Pamela Flood

Inhaled anesthetics and immobility: Mechanisms, mysteries, and minimum alveolar anesthetic concentration

Studies using molecular modeling, genetic engineering, neurophysiology/pharmacology, and whole animals have advanced our understanding of where and how inhaled anesthetics act to produce immobility (minimum alveolar anesthetic concentration; MAC) by actions on the spinal cord. Numerous ligand- and voltage-gated channels might plausibly mediate MAC, and specific animo acid sites in certain receptors present likely candidates for mediation. However, in vivo studies to date suggest that several channels or receptors may not be mediators (e.g., &ggr;-aminobutyric acid A, acetylcholine, potassium, 5-hydroxytryptamine-3, opioids, and &agr;2-adrenergic), whereas other receptors/channels (e.g., glycine, N-methyl-d-aspartate, and sodium) remain credible candidates.

Alpha4beta2 Neuronal Nicotinic Acetylcholine Receptors in the Central Nervous System Are Inhibited by Isoflurane and Propofol, but alpha7-type Nicotinic Acetylcholine Receptors Are Unaffected

Background: The mechanisms of action of general anesthetics are not completely understood. Many general anesthetics are reported to potentiate gamma‐aminobutyric acid (GABAA) and glycine receptors in the central nervous system (CNS) and to inhibit the muscle‐type nicotinic acetylcholine receptor (nAChR). The effects of general anesthetics on another family of ligand‐gated ion channel in the CNS, the nAChRs, have not been defined. Methods: Two types of CNS acetylcholine receptor, the alpha4beta2 receptor or the alpha7 homomeric receptor, were expressed heterologously in Xenopus laevis oocytes. Using the standard two‐microelectrode voltage‐clamp technique, peak acetylcholine‐gated current was measured before and after coapplication of isoflurane or propofol. Results: Coapplication of either isoflurane or propofol with acetylcholine resulted in potent, dose‐dependent inhibition of the alpha4beta2 receptor current with median inhibitory concentrations of 85 and 19 micro Meter, respectively. The inhibition of the alpha4beta2 receptor by both isoflurane and propofol appears to be competitive with respect to acetylcholine. The alpha7 receptor current was not effected by either anesthetic. Conclusions: The CNS‐type nAChRs are differentially affected by isoflurane and propofol. The alpha4beta2 receptor is affected by isoflurane more potently than the most sensitive GABAA or glycine receptor that has been reported, whereas the alpha7 homomeric receptor is not affected by either anesthetic. Inhibition of specific subtypes of nAChRs in the CNS, along with potentiation of GABAA and glycine receptors, may contribute to the effects and side effects of general anesthetics.

Advances in neurobiology of the neuromuscular junction: implications for the anesthesiologist.

THE mammalian neuromuscular junction (NMJ) is one of the most studied and best understood synapses. Recent work has brought forth new information as to development, maturation, and function of this fundamental synapse, both in health and disease. The healthy function of the NMJ underlies one important measurement of the response to general anesthetics, immobility. “Neuromuscular blockers” acting directly at the NMJ are used as a component of many balanced anesthetic techniques, and the health of the NMJ profoundly influences anesthetic technique. For these reasons, it is imperative that anesthesiologists be aware of new developments in the field. The normal development, maturation, and function of the NMJ are discussed. Diseases of the NMJ are also reviewed with emphasis on new etiologic, pathologic, and treatment-oriented information.

Intravenous anesthetics differentially modulate ligand-gated ion channels

Background Heteromeric neuronal nicotinic acetylcholine receptors (nAChRs) are potently inhibited by volatile anesthetics, but it is not known whether they are affected by intravenous anesthetics. Ketamine potentiates &ggr;-aminobutyric acid type A (GABAA) receptors at high concentrations, but it is unknown whether there is potentiation at clinically relevant concentrations. Information about the effects of intravenous anesthetics with different behavioral profiles on specific ligand-gated ion channels may lead to hypotheses as to which ion channel effect produces a specific anesthetic behavior. Methods A heteromeric nAChR composed of &agr;4 and &bgr;4 subunits was expressed heterologously in Xenopus laevis oocytes. Using the two-electrode voltage clamp technique, peak ACh-gated current was measured before and during application of ketamine, etomidate, or thiopental. The response to GABA of &agr;1&bgr;2&ggr;2s GABAA receptors expressed in human embryonic kidney cells and Xenopus oocytes was compared with and without coapplication of ketamine from 1 &mgr;m to 10 mm. Results Ketamine caused potent, concentration-dependent inhibition of the &agr;4&bgr;4 nAChR current with an IC50 of 0.24 &mgr;m. The inhibition by ketamine was use-dependent; the antagonist was more effective when the channel had been opened by agonist. Ketamine did not modulate the &agr;1&bgr;2&ggr;2s GABAA receptor response in the clinically relevant concentration range. Thiopental caused 27% inhibition of ACh response at its clinical EC50. Etomidate did not modulate the &agr;4&bgr;4 nAChR response in the clinically relevant concentration range, although there was inhibition at very high concentrations. Conclusions The &agr;4&bgr;4 nAChR, which is predominantly found in the central nervous system (CNS), is differentially affected by clinically relevant concentrations of intravenous anesthetics. Ketamine, commonly known to be an inhibitor at the N-methyl-d-aspartate receptor, is also a potent inhibitor at a central nAChR. It has little effect on a common CNS GABAA receptor in a clinically relevant concentration range. Interaction between ketamine and specific subtypes of nAChRs in the CNS may result in anesthetic behaviors such as inattention to surgical stimulus and in analgesia. Thiopental causes minor inhibition at the &agr;4&bgr;4 nAChR. Modulation of the &agr;4&bgr;4 nAChR by etomidate is unlikely to be important in anesthesia practice based on the insensitivity of this receptor to clinically used concentrations.

Anaesthetic considerations for non-obstetric surgery during pregnancy

Surgery during pregnancy is complicated by the need to balance the requirements of two patients. Under usual circumstances, surgery is only conducted during pregnancy when it is absolutely necessary for the wellbeing of the mother, fetus, or both. Even so, the outcome is generally favourable for both the mother and the fetus. All general anaesthetic drugs cross the placenta and there is no optimal general anaesthetic technique. Neither is there convincing evidence that any particular anaesthetic drug is toxic in humans. There is weak evidence that nitrous oxide should be avoided in early pregnancy due to a potential association with pregnancy loss with high exposure. There is evidence in animal models that many general anaesthetic techniques cause inappropriate neuronal apoptosis and behavioural deficits in later life. It is not known whether these considerations affect the human fetus but studies are underway. Given the general considerations of avoiding fetal exposure to unnecessary medication and potential protection of the maternal airway, regional anaesthesia is usually preferred in pregnancy when it is practical for the medical and surgical condition. When surgery is indicated during pregnancy maintenance of maternal oxygenation, perfusion and homeostasis with the least extensive anaesthetic that is practical will assure the best outcome for the fetus.

Anesthesia Matters: Patients Anesthetized with Propofol Have Less Postoperative Pain than Those Anesthetized with Isoflurane

BACKGROUND:Preclinical studies have suggested that some volatile anesthetics induce a hyperalgesic state that may be secondary to nicotinic inhibition. A previous trial of treatment with nicotine nasal spray demonstrated postoperative analgesia in women anesthetized with isoflurane. To determine whether the effect of nicotine was reversing hyperalgesia induced by isoflurane, or simply acting as an analgesic, we studied the effect of nicotine on postoperative pain in women anesthetized with isoflurane or propofol, with fentanyl. METHODS:In a randomized, prospective, double-blind trial, we assigned 80 women having open uterine surgery to be anesthetized with isoflurane or propofol. Within each anesthetic group, the subjects were further randomly assigned to receive nicotine 3 mg or placebo. Pain reported with a numerical analog scale was the primary outcome variable. RESULTS:The patient demographics were similar. Women who were anesthetized with propofol reported less pain and used less morphine during the first day after surgery than women who were anesthetized with isoflurane (P < 0.01, P < 0.01). Nicotine treatment did not change pain report or morphine use in either anesthetic group (P > 0.05). CONCLUSIONS:General anesthesia with propofol and is associated with less postoperative pain and morphine use than general anesthesia with isoflurane. Nicotine was not analgesic in this trial. If these results are repeated in other populations, reduced postoperative pain can be added to the previously described improvement in nausea and vomiting as a potential benefit of anesthesia with propofol.

Randomized Controlled Crossover Trial of Ketamine in Obsessive-Compulsive Disorder: Proof-of-Concept

Serotonin reuptake inhibitors (SRIs), the first-line pharmacological treatment for obsessive-compulsive disorder (OCD), have two limitations: incomplete symptom relief and 2–3 months lag time before clinically meaningful improvement. New medications with faster onset are needed. As converging evidence suggests a role for the glutamate system in the pathophysiology of OCD, we tested whether a single dose of ketamine, a non-competitive N-methyl-D-aspartate (NMDA) glutamate receptor antagonist, could achieve rapid anti-obsessional effects. In a randomized, double-blind, placebo-controlled, crossover design, drug-free OCD adults (n=15) with near-constant obsessions received two 40-min intravenous infusions, one of saline and one of ketamine (0.5 mg/kg), spaced at least 1-week apart. The OCD visual analog scale (OCD-VAS) and the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) were used to assess OCD symptoms. Unexpectedly, ketamine’s effects within the crossover design showed significant (p<0.005) carryover effects (ie, lasting longer than 1 week). As a result, only the first-phase data were used in additional analyses. Specifically, those receiving ketamine (n=8) reported significant improvement in obsessions (measured by OCD-VAS) during the infusion compared with subjects receiving placebo (n=7). One-week post-infusion, 50% of those receiving ketamine (n=8) met criteria for treatment response (⩾35% Y-BOCS reduction) vs 0% of those receiving placebo (n=7). Rapid anti-OCD effects from a single intravenous dose of ketamine can persist for at least 1 week in some OCD patients with constant intrusive thoughts. This is the first randomized, controlled trial to demonstrate that a drug affecting glutamate neurotransmission can reduce OCD symptoms without the presence of an SRI and is consistent with a glutamatergic hypothesis of OCD.

Ketamine and its preservative, benzethonium chloride, both inhibit human recombinant α7 and α4β2 neuronal nicotinic acetylcholine receptors in Xenopus oocytes

Ketamine is a dissociative anaesthetic that is formulated as Ketalar, which contains the preservative benzethonium chloride (BCl). We have studied the effects of pure racemic ketamine, the preservative BCl and the Ketalar mixture on human neuronal nicotinic acetylcholine receptors (nAChRs) composed of the α7 subunit or α4 and β2 subunits expressed in Xenopus laevis oocytes. Ketamine inhibited responses to 1 mM acetylcholine (ACh) in both the human α7 and α4β2 nAChRs, with IC50 values of 20 and 50 μM respectively. Inhibition of the α7 nAChRs occurred within a clinically relevant concentration range, while inhibition of the α4β2 nAChR was observed only at higher concentrations. The Ketalar formulation inhibited nAChR function more effectively than was expected given its ketamine concentration. The surprising increased inhibitory potency of Ketalar compared with pure ketamine appeared to be due to the activity of BCl, which inhibited both α7 (IC50 value of 122 nM) and α4β2 (IC50 value of 49 nM) nAChRs at concentrations present in the clinical formulation of Ketalar. Ketamine is a noncompetitive inhibitor at both the α7 and α4β2 nAChR. In contrast, BCl causes a parallel shift in the ACh dose‐response curve at the α7 nAChR suggesting competitive inhibition. Ketamine causes both voltage‐dependent and use‐dependent inhibition, only in the α4β2 nAChR. Since α7 nAChRs are likely to be inhibited during clinical use of Ketalar, the actions of ketamine and BCl on this receptor subtype may play a role in the profound analgesia, amnesia, immobility and/or autonomic modulation produced by this anaesthetic.

Intranasal Nicotine for Postoperative Pain Treatment

Background:Despite pharmacological treatment, 70–80% of patients report moderate to severe pain after surgery. Because nicotine has been reported to have analgesic properties in animal and human volunteer studies, the authors assessed the analgesic efficacy of a single 3 mg dose of nicotine nasal spray administered before emergence from general anesthesia. Methods:The authors conducted a randomized, double blind, placebo controlled trial of 20 healthy women (mean age 45 (SD 8) yr) who were to undergo uterine surgery through a low transverse incision. After the conclusion of surgery but before emergence from general anesthesia, the anesthesiologist administered either nicotine nasal spray or a placebo. Numerical analog pain score and morphine utilization and hemodynamic values were measured for 24 h. Results:The patients treated with nicotine reported lower pain scores during the first hour after surgery (peak numerical analog score, 7.6 (SD 1.4) versus 5.3 (SD 1.6); P < 0.001) and used half the amount of morphine as the control group (12 (SD 6) versus 6 (SD 5) mg; P < 0.05). Patients who received nicotine still reported less pain than those in the control group 24 h after surgery (1.5 (SD 0.5) versus 4.9 (SD 1.4); P < 0.01). Systolic blood pressure was lower in the group that received nicotine (105 (SD 3) versus 122 (SD 3); P < 0.001), but there was no difference in diastolic blood pressure or heart rate. Conclusions:Treatment with a single dose of nicotine immediately before emergence from anesthesia was associated with significantly lower reported pain scores during the first day after surgery. The decreased pain was associated with a reduction in morphine utilization and the analgesic effect of nicotine was not associated with hypertension or tachycardia.

Isoflurane Hyperalgesia Is Modulated by Nicotinic Inhibition

Background The inhaled anesthetic isoflurane inhibits neuronal nicotinic acetylcholine receptors (nAChRs) at concentrations lower than those used for anesthesia. Isoflurane produces biphasic nociceptive responses, with both hyperalgesia and analgesia within this concentration range. Because nicotinic agonists act as analgesics, the authors hypothesized that inhibition of nicotinic transmission by isoflurane causes hyperalgesia. Methods The authors studied female mice at 6–8 weeks of age. They measured hind paw withdrawal latency at isoflurane concentrations from 0 to 0.98 vol% after the animals had received a nicotinic agonist (nicotine), a nicotinic antagonist (mecamylamine or chlorisondamine), or saline intraperitoneally. In addition, the authors tested the interactions between mecamylamine and isoflurane and nicotine and isoflurane in heterologously expressed &agr;4&bgr;2 nAChRs. Results Female mice had significant hyperalgesia from isoflurane. Nicotine administration prevented isoflurane-induced hyperalgesia without altering the antinociception produced by higher isoflurane concentrations. Mecamylamine treatment caused a biphasic nociceptive response similar to that caused by isoflurane. Mecamylamine and isoflurane had an additive effect, both at heterologously expressed &agr;4&bgr;2 nAChRs and on the production of hyperalgesia in vivo. Mecamylamine thus potentiated hyperalgesia but did not affect analgesia. Conclusions Since hyperalgesia occurs in vivo at isoflurane doses that antagonize nAChRs in vitro, is prevented by a nicotinic agonist, and is mimicked and potentiated by nicotinic antagonists, the authors conclude that isoflurane inhibition of nAChRs activation is involved in the pathway that causes hyperalgesia. At subanesthetic doses, isoflurane can either enhance pain responses (produce hyperalgesia) or be analgesic (antinociceptive). In rats, low volatile anesthetic concentrations (0.1–0.2 minimum alveolar concentration [MAC]) elicit hyperalgesia, while 0.4–0.6 MAC elicits antinociception.