the conditions studied, it appears that for other than gross signal dropout, the strong background variability in the EEG makes it have little value for detecting harbingers of brain injury.

Left ventricular ejection fraction: single-plane and multiplanar transesophageal echocardiography versus equilibrium gated-pool scintigraphy.

The relative accuracy and precision of estimating left ventricular ejection fraction (EF) in dogs were assessed by two-dimensional transesophageal echocardiography (2D-TEE) and by three-dimensional transesophageal echocardiographic (3D-TEE) imaging and reconstruction. This assessment was accomplished by comparing each echocardiographic method to a gated equilibrium blood pool radionuclide (RN) standard. By using both correlation and regression analysis, 2D-TEE performed reasonably well in estimating RNEF (correlation coefficient [r] = 0.80, slope = 1.01, intercept = 6.37, standard error of the estimate [SEE], 8.98), but not as well as 3D-TEE (r = 0.86, slope = 0.83, intercept = 3.38, SEE, 5.74). Using Altman and Bland's methods of comparison analysis, it was found that 2D-TEE overestimated RNEF by 7% (standard deviation [SD], 8.8). This degree of overestimation was not consistent across the range of measurement. In contrast, 3D-TEE slightly underestimated RNEF by less than 3% and showed less variability (SD, 6.0). The accuracy of the 3D-TEE determinations was not dependent on the magnitude of EF. Additionally, a significantly higher proportion of the 2D-TEE measurements (0.30) compared with the 3D-TEE measurements (0.10) differed from RN values by more than 10% (P = 0.009, McNemar's test). At the clinically important low end of the EF range (RNEF less than or equal to 35%), 2D-TEE may be expected (with 95% confidence) to be within -15% to +28% EF of reference values, whereas 3D-TEE can be expected to be within -8% to +5% EF relative to RN.(ABSTRACT TRUNCATED AT 250 WORDS)

Preoperative aspirin therapy and reoperation for bleeding after coronary artery bypass surgery.

We performed a case-control study to estimate the relative risk of reoperation for bleeding in coronary artery bypass graft patients who had taken aspirin within the 7 days preceding surgery. Comparison of 90 cases of reoperation with 180 matched control subjects gave an estimated odds ratio for reoperation of 1.82 (95% confidence interval, 1.23 to 3.32). Although their preoperative coagulation values were similar, cases used significantly more whole blood (cases, 9.5 +/- 5.2 units; control subjects, 3.0 +/- 2.0 units; median +/- interquartile range), packed red blood cells (cases, 2.1 +/- 4.0 units; control subjects, 0.9 +/- 2.0 units), and platelets (cases, 12.2 +/- 12.0 units; control subjects, 2.9 +/- 4.0 units) than control subjects. Cases had intensive care unit stays of 4.7 +/- 5.7 days (mean +/- SD) vs 2.1 +/- 1.9 days for control subjects and postoperative hospitalizations of 10.9 +/- 8.2 days vs 7.0 +/- 3.2 days for control subjects. We conclude that aspirin exposure within 7 days before coronary bypass surgery is associated with an increased rate of reoperation for bleeding and that reoperation is associated with large increases in transfusion requirements and intensive care unit and hospital stays.

A randomized study of carbon dioxide management during hypothermic cardiopulmonary bypass.

Eighty-six patients undergoing coronary artery bypass graft (n = 63) or intracardiac (n = 23) surgery were randomly assigned with respect to the target value for PaCO2 during cardiopulmonary bypass. In 44 patients the target PaCO2 was 40 mmHg, measured at the standard electrode temperature of 37 degrees C, while in 42 patients the target PaCO2 was 40 mmHg, corrected to the patient's rectal temperature (lowest value reached: mean 30.1, SD 1.9 degrees C). Other salient features of bypass management include use of bubble oxygenators without arterial filtration, flows of 1.8-2.4 l.min-1.m-2, mean hematocrit of 23%, and mean arterial blood pressure of approximately 70 mmHg, achieved by infusion of phenylephrine or sodium nitroprusside. Neuropsychologic function was assessed with series of tests administered on the day prior to surgery, just before discharge from the hospital (mean 8.0, SD 5.8 days postoperatively, n = 82), and again 7 months later (mean 220.7, SD 54.4 days postoperatively, n = 75). The scores at 8 days showed wide variability and generalized impairment unrelated to the PaCO2 group or to hypotension during cardiopulmonary bypass. At 7 months no significant difference was observed in neuropsychologic performance between the PaCO2 groups. Regarding cardiac outcome, there were no significant differences between groups in the appearance of new Q-waves on the electrocardiogram, the postoperative creatine kinase-MB fraction, the need for inotropic or intraaortic balloon pump support, or the length of postoperative ventilation or intensive care unit stay. These findings support the hypothesis that CO2 management during cardiopulmonary bypass at moderate hypothermia has no clinically significant effect on either neurobehavioral or cardiac outcome.

Neurobehavioral outcomes in cardiac operations. A prospective controlled study.

To assess the severity and duration of new organic brain dysfunction after cardiac operations, we used an extensive battery of neuropsychologic tests to evaluate 65 patients undergoing coronary artery bypass grafting and 25 patients undergoing intracardiac operations with cardiopulmonary bypass. Patients were tested the day before the operation, before discharge from the hospital, and approximately 7 months later. Compared to 47 nonsurgical control subjects tested at comparable time intervals, surgical subjects showed generalized impairment of neuropsychologic abilities near the time of discharge from the hospital. At follow-up testing, there was no evidence of residual impairment among the surgically treated patients as a whole. In fact, they showed greater improvement compared to initial test scores than did control subjects. However, performance of 10 patients (11%) declined on half of the neuropsychologic variables between preoperative and follow-up testing. Neurobehavioral outcome was not related to the type of operation (coronary bypass versus intracardiac), to factors of cardiopulmonary bypass (duration, aortic occlusion time, hypotension, arterial carbon dioxide tension, minimum hematocrit value, minimum temperature). The only predictor of negative outcome was advanced age. We conclude that, although neurobehavioral impairment is common during hospitalization after cardiac operations, the prognosis for eventual full recovery is favorable, although less so among the elderly.

Transdermal fentanyl for postoperative pain management. A double-blind placebo study.

A double-blind, placebo-controlled, randomized design was used to evaluate the safety and efficacy of transdermal fentanyl citrate for postoperative pain management in 42 healthy adult patients undergoing major shoulder surgery. Transdermal systems rated to deliver fentanyl citrate at a rate of 75 micrograms/h were applied to the skin immediately prior to surgery and worn for 24 hours. Patients in the active group required significantly less morphine than the placebo group during the 24-hour period that systems were in place (0.8 +/- 0.61 vs 1.3 +/- 0.64 mg/h) and for the first 12 hours after removal (0.3 +/- 0.36 vs 0.5 +/- 0.32 mg/h). The incidence of vomiting was more frequent in the active group than in the placebo group (73% vs 30%), and respiratory rate in the active group was lower than in the placebo group during the 13- to 24-hour interval of system application (14 +/- 3 vs 16 +/- 2 breaths per minute). Nevertheless, transdermal fentanyl appears to be safe and effective after orthopedic surgery in healthy adult patients.

Clinical assessment of a flow-through fluorometric blood gas monitor.

We performed an observational study to evaluate a flow-through fluorometric instrument (Gas-STAT) that continuously measures the carbon dioxide tension (PCO2), oxygen tension (PO2), and pH of blood in the cardiopulmonary bypass circuit. Setup and calibration of the instrument typically required 20 minutes. During bypass, 129 blood samples were drawn from 16 patients for comparison with conventional measurements obtained with a blood gas machine. Data for each variable, within each sensor, were analyzed by linear regression. The ranges of the standard errors of the estimate were 0.7 to 4.2 mm Hg for PCO2, 18.3 to 78.7 mm Hg for the high PO2 range, 1.4 to 7.1 mm Hg for the low PO2 range, and 0.008 to 0.049 for pH. The regression lines differed from the identity line (P less than 0.05) in at least one variable in most patients, and large deviations from the line of identity in both slope and intercept were common. Among 58 sensors evaluated, failures occurred in 5 (2.9%) of the 174 optodes, and minor leakage occurred in 2 (3.4%) of the flow-through cells. We conclude that although this flow-through fluorometric instrument is an adequate monitor of trends in blood gases during cardiopulmonary bypass, it is not accurate enough to supplant conventional laboratory measurements.

Effects of breathing 80% oxygen on water and albumin accumulation in oleic acid-injured rabbit lungs.

This study was done to determine whether breathing 80% oxygen would enhance edema formation in oleic acid (OA) lung injury. Rabbits breathed air (n = 51) or 80% oxygen (n = 51) for 1 to 7 days after OA lung injury (0.09 ml/kg iv). Control groups breathed 80% oxygen (n = 37) or room air (n = 8) without OA injury. Pulmonary vascular permeability was assessed by measuring 131I-albumin (RISA) concentration in extravascular, extracellular lung water (EVECW) relative to plasma (RISAL/RISAPL). EVECW (ml/g dry lung) was measured by 24Na, and total lung water (TLW) by wet/dry weight (g/g dry lung). Air-breathing control values were 4.53 +/- 0.25 (SD) for TLW and 0.40 +/- 0.09 for RISAL/RISAPL. In the air-breathing OA group, TLW and RISAL/RISAPL increased to 8.32 +/- 0.85 and 0.93 +/- 0.16, respectively, 2 h after OA (p less than .001) but by 24 h, were equal to air-breathing controls. TLW and RISAL/RISAPL in the oxygen treated OA group did not differ from the air breathing OA group on days 2 through 7 inclusive, suggesting that 80% oxygen had no effect on edema formation in the OA-injured lung. Breathing 80% oxygen alone, without OA injury, significantly (p less than .005) increased TLW and RISAL/RISAPL on days 5 and 6. Thus, preexisting lung injury had a protective effect against edema formation from a high fraction of inspired oxygen.