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PubMed2001

Neither GABA(A) nor strychnine-sensitive glycine receptors are the sole mediators of MAC for isoflurane.

UNLABELLED: Inhaled anesthetics produce immobility (a cardinal aspect of general anesthesia) by an action on the spinal cord, possibly by potentiating the responses of gamma-amino-n-butyric acid (GABA(A)) and glycine receptors to GABA and glycine. In this study, we antagonized GABA(A) and glycine responses by intrathecal administration of picrotoxin (a noncompetitive GABA(A) antagonist), strychnine (a competitive glycine antagonist), or combinations of these drugs. We measured the capacity of antagonist infusion to increase isoflurane MAC (the minimum alveolar concentration of anesthetic that prevents movement in response to noxious stimuli in 50% of subjects). We found that these potent GABA(A) and glycine receptor antagonists had a ceiling effect, either alone or in combination increasing the MAC of isoflurane by at most 47%. IMPLICATIONS: gamma-amino-n-butyric acid and glycine receptors may in part be responsible for the immobilizing action of isoflurane. They are not, however, the only receptors that contribute to isoflurane-induced immobility (i.e., that determine the MAC of isoflurane).

Absorption↗
PubMed2002

Brain temperature measured by 1H-NMR in conjunction with a lanthanide complex.

In vivo data on temperature distributions in the intact brain are scarce, partly due to lack of noninvasive methods for the region of interest. NMR has been exploited for probing a variety of brain activities in vivo noninvasively within the region of interest. Here we report the use of a thulium-based thermometric sensor, infused through the blood, for monitoring absolute temperature in rat brain in vivo by (1)H-NMR and validated by direct temperature measurements with thermocouple wires. Because the (1)H chemical shifts also demonstrate pH sensitivity, detection of multiple resonances was used to measure both temperature and pH simultaneously with high sensitivity. Examination of blood plasma and cerebral spinal fluid samples removed from rats infused with the thermometric sensor suggests that the complex, despite its negative charge, crosses the blood-brain barrier to enter the extracellular milieu. In the future, the thulium-based thermometric sensor may be used for monitoring temperature (and pH) distributions throughout the entire brain, examining response to therapy and evaluating changes induced by alterations in neuronal activity.

Animals↗
PubMed2002

Convection-enhanced delivery into the rat brainstem.

OBJECT: Convection-enhanced delivery (CED) can be used safely to achieve high local infusate concentrations within the brain and spinal cord. The use of CED in the brainstem has not been previously reported and may offer an alternative method for treating diffuse pontine gliomas. In the present study the authors tested CED within the rat brainstem to assess its safety and establish distribution parameters. METHODS: Eighteen rats underwent stereotactic cannula placement into the pontine nucleus oralis without subsequent infusions. Twenty rats underwent stereotactic cannula placement followed by infusion of fluorescein isothiocyanate (FITC)-dextran at a constant rate (0.1 microl/minute) until various total volumes of infusion (V(i)s) were reached: 0.5, 1, 2, and 4 microl. Additional rats underwent FITC-dextran infusion (V, 4 microl) and were observed for 48 hours (five animals) or 14 days (five animals). Serial (20-microm thick) brain sections were imaged using confocal microscopy with ultraviolet illumination, and the volume of distribution (Vd) was calculated using computer image analysis. Histological analysis was performed on adjacent sections. No animal exhibited a postoperative neurological deficit, and there was no histological evidence of tissue disruption. The Vd increased linearly (range 15.4-55.8 mm3) along with increasing Vi, with statistically significant correlations for all groups that were compared (p < 0.022). The Va/Vi ratio ranged from 14 to 30.9. The maximum cross-sectional area of fluorescence (range 9.8-20.9 mm2) and the craniocaudal extent of fluorescence (range 2.8-5.1 mm) increased with increasing Vi. CONCLUSIONS: Convection-enhanced delivery can be safely applied to the rat brainstem with substantial and predictable V(d)s. This study provides the basis for investigating delivery of various candidate agents for the treatment of diffuse pontine gliomas.

Animals↗
PubMed1990

Possible interaction between SPPS and enalapril.

A patient undergoing groin lymph node dissection with spinal and general anaesthesia was receiving enalapril to control hypertension. Infusion of stable plasma protein solution (Commonwealth Serum Laboratories, Australia) was associated with significant hypotension and flushing. A brief review of stable plasma protein solution and angiotensin converting enzyme inhibitor pharmacology is presented to provide a possible mechanism for these events. This mechanism implies that angiotensin converting enzyme inhibitor therapy is a relative contraindication to rapid SPPS infusion.

Aged↗
PubMed2002

Dose response of intrathecal adenosine in experimental pain and allodynia.

BACKGROUND: Intrathecal adenosine reduces areas of mechanical hypersensitivity and provides analgesia in patients with neuropathic pain. Adenosine also causes side effects, yet its dose response for either efficacy or side effects has not been examined in double blind studies. We studied two doses of intrathecal adenosine in humans with experimental hypersensitivity and the ability of the adenosine receptor antagonist, aminophylline, to reverse adenosine's effects. METHODS: Following Internal Review Board approval and written informed consent, 35 volunteers were studied. Five volunteers were studied to confirm the stability of a new method of inducing hypersensitivity with capsaicin. The remaining 30 volunteers received, in a randomized, double-blind manner, saline, or adenosine, 0.5 or 2.0 mg, by intrathecal injection 40 min after areas of allodynia and hyperalgesia were established from capsaicin. Two hr later, volunteers were randomized to receive intravenous saline or aminophylline, 5 mg/kg. RESULTS: Topical capsaicin with intermittent heating resulted in stable areas of allodynia and hyperalgesia. Intrathecal adenosine, but not saline, reduced areas of allodynia and hyperalgesia from capsaicin, with no differences between doses. Side effects occurred in 1, 2, and 6 volunteers receiving saline, 0.5 mg and 2.0 mg adenosine, respectively. Aminophylline failed to reverse adenosine's effects. CONCLUSIONS: There is no difference in efficacy to experimental hypersensitivity between the largest approved dose of intrathecal adenosine and a dose 25% this size, but side effects are more common with the larger dose. Failure of aminophylline to reverse adenosine's effects could reflect inadequate concentrations at receptors in the spinal cord after intravenous injection.

Adenosine↗
PubMed1998

Adenosine modulation: a novel approach to analgesia and inflammation.

Adenosine (ADO) is an endogenous purine nucleoside that functions as an extracellular signalling molecule. It is released locally at sites of cellular trauma, and acts on specific cell-surface purinergic receptors (termed P1 receptors) near its site of release to exert its effects. Four subtypes of the P1 family of G-protein-coupled receptors have been identified and cloned: A1, A2A, A2B and A3. A considerable body of evidence, including experimental animal data and preliminary clinical reports, indicates that ADO is involved in modulating endogenous antinociceptive processes in the brain and spinal cord. ADO analogues provide analgesic activity after systemic or spinal administration in a broad spectrum of animal pain models. In addition, iv. ADO infusion has shown benefit in human pain states. The spinal cord is a key site for ADO-mediated modulation of nociception. ADO is well known to act as an inhibitory neuromodulator in the central and peripheral nervous system, and it may act to control N-methyl-D-aspartate (NMDA)- and substance P-mediated events in nociception and central sensitisation at the spinal level. ADO is also released at sites of inflammation and it exerts anti-inflammatory effects via multiple mechanisms involving several cell types. These include effects on neutrophil function, endothelial cell permeability, in vivo and in vitro release of tumour necrosis factor (TNF-alpha and collagenase expression in synoviocytes. Accordingly, ADO analogues are effective in several animal models of inflammation, including the rat adjuvant arthritis model. Several therapeutic approaches to pain and inflammation, based on mimicking or modulating the effects of endogenous ADO, are currently under preclinical and clinical investigation. These include the use of ADO itself, the use of direct-acting ADO receptor agonists and the use of agents designed to modulate the levels and, therefore, the actions of ADO in the extracellular space (ADO kinase (AK) inhibitors). Data emerging in the next several years should indicate whether these strategies represent a therapeutically useful new approach to analgesia and inflammation.

Journal Article↗
PubMed2002

Continuous spinal analgesia for labor and delivery in a parturient with hypertrophic obstructive cardiomyopathy.

Induction of labor under analgesia was planned for a 30-year-old-primiparous patient with hypertrophic obstructive cardiomyopathy (HOCM), as her fetal evaluation revealed intrauterine growth restriction at 38 weeks' gestation. However, regional analgesia during labor may present a potential risk for hemodynamic instability in patients with HOCM due to the possibility of a sympathetic block, as a result of vasodilation associated with the administration of local anesthesia. This case report demonstrates the successful management of the patient with analgesia provided by a continuous spinal catheter dosed with a continuous infusion of fentanyl and supplemental meperidine. Fetal surveillance monitoring included fetal pulse oximetry in addition to conventional cardiotocography, on the basis of which cesarean section was avoided.

Adult↗
PubMed2001

Spinal and cranial contributions to total cerebrospinal fluid transport.

In this study, we quantified cerebrospinal fluid (CSF) transport from the cranial and spinal subarachnoid spaces separately in sheep and determined the relative proportion of total CSF drainage that occurred from both CSF compartments. Cranial and spinal CSF systems were separated by placement of an extradural ligature over the spinal cord between C(1) and C(2). In one approach, two different radiolabeled human serum albumins (HSA) were introduced into the appropriate CSF compartment by a perfusion system (method 1) or as a bolus injection (method 2). Plasma tracer recoveries in conjunction with a mass balance equation were used to estimate CSF transport. In method 3, catheters connected to reservoirs filled with artificial CSF were introduced into the cranial and spinal CSF compartments. Incremental CSF pressures were established in each CSF system, and the corresponding steady-state flow rates were measured. Total CSF drainage ranged from 0.51 to 0.75 ml. h(-1). cmH(2)O(-1). Expressed as a percentage of the total CSF transport, the ratios of cranial-to-spinal clearance estimated from methods 1, 2, and 3 were 75:25, 88:12, and 75:25, respectively. Primarily on the basis of the data derived from methods 1 and 3, we conclude that the spinal subarachnoid compartment has an important role in CSF clearance and is responsible for approximately one-fourth of total CSF transport.

Animals↗
PubMed2000

Effect of brain-derived neurotrophic factor, nerve growth factor, and neurotrophin-3 on functional recovery and regeneration after spinal cord injury in adult rats.

This study examined whether continuous intramedullary infusion of brain-derived neurotrophic factor (BDNF), nerve growth factor (NGF), or neurotrophin-3 (NT-3) had either an early neuroprotective effect or a delayed effect on regeneration after spinal cord injury (SCI) in adult rats. BDNF, NGF, NT-3 or vehicle was infused at a rate of 625 ng/h into the SCI site at T3 through an implanted cannula attached to an osmotic pump. This infusion was maintained for 14 days after a 35-g clip compression injury. At 4 weeks after injury, the axonal tracer fluorogold (FG) was introduced into the spinal cord caudal to the lesion and the animals sacrificed 3 days later following behavioral assessment. The inclined plane score was significantly higher in BDNF-treated animals (45 +/- 3 degrees) compared to control animals (36 -/+ 1 degrees) at 1 week after injury (p < 0.05), although the scores were not significantly different at later times. BDNF-treated animals also showed more FG-labeled cells in the red nucleus and sensorimotor cortex (1,638 +/- 350 and 124 +/- 83, respectively) compared to controls (1,228 +/- 217 and 36 +/- 15, respectively) and a lower percent cavitation at the injury site (21.4 +/- 10.4%) compared to control animals (32.3 +/- 11.7%). Invasion & proliferation of Schwann cells and formation of peripheral myelin were more prominent at the injury site in the BDNF-treated animals than in the other groups. These results indicate that continuous intramedullary infusion of BDNF provides neuroprotection and enhances some regenerative activity after SCI.

Animals↗
PubMed1993

Epidural versus intravenous fentanyl for reducing hormonal, metabolic, and physiologic responses after thoracotomy.

BACKGROUND: Previous attempts to prevent all the unwanted postoperative responses to major surgery with an epidural hydrophilic opioid, morphine, have not succeeded. The authors' hypothesis was that the lipophilic opioid fentanyl, infused epidurally close to the spinal-cord opioid receptors corresponding to the dermatome of the surgical incision, gives equal pain relief but attenuates postoperative hormonal and metabolic responses more effectively than does systemic fentanyl. METHODS: Forty patients were randomly assigned to receive either fentanyl epidurally and saline intravenously, or fentanyl intravenously and saline epidurally, in a double-blind fashion for the first 20 h after thoracotomy. For each patient, the fentanyl infusion was titrated to the rate required for pain relief (pain score < 3, maximum 10). Postoperative changes in blood pressure, heart rate, rectal temperature, and blood concentrations of adrenocorticotrophic hormone, beta-endorphin immunoreactivity, cortisol, growth hormone, prolactin, glucose, and leukocytes were assessed. RESULTS: Patients reported similar median pain scores, but the epidural group required about 40% less fentanyl than the intravenous group. Four hours postoperatively, the beta-endorphin immunoreactivity concentrations were less in the epidural than in the intravenous group. Plasma cortisol increased in a similar manner in both groups within 4 h of surgery, but the increase persisted to the next morning only in patients receiving intravenous fentanyl. Adrenocorticotropin, growth hormone, and prolactin responses were similar in both groups. The postoperative hyperglycemic response, leukocytosis, and blood pressure were greater, and mean rectal temperature was lower, in the intravenous than in the epidural fentanyl group. CONCLUSIONS: The authors' results indicate that some aspects of the hormonal response to surgery are blocked more completely with epidural than with intravenous fentanyl. Adequate pain relief with epidural fentanyl, with a smaller mean dose, led to a smaller increase of some hormonal, metabolic, and physiologic responses after thoracotomy than in association with the adequate pain relief provided by intravenous fentanyl.

Adrenocorticotropic Hormone↗
PubMed1998

[Sedative and hypnotic properties of propofol during epidural or spinal anesthesia].

The sedative and hypnotic properties of propofol were studied in 40 patients undergoing elective gynecologic or orthopedic surgery using epidural (epidural group, n = 20) or spinal (spinal group, n = 20) anesthesia. Patients were given a bolus dose of 1 mg.kg-1 immediately followed by a continuous infusion of 4 mg.kg-1.h-1 of propofol after epidural or spinal anesthesia. The patients were asked to open their eyes on command at 10-sec interval from the end of the bolus infusion of propofol. We administered oxygen when SpO2 decreased below 93%. The mean induction time to reach the level of sedation, no response to verbal command to open their eyes, was 6 +/- 10 (SD) min in the epidural group, and 7 +/- 17 min in the spinal group. The mean recovery times, judged by ability to open eyes and recall date of birth, were 4 +/- 4 min and 7 +/- 6 min in the epidural group, and 4 +/- 4 min and 5 +/- 5 min in the spinal group, respectively. There were no differences in all recorded times between the two groups. Oxygen inhalation was needed in 75% of the patients in the epidural group and 100% in the spinal group. These results indicate that bolus and continuous infusion of propofol produces rapid induction, deep level of sedation, and rapid recovery during epidural or spinal anesthesia. However, respiratory depression appeared at this infusion rate during regional anesthesia.

Adjuvants, Anesthesia↗
PubMed2003

Treatment of chronic mechanical spinal pain with intravenous pamidronate: a review of medical records.

We explored the effect of intravenous infusions of a bisphosphonate, pamidronate, in the management of chronic mechanical spinal pain, a worldwide public health problem in terms of lost workdays, medical treatment costs, and suffering. Bisphosphonates have an anti-nociceptive effect in animals. In humans, intravenous pamidronate relieves numerous painful conditions, including metastatic bone pain, ankylosing spondylitis, rheumatoid arthritis, and complex regional pain syndrome. We reviewed the charts of 25 patients who had experienced disabling spinal pain for several years, and whom we treated with intravenous pamidronate. None had a history of osteoporotic vertebral fractures or metastatic disease. Pain rating scores decreased in 91% of patients: on a 0-10 numeric rating scale, the mean pain change was -3.6 points and mean percentage change was -41% (P<0.0001). There was no increase in opioid or nonopioid analgesic medications associated with pain relief. The apparent analgesic effect of pamidronate for chronic mechanical spinal pain needs to be confirmed with placebo-controlled trials.

Adult↗
PubMed2006

Intrathecal infusions of anisomycin impact the learning deficit but not the learning effect observed in spinal rats that have received instrumental training.

Previous research has shown that spinally transected rats will learn to maintain a flexion response when administered shock contingent upon leg position. In short, a contingency is arranged between shock delivery and leg extension so that Master rats exhibit an increase in flexion duration that lasts throughout the training session. Furthermore, when Master rats are later tested they reacquire the flexion response in fewer trials, indicative of some savings. As a control, a second group of spinal rats (Yoked rats) are given shock irrespective of leg position (noncontingent shock). These animals fail to show the same increase in leg flexion duration. Interestingly, when Yoked rats are later tested with a shock contingency in place, they still fail to learn (learning deficit). The present experiments were designed to determine whether both forms of instrumental learning in spinal animals require de novo protein synthesis. As such, we administered various doses of anisomycin intrathecally prior to training. Additionally, spinal rats were trained and tested either immediately or 24 h after test. We found that only the highest dose of anisomycin (125 microg/microl) had an effect in Yoked animals that were tested 24 h after training. Specifically, the highest dose of anisomycin reversed the learning deficit in those animals. Moreover, anisomycin had a similar effect when administered prior to training and immediately following training, but not 6 h after training. Finally, the results demonstrated that the observed effect of anisomycin was not due to state-dependency.

Animals↗
PubMed1992

Long-term intrathecal baclofen treatment in supraspinal spasticity.

Baclofen, a derivate of gamma-amino butyric acid (GABA), is known to be a useful drug in spasticity treatment. To achieve a good therapeutic response higher oral dosages have to be administered related with central side effects. Intrathecal application of Baclofen in microgram range dosages is proved to be effective in spinal spasticity. The efficiency of intrathecal Baclofen in patients suffering from supraspinal spasticity is discussed controversially. We report on 9 patients with long-term intrathecal Baclofen treatment, all of them responding well presenting a marked reduced muscle tone. In most cases an improvement of motor performance and in two cases improved bladder function was observed. The therapeutical dosages administered to patients with supraspinal spasticity exceed those administered to patients with spinal spasticity by approximately 100% without provoking central side effects. Despite the risks connected with this method it has to be considered as treatment of choice in cases of severe supraspinal spasticity.

Adult↗
PubMed1993

Cutaneous, musculoskeletal and bone flow scintiscan by intravenous infusion of 99mTc-MDP (Diphosphonate) in the evaluation and control of patients treated with spinal cord stimulation for ischaemic pain.

In patients affected by unbearable pain secondary to peripheral vascular disorders beyond surgical repair such as thromboangitis obliterans, diabetic microangiopathy, arteriosclerosis obliterans, there is a need to establish the degree of micro-circulation functionality before proceeding with invasive pain therapy, such as Spinal Cord Stimulation (SCS). From our series some cases of refractory ischaemic pain subjected to nuclear medicine techniques assessment before and after SCS implant will be presented; these data suggest that the use of radionuclides for quantifying regional perfusion, in view of the information it offers us both in the dynamic angiographic phase and in the later static phase, constitutes a very valid aid in the diagnosis and treatment of chronic pain conditions of ischaemic origin. Cutaneous, musculoskeletal and bone flow scintiscan is a non-invasive procedure which allowed us to make an objective selection of patients who are candidates for prolonged conservative treatment thus limiting the incidence of ineffective permanent SCS implants.

Adult↗