Increased stress associated with head-out plethysmography testing can exacerbate respiratory effects and lead to mortality in rats.

INTRODUCTION: DSM421, a dihydroorotate dehydrogenase inhibitor, was in preclinical development as a potential treatment option for malaria. When tested in a core battery of safety pharmacology assays, DSM421 did not produce any effects at oral doses up to 750 mg/kg in an Irwin test in rats, but a respiratory study in rats using head-out plethysmography resulted in substantial changes in respiratory function as well as moribundity and mortality at that and lower doses. An investigation was performed to determine the source of this discrepancy. METHODS: Potential testing errors, differences in types of plethysmography testing chambers, effects on stress indicators, and off-target activity were investigated. RESULTS: Respiratory changes and toxicity (resulting in euthanasia in extremis) were confirmed in a repeat, head-out plethysmography test, but the effects of DSM421 were much less severe overall when the rats were tested in whole-body chambers. Additionally, at the end of the 5-h post-dosing respiratory monitoring periods, levels of stress-related hormones (particularly corticosterone) were higher overall in the head-out, than in the whole-body, tested rats. Furthermore, DSM421 was found to produce changes in cardiovascular function in unrestrained rats, and it was shown to have off-target binding affinity at the adenosine A3 receptor (which is associated with bronchoconstriction). DISCUSSION: The generalized stress inherent to head-out plethysmography testing exacerbated the respiratory effects of DSM421 and was possibly compounded by DSM421's cardiovascular effects, thus artifactually resulting in moribundity and mortality in rats. Care should be taken when choosing whether to use head-out versus whole-body plethysmography chambers during respiratory function testing in animals.

Preclinical abuse liability assessment of ABT-126, an agonist at the α7 nicotinic acetylcholine receptor (nAChR).

ABT-126 is a nicotinic acetylcholine receptor (nAChR) agonist that is selective for the α7 subtype of the receptor. nAChRs are thought to play a role in a variety of neurocognitive processes and have been a pharmacologic target for disorders with cognitive impairment, including schizophrenia and Alzheimer's disease. As part of the preclinical safety package for ABT-126, its potential for abuse was assessed. While the involvement of the α4ß2 subtype of the nicotinic receptor in the addictive properties of nicotine has been demonstrated, the role of the α7 receptor has been studied much less extensively. A number of preclinical assays of abuse potential including open-field, drug discrimination and self-administration were employed in male rats. ABT-126 had modest effects on locomotor activity in the open-field assay. In nicotine and d-amphetamine drug discrimination assays, ABT-126 administration failed to produce appreciable d-amphetamine-like or nicotine-like responding, suggesting that its interoceptive effects are distinct from those of these drugs of abuse. In rats trained to self-administer cocaine, substitution with ABT-126 was similar to substitution with saline, indicating that it lacks reinforcing effects. No evidence of physical dependence was noted following subchronic administration. Overall, these data suggest that ABT-126 has a low potential for abuse. Together with other literature on this drug class, it appears that drugs that selectively activate α7 nAChRs are not likely to result in abuse or dependence.

Robotic mitral valve repair: a review of anesthetic management of the first 200 patients.

OBJECTIVE: The aim of this study was to describe the evolution in anesthetic technique used for the first 200 patients undergoing robotic mitral valve surgery. DESIGN: A retrospective review. SETTING: A single tertiary referral academic hospital. PARTICIPANTS: Two hundred consecutive patients undergoing robotic mitral valve surgery using the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA) at Mayo Clinic Rochester. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: After obtaining institutional review board approval, surgical and anesthetic data were recorded. For analysis, patients were placed in 4 groups, each containing 50 consecutive patients, labeled Quartiles 1 to 4. Over time, there were statistically significant decreases in cardiopulmonary bypass and aortic cross-clamp times. Significant differences in the anesthetic management were shown, with a reduction of intraoperative fentanyl and midazolam doses, and the introduction of paravertebral blockade in Quartile 2. There was a reduction of time between incision closure and extubation, and nearly 90% of patients were extubated in the operating room in Quartiles 3 and 4. Despite changes to the intraoperative analgesic management, and focus on earlier extubation, there were no differences seen in visual analog scale (VAS) pain scores over the 4 quartiles. Reductions were seen in total intensive care unit and hospital length of stay during the study period. CONCLUSIONS: Changes to the practice, including efforts to limit intraoperative opioid administration and the addition of preoperative paravertebral blockade, helped facilitate earlier extubation. In the second half of the study period, close to 90% of patients were extubated in the operating room safely and without delaying patient transition to the intensive care unit.

The incidence of vasoplegia in adult patients with right-sided congenital heart defects undergoing cardiac surgery and the correlation with serum vasopressin concentrations.

BACKGROUND: In adults with right-sided congenital heart disease, vasoplegia during and after cardiopulmonary bypass appears to be a frequent complication. The incidence of vasoplegia in the general adult and pediatric cardiac surgical population has been investigated, but the incidence in adult patients with right-sided congenital heart disease is unknown. Perioperative vasopressin levels during cardiac surgery have been studied in other cardiac surgical patients, but are not known in adults with right-sided congenital heart disease. The purpose of this study was to investigate the incidence of vasoplegia in adult patients undergoing right-sided cardiac surgical procedures requiring cardiopulmonary bypass and to determine the vasopressin response to cardiac surgery in this population. METHODS: Twenty patients were enrolled and demographic, hemodynamic, cardiopulmonary bypass, and use of vasoactive medication data were collected. In addition, perioperative serum vasopressin levels were measured. Sixty adult patients undergoing left-sided cardiac surgery served as controls. RESULTS: The incidence of vasoplegia in the control patients was 10% and the incidence in the adult patients with right-sided congenital heart disease was 20%. Vasopressin levels were low at baseline (0.5 ± 0.5 pg/mL), increased slightly after induction of anesthesia (0.6 ± 0.6 pg/mL), increased after initiation of cardiopulmonary bypass (99.7 ± 168.2 pg/mL), and decreased after surgery (31.3 ± 43.6 pg/mL). CONCLUSIONS: This study showed that the incidence of vasoplegia (20%) in patients with right-sided congenital heart disease undergoing cardiac surgery was double that of a population of patients undergoing aortic valve surgery (10%). Serum vasopressin concentration was not associated with vasoplegia in this population of congenital cardiac surgical patients.

Simulation-based postcardiotomy extracorporeal membrane oxygenation crisis training for thoracic surgery residents.

BACKGROUND: We developed and tested a clinical simulation program in the principles and conduct of postcardiotomy extracorporeal membrane oxygenation (ECMO) with the aim of improving confidence, proficiency, and crisis management. METHODS: Twenty-three thoracic surgery residents from unique residency programs participated in an ECMO course involving didactic lectures and hands-on simulation. A current postcardiotomy ECMO circuit was used in a simulation center to give residents training with basic operations and crisis management. Pretraining and posttraining assessments concerning confidence and knowledge were administered. Before and after the training, residents were asked to identify components of the ECMO circuit and manage crisis scenarios, including venous line collapse, arterial hypertension, and arterial desaturation. RESULTS: In the hands-on portion, residents had difficulty identifying the gas source and flow rate, centrifugal pump head inlet, and oxygenator outflow line. Timely and accurate ECMO component identification improved significantly after training. The arterial desaturation crisis scenario gave the residents difficulty, with only 22% providing the appropriate treatment recommendations in a timely and accurate fashion. At the end of the simulation training, most residents were able to manage the crises correctly in a timely manner. Posttraining confidence-related scores increased significantly. Most of the residents strongly recommended the course to their peers and reported simulation-based training was helpful in their postcardiotomy ECMO education. CONCLUSIONS: We developed a simulation-based postcardiotomy ECMO training program that resulted in improved ECMO confidence in thoracic surgery residents. Crisis management in a simulated environment enabled residents to acquire technical and behavioral skills that are important in managing critical ECMO-related problems.

Coronary artery spasm after Cryo Maze III procedure.

The Cox Maze III procedure has been simplified with the availability of tissue ablation devices; however, complications related to their use are recognized. We report a case of 45-year-old woman who underwent mitral valve repair and concomitant Cryo-Maze procedure. She had reversible right coronary artery spasm develop after the procedure demonstrated by ST-segment elevation changes and coronary angiography, which was reversed with intracoronary nitroglycerin. The region of spasm suggested it as a consequence of proximity of the right coronary artery to the right atrial ablation lines.

Use of paravertebral blockade to facilitate early extubation after minimally invasive cardiac surgery.

We retrospectively reviewed the first 14 patients who received preoperative paravertebral blockade prior to minimally invasive cardiac surgical procedures. The use of paravertebral blockade along with an anesthetic technique designed to facilitate rapid recovery allowed early extubation in the operating room or intensive care unit in all but one patient. Extubated patients leaving the operating room were comfortable. No postoperative respiratory complications occurred.

Clinical application of a novel video camera laryngoscope: a case series venturing beyond the normal airway.

The McGRATH Video Laryngoscope Series 5 is an example of indirect laryngoscopic equipment. Experience using this device to safely intubate the trachea of awake and asleep patients with known or anticipated difficult airways is presented.

The successful application of simulation-based training in thoracic surgery residency.

OBJECTIVE: We developed and tested a clinical simulation program in the principles and conduct of cardiopulmonary bypass with the aim of improving confidence and proficiency in this critical aspect of cardiac surgical care. METHODS: Fifteen residents from 6 resident-training programs who reported no prior cardiopulmonary bypass observation or simulation-based perfusion experience participated in a cardiopulmonary bypass course involving both didactic lectures and hands-on simulation. A computer-controlled hydraulic model of the human circulation was used in a specifically designed multidisciplinary simulation center environment to give the participants hands-on training with both basic operations and specific perfusion crisis scenarios. Pretraining and posttraining assessments concerning confidence, knowledge, and applications with regard to cardiopulmonary bypass were administered and compared. RESULTS: Likert scale scores on confidence-related items increased significantly (P < .001), from 59% +/- 16% to 92% +/- 8%. Pretraining versus posttraining scores (72% +/- 14%) on similar cognitive items were not significantly different (P=.3636). Scores on similar open-ended application items before and after training improved from 62% +/- 25% to 85+/-10% (P < .0001). All subjects agreed that simulation-based cardiopulmonary bypass training was superior to classroom- and clinic-based education and that the scenarios enhanced their learning experience. CONCLUSIONS: Simulation-based cardiopulmonary bypass training appears to be an effective technique to build the confidence of thoracic surgery residents regarding knowledge and applications. Scenario-based practice in a specifically designed simulated environment is a valuable adjunct to traditional educational methods and has the potential to improve the training of thoracic residents.

Magnetic resonance imaging clarity of the Bryan, Prodisc-C, Prestige LP, and PCM cervical arthroplasty devices.

STUDY DESIGN: Prospective, randomized, controlled and double-blinded study on imaging of artificial discs. OBJECTIVE: The purpose of this study is to compare postoperative imaging characteristics of the 4 currently available cervical arthroplasty devices at the level of implantation and at adjacent levels. SUMMARY OF BACKGROUND DATA: Cervical arthroplasty is being performed increasingly frequently for degenerative disc disease and, in most cases, with frank neural compression. Unlike lumbar arthroplasty, performed mainly for axial back pain, decompression of neural elements may need to be confirmed with postoperative imaging after cervical arthroplasty. METHODS: Preoperative and postoperative magnetic resonance imaging scans of 20 patients who had undergone cervical arthroplasty were assessed for imaging quality. Five cases each of the Bryan (Medtronic Sofamor Danek, Memphis, TN), Prodisc-C (Synthes Spine, Paoli, PA), Prestige LP (Medtronic Sofamor Danek), and PCM devices (Cervitech, Rockaway, NJ) were analyzed. Six blinded spinal surgeons scored twice sagittal and axial T2-weighted images using the Jarvik 4-point scale. Statistical analysis was performed comparing quality before surgery and after disc implantation at the operated and adjacent levels and between implant types. RESULTS.: Moderate intraobserver and interobserver reliability was noted. Preoperative images of patients in all implant groups had high-quality images at operative and adjacent levels. The Bryan and Prestige LP devices allowed satisfactory visualization of the canal, exit foramina, cord, and adjacent levels after arthroplasty. Visualization was significantly impaired in all PCM and Prodisc-C cases at the operated level in both the spinal canal and neural foramina. At the adjacent levels, image quality was statistically poorer in the PCM and Prodisc-C than those of Prestige LP or Bryan. CONCLUSIONS.: Postoperative visualization of neural structures and adjacent levels after cervical arthroplasty is variable among current available devices. Devices containing nontitanium metals (cobalt-chrome-molybdenum alloys in the PCM and Prodisc-C) prevent accurate postoperative assessment with magnetic resonance imaging at the surgical and adjacent levels. Titanium devices, with or without polyethylene (Bryan disc or Prestige LP), allow for satisfactory monitoring of the adjacent and operated levels. This information is crucial for any surgeon who wishes to assess adequacy of neural decompression and where monitoring of adjacent levels is desired.

Synovial cysts of the thoracic spine.

OBJECT: Thoracic synovial cysts (TSCs) are rare and are usually the subject of case reports. The authors studied the clinical manifestations, radiological aspects, and surgical treatment in a series of patients at their institution who harbored TSCs. They also review the literature to discuss the potential factors involved in the pathogenesis of this lesion. METHODS: A database search of 16,000 patients who underwent decompressive spine surgery at the Mayo Clinic (Rochester, MN) between 1976 and 2003 disclosed nine patients (0.06%) in whom a diagnosis of TSC had been made. All patients were men. The mean age at presentation was 73 +/- 5 years and mean duration of symptoms was 5 +/- 3 months. The mean duration of follow up was 4 +/- 3 years. The patients had no history of trauma or spine surgery. All patients had spastic paraparesis; two had urinary difficulties. Detailed neurological examination revealed myelopathy and radiculopathy with a sensory level of T10-L4. Magnetic resonance imaging revealed bilateral cysts in four patients and unilateral lesions in five. Three of the cysts were at the T-10 interspace, seven at the T-11 interspace, and three at the T-12 interspace. Seven cysts were on the right and six were on the left. Computerized tomography myelography performed in five patients revealed a gas bubble in the TSC in two patients. All patients underwent laminectomy/partial facetectomy, excision of the cyst, and decompression of the thecal sac and nerve root without any complications. None of these patients underwent a fusion. Eight patients (89%) experienced moderate to excellent relief of their preoperative signs and symptoms and one patient (11%) remained stable. There was no evidence of cyst recurrence at the site of surgery or other spinal segments at follow-up examination in any patient. CONCLUSIONS: When compared with their lumbar and cervical spine counterparts, TSCs are exceedingly rare. Their rarity may be explained by the decreased mobility of the thoracic spinal segments. The origin of TSCs is more likely degenerative rather than traumatic. Based on their experience and the follow-up duration, surgery provided durable relief from symptoms.

Attenuation of mechanical allodynia by clinically utilized drugs in a rat chemotherapy-induced neuropathic pain model.

Chemotherapy-induced peripheral neuropathy is a common, dose-limiting side effect of cancer chemotherapeutic agents, including the vinca alkaloids such as vincristine. The resulting symptoms, which frequently include moderate to severe pain, can often be disabling. The current study utilized a vincristine-induced neuropathic pain animal model [Pain 93 (2001) 69], in which rats were surgically implanted with mini-osmotic pumps set to deliver vincristine sulfate (30 microg kg(-1)day(-1), i.v.), to examine the time course of progression of various pain modalities and to compare the dose-response effects of clinically utilized drugs on mechanical allodynia to further validate the relevance of this model to clinical pathology. Vincristine infusion resulted in significant cold allodynia after 1 week post-infusion, however mechanical and thermal nociception showed little to no effect. In contrast, marked mechanical allodynia occurred by 1 week of vincristine infusion and returned nearly to pre-infusion levels by the 4th week after infusion pump implantation. ED(50) values (micromol/kg, p.o.) were determined in the mechanical allodynia assay for lamotrigine (82), dextromethorphan (94), gabapentin (400), acetaminophen (1100) and carbamazepine (3600); however, aspirin and ibuprofen had no effects up to 300 and 1000 micromol/kg, respectively. Additionally, ED(50) values (micromol/kg, i.p.) were determined in the mechanical allodynia assay for clonidine (0.35) and morphine (0.62), but desipramine and celecoxib had no effects up to 66 and 260 micromol/kg, respectively. Findings from the current, preclinical study further validate this model as clinically relevant for chemotherapy-induced pain. The surprisingly good effects observed with acetaminophen warrant further investigation of its mechanism(s) of action in neuropathic pain.

K-ATP opener-mediated attenuation of spontaneous bladder contractions in ligature-intact, partial bladder outlet obstructed rats.

Symptoms of urinary frequency and urgency secondary to benign prostatic obstruction are common in elderly men. In many patients, these symptoms correspond to the urodynamic finding of involuntary detrusor contractions during filling cystometry (i.e., detrusor instability). Spontaneous non-voiding contractions during filling can be modeled in animals by subchronic, partial urethral obstruction. However, many investigators remove the obstructive ligature a few days prior to cystometrical evaluation (which may not be an ideal representation of the clinical situation where obstruction is still present), and all perform cystometry within 3 days post-bladder catheterization surgery (i.e., while considerable wound healing is present). In the current study, we evaluated the effects, after oral dosing, of three structurally diverse ATP-sensitive potassium channel openers (KCOs) on spontaneous contractions secondary to obstruction in rats with an intact obstructive ligature at the time of testing and 2 weeks post-bladder catheterization. ZD6169, WAY-133537 and a novel dihydropyridine KCO, A-278637, all significantly decreased spontaneous bladder contractions at 30 min post-dosing (p.o.). However, only ZD6169 (10 micromol/kg) and A-278637 (3 micromol/kg) attenuated such bladder contractions at doses that did not concurrently, significantly affect mean arterial blood pressure and heart rate. These data confirm the efficacy of KCOs to inhibit unstable contractions in obstructed rats, and they further demonstrate the positive effect of a novel, bladder-selective KCO, A-278637, in an animal model with potentially less artifact than in previous such models.

Surgical treatment of fibrous dysplasia of the skull in children.

INTRODUCTION: We evaluate the role of surgery in the treatment of fibrous dysplasia of the skull in children. METHODS: We identified 48 consecutive cases of fibrous dysplasia of the skull that were surgically treated at a single institution over a 23-year interval. The 28 patients that initially presented during the first two decades of life were selected for further analysis. Presenting symptoms, signs, surgical treatment, surgical outcome and the state of the disease at the extended follow-up interval were recorded. RESULTS: Fibrous dysplasia of the skull in children most often involved the frontal, sphenoid and ethmoid bones. Most patients presented with facial asymmetry or proptosis. A gross total resection was achieved in 7 patients, subtotal resection in 17 patients, and 4 patients underwent biopsy alone. Over the follow-up interval, 7 patients had symptomatic progression of subtotally resected fibrous dysplasia and 3 patients had asymptomatic progression. The extent of resection was correlated with recurrence risk. CONCLUSIONS: In order to prevent progression of disease, an attempt at gross total resection is indicated in cases of fibrous dysplasia of the skull in childhood where the risk of neurologic morbidity is low and cosmetic results will be acceptable.