Intrathecal Drug Delivery Research Articles

Plain radiography in patients treated with intrathecal drug delivery using an implantable pump device

ObjectivesIntrathecal drug administration using an implanted pump system is well established in intractable spasticity and pain. However, despite continuous advancements in manufacturing technology, adverse events related to the pump and catheter still occur. Most of them, such as migration, damage, disconnection and occlusion, are related to the spinal catheter. The aim of this overview is to update radiologists on how plain radiography of the implanted delivery system for intrathecal drug administration should be interpreted and to increase awareness for the need of urgent and timely multidisciplinary troubleshooting.MethodsPlain radiographic images of patients treated with intrathecal drug administration using an implantable drug delivery system were analysed in a multidisciplinary setting at our (university) referral centre for complications in intrathecal drug administration.ResultsExamples of catheter-related adverse events are described and a proposal is made for stepwise interpretation of standard plain radiographic images.ConclusionsPlain radiological images are the mainstay for the diagnosis of catheter-related adverse events in intrathecal drug delivery. Radiologists play an important role in an early diagnosis. An awareness of abnormal radiological findings seems important to avoid a life-threatening withdrawal syndrome.Teaching points• Untimely cessation of intrathecal drug delivery can lead to a life-threatening withdrawal syndrome.• Initially mild symptoms can lead to an exacerbation of a withdrawal syndrome.• Most intrathecal catheter-related problems are visible on plain radiography.• Common causes of catheter problems are migration, lacerations, occlusion and disconnection.• Knowledge on implanted intrathecal catheters is crucial for interpretation of plain radiography.

‘Was it worth it?’ Intrathecal analgesia for cancer pain: A qualitative study exploring the views of family carers

Background: Intrathecal drug delivery is known to reduce pain in patients where conventional systemic analgesia has been ineffective or intolerable. However, there is little information regarding the effects of intrathecal drug delivery on quality of life and function in those with advanced, incurable cancer. Aim: Retrospective exploration of the views of bereaved carers regarding the physical and psychosocial effects of external tunnelled intrathecal drug delivery in patients with advanced incurable cancer. Design: Thematic analysis of qualitative interviews with carers of deceased individuals who received percutaneous external tunnelled intrathecal drug delivery as part of their pain management, within two UK centres. Setting: A total of 11 carers were recruited from two UK Palliative Care centres. Family carers of adult patients who had received external tunnelled intrathecal drug delivery analgesia for cancer pain and had died between 6 and 48 months prior to contact were included. Carer relatives who were considered likely to be too vulnerable or who had lodged a complaint about treatment within the recruiting department or who had been treated directly by the interviewer were excluded. Results: In total, 11 interviews took place. The emerging themes were (1) making the decision to have the intrathecal – relatives described desperate situations with severe pain and/or sedation, meaning that the individual would try anything; (2) timing and knowing they were having the best – an increased access to pain and palliative care services, meant carers felt everything possible was being done, making the situation more bearable; (3) was it worth it? – the success of the external tunnelled intrathecal drug delivery was judged on its ability to enable the individual to be themselves through their final illness. Side effects were often considered acceptable, if the external tunnelled intrathecal drug delivery enabled improvements in quality of life. Conclusion: Carers perceived external tunnelled intrathecal drug delivery as most valuable when it improved quality of life towards the end of life, by reducing pain and side effects of conventional systemic analgesia to enable individuals ‘to be themselves’. Under these circumstances, the carers judged significant side effects to be acceptable.

6 Neurosurgical interventions in psychiatry

<i>Retired from clinical practice Jan 2014.</i> <i>Brian qualified from Cambridge University (with Part 2 in Experimental Psychology) and The London Hospital Medical College, 1973. FRCS (England) 1978. Wellcome Trust Research Fellowship – studies on functions of the dopamine systems led to MD (Cantab). Neurosurgical training at the (Royal) London Hospital, with additional special interest in functional neurosurgery. Appointed consultant neurosurgeon at University Hospital of Wales, Cardiff, 1988. Service development: surgical management of intractable pain. Service development: neurosurgery for mental disorder. President, International Neuromodulation Society, 2000–2003. Published widely on therapeutic neurostimulation.</i> <i>2016 – Senior editor, series of evidence-based guidelines on therapeutic neurostimulation and on intrathecal drug delivery.</i> The evolution of “psychosurgery”, now better referred to as Neurosurgery for Mental Disorders (NMD), will be reviewed and discussed in relation to historical context and attitudes. Key considerations for the future will be highlighted. The early history is often regarded now with embarrassment and even horror. The eminent physiologist John Fulton, whose 1935 London lecture triggered the notorious epidemic of radical and relatively indiscriminate frontal lobe surgery, had serious reservations. He knew that intellectual and affective functions could be separated anatomically and was probably the first to advocate more selective procedures, to avoid the sometimes devastating side effects. However, “lobotomy” was given impetus by the eminence of its pioneers, Moniz and Freeman, and by respected neurosurgeons elsewhere, including the UK. The socio-economic benefit of the liberation from asylums of large numbers of indefinite-stay patients for whom, it should be remembered, no drug treatment was available until 1954 (chlorpromazine; antidepressants in 1958), clearly provided great encouragement. However, Walter Freeman’s cavalier approach in the USA helped to close this first chapter. A technically much more specific approach (“Chapter 2”) became available in 1947 when stereotactic neurosurgery for humans (it had long been used in animal experiments) was introduced. Case-selection also gradually improved, moving away from treating schizophrenia and from “correcting” behaviour, towards relieving affective disorders. Anterior capsulotomy was introduced in 1951 and (stereotactic) cingulotomy in 1962. Developments continued, for example subcaudate tractotomy using yttrium⁹⁰ seeds, of which more than 1300 were performed in London from 1961 until the 1990s. There was still much opposition but when a US Congress Commission was convened in 1974, expecting to ban “psychosurgery”, the evidence of benefit and relative absence of harm was now so compelling that it won official approval. The more refined procedures have continued with demonstrable success but in relatively small numbers. Between 1993 and 2008, 55 patients underwent bilateral anterior capsulotomy in Cardiff, 45 for depression. The 24 for whom full datasets were available showed an overall improvement of 52%, with a 75% -or-more improvement in 10. There were no significant changes in executive function, attention and concentration, or immediate and delayed memory, and the adverse-effect profile showed it to be safe. However, antagonism continued to be encountered. Deep brain stimulation (DBS) for psychiatric disorders is not new but it re-emerged in 1999 as a more flexible and superficially more acceptable alternative to traditional lesioning (“Chapter 3 ”). The relative advantages and disadvantages will be discussed. The future for NMD (“Chapter 4”) for otherwise intractable cases should be exciting, with developments in imaging and other technologies and with increasing understanding of targeted conditions. However, the need to exercise great caution, along with issues of consent and regulation, are paramount. NMD is only one tool and its successful and continuing use depends heavily upon cultural attitudes.

Personalized Intrathecal Drug Delivery: Models, Targets, and Approaches.

While delivering medications through the intrathecal route can be effective for providing pain relief with fewer side effects, limited resources are available to guide selection of drug and pump settings. Understanding the contribution of variability in patient anatomy to drug delivery may be essential to optimizing intrathecal administration. In this infographic, we describe progress using in silico and in vitro simulation for determining optimal intrathecal drug delivery.1

Local delivery of chondroitinase ABC with or without stromal cell-derived factor 1α promotes functional repair in the injured rat spinal cord.

Traumatic spinal cord injury (SCI) is a devastating event for which functional recovery remains elusive. Due to the complex nature of SCI pathology, a combination treatment strategy will likely be required for success. We hypothesized that tissue and functional repair would be achieved in a rat model of impact-compression SCI by combining degradation of the glial scar, using chondroitinase ABC (ChABC), with recruitment of endogenous neural precursor cells (NPCs), using stromal cell-derived factor 1α (SDF). To test this hypothesis, we designed a crosslinked methylcellulose hydrogel (XMC) for minimally invasive, localized, and sustained intrathecal drug delivery. ChABC was released from XMC using protein-peptide affinity interactions while SDF was delivered by electrostatic affinity interactions from polymeric nanoparticles embedded in XMC. Rats with SCI were treated acutely with a combination of SDF and ChABC, SDF alone, ChABC alone, or vehicle alone, and compared to injury only. Treatment with ChABC, both alone and in combination with SDF, resulted in faster and more sustained behavioural improvement over time than other groups. The significantly reduced chondroitin sulfate proteoglycan levels and greater distribution of NPCs throughout the spinal cord tissue with ChABC delivery, both alone and in combination with SDF, may explain the improved locomotor function. Treatment with SDF alone had no apparent effect on NPC number or distribution nor synergistic effect with ChABC delivery. Thus, in this model of SCI, tissue and functional repair is attributed to ChABC.

A Contemporary Medicolegal Analysis of Implanted Devices for Chronic Pain Management.

Analysis of closed malpractice claims allows the study of rare but serious complications and likely results in improved patient safety by raising awareness of such complications. Clinical studies and closed claims analyses have previously reported on the common complications associated with intrathecal drug delivery systems (IDDS) and spinal cord stimulators (SCS). This study provides a contemporary analysis of claims from within the past 10 years. We performed a closed claims analysis for a period January 1, 2009 to December 31, 2013 for cases with pain medicine as the primary service. These cases were identified using the Controlled Risk Insurance Company (CRICO) Comparative Benchmarking System (CBS), a database containing more than 300,000 malpractice claims from more than 400 academic and community institutions, representing approximately 30% of malpractice cases in the United States. The clinical narratives, which included medical files, claims files, depositions, and expert witness testimony, were reviewed by the authors, as were the CRICO coded variables, which included algorithmically determined contributing factors to the patient injury. Intrathecal drug delivery systems represented 17 of the closed claims; spinal cord stimulators represented 11 of the closed claims. The most common chronic pain diagnoses for which a device was implanted included failed back surgery syndrome and spasticity. The average total incurred for pain medicine claims was $166,028. Damaging events included IDDS refill errors (eg, subcutaneous administration of medication, reprogramming errors), intraoperative nerve damage, and postoperative infection (eg, epidural abscess, meningitis). High-severity outcomes included nerve damage (eg, paraplegia) and death. Medium-severity outcomes included drug reactions (eg, respiratory arrest from opioid overdose) and the need for reoperation. For both IDDS and SCS, deficits in technical skill were the most common contributing factor to injury, followed by deficits in clinical judgment, communication, and documentation. Implanted devices used for pain management involve a significant risk of morbidity and mortality. Proper education of providers and patients is essential. Providers must acquire the technical skills required for the implantation and refilling of these devices and the clinical skills required for the identification and management of complications such as intrathecal granuloma. Proper patient selection and clear communication between the provider and the patient about these possible complications are of paramount importance.

A numerical investigation of intrathecal isobaric drug dispersion within the cervical subarachnoid space.

Intrathecal drug and gene vector delivery is a procedure to release a solute within the cerebrospinal fluid. This procedure is currently used in clinical practice and shows promise for treatment of several central nervous system pathologies. However, intrathecal delivery protocols and systems are not yet optimized. The aim of this study was to investigate the effects of injection parameters on solute distribution within the cervical subarachnoid space using a numerical platform. We developed a numerical model based on a patient-specific three dimensional geometry of the cervical subarachnoid space with idealized dorsal and ventral nerve roots and denticulate ligament anatomy. We considered the drug as massless particles within the flow field and with similar properties as the CSF, and we analyzed the effects of anatomy, catheter position, angle and injection flow rate on solute distribution within the cerebrospinal fluid by performing a series of numerical simulations. Results were compared quantitatively in terms of drug peak concentration, spread, accumulation rate and appearance instant over 15 seconds following the injection. Results indicated that solute distribution within the cervical spine was altered by all parameters investigated within the time range analyzed following the injection. The presence of spinal cord nerve roots and denticulate ligaments increased drug spread by 60% compared to simulations without these anatomical features. Catheter position and angle were both found to alter spread rate up to 86%, and catheter flow rate altered drug peak concentration up to 78%. The presented numerical platform fills a first gap towards the realization of a tool to parametrically assess and optimize intrathecal drug and gene vector delivery protocols and systems. Further investigation is needed to analyze drug spread over a longer clinically relevant time frame.

Bleeding Complications in Patients Undergoing Intrathecal Drug Delivery System Implantation.

Intrathecal drug delivery systems (IDDSs) have dramatically improved analgesia and the functional status of cancer patients and those with chronic pain states. However, given the close proximity to the neuraxis and frequent concomitant use of antiplatelet or anticoagulant medications, this intervention is not without risk. The goal of this investigation was to determine the incidence of bleeding complications following IDDS placement. This is a retrospective review from 2005 through 2014 of adult patients undergoing IDDS implantation or revision at a tertiary care center. The primary outcome was a bleeding-related neurological complication requiring emergency medicine, neurology, or neurosurgical evaluation within 31 days. A total of 247 procedures were performed on 216 unique patients. Patients received aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs) within seven days of needle placement for 64 procedures (25.9%). A preprocedural platelet count or international normalized ratio (INR) was available within 30 days for 138 procedures (55.9%). Of these, two patients had a platelet count lower than 100 x 109/L and one patient had an INR of 1.5 or higher at the time of the procedure. One neurological complication was identified (0.4%) that was not related to procedural bleeding. Similarly, three patients (1.2%) received a periprocedural red blood cell transfusion, none of which were related to procedural bleeding. No cases of bleeding-related neurological complications were identified following IDDS placement or revision, including in those receiving aspirin or NSAIDs. Future investigations with larger numbers are needed to further explore the safety of antithrombotic therapy continuation or discontinuation periprocedurally.

Evaluation of intrathecal drug delivery system for intractable pain in advanced malignancies

Pain is prevalent in advanced malignancies; however, some patients cannot get adequate pain relief by conservative routes of analgesic administration or experience serious side effects related to high dose of opioids. For those who have exhausted multimodal conservative analgesic, intrathecal drug delivery is an alternative intervention for truly effective pain management. The objective of this study was to evaluate the clinical efficacy and safety of intrathecal drug delivery system (IDDS) for the treatment of intractable pain in advanced cancer patients.A prospective cohort study was performed between July 2015 and October 2016. Fifty-three patients undergoing intractable cancer-related pain or intolerable drug-related adverse effects were recruited and received IDDS therapy with a patient-controlled intrathecal analgesia pump. The assessment was conducted during admission, in titration period, and followed up monthly to death by scheduled refill visits. Pain numeric rating scale scores, comprehensive toxicity scores, quality of life scores, systemic opioid use (basal and breakthrough dose), intrathecal morphine use (basal and patient-controlled intrathecal analgesia dose), and complications were recorded to evaluate the curative effect and safety.Between baseline and all subsequent follow-ups, statistically significant decreases in pain numeric rating scale scores and comprehensive toxicity scores were verified. A statistical improvement in quality of life scores was found after starting IDDS therapy. Both basal and breakthrough doses of systemic opioid showed a significant decrease during the follow-up period. And there was a modest escalation in the intrathecal morphine dose throughout the duration of study. No infective, device-related, and catheter-related complications were observed.The findings showed that IDDS therapy allowed for rapid and highly effective pain relief with less toxicity in comparison to conservative medications. Patients with advanced malignancies would also benefit from an improvement in the life quality after the procedure. IDDS therapy represented a valuable option for intractable cancer-related pain management.

Cerebrospinal Fluid Leak Presenting with Radiculitis and Delayed Onset Headache Following Intrathecal Pump Implantation

The issue of cerebrospinal fluid (CSF) leak due to catheter-related failure persists despite new approaches to surgical techniques. There is limited literature about atypical presentations of post dural puncture headaches post intrathecal drug delivery system (IDDS) implantation. A 59-year-old woman with a past medical history of lumbar postlaminectomy syndrome, chronic pain, and lower back pain underwent an intrathecal drug delivery system implantation after exhausting other modalities for pain relief. The patient presented to the office one-month postoperatively with symptoms of lower back pain, left lower extremity radiculopathy, and lower back subcutaneous fluid collection. A dye study using catheter access port access revealed a patent intrathecal catheter with no fluid leakage or collection after injecting contrast dye through the catheter access port. A fine needle aspiration performed under ultrasound guidance revealed a clear fluid. Using laboratory evaluation, this was confirmed to be CSF using laboratory evaluation. An epidural blood patch was performed, which provided minimal radicular pain relief. Several days after, she began experiencing fronto-occipital headaches and the lumbar fluid collection reaccumulated. An intrathecal dye study again was done and showed retrograde flow from the catheter causing a lumbar fluid collection. A catheter exchange was performed resolving the CSF leak and the patient’s symptoms. Post dural puncture headaches after IDDS implantation may have an atypical presentation. Providers should ensure the intrathecal catheter is well secured and firmly anchored to prevent migration. Patient symptoms after IDDS implantation may necessitate further investigation, including: patient evaluation, confirming catheter continuity, and minimally invasive or surgical management. Complications from IDDS may be reduced with further research on equipment and implantation techniques. Key words: Intrathecal drug delivery system, neuraxial analgesia, chronic pain, post dural puncture headache, post laminectomy syndrome, intrathecal catheters

The Application of Failure Modes and Effects Analysis Methodology to Intrathecal Drug Delivery for Pain Management

ObjectiveThis study aimed to utilize failure modes and effects analysis (FMEA) to transform clinical insights into a risk mitigation plan for intrathecal (IT) drug delivery in pain management.MethodsThe FMEA methodology, which has been used for quality improvement, was adapted to assess risks (i.e., failure modes) associated with IT therapy. Ten experienced pain physicians scored 37 failure modes in the following categories: patient selection for therapy initiation (efficacy and safety concerns), patient safety during IT therapy, and product selection for IT therapy. Participants assigned severity, probability, and detection scores for each failure mode, from which a risk priority number (RPN) was calculated. Failure modes with the highest RPNs (i.e., most problematic) were discussed, and strategies were proposed to mitigate risks.ResultsStrategic discussions focused on 17 failure modes with the most severe outcomes, the highest probabilities of occurrence, and the most challenging detection. The topic of the highest‐ranked failure mode (RPN = 144) was manufactured monotherapy versus compounded combination products. Addressing failure modes associated with appropriate patient and product selection was predicted to be clinically important for the success of IT therapy.ConclusionsThe methodology of FMEA offers a systematic approach to prioritizing risks in a complex environment such as IT therapy. Unmet needs and information gaps are highlighted through the process. Risk mitigation and strategic planning to prevent and manage critical failure modes can contribute to therapeutic success.

New Cancer Pain Treatment Options.

Cancer pain is often incapacitating and discouraging to patients; is demoralizing to family members and care takers; and is taxing and difficult to subdue for the pain specialists. The consequences of implementing suboptimal treatment are far-reaching; therefore, effective treatment methods are in a great demand. The face of cancer pain management has changed in considerable ways, and interventional procedures have become an integral part of providing multimodal analgesia in cancer pain treatment. The goals of this review are to draw attention to the critical role that regional anesthetic nerve blocks and interventional pain management techniques play in treating malignancy-related pain and emphasize the benefits provided by the aforementioned treatment strategies. A large proportion of cancer patients continues to struggle with an inadequately treated pain despite a strict adherence to the WHO analgesic step ladder. The previous pain treatment algorithm has been modified to include peripheral neural blockade, neuro-destructive techniques, neuromodulatory device use, and intrathecal drug delivery systems. The accumulated evidence highlights the opioid-sparing qualities and other benefits afforded by these modalities: decreasing medication-induced side effects, reducing economic burden of poor analgesia, and overall improvement in quality of life of the patients afflicted with a painful neoplastic disease. The rising prevalence of cancer-related pain syndromes is paralleled by an unmatched growth of innovative treatment strategies. Modified WHO analgesic ladder represents one of the greatest paradigm shifts within the domain of oncologic pain treatment. The cancer patient population requires a prompt and liberal, albeit judicious, delivery of unorthodox pain treatment options freed from the rigid bonds of conventional guidelines and standard practices.

Influence factors of intrathecal drug delivery systems for chronic intractable pain

Background Implantable drug delivery systems (IDDS) is an effective option for the treatment of chronic intractable pain. However, not all patients can achieve ideal effect in clinical application. Objective To summarize the factors that affect chronic pain patients' IDDS, and provide new methods and ideas for clinical practice. Content Proper patient selection, drug selection and management are very important for the IDDS analgesia. The position of the catheter tip, choice of drug, transmission model and so on influence the IDDS analgesic effect. Trend Patients with chronic pain treatment requirements are constantly improve, therefore, application of IDDS will provide effective analgesia for patients with chronic intractable pain. The progress in pharmacokinetic of cerebrospinal fluid, drugs for intrathecal injection, implantation procedure, good perioperation management and so on will improve the effects of IDDS. Key words: Intrathecal injection; Chronic pain; Analgesics, opioid; Cerebrospinal fluid

The Pharmacology of Spinal Opioids and Ziconotide for the Treatment of Non-Cancer Pain

BackgroundIntrathecal drug delivery has undergone a revitalization following a better understanding of this delivery route and its pharmacokinetics. Driven by patient safety and outcomes, clinicians are motivated to rethink the traditional spinal infusion pump patient selection criteria and indications. We review the current understanding of the pharmacology of commonly employed intrathecal agents and the clinical relevance.MethodsSearch strategies for data acquisition included Medline database, PubMed, Google scholar, along with international and national professional meeting content, with key words including pharmacology of opioids, intrathecal therapy, ziconotide, pharmacokinetics, and intrathecal drug delivery. The search results were limited to the English language.ResultsOver 300 papers were identified. The literature was condensed and digested to evaluate the most commonly used medications in practice, sto serve as a foundation for review. We review on-label medications: ziconotide and morphine, and off label medications including fentanyl, sufentail, and hydromorphine.ConclusionIntrathecal therapy has level-one evidence for use for malignant pain and nonmalignant pain, with continued cost savings and improved safety. To most effectively serve our patients, a clear appreciation for the pharmacology of these commonly employed medication is paramount..

Intrathecal Catheter Insertion and Analgesia is a Safe and Effective Method of Pain Control in Patients with Advanced and Intractable Cancer Pain

Introduction: Pain affects the quality of life in cancer patients. The World Health Organization established a simple three-step “ladder” approach in 1986, beginning with nonopioid drugs and progressing to stronger opioids as necessary. The implementation of this guideline enables analgesia to be achieved in 75% to 90% of patients. The remaining patients suffer from intractable pain requiring intrathecal analgesia. Advances in intrathecal analgesia and intrathecal drug delivery systems have allowed for a range of medications to be used in the control of pain in the remaining 20% of patients with intractable cancer pain. This technique allows for reduced medication doses that can decrease the side effects typically associated with oral or parenteral drug delivery. We aim to analyse the pain intensity before and after intrathecal analgesia and review the complications associated with the implantation and the care of the intrathecal device. Materials and Methods: We retrospectively analysed medical records of all cancer patients whose pain were managed by intrathecal catheter implants in our centre from February 2005 to December 2014. The pain intensity was reviewed at the time prior to administration of intrathecal analgesia and at physician review prior to hospital discharge or death. Complications related to intrathecal analgesia were reviewed from the patients’ medical records. Results: We analysed the data obtained from 44 patients. 86.4% had metastatic cancer. Pain intensity was reduced significantly at the time of discharge from hospital (P<0.001). Opioids side effects were reduced after intrathecal treatment. The main catheter-related complications were catheter displacement and infection. Conclusion: Intrathecal catheter insertion and analgesia is a safe and effective method of pain control in patients with intractable cancer pain.

Feasibility of Neurapheresis™ as a Therapy for Multidrug Resistant Gram-negative Bacterial Meningitis

BackgroundThe World Health Organization has identified Pseudomonas, Acinetobacter and Klebsiella (PAK) as three multidrug resistant (MDR) gram-negative pathogens that pose a threat to human health. The greatest threat lies in hospitals, nursing homes, and patients with devices such as intravenous catheters and ventilators. Gram-negative bacterial meningitis (GBM) manifests when these bacteria invade the central nervous system. Due to the threat of increasing antibiotic resistance and the high mortality associated with MDR GBM, we have tested a closed-loop, extracorporeal cerebrospinal fluid (CSF) filtration system (NeurapheresisTM) for its applicability in this context. Here we demonstrate feasibility of Neurapheresis for MDR GBM and characterize system parameters for bacterial clearance.Methods PAK cultures were grown and diluted to 1 × 107 cells/mL in artificial CSF or Luria-Miller broth. Both single pass and closed loop filtration were performed with various tangential flow filtration (TFF) and dead-end filter paradigms. Samples were taken either immediately post-filter or after every full CSF volume cycle (150 mL) during a long-term closed loop experiment. Bacterial load, endotoxin and cytokines were quantified.ResultsIn single pass tests, 5kDa and 100kDa TFF filters and 0.2µm and 0.45µm dead-end filters excluded all PAK organisms completely. The 100kDa and 5kDa TFF filters significantly reduced endotoxin concentration by >95% and >99% of baseline, respectively. The 5 kDa TFF filters produced a 2-log (>99%) reduction in cytokines (IL-1ra, IL-6, TNF, CRP, and CXCL10). In closed-loop experiments, both TFF filters demonstrated a 1–2 Log CFU (90–99%) reduction of all PAK organisms over 4 filtration cycles.ConclusionNeurapheresis shows potential to be an efficient multi-modal tool for controlling and treating MDR GBM in this in vitro model. Extending closed loop filtration over time demonstrates capability for rapid sterilization of the CSF. Future iterations may include adjunctive intrathecal drug delivery to further accelerate elimination of bacteria. Reduction of both endotoxin and cytokines by Neurapheresis may have significant implications for controlling the damaging neuro-inflammatory response during MDR GBM.Disclosures B. Hedstrom, Minnetronix, Inc.: Employee, Salary; L. Zitella Verbick, Minnetronix, Inc.: Employee, Salary; A. Mccabe, Minnetronix, Inc.: Employee, Salary; S. P. Lad, Minnetronix, Inc.: Collaborator and Scientific Advisor, Licensing agreement or royalty, Research grant and Research support; V. Fowler Jr., Pfizer, Novartis, Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect: Consultant, Consulting fee; NIH, MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius: Grant Investigator, Grant recipient; Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm: Consultant, Consulting fee; UpToDate: Royalties, Royalties

Advancing Safety in Intrathecal Analgesia: A Novel Web-Based Pharmacologic Requisition Platform and Data Repository for Intrathecal Drug Delivery Devices.

Advancing Safety in Intrathecal Analgesia: A Novel Web-Based Pharmacologic Requisition Platform and Data Repository for Intrathecal Drug Delivery Devices.

Direct, long-term intrathecal application of therapeutics to the rodent CNS.

Systemic application of therapeutics to the CNS tissue often results in subtherapeutic drug levels, because of restricted and selective penetration through the blood-brain barrier (BBB). Here, we give a detailed description of a standardized technique for intrathecal drug delivery in rodents, analogous to the technique used in humans. The intrathecal drug delivery method bypasses the BBB and thereby offers key advantages over oral or intravenous administration, such as maximized local drug doses with minimal systemic side effects. We describe how to deliver antibodies or drugs over several days or weeks from a s.c. minipump and a fine catheter inserted into the subdural space over the spinal cord (20 min operative time) or into the cisterna magna (10 min operative time). Drug levels can be sampled by quick and minimally invasive cerebrospinal fluid (CSF) collection from the cisterna magna (5 min procedure time). These techniques enable targeted application of any compound to the CNS for therapeutic studies in a wide range of CNS disease rodent models. Basic surgery skills are helpful for carrying out the procedures described in this protocol.

Intrathecal Drug Delivery Systems (IDDS): The Implantable Systems Performance Registry (ISPR)

ObjectivesThe ISPR was initially created to monitor the product performance of Medtronic implanted intrathecal drug infusion and spinal cord systems available in the United States.Materials and MethodsData were collected from 50 representative sites implanting and following patients with intrathecal drug delivery systems across the United States between August 7, 2003 and January 31, 2014. Device performance over time was estimated using life table survival methods.ResultsOf the 6093 patients enrolled in the ISPR, 3405 (55.9%) were female and 2675 (43.9%) were male, and 13 (0.2%) did not provide gender data. The average age at enrollment was 52.9 years (SD =17.6 years) and average follow‐up time was 29.6 months. Currently, the estimates of device survival from pump‐related events exceed 90% for all pump models across the applicable follow‐up time points. The majority of product performance events were catheter‐related. At 5 years of follow‐up, all applicable catheter models, with the exception of revised not as designed or grafted not as designed catheters, had greater than 81% survival from catheter‐related events.ConclusionsThe ISPR is designed to serve as an ongoing source of system and device‐related information with a focus on “real‐world” safety and product performance. ISPR data continue to be used to guide future product development efforts aimed at improving product reliability and quality.

Ziconotide intrathecal delivery as treatment for secondary therapeutic failure of motor cortex stimulation after 6 years

IntroductionMotor cortex stimulation is a well-known treatment modality for refractory neuropathic pain. Nevertheless, some cases of therapeutic failure have been described but alternative therapies for these cases are rarely reported. Case reportThe patient presented with neuropathic pain in his right arm due to a cervical syrinx which was surgically treated by a shunt in 2003 with no clinical improvement. As alternative therapy, after an evaluation by repetitive magnetic transcranial stimulation with significant benefit, motor cortex stimulation was successfully implanted in 2004. In 2010, a similar pain occurred in the same territory. Local mean pain visual analogical scale (VAS) increased to 82/100. A newer generation stimulation device was then implanted and, within a period of 8months, different stimulation parameter settings were tested, without any pain relief. An intrathecal drug delivery pump was then implanted in 2011, and the upper extremity catheter was located at the cervicothoracic junction. There was no postoperative complication. A bitherapy was initiated at a daily dosage of 0.2mg morphine and 1.3μg ziconotide, not modified since August 2013. At 43months follow-up, mean VAS was 21/100 with improvement of daily life and spare-time activities, anxiety and depression, quality of life (as measured by the SF-36 survey and EQ5D-3L questionnaire). DiscussionRefractory neuropathic pain treated by motor cortex stimulation may be considered in palliative situations, and secondary therapeutic failure offers only a few perspectives. Intrathecal ziconotide, indicated as a first-line drug in non-cancer pain, could be proposed in such cases. ConclusionIntrathecal drug delivery including ziconotide in refractory neuropathic pain represents a reasonable option with a good clinical tolerance.