H. Buerkle

Central and Peripheral Analgesia Mediated by the Acetylcholinesterase-Inhibitor Neostigmine in the Rat Inflamed Knee Joint Model

Intrinsic cholinergic inhibitory pathways present a key modulating system in pain perception.The use of intrathecal (IT) acetylcholinesterase-inhibitors, such as neostigmine, result in analgesia in both preclinical and clinical models. However, whether IT neostigmine suppresses tonic persistent pain or has peripheral sites of antinociceptive action has not been determined. Thus, we studied central (IT) and peripheral (intraarticular; IA) neostigmine in a rat inflamed knee joint model. Inhibition of thermal and mechanical hyperalgesia was assessed over 28 h using a modified Hargreaves box and von Frey hairs, respectively. IT neostigmine resulted in a dose-dependent thermal analgesia (50% of maximal effective dose [ED50] 0-4 h: 6.6 [micro sign]g, 24-28 h: 9.4 [micro sign]g) and mechanical analgesia (ED (50) 0-4 h: 3.5 [micro sign]g, 24-28 h: 4.3 [micro sign]g). IT atropine reversed analgesia by IT neostigmine. IA neostigmine also resulted in an IA atropine reversible dose-dependent increase of thermal analgesia, although it did not exceed 60% of a maximal possible analgesic effect with the largest applied dose (ED50 0-4 h: 76.2 [micro sign]g, 24-28 h: 140.1 [micro sign]g). Partial suppression of mechanical hyperalgesia was observed after IA neostigmine. We conclude that centrally administered neostigmine modulates thermal and mechanical antinociception in this animal model of inflammatory pain. These data suggest a peripheral site of muscarinic antinociception. Implications: This animal study shows that administration of the acetylcholinesteraseinhibitor neostigmine results in enhanced levels of the endogenous neurotransmitter acetylcholine, which seems to act as one of a group of analgesia-modulating compounds at central and peripheral sites in inflammatory pain. (Anesth Analg 1998;86:1027-32)

Remifentanil Directly Activates Human N-methyl-D- aspartate Receptors Expressed in Xenopus laevis Oocytes

Background: Clinical studies suggest that intraoperative administration of the clinical remifentanil formulation Ultiva® (GlaxoWellcome GmbH & Co, Bad Oldesloe, Germany) increases postoperative pain and postoperative analgesic requirements, but mechanisms remain unclear. N-methyl-d-aspartate (NMDA) receptors are thought to play a major role in development of postoperative pain and opiate tolerance. The authors hypothesized that Ultiva® directly stimulates human NMDA receptors. Methods: To test this hypothesis, the authors expressed human NR1A/NR2A and NR1A/NR2B NMDA receptors in Xenopus laevis oocytes by injection of messenger RNA prepared in vitro. After protein expression, they used a two-electrode voltage clamp to measure currents induced by NMDA receptor agonists and opioids. Results: Noninjected cells were unresponsive to all compounds tested. Glutamate/glycine (1 nm–1 mm each) or Ultiva® (0.01 pm–0.1 mm) stimulated NMDA receptors concentration dependently. NR1A/2A EC50 values were 8.0 μM/12 μM for glutamate/glycine and 3.5 nM for Ultiva®, and NR1A/2B EC50 values were 3.9 μM/1.9 μM for glutamate/glycine and 0.82 μM for Ultiva®. Glycine in combination with Ultiva® showed no additive effect compared with Ultiva® alone. Ultiva®-induced currents were inhibited by MK-801 (pore blocker) but not by 7-CK (glycine antagonist), D-AP5 (glutamate antagonist), or naloxone. Fentanyl (10 μM) did not stimulate NMDA receptors. Conclusion: These data indicate that Ultiva® but not fentanyl stimulates NMDA receptors of different subunit combinations (NR1A/2A, NR1A/2B). The mechanism seems to be allosteric activation of the NMDA receptor.

Effect of pretreatment with ketorolac on propofol injection pain.

Background:  Pain on injection is still a major problem with propofol. We performed this study to compare different doses of intravenous (i.v.) ketorolac with and without venous occlusion and its effect on the incidence and the severity of the pain after propofol injection.

The thermal and mechanical anti-hyperalgesic effects of pre- versus post-intrathecal treatment with lamotrigine in a rat model of inflammatory pain.

UNLABELLED Intrathecal (IT) lamotrigine, a sodium channel blocker which suppresses neuronal release of glutamate, has been shown to produce a long-lasting antihyperalgesic effect in the neuropathic pain models. In the present study, we examined the anti-hyperalgesic effects of pre- versus post-treatment of IT lamotrigine in an animal inflammatory pain model, the inflamed knee joint model of the rat. Thermal and mechanical antinociception was assessed in rats using a modified Hargreaves box and von Frey hairs. Induction of tonic persistent inflammatory pain was induced by intra-articular injection (i.a.) of a carrageenan-kaolin mixture (CK) into the right knee-joint. Rats were randomly assigned to the groups receiving IT lamotrigine in distinct doses of 5, 50 or 100 ug either pre- (10 min before CK injection) or post-inflammation induction (4 h or 23 h). We observed that CK injection resulted in a significant thermal and mechanical hyperalgesia throughout a 24-h observation period. Pre-treatment with IT lamotrigine revealed a time and dose-dependent suppression of thermal and mechanical hyperalgesia, whereas the post-treatment with IT lamotrigine only showed an effect for mechanical nociception. CONCLUSION IT Lamotrigine is antihyperalgesic at a dose larger than 50 ug in the early phase of inflammatory pain model. It reverses tactile allodynia but not thermal hyperalgesia when given after the inflammation induction.

Myocardial ischaemia in patients with impaired left ventricular function undergoing coronary artery bypass grafting — milrinone versus nifedipine

Background and objective: Myocardial ischaemia and infarction are major complications immediately after coronary artery bypass grafting. They may be due to incomplete surgical revascularization, perioperative anaesthetic management or vasospasm of arterial grafts, e.g. the internal mammary artery. Infusions of nifedipine or milrinone have been advocated to prevent spasm of the mammary artery. The study compared the incidence of myocardial ischaemia after continuous infusion of either nifedipine (0.2 μg kg−1 min−1) or milrinone (0.375 μg kg−1 min−1) in patients with compromised left ventricular function scheduled for elective coronary artery bypass graft. Methods: After Institutional Review Board approval, this double-blinded randomized clinical study enrolled 30 adult patients with compromised left ventricular function (ejection fraction <0.4) scheduled for elective coronary artery bypass grafting after written informed consent had been obtained. Ischaemia was detected by Holter electrocardiographic monitoring. The incidence of myocardial cell death was monitored by serial determinations of the creatine kinase-MB (CK-MB) and troponin-I. Results: New ST elevation ⩾0.2 mV or new ST depression ⩽0.1 mV occurred in five of 15 patients in the milrinone group (33.3%) and in 13 of 15 patients (86.6%) in the nifedipine group (P < 0.05). There were increases in CK-MB and troponin-I in both groups. Twenty-four hours postoperatively, CK-MB (P = 0.003) and troponin-I (P = 0.001) were significantly higher in the nifedipine group. Conclusions: Perioperative continuous infusion of milrinone, compared with nifedipine, results in a significantly lower incidence of myocardial ischaemia and myocardial cell damage after elective coronary artery bypass grafting.

Assessment of volume preload on uteroplacental blood flow during epidural anaesthesia for Caesarean section.

Background and objective: Epidural and spinal anaesthesia are the preferred mode of anaesthesia for Caesarean section. Volume preloading is recommended to prevent maternal hypotension and a reduction in uteroplacental blood flow, although positive effects of volume preloading on maternal cardiac output and arterial pressure are debatable. Doppler measurements of the umbilical artery beyond deriving pulsatility indices are not routinely performed. Methods: After Institutional Review Board approval and written informed consent, 14 consecutive women with epidural anaesthesia for Caesarean section received either hydroxyethyl starch 500 mL or gelatine 500 mL. Haemodynamic variables monitored were maternal arterial pressure, maximal blood flow velocity and pulsatility indices of the uterine artery derived from Doppler measurements. Conclusions: Maternal arterial pressure and pulsatility indices in both groups did not change from baseline after intravenous colloid infusion. However, uterine blood flow increased significantly in both groups. The effectiveness of volume preloading may therefore be better described by changes in maximum uterine blood flow velocity than by pulsatility indices or maternal arterial pressure.

Failure of prevention against postoperative vomiting by ondansetron or prochlorperazine in patients undergoing gynecological laparoscopy.

BACKGROUND Ondansetron has been approved for the treatment and prevention of postoperative emesis. Since it is presumably considered to possess potent antiemetic effect with fewer side effects, the administration of ondansetron to inhibit emesis in patients following gynecological laparoscopic surgery might be recommendable. Hence, we examined the effects of intravenous ondansetron at dosage of 4 and 8 mg in comparison with intravenous prochlorperazine at 5 mg and placebo. METHODS A total of 120 patients were allocated randomly into 3 groups. Group 1 patients who served as control were given NaCl 0.9% 4 mL (placebo) intravenously (i.v.); patients in group 2 and group 3 were given ondansetron 4 mg ondansetron 8 mg i.v. respectively; patients in group 4 were given prochlorperazine 5 mg i.v. Premedication was omitted. RESULTS Logistic regression analysis adjusted for prognostic factors revealed no significant difference between 5 mg prochlorperazine group and 4 mg or 8 mg ondansetron group as compared over the 24 h study period. CONCLUSIONS The results of this study suggest that i.v. 4 or 8 mg ondansetron and 5 mg prochlorperazine were not effective in prevention of postoperative emesis in patients undergoing gynecological laparoscopy. Since the cost of ondansetron is high, its routine use for prevention against postoperative nausea and vomiting is not be recommended clinically because of its uncertain benefit.

The use of concomitant antiplatelet drugs during neuraxial anesthesia is contraindicated in Germany

would have appreciated an alternative proposal or theory, rather than just simply a disagreement with our explanation. 2. We are unsure what is meant by “we strongly hope that the paravertebral technique of the authors will not lead them to perform a paravertebral blockade.” In the reference that they cited,3 7.5% phenol solution was used and the relevance or meaning of this statement escapes us because the relative risks of injecting local anesthetic and neurolytic solutions are obviously not identical. 3. No comparative studies have yet been done between the paravertebral and interscalene block. To compare the motor blockade of these 2 blocks at this stage would be premature and speculative, but we agree with Blumenthal et al. that motor blockade for continuous interscalene block depends on the local anesthetic and its concentration amongst other things. Our experience, however, with the posterior approach prompted us to adopt a less dogmatic attitude because it appears that the motor function is less affected with this approach. Local anesthetic concentration may not be the only factor. 4. We have not stated that an interscalene catheter increases the incidence of side effects and complications, such as paresthesias and dysesthesias. We merely expressed our concern about the relatively high incidence of these complications reported by Borgeat et al.4 Unlike Blumenthal et al., we do not have access to their prospective study that is currently in press, but we are anxiously awaiting this report. 5. We agree that a thorough knowledge of anatomy is a prerequisite for performing regional anesthesia. We do, however, have no doubt that our Swiss colleagues must also have observed many trainee anesthesiologists (and even many experienced anesthesiologists) placing interscalene blocks on rhomboid twitches because of dorsal scapular nerve stimulation. 6. Obviously, 200 to 300 ms is a very long impulse duration and a printing error. We apologize for this and thank the authors for bringing this to our attention. It should read 200 to 300 s.

Apraclonidine attenuates the increases in spinal excitatory amino acid release in rats with adjuvant-induced inflammation

The release of excitatory amino acids (EAAs), nitric oxide, and prostaglandins plays a critical role in the development of peripheral tactile and thermal hypersensitivity after the induction of knee joint inflammation. In this study, we used a model of chronic spinal microdialysis to examine the effect of complete Freund’s adjuvant (CFA)-induced inflammation on the spinal release of EAAs and also assessed the antinociceptive effect of a new &agr;2-adrenergic agonist, apraclonidine, by using this model. Male Sprague-Dawley rats were implanted with microdialysis catheters. CFA was injected into the plantar surface of the left hindpaw to induce inflammation. Concentrations of amino acids in dialysate and thermal and tactile withdrawal latency were evaluated for 1 wk. Intraplantar injection of CFA evoked a significant release of glutamate, aspartate, and citrulline for 6 days. Three milligrams of intraperitoneal apraclonidine significantly suppressed the release of EAAs and citrulline. Apraclonidine was given intraperitoneally 2–3 days after CFA injection. Prominent thermal and tactile allodynia was observed for 6 days. Our results show that the significant modulatory effect of the &agr;2-adrenergic agonist apraclonidine on the release of EAAs may account for its antinociceptive properties in adjuvant-induced inflammation.

The quality of epidural anesthesia is crucial in the assessment of perioperative outcome: Letter to the editor

experience with this technique. Data from patients with previously inserted thoracic epidural catheters undergoing cardiopulmonary bypass while being fully heparinized suggest that epidural anesthesia can be safe even under these conditions (5). Finally, coagulation tests in our donors confirm that this management is feasible, considering that epidural catheters were exclusively inserted in donors with normal preanesthesia coagulation tests and pulled postoperatively while coagulation tests were within normal limits (see Figure1). Obviously, there is no sound rationale to withhold an established therapy, epidural anesthesia, to living donors when considering it worthwhile for no donor patients undergoing liver resection. Needless to say that we are used to administer epidural bupivacaine with respect to hemodynamic stability and perfusion pressures. We congratulate the authors for not even being dependent on blood salvage techniques but have not seen these data published. However, considering that maximum safety of the donor clearly is the goal we do not understand why these techniques are not used by Takaoka et al.