General Anesthetic Agents Research Articles

Human Patient Simulator for Training Oral and Maxillofacial Surgery Residents in General Anesthesia and Airway Management

Since Horace Wells discovered nitrous oxide as a general anesthetic agent for the extraction of teeth in 1844, oral and maxillofacial surgeons have been intimately involved in the development, use, and promotion of anesthesia. 1 Anesthesia has been most instrumental in shaping our specialty’s place in the health care field and a few far-sighted dentists who had extraordinary compassion for their patients, helped to promote the importance of anesthesia to the profession of oral and maxillofacial surgery. The first oral and maxillofacial surgery residencies were established at Cincinnati General and the University of Michigan Hospitals in 1917. In the early years, anesthesia training for oral and maxillofacial surgeons involved preceptorship, with pioneering oral surgeons acting as the instructors and their offices serving as the training facilities; while others gained their anesthesia training in nurse anesthetist programs. Hospital anesthesia in the United States was administered primarily by nurse anesthetists until the establishment of a medical specialty of anesthesiology after World War II. When the medical specialty developed, it controlled residency training for anesthesiologists and took over the training of nurse anesthetists as well. As time progressed, physician anesthesiologists replaced nurse anesthetists as the persons responsible for hospital anesthesia training programs. During the late 1940s and into the 1950s, the American Society of Oral Surgeons did much to persuade training centers to establish hospital-based anesthesia programs for oral surgeons. Because oral surgeons use significant intravenous and inhalational analgesia and anesthesia in their practice, 2 it became imperative that they were competent in the basics of sedation and airway management. Structured training and experience in general anesthesia finally became available during this time, and oral surgery trainees began to receive training in departments of anesthesiology. Traditionally residents have been trained in anesthesia with a combination of classroom learning and hands-on clinical application in the operating room. Today, with the advent of human patient simulators, the method to train oral and maxillofacial surgery residents in anesthesia and sedation, along with anesthesia residents themselves, is evolving. Because patient simulators have demonstrated educational value for teaching critical care skills including advanced cardiac life support without exposing real patients to risk, 3 we developed a training program to help oral and maxillofacial residents gain the required sedation, analgesic, and airway management skills necessary for modern oral surgery practice. We present the use of the METI (Medical Educational Technologies Incorporated, Sarasota, FL) human patient simulator (HPS) for the structured training of oral and maxillofacial surgery (OMS) residents in the basics of general anesthesia, intravenous analgesia/sedation, and airway management skills.

Intravenous conscious sedation for dental treatment: am I my brother's keeper?

Intravenous conscious sedation for dental treatment: am I my brother's keeper?

Central Nervous System Dysfunction after Noncardiac Surgery and Anesthesia in the Elderly

Central Nervous System Dysfunction after Noncardiac Surgery and Anesthesia in the Elderly

Mapping the contribution of β3-containing GABAA receptors to volatile and intravenous general anesthetic actions

BackgroundAgents belonging to diverse chemical classes are used clinically as general anesthetics. The molecular targets mediating their actions are however still only poorly defined. Both chemical diversity and substantial differences in the clinical actions of general anesthetics suggest that general anesthetic agents may have distinct pharmacological targets. It was demonstrated previously that the immobilizing action of etomidate and propofol is completely, and the immobilizing action of isoflurane partly mediated, by β3-containing GABAA receptors. This was determined by using the β3(N265M) mice, which carry a point mutation known to decrease the actions of general anesthetics at recombinant GABAA receptors. In this communication, we analyzed the contribution of β3-containing GABAA receptors to the pharmacological actions of isoflurane, etomidate and propofol by means of β3(N265M) mice.ResultsIsoflurane decreased core body temperature and heart rate to a smaller degree in β3(N265M) mice than in wild type mice, indicating a minor but significant role of β3-containing GABAA receptors in these actions. Prolonged time intervals in the ECG and increased heart rate variability were indistinguishable between genotypes, suggesting no involvement of β3-containing GABAA receptors. The anterograde amnesic action of propofol was indistinguishable in β3(N265M) and wild type mice, suggesting that it is independent of β3-containing GABAA receptors. The increase of heart rate variability and prolongation of ECG intervals by etomidate and propofol were also less pronounced in β3(N265M) mice than in wild type mice, pointing to a limited involvement of β3-containing GABAA receptors in these actions. The lack of etomidate- and propofol-induced immobilization in β3(N265M) mice was also observed in congenic 129X1/SvJ and C57BL/6J backgrounds, indicating that this phenotype is stable across different backgrounds.ConclusionOur results provide evidence for a defined role of β3-containing GABAA receptors in mediating some, but not all, of the actions of general anesthetics, and confirm the multisite model of general anesthetic action. This pharmacological separation of anesthetic endpoints also suggests that subtype-selective substances with an improved side-effect profile may be developed.

A Case of Propofol-Induced Delayed-Onset Refractory Myoclonic Seizures

Propofol, a GABA-mediated inhibitor of excitatory neurotransmitter, is a popular intravenous agent for general anesthesia and sedation. Its side effects reportedly include opisthotonus, seizures, and myoclonus, and are usually manageable. We present a patient who developed propofol-induced delayed-onset refractory myoclonic seizures that resisted antiepileptic drugs.

Identification of a Molecular Target Mediating the General Anesthetic Actions of Pentobarbital

Barbiturates were introduced into medical practice in 1934. They are widely used today as general anesthetics. Although in vitro studies revealed that the activity of a variety of ligand-gated channels is modulated by barbiturates, the target(s) mediating the anesthetic actions of barbiturates in vivo are unknown. Studying pentobarbital action in beta3(N265M) mice harboring beta3-containing GABAA receptors insensitive to a variety of general anesthetic agents, we found that the immobilizing action of pentobarbital is mediated fully, and the hypnotic action is mediated in part by this receptor subtype. It was surprising that the respiratory depressant action of pentobarbital is indistinguishable between beta3(N265M) and wild-type mice and thus is mediated by other as-yet-unidentified targets. Whereas the target for the immobilizing and hypnotic actions of pentobarbital seems to be the same as for etomidate and propofol, these latter agents' respiratory depressant actions are mediated by beta3-containing GABAA receptors. Thus, in contrast to etomidate and propofol, pentobarbital can elicit respiratory depression by a beta3-independent pathway. Pentobarbital reduced heart rate and body temperature to a slightly smaller extent in beta3(N265M) mice compared with wild-type mice, indicating that these actions are largely mediated by other targets. Pentobarbital-induced increase of heart rate variability and prolongation of ECG intervals are seen in both beta3(N265M) mice and wild-type mice, suggesting that they are not dependent on beta3-containing GABAA receptors. In summary, we show a clear pharmacological dissociation of the immobilizing/hypnotic and respiratory/cardiovascular actions of pentobarbital.

Suppressing consciousness: Mechanisms of general anesthesia

Understanding the neuronal mechanism of general anesthesia both helps and benefits from research into the neurobiological basis of consciousness. Although several theories have been proposed, current evidence from sensory electrophysiology, event-related potentials, and functional brain imaging suggests that the failure of conscious perception at a critical depth of anesthesia may best be interpreted as “information received but not perceived” due to the disintegration of cortical information processing. Cortico-cortical and thalamocortical information transfer may depend on the synchronization or coherence of gamma oscillations that may be suppressed by general anesthetic agents; however, the exact mechanism of these effects is yet unclear. The extent of thalamic involvement in the cortico-cortical disintegration of information processes in anesthesia needs further investigation. It is likely that different anesthetic agents affect different neuronal pathways in their action to produce unconsciousness. A common effect of several volatile anesthetic agents may be the suppression of recurrent feedback signaling between cortical sensory and higher association regions. Elucidation of the neurofunctional systems involved in anesthetic-induced unconsciousness is among the important future challenges for anesthesia research.

The Concerted Contribution of the S4-S5 Linker and the S6 Segment to the Modulation of a Kv Channel by 1-Alkanols

Gating of voltage-gated K(+) channels (K(v) channels) depends on the electromechanical coupling between the voltage sensor and activation gate. The main activation gate of K(v) channels involves the COOH-terminal section of the S6 segment (S6-b) and the S4-S5 linker at the intracellular mouth of the pore. In this study, we have expanded our earlier work to probe the concerted contribution of these regions to the putative amphipathic 1-alkanol site in the Shaw2 K(+) channel. In the S4-S5 linker, we found a direct energetic correlation between alpha-helical propensity and the inhibition of the Shaw2 channel by 1-butanol. Spectroscopic structural analyses of the S4-S5 linker supported this correlation. Furthermore, the analysis of chimeric Shaw2 and K(v)3.4 channels that exchanged their corresponding S4-S5 linkers showed that the potentiation induced by 1-butanol depends on the combination of a single mutation in the S6 PVPV motif (PVAV) and the presence of the Shaw2 S4-S5 linker. Then, using tandem-heterodimer subunits, we determined that this potentiation also depends on the number of S4-S5 linkers and PVAV mutations in the K(v) channel tetramer. Consistent with the critical contribution of the Shaw2 S4-S5 linker, the equivalent PVAV mutation in certain mammalian K(v) channels with divergent S4-S5 linkers conferred weak potentiation by 1-butanol. Overall, these results suggest that 1-alkanol action in Shaw2 channels depends on interactions involving the S4-S5 linker and the S6-b segment. Therefore, we propose that amphiphilic general anesthetic agents such as 1-alkanols may modulate gating of the Shaw2 K(+) channel by an interaction with its activation gate.

Anaesthetic relevance of drugs used to treat cancer

The potential threat of drug interactions when patients receiving chemotherapy undergo anaesthesia is poorly documented, and it is very difficult to derive a method of predicting when interactions are likely to occur and their severity. However, there are reported interactions between anti-cancer drugs and anaesthetic agents and medicinal gases as well as with drugs such as anti-emetic agents, which have uses in both anaesthesia and chemotherapy. In addition, interactions with some of the newer agents, such as monoclonal antibodies, cancer vaccines, proteosome inhibitors, kinase inhibitors and integrin antagonists etc, are yet to be revealed. It should also be borne in mind that immunosuppressive activity is a property not only of virtually all general anaesthetic agents but also virtually all cytotoxics.

Propofol for Office Oral and Maxillofacial Anesthesia: The Case Against Low-Dose Ketamine

R t v c a h m e p n t i o t t K p t he recent hiatus in the use of Brevital (methohexital) as made other general anesthetic agents more poplar. Doctors who had used Brevital for years were orced to change their anesthetic techniques. Propool and low-dose ketamine moved to the top of the list or oral and maxillofacial surgery offices. How does one choose which anesthetic to use? irst one must know what qualities make an ideal nesthetic. The ideal anesthetic agent has a rapid nset, short duration of action, high clearance rate, imited cardiorespiratory effects, and no active metablites. I prefer one that is easy to use, safe with few ide-effects, and which has a fast onset and a quick ecovery. Propofol is as close to the perfect anesthetic gent as I have seen. Ketamine, on the other hand, has everal problems associated with it.

General Anesthetic-induced Seizures Can Be Explained by a Mean-field Model of Cortical Dynamics

General Anesthetic-induced Seizures Can Be Explained by a Mean-field Model of Cortical Dynamics

The Clinical Development of γ-Hydroxybutyrate (GHB)

The discovery of gamma-hydroxybutyrate (GHB) over 40 years ago led to its immediate use as a general anesthetic agent. Subsequent research demonstrated that GHB is an endogenous compound in the mammalian brain and current research suggests that GHB is a probable neurotransmitter. In the United States, reports of anabolic effects lead to its misuse among body builders during the 1980's while the intoxicating properties of the drug lead to its popularization as a substance of abuse during the 1990's. GHB became associated with reports of drug-facilitated sexual assault and cases of physical dependence and withdrawal. Efforts to ban GHB caused increased use of GHB analogues and pro-drugs. Against this backdrop, GHB was being developed for the treatment of narcolepsy, leading to the approval of Xyrem (sodium oxybate) oral solution in 2002 for the treatment of cataplexy in patients with narcolepsy. A risk management program permits the safe handling and distribution of the approved product, minimizes the risk for diversion, provides professional and patient education about the risks and benefits of sodium oxybate, and includes physician and patient registries. Post-marketing surveillance indicates sodium oxybate has an acceptable safety profile and presents minimal risk for the development of physical dependence.

Central apnoea after balanced general anaesthesia that included dexmedetomidine

Dexmedetomidine is an alpha(2)-adrenoreceptor agonist that, in spite of its potent sedative, amnesic, and analgesic properties, has minimal respiratory depressant effect. Even at doses adequate for general anaesthesia, it does not cause central apnoea. Thus, it has been claimed that "combining alpha(2)-agonists with opiate narcotics or non-steroidal anti-inflammatory drugs can enhance the analgesic efficacy without increasing the respiratory depressant effect of the latter" and "the combination of alpha(2)-adrenoceptor agonists with opioids does not lead to further ventilatory depression". We present a case of central apnoea after general anaesthesia that included opioids and dexmedetomidine, and remind the readers that in susceptible patients, dexmedetomidine may cause life-threatening respiratory depression through potentiation of co-administered central nervous system depressants.

Alcohol and anesthetic action at the gate of a voltage-dependent K+ channel

The role of direct interactions between ion channels and general anesthetic agents, including 1-alkanols, is broadly recognized. Relevant models that may allow direct visualization of these interactions are critical for understanding the molecular bases of general anesthesia and alcohol intoxication. The Drosophila Shaw2 K+ channel is selectively modulated by 1-alkanols at pharmacologically relevant concentrations. From our studies, we have concluded that: (1) amphiphilic interactions control the binding of 1-alkanols to an intracellularly accessible site in the Shaw2 protein; and (2) the modulation (inhibition or potentiation) depends on the secondary structures of the S4–S5 loop and the distal region of the S6 segment, which are components of the main activation gate and may directly contribute to the 1-alkanol binding site. Here, we summarize our work and discuss ideas that may shed light on the structural basis of the modulation of the Shaw2 K+ channel by 1-alkanols.

From the FDA

DRUG labeling is of vital importance in guiding the safe and effective use of approved drugs. Drug labels represent the most visible expression of months or years of scientific review by physicians and scientists at the U.S. Food and Drug Administration (FDA), and they are also fundamental to the purpose and mission of the FDA. Creation of the FDA dates to the 1906 passage of the Food and Drugs Act, which prohibited the manufacture and interstate shipment of adulterated and misbranded foods and drugs.† A 1937 disaster, in which more than 100 people died after ingestion of Elixir Sulfanilamide, precipitated the Federal Food, Drug, and Cosmetic Act of 1938, which, for the first time in U.S. history, required demonstration of safety before marketing new drugs. Elixir Sulfanilamide contained diethylene glycol and had never been tested for safety. In 1960, a marketing application for the drug thalidomide was submitted to the FDA. Withstanding enormous pressure from the applicant, FDA reviewers, including Frances Kelsey, M.D., Ph.D., a medical officer at the Center for Drug Evaluation and Research at the FDA (Washington D.C.),‡ determined that inadequate data were available to support the safety of the drug product despite its already widespread use throughout the rest of the world. The application was not approved. After thousands of children in 46 countries were born with deformities as a consequence of thalidomide use, leaving the United States relatively unscathed, a political movement for tighter drug controls in the United States gained popular support. The Drug Amendments of 1962 were the first to require demonstration of effectiveness before marketing, recognizing that the assessment of safety must also consider benefit. Since 1962, more than a thousand prescription drugs have had their labeling changed or have been taken off the market to reflect the scientific evidence (or lack thereof) documenting their safety and/or effectiveness.§ Section 505 of the Federal Food, Drug, and Cosmetic Act (21 USC 355) currently specifies that approved drugs must be safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling. Current regulations stipulate the following labeling requirements:

Do inhalation general anesthetic drugs induce the neuronal release of endogenous opioid peptides?

The antagonism of some effects of inhalation general anesthetic agents by naloxone suggests that there may be an opioid component to anesthetic action. There is evidence that this opioid action component is due to neuronal release of endogenous opioid peptides. The strongest evidence is provided by studies that monitor changes in the concentration of opioid peptides in the perfused brain following inhalation of the anesthetic. Indirect or circumstantial evidence also comes from studies of anesthetic effects on regional brain levels of opioid peptides, antagonism of selected anesthetic effects by antisera to opioid peptides and anesthetic-induced changes radioligand binding to opioid receptors. It is likely that some inhalation general anesthetics (e.g., nitrous oxide) can induce neuronal release of opioid peptides and that this may contribute to certain components of general anesthesia (e.g., analgesia). More definitive studies utilizing in vivo microdialysis or autoradiography in selected areas of the brain during induction and successive states of general anesthesia have yet to be conducted.

Systemic ketamine inhibits hypersensitivity after surgery via descending inhibitory pathways in rats

Systemic ketamine suppresses several types of chronic pain. Although ketamine is used as a general anesthetic agent, the analgesic effect of systemic ketamine for early-stage postoperative pain is not clear. We investigated the efficacy and mechanism of systemic ketamine in a rat model of postoperative pain. An incision was made in the plantar aspect of the left hind paw in male Wistar rats. Mechanical hypersensitivity was measured using calibrated von Frey filaments. The anti-hypersensitivity effect of systemic or intrathecal administration of ketamine was determined every hour after making the incision. We examined the effects of intrathecal pretreatment with yohimbine, an alpha2-adrenoceptor antagonist, and methysergide, a serotonergic receptor antagonist, on the anti-hypersensitivity effect of ketamine. We also examined the effect of systemic ketamine on the c-fos immunoreactivity in the spinal cord. Systemic administration of ketamine at doses from 3 to 30 mg.kg(-1) produced anti-hypersensitivity effects in a dose-dependent manner. Intrathecal administration of ketamine had no effect. There was no significant difference between effects of pre- and post-incisional administration. Intrathecal pretreatment with yohimbine (10 microg) or methysergide (15 microg) completely reversed the anti-hypersensitivity effects of systemic ketamine. Systemic ketamine reduced fos expression in laminae I-II in the dorsal horn of the lumbar spinal cord ipsilateral to the paw incision. The results suggest that systemic administration of ketamine perioperatively suppresses early-stage postoperative pain via monoaminergic descending inhibitory pathways.

The Anesthetic Cascade

The Anesthetic Cascade

Impact of Sedation and Anesthesia on the Rectoanal Inhibitory Reflex in Children

ABSTRACTObjectiveThe study objective was to determine whether the rectoanal inhibitory reflex (RAIR) can be elicited during limited anorectal manometry (ARM) performed under general anesthesia (GA).MethodsIn this retrospective study, patients with intractable constipation who underwent ARM under GA from November 1999 to March 2002 were evaluated. Rectal biopsy specimens were examined for the presence of ganglion cells.ResultsEighty consecutive patients aged 5 months to 16 years were evaluated. Three patients with Hirschsprung disease were excluded from analysis. Ganglion cells were found in rectal biopsy specimens from 76 patients. RAIR was positive in 69 (90%) and negative in 8 (10%). Forty‐five patients received preoperative medications: midazolam (n = 36), midazolam + atropine (n = 3), atropine (n = 1), midazolam + glycopyrrolate (n = 3), and glycopyrrolate (n = 2). Different combinations of general anesthetic medications were used. Ten patients received neuromuscular blockers. The use of preoperative midazolam or atropine did not affect the presence or absence of RAIR; however, the proportion of patients with negative RAIR was higher in those receiving glycopyrrolate (P = 0.007) than in those receiving other medications. There was no significant difference in the effect of the general anesthetic agents or neuromuscular blockers used on the presence or absence of RAIR.ConclusionsThe rectoanal inhibitory reflex in children can be elicited even when anorectal manometry is performed under general anesthesia. Glycopyrrolate, an anticholinergic, appears to inhibit the demonstration of the RAIR.

Impact of sedation and anesthesia on the rectoanal inhibitory reflex in children.

The study objective was to determine whether the rectoanal inhibitory reflex (RAIR) can be elicited during limited anorectal manometry (ARM) performed under general anesthesia (GA). In this retrospective study, patients with intractable constipation who underwent ARM under GA from November 1999 to March 2002 were evaluated. Rectal biopsy specimens were examined for the presence of ganglion cells. Eighty consecutive patients aged 5 months to 16 years were evaluated. Three patients with Hirschsprung disease were excluded from analysis. Ganglion cells were found in rectal biopsy specimens from 76 patients. RAIR was positive in 69 (90%) and negative in 8 (10%). Forty-five patients received preoperative medications: midazolam (n = 36), midazolam + atropine (n = 3), atropine (n = 1), midazolam + glycopyrrolate (n = 3), and glycopyrrolate (n = 2). Different combinations of general anesthetic medications were used. Ten patients received neuromuscular blockers. The use of preoperative midazolam or atropine did not affect the presence or absence of RAIR; however, the proportion of patients with negative RAIR was higher in those receiving glycopyrrolate (P = 0.007) than in those receiving other medications. There was no significant difference in the effect of the general anesthetic agents or neuromuscular blockers used on the presence or absence of RAIR. The rectoanal inhibitory reflex in children can be elicited even when anorectal manometry is performed under general anesthesia. Glycopyrrolate, an anticholinergic, appears to inhibit the demonstration of the RAIR.