Effectiveness of the advisory display SmartPilot® view in the assessment of anesthetic depth in low risk gynecological surgery patients: a randomized controlled trial.

BACKGROUND: Assessment of appropriate anesthetic depth is crucial to prevent harm to patients. Unnecessary deep anesthesia can be harmful, potentially causing acute renal failure, myocardial injury, delirium, and an increased mortality rate. Conversely, too light anesthesia combined with muscle relaxants can result in intraoperative patient awareness and lead to serious psychological trauma. This trial aimed to ascertain the effectiveness of the advisory display SmartPilot® View (SPV), as a supplemental measure in the assessment of anesthetic depth in low risk gynecological surgery patients. The hypothesis was that the use of the SPV would increase the precision of assessment, and result in a higher mean arterial pressure. METHODS: This trial used a randomized, controlled, single-blind design with a homogeneous sample. Patients undergoing minor, low risk gynecological surgery were randomly assigned to two groups: a test group wherein current standards were supplemented with the advisory display SPV and a control group assessed using only the current standards. Female patients aged between 18 and 75 years with American Society of Anesthesiologists Physical Status Classification System scores of 1-3 undergoing planned general anesthesia using the total intravenous anesthetic method, combining propofol and remifentanil, were included. The exclusion criteria included a body mass index ≥ 35 kg/m2, a history of alcoholism, drug intake affecting propofol and remifentanil dynamics, and inability to consent. The independent sample t-test and chi-square test or Fisher's exact test were used to assess the statistical significance of differences between the two groups. RESULTS: A total of 114 patients were included in the analysis (test group n = 58, control group n = 56). No significant differences in the mean arterial pressure, heart rate, bispectral index, extubation delay, or post-anesthesia care unit stay were found between groups. CONCLUSIONS: The addition of the advisory display SmartPilot® View to current standards in the evaluation of anesthetic depth had no significant effect on the outcome. TRIAL REGISTRATION: The trial was registered on January 16th 2019 with ClinicalTrials.gov (ref: NCT03807271 ).

Economic choice between remifentanil and food in squirrel monkeys.

Traditional approaches for evaluating if compounds are reinforcing, and thus a risk for abuse, include preclinical self-administration procedures conducted in the absence of alternative reinforcers. While the track record of this approach for determining abuse potential is good, that for predicting efficacy of addiction treatments is not. An alternate approach would be economic choice between drug and nondrug rewards, with parametrically varied options from trial to trial. This would promote goal-directed decisions between reward modalities and should provide metrics that reflect changes in internal state that influence desirability of a given option. We report herein a high throughput economic choice procedure in which squirrel monkeys choose between a short-lived opiate, remifentanil, and a palatable food reward. Stimuli on touchscreens indicate the amount of each reward type offered by varying the number of reward-specific elements. The rapid clearance of remifentanil avoids accumulation of confounding levels of drug, and permits a large number of trials with a wide range of offers of each reward modality. The use of a single metric encompassing multiple values of each reward type within a session enables estimation of indifference values using logistic regression. This indifference value is sensitive to reward devaluation within each reward domain, and is therefore a useful metric for determining shifts in reward preference, as shown with satiation and pharmacological treatment approaches.

Uso de Remifentanilo en pacientes COVID-19 críticos hospitalizados con ventilación mecánica / Use of Remifentanil in critical COVID-19 patients hospitalized with mechanical ventilation

ANTECEDENTES: El objetivo del presente informe es: Describir el proceso para la elaboración de recomendaciones por el grupo de trabajo designado por el Ministerio de Salud, en adelante denominado grupo de trabajo. Trasladar las Recomendaciones efectuadas por dicho grupo de trabajo en atención al uso de remifentanilo en pacientes COVID-19 críticos hospitalizados con ventilación mecánica, según la pregunta PICO (P: Población, I:Intervención, C:Comparador, O: Outcome o desenlaces) priorizada por el grupo de trabajo. La metodología considerada para arribar a la recomendación fue el Marco de Evidencia a la Decisión/Recomendación (EtD) desarrollado por el Grupo de Trabajo GRADE (1,2). ANALISIS: Formulación de la pregunta: En personas con COVID-19 crítico en ventilación mecánica invasiva ¿Qué analgésico opioide endovenoso debe utilizarse: Remifentanilo vs fentanilo? ¿Cuál es la dosis que debe administrarse? Identificación de la evidencia para la pregunta PICO: Se siguieron las orientaciones establecidas en el documento interno de UNAGESP: Orientaciones para el soporte metodológico otorgado al grupo de trab

Assessment of remifentanil for rapid sequence induction and intubation in patients at risk of pulmonary aspiration of gastric contents compared to rapid-onset paralytic agents: study protocol for a non-inferiority simple blind randomized controlled trial (the REMICRUSH study).

BACKGROUND: Rapid-onset paralytic agents are recommended to achieve muscle relaxation and facilitate tracheal intubation during rapid sequence induction in patients at risk of pulmonary aspiration of gastric contents. However, opioids are frequently used in this setting. The study's objective is to demonstrate the non-inferiority of remifentanil compared to rapid-onset paralytic agents, in association with an hypnotic drug, for tracheal intubation in patients undergoing  procedure under general anesthesia and at risk of pulmonary aspiration of gastric contents. METHODS: The REMICRUSH (Remifentanil for Rapid Sequence Induction of Anaesthesia) study is a multicenter, single-blinded, non-inferiority randomized controlled trial comparing remifentanil (3 to 4 µg/kg) with rapid-onset paralytic agents (succinylcholine or rocuronium 1 mg/kg) for rapid sequence induction in 1150 adult surgical patients requiring tracheal intubation during general anesthesia. Enrolment started in October 2019 in 15 French anesthesia units. The expected date of the final follow-up is October 2021. The primary outcome is the proportion of successful tracheal intubation without major complications. A non-inferiority margin of 7% was chosen. Analyses of the intent-to-treat and per-protocol populations are planned. DISCUSSION: The REMICRUSH trial protocol has been approved by the ethics committee of The Comité de Protection des Personnes Sud-Ouest et Outre-Mer II and will be carried out according to the principles of the Declaration of Helsinki and the Good Clinical Practice guidelines. The results of this study will be disseminated through presentations at scientific conferences and publications in peer-reviewed journals. The REMICRUSH trial is the first randomized controlled trial powered to investigate whether remifentanil with hypnotics is non-inferior to rapid-onset paralytic agents with hypnotic in rapid sequence induction of anesthesia for full stomach patients considering successful tracheal intubation without major complication. TRIAL REGISTRATION: ClinicalTrials.gov NCT03960801. Registered on May 23, 2019.

Electromyographic assessment of blink reflex throughout the transition from responsiveness to unresponsiveness during induction with propofol and remifentanil.

General anesthesia is a reversible drug-induced state of altered arousal characterized by loss of responsiveness due to brainstem inactivation. Precise identification of the moment in which responsiveness is lost during the induction of general anesthesia is extremely important to provide information regarding an individual's anesthetic requirements and help intraoperative drug titration. To characterize the transition from responsiveness to unresponsiveness more objectively, we studied neurophysiologic-derived parameters of electromyographic records of electrically evoked blink reflex as a means of identifying the precise moment of loss of responsiveness. Twenty-five patients received a slow infusion of propofol until loss of corneal reflex while successive blink reflexes were elicited and recorded every 6 s. The level of anesthesia was assessed using an adapted version of the Richmond Agitation-Sedation Scale. Different variables of the blink reflex components were calculated and compared to the adapted version of the Richmond Agitation-Sedation score and the estimated effect-site propofol concentration. Baselines of the blink reflex responses were similar to those in literature. After propofol infusion started, the most susceptible component of the blink reflex to propofol was R2 (EC50 = 1.358 (95% CI 1.321, 1.396) µg/mL) and the most resistant was R1 (EC50 = 3.025 (95% CI 2.960, 3.090) µg/mL). Most of the patients (24 out of 25) lost the R1 component when they were still responsive to shaking and shouting and corneal reflex could be elicited clinically (time = 102.48 ± 33.00 s). Habituation was present in R2 but not in R1. The R1 component of the blink reflex was found to have a strong correlation with the adapted version of the Richmond Agitation-Sedation Scale, with amplitude correlating better than areas (ρ = - 0.721 (0.123) versus ρ = - 0.688 (0.165)). We found a strong correlation between the R1 component with the estimated propofol effect-site concentration, with amplitude correlating better than areas (ρ = - 0.838 (0.113) versus ρ = - 0.823 (0.153)) and between the clinical scale and the propofol concentration (ρ = 0.856 (0.060)). The area and amplitude of the R1 component showed to be indicators of predicting different levels of anesthesia (Pk = 0.672 (0.183) versus Pk = 0.709 (0.134)) and these are connected to the propofol concentrations (Pk = 0.593 (0.10)). Our results suggest that electrically evoked blink reflex could be used during the induction of anesthesia as a surrogate of the Richmond Agitation-Sedation Scale to provide an objective endpoint as far as a - 4. At this point, at the moment of loss of R1, the propofol infusion may be stopped, as overshooting increases slightly the effect-site concentration afterward and eventually reaching loss of responsiveness. If the desired target is not achieved, the infusion can then be resumed.

Interactions between opioids and cannabinoids: Economic demand for opioid/cannabinoid mixtures.

BACKGROUND: Opioid abuse remains a significant public health challenge. With continuing emergence of novel psychoactive substances (e.g., synthetic cannabinoids found in "K2" or "spice" preparations), the co-administration of opioids and other novel drugs is likely to become more prevalent, which might increase the risk for abuse and other adverse effects. This study examined whether the synthetic cannabinoid receptor agonist JWH-018 alters the reinforcing effectiveness of the mu opioid receptor agonist remifentanil in rhesus monkeys (n = 4) using economic demand analyses. METHODS: Lever presses delivered intravenous infusions of a drug or drug mixture according to a fixed-ratio schedule. For each condition, the ratio progressively increased in quarter-log unit steps across sessions yielding a demand curve: consumption (infusions obtained) was plotted as a function of price (fixed-ratio value). RESULTS: When available alone, remifentanil (0.00032 mg/kg/infusion) occasioned the highest consumption at the lowest cost and highest essential value, while JWH-018 (0.0032 mg/kg/infusion) alone occasioned lower unconstrained demand and essential value. Unconstrained demand for a mixture of remifentanil and JWH-018 was lower than for remifentanil alone, but essential value of the mixture was not significantly different from that of remifentanil alone. CONCLUSION: These data indicate that synthetic cannabinoids such as JWH-018 might alter some aspects of opioid self-administration (i.e., decreased consumption at the lowest price) but do not enhance reinforcing effectiveness as measured by sensitivity of consumption to increasing costs. Opioid/cannabinoid mixtures do not appear to have greater or lesser abuse potential compared with opioids alone.

Insights into the Chemical Discovery of Remifentanil.

Design, Synthesis, and Pharmacological Evaluation of Ultrashort- to Long-acting Opioid Analgetics. By Feldman PL, James MK, Brackeen MF, Bilotta JM, Schuster SV, Lahey AP, Lutz MW, Johnson MR, Leighton HJ. J Med Chem 1991; 34:2202-8. Copyright 1991 American Chemical Society. Reprinted with permission.In an effort to discover a potent ultrashort-acting µ-opioid analgetic that is capable of metabolizing to an inactive species independent of hepatic function, several classes of 4-anilidopiperidine analgetics were synthesized and evaluated. One series of compounds displayed potent µ-opioid agonist activity with a high degree of analgesic efficacy and an ultrashort to long duration of action. These analgetics, 4-(methoxycarbonyl)-4-[1-oxopropyl)phenylamino]-1-piperidinepropanoic acid alkyl esters, were evaluated in vitro in the guinea pig ileum for µ-opioid activity, in vivo in the rat tail withdrawal assay for analgesic efficacy and duration of action, and in vitro in human whole blood for their ability to be metabolized in blood. Compounds in this series were all shown to be potent µ agonists in vitro, but depending upon the alkyl ester substitution, the potency and duration of action in vivo varied substantially. The discrepancies between the in vitro and in vivo activities and variations in duration of action are probably due to different rates of ester hydrolysis by blood esterase(s). The [structure-activity relationships] with respect to analgesic activity and duration of action as a function of the various esters synthesized is discussed. It was also demonstrated that the duration of action for the ultrashort-acting analgetic, 8, does not change upon prolonged infusion or administration of multiple bolus injections.

Orexin-1 Receptor Signaling in Ventral Pallidum Regulates Motivation for the Opioid Remifentanil.

Signaling at the orexin-1 receptor (OxR1) is important for motivated drug taking. Using a within-session behavioral economics (BE) procedure, we previously found that pharmacologic blockade of the OxR1 decreased motivation (increased demand elasticity) for the potent and short-acting opioid remifentanil and reduced low-effort remifentanil consumption. However, the mechanism through which orexin regulates remifentanil demand is currently unknown. Previous work implicated OxR1 signaling within ventral pallidum (VP) as a potential target. VP is densely innervated by orexin fibers and is known to regulate opioid reward. Accordingly, this study sought to determine the role of VP OxR1 signaling in remifentanil demand and cue-induced reinstatement of remifentanil seeking in male rats. Intra-VP microinjections of the OxR1 antagonist SB-334867 (SB) decreased motivation (increased demand elasticity; α) for remifentanil without affecting remifentanil consumption at low effort. Baseline α values predicted the degree of cue-induced remifentanil seeking, and microinjection of SB into VP attenuated this behavior without affecting extinction responding. Baseline α values also predicted SB efficacy, such that SB was most effective in attenuating reinstatement behavior in highly motivated rats. Together, these findings support a selective role for VP OxR1 signaling in motivation for the opioid remifentanil. Our findings also highlight the utility of BE in predicting relapse propensity and efficacy of treatment with OxR1 antagonists.SIGNIFICANCE STATEMENT Abuse of opioids has risen rapidly and continues to be a major health crisis. Thus, there is an urgent need to better understand the neurobiological and behavioral mechanisms underlying opioid addiction. Here, we investigate the role of orexin-1 receptor signaling (OxR1) within ventral pallidum (VP) in remifentanil demand and cue-induced reinstatement of remifentanil seeking. Using a within-session behavioral economics procedure, we show that intra-VP microinjections of the OxR1 antagonist SB-334867 decreased motivation (increased demand elasticity) without affecting remifentanil consumption at low effort. We also found that SB microinjected intra-VP attenuated cue-induced reinstatement of remifentanil seeking. Together, our results support a role for VP OxR1 signaling in opioid reward.

[Analgesia Nociception Index: assessment of acute postoperative pain]. / Índice de Analgesia/Nocicepção: avaliação da dor aguda pós­operatória.

BACKGROUND AND OBJECTIVES: Patient self-rating based scales such as Numerical Rating Scale, Visual Analog Scale that is used for postoperative pain assessment may be problematic in geriatric or critically ill patients with communication problems. A method capable of the assessment of pain in objective manner has been searched for years. Analgesia nociception index, which is based on electrocardiographic data reflecting parasympathetic activity, has been proposed for this. In this study we aimed to investigate the effectiveness of analgesia nociception index as a tool for acute postoperative pain assessment. Our hypothesis was that analgesia nociception index may have good correlation with Numerical Rating Scale values. METHODS: A total of 120 patients of American Society of Anesthesiologists (ASA) physical status I and II undergoing any surgical procedure under halogenated-based anesthesia with fentanyl or remifentanil were enrolled for the study. At the 15th minute of arrival to the Postoperative Care Unit the patients' pain was rated on a 0-10 point Numerical Rating Scale. The patients' heart rate, blood pressure, and analgesia nociception index scores were simultaneously measured at that time. The correlation between analgesia nociception index, heart rate, blood pressure and Numerical Rating Scale was examined. RESULTS: The study was completed with 107 patients, of which 46 were males (43%). Mean (SD) analgesia nociception index values were significantly higher in patients with initial Numerical Rating Scale ≤ 3, compared with Numerical Rating Scale> 3 (69.1 [13.4] vs. 58.1 [12.9] respectively, p <0.001). A significant negative linear relationship (r2=-0.312, p=0.001) was observed between analgesia nociception index and Numerical Rating Scale. CONCLUSION: Analgesia nociception index measurements at postoperative period after volatile agent and opioid-based anesthesia correlate well with subjective Numerical Rating Scale scores.

Analgesia Nociception Index: assessment of acute postoperative pain / Índice de Analgesia/Nocicepção: avaliação da dor aguda pós-operatória

Abstract Background and objectives Patient self-rating based scales such as Numerical Rating Scale, Visual Analog Scale that is used for postoperative pain assessment may be problematic in geriatric or critically ill patients with communication problems. A method capable of the assessment of pain in objective manner has been searched for years. Analgesia nociception index, which is based on electrocardiographic data reflecting parasympathetic activity, has been proposed for this. In this study we aimed to investigate the effectiveness of analgesia nociception index as a tool for acute postoperative pain assessment. Our hypothesis was that analgesia nociception index may have good correlation with Numerical Rating Scale values. Methods A total of 120 patients of American Society of Anesthesiologists (ASA) physical status I and II undergoing any surgical procedure under halogenated-based anesthesia with fentanyl or remifentanil were enrolled for the study. At the 15th minute of arrival to the Postoperative Care Unit the patients' pain was rated on a 0-10 point Numerical Rating Scale. The patients' heart rate, blood pressure, and analgesia nociception index scores were simultaneously measured at that time. The correlation between analgesia nociception index, heart rate, blood pressure and Numerical Rating Scale was examined. Results The study was completed with 107 patients, of which 46 were males (43%). Mean (SD) analgesia nociception index values were significantly higher in patients with initial Numerical Rating Scale ≤3, compared with Numerical Rating Scale >3 (69.1 [13.4] vs. 58.1 [12.9] respectively, p < 0.001). A significant negative linear relationship (r 2 = -0.312, p = 0.001) was observed between analgesia nociception index and Numerical Rating Scale. Conclusion Analgesia nociception index measurements at postoperative period after volatile agent and opioid-based anesthesia correlate well with subjective Numerical Rating Scale scores.

Resumo Justificativa e objetivo As escalas baseadas na autoavaliação de pacientes, como a Escala Visual Numérica e a Escala Visual Analógica, que são usadas para avaliar a dor pós-operatória podem ser problemáticas em pacientes geriátricos ou em estado crítico com problemas de comunicação. Portanto, um método capaz de avaliar a dor de maneira objetiva vem sendo pesquisado há anos. O índice de analgesia/nocicepção, baseado em dados eletrocardiográficos que refletem a atividade parassimpática, tem sido proposto para tal avaliação. Neste estudo, objetivamos investigar a eficácia do índice de analgesia/nocicepção como uma ferramenta para a avaliação da dor pós-operatória aguda. Nossa hipótese foi que o índice de analgesia/nocicepção pode ter boa correlação com os valores da Escala de Classificação Numérica. Métodos Um total de 120 pacientes com estado físico ASA I e II, submetidos a qualquer procedimento cirúrgico com o uso de anestésicos halogenados associados a fentanil ou remifentanil, foi incluído no estudo. No 15º minuto após a chegada à sala de recuperação pós-anestesia, a dor dos pacientes foi avaliada em uma escala numérica de 0-10 pontos. Os escores de frequência cardíaca, pressão arterial e o índice de analgesia/nocicepção dos pacientes foram medidos simultaneamente naquele momento. A correlação entre o índice de analgesia/nocicepção, frequência cardíaca, pressão arterial e a Escala Visual Numérica foi avaliada. Resultados O estudo foi concluído com 107 pacientes, dos quais 46 eram do sexo masculino (43%). Os valores da média (DP) do índice de analgesia/nocicepção foram significativamente maiores nos pacientes com valor inicial na Escala Visual Numérica ≤ 3, em comparação com valor na mesma escala > 3 (69,1 [13,4] vs. 58,1 [12,9], respectivamente, p < 0,001). Uma relação linear negativa significativa (r2 = -0,312, p = 0,001) foi observada entre o índice de analgesia/nocicepção e a Escala Visual Numérica. Conclusão As mensurações do índice de analgesia/nocicepção no pós-operatório após anestesia com agentes halogenados e opioides mostraram boa correlação com os escores subjetivos da Escala Visual Numérica.

An economic analysis of patient controlled remifentanil and epidural analgesia as pain relief in labour (RAVEL trial); a randomised controlled trial.

OBJECTIVE: To compare the costs of a strategy of patient controlled remifentanil versus epidural analgesia for pain relief in labour. DESIGN: We performed a multicentre randomised controlled trial in 15 hospitals in the Netherlands, the RAVEL trial. Costs were analysed from a health care perspective alongside the RAVEL trial. POPULATION: Pregnant women of intermediate to high risk beyond 32 weeks gestation who planned vaginal delivery. METHODS: Women were randomised before the onset of labour, to receive either patient controlled remifentanil or epidural analgesia when pain relief was requested during labour. MAIN OUTCOME MEASURES: Primary outcome for effectiveness was satisfaction with pain relief, expressed as the area under the curve (AUC). A higher AUC represents higher satisfaction with pain relief. Here, we present an economic analysis from a health care perspective including costs from the start of labour to ten days postpartum. Health-care utilization was documented in the Case Report Forms and by administering an additional questionnaire. RESULTS: The costs in the patient controlled remifentanil group (n = 687) and in the epidural group (n = 671) were €2900 versus €3185 respectively (mean difference of -€282 (95% CI -€611 to €47)). The (non-significant) higher costs in the epidural analgesia group could be mainly attributed to higher costs of neonatal admission. CONCLUSION: From an economic perspective, there is no preferential pain treatment in labouring intermediate to high risk women. Since patient controlled remifentanil is not equivalent to epidural analgesia with respect to AUC for satisfaction with pain relief we recommend epidural analgesia as the method of choice. However, if appropriately counselled on effect and side effects there is, from an economic perspective, no reason to deny women patient controlled remifentanil.

Comparison of the qCON and qNOX indices for the assessment of unconsciousness level and noxious stimulation response during surgery.

The objective of this work is to compare the performances of two electroencephalogram based indices for detecting loss of consciousness and loss of response to nociceptive stimulation. Specifically, their behaviour after drug induction and during recovery of consciousness was pointed out. Data was recorded from 140 patients scheduled for general anaesthesia with a combination of propofol and remifentanil. The qCON 2000 monitor (Quantium Medical, Barcelona, Spain) was used to calculate the qCON and qNOX. Loss of response to verbal command and loss of eye-lash reflex were assessed during the transition from awake to anesthetized, defining the state of loss of consciousness. Movement as a response to laryngeal mask (LMA) insertion was interpreted as the response to the nociceptive stimuli. The patients were classified as movers or non-movers. The values of qCON and qNOX were statistically compared. Their fall times and rise times defined at the start and at the end of the surgery were calculated and compared. The results showed that the qCON was able to predict loss of consciousness such as loss of verbal command and eyelash reflex better than qNOX, while the qNOX has a better predictive value for response to noxious stimulation such as LMA insertion. From the analysis of the fall and rise times, it was found that the qNOX fall time (median: 217 s) was significantly longer (p value <0.05) than the qCON fall time (median: 150 s). At the end of the surgery, the qNOX started to increase in median at 45 s before the first annotation related to response to stimuli or recovery of consciousness, while the qCON at 88 s after the first annotation related to response to stimuli or recovery of consciousness (p value <0.05). The indices qCON and qNOX showed different performances in the detection of loss of consciousness and loss of response to stimuli during induction and recovery of consciousness. Furthermore, the qCON showed faster decrease during induction. This behaviour is associated with the hypothesis that the loss of response to stimuli (analgesic effect) might be reached after the loss of consciousness (hypnotic effect). On the contrary, the qNOX showed a faster increase at the end of the surgery, associated with the hypothesis that a higher probability of response to stimuli might be reached before the recovery of consciousness.

Individual differences in orexin-I receptor modulation of motivation for the opioid remifentanil.

Orexin-1 receptors (Ox1Rs) have been implicated in the motivation for drugs of abuse. Here, we utilized a within-session behavioral-economics threshold procedure to screen for individual differences in economic demand for the ultra-short-acting opioid remifentanil and to test whether antagonism of Ox1Rs reduces remifentanil demand. The behavioral-economics procedure revealed robust individual differences in free consumption of remifentanil (Q0 parameter; hedonic set point). Rats with low baseline Q0 (low takers) displayed high demand elasticity (α parameter; reduced responding as drug price increased indicating low motivation for drug), whereas subjects with a higher Q0 (high takers) exhibit low demand elasticity (low α) by continuing to self-administer remifentanil despite increased cost (reflecting higher motivation for drug). In a punished responding paradigm utilizing footshock, subjects that were classified as high takers at baseline withstood twice as much shock as low takers to continue self-administering remifentanil. Interestingly, Ox1R antagonism with SB-334867 reduced Q0 and increased α in low takers but not in high takers. Similarly, the Ox1R antagonist attenuated cue-induced, but not drug-induced, reinstatement of remifentanil seeking in low takers but had no significant effect on reinstatement of drug seeking in high takers. Together, these data reveal a novel role of orexins in demand for remifentanil: Ox1Rs modulate demand in low takers but not in individuals that exhibit addictive-like behaviors (high takers). Finally, the behavioral assays in this study can serve as a novel laboratory model for studying individual differences in opioid use disorders.

Analgosedation: Improving Patient Outcomes in ICU Sedation and Pain Management.

Sedation practices in the critical care unit have been trending toward lighter sedation since the start of the new millennium, but patients continue to experience inadequate pain management and excessive sedation. This paper includes a brief examination of the problem of pain management in the ICU; trends in sedation practices, including light sedation and the daily interruption of sedation; and a literature review of analgosedation. While the analgosedation literature is relatively sparse, it offers a promising, patient-centered method for managing the triad of pain, agitation, and delirium, while reducing common complications associated with long-term ventilation. This paper concludes with a recommended method for analgosedation, the nursing implications, and a discussion of limitations and recommendations.

Refining Target-Controlled Infusion: An Assessment of Pharmacodynamic Target-Controlled Infusion of Propofol and Remifentanil Using a Response Surface Model of Their Combined Effects on Bispectral Index.

BACKGROUND: Propofol and remifentanil are commonly combined for total IV anesthesia. The pharmacokinetics (PK), pharmacodynamics (PD), and drug interactions of the combination are well understood, but the use of a combined PK and PD model to control target-controlled infusion pumps has not been investigated. In this study, we prospectively tested the accuracy of a PD target-controlled infusion algorithm for propofol and remifentanil using a response surface model of their combined effects on Bispectral Index (BIS). METHODS: Effect-site, target-controlled infusions of propofol and remifentanil were given using an algorithm based on standard PK models linked to a PD response surface model of their combined effects on BIS. The combination of a targeted BIS value and adjustable ratio of propofol to remifentanil was used to adjust infusion rates. The standard model performance measures of median performance error (bias) and median absolute performance error (inaccuracy), expressed as percentages, were used to assess accuracy of the infusions in a convenience sample of 50 adult patients undergoing surgery with general anesthesia. The influence of age and weight on the performance of the model was also assessed. RESULTS: Patients had a mean (range) age of 48 (19-73) years, weight of 80 (45-169) kg, and body mass index of 28 (19-45) kg/m. The overall model had a bias of 8% (SD 24%) and inaccuracy of 25% (SD 13%). Performance was least accurate during the early induction phase of anesthesia. There was no significant bias in BIS predictions with increasing age (P = 0.44) or weight (P = 0.56). CONCLUSIONS: The algorithm performed adequately in a clinical setting. The algorithm could be further refined, and assessment of its accuracy and utility in comparison to current clinical practice for giving IV anesthesia is warranted.

Assessment of sedation-analgesia by means of Poincaré analysis of the electroencephalogram.

Monitoring the levels of sedation-analgesia may be helpful for managing patient stress on minimally invasive medical procedures. Monitors based on EEG analysis and designed to assess general anesthesia cannot distinguish reliably between a light and deep sedation. In this work, the Poincaré plot is used as a nonlinear technique applied to EEG signals in order to characterize the levels of sedation-analgesia, according to observed categorical responses that were evaluated by means of Ramsay Sedation Scale (RSS). To study the effect of high frequencies due to EMG activity, three different frequency ranges (FR1=0.5-110 Hz, FR2=0.5-30 Hz and FR3=30-110 Hz) were considered. Indexes from power spectral analysis and plasma concentration of propofol and remifentanil were also compared with the bispectral index BIS. An adaptive Neurofuzzy Inference System was applied to model the interaction of the best indexes with respect to RSS score for each analysis, and leave-one-out cross validation method was used. The ability of the indexes to describe the level of sedation-analgesia, according with the RSS score, was evaluated using the prediction probability (Pk). The results showed that the ratio SD1/SD2FR3 contains useful information about the sedation level, and SD1FR2 and SD2FR2 had the best performance classifying response to noxious stimuli. Models including parameters from Poincaré plot emerge as a good estimator of sedation-analgesia levels.

Limiting the accessibility of cost-prohibitive drugs reduces overall anesthetic drug costs: a retrospective before and after analysis.

PURPOSE: Cost effectiveness is becoming increasingly important in today's healthcare environment. Remifentanil, dexmedetomidine, and desflurane are costly agents that often have suitable alternatives to their use. We sought to identify changes in cost and outcomes following interventions that limited the availability of these drugs. METHODS: We calculated anesthetic drug costs for all operating room procedures performed before and after the accessibility interventions. We retrospectively compared drug costs per case and the frequency of agent use before and after the interventions. In addition, we analyzed the incidence of adverse outcomes, including delayed out-of-room times, postoperative nausea and vomiting (PONV), unplanned intubations, use of naloxone, and reintubations. Wilcoxon-Mann-Whitney and Chi square analyses were used to quantify differences in cost, use, and outcomes between cohorts. RESULTS: Of the 27,233 cases we identified, 24,201 cases were analyzed. The mean anesthetic drug costs per case were significantly lower after the interventions vs before at ($21.44 vs $32.39, respectively), a cost savings of $10.95 (95% confidence interval, $9.86 to $12.04; P < 0.001). Additionally, a comparison of data after vs before the interventions revealed the following results: remifentanil use was significantly lower (3.5% vs 9.2% of cases; P < 0.001). Dexmedetomidine use did not differ significantly (0.4% vs 0.5% of cases; P = 0.07), and desflurane use was significantly lower (0.6% vs 20.2% of cases; P < 0.001). There was no significant relationship between the interventions and the frequency of delayed out-of-room times (15.5% vs 15.9%; P = 0.41), unplanned intubations (0.02% vs 0.03%; P = 0.60), and reintubations (0.01% vs 0.03%; P = 0.28). Postoperative nausea and vomiting decreased significantly after the interventions (22.8% vs 24.4%; P = 0.003), and naloxone use showed a significant increase (0.22% vs 0.11% of cases; P = 0.04). CONCLUSIONS: Reducing the accessibility of these cost-prohibitive agents resulted in significant anesthetic drug cost savings and decreased utilization of remifentanil and desflurane. The interventions had no significant effect on patient recovery time, incidence of unplanned intubations, or incidence of reintubation, but they were associated with a decrease in PONV and an increase in naloxone use.

A specialized post anaesthetic care unit improves fast-track management in cardiac surgery: a prospective randomized trial.

INTRODUCTION: Fast-track treatment in cardiac surgery has become the global standard of care. We compared the efficacy and safety of a specialised post-anaesthetic care unit (PACU) to a conventional intensive care unit (ICU) in achieving defined fast-track end-points in adult patients after elective cardiac surgery. METHODS: In a prospective, single blinded, randomized study, 200 adult patients undergoing elective cardiac surgery (coronary artery bypass graft (CABG), valve surgery or combined CABG and valve surgery), were selected to receive their postoperative treatment either in the ICU (n = 100), or in the PACU (n = 100). Patients who, at the time of surgery, were in cardiogenic shock, required renal dialysis, or had an additive EuroSCORE of more than 10 were excluded from the study. The primary end points were: time to extubation (ET), and length of stay in the PACU or ICU (PACU/ICU LOS respectively). Secondary end points analysed were the incidences of: surgical re-exploration, development of haemothorax, new onset cardiac arrhythmia, low cardiac output syndrome, need for cardio-pulmonary resuscitation, stroke, acute renal failure, and death. RESULTS: Median time to extubation was 90 [50; 140] min in the PACU vs. 478 [305; 643] min in the ICU group (P < 0.001). Median length of stay in PACU was 3.3 [2.7; 4.0] hours vs. 17.9 [10.3; 24.9] hours in the ICU (P < 0.001). Of the adverse events examined, only the incidence of new onset cardiac arrhythmia (25 in PACU vs. 41 in ICU, P = 0.02) was statistically different between groups. CONCLUSIONS: Treatment in a specialised PACU rather than an ICU, after elective cardiac surgery leads to earlier extubation and quicker discharge to a step down unit, without compromising patient safety. TRIAL REGISTRATION: ISRCTN71768341. Registered 11 March 2014.

[Incorrect programming of a target controlled infusion pump. Case SENSAR of the trimester]. / Programación errónea de una bomba de TCI. Caso SENSAR del trimestre.

We report the case of a patient who underwent surgical aortic valve replacement. During general anaesthesia maintenance, the patient received a remifentanyl infusion via a target controlled infusion (TCI) system. The infusion pump that was prepared to deliver the infusion showed malfunction at the beginning of the surgery, so it was quickly replaced with a second pump. After a few minutes into the surgery, the patient presented with hypotension refractory to treatment. The remifentanyl syringe also emptied faster than expected. On reviewing the TCI pump, it was found that it was erroneously programmed for propofol instead of remifentanyl, thus the patient had received a very high dose of remifentanyl that was probably the cause of the haemodynamic disturbances. The incident was an error in equipment use, facilitated by hurry, lack of checking of the equipment prior to its use, and the complex and unclear design of the devices' screens. After analysis of this incident, all TCI pumps were reviewed, and all the programs for infrequently used drugs were deleted. Furthermore, 2 pumps were selected for exclusive use in the cardiac surgery theatre, one with propofol-only programming, and the other with remifentanyl-only programming, both clearly marked and situated in fixed places in that theatre.