Factors Affecting the Pharmacokinetic Characteristics of Rapacuronium

Background: Rapacuronium is a new nondepolarizing muscle relaxant with rapid onset and offset. As part of a study to determine its neuromuscular effects, the authors sampled plasma sparsely to determine the influence of age, gender, and other covariates on its pharmacokinetic characteristics.

Methods: Of 181 patients receiving a single bolus dose of 0.5-2.5 mg/kg rapacuronium, 43 (aged 24-83 yr) had plasma sampled 3 or 4 times to determine plasma concentrations of rapacuronium and its metabolite, ORG9488. Pharmacokinetic analysis was performed using a population approach (mixed-effects modeling) to determine the influence of demographic characteristics and preoperative laboratory values on the pharmacokinetic parameters.

Results: Rapacuronium's weight-normalized plasma clearance was 7.03 [middle dot] (1 - 0.0507 [middle dot] (HgB - 13)) ml [middle dot] kg-1 [middle dot] min-1, where HgB is the patient's preoperative value for hemoglobin (g/100 ml); however, rapacuronium's blood clearance (11.4 +/- 1.4 ml [middle dot] kg-1 [middle dot] min-1, mean +/- SD) did not vary with hemoglobin. Rapacuronium's weight-normalized pharmacokinetic parameters were not influenced by age, gender, or other covariates examined. Plasma concentrations of ORG9488 were typically less than 14% those of rapacuronium during the initial 30 min after rapacuronium administration.     

Electroporation enhances transfection efficiency in murine cutaneous wounds

Transfection of wounds with DNA-encoding growth factors has the potential to improve healing, but current means of nonviral gene delivery are inefficient. Repeated high doses of DNA, necessary to achieve reliable gene expression, are detrimental to healing. We assessed the ability of in vivo electroporation to enhance gene expression. Full-thickness cutaneous excisional wounds were created on the dorsum of female mice. A luciferase- encoding plasmid driven by a CMV promoter was injected at the wound border. Following plasmid administration, electroporative pulses were applied to injection sites. Pulse parameters were varied over a range of voltage, duration, and number. Animals were euthanized at intervals after transfection and the luciferase activity measured. Application of electric pulses consistently increased luciferase expression. The electroporative effect was most marked at a plasmid dose of 50 micro g, where an approximate tenfold increase was seen. Six 100- micro s-duration pulses of 1750 V/cm were found to be the most effective in increasing luciferase activity. High numbers of pulses tended to be less effective than smaller numbers. This optimal electroporation regimen had no detrimental effect on wound healing. We conclude that electroporation increases the efficiency of transgene expression and may have a role in gene therapy to enhance wound healing.     

Parathyroid Autotransplantation during Total Thyroidectomy—Does the Number of Glands Transplanted Affect Outcome?

Parathyroid autotransplantation is a technique for ensuring the continued function of parathyroid tissue at the time of total thyroidectomy (TT). The aim of this study was to ascertain whether the number of parathyroids transplanted affects the incidence of temporary and permanent hypoparathyroidism. A retrospective cohort study included all patients undergoing a TT in a single unit between July 1998 and June 2003. The number of parathyroids transplanted, the final pathology, and the incidence of temporary and permanent hypoparathyroidism were documented. Fisher’s exact test was used for statistical analysis. A total of 1196 patients underwent a TT during the 5 years studied. Of these, 306 (25.6%) had no parathyroids transplanted, 650 (54.3%), 206 (17.2%), 34 (2.8%) had 1,2, or 3 glands autotransplanted, respectively. The incidence of temporary hypoparathyroidism was 9.8% for no gland transplants, 11.9%, 15.1%, and 31.4% for 1,2,and 3 gland transplants, respectively (p < 0.05). The incidence of permanent hypoparathyroidism was 0.98%, 0.77%, 0.97%, and 0%, respectively (p = NS). The incidence of temporary hypoparathyroidism was higher when surgery was performed for Graves’ disease. Temporary hypocalcemia is closely related to the number of autotransplanted parathyroids during TT. The long-term outcome is not affected by the number of parathyroids autotransplanted. A “ready selective” approach to parathyroid autotransplantation is an effective strategy for minimizing the rate of permanent hypoparathyroidism.     

Significance of Histological Response to Preoperative Chemoradiotherapy for Pancreatic Cancer

Background Neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer offers theoretical advantages over the standard approach of surgery followed by adjuvant CRT. We hypothesized that histological responses to CRT would be significant prognostic factors in patients undergoing neoadjuvant CRT followed by resection. Methods Since 1994, 193 patients with biopsy-proven pancreatic adenocarcinoma have completed neoadjuvant CRT, and 70 patients have undergone resection. Specimens were retrospectively examined by an individual pathologist for histological responses (tumor necrosis, tumor fibrosis, and residual tumor load) and immunohistochemical staining for p53 and epidermal growth factor receptor. Factors influencing overall survival were analyzed with the Kaplan-Meier (univariate) and Cox proportional hazards (multivariate) methods.Results The estimated overall survival (median±SE) in the entire group of patients undergoing resection was 23±4.2 months, with an estimated 3-year survival of 37%±6.6% and a median follow-up of 28 months. Complete histological responses occurred in 6% of patients. Overexpression of p53 was more common in patients with large residual tumor loads. Tumor necrosis was an independent negative prognostic factor, as were positive lymph nodes, a large residual tumor load, and poor tumor differentiation.Conclusions Histological response to neoadjuvant CRT—as measured by residual tumor load—may be useful as a surrogate marker for treatment efficacy. Characterization of the tumor cells that survive neoadjuvant CRT may help us to identify new or more appropriate targets for systemic therapy.     

AneuRx Device Migration: Incidence, Risk Factors, and Consequences

Success after endovascular abdominal aortic aneurysm repair (EVAR) is dependent on device positional stability. The quest for such stability has motivated different endograft designs, and the risk factors entailed remain the subject of debate. This study aims at defining the incidence, risk factors, and clinical implications of device migration after EVAR with the AneuRx® endograft. In this study we included all consecutive 109 patients submitted to primary AneuRx placement for infrarenal aortic or aortoiliac aneurysms. Preoperative computed tomography (CT) scans were reviewed for the following anatomic characteristics: neck length, diameter, angulation, calcification, and thrombus load; and sac diameter and thrombus load. Percentage of device oversizing relative to the proximal neck diameter was determined. All postoperative CT scans were reviewed, and the distance between the lowest renal artery and the craniad end of the device was measured. A 5-mm increase in such distance was considered indicative of device migration. Migration cumulative incidence was estimated by the Kaplan-Meier method, and its association with any of the preoperative anatomical characteristics was tested using Cox proportional hazards models. Median follow-up time was 9 (range, 1-31) months. Migration occurred in nine patients, corresponding to a 15.6% estimated probability of migration at 30 months (SE=5.1%). Migration was associated with the risk of proximal type I endoleak (hazard ratio=3.39, 95% confidence interval=1.46-7.87; p=0.007). This type of endoleak occurred in three of the migration-affected patients (33.3%); all of them were resolved by additional cuff placement at the proximal landing zone. No other migration-related reinterventions were performed. The only significant associations between anatomic factors and device migration probability were the protective effects of longer necks (odds ratio [OR]=0.71 for each additional 5 mm, p=0.045) and longer overlapped portions of neck and device (OR=0.56 for each additional 5 mm, p=0.003). There was a trend toward higher probability of migration among reverse-tapered necks (OR=1.75, p=0.109). Percentage of device oversizing correlated with early neck dilation (between preoperative and first postoperative diameters, correlation coefficient=0.4, p < 0.0001), but not with late neck dilatation (between first postoperative and 1.5-year scan diameters, correlation coefficient=0.29, p=0.112). There was a trend toward higher mean percentage of late dilation among migrators (11.4%, standard error of the mean [SEM] 2.6) than nonmigrators (5.7%, SEM=1) (p=0.08), but both groups had similar mean percentages of early dilation (3%, SEM=1.6%, vs. 5.5%, SEM=0.6%; p=0.365). This result indicates that device migration is not a rare event after AneuRx implantation. This phenomenon is associated with proximal type I endoleaks. Deployment of the endograft immediately below the renal arteries might help to prevent migration, since use of greater lengths of overlapped device relative to the proximal neck has a protective effect. Migration seems to be independent of the degree of device oversizing.Presented at the 29th Annual Meeting of the Peripheral Vascular Surgery Society, Anaheim, CA, June 4-5, Sergio M. Sampaio is a recipient of the Edward S. Rogers Clinical Research Fellowship in Vascular Surgery.     

A Comparison of the Intubation Conditions between Mivacurium and Rocuronium during Balanced Anesthesia

Background: Comparisons of the intubation conditions with mivacurium and rocuronium from previous reports are confounded by the use of varied induction regimens. The authors compared intubation conditions of mivacurium, rocuronium, and a placebo at 90 s and their recovery profiles during anesthesia with nitrous oxide, oxygen, and propofol.

Methods: After induction with midazolam, fentanyl, and propofol in a randomized blinded study, 100 patients received one of the following treatments: 0.25 mg/kg mivacurium in divided doses (0.15 mg/kg followed by 0.1 mg/kg 30 s later); 0.45, 0.6, 0.9, or 1.2 mg/kg rocuronium; or placebo. Evoked thumb adduction was measured throughout. Intubation was attempted 90 s after the initial dose of mivacurium and other treatment doses by a "blinded" physician. Intubating conditions were graded as excellent, good, poor, or not possible. Spontaneous recovery was studied until a 25% initial twitch height was reached. Mean arterial blood pressure and heart rate changes between groups were determined before induction through 6 min after administration of the study drugs.

Results: There were no important changes or intergroup differences in mean arterial blood pressure and heart rate. Intubation conditions were good or excellent for both mivacurium and rocuronium at the 0.9 mg/kg dose (93%) and at the 1.2 mg/kg dose (100%). Rocuronium at the 0.6 mg/kg dose was excellent in 27% of patients, whereas rocuronium at the 0.45 mg/kg dose had the least number of excellent conditions and the most poor or not possible assessments. Patients given placebo could not be intubated. Times to maximum blockade for 0.9 and 1.2 mg/kg rocuronium were the shortest. The times to 25% recovery for 0.6 mg/kg rocuronium (mean +/- SD = 27 +/- 8.6 min), 0.9 mg/kg (43.1 +/- 10.8), and 1.2 mg/kg (62.3 +/- 17.4 min) were significantly longer than were those for mivacurium (17.4 +/- 6.2 min).