Intercompartmental communication between the cerebrospinal and adjacent spaces during intrathecal infusions in an acute ovine in-vivo model

Introduction The treatment of hydrocephalus has been a topic of intense research ever since the first clinically successful use of a valved cerebrospinal fluid shunt 72 years ago. While ample studies elucidating different phenomena impacting this treatment exist, there are still gaps to be filled. Specifically, how intracranial, intrathecal, arterial, and venous pressures react and communicate with each other simultaneously. Methods An in-vivo sheep trial (n = 6) was conducted to evaluate and quantify the communication existing within the cranio-spinal, arterial, and venous systems (1 kHz sampling frequency). Standardized intrathecal infusion testing was performed using an automated infusion apparatus, including bolus and constant pressure infusions. Bolus infusions entailed six lumbar intrathecal infusions of 2 mL Ringer’s solution. Constant pressure infusions were comprised of six regulated pressure steps of 3.75 mmHg for periods of 7 min each. Mean pressure reactions, pulse amplitude reactions, and outflow resistance were calculated. Results All sheep showed intracranial pressure reactions to acute increases of intrathecal pressure, with four of six sheep showing clear cranio-spinal communication. During bolus infusions, the increases of mean pressure for intrathecal, intracranial, arterial, and venous pressure were 16.6 ± 0.9, 15.4 ± 0.8, 3.9 ± 0.8, and 0.1 ± 0.2 mmHg with corresponding pulse amplitude increases of 2.4 ± 0.3, 1.3 ± 0.3, 1.3 ± 0.3, and 0.2 ± 0.1 mmHg, respectively. During constant pressure infusions, mean increases from baseline were 14.6 ± 3.8, 15.5 ± 4.2, 4.2 ± 8.2, and 3.2 ± 2.4 mmHg with the corresponding pulse amplitude increases of 2.5 ± 3.6, 2.5 ± 3.0, 7.7 ± 4.3, and 0.7 ± 2.0 mmHg for intrathecal, intracranial, arterial, and venous pulse amplitude, respectively. Outflow resistances were calculated as 51.6 ± 7.8 and 77.8 ± 14.5 mmHg/mL/min for the bolus and constant pressure infusion methods, respectively—showing deviations between the two estimation methods. Conclusions Standardized infusion tests with multi-compartmental pressure recordings in sheep have helped capture distinct reactions between the intrathecal, intracranial, arterial, and venous systems. Volumetric pressure changes in the intrathecal space have been shown to propagate to the intraventricular and arterial systems in our sample, and to the venous side in individual cases. These results represent an important step into achieving a more complete quantitative understanding of how an acute rise in intrathecal pressure can propagate and influence other systems.

Ropivacaine: An Unusual Cause of Neuroleptic Malignant-Like Syndrome

Ropivacaine is commonly used for post-operative pain management. We describe a case of neuroleptic malignant-like syndrome in a woman administered ropivacaine delivered using a drug infusion balloon. The presenting symptoms were confusion, agitation and fever. Blood analysis showed elevated C-reactive protein, leucocytosis and increased creatine phosphokinase. As intoxication was suspected, ropivacaine was suspended and the patient gradually improved. Possible leakage of ropivacaine into the intrathecal space may have resulted in central nervous system toxicity.

USG SAVED THE DAY: PRE-PROCEDURAL USG SPINE FOR SPINAL ANAESTHESIA IN A PARTURIENT WITH THORACO-LUMBAR SCOLIOSIS WITH POST BURN CONTRACTURE NECK

Introduction: Incidence of Scoliosis is approximately 2% and higher in females. Therefore, anaesthesiologist should be familiar with its implications for safe anaesthetic management1. Such parturients present unique challenges for administration of regional anaesthesia. Reporting one such case with a successful outcome using pre procedural Ultrasound spine for spinal anaesthesia. A 27 years, 39 weeks Case Report: primigravida of height 132 cm, with cephalo pelvic disproportion in labour with grade III scoliosis and post burn contractures involving neck, was posted for emergency cesarean section. Patient underwent surgery successfully under SAB after accessing spine by ultrasonography for identifying point of insertion, depth of intrathecal space & needle trajectory.2 Ultrasound is Conclusion: boon for accessing spine in patient with difcult spinal anatomy and pregnancy for deciding correct spinal interspace and successful outcome with fewer attempts.

Theory about traumatic brain injury effects. Part I. Definitions, classification, clinical signs and quantitative tomography

The paper presents the experience of assessment and treatment of 5000 cases of various traumatic brain injury (TBI) effects using brain imaging methods, minimally invasive and reconstructive neurosurgery. Definitions of TBI “effects” and “complications” have been proposed for the first time. Clinical and morphological classification of those has been developed, which identifies tissue effects, effects on cerebrospinal fluid system dynamics, and vascular effects of TBI. The major clinical symptoms of TBI effects have been described: neurologic deficit, mental dysfunctions, disturbances of vegetative function, epilepsy. Focal and diffuse alterations in brain tissue, intrathecal space and ventricular system resulting from TBI, identified by x-ray computed tomography, have been systematized. This has become the basis for investigation of pathogenesis and sanogenesis of brain disorders resulting from TBI, as well as for developing theory about the TBI effects.

Targeting the nociceptive somatosensory system with AAV9 and AAV2retro viral vectors

Adeno-associated viral (AAV) vectors allow for site-specific and time-dependent genetic manipulation of neurons. However, for successful implementation of AAV vectors, major consideration must be given to the selection of viral serotype and route of delivery for efficient gene transfer into the cell type being investigated. Here we compare the transduction pattern of neurons in the somatosensory system following injection of AAV9 or AAV2retro in the parabrachial complex of the midbrain, the spinal cord dorsal horn, the intrathecal space, and the colon. Transduction was evaluated based on Cre-dependent expression of tdTomato in transgenic reporter mice, following delivery of AAV9 or AAV2retro carrying identical constructs that drive the expression of Cre/GFP. The pattern of distribution of tdTomato expression indicated notable differences in the access of the two AAV serotypes to primary afferent neurons via peripheral delivery in the colon and to spinal projections neurons via intracranial delivery within the parabrachial complex. Additionally, our results highlight the superior sensitivity of detection of neuronal transduction based on reporter expression relative to expression of viral products.

A Novel Chronic Dural Port Platform for Continuous Collection of Large Volumes of Cerebrospinal Fluid and Intrathecal Drug Delivery in Free-Moving Mice.

BackgroundCerebrospinal fluid (CSF) provides a direct representation of the pathophysiological changes occurring in the central nervous system (CNS); therefore, it has been used for pathogenesis research and biomarker development for CNS disorders. The CSF obtained from valid mouse models relevant to CNS disorders can be an important resource for successful biomarker and drug development. However, the limited volume of CSF that can be collected from the tiny intrathecal space and the technical difficulties involved in CSF sampling have been bottlenecks that have hindered the detailed analysis of CSF in mouse models. ResultsWe have developed a novel chronic dural port (CDP) method without cannulation for mouse CSF collection. This method allows easy and repeated access to the intrathecal space in a free-moving, unanesthetized mouse, thereby enabling continuous long-term CSF collection with minimal tissue damage and providing a large volume of high-quality CSF from a single mouse. When combined with chemical biosensors, the CDP method allows real-time monitoring of the dynamic changes in neurochemicals in the CSF at a one-second temporal resolution in free-moving mice. The CDP can also serve as a direct access point for intrathecal injection of CSF tracers and drugs. The spatio-temporal distribution of CSF tracers delivered via CDP revealed a dynamic metabolism of CSF at distinct brain areas. Direct intrathecal delivery of centrally acting drugs via CDP enabled real-time behavioral assessment in free-moving mice. ConclusionsThe CDP method allows collection of a large volume of high-quality CSF and direct intrathecal drug administration with real-time behavioral assessment in free-moving mice. Combined with animal models relevant to CNS disorders, this method provides a unique and valuable platform for biomarker and therapeutic drug research.

Anesthetic considerations in patients with implantable devices and chronic pain surgery

The use of advanced invasive techniques for the control of chronic pain in patients with multiple comorbidities is becoming increasingly common. Neuromodulation offers a new management alternative involving the infusion of one or more drugs into the epidural or intrathecal space through a fully implantable infusion pump. It also involves spinal stimulation, a minimally invasive technique in which electrodes are positioned in the epidural space and connected to a pulse generator that is implanted subcutaneously and generates pulses designed to suppress the noxious stimulus. This article will describe the anesthetic considerations in cases of implantable drug delivery systems, and spinal and peripheral nerve stimulation devices. Additionally, patients with electrical or drug neuromodulation devices may present to anesthetic practice for surgical indications unrelated to their chronic pain pathology. Hence the importance of being familiar with the basic components of these devices, how they work, what drugs they use and the potential associated complications in the perioperative context, in order to ensure proper management and patient safety.

Complications associated with intrathecal drug delivery in a paediatric patient with Niemann-Pick type C

We report on a male subject with a diagnosis of Niemann-Pick type C (NPC). He received an experimental medicinal product intrathecally initially via lumbar puncture (LP) and eventually via intrathecal drug delivery device. Shortly after implantation, the device catheter migrated outside of the intrathecal space and coiled subcutaneously. The treatment continued via LP after removal of the device. A subdural haematoma developed after repeated LPs. It was surgically evacuated and the patient recovered with sequelae. Surgically implanted drug delivery devices are designed to bypass the blood–brain barrier and deliver a medicinal product directly into the cerebrospinal fluid circulation. Their use has extended into the field of neurodegenerative disorders. Significant adverse events can occur at any given time after implantation including neurological injury, dislodgement or displacement of any of its components, infection and drug-related complications; all can significantly affect the quality of life of patients. Repeated LPs also carry significant risk.

Self-buffering capacity of a human sulfatase for central nervous system delivery

Direct delivery of therapeutic enzymes to the Central Nervous System requires stringent formulation design. Not only should the formulation design consider the delicate balance of existing ions, proteins, and osmolality in the cerebrospinal fluid, it must also provide long term efficacy and stability for the enzyme. One fundamental approach to this predicament is designing formulations with no buffering species. In this study, we report a high concentration, saline-based formulation for a human sulfatase for its delivery into the intrathecal space. A high concentration formulation (≤ 40 mg/mL) was developed through a series of systematic studies that demonstrated the feasibility of a self-buffered formulation for this molecule. The self-buffering capacity phenomenon was found to be a product of both the protein itself and potentially the residual phosphates associated with the protein. To date, the self-buffered formulation for this molecule has been stable for up to 4 years when stored at 5 ± 3 °C, with no changes either in the pH values or other quality attributes of the molecule. The high concentration self-buffered protein formulation was also observed to be stable when exposed to multiple freeze–thaw cycles and was robust during in-use and agitation studies.