Comparison of the effects of osmotic pump implantation with subcutaneous injection for administration of drugs after total body irradiation in mice.

The increasing potential for radiation exposure from nuclear accidents or terrorist activities has intensified the need to develop pharmacologic countermeasures against injury from total body irradiation (TBI). Many initial experiments to develop and test these countermeasures utilize murine irradiation models. Yet, the route of drug administration can alter the response to irradiation injury. Studies have demonstrated that cutaneous injuries can exacerbate damage from radiation, and thus surgical implantation of osmotic pumps for drug delivery could adversely affect the survival of mice following TBI. However, daily handling and injections to administer drugs could also have negative consequences. This study compared the effects of subcutaneous needlesticks with surgical implantation of osmotic pumps on morbidity and mortality in a murine model of hematopoietic acute radiation syndrome (H-ARS). C57BL/6 mice were sham irradiated or exposed to a single dose of 7.7 Gy 60Co TBI. Mice were implanted with osmotic pumps containing sterile saline seven days prior to irradiation or received needlesticks for 14 days following irradiation or received no treatment. All irradiated groups exhibited weight loss. Fewer mice with osmotic pumps survived to 30 days post irradiation (37.5%) than mice receiving needlesticks or no treatment (70% and 80%, respectively), although this difference was not statistically significant. However, mice implanted with the pump lost significantly more weight than mice that received needlesticks or no treatment. These data suggest that surgical implantation of a drug-delivery device can adversely affect the outcome in a murine model of H-ARS.

A Surgical Procedure for the Administration of Drugs to the Inner Ear in a Non-Human Primate Common Marmoset (Callithrix jacchus).

Hearing research has long been facilitated by rodent models, although in some diseases, human symptoms cannot be recapitulated. The common marmoset (Callithrix jacchus) is a small, easy-to-handle New World monkey which has a similar anatomy of the temporal bone, including the middle ear ossicular chains and inner ear to humans, than in comparison with that of rodents. Here, we report a reproducible, safe, and rational surgical approach to the cochlear round window niche for the drug delivery to the inner ear of the common marmoset. We adopted posterior tympanotomy, a procedure used clinically in human surgery, to avoid manipulation of the tympanic membrane that may cause conductive hearing loss. This surgical procedure did not lead to any significant hearing loss. This approach was possible due to the large bulla structure of the common marmoset, although the lateral semicircular canal and vertical portion of the facial nerve should be carefully considered. This surgical method allows us to perform the safe and accurate administration of drugs without hearing loss, which is of great importance in obtaining pre-clinical proof of concept for translational research.

Readmission and complications within 30 days after intrathecal baclofen pump placement.

AIM: To describe 30-day outcomes after intrathecal baclofen (ITB) pump placement in children and identify risk factors for readmission, reoperation, and perioperative complication using the National Surgical Quality Improvement Program-Pediatric (NSQIP-P) database. METHOD: Patients aged 0 to 18 years who underwent ITB pump placement (2012-2014) comprised the study cohort defined in the database. Multivariate regression analysis was performed using preoperative and perioperative data from the American College of Surgeons' NSQIP-P database. Outcomes of interest within 30 days of surgery were (1) unplanned reoperation; (2) unplanned readmission; and (3) composite postoperative event, including complication, reoperation, and/or readmission. RESULTS: We identified 423 surgeries; 246 (58.2%) patients were male, 177 (41.8%) patients were female. Median age was 12 years and 11 months. Median operative time was 70 minutes (interquartile range 56-97min). Mean length of stay was 3.8 days. The patient population had a high number of medical comorbidities. The overall readmission rate was 7.3%; mean postoperative admission date was 14.1 days after surgery. Of readmitted patients, 64.5% underwent reoperation. The most common indication for reoperation was surgical site infection. Female sex was associated with decreased risk of readmission (odds ratio [OR] 0.25, 95% confidence interval [CI] 0.09-0.65; p=0.01); American Society of Anesthesiologists Classification of greater than or equal to 3 was associated with decreased risk of unplanned return to surgery (OR 0.26, 95% CI 0.11-0.66; p=0.04); length of stay greater than or equal to 3 days at index surgery was associated with increased risk of composite 30-day perioperative event (OR 2.33, 95% CI 1.29-4.20; p=0.01). INTERPRETATION: Our data provide national perspectives on 30-day perioperative outcomes for ITB pump placement in children. Results illustrate NSQIP-P database collection methodology and highlight opportunities for quality improvement in clinical practice. WHAT THIS PAPER ADDS: Seven percent of patients who underwent intrathecal baclofen pump placement required readmission within 30 days. The most common indication for reoperation was surgical site infection.

Injury and Liability Associated with Implantable Devices for Chronic Pain.

BACKGROUND: Due to an increase in implantable device-related anesthesia pain medicine claims, the authors investigated anesthesia liability associated with these devices. METHODS: After institutional review board approval, the authors identified 148 pain medicine device claims from 1990 or later in the Anesthesia Closed Claims Project Database. Device-related damaging events included medication administration events, infections, hematomas, retained catheter fragments, cerebrospinal fluid leaks, cord or cauda equina trauma, device placed at wrong level, stimulator incorrectly programmed, delay in recognition of granuloma formation, and other issues. RESULTS: The most common devices were implantable drug delivery systems (IDDS; 64%) and spinal cord stimulators (29%). Device-related care consisted of surgical device procedures (n = 107) and IDDS maintenance (n = 41). Severity of injury was greater in IDDS maintenance claims (56% death or severe permanent injury) than in surgical device procedures (26%, P < 0.001). Death and brain damage in IDDS maintenance claims resulted from medication administration errors (n = 13; 32%); spinal cord injury resulted from delayed recognition of granuloma formation (n = 9; 22%). The most common damaging events for surgical device procedures were infections, inadequate pain relief, cord trauma, retained catheter fragments, and subcutaneous hygroma. Care was more commonly assessed as less than appropriate (78%) and payments more common (63%) in IDDS maintenance than in surgical device procedure claims (P < 0.001). CONCLUSIONS: Half of IDDS maintenance claims were associated with death or permanent severe injury, most commonly from medication errors or failure to recognize progressive neurologic deterioration. Practitioners implanting or managing devices for chronic pain should exercise caution in these areas to minimize patient harm.

The behavioural and neuropathological impact of intranigral AAV-α-synuclein is exacerbated by systemic infusion of the Parkinson's disease-associated pesticide, rotenone, in rats.

Despite the widely held belief that Parkinson's disease is caused by both underlying genetics and exposure to environmental risk factors, it is still widely modelled in preclinical models using a single genetic or neurotoxic insult. This single-insult approach has resulted in a variety of models that are limited with respect to their aetiological, construct, face and/or predictive validity. Thus, the aim of the current study was to investigate the interplay between genes and the environment as an alternative approach to modelling Parkinson's disease. To do so, rats underwent stereotaxic surgery for unilateral delivery of the Parkinson's disease-associated gene, α-synuclein, into the substantia nigra (using AAV vectors). This was followed 13 weeks later by subcutaneous implantation of an osmotic minipump delivering the Parkinson's disease-associated pesticide, rotenone (2.5mgkg(-1)day(-1) for 4 weeks). The effect of the genetic and environmental insults alone or in combination on lateralised motor performance (Corridor, Stepping and Whisker Tests), nigrostriatal integrity (tyrosine hydroxylase immunohistochemistry) and α-synucleinopathy (α-synuclein immunohistochemistry) was assessed. We found that exposing AAV-α-synuclein-treated rats to rotenone led to a model in which the classical Parkinson's disease triad of progressive motor dysfunction, nigrostriatal neurodegeneration and α-synucleinopathy was evident. However, delivering rotenone systemically was also associated with bilateral motor dysfunction and loss of body weight. Thus, although we have shown that Parkinson's disease can be modelled in experimental animals by combined exposure to both genetic and environmental risk factors, this approach is limited by systemic toxicity of the pesticide rotenone. Direct intracerebral delivery of rotenone may be more useful in longer-term studies as we have previously shown that it overcomes this limitation.

Orthopedic surgery in children with intrathecal baclofen pumps.

AIMS: Children with cerebral palsy often have severe spasticity leading to deformity that requires multiple orthopedic surgeries. Intrathecal baclofen pump implantation effectively decreases severe spasticity. The objective of this study was to determine whether children who have a baclofen pump implanted at a young age have fewer orthopedic surgeries than those who have a baclofen pump implanted at later ages. METHODS: In this retrospective study of 310 children, we compared occurrence of surgery in relation to having or not having the baclofen pump, by using survival analysis with surgery as the outcome, presence of baclofen pump as the exposure of interest, modeled as a time-dependent variable, and age as the time scale. RESULTS: There was no significant effect of pump placement on overall surgery frequency. Analyses by type of surgery showed that those without a pump in place had a 64% lower hazard of scoliosis surgery. CONCLUSIONS: No evidence was found to indicate that children who have a baclofen pump implanted at a young age have fewer orthopedic surgeries than those who have a baclofen pump implanted at later ages.

Vascular response to zotarolimus-coated balloons in injured superficial femoral arteries of the familial hypercholesterolemic Swine.

BACKGROUND: Drug-coated balloons are rapidly emerging as a therapeutic alternative for the interventional treatment of peripheral vascular disease. The purpose of this study was to test the hypothesis that an angioplasty balloon coated with the mTOR inhibitor zotarolimus (ZCB) would inhibit neointimal hyperplasia in a novel injury-based superficial femoral artery model in the familial hypercholesterolemic swine. METHODS AND RESULTS: A total of 44 familial hypercholesterolemic swine were included (12 designated to study tissue pharmacokinetics and 32 to study safety and efficacy). Fogarty balloon denudation was performed in all superficial femoral artery segments, followed by balloon angioplasty. In the pharmacokinetic study, a total of 24 ZCBs (300 µg/cm(2)) were used. Zotarolimus was detected in arterial tissue at 5 minutes (162 ng/mg of tissue), 24 hours (5.9 ng/mg of tissue), and 28 days (0.007 ng/mg of tissue) after ZCB inflation. In the safety and efficacy study, superficial femoral artery segments were randomized to either high-dose (600 µg/cm(2), n=16), low-dose (300 µg/cm(2), n=16), or paired uncoated balloons (high-dose ZCB control, n=16; low-dose ZCB control, n=16). At 28 days, the percentage of angiographic stenosis was similar among all tested groups. Histological analysis demonstrated a reduction in neointimal formation in both ZCB groups compared with controls (high-dose ZCB 44% reduction, P=0.007; low-dose ZCB 22% reduction, P=0.08). There was no evidence of delayed arterial healing or vascular toxicity in any of the ZCB groups. CONCLUSIONS: The single delivery of zotarolimus via coated balloon is feasible, and therapeutic levels are maintained up to 28 days. The ZCB technology appears to be effective in the reduction of neointimal proliferation in the superficial femoral artery of the familial hypercholesterolemic swine.

Increased use of percutaneous technique for totally implantable venous access devices. Is it real progress? A 27-year comprehensive review on early complications.

BACKGROUND: First implantation of a totally implantable venous access device (TIVAD) was performed in 1982 with surgical technique. Since then, these devices have permitted infusion of total parenteral nutrition, antibiotics, blood products, and, above all, they have definitively changed the quality of life of patients with cancer. However, with the increase of percutaneous procedures, we have assisted with a concomitant raise of immediate postprocedural life-threatening complications. The aim of this study was to review the literature during a 27-year period, with regard to the changes of incidence of immediate complications after percutaneous or surgical cutdown for TIVAD's implant. MATERIALS AND METHODS: An extensive search of relevant literature was carried out by using MEDLINE (PubMed) and Google Scholar. We gathered articles from 1982 to 2009 that quoted patient's number, type of pathology, specialist involved, number of devices implanted, site and technique of implantation (surgical cutdown or percutaneous technique), and immediate complications occurrence. RESULTS: A total of 952 reports were screened, and finally only 45 articles addressing all inclusion criteria were used for the present study. A total of 11,430 TIVADs implanted in 11,381 patients were analyzed. Pneumothorax, hemothorax, arterial puncture, and hemoptysis developed only after percutaneous procedures. Atrial fibrillation, hematomas, and malpositioning were more frequent after percutaneous approach. The total amount of immediate complications in patients submitted to percutaneous implant was 4.5%, compared with 0.9% subsequent to cutdown technique. CONCLUSIONS: Despite the increased use of percutaneous technique for TIVADs' implantation, surgical cutdown, because of its safety, remains the best approach to avoid possible fatal immediate complications.

[Methods of correcting hepatic arterial blood supply for subsequent implantation of the "port-catheter" infusion system].

The study was undertaken to investigate the feasibility of using surgical and roentgenoendovascular redistribution of the hepatic arterial blood flow for adequate implantation of the "port-catheter" infusion system. Between December 2001 and March 2008, we performed surgical (n = 25) or transcutaneous (n = 22) implantations of the infusion systems for carrying out regional chemotherapy in a total of forty-seven patients presenting with hepatic metastases of colorectal carcinoma. Anatomical variants of the hepatic arteries were observed in eleven cases. The blood stream was corrected by means of either transcatheter embolization (n = 7), ligation (n = 2), or transposition (n = 2) of the aberrant arteries. No complications were encountered. In all the cases, the "port-catheter" system was implanted successfully, with adequate hepatic perfusion achieved. Both transcatheter embolization and surgical reconstruction turned out to be efficient methods in correction of the blood flow in various anatomical structures of the hepatic arteries, thus favourably contributing to increased efficacy of regional chemotherapy.

Practice choices and challenges in the current intrathecal therapy environment: an online survey.

OBJECTIVE: The objective of this study was to evaluate current practice characteristics, treatment choices, clinical experiences, and economic concerns associated with intrathecal therapy. DESIGN: Health care professionals in the United States, who were known to actively use intrathecal therapy in their practices, were recruited to participate in an online survey; contact information was obtained via Internet searches, university Websites, association memberships, industry databases, and personal contacts. Survey responses were summarized descriptively. RESULTS: Of the 329 practitioners who were contacted, 87 participated in the survey. Most participants specialized in anesthesiology (77.0%), worked in a private practice or private hospital (74.7%), and had been practicing pain management for more than 10 years (64.4%). Morphine was the most frequently used opioid for the initiation of intrathecal therapy (80.7% of practitioners), and 81.9% had used ziconotide in their practice. Most practitioners (63.9%) had treated at least one patient who developed a granuloma, and 66.0% of those practitioners had a patient experience permanent or temporary neurological injury due to a granuloma. Fewer than half of practitioners were satisfied with reimbursement from private insurance companies (25.3%) or workers compensation (34.9%), and 90.5% believed reimbursement rates for filling, refilling, and programming patient pumps are not adequate to cover practice costs. The majority of practitioners (56.6%) use fewer pumps in their practices because of reimbursement issues. CONCLUSIONS: Intrathecal pain management practices continue to evolve as the options for treatment increase, and the body of applicable scientific literature grows; however, economic considerations can influence clinical decisions and may interfere with treatment choice and patient access to therapy.

Survey of the practice of spinal cord stimulators and intrathecal analgesic delivery implants for management of pain in Canada.

BACKGROUND: In 2006, the Canadian Neuromodulation Society was formed. The present survey characterizes the practice of spinal cord stimulator (SCS) and intrathecal analgesic delivery pump (IADP) implantation for pain management in different centres across Canada. METHOD: A structured questionnaire was designed to examine the funding source, infrastructure and patient screening process in different centres implanting SCSs and IADPs. Centres that performed more than 10 implants per year were surveyed. The survey was centre-based, ie, each centre received one questionnaire regardless of the number of staff involved in neuromodulation practice. RESULTS: Fourteen centres were identified and 13 responded. Implantation of SCS and IADP was performed in 12 and 10 centres, respectively. In most centres, failed back surgery syndrome was the most frequent indication for SCS and IADP implantation. For SCS, all centres always performed a trial; the majority used percutaneous electrode (83%) before the SCS implantation. Routine psychological screening was performed in 25% of centres before any SCS trial procedure. For IADP, all centres performed a trial injection or infusion before implantation. Five centres (50%) performed psychological screening in almost all patients. Continuous infusion techniques were the most popular (50%) used for the trial. CONCLUSION: The present survey provides a 'snapshot' of the practice of SCS and IADP implantation in Canada. A review of SCS and IADP trials indicated that Canadian practices are mostly, but not always, consistent with those elsewhere.

Intrathecal opioid treatment for chronic non-malignant pain: a 3-year prospective study.

Intrathecal (IT) opioid therapy is a treatment alternative for patients with severe chronic non-malignant pain. Several uncontrolled retrospective and prospective outcome studies have suggested a benefit in chronic non-malignant pain patients, but uncertainties about patient selection in these studies weaken the results. This study evaluated long-term outcome of IT opioid therapy in chronic non-malignant pain prospectively, and included two comparative groups to improve understanding of selection criteria and relative severity of intrathecal pump recipients (PRs). The study subjects included 38 PRs while the comparative groups included 31 intrathecal candidates who either had an unsuccessful trial, or declined the IT therapy, and another group of 41 newly referred patients. The following data were analyzed at study entry, and at 6 monthly intervals for a 3-year period: Symptom Check List 90 (SLC-90), SF-36 Health survey, Beck Depression Inventory, McGill Pain Questionnaire (short form), Oswestry Disability Index, Pain Drawings and Pain rating on visual analogue scale. Data analysis suggests the study group of PRs had improvements in pain, mood, and function from baseline to 36 months. These same parameters improved among new referrals (less severe patients receiving conservative pain management) while non-recipients significantly worsened. Although PRs improved, they were still worse off at 36 months than new referrals were at baseline. The study showed that when patients with extremely severe pain problems are selected as pump candidates, they will likely improve with the therapy, but their overall severity of pain and symptoms still remains high.

Interventional approach to cancer pain.

Cancer pain is a significant problem despite the advent of the World Health Organization's cancer pain guidelines, the US government's cancer pain guidelines, and the Joint Commission's mandate for hospital pain evaluation and treatment. Ninety percent of patients with cancer pain can be effectively treated with oral conservative medications. The remaining 10% need more invasive treatments to control their pain. This article reviews current methods of controlling cancer pain using intrathecal catheters, nerve blocks, and neurosurgical procedures.

[Home anti-cancer chemotherapy with continuous infusion of 5-FU combined with low-dose cisplatin injection via implantable venous port with portable balloon pump].

Home anti-cancer chemotherapy was performed for patients with advanced cancer of the digestive plantable venous port placed beneath the skin via the subclavian vein. 128 patients under 75 years old (enrolled: 6 patients with esophageal, 65 with gastric, 44 with colorectal, 5 with cholangio, 5 with pancreatic, one with hepatic and one with ileal cancer) were treated. Continuous intravenous infusion of 5-FU (300-400 mg/body/day) combined with low-dose injection of cisplatin (5 mg/body/day) was continued for 10 days, and repeated 3 times for 6 weeks. The response rate was 23.6% in 72 patients with valuation of tumor mass. In 83 patients for whom a tumor marker evaluation was also performed, an effect was seen in 30.1%. No severe side effects such as renal dysfunction were observed, and no special infusions were needed. Therefore, a quality of life was maintained in which bathing was possible and patients were released from the hospital. Hyperalimentation through the venous port, and palliation during the terminal stage, is easily accomplished. It is useful method for surgery, chemotherapy and palliative therapy in the treatment of cancer.

Surgical experience with implantable insulin pumps. Department of Veterans Affairs Implantable Insulin Pump Study Group.

BACKGROUND: A recent Veterans Affairs cooperative trial demonstrated that intensive insulin therapy via an implantable pump with intraperitoneal insulin delivery reduced glycemic variability and improved quality of life compared with multiple daily insulin injections. Our aim was to determine perioperative morbidity and assess long-term function of the implantable insulin pump. METHODS: Fifty-one adult patients with type 2 diabetes had infusion pumps placed over a 2-year period at seven VA Medical Centers as part of a randomized prospective study. RESULTS: All pumps were placed successfully. There were two (4%) perioperative complications. There were no wound complications. Duration of pump use ranged from 12 to 25 months (mean 20). Catheter obstruction (57%) and pump malfunction (25%) were the most common reasons for pump explantation. Catheter occlusions increased after 12 months. Catheter occlusion was treated by percutaneous rinse procedure in 75% and revisional procedures in 31% of patients. CONCLUSIONS: Implantable insulin pumps can be placed with minimal surgical morbidity. Attention to surgical detail and infusion protocol permits satisfactory long-term function. Pump/catheter complications increase with time but are usually resolvable by either operative or percutaneous manipulations.