Preoperative anxiety and need for support - A qualitative analysis in 1000 patients.

OBJECTIVES: Preoperative anxiety is prevalent, emotionally distressing for many patients, and can have harmful effects on postoperative outcomes. Despite its high prevalence, there has been little research on preoperative anxiety using qualitative methods. This study's main goal was to qualitatively examine factors that may contribute to preoperative anxiety in a large sample. METHODS: In a survey, a total of 1000 patients awaiting surgery were asked open questions i) about reasons which they associate with their preoperative anxiety and ii) which coping strategies they would prefer in addition to premedication. RESULTS: The qualitative analysis indicated five overarching domains, 16 themes, and 54 subthemes of preoperative anxiety. Intra- or postoperative complications was the most common theme regarding preoperative anxiety (n = 516). Personal conversation was the most frequently desired supportive measure in addition to premedication. CONCLUSIONS: This study indicated a considerable heterogeneity of reasons associated with preoperative anxiety based on an unbiased assessment in a large sample. The study further suggests that a personal conversation is a clinically important coping strategy in addition to premedication. PRACTICE IMPLICATIONS: Providers should assess patients' preoperative anxiety and the resulting need for support individually to offer supportive measures adapted to the patients' needs.

Patients' desires for anxiolytic premedication - an observational study in adults undergoing elective surgery.

BACKGROUND: Most patients experiencing preoperative anxiety would welcome support in coping with their anxiety. Anxiolytic medication is a common way to address preoperative anxiety. However, the proportion of patients who welcome anxiolytic medication preoperatively and the preferred time of taking it have not been studied thoroughly. METHODS: Adult patients (n = 1000) scheduled to undergo elective surgery under general anesthesia were eligible to participate in this single-center observational study. Primary outcomes were the ratio of patients desiring anxiolytic medication (no/yes/on request) and the preferred time of taking it (evening before surgery/morning of day of surgery/on call to the operating room). Secondary outcomes included associations between different measures of anxiety (i.e., anxiety level according to the Amsterdam Preoperative Anxiety and Information Scale (APAIS) and anxiety status (no/yes)) and desire for anxiolytic medication (no/yes/on request). Primary outcomes were analyzed descriptively, and secondary outcomes were analyzed using multinomial logistic regressions. RESULTS: Three hundred fifty-six (35.6%) out of 1000 patients desired anxiolytic medication and 239 (23.9%) patients would welcome anxiolytic medication on request. In patients reporting anxiety (no/yes; n = 493), 228 (46.2%) stated a clear desire for anxiolytic medication (yes) and 142 (28.8%) considered anxiolytic medication (on request). Patients' preferences concerning the timing of premedication vary widely. In patients reporting a clear desire for anxiolytic medication (n = 356), the "morning of the day of surgery" was most frequently (n = 111, 31.2%) stated as the preferred time to get anxiolytic medication, followed by "on call to the operating room" (n = 51, 14.3%). All anxiety measures were significantly associated with desire for anxiolytic medication (p < 0.05). CONCLUSIONS: Given the importance of preoperative anxiety to patients, patients' desire for anxiolytic medication should be considered when discussing the pros and cons of premedication. Individualized instead of standardized prescription and timing of premedication is recommended. TRIAL REGISTRATION: German Clinical Trials Register ( DRKS 00013319 , approved 23/11/2017).

Preoperative anxiety and its association with patients' desire for support - an observational study in adults.

BACKGROUND: Preoperative anxiety is prevalent and has harmful effects on postoperative outcomes. However, to date, it is still unclear (i) to what extent patients perceive preoperative anxiety as emotionally distressful, (ii) whether patients would welcome support from anesthesiologists in coping with their anxiety, and (iii) whether anxiety scores are useful for everyday clinical practice to determine patients' need for support. METHODS: 1082 patients scheduled to undergo elective procedures under general anesthesia were eligible for this cross-sectional study carried out at a university hospital. Preoperative anxiety, resulting in emotional distress, and patients' desire for anesthesiologists' support in coping with their anxiety were assessed dichotomously (no vs. yes) and analyzed descriptively. The intensity of anxiety was evaluated using the Amsterdam Preoperative Anxiety and Information Scale (range 4-20). Associations between the intensity of anxiety and the resulting desire for support were analyzed using logistic regression. Receiver operating characteristic analyses were performed to identify anxiety levels that best predict desire for support. RESULTS: Among the 1000 (537 female; M (SD) 57 (18) years) subjects evaluated, 493 (318 (65 %) female) reported anxiety. Anxiety was associated with emotional distress in 320 (65 %) and desire for support in 291 (59 %) patients. Increased preoperative anxiety levels were associated with higher rates of desire for support (B= 0.270; odds ratio 1.31 [95 % CI 1.22-1.41]). An anxiety score > 9 was best to predict a desire for support (sensitivity 0.861, specificity 0.724). However, desire for support was even present in some patients with lowest anxiety scores (5 or 6). CONCLUSIONS: All patients undergoing surgery should be screened for preoperative anxiety and the resulting desire for support to be able to determine who would welcome support. Anxiety scoring tools do not seem to be useful to identify these patients. By helping patients experience less preoperative anxiety, anesthesiologists may not only reduce patients' emotional distress but also have a positive impact on postoperative outcome. TRIAL REGISTRATION: German Clinical Trials Register (DRKS 00013319, 23 November 2017).

Preoperative anxiety in adults - a cross-sectional study on specific fears and risk factors.

BACKGROUND: Preoperative anxiety comprising anesthesia and surgery related anxiety is common and perceived by many patients as the worst aspect of the surgical episode. The aim of this study was to identify independent predictors of these three anxieties dimensions and to quantify the relevance of specific fears particularly associated with anesthesia. METHODS: This study was part of a cross-sectional survey in patients scheduled to undergo elective surgery. Anxiety levels were measured with the Amsterdam Preoperative Anxiety and Information Scale (APAIS). Modified numeric rating scales (mNRS, range 0-10) were used to assess the severity of eight selected specific fears which were predominantly analyzed descriptively. Multivariate stepwise linear regression was applied to determine independent predictors of all three anxiety dimensions (APAIS anxiety subscales). RESULTS: 3087 of the 3200 enrolled patients were analyzed. Mean (SD) total preoperative anxiety (APAIS-A-T, range 4-20) was 9.9 (3.6). High anxiety (APAIS-A-T > 10) was reported by 40.5% of subjects. Mean (SD) levels of concern regarding the eight studied specific fears ranged from 3.9 (3.08) concerning "Anesthesiologist error" to 2.4 (2.29) concerning "Fatigue and drowsiness" with an average of 3.2 (2.84) concerning all specific fears. Ranking of all specific fears according to mean mNRS scores was almost identical in patients with high versus those with low anxiety. Among nine independent predictors of anxiety, only 3 variables (female gender, negative and positive anesthetic experience) independently predicted all three APAIS anxiety subscales. Other variables had a selective impact on one or two APAIS anxiety subscales only. Female gender had the strongest impact on all three APAIS anxiety subscales. Adjusted r2 values of the three models were all below 13%. CONCLUSIONS: The high variability of importance assigned to all specific fears suggests an individualized approach is advisable when support of anxious patients is intended. Considering independent predictors of anxiety to estimate each patient's anxiety level is of limited use given the very low predictive capacity of all three models. The clinical benefit of dividing patients into those with high and low anxiety is questionable. TRIAL REGISTRATION: German Registry of Clinical Trials (DRKS00016725), retrospectively registered.

Bispectral index to guide induction of anesthesia: a randomized controlled study.

BACKGROUND: It is unknown to what extent hypotension frequently observed following administration of propofol for induction of general anesthesia is caused by overdosing propofol. Unlike clinical signs, electroencephalon-based cerebral monitoring allows to detect and quantify an overdose of hypnotics. Therefore, we tested whether the use of an electroencephalon-based cerebral monitoring will cause less hypotension following induction with propofol. METHODS: Subjects were randomly assigned to a bispectral index (BIS)-guided (target range 40-60) or to a weight-related (2 mg.kg- 1) manual administration of propofol for induction of general anesthesia. The primary endpoint was the incidence of hypotension following the administration of propofol. Secondary endpoints included the degree of hypotension and correlations between BIS and drop in mean arterial pressure (MAP). Incidences were analyzed with Fisher's Exact-test. RESULTS: Of the 240 patients enrolled into this study, 235 predominantly non-geriatric (median 48 years, 25th - 75th percentile 35-61 years) patients without severe concomitant disease (88% American Society of Anesthesiology physical status 1-2) undergoing ear, nose and throat surgery, ophthalmic surgery, and dermatologic surgery were analyzed. Patients who were manually administered propofol guided by BIS (n = 120) compared to those who were given propofol by weight (n = 115) did not differ concerning the incidence of hypotension (44% vs. 45%; p = 0.87). Study groups were also similar regarding the maximal drop in MAP compared to baseline (33% vs. 30%) and the proportion of hypotensive events related to all measurements (17% vs. 19%). Final propofol induction doses in BIS group and NON-BIS group were similar (1.93 mg/kg vs. 2 mg/kg). There was no linear correlation between BIS and the drop in MAP at all times (r < 0.2 for all) except for a weak one at 6 min (r = 0.221). CONCLUSION: Results of our study suggest that a BIS-guided compared to a weight-adjusted manual administration of propofol for induction of general anesthesia in non-geriatric patients will not lower the incidence and degree of arterial hypotension. TRIAL REGISTRATION: German Registry of Clinical Trials ( DRKS00010544 ), retrospectively registered on August 4, 2016.

Pain During Venous Cannulation.

BACKGROUND: The pain of venous puncture for the cannulation of peripheral veins is disturbing to many patients. This is the first clinical trial of the efficacy of local anesthesia in comparison to placebo (no pretreatment) in a control group, as a function of the size of the cannula. METHODS: A randomized, controlled trial of fully factorial design was performed to study pain during venipuncture after local anesthesia either with intra - dermally injected lidocaine or with a vapocoolant spray, in comparison to placebo. A standardized protocol was used for structured communication with the patient to provide the greatest feasible degree of patient blinding (trial registration number DRKS00010155). The primary endpoints were the subjective discomfort of the patient during preparation and puncture of a vein of the dorsum of the hand, assessed on a numerical rating scale (NRS) from 0 (no discomfort) to 10 (unbearable discomfort), and the rate of unsuccessful puncture. RESULTS: The intention-to-treat analysis of all 450 patients revealed that the reported degree of pain during venipuncture depended to a large extent on the caliber of the chosen venous cannula. For a 17-gauge (17G) cannula, both the vapocoolant spray (NRS = 2.6 ± 1.3) and lidocaine (NRS = 3.5 ± 2.2) lessened the discomfort due to venipuncture compared to control treatment (5.0 ± 1.5). The effect of vapocoolant spray compared to the control was both clinically relevant and statistically significant (p < 0.0001). When a smaller 20G cannula was used, however, vapocoolant spray improved discomfort by only 0.8 NRS points, which, though still statistically significant (p = 0.0056), was no longer clinically relevant. The rate of unsuccessful puncture was higher after lidocaine pretreatment (12.7%) than after either vapocoolant spray (4.7%; p = 0.0066) or no pretreatment (4.0%; p = 0.0014). CONCLUSION: Local anesthesia can be recommended before venipuncture only if a large cannula is used (e.g., ≥ 17G). Vapocoolant spray may be at least as useful as lidocaine injection; it prevents pain to a similar extent and is associated with a lower rate of unsuccessful puncture.

Vapocoolant Spray Versus Lidocaine Infiltration for Radial Artery Cannulation: A Prospective, Randomized, Controlled Clinical Trial.

OBJECTIVES: Local infiltration with lidocaine is a frequently used measure to prevent pain during arterial cannulation. Its administration is associated with pain. Vapocoolants like ethyl chloride or alkanes also affect rapid-onset anesthesia. However, their administration causes less discomfort compared with administration of lidocaine. The effectiveness of vapocoolants in mitigating discomfort associated with arterial cannulation never has been studied. The authors therefore compared vapocoolant with lidocaine for reducing discomfort caused by arterial cannulation. DESIGN: Prospective, randomized, controlled study. SETTING: University hospital, single center. PARTICIPANTS: One hundred sixty adult patients requiring arterial cannulation before induction of general anesthesia for cardiac surgery or carotid endarterectomy. INTERVENTIONS: Patients received either lidocaine infiltration or vapocoolant spray prior to arterial cannulation. Overall discomfort resulting from the whole procedure (applying local/topical anesthesia followed by arterial puncture) was rated on a 0 to 10 numerical rating scale. Puncture failure rate and time required for the intervention also were recorded. MEASUREMENTS AND MAIN RESULTS: One hundred forty-three patients were included in the per-protocol analysis. Mean pain scores in the vapocoolant group were 3.4 (±1.58) compared with 4.5 (±2.29) in the lidocaine group (difference 1.1±0.33; p = 0.032; Mann-Whitney U-test). The higher puncture failure rate in the lidocaine group (n = 11 v 4) was not significant (p = 0.06; Fisher's exact test). The time required for the intervention was longer in the lidocaine group (138±44 s v 128±44 s; p = 0.019; Mann-Whitney U-test). CONCLUSIONS: Vapocoolant spray is an alternative to lidocaine infiltration to mitigate discomfort associated with arterial cannulation.

Coping strategies in anxious surgical patients.

BACKGROUND: Anaesthesia and surgery provoke preoperative anxiety and stress. Patients try to regain control of their emotions by using coping efforts. Coping may be more effective if supported by specific strategies or external utilities. This study is the first to analyse coping strategies in a large population of patients with high preoperative anxiety. METHODS: We assessed preoperative anxiety and coping preferences in a consecutive sample of 3087 surgical patients using validated scales (Amsterdam Preoperative Anxiety and Information Scale/Visual Analogue Scale). In the subsample of patients with high preoperative anxiety, patients' dispositional coping style was determined and patients' coping efforts were studied by having patients rate their agreement with 9 different coping efforts on a four point Likert scale. Statistical analysis included correlational analysis between dispositional coping styles, coping efforts and other variables such as sociodemographic data. Statistical significance was considered for p < 0.05. RESULTS: The final analysis included 1205 patients with high preoperative anxiety. According to the initial self-assessment, about two thirds of the patients believed that information would help them to cope with their anxiety ("monitors"); the remainder declined further education/information and reported self-distraction to be most helpful to cope with anxiety ("blunters"). There was no significant difference between these two groups in anxiety scores. Educational conversation was the coping effort rated highest in monitors whereas calming conversation was the coping effort rated highest in blunters. Coping follows no demographic rules but is influenced by the level of education. Anxiolytic Medication showed no reliable correlation to monitoring and blunting disposition. Both groups showed an exactly identical agreement with this coping effort. Demand for medical anxiolysis, blunting or the desire for more conversation may indicate increased anxiety. The use of the internet was independent of the anxiety level and the demand of information. CONCLUSION: Conversation with medical staff proved to be the most popular coping strategy. Acknowledgment of the division between information-seeking and blunting-like personalities is central to supporting the patient's individual coping efforts. Internet access may be the easiest way to support coping today.

Impact of medical training and clinical experience on the assessment of oxygenation and hypoxaemia after general anaesthesia: an observational study.

In Germany it is common practice to use pulse oximetry and supplementary oxygen only on request in patients breathing spontaneously transferred to the post-anaesthesia care unit (PACU) following surgery under general anaesthesia. The main aim was to study the influence of medical training and clinical experience on assessing SpO(2) and detecting hypoxaemia in these patients. The second aim was to do a preliminary assessment whether this practice can be found in countries other than Germany. Anaesthetists, nurses and medical students estimated SpO(2) in patients breathing room air at the end of transfer to the PACU following surgery (including all major surgical fields) under general anaesthesia. Estimated SpO(2) was compared to SpO(2) measured by pulse oximetry. A survey was carried out among European anaesthesists concerning the use of pulse oximetry and supplementary oxygen during patient transfer to the PACU. Hypoxaemia (SpO(2) < 90 %) occurred in 154 (13.5 %) out of 1,138 patients. Anaesthetists, nurses, and medical students identified only 25, 23, and 21 patients of those as being hypoxaemic, respectively. Clinical experience did not improve detection of hypoxaemia both in anaesthetists (p = 0.63) and nurses (p = 0.18). Use of pulse oximetry and supplemental oxygen during patient transfer to the PACU in European countries differs to a large extent. It seems to be applied only on request in many hospitals. Considering the uncertainty about deleterious effects of transient, short lasting hypoxaemia routine use of pulse oximetry is advocated for patient transfer to the PACU.

Activity-based cost analysis of opioid-related nausea and vomiting among inpatients.

OBJECTIVE: Nausea and/or vomiting (N/V) are frequent side effects of opioid drugs. These are of major concerns to patients and caregivers and only few studies have focused on their economical costs. DESIGN: This is a prospective, nonproduct-related, activity-based evaluation of personnel and material costs of opioid-related N/V among inpatients. SETTING: Data were obtained from surgical, general medicine, and palliative care wards at 16 German hospitals of different size, healthcare mandate, and ownership. PATIENTS, PARTICIPANTS: According to predefined criteria, of 462 documented N/V events, 340 were diagnosed as opioid related. INTERVENTIONS: Elicited activities and pharmacological interventions for N/V episodes followed local standards. MAIN OUTCOME MEASURE: Both materials used and the time engaged to treat patients with N/V were documented on an "ad hoc" activity recording form. The total cost of an opioid-related N/V episode was calculated based on standard wages of the involved personnel and standard costs of the inherent materials used. RESULTS: Mean staff tenure time for handling an episode of N/V was 26.2 ± 19.8 minutes (nausea 16.9 ± 28.7 minutes; nausea + vomiting: 33.4 ± 26.8 minutes). In the German context, this corresponds to average personnel costs of €18.06 ± 13.64. Material cost contributes to another €13.49 ±13.38 of costs mainly depending on acquisition costs of antiemetic drugs. CONCLUSIONS: N/V showed to have impact on workload of nurses and (to lesser extent) physicians and economic burden of €31 ± 22 for each N/V episode. In view of these results, the potential costs of strategies to minimize the incidence of N/V (use of antiemetics and/or the use of new analgesics) should be outweighed against the incurred costs of N/V.

[Postoperative nausea and vomiting (PONV) - recommendations for risk assessment, prophylaxis and therapy - results of an expert panel meeting]. / Übelkeit und Erbrechen nach Operationen in Allgemeinanästhesie - Empfehlungen zur Risikoeinschätzung, Prophylaxe und Therapie.

BACKGROUND: The aim was to update recommendations concerning the management of postoperative nausea and vomiting (PONV) for German speaking countries. METHODS: An expert panel produced evidence-based, consented statements graded according to the Scottish Intercollegiate Guidelines Network (SIGN). RESULTS: Relevant risk factors for PONV include female gender, non-smoking status, history of PONV, history of motion sickness, use of intra- and postoperative opioids, volatile anesthetics and nitrous oxide. PONV scoring systems allow for an approximative risk assessment as a basis for a risk adapted approach. Since a risk-adapted prophylaxis vs. a risk-independent, fixed (combined) prophylaxis has not yet proven superior and because of inherent limitations of PONV scoring systems a fixed prophylaxis may be favourable. Regardless of the strategy for prophylaxis of PONV, high risk patients must be given a multimodal prophylaxis by avoiding known risk factors and applying multiple validated and effective antiemetic interventions. In the case of PONV immediate treatment is indicated due to its relevance for patients as well as the economic and medicolegal implications PONV may have. CONCLUSIONS: Given the impact of PONV on patient satisfaction and the availability of effective and safe measures to prevent and treat PONV, further efforts should be taken to actually implement present evidence in order to improve patient?s outcome following surgical procedures.

Nausea and vomiting after surgery under general anesthesia: an evidence-based review concerning risk assessment, prevention, and treatment.

BACKGROUND: The German-language recommendations for the management of postoperative nausea and vomiting (PONV) have been revised by an expert committee. Major aspects of this revision are presented here in the form of an evidence-based review article. METHODS: The literature was systematically reviewed with the goal of revising the existing recommendations. New evidence-based recommendations for the management of PONV were developed, approved by consensus, and graded according to the scheme of the Scottish Intercollegiate Guidelines Network (SIGN). RESULTS: The relevant risk factors for PONV include female sex, nonsmoker status, prior history of PONV, motion sickness, use of opioids during and after surgery, use of inhalational anesthetics and nitrous oxide, and the duration of anesthesia. PONV scoring systems provide a rough assessment of risk that can serve as the basis for a risk-adapted approach. Risk-adapted prophylaxis, however, has not been shown to provide any greater benefit than fixed (combination) prophylaxis, and PONV risk scores have inherent limitations; thus, fixed prophylaxis may be advantageous. Whichever of these two approaches to manage PONV is chosen, high-risk patients must be given multimodal prophylaxis, involving both the avoidance of known risk factors and the application of multiple validated and effective antiemetic interventions. PONV should be treated as soon as it arises, to minimize patient discomfort, the risk of medical complications, and the costs involved. CONCLUSION: PONV lowers patient satisfaction but is treatable. The effective, evidence-based measures of preventing and treating it should be implemented in routine practice.

Photo-activated azi-etomidate, a general anesthetic photolabel, irreversibly enhances gating and desensitization of gamma-aminobutyric acid type A receptors.

BACKGROUND: The general anesthetic etomidate acts via gamma-aminobutyric acid type A (GABA(A)) receptors, enhancing activation at low GABA and prolonging deactivation. Azi-etomidate is a photo-reactive etomidate derivative with similar pharmacological actions, which has been used to identify putative binding sites. The authors examine the irreversible effects of azi-etomidate photo-modification on functional GABA(A) receptors in cell membranes. METHODS: GABA(A) receptors (alpha1beta2gamma2L) were expressed in both Xenopus oocytes and human embryonic kidney cells exposed to 365 nm light-activated azi-etomidate with or without GABA, then extensively washed. Receptor-mediated chloride currents were measured using voltage clamp electrophysiology to assess the ratio of peak responses at 10 microm and 1 mm GABA (I10/I1000) and deactivation time course. RESULTS: After azi-etomidate photo-modification, I10/I1000 ratios were persistently enhanced and deactivation was prolonged, mimicking reversible azi-etomidate actions. Azi-etomidate and ultraviolet light were required to produce irreversible receptor modulation. Adding GABA during photo-modification greatly enhanced irreversible modulation. Azi-etomidate modification also dose-dependently reduced maximal GABA-activated currents, consistent with accumulation of permanently desensitized receptors. Excess etomidate during azi-etomidate photo-modification competitively reduced permanent desensitization. Persistent channel modulation was blocked by 320-fold excess etomidate but enhanced when 32-fold excess etomidate was present. CONCLUSIONS: Azi-etomidate efficiently photo-modifies etomidate sites on GABA(A) receptors in intact cells, producing persistent functional changes that mimic its reversible effects. The results demonstrate sequential modification at more than one etomidate site per receptor. The sites display reciprocal positive cooperativity. In combination with focal photo-activation, azi-etomidate may prove useful for studies of anesthetic actions in neural circuits.

Inhibition of human 5-HT(3A) and 5-HT(3AB) receptors by etomidate, propofol and pentobarbital.

The actions of intravenous anaesthetics on 5-HT(3AB) receptors have not been studied. Using oocyte electrophysiology, the effects of etomidate, propofol, and pentobarbital on human 5-HT(3A) and 5-HT(3AB) receptors were studied and compared. Inhibition of peak currents by all three compounds in both receptor subtypes was anaesthetic concentration-dependant and non-competitive. Because the half-maximal inhibitory concentrations for etomidate, propofol and pentobarbital in 5-HT(3A) and 5-HT(3AB) receptors were all above their respective anaesthetic concentrations, the results of our study suggest that neither 5-HT(3) receptor subtype contributes to the anaesthetic actions of etomidate, propofol or pentobarbital.

Subunit-dependent modulation of the 5-hydroxytryptamine type 3 receptor open-close equilibrium by n-alcohols.

5-Hydroxytryptamine (5-HT, serotonin) type 3 (5-HT(3)) receptors belong to the alcohol-sensitive superfamily of Cys-loop ligand-gated ion channels, and they are thought to play an important role in alcoholism. Alcohols with small molecular volumes increase the amplitude of currents evoked by low 5-HT concentrations and shift the 5-HT concentration-response curve for 5-HT(3) receptor activation leftward, indicative of increased receptor sensitivity to agonist. This action is significantly smaller when currents are mediated by heteromeric 5-HT(3AB) receptors compared with homomeric 5-HT(3A) receptors. In this study, we used the highly inefficacious 5-HT(3) receptor agonist dopamine to determine whether this difference between 5-HT(3A) and 5-HT(3AB) receptors reflects differential alcohol modulation of agonist binding affinity or channel gating efficacy. Human recombinant 5-HT(3A) and 5-HT(3AB) receptors were expressed in Xenopus oocytes, and currents were measured in the absence and presence of alcohols using the two-electrode voltage-clamp technique. Modulation by alcohols of peak currents elicited by maximally activating concentrations of dopamine was alcohol concentration-dependent. Potentiation by smaller alcohols was consistently significantly greater in 5-HT(3A) than in 5-HT(3AB) receptors, whereas inhibition by larger alcohols was not. A representative small (butanol) and large (octanol) alcohol failed to alter the EC(50) value for channel activation by dopamine. We conclude that the presence of the 5-HT(3B) subunit in 5-HT(3AB) receptors significantly reduces the enhancement of gating efficacy by small alcohols without altering the inhibitory actions of large alcohols.

Prospective application of a simplified risk score to prevent postoperative nausea and vomiting.

PURPOSE: To compare the risk-adapted approach with ondansetron against ondansetron plus dexamethasone to prevent postoperative nausea and vomiting (PONV) in a randomized clinical trial. METHODS: 460 patients scheduled for elective surgery were enrolled in this prospective study and stratified according to a simplified risk score for PONV. Patients having no or one risk factor were considered at low risk (group L) and did not receive study medication. Those with two to four risk factors were considered high risk and were randomized to receive 4 mg ondansetron plus placebo (group H-O) or 4 mg ondansetron plus 8 mg dexamethasone (group H-OD). Incidence and intensity of PONV were observed for 24 hr after surgery. Data were analyzed with Fisher's exact or Student's t tests; P < 0.05 was considered statistically significant. RESULTS: The incidence of PONV was 9% in group L (n = 87), 31% in those receiving ondansetron (group H-O, n = 185), and 22% in those receiving both drugs (group H-OD, n = 181). The incidence of PONV was significantly smaller in both high-risk groups than predicted without treatment (P < 0.001). While the incidence of PONV failed statistical significance between the two intervention groups (P = 0.08), the mean number of episodes of PONV and the mean maximal intensity of each episode of PONV were lower in group H-OD (P = 0.03 and P = 0.01, respectively). Patients of group H-OD required less antiemetic rescue therapy (P = 0.004). CONCLUSIONS: Ondansetron plus dexamethasone prevents PONV more effectively than ondansetron alone in patients at high risk for PONV.

Molecular properties important for inhaled anesthetic action on human 5-HT3A receptors.

Although inhaled anesthetics have diverse effects on 5-hydroxytryptamine type 3 (5-HT3A) receptors, the mechanism accounting for this diversity is not understood. Studies have shown that modulation of 5-HT3A receptor currents by n-alcohols depends on molecular volume, suggesting that steric interactions between n-alcohols and their binding sites define their action on this receptor. Electrostatic interactions also play an important role in anesthetic action on other ligand-gated receptors. We aimed to determine the contribution of molecular volume and electrostatics in defining volatile anesthetic actions on 5-HT3A receptors. Human 5-HT3A receptors were expressed in, and recorded from, Xenopus oocytes using the two-electrode voltage-clamp technique. The effects of a range of volatile anesthetics, n-alcohols, and nonhalogenated alkanes on submaximal serotonin-evoked peak currents, and full serotonin concentration-response curves were defined. Volatile anesthetics and n-alcohols, but not alkanes, smaller than 0.120 nm3 enhanced submaximal serotonin-evoked peak currents whereas all larger agents reduced currents. Most compounds tested inhibited maximal serotonin-evoked peak currents to varying degrees. However, only agents smaller than 0.120 nm3 shifted the 5-HT3A receptor's serotonin concentration-response curve to the left, whereas larger anesthetics shifted them to the right. Modulation of human 5-HT3A-mediated currents by volatile anesthetics exhibits a dependence on molecular volume consistent with the n-alcohols, suggesting that both classes of agents may enhance 5-HT3A receptor function via the same mechanism. Furthermore, the enhancing but not inhibiting effects of anesthetic compounds on 5-HT3A receptor currents are modulated by electrostatic interactions.

Modulation of human 5-hydroxytryptamine type 3AB receptors by volatile anesthetics and n-alcohols.

Functional 5-hydroxytryptamine type 3 (5-HT3) receptors can be formed by 5-HT3A subunits alone or in combination with the 5-HT3B subunit, but only the 5-HT3A receptor has been previously studied with respect to the modulation by volatile anesthetics and n-alcohols. Using two-electrode voltage-clamp, we show for the first time the modulation of heteromeric human (h)5-HT3AB receptors, expressed in Xenopus oocytes, by a series of n-alcohols and halogenated volatile anesthetics. At twice their anesthetic concentration, compounds having a molecular volume of less than 110 A3 enhanced submaximal 5-HT-evoked current. Compounds larger than 110 A3 inhibited submaximal 5-HT-evoked current. In experiments examining 5-HT concentration-response relationships, chloroform and butanol caused a slight decrease in the 5-HT EC50. Sevoflurane and octanol inhibited 5-HT-evoked current at all 5-HT concentrations tested but had no effect upon the 5-HT EC50. Compared with previous data on homomeric h5-HT3A receptors, the presence of the h5-HT3B subunit reduces the enhancement of h5-HT3 receptors by smaller halogenated volatile anesthetics and n-alcohols. In summary, these results suggest that heteromeric h5-HT3AB receptors are modulated by halogenated volatile anesthetics at clinically relevant concentrations, in addition to n-alcohols, suggesting that these receptors may be another physiological target for these compounds. The modulation is dependent upon the molecular volume of the compound, further supporting the concept of an anesthetic binding pocket of limited volume common on other Cys-loop ligand-gated ion channels. Incorporation of the 5-HT3B subunit alters either the anesthetic binding site or the allosteric interactions between anesthetic binding and channel opening.

Classic benzodiazepines modulate the open-close equilibrium in alpha1beta2gamma2L gamma-aminobutyric acid type A receptors.

BACKGROUND: Classic benzodiazepine agonists induce their clinical effects by binding to a site on gamma-aminobutyric acid type A (GABAA) receptors and enhancing receptor activity. There are conflicting data regarding whether the benzodiazepine site is allosterically coupled to gamma-aminobutyric acid binding versus the channel open-close (gating) equilibrium. The authors tested the hypothesis that benzodiazepine site ligands modulate alpha1beta2gamma2L GABAA receptor gating both in the absence of orthosteric agonists and when the orthosteric sites are occupied. METHODS: GABAA receptors were recombinantly expressed in Xenopus oocytes and studied using two-microelectrode voltage clamp electrophysiology. To test gating effects in the absence of orthosteric agonist, the authors used spontaneously active GABAA receptors containing a leucine-to-threonine mutation at residue 264 on the alpha1 subunit. To examine effects on gating when orthosteric sites were fully occupied, they activated wild-type receptors with high concentrations of a partial agonist, piperidine-4-sulfonic acid. RESULTS: In the absence of orthosteric agonists, the channel activity of alpha1L264Tbeta2gamma2L receptors was increased by diazepam and midazolam and reduced by the inverse benzodiazepine agonist FG7142. Flumazenil displayed very weak agonism and blocked midazolam from further activating mutant channels. In wild-type receptors activated with saturating concentrations of piperidine-4-sulfonic acid, midazolam increased maximal efficacy. CONCLUSIONS: Independent of orthosteric site occupancy, classic benzodiazepines modulate the gating equilibrium in alpha1beta2gamma2L GABAA receptors and are therefore allosteric coagonists. A Monod-Wyman-Changeux coagonist gating model quantitatively predicts these effects, suggesting that benzodiazepines minimally alter orthosteric ligand binding.

Gating allosterism at a single class of etomidate sites on alpha1beta2gamma2L GABA A receptors accounts for both direct activation and agonist modulation.

At clinical concentrations, the potent intravenous general anesthetic etomidate enhances gamma-aminobutyric acid, type A (GABA(A)) receptor activity elicited with low gamma-aminobutyric acid (GABA) concentrations, whereas much higher etomidate concentrations activate receptors in the absence of GABA. Therefore, GABA(A) receptors may possess two types of etomidate sites: high affinity GABA-modulating sites and low affinity channel-activating sites. However, GABA modulation and direct activation share stereoselectivity for the (R)(+)-etomidate isomer and display parallel dependence on GABA(A) beta subunit isoforms, suggesting that these two actions may be mediated by a single class of etomidate site(s) that exert one or more molecular effects. In this study, we assessed GABA modulation by etomidate using leftward shifts of electrophysiological GABA concentration responses in cells expressing human alpha1beta2gamma2L receptors. Etomidate at up to 100 microm reduced GABA EC(50) values by over 100-fold but without apparent saturation, indicating the absence of high affinity etomidate sites. In experiments using a partial agonist, P4S, etomidate both reduced EC(50) and increased maximal efficacy, demonstrating that etomidate shifts the GABA(A) receptor gating equilibrium toward open states. Results were quantitatively analyzed using equilibrium receptor gating models, wherein a postulated class of equivalent etomidate sites both directly activates receptors and enhances agonist gating. A Monod-Wyman-Changeux co-agonist mechanism with two equivalent etomidate sites that allosterically enhance GABA(A) receptor gating independently of agonist binding most simply accounts for direct activation and agonist modulation. This model also correctly predicts the actions of etomidate on GABA(A) receptors containing a point mutation that increases constitutive gating activity.