Difficult Labor Epidural: Intrathecal Catheter Management

Labor epidural analgesia is the most common method used to control pain associated with labor and vaginal delivery in the United States. However, the epidural catheter placement can cause accidental dural puncture in about 1 to 6% of laboring patients. Initiation of continuous intrathecal analgesia provides a good alternative to another attempt of epidural placement in certain types of the laboring population. While other countries have published referral guidelines of managing accidental dural puncture, the United States lacks such practice standards. The application of Accidental Dural Puncture Management with Intrathecal Catheter (ADPMIC) guidelines, used in other countries for difficult epidural placement in parturients, have offered effective and safe analgesia and anesthesia with fewer complications, and better patient outcomes. The anesthesia providers at the host institution had limited understanding of continuous intrathecal catheter’s benefits and uses. The purpose of this project was to educate anesthesia providers on ADPMIC principles and introduce a management protocol for laboring patients customized to host facility resources. An educational PowerPoint presentation was used to lecture on the ADPMIC principles and introduce the evidence-based protocol. A post-presentation survey was used to assess protocol understanding and willingness towards implementation. Survey results verified providers improved comprehension of the ADPMIC principles. Additionally, anesthesia providers expressed a high intent to implement the protocol into their practice. The immediate impact of the project was appreciated by provider adoption of the standardized reference tool for a visual and modifiable step-by-step when anesthesia providers encounter difficult epidural placement in laboring patients

Stress Affects a Gastrin-Releasing Peptide System in the Spinal Cord That Mediates Sexual Function: Implications for Psychogenic Erectile Dysfunction

Many men suffering from stress, including post-traumatic stress disorder (PTSD), report sexual dysfunction, which is traditionally treated via psychological counseling. Recently, we identified a gastrin-releasing peptide (GRP) system in the lumbar spinal cord that is a primary mediator for male reproductive functions.To ask whether an acute severe stress could alter the male specific GRP system, we used a single-prolonged stress (SPS), a putative rat model for PTSD in the present study. Exposure of SPS to male rats decreases both the local content and axonal distribution of GRP in the lower lumbar spinal cord and results in an attenuation of penile reflexes in vivo. Remarkably, pharmacological stimulation of GRP receptors restores penile reflexes in SPS-exposed males, and induces spontaneous ejaculation in a dose-dependent manner. Furthermore, although the level of plasma testosterone is normal 7 days after SPS exposure, we found a significant decrease in the expression of androgen receptor protein in this spinal center.We conclude that the spinal GRP system appears to be a stress-vulnerable center for male reproductive functions, which may provide new insight into a clinical target for the treatment of erectile dysfunction triggered by stress and psychiatric disorders

Antinociceptive Interactions between Intrathecal Gabapentin and MK801 or NBQX in Rat Formalin Test

Antagonists for spinal N-methyl-D-aspartate (NMDA) and amino-hydroxy-methtyl-isoxazolepropionate (AMPA) receptors are effective in attenuating acute nociception or injury-induced hyperalgesia. The antinociception of spinal gabapentin is developed in injury-induced hyperalgesia without affecting acute nociception. The authors evaluated the effects of intrathecal gabapentin, NMDA antagonist (MK801) and AMPA antagonist (NBQX) in the formalin test which shows injury-induced hyperalgesia as well as acute pain. We further assessed the interactions between gabapentin and either MK801 or NBQX. Male Sprague-Dawley rats were implanted with intrathecal catheters. To evoke pain, 50 µL of 5% formalin solution was injected into the hindpaw. The interaction was investigated by a fixed dose analysis or an isobolographic analysis. MK801 and NBQX suppressed flinching responses during phase 1 of the formalin test, while gabapentin had little effect on phase 1. All three agents decreased the phase 2 flinching response. A fixed dose analysis in phase 1 showed that gabapentin potentiated the antinociceptive effect of MK801 and NBQX. Isobolographic analysis in phase 2 revealed a synergistic interaction after coadministration of gabapentin-MK801 or gabapentin-NBQX. Correspondingly, spinal gabapentin with NMDA or AMPA antagonist may be useful in managing acute pain and injury-induced hyperalgesia

Prepontine placement of an intrathecal baclofen pump catheter for treatment of dystonia

Background: Cerebral palsy with medically refractory spasticity and dystonia is a condition that often benefits from intrathecal baclofen pump therapy to treat these symptoms. In this case report, an intracranial baclofen catheter was placed in the prepontine space to improve withdrawal symptoms in a patient unable to undergo new lumbar catheter placement due to infection. Case description: A 22-year-old female with past medical history of cerebral palsy presented with baclofen pump failure and was unable to undergo placement of a new lumbar baclofen catheter due to an infection in her lower back precluding safe and efficacious catheter placement. It was decided the patient would benefit from intrathecal baclofen administered in the prepontine space as a means to avoid a lumbar catheter and thus bypass this prior infection site. An endoscopic third ventriculostomy (ETV) was performed with the endoscope and the distal end of the baclofen pump catheter was fed through this ETV into the prepontine space. Placement in the prepontine space was confirmed by a follow-up head computed tomography. There was a significant improvement in autonomic symptoms and spasticity. By postoperative day 5, the patient was surgically and medically cleared for discharge. Conclusion: In cases of severe baclofen withdrawal due to dysfunctional pumps, immediate reversal is preferred but may not be feasible due to factors such as infection. This case report has demonstrated that prepontine catheter placement can be effective for the administration of baclofen to reverse withdrawal symptoms in these types of patients

Subtype-selective GABAA receptor mimetics—novel antihyperalgesic agents?

Agonists at the benzodiazepine-binding site of ionotropic γ-aminobutyric acid (GABAA) receptors are in clinical use as hypnotics, anxiolytics, and anticonvulsants since the early 1960. Analgesic effects of classical benzodiazepines have occasionally been reported in certain subgroups of patients suffering from chronic pain or after spinal delivery through intrathecal catheters. However, these drugs are generally not considered as analgesics but should in fact be avoided in patients with chronic pain. Recent evidence from genetically modified mice now indicates that agents targeting only a subset of benzodiazepine (GABAA) receptors should provide pronounced antihyperalgesic activity against inflammatory and neuropathic pain. Several such compounds have been developed recently, which exhibit significant antihyperalgesia in mice and rats and appear to be devoid of the typical side-effects of classical benzodiazepine

Activation of protein kinase C in the spinal cord produces mechanical hyperalgesia by activating glutamate receptors, but does not mediate chronic muscle-induced hyperalgesia

BACKGROUND: Protein kinase C (PKC) in the spinal cord appears to mediate chronic injury-induced pain, but not acute nociceptive pain. Muscle insult results in increased release of glutamate spinally, and hyperalgesia that is reversed by spinal blockade of NMDA and non-NMDA glutamate receptors. Therefore, we hypothesized that spinal activation of PKC 1) mediates the late phase of hyperalgesia 1 week after muscle insult, and 2) produces mechanical hyperalgesia through activation of NMDA and non-NMDA glutamate receptors. RESULTS: Rats were implanted with intrathecal catheters for delivery of drugs directly to the spinal cord. Mechanical withdrawal thresholds of the paw were determined using von Frey filaments. Intrathecal phorbol 12,13 dibutyrate (PDBu) produced a dose-dependent decrease in the mechanical withdrawal threshold of the paw that was prevented by pretreatment with the PKC inhibitor, GF109203X. Pretreatment with an NMDA receptor antagonist (AP5) or a AMPA/kainate receptor antagonist (NBQX) prevented the decrease in mechanical withdrawal threshold by PDBu. Two injections of acidic saline in the gastrocnemius muscle decreased the mechanical withdrawal thresholds of the paw bilaterally 24 h and 1 week after the second injection. However, blockade PKC in the spinal cord had no effect on the decreased withdrawal thresholds of the paw when compared to vehicle controls. CONCLUSION: Spinal activation of PKC produces mechanical hyperalgesia of the paw that depends on activation of NMDA and non-NMDA receptors. Chronic muscle-induced mechanical hyperalgesia, on the other hand, does not utilize spinal PKC

Marked central nervous system pathology in CD59 knockout rats following passive transfer of Neuromyelitis optica immunoglobulin G.

Neuromyelitis optica spectrum disorders (herein called NMO) is an inflammatory demyelinating disease of the central nervous system in which pathogenesis involves complement-dependent cytotoxicity (CDC) produced by immunoglobulin G autoantibodies targeting aquaporin-4 (AQP4-IgG) on astrocytes. We reported evidence previously, using CD59-/- mice, that the membrane-associated complement inhibitor CD59 modulates CDC in NMO (Zhang and Verkman, J. Autoimmun. 53:67-77, 2014). Motivated by the observation that rats, unlike mice, have human-like complement activity, here we generated CD59-/- rats to investigate the role of CD59 in NMO and to create NMO pathology by passive transfer of AQP4-IgG under conditions in which minimal pathology is produced in normal rats. CD59-/- rats generated by CRISPR/Cas9 technology showed no overt phenotype at baseline except for mild hemolysis. CDC assays in astrocyte cultures and cerebellar slices from CD59-/- rats showed much greater sensitivity to AQP4-IgG and complement than those from CD59+/+ rats. Intracerebral administration of AQP4-IgG in CD59-/- rats produced marked NMO pathology, with astrocytopathy, inflammation, deposition of activated complement, and demyelination, whereas identically treated CD59+/+ rats showed minimal pathology. A single, intracisternal injection of AQP4-IgG in CD59-/- rats produced hindlimb paralysis by 3 days, with inflammation and deposition of activated complement in spinal cord, optic nerves and brain periventricular and surface matter, with most marked astrocyte injury in cervical spinal cord. These results implicate an important role of CD59 in modulating NMO pathology in rats and demonstrate amplification of AQP4-IgG-induced NMO disease with CD59 knockout

The role of spinal GABAB receptors in cancer-induced bone pain in rats

Cancer-induced bone pain (CIBP) remains a major challenge in advanced cancer patients due to our lack of understanding of its mechanisms. Previous studies have demonstrated the vital role of GABAB receptors (GABABRs) in regulating nociception and various neuropathic pain models have shown diminished activity of GABABRs. However, the role of spinal GABABRs in CIBP remains largely unknown. In this study, we investigated the specific cellular mechanisms of GABABRs in the development and maintenance of CIBP in rats. Our behavioral results show that both acute and chronic intrathecal treatment with baclofen, a GABABR agonist, significantly attenuated CIBP-induced mechanical allodynia and ambulatory pain. The expression levels of GABABRs were significantly decreased in a time-dependent manner and colocalized mostly with neuron and a minority with astrocyte and microglia. Chronic treatment with baclofen restored the expression of GABABRs and markedly inhibited the activation of cAMP-dependent protein kinase (PKA) and the cAMP-response element-binding protein (CREB) signaling pathway

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

Objectives: Intrathecal 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. Methods: Plain 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. Results: Examples of catheter-related adverse events are described and a proposal is made for stepwise interpretation of standard plain radiographic images. Conclusions: Plain 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