Chen-Hwan Cherng

Effects of NMDA receptor antagonists on inhibition of morphine tolerance in rats: binding at μ-opioid receptors

Past studies have shown antagonists of excitatory amino acid receptors, both N-methyl-D-aspartate (NMDA) and non-NMDA, to produce an antinociceptive effect in vitro and in vivo. Additionally, NMDA receptor antagonists have been demonstrated to prevent morphine tolerance. We had found that one NMDA receptor antagonist, ketamine, potentiates morphines analgesic effect in post-operative patients. Our latest experiment was performed to examine the modulatory effect of competitive and non-competitive NMDA receptor antagonists on morphine antinociception and tolerance. A PE10 catheter was intrathecally (i.t.) implanted in male Sprague-Dawley rats for drug administration. The antinociceptive effect of morphine, D-(-)-2-amino-5-phosphonovaleric acid (D-AP5) and (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d] cyclohepten-5,10-imine maleate (MK-801) was measured using the hot-water tail immersion test. Neither competitive nor non-competitive NMDA receptor antagonists had an antinociceptive effect by themselves, but they did potentiate the antinociceptive effect of morphine. Both D-AP5 (AD50 = 0.18 micrograms) and MK-801 (AD50 = 0.57 micrograms) shifted the antinociceptive dose-response curve of morphine (AD50 = 4.2 micrograms) to the left. Both D-AP5 (4 micrograms/h) and MK-801 (10 micrograms/h) when co-administered with i.t. morphine infusions (10 micrograms/h) also inhibited the development of tolerance. In [3H][D-Ala2,N-Me-Phe4,Gly5-ol]enkephalin ([3H]DAMGO) binding assays, MK-801 (Bmax = 32.90 +/- 3.33 fmol/mg) treatment prevented the down-regulation of mu-opioid receptor high-affinity sites induced by continuous morphine infusions alone (Bmax = 13.97 +/- 1.47 fmol/mg). D-AP5 (Bmax = 20.78 +/- 3.36 fmol/mg) did not prevent the reduction of mu-opioid receptor high-affinity sites. However, high-affinity sites in rats treated with D-AP5 and morphine displayed a higher affinity (KD = 0.45 +/- 0.09 nM) than those of control animals (KD = 0.95 +/- 0.08 nM). Results of this study indicate that competitive as well as non-competitive NMDA receptor antagonists enhance morphines antinociceptive effect, and prevent the development of morphine tolerance. Thus, in our opinion, there opens a new frontier in clinical pain management, especially for those patients who require long-term opioid treatment for pain relief.

Pre-emptive analgesia with ketamine, morphine and epidural lidocaine prior to total knee replacement

PurposePre-emptive analgesia can improve postoperative pain management. The purpose of this study was to examine the effectiveness of ketamine as a pre-emptive analgesic as previous studies have shown the involvement of N-methyl-D-Aspartate (NMDA) receptor in neuroplasticity.MethodsForty-five ASA 1–2 patients, undergoing unilateral total knee replacement were studied. In the study groups, epidural lidocaine was used as the primary anaesthestic. Patients received ketamine + morphine epidurally 30 min either before (group EB) or after skin incision (group EA). Group G patients received general anaesthesia and ketamine + morphine were given 30 min after skin incision via an epidural catheter used for postoperative pain control. Epidural morphine and ketamine in lidocaine was given to all patients at the end of surgery and every 12 hr for three days for analgesia supplemented with PCA morphine. The time until first PCA trigger, morphine consumption, pain scores, satisfaction scores, and morphine related side effects were recorded at 6, 12, 24, 48 and 72 hr after surgery.ResultsEpidural ketamine plus morphine with lidocaine before surgical incision produced better pain relief and patient satisfaction than when given after incision. A longer time to PCA and decreased morphine consumption were observed in group EB than in group G. In group EA, epidural anaesthesia also produced some pre-emptive analgesic effect compared with general anaesthesia shown by decreased morphine consumption.ConclusionsAdministration of ketamine plus morphine with epidural lidocaine anaesthesia before surgery provided improved postoperative analgesia compared with general anaesthesia alone or when analgesics were given after skin incision.RésuméObjectifLa coanalgésie (pre-emptive analgesia) peut améliorer le traitement de la douleur postopératoire. L’objectif de cette étude était d’évaluer l’efficacité de la kétamine comme analgésique préventif en s’appuyant sur plusieurs études qui ont montré l’influence des récepteurs du N-méthyl-D-aspartate (NMDA) sur la neuroplasticité.MéthodesQuarante-cinq patients ASA 1 et 2 opérés pour un remplacement total d’un seul genou participaient à l’étude. Dans ce groupe, la lidocaïne épidurale constituait l’anesthésie principale. Les patients recevaient de la kétamine avec de la morphine 30 min soit avant (groupe EB) soit après l’incision de la peau (groupe EA). Le groupe G recevait une anesthésie générale et de la kétamine avec de la morphine après l’incision par le cathéter épidural utilisé pour le contrôle de la douleur postopératoire. De la morphine associée à de la kétamine dans de la lidocaïne épidurale était administrée à tous les patients à la fin de la chirurgie et à toutes les 12 heures pendant trois jours pour l’analgésie avec ajout de morphine en PCA Le moment de la première activation de la PCA, la consommation de morphine, les scores de douleur et les effets secondaires étaient enregistrés 6, 12, 24, 48 et 72 h après la chirurgie.RésultatsL’association kétamine-morphine épidurale avec de la lidocaïne administrée avant l’incision procure un meilleur soulagement et une satisfaction plus grande au patient que lorsqu’elle est administrée après l’incision. Dans le groupe EB, un délai était plus long avant la PCA et la consommation de morphine était plus faible que dans le groupe G. Dans le groupe EA, l’anesthésie épidurale produisait aussi une analgésie préventive contrairement à l’anesthésie générale comme l’a montré une diminution de la consommation de morphine.ConclusionLadministration avant la chirurgie de la kétamine associée à la morphine avec l’anesthésie épidurale à la lidocaïne améliore l’analgésie comparativement à l’anesthésie générale seule ou lorsque des analgésiques sont administrés après l’incision de la peau.

Increasing of intrathecal CSF excitatory amino acids concentration following morphine challenge in morphine-tolerant rats

Excitatory amino acids (EAAs) are involved in the development of opioid tolerance. The present study reveals that an increasing of CSF EAAs concentration might be responsible for the losing of morphines antinociceptive effect in morphine tolerant rats. Male Wistar rats were implanted with two intrathecal (i.t.) catheters and one microdialysis probe, then continuously infused i.t. for 5 days with saline (1 microl/h; control group), morphine (15 micrograms/h), the NMDA antagonist, MK-801 (5 micrograms/h), or morphine (15 micrograms/h) plus MK-801 (5 micrograms/h). Each day, tail-flick responses were measured; in addition, CSF dialysates were collected and CSF amino acids measured by high performance liquid chromatography using a fluorescence detector. Morphine started to lose its analgesic effect on day 2 and this effect was overcome by MK-801. The AD(50) (AD: analgesic dose) was 1.33 micrograms in control animals, 83.83 micrograms in morphine-tolerant rats (a 63-fold shift), and 11.2 micrograms (a 8.4-fold shift) in rats that had received MK-801 plus morphine. No significant differences were observed in CSF amino acid release between the groups from day 1 to day 5. On day 5, after basal dialysate collection, a 10-micrograms challenge of morphine was administered i.t., and CSF samples collected over the next 3 h. After morphine challenge, morphine-tolerant rats showed a significant increase in the release of glutamate and aspartate (131+/-9.5% and 156+/-12% of basal levels, respectively), and no antinociceptive effect in the tail-flick latency test, while MK-801/morphine co-infused rats showed no increase in morphine-induced EAA release and a partial antinociceptive effect (MPE=40%). The present study provides direct evidence for a relationship between EAA release and a lack of an antinociceptive response to morphine, and shows that the NMDA antagonist, MK-801, attenuates both of these effects.

Airway length in adults: estimation of the optimal endotracheal tube length for orotracheal intubation

STUDY OBJECTIVE To estimate the optimal endotracheal tube (ETT) length in orotracheally intubated patients. DESIGN Prospective study. SETTING Operating room of a medical center hospital. PATIENTS 293 ASA physical status I and II patients (150 male and 143 female), requiring general anesthesia and orotracheal intubation. INTERVENTIONS We used fiberoptic bronchoscope within the ETT to identify the carina and vocal cords. MEASUREMENTS The length from carina to vocal cords, vocal cords to right mouth angle (corner), and carina to right mouth angle were measured. The optimal ETT tip was defined as 5 cm above the carina. Patients height and sternum length were recorded. MAIN RESULTS The correlation between airway length and body height was significant. By linear regression, a formula was obtained to estimate the optimal ETT length in orotracheally intubated patients: the length from 5 cm above carina to right mouth angle (cm) =< body height (cm)/5> - 13. CONCLUSION The optimal insertion length of the ETT for orotracheally intubated adult patients with the head placed in a neutral position is correlated with body height. The proposed formula can provide a useful guide to determine the optimal ETT tip position in most of the patients who required orotracheal intubation.

Effect on postoperative sore throat of spraying the endotracheal tube cuff with benzydamine hydrochloride, 10% lidocaine, and 2% lidocaine.

BACKGROUND:Postoperative sore throat (POST) is a common complication after endotracheal intubation. We compared the effectiveness on POST of spraying the endotracheal tube (ETT) cuff with benzydamine hydrochloride, 10% lidocaine, and 2% lidocaine. METHODS:Three hundred seventy-two patients were randomly allocated into 4 groups. The ETT cuffs in each group were sprayed with benzydamine hydrochloride, 10% lidocaine hydrochloride, 2% lidocaine hydrochloride, or normal saline before endotracheal intubation. After insertion, the cuffs were inflated to an airway leak pressure of 20 cm H2O. Anesthesia was maintained with propofol. The patients were examined for sore throat (none, mild, moderate, or severe) at 1, 6, 12, and 24 hours after extubation. RESULTS:The highest incidence of POST occurred at 6 hours after extubation in all groups. There was a significantly lower incidence of POST in the benzydamine group than 10% lidocaine, 2% lidocaine, and normal saline groups (P < 0.05) at each observation time point. At 6 hours after extubation, the incidence of POST was significantly lower in the benzydamine group (17.0%) compared with 10% lidocaine (53.7%), 2% lidocaine (37.0%), and normal saline (40.8%) groups (P < 0.05). The benzydamine group had significantly decreased severity of POST compared with the 10% lidocaine, 2% lidocaine, and normal saline groups (P < 0.05) at each observation time point. Compared with the 2% lidocaine and normal saline groups, the 10% lidocaine group had significantly increased severity of POST at 1, 6, and 12 hours after extubation. There were no significant differences among groups in local or systemic side effects. CONCLUSIONS:Spraying benzydamine hydrochloride on the ETT cuff is a simple and effective method to reduce the incidence and severity of POST.

Intracranial subdural hematoma after unintended durotomy during spine surgery.

PurposeTo report a case of intracranial subdural hematoma occurring after a spinal dural tear that was made unintentionally during the course of a posterior laminectomy and spinal fusion at the L5-S1 level. The possible physiopathological mechanisms are discussed.Clinical featuresOn the fourth postoperative day, a 59-yr-old woman displayed persistent headache following unintended durotomy during spine implant revision. Perioperative blood loss was 2840 mL and intravascular replacement was about 3000 mL. She was hydrated with iv fluids and treated with non-steroidal antiinflammatory drugs. The symptoms improved but persisted. With the aggravation of the headache complicated with unconsciousness and the appearance of focal neurological signs on the eighth day, a computed tomography was obtained and revealed a right subdural hematoma. Following surgical drainage, the patient made an uneventful recovery.ConclusionThis case reminds us that subdural hematoma formation can complicate durotomy during spine surgery. Neurological deterioration in the postoperative period should prompt clinicians to rule out the diagnosis and intervene rapidly as appropriate.RésuméObjectifRapporter un cas d’hématome sous-dural intracrânien survenu après une brèche involontaire de la dure-mère spinale au cours d’une laminectomie postérieure et d’une arthrodèse au niveau L5-S1. Les mécanismes physiopathologiques possibles sont discutés.Éléments cliniquesAu quatrième jour postopératoire, une femme de 59 ans présentait des céphalées persistantes après une durotomie involontaire survenue pendant la reprise d’un implant rachidien. La perte sanguine périopératoire a été de 2 840 mL et le remplissage vasculaire d’environ 3 000 mL. La patiente a été hydratée avec des liquides iv et traitée par des anti-inflammatoires non stéroïdiens. Ce qui a diminué les symptômes sans les éliminer. Étant donné l’aggravation des céphalées, compliquées d’inconscience, et de l’apparition de signes neurologiques le huitième jour, on a demandé un examen tomodensitométrique qui a révélé un hématome sous-dural droit. Après le drainage chirurgical, la patiente s’est bien rétablie.ConclusionCe cas rappelle que la formation d’un hématome sousdural peut compliquer la durotomie survenant pendant une opération à la colonne vertébrale. La détérioration neurologique postopératoire incite à poser rapidement le diagnostic et à intervenir en conséquence.

A comparison of 3% hypertonic saline and mannitol for brain relaxation during elective supratentorial brain tumor surgery.

BACKGROUND: In this study, we compared the effects of 3% hypertonic saline (HTS) and 20% mannitol on brain relaxation during supratentorial brain tumor surgery, intensive care unit (ICU) stays, and hospital days. METHODS: This prospective, randomized, and double-blind study included patients who were selected for elective craniotomy for supratentorial brain tumors. Patients received either 160 mL of 3% HTS (HTS group, n = 122) or 150 mL of 20% mannitol infusion (M group, n = 116) for 5 minutes at the start of scalp incision. The Pco2 in arterial blood was maintained within 35 to 40 mm Hg, arterial blood pressure was controlled within baseline values ±20%, and positive fluid balance was maintained intraoperatively at a rate of 2 mL/kg/h. Outcome measures included fluid input, urine output, arterial blood gases, serum sodium concentration, ICU stays, and hospital days. Surgeons assessed the condition of the brain as “tight,” “adequate,” or “soft” immediately after opening the dura. RESULTS: Brain relaxation conditions in the HTS group (soft/adequate/tight, n = 58/43/21) were better than those observed in the M group (soft/adequate/tight, n = 39/42/35; P = 0.02). The levels of serum sodium were higher in the HTS group compared with the M group over time (P < 0.001). The average urine output in the M group (707 mL) was higher than it was in the HTS group (596 mL) (P < 0.001). There were no significant differences in fluid input, ICU stays, and hospital days between the 2 groups. CONCLUSIONS: Our results suggest that HTS provided better brain relaxation than did mannitol during elective supratentorial brain tumor surgery, whereas it did not affect ICU stays or hospital days.

The Effectiveness of Benzydamine Hydrochloride Spraying on the Endotracheal Tube Cuff or Oral Mucosa for Postoperative Sore Throat

BACKGROUND:The etiology of postoperative sore throat (POST) is considered to be the result of laryngoscopy, intubation damage, or inflated cuff compression of the tracheal mucosa. In this study, we compared the effectiveness in alleviating POST using different approaches to benzydamine hydrochloride (BH) administration by spraying the endotracheal tube (ET) cuff or the oropharyngeal cavity, or both. METHODS:Three hundred eighty patients were included in this prospective and double-blind study, which was randomized into 4 groups: group A, oropharyngeal cavity spray of BH, and distilled water on the ET cuff; group B, both the oropharyngeal cavity and the ET cuff received BH spray; group C, the ET cuff received BH spray, and the oropharyngeal cavity received distilled water; and group D, distilled water sprayed on both the ET tube and into the oropharyngeal cavity. The patients were examined for sore throat (none, mild, moderate, severe) at 0, 2, 4, and 24 hours postextubation. RESULTS:The incidence of POST was 23.2%, 13.8%, 14.7%, and 40.4% in groups A, B, C, and D, respectively. POST occurred significantly less frequently in groups B and C compared with group D (odds ratio: 0.36; 95% confidence interval: 0.21–0.60; P < 0.05). However, there was no significant difference between groups A and D (odds ratio: 0.62; 95% confidence interval: 0.38–1.01). Moreover, there was no significant interaction between spraying BH over the oropharyngeal cavity and the ET cuff on the incidence of POST (P = 0.088). The severity of POST was significantly more intense in group D compared with groups B and C (P < 0.001). Group B had a significantly higher incidence of local numbness, burning, and/or stinging sensation compared with patients in group D (P < 0.05). CONCLUSIONS:This study indicates that spraying BH on the ET cuff decreases the incidence and severity of POST without increased BH-related adverse effects.

Neuroprotective effect of curcumin in an experimental rat model of subarachnoid hemorrhage.

BACKGROUND Subarachnoid hemorrhage (SAH) causes a high mortality rate and morbidity. It was suggested that oxidant stress plays an important role in neuronal injury after SAH. Therefore, we assessed the effect of curcumin on reducing cerebral vasospasm and neurologic injury in a SAH model in rat. METHODS A double-hemorrhage model was used to induce SAH in rats. Groups of animals were treated with intraperitoneal injection of 20 mg/kg curcumin (curcumin group, n = 24) or dimethyl sulfoxide (vehicle group, n = 33), normal saline (SAH group, n = 34) or normal saline (sham group, n = 22), 3 h after SAH induction and daily for 6 days. Glutamate was measured before SAH induction and once daily for 7 days. Glutamate transporter-1, wall thickness and the perimeter of the basilar artery, neurologic scores, neuronal degeneration, malondialdehyde, superoxide dismutase, and catalase activities were assessed. RESULTS Changes of glutamate levels were lower in the curcumin group versus the SAH and vehicle groups, especially on day 1 (56 folds attenuation vs. vehicle). Correspondingly, glutamate transporter-1 was preserved after SAH in curcumin-treated rats. In the hippocampus and the cortex, malondialdehyde was attenuated (30% and 50%, respectively). Superoxide dismutase (35% and 64%) and catalase (34% and 38%) activities were increased in the curcumin rats compared with the SAH rats. Mortality rate (relative risk: 0.59), wall thickness (30%) and perimeter (31%) of the basilar artery, neuron degeneration scores (39%), and neurologic scores (31%) were improved in curcumin-treated rats. CONCLUSIONS Curcumin in multiple doses is effective against glutamate neurotoxicity and oxidative stress and improves the mortality rate in rats with SAH.

Intrathecal administration of excitatory amino acid receptor antagonists or nitric oxide synthase inhibitor reduced autotomy behavior in rats

Peripheral nerve injury may produce neuropathic pain.At the spinal cord level, excitatory amino acid receptors play a role in nociceptive signal modulation. N-methyl-D-aspartate (NMDA) receptor activation initiates the NO-cGMP pathway and further modulates nociceptive signal. Using the autotomy model, we examined the effect of an NMDA and a non-NMDA receptor antagonist, and nitric oxide synthase inhibitor in the treatment of autotomy behavior in rats. A right-side brachial plexus (C5-T1) transection was performed in all rats. In the treatment groups, MK-801, 1-(4-chlorobenzoyl)-piperazine-2,3-dicarboxylic acid (a non-NMDA antagonist), and L-NG-nitro arginine methyl ester (L-NAME) were infused intrathecally via an osmotic pump for 7 days at doses of 10, 4, and 400 [micro sign]g/h, respectively. Saline was infused to control animals. Autotomy behavior was observed daily for 8 wk. The incidence of autotomy was 85% in the control group. MK-801, the non-NMDA antagonist, and L-NAME reduced the autotomy incidence to 10%, 20%, and 10% (P < 0.0001), respectively. All treatments delayed the onset of the autotomy behavior from 15 +/- 4.5 days in the control group to 52 +/- 3.8, 43 +/- 5.6, and 54 +/- 2.9 (P < 0.001) days in the treatment groups, respectively. The average autotomy scores were also attenuated significantly by these treatments. We conclude that the excitatory amino acid receptors and their intracellular signal messenger NO play a role in deafferentation behavior development. Inhibition of this signaling pathway may be of use for neuropathic pain relief. Implications: The excitatory amino acid receptors and their intracellular signal messenger NO play a role in deafferentation behavior development. Inhibition of this signaling pathway may be of use for neuropathic pain relief. (Anesth Analg 1998;87:605-8)