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Addition of noradrenaline to intrathecal morphine augments the postoperative suppression of natural killer cell activity.

PURPOSE: Intrathecal administration of morphine has been shown to suppress natural killer (NK) cell activity. We tested the hypothesis that combined administration of morphine and noradrenaline would further modify NK cell activity in patients undergoing hysterectomy. METHODS: Thirty female patients were randomly divided into three groups of ten patients each. Groups MN and M received intrathecal morphine (0.5 mg) dissolved in 5 ml of physiological saline with and without 5 micro g noradrenaline, respectively. Group C received saline alone. After the intrathecal administration, general anesthesia was induced. Blood samples were withdrawn before and 2 h after surgery and on postoperative days 1, 2, and 7 to determine the NK cell activity, the ratio of T-helper/inducer cells (CD4) to T-suppressor/cytotoxic cells (CD8), the levels of interleukin-6 (IL-6) and interleukin-8 (IL-8), and the plasma concentrations of catecholamines and cortisol. RESULTS: NK cell activity decreased on postoperative day 1 in groups MN (12.0 +/- 2.7%) and M (25.4 +/- 9.6%) compared with their respective baseline levels. In group MN, NK cell activity remained lower (23.7 +/- 8.0%) on postoperative day 2 than the baseline value before surgery. CONCLUSION: Intrathecal administration of morphine causes a decrease in NK cell activity, and its combined use with noradrenaline prolongs the suppression of NK cell activity.

Adult↗

Subcutaneous formalin-induced activity of dorsal horn neurones in the rat: differential response to an intrathecal opiate administered pre or post formalin.

Many studies of pain and nociception use short-lasting acute stimuli which may have limited relevance to prolonged or chronic pain states. Using extracellular single-unit recording in the dorsal horn of the rat lumbar spinal cord the present study examines the response of neurones to a long-lasting nociceptive stimulus, i.e., 50 microliter 5% formalin injected into the corresponding receptive field in the ipsilateral hind paw, and modulation of this response by an opioid. Formalin produced a distinct biphasic excitatory response in all convergent neurones tested; an immediate acute or phasic peak of neuronal firing (mean maximum 22 spikes/sec) 0-10 min post injection, and a second more prolonged tonic excitatory response (mean maximum 12 spikes/sec) over a period 20-65 min after formalin. Cells only activated by innocuous stimuli were not excited by formalin indicating the involvement of C fibre afferents in the excitatory response of convergent neurones to formalin. Both the biphasic nature and the time course of the neuronal response are similar to those observed in behavioural studies. Intrathecal DAGO (Tyr-D-AlaGlyMePheGly-ol), a potent and selective mu opioid receptor agonist, applied 20 min prior to formalin completely inhibited both peaks of excitation. Co-administration of intrathecal naloxone with the agonist restored the biphasic response. By contrast, when the administration of naloxone was delayed to 2 min post formalin so that inhibition of the first peak by DAGO pretreatment occurred, there was no subsequent second peak of activity although antagonism of the opioid would have occurred. When DAGO was applied 2 min post formalin so the initial acute response occurred, the inhibitory effect of the agonist on the second peak was far less. Thus the relative ability of DAGO to modulate the biphasic excitatory response of cells to formalin depends on whether the agonist is administered prior to or after the formalin and the appearance of the second peak may depend on the presence of the first. These results are discussed in light of the role of these neurones in nociception, opioid effects and changes in neural systems following peripheral stimuli.

Animals↗

Hemodynamic effects of intrathecal fentanyl in nonlaboring term parturients.

STUDY OBJECTIVE: To determine the effect of intrathecal fentanyl on maternal hemodynamics. DESIGN: Prospective. SETTING: Labor and delivery suite of a university medical center. PATIENTS: 23 ASA status I nonlaboring term parturients presenting for elective cesarean section. INTERVENTIONS: Patients were given either 1,200 ml lactated Ringer's Solution (Group 1, n = 12) or no intravenous (i.v.) fluid (Group 2, n = 11). A combined spinal-epidural technique was then performed. Fentanyl 25 micrograms was administered intrathecally through a 24-gauge Sprotte or 25-gauge Whitacre spinal needle. After completion of the hemodynamic study, a catheter was threaded into the epidural space for local anesthetic administration. MEASUREMENTS AND MAIN RESULTS: Baseline hemodynamic data [systolic (SBP), diastolic, and mean arterial pressure, heart rate, stroke volume, cardiac output, end-diastolic volume, and ejection fraction] were obtained in triplicate using noninvasive blood pressure monitoring and impedance cardiography. After administration of intrathecal fentanyl, hemodynamic measurements were recorded at 3-minute intervals for 30 minutes. These values were compared with baseline for both groups. Ten patients in each group completed the study. Intrathecal fentanyl administration did not result in any maternal hemodynamic changes in Group 1, and a few small statistically significant changes in Group 2. Measured SBP was always greater than 100 mmHg in all patients during the study. CONCLUSION: Intrathecal administration of fentanyl 25 micrograms in nonlaboring term parturients does not produce clinically important maternal hemodynamic changes.

Adult↗

dextro- and levo-morphine attenuate opioid delta and kappa receptor agonist produced analgesia in mu-opioid receptor knockout mice.

We have demonstrated that the antianalgesia induced by dextro-morphine and levo-morphine is not mediated by the stimulation of mu-opioid receptors in male CD-1 mice. We now report that the dextro-morphine and levo-morphine attenuated antinociception produced by delta-opioid receptor agonist deltorphin II and kappa-opioid receptor agonist U50,488H given spinally in the male mu-opioid receptor knockout mice. The tail-flick response was used for the antinociceptive test. Intrathecal injection of levo-morphine (3 nmol) markedly inhibited the tail-flick response in wild type, partially in heterozygous, but not in homozygous mu-opioid receptor knockout mice. Intrathecal pretreatment with dextro-morphine (33 fmol) or levo-morphine (0.3 nmol) for 45 min also attenuated levo-morphine-produced antinociception in wide type mice. Intrathecal pretreatment with dextro-morphine (33 fmol) or levo-morphine (0.3 nmol) for 45 min attenuated the tail-flick inhibition produced by deltorphin II (12.8 nmol) and U50,488H (123.3 nmol) in wide type, heterozygous and homozygous mu-opioid receptor knockout mice. The findings provide additional evidence that mu-opioid receptors are not involved in the antianalgesia induced by dextro-morphine and levo-morphine.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗

A role for nerve growth factor in sympathetic sprouting in rat dorsal root ganglia.

The role of nerve growth factor (NGF) and glial-derived neurotrophic factor (GDNF) in sympathetic sprouting within the dorsal root ganglion was investigated. In nerve-intact rats, intrathecal NGF (1 mg/ml, 14 days) but not GDNF (1 mg/ml, 14 days) induced extensive sprouting of tyrosine hydroxylase immunoreactive (TH-IR) fibres and formation of pericellular TH-IR baskets within lumbar DRGs. TH-IR baskets were distributed equally to trkA-expressing and trkA-negative neuronal profiles. Sciatic nerve transection (14-21 days) induced TH-IR baskets within lumbar DRG's around neuronal profiles with both intact and lesioned axons. The percentage of neuronal profiles surrounded by TH-IR baskets following sciatic transection was unaffected following peripheral application of the NGF sequestering antibody, trkA-IgG (1 mg/ml, 14 days). Intracellular responses were recorded from sensory neurons in an in vitro DRG/peripheral nerve preparation following bath application of noradrenaline. In preparations from animals treated 14 days previously with intrathecal NGF, 69% of neurons responded with depolarizing responses whilst 18% of neurons responded to bath applied noradrenaline in tissue prepared from naive animals. Our data indicate that sympathetic neurons sprout into the DRG in response to sciatic nerve injury and intrathecal NGF but not GDNF. Distribution of sympathetic sprouts within the DRG is independent of whether target neurons are injured or express trkA. Sequestration of NGF at the peripheral injury site does not influence basket formation within the DRG. It is likely that functional noradrenergic connections exist between sympathetic sprouts and sensory neuron cell bodies following exogenous NGF.

Animals↗

Comparison of the effects of two intrathecal anaesthetic techniques for transurethral prostatectomy on haemodynamic and pulmonary function.

BACKGROUND AND OBJECTIVE: Transurethral prostatectomy is routinely performed under spinal anaesthesia. This technique can cause hypotension, which is particularly undesirable in the elderly. The objective was to compare spinal anaesthesia for transurethral prostatectomy using hyperbaric bupivacaine 15 mg (control group) and hyperbaric bupivacaine 10 mg (limiting spread by maintaining the upright position for 15 min) and fentanyl 25 microg (fentanyl group) in terms of haemodynamic and pulmonary function. METHODS: Thirty ASA I-III patients were randomly selected and underwent spinal anaesthesia with either hyperbaric bupivacaine 15 mg (immediately positioned supine) or hyperbaric bupivacaine 10 mg (upright for 15 min) and fentanyl 25 microg. RESULTS: The greatest changes in mean arterial pressure (P = 0.9), ephedrine requirements (P = 0.8) and mean maximum change in forced vital capacity (P = 0.5) were similar in both groups. CONCLUSIONS: The addition of fentanyl 25 microg to bupivacaine 10 mg and limiting the spread of the block does not improve either haemodynamic or pulmonary function compared with bupivacaine 15 mg in patients undergoing transurethral prostatectomy.

Adjuvants, Anesthesia↗

Gabapentin produces dose-dependent antinociception in the orofacial formalin test in the rat.

BACKGROUND AND OBJECTIVES: High neuraxial drug infusion has been advocated for the treatment of intractable cranial and facial pain in humans. Currently, parallel animal models have not been characterized to support this methodology. We combined an accepted animal model of pain of cranial origin with a novel technique of cervico-medullary drug delivery to determine the antinociceptive potential of gabapentin. Gabapentin was chosen because of its reported efficacy in a wide array of complex cranial pain syndromes. METHODS: Male Wistar rats were implanted with intrathecal catheters that were advanced cephalad through a lumbar guide cannula to terminate in the high cervical spinal cord (C1-C4). Antinociception was assessed by the orofacial formalin test. Vehicle or gabapentin (3, 10, 30, 100 microg) was injected intrathecally followed 10 minutes later by injection of 2.5% formalin solution into the vibrissal pad. Motor assessment was evaluated in a separate group of animals. RESULTS: Intrathecal gabapentin (10, 30, 100 microg) produced a dose-dependent decrease in the second phase of the behavioral response to formalin (P <.05). First-phase responses were unaffected by all doses of gabapentin. The ED50 (95% confidence limit) value for the second phase was 8.27 microg (3.50 to 14.5). No overt motor dysfunction or behavioral impairment was observed. CONCLUSIONS: Gabapentin produced dose-dependent antinociception in the second phase of the orofacial formalin test in the rat after injection into the cervico-medullary cerebrospinal fluid. This animal model may be useful to assess analgesics designed for parallel clinical application in humans for the treatment of intractable head and neck pain that is refractory to conventional modalities.

Acetates↗

Intrathecal midazolam increases the analgesic effects of spinal blockade with bupivacaine in patients undergoing haemorrhoidectomy.

In the present double-blind study we aimed to evaluate the postoperative analgesic effects of intrathecal midazolam with bupivacaine following haemorrhoidectomy. Forty-five patients were randomly allocated to one of three groups: the control group received 1 ml of 0.5% heavy bupivacaine plus 0.2 ml of 0.9% saline intrathecally, group BM1 received 1 ml of 0.5% bupivacaine plus 0.2 ml of 0.5% preservative-free midazolam and group BM2 received 1 ml of 0.5% bupivacaine plus 0.4 ml of 0.5% midazolam. Time to first analgesia was significantly greater in the midazolam groups than in the placebo and significantly less in the BM1 group than in the BM2 group.

Adjuvants, Anesthesia↗

Effects of verapamil on spinal anesthesia with local anesthetics.

The primary mode of action of local anesthetics is through sodium channel and axonal conduction blockade. Local anesthetics also have extensive effects on presynaptic calcium channels that must function to stimulate the release of neurotransmitters. Thus, interference with calcium channel conductance may enhance spinal anesthesia with local anesthetics. The present study was designed to investigate the effects of the intrathecal calcium channel blocker, verapamil, on the spinal anesthesia from lidocaine and tetracaine. Male Sprague-Dawley rats were chronically implanted with lumbar intrathecal catheters. Tail-flick (TF) and mechanical paw pressure (MPP) tests were used to assess thermal and mechanical nociceptive threshold, respectively. Motor function was assessed using a modified Langerman's scale. Intrathecal lidocaine or tetracaine alone showed the prolongation of TF latency, the increase of MPP threshold, and the increase in motor function scale in a time- and dose-dependent manner. Although intrathecal verapamil alone demonstrated neither sensory nor motor block at the doses used (50-200 micrograms), the combination of lidocaine (20, 50, 100, or 200 micrograms) or tetracaine (10, 20, 50, or 100 micrograms) and verapamil (50 micrograms) produced the more potent and prolonged antinociception and motor block when compared with local anesthetics alone. We interpreted these results to indicate that the intrathecal calcium channel blocker, verapamil, potentiates spinal anesthesia with local anesthetics.

Anesthesia, Spinal↗

Spinal anesthesia with meperidine. Effects of added alpha-adrenergic agonists: epinephrine versus clonidine.

We determined the effects of intrathecally administered epinephrine and clonidine on the duration and quality of a meperidine spinal block. Forty-five patients scheduled for orthopedic surgery, divided into three groups, received spinal anesthesia with 1 mg/kg 5% meperidine, alone or with 200 microg epinephrine or 2 microg/kg clonidine. Using a double-blind method, the onset, extension, and duration of sensory block (to pinprick) and the duration and degree of motor block (Bromage scale) were assessed. Hemodynamic responses, duration of postoperative analgesia, degree of sedation, and occurrence of side effects were also recorded. The addition of epinephrine to the meperidine solution prolonged the sensory block (P<0.01) but did not affect its onset or extent. A similar potentiating effect was demonstrated for clonidine (P<0.001). The duration and degree of motor block were increased by addition of both epinephrine and clonidine. A tendency toward bradycardia and a decrease of mean arterial pressure was potentiated by clonidine but not by the epinephrine. Only the addition of clonidine prolonged the postoperative analgesia (P<0.001), but was associated with an increased sedation score. The incidence of other side effects did not differ between the groups. We conclude that coadministration of epinephrine or clonidine with meperidine enhances the duration and degree of spinal anesthesia and that adding clonidine prolongs the duration of postoperative analgesia.

Adjuvants, Anesthesia↗

Intrathecal fentanyl is superior to intravenous ondansetron for the prevention of perioperative nausea during cesarean delivery with spinal anesthesia.

This study compares intrathecal (IT) fentanyl with IV ondansetron for preventing intraoperative nausea and vomiting during cesarean deliveries performed with spinal anesthesia. Thirty healthy parturients presenting for elective cesarean delivery with standardized bupivacaine spinal anesthesia were randomized to receive 20 microg IT fentanyl (Group F) or 4 mg IV ondansetron (Group O) by using double-blinded methodology. At eight specific intervals during the surgery, a blinded observer questioned the patient about nausea (1 = nausea, 0 = no nausea), observed for the presence of retching or vomiting (1 = vomiting or retching, 0 = no vomiting or retching), and recorded a verbal pain score (0-10, 0 = no pain, 10 = worst pain imaginable). Cumulative nausea, vomiting, and pain scores were calculated as the sum of the eight measurements. Intraoperative nausea was decreased in the IT fentanyl group compared with the IV ondansetron group: the median (interquartile range) difference in nausea scores was 1 (1, 2), P = 0.03. The incidence of vomiting and treatment for vomiting was not different (P = 0.7). The IT fentanyl group had a lower cumulative perioperative pain score than the IV ondansetron group; the median difference in the cumulative pain score was 12 (8, 16) (P = 0.0007). The IT fentanyl group required less supplementary intraoperative analgesia. The median difference in the cumulative fentanyl dose was 100 (75, 100) microg fentanyl, (P = 0.0002).

Adjuvants, Anesthesia↗

Subdural block complicating spinal anesthesia?

IMPLICATIONS: Features suggestive of subdural block appeared after an apparently normal subarachnoid block. The long bevel of the reusable Quincke-type spinal needle may have contributed to the development of this complication. We propose that spinal needles should have a smaller bevel to minimize the possibility of such a complication.

Anesthesia, Spinal↗

Functional recovery in chronic paraplegia after bone marrow stromal cells transplantation.

Previous reports showed the therapeutic effect of transplants of bone marrow stromal cells (BMSC) after incomplete traumatic spinal cord lesions. We studied the effect of this form of therapy in chronically paraplegic Wistar rats due to severe spinal cord injury (SCI). Rats were subjected to weight-drop impact causing paraplegia, and BMSC or phosphate buffered saline (PBS) was injected into spinal cord 3 months after injury. Functional outcome was measured using the Basso-Beattie-Bresnehan score until sacrifice of the animals, 4 weeks after transplantation. At this time, samples of spinal cord tissue were studied histologically. The results showed a clear and progressive functional recovery of the animals treated with BMSC transplantation, compared to controls. Grafted BMSC survived into spinal cord tissue, forming cell bridges within the traumatic centromedullary cavity. In this tissue, cells expressing neuronal and astroglial markers can be seen, together with a marked ependymal proliferation, showing nestin-positivity. These findings suggest the utility of BMSC transplantation in chronically established paraplegia.

Animals↗

Premedication with promethazine and transdermal scopolamine reduces the incidence of nausea and vomiting after intrathecal morphine.

Intrathecal morphine provides effective postoperative pain relief in major orthopaedic surgery. In use, however, is associated with unpleasant side effects like nausea and vomiting. The effect of different premedications on postoperative emetic sequelae induced by intrathecal morphine was studied in a prospective, double blind study. Sixty patients scheduled for arthroplasty surgery of the lower extremity were anaesthetized with spinal anaesthesia with a combination of isobaric bupivacaine 20 mg and morphine 0.3 mg. For premedication the patients were randomised to three groups of equal size. They received either oral diazepam (5-15 mg), oral promethazine (10 mg) or a combination of promethazine and transdermal scopolamine (1.5 mg). Sixty percent of the patients with both promethazine and transdermal scopolamine were totally free from postoperative nausea and vomiting (PONV) symptoms compared to those premedicated with diazepam (40%) or promethazine alone (30%). Promethazine together with transdermal scopolamine reduced significantly the number of patients with vomiting (to 25%) and also vomiting episodes. This combination was also more efficient in reducing the incidence of nausea (to 25%) and nausea episodes than promethazine along (P < 0.05). Combination also reduced the requests for additional pain relief (P < 0.05). PONV occurred in a majority of patients during the first 12 hours of the 24 hour study period and the need for additional analgesics thereafter. The incidence of itching (50-65%) and urinary catheterisation (55-70%) was similar in all groups. In conclusion, the combination of oral promethazine and transdermal scopolamine was most effective in reducing PONV symptoms and also reduced the need for postoperative pain treatment.

Administration, Cutaneous↗

Low-dose bupivacaine spinal anaesthesia for percutaneous nephrolithotomy: the suitability and impact of adding intrathecal fentanyl.

BACKGROUND: Unilateral spinal anaesthesia has been used for lower limb surgery with a stable cardiovascular state and a short recovery unit stay. We sought to test the suitability of low-dose bupivacaine spinal anaesthesia for percutaneous nephrolithotomy, a procedure hitherto performed under general anaesthesia. Furthermore, we hypothesized that adding intrathecal fentanyl to bupivacaine may improve the quality of anaesthesia. METHODS: We randomly allocated, through computer-generated randomization, 108 patients subjected to percutaneous nephrolithotomy to receive either 7.5 mg of hyperbaric bupivacaine 5 mg/ml alone or with the addition of 10 microg of fentanyl. Drugs were given at the L(2)-L(3) interspace with the patient in the lateral decubitus position. The patients remained in this position for 10 min, after which the sensory and motor blocks were assessed. Intra-operative analgesic supplementation, when deemed necessary, was achieved with intravenous fentanyl boluses (25 microg). RESULTS: The sensory and motor blocks after intrathecal bupivacaine and bupivacaine-fentanyl were similar. Sensory block, in both groups, reached the fifth and eighth thoracic dermatomes on the operative and non-operative sides, respectively. Deep motor block occurred on the operative side in all patients and in nearly 50% of patients on the non-operative side. The patients in the bupivacaine-fentanyl group required less intra-operative and post-operative analgesics, and both patients and endoscopists were better satisfied. CONCLUSION: This study demonstrated, for the first time, that intrathecal low-dose bupivacaine and fentanyl offers a reliable neuraxial block for patients subjected to percutaneous nephrolithotomy, with stable haemodynamics, good post-operative analgesia and acceptable patient and endoscopist satisfaction.

Analgesics, Opioid↗