Comparative histopathology of epidural hydrogel and silicone elastomer catheters following 30 and 180 days implant in the ewe.

New catheter materials, termed Hydrogels, have been developed recently that are stiff until exposed to hydration. The purpose of this study was to compare the 30 and 180 day histopathology of catheters composed of a common silicone elastomer versus a Hydrogel elastomer blend (HEB). Epidural catheters composed of either silicone or HEB were implanted in 19 yearling ewes for either 30 or 180 days. The degree of fibrotic reaction in the epidural space, muscle and subcutaneous tissue was assessed using both histopathology and quantitative imaging analysis. A separate subset of three ewes were implanted with HEB epidural catheters connected to subcutaneously implanted ports through which twice weekly injections of saline were given. There was no evidence of significant neurotoxicology associated with either the silicone or the HEB catheter materials. However, the silicone elastomer group had a quantifiably greater degree of fibrosis than the HEB group of both implant durations. The mean cross sectional area (sq. mm) of epidural pericatheter fibrosis was significantly smaller in the HEB group compared with the silicone group (0.491 in the HEB group and 1.585 in the silicone group at 30 days [P = 0.02] and 0.28 and 1.401 at 180 days [P = 0.0001]. The HEB catheter was easily inserted with standard epidural needles facilitated by the inherent stiffness of the catheter prior to hydration. HEB catheters remained patent throughout 30 days of saline injections per implanted ports. Silicone catheters demonstrated increased fibrosis relative to the HEB catheter material in the epidural space and in subcutaneous tissue.

Comparative spinal neuropathology of hydromorphone and morphine after 9- and 30-day epidural administration in sheep.

Despite extensive clinical use of epidural morphine and to a lesser extent hydromorphone, the neurotoxicologic effects of large-dose epidural administration have not been reported. We compared the impact on behavior, blood and cerebrospinal fluid (CSF) chemistry and hematology, and neuropathology of both epidural morphine (M) and hydromorphone (H) versus preservative-free normal saline (S) given to control animals. Silicone lumbar epidural catheters were implanted in adult sheep and attached to either a subcutaneous port (acute 9-day study) or continuous flow type implantable drug pump (chronic 30-day study) through which the ewes were repeatedly exposed to either the epidural test drug or to similar volumes of saline. The 9-day groups received 5 mL of epidural injections twice daily with the dose incrementally increased as follows: M (n = 6) 40 mg/d, 4 mg/mL; H (n = 6), 16 mg/d, 1.6 mg/mL; S (n = 3), preservative-free normal saline. The 30-day M and H groups were continuously infused epidurally with increasing concentrations eventually augmented with daily epidural boluses: M group (n = 3), 100 mg maximum daily dose, 25 mg/mL maximum concentration; H group (n = 3), 30 mg maximum daily dose, 10 mg/mL maximum concentration; S group (n = 3).(ABSTRACT TRUNCATED AT 250 WORDS)

The ganglioside GM1 decreases autotomy but not substance P depletion in a peripheral mononeuropathy rat model.

The effect of the ganglioside GM1 on autotomy, a nociceptive behavioral marker for neuropathic pain, and substance P depletion was determined in a rat model of peripheral mononeuropathy, sciatic cryoneurolysis (SCN). SCN is produced by the application of a cryoprobe to the common sciatic nerve using a freeze-thaw-freeze cycle. Due to structural sparing of the nerve, regenerative processes are not precluded. After this peripheral nerve insult, behavioral and neurochemical changes occur that support the use of SCN as a neuropathic pain model. These changes include: autotomy with coincident transient weight loss and paling of eye color suggestive of increased sympathetic activity, spontaneous nociceptive behaviors, touch-evoked allodynia, prolonged mechanical allodynia, ipsilateral decrease of immunoreactive substance P, and increases in spinal cord dynorphin expression. Incidence and severity of autotomy were assessed after the intraperitoneal administration of GM1 (1, 10, and 20 mg/kg) or saline injected daily for 2 days before SCN, the day of surgery, and for 14 days after surgery. In a subset of two rats from each treatment group, transcardiac perfusion was performed and spinal cords were processed for substance P immunoreactivity. GM1 at 10 and 20 mg/kg doses significantly attenuated autotomy as compared with saline-treated rats (P = 0.007 and 0.0001, respectively). However, GM1, at the doses studied, failed to alter the spinal substance P depletion 21 days after SCN. These results indicate that the ganglioside GM1 may have a role in the clinical management of neuropathic pain after peripheral nerve injury.

Neurotoxicology of chronic infusion of the ganglioside GM1 in the ewe: phase I. intrathecal administration.

Gangliosides, including GM1, provide a measure of improved functional recovery after ischemic, toxic, and traumatic brain injuries in animal studies. Since systemically injected GM1 has provided equivocal results in a variety of human neurodegenerative conditions, the possibility exists that intrathecal or intracerebroventricular delivery might provide more effective concentrations along the neuroaxis. In preparation to consider clinical trials, the potential neurotoxicologic effects of chronic intrathecal GM1 were studied in ewes. Preliminary in vitro tests first demonstrated the stability and compatibility of GM1 in implanted pumps. Two groups of adult ewes were then implanted with either Therex or Infusaid continuous flow implantable pumps and chronic intrathecal catheters. Ewes were infused intrathecally with either preservative-free normal saline (n = 5) or GM1 (n = 7) 100 micrograms-10,000 micrograms/d for up to 24 wk. No abnormal behavioral responses were noted. Cerebrospinal fluid analyzed for GM1 concentrations by thin layer chromatography revealed no evidence of GM1 accumulation. After the animals were killed, spinal cords were removed, fixed, sectioned, and stained. Histologic analysis revealed no generalized pattern of neuronal damage, demyelination, gliosis, or axonopathy to distinguish intrathecal normal saline or GM1. In both treated and control groups, the only consistent finding was a pericatheter-associated compression of white matter with axonal dilation, vacuolation, and occasional neuronal loss. Catheter tracts in both groups were also associated with variable leptomeningeal fibroproliferative changes in adjacent dura and pia, at times in conjunction with more generalized duromeningeal thickening. In summary, chronic intrathecal GM1 in doses up to 10 mg/d had no definable neuropathologic consequences.

Testing an implantable intraspinal drug delivery device in the ewe.

OBJECTIVE: The authors report the use of multiple implanted intraspinal port and catheter systems per test animal to study the in vivo functional characteristics and reliability of a new implantable spinal drug delivery port system. METHODS: Four ewes were each implanted with two epidural and one subarachnoid silicone elastomer catheters at the lumbar level. Each catheter was connected in series to one of three Therex filtered spinal delivery ports implanted subcutaneously in a similar grid pattern in each ewe to facilitate percutaneous identification. Saline (2 ml) was injected 3 times weekly in each port. The ease of injection and behavioral responses were recorded for 207-213 days of implantation until sacrifice/necropsy. RESULTS: All ports functioned reliably during the study. However, injection through two of the four subarachnoid catheters resulted in behavioral withdrawal responses intermittently. This behavioral pattern was much less common after epidural port injections. All four subarachnoid and four of eight epidural port and catheter systems were tested with local anesthetic just before sacrifice. Motor block was observed in three of four subarachnoid and three of four epidural port and catheter systems tested. Integrity of the other four epidural ports was tested by injection of methylene blue at sacrifice. This dye did not distribute in the epidural space in one of the latter four epidural ports (not local anesthetic tested) because of a concentric fibrotic reaction about the catheter. Similar fibrotic reactions surrounded the catheters that failed a functional test with local anesthetic. CONCLUSIONS: The implantable intraspinal port system tested functions reliably under repetitive percutaneous access. However, filtering such ports, though desirable to prevent entry of debris into the spinal canal, did not eliminate pericatheter chronic subarachnoid and epidural reaction. The number of test animals required to test 12 ports chronically was reduced by two-thirds without undue trauma to the individual test subject. Chronic percutaneous injection of an implanted subarachnoid system is feasible but may be associated with behavioral effects similar to that seen with chronic epidural systems. Fibrosis around chronic silicone catheters limited functional utility in one-fourth of the implanted test systems. Further study of the potential reactivity of chronic epidural and subarachnoid catheters is indicated.

Intrathecal catheterization alone reduces autotomy after sciatic cryoneurolysis in the rat.

There is substantial evidence that sciatic cryoneurolysis (SCN, freeze lesion of the sciatic nerve) is a neuropathic pain model in the rat. During characterization of this model, SCN was performed 4 days after either a sham operation or the insertion of an indwelling intrathecal catheter preparatory to selective spinal drug administration. Body weight and autotomy scores were recorded for the next 22 days until sacrifice. The catheter group experienced significant weight loss (7.5%) by 4 days but rapidly regained to parity with the sham group. Autotomy scores and the frequency of severe autotomy (score > 3) were less at day 22 in the catheter group as compared with the sham-control group (p < 0.005, p < 0.03, respectively). Intrathecal catheterization itself effects the degree of behavioral response to neurogenic pain and thus, should be controlled for in studies using nociceptive animal models.

Acute toxicology of an enkephalinase inhibitor (SCH 32615) given intrathecally in the ewe.

Intrathecal application of the enkephalinase inhibitor, SCH 32615, yields antinociception in animal paradigms. Our purpose was to identify possible acute behavioral effects, neurotoxicity, or systemic toxicity of intrathecal SCH 32615 administration during 9 days in the ewe. Seventeen ewes were implanted with lumbar silicone intrathecal catheters and subcutaneous access ports for repeated injection. Baseline and serial daily behavioral assessments were made during 9 days of 2-mL intrathecal injection twice daily of either normal saline (SAL group) or a 20 mg/mL isotonic sterile solution of SCH 32615 (SCH group). Data were analyzed by treatment group (SCH versus SAL) by taking the group means of individual ewe cumulative scores during 9 days. At 15-18 h after the last injection, the ewes were euthanized and the spinal cords and leptomeninges were grossly examined and prepared for histological assessment. Histological evaluation of the lumbar (at catheter entrance site and catheter tip), thoracic, and cervical sections of all animals was performed by two neuropathologists. Several mild, reversible, and apparently nonprogressive behaviors (Stepping/Placing and Hindlimb Stretching/Splaying) were observed almost exclusively in SCH-treated ewes. These behaviors were interpreted as mild temporary irritative effects, without significant neuropathological sequelae. Pathological findings primarily consisted of mild, focal dural thickening and white matter compression. These changes were distributed equally between drug-treated and control groups and were attributable to catheter implantation and local compressive effects. There were no pathological bases identified in this study to preclude the clinical study of SCH 32615 within the dose range studied.