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PubMed1987

The effect of chronic subarachnoid bupivacaine infusion in dogs.

A functional and histologic examination of the effect of the continuous intrathecal administration of bupivacaine was made in five dogs. After a partial laminectomy at L5, a silicone rubber catheter was inserted into the subarachnoid space and advanced 10 cm cranially. A model 400 Infusaid pump, used for drug delivery, was placed in a subcutaneous pocket between the 13th rib and iliac crest. Drug infusions were individually adjusted and maintained at a concentration such that the animal just exhibited slight gait impairment. Daily bupivacaine doses ranged from 5.7-11.1 mg. Infusions were maintained for a period of 3-16 weeks. Light microscopic examination of spinal cord and roots revealed no abnormalities. A focal mononuclear cell infiltration of the leptomeninges was seen in two drug animals, as well as one catheter control animal. One of the 16-week animals had a residual limp upon drug removal. While we were not able to quantitatively assess the degree of sensory motor dissociation, the results of this study suggest that chronic intrathecal bupivacaine infusion through an implantable pump system may be a short-term alternative to intrathecal morphine in the control of cancer pain.

Anesthesia, Spinal↗
PubMed2000

Successful treatment of active ankylosing spondylitis with the anti-tumor necrosis factor alpha monoclonal antibody infliximab.

OBJECTIVE: Tumor necrosis factor alpha (TNFalpha) has been detected in sacroiliac joint biopsy specimens from patients with spondylarthropathy. The present open pilot study was undertaken to test the efficacy of the anti-TNFalpha monoclonal antibody infliximab in the treatment of active ankylosing spondylitis (AS). METHODS: Eleven patients with AS of short duration (median 5 years, range 0.5-13 years) that had been active for at least 3 months (range 3-72 months) were treated with 3 infusions of infliximab (at weeks 0, 2, and 6), in a dosage of 5 mg/kg. Ten of the 11 patients had elevated C-reactive protein (CRP) levels (>6 mg/liter) before treatment; these elevations were known to have had persisted > 1 year in at least 3 patients. The Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI), pain as measured on a visual analog scale, and the Bath AS Metrology Index (BASMI) were assessed. Quality of life was assessed using the Short Form 36 instrument. Laboratory markers of disease activity, including interleukin-6 (IL-6) levels, were determined. Dynamic magnetic resonance imaging (MRI) of the spine was performed in 5 patients. RESULTS: One patient withdrew from the study due to the occurrence of urticarial xanthoma 8 days after the first infusion. At study enrollment, 3 of 5 patients had evidence of spinal inflammation (spondylitis and spondylodiscitis) as detected by MRI; followup MRI 2-6 weeks after the third infusion revealed improvement in 2. Improvement of > or = 50% in activity, function, and pain scores was documented in 9 of 10 patients; the median improvement in the BASDAI after 4 weeks was 70% (range 41-94%). This clear-cut benefit lasted for 6 weeks after the third infusion in 8 of 10 patients. The median CRP level decreased from 15.5 mg/liter (range <6-90.8) to normal, and the median IL-6 level from 12.4 mg/liter (range 0-28.4) to normal (<5). There was improvement in all 9 SF-36 concepts; the improvement was significant for 6 concepts. CONCLUSION: These data suggest that anti-TNFalpha therapy is very effective for several weeks in AS. Whether this therapy, in addition to its antiinflammatory effect, prevents ankylosis remains to be determined.

Adult↗
PubMed2000

Warm or cold saline for volume preload before spinal anaesthesia for caesarean section?

In this study, we compared the effect of prophylactic administration of warm and cold saline against spinal anaesthesia induced hypotension in parturients undergoing elective caesarean section. One hundred and thirteen parturients with singleton pregnancies received an i.v. infusion of isotonic saline 20 mL x kg(- 1)during the 15 min before spinal injection followed by 10 mL x kg(- 1)during the 20 min after spinal injection. Fifty-seven patients were allocated to the warm saline group (37 degrees C) and 56 to the cold saline group (21 degrees C). Discomfort in the infusion arm was less in the warm saline group (P<0.01), whereas the incidence of shivering was similar in the two groups. Following induction of spinal anaesthesia, blood pressures were significantly higher in the cold saline infusion group compared to the warm saline group (P<0.05). However, the group mean difference in mean arterial pressure was only about 5 mmHg, and the amount of ephedrine administered and the incidence of clinical significant hypotension did not differ between groups. In conclusion, the temperature of the fluid used for i.v. preload and maintenance at caesarean section under spinal anaesthesia is not clinically important.

Journal Article↗
PubMed2004

Galectin-1 expression correlates with the regenerative potential of rubrospinal and spinal motoneurons.

Axotomized spinal motoneurons are able to regenerate to their peripheral targets, whereas injured rubrospinal neurons that lie completely within the CNS fail to regenerate. The differing cell body reactions to axotomy of these two neuronal populations have been implicated in their disparate regenerative ability. Recently, the lectin galectin-1 has been shown to be involved in both spinal motoneurons and primary afferent regeneration. Using in situ hybridization, we compared the endogenous galectin-1 mRNA expression in spinal motoneurons and rubrospinal neurons after axotomy. We found that 7 and 14 days after axotomy, galectin-1 mRNA increased in spinal motoneurons but decreased in rubrospinal neurons. Infusion of the brain-derived neurotrophic factor into the vicinity of the injured rubrospinal nucleus, which we have previously shown to increase the regenerative capacity of rubrospinal neurons, significantly increased galectin-1 mRNA compared with uninjured control levels. Thus, the expression of galectin-1 in neurons correlates with the regenerative propensity.

Analysis of Variance↗
PubMed1998

Pre-emptive intrathecal Mk-801, a non-competitive N-methyl-D-aspartate receptor antagonist, inhibits the up-regulation of spinal dynorphin mRNA and hyperalgesia in a rat model of chronic inflammation.

The effects of N-methyl-D-aspartate(NMDA) receptor antagonist, Mk-801, on the expression of spinal dynorphin (DYN) mRNA and the hyperalgesia induced by peripheral inflammation were studied by Northern analysis and behavioral test. Following an unilateral injection of complete Freund's adjuvant (CFA) into the rat hindpaw, there appeared a significant hyperalgesia of inflamed hindpaw and up-regulation of ipsilateral spinal DYN mRNA; while the pre-emptive and continuous intrathecal administration of Mk-801 (10 microg/microl per h) could significantly suppress both the hyperalgesia and the up-regulation of spinal DYN mRNA induced by peripheral inflammation. The results suggest that NMDA receptor activation may contribute to the development and maintenance of the thermal hyperalgesia that is associated with the up-regulation of DYN expression in spinal dorsal horn.

Animals↗
PubMed2001

Simulation of acute spinal cord injury: effects on respiration.

The respiratory effects of acute spinal injury and paralysis are difficult to study. Urgent medical needs of human spinal cord injury victims usually preclude study, while induction of spinal cord lesions in awake animals is not feasible ethically. We utilized controlled, segmental infusion of epidural anesthetic in awake, highly trained, implanted canines to reversibly simulate the effects of thoracic and cervical (paraplegic and quadriplegic) spinal cord injury. We studied six animals, an average of 29 days after implantation with electromyogram and sonomicrometry transducers in transversus abdominis, external intercostal, parasternal intercostal and costal diaphragm muscles. Anesthetic was infused through an epidural catheter inserted percutaneously, under fluoroscopic guidance. Asymmetrical motor blockade was prevented using repositioning during epidural infusions. By sequential infusion we were able to induce three distinct, functional levels of spinal paralysis showing cumulative paralysis of abdominal, external intercostal, and parasternal intercostal muscles. Paralysis of the abdomen and chest wall, sparing only the diaphragm, showed unexpected bradypnea and failure to maintain minute ventilation.

Acute Disease↗
PubMed2003

Soluble cell adhesion molecule L1-Fc promotes locomotor recovery in rats after spinal cord injury.

Previous studies suggest that the cell adhesion molecule L1 promotes neurite growth by neutralizing white matter associated inhibitors of axonal growth. We made a soluble chimeric dimer by linking mouse L1 to human Fc. This L1-Fc construct (40 microg/mL) markedly facilitated neurite outgrowth, as well as neuronal adhesion to white matter on frozen sections of spinal cord. We applied L1-Fc intrathecally (200 microg/mL at 0.5 microL/h) to rat spinal cords for 2 weeks after a 25-mm weight drop contusion of the T13 spinal cord. Initial experiments indicated that L1-Fc is present in the spinal cord after 2 weeks of intrathecal infusion and significantly improved locomotor recovery by 6-12 weeks after injury. We then randomized 45 rats to intrathecal infusion of L1-Fc (L1), phosphate-buffered saline controls (PBS), and a mouse monoclonal IgM antibody (M1). By 12 weeks after injury, L1-treated rats recovered significantly (p < 0.005) better locomotor function (BBB score 10.57 +/- 0.25, n = 14) than PBS-treated rats (BBB score 9.00 +/- 0.33, n = 14) or M1-treated (BBB score 8.71 +/- 0.16, n = 14). Only two rats of 22 treated with saline recovered weight-supported ambulation. Of 20 L1-Fc-treated rats, however, 18 recovered weight-supported walking by 12 weeks. The L1-Fc-treated rats also showed more consistent hindlimb contact placing than saline controls. We injected biotinylated dextran amine (BDA) into the motor cortices of 14 rats treated with L1-Fc to label corticospinal axons, comparing these with 13 rats treated with saline. In saline-treated rats, BDA-labeled corticospinal axons often grew up to the impact edge and occasionally into the impact site. L1-treated rats showed longer corticospinal tract growth at the injury site. Three rats had BDA-labeled axons that extended beyond the impact center. One L1-Fc-treated rat showed axonal extension and synapse formation in cord distal to the injury. These results indicate that soluble L1-Fc promotes axonal growth and functional recovery after spinal cord injury. However, the limited corticospinal tract growth across the injury site cannot account for the observed locomotor recovery. Thus, L1 may be stimulating growth of other motor tracts or protecting axons and neurons. More studies are required to elucidate the mechanisms of L1-Fc-induced locomotor recovery.

Animals↗
PubMed1986

Selective route of doxorubicin administration improves outcome in experimental malignant epidural cord compression.

Epidural spinal cord compression was produced in adult Fischer rats by injection of 10(6) viable cells of malignant fibrous histiocytoma anterior to the T-13 vertebral body. Using a tracer dye, it was demonstrated that a portion of the inoculum was always present in the anterior epidural space at the time of inoculation. Paraplegia and incontinence occurred consistently on Days 14 to 27 (median, 23 +/- 3.0). By sequential computed tomographic scans, the growth of the paravertebral tumor was documented and its volume was calculated. A single dose of cisplatin (i.p., 6 mg/kg) or doxorubicin (DXR, i.v. jugular, 6 mg/kg) was administered on Day 1. On Day 18, tumor volume was significantly reduced by DXR (P less than 0.001) and cisplatin (P less than 0.01), but paraplegia continued to occur as in the untreated rats. Comparison of treatment outcome with DXR administered via the jugular vs. the tail vein revealed that both were equally effective in retarding the growth of the paravertebral tumor, and both caused a similar transient leukopenia. However, only the tail DXR brought about a significant delay in the onset of paraplegia (P less than 0.004) and significantly increased the survival (P less than 0.001). It is suggested that the lack of efficacy of systemic chemotherapy for tumors located in the epidural space is probably related to inadequate drug exposure. The improved outcome with tail DXR infusion may be explained by the regional spinal venous perfusion, which allows an increase in the local drug concentration during its first passage through the epidural venous plexus.

Animals↗
PubMed2001

Modulations of spinal serotonin activity affect the development of morphine tolerance.

To test whether modulations of spinal serotonin (5-HT) levels would affect the development of morphine tolerance, we treated rats with either intrathecal 5-HT or 5,7-dihydroxytryptamine (5,7-DHT; a 5-HT neurotoxin) in addition to systemic infusion with morphine (2 mg x kg(-1) x h(-1)). Continuous infusion of 5-HT (10 microg x 6 microL(-1) x h(-1)) into the lumbar subarachnoid space of rats for 9 h accelerated the development of morphine tolerance. The area under the curve for the tail-flick latency test was 454.1 +/- 35.1 in the Sham Control group vs 327.6 +/- 41.0 in the 5-HT-Infused group. mu-opioid receptor binding in the lumbar spinal cord showed a decrease in the Bmax (maximal binding -46.5%), but not the binding affinity (Kd), in 5-HT-infused rats. However, intrathecal injection of 5,7-DHT (50 microg), which resulted in a 48% reduction in 5-HT and 51% reduction in 5-hydroxyindoleacetic acid concentrations, led to an attenuation of morphine tolerance (the area under the curve was 613.0 +/- 24.7 in the 5,7-DHT-Lesioned group). The binding study indicated that the affinity of lumbar micro-opioid receptors decreased 196% in 5-HT-depleted rats, whereas there was no effect on apparent binding. The infusion of 5-HT (10 microg x 6 microL(-1) x h(-1)) was not analgesic and the 5,7-DHT-induced lesion did not affect acute morphine-induced analgesia. We conclude that activity of spinal 5-HT-containing neurons plays a crucial role during the development of morphine tolerance.

5,7-Dihydroxytryptamine↗
PubMed2001

[Usefulness of a simple expiratory gas monitor during sedation under spinal anesthesia].

We introduce a simple expiratory gas monitor during sedation under spinal anesthesia. A small extension tube for infusion used as a gas sampling line is placed in the nasal vestibule. It is necessary to make it sure that the point of the tube should not contact with the mucous membrane of the nose. Our method needs no special equipments such as Capnoxygen or Nazorcap, but a cheap extension tube available in any operating room. Therefore this is a simple method. Expiratory gas monitor can detect apnea early, airway obstruction and stenosis and predict PaCO2 during sedation. The change of fractional concentration of oxygen in inspired gas predicts the change of tidal volume. Increase in the former reflects a decrease in the latter under the administration of oxygen. It is possible to evaluate whether sedation became steady with analysis of respiratory pattern. However, nasal discharge may interrupt monitoring expiratory gas. Our simple method to monitor expiratory gas is useful during sedation under regional anesthesia.

Anesthesia, Spinal↗
PubMed2006

Preventing vincristine administration errors: Does evidence support minibag infusions?

Although vincristine sulfate is indicated for IV use only, it has been inadvertently administered intrathecally. Accidental vincristine administration via the spinal route (intrathecally via a lumbar puncture or intraventricularly via an Ommaya reservoir) causes rapid sensory and motor dysfunction, usually followed by encephalopathy, coma, and death (Schulmeister, 2004). Autopsy findings include grossly edematous and congested brain and spinal cord tissue, with axonal degeneration and myelin loss of the spinal nerves (Kwack et al., 1999; Williams et al., 1983).

Adult↗
PubMed2006

Supraspinal anesthesia: behavioral and electroencephalographic effects of intracerebroventricularly infused pentobarbital, propofol, fentanyl, and midazolam.

BACKGROUND: Anesthetic endpoints of unconsciousness and immobility result from agent effects on both brain and spinal cord that are difficult to separate during systemic administration. To investigate cerebral mechanism of anesthetic-induced unconsciousness, the authors studied behavioral and electrophysiologic effects of four anesthetics infused intracerebroventricularly to conscious rats. The authors aimed to produce progressively increasing anesthetic depths, indicated by electro-encephalographic synchronization and behavioral change. METHODS: During anesthesia, rats were equipped with intracerebroventricular infusion catheters, hind-paw stimulation, and epidural electrodes to record the electroencephalogram from the somatosensory cortex. Silicone bolus was injected into the fourth ventricle to minimize drug distribution to the spinal cord. 60 min later, 50-min infusion of pentobarbital (6.0 mg/h), fentanyl (0.75 microg/h), propofol (3.0 mg/h), or midazolam (0.24 mg/h) was initiated. Vibrissal, olfactory, corneal, and tail-pinch responses were tested every 10 min. RESULTS: All agents depressed vibrissal, olfactory, and corneal responses; propofol and pentobarbital produced the strongest effect. All agents except propofol depressed tail-pinch response; fentanyl and pentobarbital produced the strongest effect. All agents except midazolam increased delta power. Pentobarbital enhanced theta power. All agents except fentanyl enhanced alpha and beta power. Pentobarbital and midazolam slightly increased, whereas fentanyl decreased, gamma power. Pentobarbital increased and midazolam decreased somatosensory evoked potential; these changes were small and apparently unrelated to behavior. CONCLUSIONS: Alpha and beta power increase may reflect sedative component of anesthesia. Simultaneous delta, alpha, and beta power increase may correlate with loss of consciousness. Theta and delta power increase may reflect surgical anesthesia. Opioid-induced gamma power decrease may reflect suppression of pain perception. Pentobarbital-, fentanyl-, and midazolam-induced immobility to noxious stimulation may be mediated supraspinally.

Anesthetics, Intravenous↗
PubMed2002

Implantable devices for pain control: spinal cord stimulation and intrathecal therapies.

Untreated chronic pain is costly to society and to the individual suffering from it. The treatment of chronic pain, a multidimensional disease, should rely on the expertise of varying health care providers and should focus not only on the neurobiological mechanisms of the process but also on the psychosocial aspects of the disease. Implantable devices are costly and invasive, and such efficacious therapies should be used only when more conservative and less costly therapies have failed to provide relief of pain and suffering. Spinal cord stimulation provides neuromodulation of neuropathic, but not nociceptive, pain signals and when used for appropriate indications in the right individuals provides approximately 60-80% long-term pain relief in 60-80% of patients trialled for efficacy. Intrathecal therapies with opioids such as morphine, fentanyl, sufentanil or meperidine--or non-opioids such as clonidine or bupivacaine--provide analgesia in patients with nociceptive or neuropathic pain syndromes. Baclofen, intrathecally, provides profound relief of muscle spasticity due to multiple sclerosis, spinal cord injuries, brain injuries or cerebral palsy.

Adrenergic alpha-Agonists↗
PubMed2003

Treatment of reactive arthritis with infliximab.

We describe two patients with acute reactive arthritis (ReA) caused by Yersinia enterocolitica who were treated with infliximab with a good response in the acute phase. In a patient with prior ankylosing spondylitis (AS) and subsequent ReA the peripheral joint disease responded well to three infliximab infusions, but later he needed retreatment with infliximab to control the spinal symptoms of AS. The other previously healthy patient with acute ReA also responded well to one infliximab infusion although he did not fully recover and needed further treatment with disease modifying antirheumatic drugs. The influence of new drugs on the short and long term prognosis of the patients with ReA remains to be evaluated.

Adult↗
PubMed2006

Postoperative outcome in Chinese patients having primary total knee arthroplasty under general anaesthesia/intravenous patient-controlled analgesia compared to spinal-epidural anaesthesia/analgesia.

OBJECTIVE: To compare postoperative outcomes in patients having primary total knee arthroplasty receiving general or regional anaesthesia. DESIGN: Randomised prospective study. SETTING: Regional hospital, Hong Kong. PATIENTS: Patients having primary total knee replacement were randomised to either general anaesthesia followed by postoperative intravenous patient-controlled analgesia with morphine, or combined spinal-epidural anaesthesia followed by postoperative epidural infusion of bupivacaine 0.1% with fentanyl 2 microg/mL. MAIN OUTCOME MEASURES: Visual analogue scale pain scores, perioperative blood loss, time to first meal and ambulation, and prevalence of postoperative complications. RESULTS: Sixty consecutive patients were enrolled in this study. Postoperative median pain scores were consistently lower at 1 (P<0.0001), 6 (P=0.08), 12 (P=0.003), 24 (P=0.14), and 48 hours (P=0.007) in those given regional anaesthesia. Although there was a trend towards fewer complications in the latter group, there were no statistically significant differences between the two groups with respect to the incidence of postoperative blood loss, haemodynamic instability, pruritus, nausea, vomiting, urinary retention, or other surgical/medical complications. Postoperatively, patients given regional anaesthesia also resumed meals earlier (P<0.0001), and showed a trend towards earlier ambulation and hospital discharge. CONCLUSION: Chinese patients undergoing total knee arthroplasty with regional anaesthesia/regionally delivered analgesia enjoyed better postoperative pain relief and resumed meals earlier than those receiving general anaesthesia/intravenous patient-controlled analgesia. The former also showed trends towards less adverse effects, postoperative complications, earlier ambulation, and earlier hospital discharge.

Analgesia, Epidural↗
PubMed2001

An adenosine A2A agonist, ATL-146e, reduces paralysis and apoptosis during rabbit spinal cord reperfusion.

BACKGROUND: We hypothesized that systemic ATL-146e, an adenosine A(2A) agonist, would decrease spinal cord reperfusion inflammatory stress and inhibit apoptosis and that these effects would correlate with improved neurologic functional outcome. METHODS: Thirty rabbits underwent cross-clamping of the infrarenal aorta for 45 minutes. One group of animals (n = 14) received 0.06 microg/kg per minute of ATL-146e infused intravenously for 3 hours, beginning 15 minutes before reperfusion. A second group of animals (n = 16) underwent spinal cord ischemia with saline vehicle alone and served as ischemic controls. Animals (n = 9, 11) from each group survived for 48 hours and assessed for neurologic impairment with the Tarlov (0-5) scoring system. Four animals from each group were humanely killed at the end of the 3-hour treatment period, and the remainder killed after 48 hours' survival. In all animals, lumbar spinal cord tissue specimens were frozen for subsequent Western blot analysis of heat shock protein 70 (HSP 70), and for the p85 fragment of poly (ADP-ribose) polymerase (PARP). Neuronal viability indices were determined at 48 hours with hematoxylin and eosin staining. RESULTS: There was improvement in neurologic function in rabbits receiving ATL-146e (P <.001) compared with ischemic controls. At the end of the 3-hour treatment period there was a 46% (P <.05) decrease in HSP 70 expression in the ATL-146e group compared with the control group, but no difference in PARP expression. At 48 hours, there was no difference between control and ATL-146e groups in HSP 70 expression, but there was a 65% (P <.05) reduction in PARP in the spinal cords of animals that had received ATL-146e. There was a significant improvement in neuronal viability indices in animals receiving ATL-146e compared with ischemic controls (P <.05). CONCLUSIONS: Systemic ATL-146e infusion during reperfusion after spinal cord ischemia results in preservation of hindlimb motor function. There is evidence of decreased spinal cord inflammatory stress immediately after treatment with ATL-146e as indicated by reduced HSP 70 induction. Treatment with ATL-146e is associated with a reduction in neuronal apoptosis as suggested by a substantial decrease in the fragmentation of PARP at 48 hours. These results suggest that inflammation during reperfusion and subsequent apoptosis contribute to paralysis after restoration of blood flow to the ischemic spinal cord.

Animals↗
PubMed1999

Neuroprotective effects of basic fibroblast growth factor following spinal cord contusion injury in the rat.

Cytokines and neurotrophic factors have been implicated in the pathophysiology of injury to the central nervous system. While some cytokines are considered pro-inflammatory, other factors promote neuronal growth and survival. The present study investigated the neuroprotective effects of interleukins 1 (IL-1), 4 (IL-4), and 6 (IL-6), nerve growth factor (NGF), ciliary neurotrophic factor (CNTF), and basic fibroblast growth factor (bFGF) in a contusion model of spinal cord injury. Female Sprague-Dawley rats (n = 55) sustained a 10-g weight-drop injury to the lower thoracic spinal cord (T10) from a height of 12.5 mm using the NYU impactor. A micro-infusion system (Alzet minipump) was used to continuously deliver drugs or vehicle directly into the epicenter of the contused spinal cord starting 1 or three h postinjury. At the end of 7 days, animals were perfused and the cords removed for histopathological analysis. Longitudinal serial sections were cut on a freezing microtome and stained with cresyl violet. Areas of central necrosis, partial preservation, and total zone of tissue injury were identified and traced by an independent reviewer using a computer based imaging system. The mean total zone of injury in five animals receiving vehicle infusion was 18.04+/-4.20 mm3. The mean zone of partial preservation in these animals was 16.46+/-3.32 mm. Basic fibroblast growth factor reduced the total zone of injury by 33% [p<0.01, least significant difference (LSD) of Fisher] in five animals and the zone of partial preservation by 32% (p<0.01, LSD of Fisher) when compared to controls. There were trends toward reduction in total zone of injury and zone of partial preservation in rats treated with IL-4, CNTF, and NGF versus vehicle; however, none of these reached statistical significance. No significant differences were observed between animals receiving vehicle versus bFGF treatment commencing 3 h after injury. These data demonstrate that the continuous intramedullary infusion of bFGF initiated one hour after moderate contusion injury of the spinal cord significantly reduces the total zone of injury and the zone of partial preservation. These results support the further investigation and possible future clinical application of bFGF in the treatment of acute spinal cord contusion injury.

Animals↗