Steady-state trumps accuracy: target-controlled infusion as a gain switch.

Target-controlled infusion (TCI) is a mature technology that enables the delivery of intravenous anaesthetics in the concentration domain. The accuracy of the pharmacologic models used by TCI systems is imperfect, especially regarding pharmacodynamic predictions. This shortcoming of TCI devices is not critical. That TCI systems produce steady-state effect-site concentrations at or near a specified target is a more important attribute than a high level of accuracy because anaesthesiologists titrate to a stable level of drug effect whatever the actual concentration is. In this sense, TCI functions as a 'gain switch'. Achieving a steady state is more important than perfect accuracy.

Variability of predicted propofol concentrations and measured sevoflurane concentrations during general anaesthesia: a single-centre retrospective cohort study.

BACKGROUND: Variability is high in predicted propofol concentrations during clinical anaesthesia titrated by target-controlled infusion (TCI) to maintain a processed EEG parameter (bispectral index [BIS]) within a specified range. We have shown that the potential for improving the pharmacokinetic model is minimal. The drug titration paradox revealed that titration challenges the classical relationship between drug dose and effect in both individuals and the population. We hypothesised that dynamic factors during surgery beyond the static genetic, epigenetic, and other factors such as age, height, and weight affect the necessary dose. We compared the variability of measured end-tidal sevoflurane concentrations with predicted effect-site propofol concentrations when titrated to a BIS range of 40-60, with the hypothesis that the variability in measured sevoflurane concentrations would not be less than the variability in estimated propofol concentrations. METHODS: Clinical data from 2280 surgical procedures >1 h in duration were included in the analysis. Anaesthesia with sevoflurane or propofol was based on an institutional protocol. The titration performance for both drugs was assessed by comparing BIS values 30 min after skin incision. The variability of the required concentrations at the same time point was calculated and compared. RESULTS: The achieved 30-min post-incision BIS ranges were not significantly different for sevoflurane or propofol TCI (30 [99% CI: 28-33] and 31 [99% CI: 27-36], respectively). The variability of sevoflurane concentrations was not significantly different from measured predicted propofol concentrations during BIS-guided anaesthesia (normalized concentration range of 0.89 [99% CI: 0.78-0.99] and 0.93 [99% CI 0.87-1.02). CONCLUSIONS: Improvements in prediction accuracy of pharmacokinetic models beyond that of those already in clinical use are unlikely to reduce variability in target anaesthetic concentrations across patients in clinical practice.

Pro-Con Debate: Should All General Anesthesia Be Done Using Target-Controlled Propofol Infusion Guided by Objective Monitoring of Depth of Anesthesia?

In this Pro-Con commentary article, we discuss whether all general anesthesia should be done using target-controlled propofol anesthesia guided by monitoring of depth of anesthesia. This is an ongoing debate since more than 25 years, representing a scientific, cultural as well as geographical divide in the anesthesia community. The Pro side argues that total intravenous anesthesia causes less postoperative nausea and higher patient satisfaction than anesthesia using volatile anesthetics. Target-controlled infusion (TCI) of anesthetic agents allows for better titration of intravenous anesthesia using pharmacokinetic models. Processed EEG monitors, such as bispectral index monitoring, allows for better assessing the effect of TCI anesthesia than solely assessment of clinical parameters, such as ECG or blood pressure. The combination of TCI propofol and objective depth of anesthesia monitoring allows creating a pharmacokinetic-pharmacodynamic profile for each patient. Finally, anesthesia using volatile anesthetics poses health risks for healthcare professionals and contributes to greenhouse effect. The Con side argues that for procedures accompanied with ischemia and reperfusion injury of an organ or tissue and for patients suffering from a severe inflammation' the use of volatile anesthetics might well have its advantages above propofol. In times of sudden shortage of drugs, volatile anesthetics can overcome the restriction in the operating theater or even on the intensive care unit, which is another advantage. Volatile anesthetics can be used for induction of anesthesia when IV access is impossible, end-tidal measurements of volatile anesthetic concentration allows confirmation that patients receive anesthetics. Taking environmental considerations into account, both propofol and volatile anesthetics bear certain harm to the environment, be it as waste product or as greenhouse gases. The authors therefore suggest to carefully considering advantages and disadvantages for each patient in its according environment. A well-balanced choice based on the available literature is recommended. The authors recommend careful consideration of advantages and disadvantages of each technique when tailoring an anesthetic to meet patient needs. Where appropriate, anesthesia providers are encouraged to account for unique features of anesthetic drug behavior, patient-reported and observed postoperative outcomes, and economic and environmental considerations when choosing any of the 2 described techniques.

Analgesic efficacy of systemic lidocaine using lean body mass based dosing regime versus placebo in bariatric surgery: a prospective, randomised, double-blind, placebo-controlled, single-centre study.

BACKGROUND: Intravenous lidocaine is used as an adjuvant analgesic agent in perioperative settings. It has been investigated in various patient populations and surgical interventions, but there are limited data on its efficacy, particularly for patients undergoing bariatric surgery. Obese patients are at high risk of postoperative respiratory complications and can be expected to benefit from anaesthetic techniques that minimise opioid administration. METHODS: We studied administration of lidocaine hydrochloride 1% i.v. to general anaesthesia at a dose of 1.5 mg kg-1 (lean body mass×1.28) or placebo in patients undergoing bariatric surgery. Subjects randomly assigned to each group were surveyed for 48 h after surgery for experienced pain (primary outcome), and administered opioids, postoperative nausea and vomiting (PONV), resumption of bowel function, and length of hospital stay (secondary outcomes). RESULTS: We recruited and randomised 140 subjects to either the lidocaine or placebo group; 137 completed the study. Subjects with pain numeric rating scale (NRS) >3 within the first 4 h postoperatively were similar in both groups (proportion of any NRS >3 within first 4 h lidocaine group: 47/68 (69%) vs placebo group: 44/69 (63%), P=0.507; within first h P=0.177, within second h P=0.513, within third h P=0.145, within fourth h P=0.510). There was no difference in maximal pain score, opioid consumption, recovery of bowel function, incidence of PONV, or length of hospital stay. CONCLUSIONS: Lidocaine does not improve postoperative pain scores, analgesia, or any secondary outcomes in patients undergoing bariatric surgery. CLINICAL TRIAL REGISTRATION: NCT03667001.

The drug titration paradox: more drug does not correlate with more effect in individual clinical data.

BACKGROUND: A fundamental concept in pharmacology is that increasing dose increases drug effect. This is the basis of anaesthetic titration: the dose is increased when increased drug effect is desired and decreased when reduced drug effect is desired. In the setting of titration, the correlation of doses and observed drug effects can be negative, for example increasing dose reduces drug effect. We have termed this the drug titration paradox. We hypothesised that this could be explained, at least in part, by intrasubject variability. If the drug titration paradox is simply an artifact of pooling population data, then a mixed-effects analysis that accounts for interindividual variability in drug sensitivity should 'flip' the observed correlation, such that increasing dose increases drug effect. METHODS: We tested whether a mixed-effects analysis could correctly reveal the underlying pharmacology using previously published data obtained during automatic feedback control of mean arterial pressure (MAP) with alfentanil (effect site concentration, CeAlf) during surgery. The relationship between MAP and CeAlf was explored with linear regression and a linear mixed-effects model. RESULTS: A linear mixed-effects model did not identify the correct underlying pharmacology because of the presence of the titration paradox in the individual data. CONCLUSIONS: The relationship between drug dose and drug effect must be determined under carefully controlled experimental conditions. In routine care, where the effect is profoundly influenced by varying clinical conditions and drugs are titrated to achieve the desired effect, it is nearly impossible to draw meaningful conclusions about the relationship between dose and effect.

Targeting Higher Intraoperative Blood Pressures Does Not Reduce Adverse Cardiovascular Events Following Noncardiac Surgery.

BACKGROUND: Intraoperative arterial hypotension is strongly associated with postoperative major adverse cardiovascular events (MACE); however, whether targeting higher intraoperative mean arterial blood pressures (MAPs) may prevent adverse events remains unclear. OBJECTIVES: This study sought to determine whether targeting higher intraoperative MAP lowers the incidence of postoperative MACE. METHODS: This single-center randomized controlled trial assigned adult patients at cardiovascular risk undergoing major noncardiac surgery to an intraoperative MAP target of ≥60 mm Hg (control) or ≥75 mm Hg (MAP ≥75). The primary outcome was acute myocardial injury on postoperative days 0-3 and/or 30-day MACE/acute kidney injury (AKI) (acute coronary syndrome, congestive heart failure, coronary revascularization, stroke, AKI, and all-cause mortality). The secondary outcome was 1-year MACE. RESULTS: In total, 458 patients were randomized (intention-to-treat population: 451). The cumulative intraoperative duration with MAP <65 mm Hg was significantly shorter in the MAP ≥75 group (median 9 minutes [interquartile range: 3 to 24 minutes] vs 23 minutes [interquartile range: 8-49 minutes]; P < 0.001). The primary outcome incidence was 48% for MAP ≥75 and 52% for control (risk difference -4.2%; 95% CI: -13% to +5%), the primary contributor being AKI (incidence 44%). Acute myocardial injury occurred in 15% (MAP ≥75) and 19% (control) of patients. The secondary outcome incidence was 17% for MAP ≥75 and 15% for control (risk difference +2.7; 95% CI: -4% to +9.5%). CONCLUSIONS: These findings do not support universally targeting higher intraoperative blood pressures to reduce postoperative complications. Despite a 60% reduction in hypotensive time with MAP <65 mm Hg, no significant reductions in acute myocardial injury or 30-day MACE/AKI could be found. (Biomarkers, Blood Pressure, BIS: Risk Stratification/Management of Patients at Cardiac Risk in Major Noncardiac Surgery [BBB]; NCT02533128).

The Drug Titration Paradox: Correlation of More Drug With Less Effect in Clinical Data.

While analyzing clinical data where an anesthetic was titrated based on an objective measure of drug effect, we observed paradoxically that greater effect was associated with lesser dose. With this study we sought to find a mathematical explanation for this negative correlation between dose and effect, to confirm its existence with additional clinical data, and to explore it further with Monte Carlo simulations. Automatically recorded dosing and effect data from more than 9,000 patients was available for the analysis. The anesthetics propofol and sevoflurane and the catecholamine norepinephrine were titrated to defined effect targets, i.e., the processed electroencephalogram (Bispectral Index, BIS) and the blood pressure. A proportional control titration algorithm was developed for the simulations. We prove by deduction that the average dose-effect relationship during titration to the targeted effect will associate lower doses with greater effects. The finding of negative correlations between propofol and BIS, sevoflurane and BIS, and norepinephrine and mean arterial pressure confirmed the titration paradox. Monte Carlo simulations revealed two additional factors that contribute to the paradox. During stepwise titration toward a target effect, the slope of the dose-effect data for the population will be "reversed," i.e., the correlation between dose and effect will not be positive, but will be negative, and will be "horizontal" when the titration is "perfect." The titration paradox must be considered whenever data from clinical titration (flexible dose) studies are interpreted. Such data should not be used naively for the development of dosing guidelines.

Relationship Between Propofol Target Concentrations, Bispectral Index, and Patient Covariates During Anesthesia.

BACKGROUND: Internationally, propofol is commonly titrated by target-controlled infusion (TCI) to maintain a processed electroencephalographic (EEG) parameter (eg, bispectral index [BIS]) within a specified range. The overall variability in propofol target effect-site concentrations (CeT) necessary to maintain adequate anesthesia in real-world conditions is poorly characterized, as are the patient demographic factors that contribute to this variability. This study explored these issues, hypothesizing that the variability in covariate-adjusted propofol target concentrations during BIS-controlled anesthesia would be substantial and that most of the remaining interpatient variability in drug response would be due to random effects, thus suggesting that the opportunity to improve on the Schnider model with further demographic data is limited. METHODS: With ethics committee approval and a waiver of informed consent, a deidentified, high-resolution, intraoperative database consisting of propofol target concentrations, BIS values, and vital signs from 13,239 patients was mined to identify patients who underwent general endotracheal anesthesia using propofol (titrated to BIS), fentanyl, remifentanil, and rocuronium that lasted at least 1 hour. The propofol target concentrations and BIS values 30 minutes after incision (CeT30 and BIS30) were considered representative of stable intraoperative conditions. The data were plotted and analyzed by descriptive statistics. Confidence intervals were computed using a bootstrap method. A linear model was fit to the data to test for correlation with factors of interest (eg, age and weight). RESULTS: A total of 4584 patients met inclusion criteria and were entered into the analysis. Of the propofol target concentrations, 95% were between 1.5 and 3.5 µg·mL-1. Higher BIS30 values were correlated with higher propofol concentrations. Except for age, all the patient-related variables analyzed entered the regression model linearly. Only 10.2% of the variability in CeT30 was explained by the patient factors of age and weight combined. CONCLUSIONS: Our hypothesis was confirmed. The variability in covariate-adjusted propofol CeT30 titrated to BIS in real-world conditions is considerable, and only a small portion of the remaining variability in drug response is explained by patient demographic factors. This finding may have important implications for the development of new pharmacokinetic (PK) models for propofol TCI.

Outcome after out-of-hospital ventricular fibrillation or pulseless ventricular tachycardia: comparison of before and after the implementation of the 2010 Guidelines in a single centre.

AIMS OF THE STUDY: Improvements to guidelines and efforts to train and equip laypersons and medical professionals are expected to result in improvements in the outcomes of patients experiencing out-of-hospital cardiac arrest (OHCA). This study aimed to evaluate changes in the survival and neurological outcomes of patients before and after the implementation of the 2010 guidelines. METHODS: In a retrospective chart review, we analysed the outcomes of 182 patients who suffered bystander-witnessed, out-of-hospital ventricular fibrillation or pulseless ventricular tachycardia of cardiac aetiology. These definitions were based on the Utstein style. Survival at hospital discharge (study period 2006 to 2015), 1-year survival (study period 2011 to 2015), neurological outcome (cerebral performance category [CPC] score) and the corresponding changes over time were evaluated. In addition, the results were compared with results obtained from a systematic review of the literature. RESULTS: Of 1423 confirmed OHCAs, 182 fulfilled our inclusion criteria. 91 were treated between 2006 and 2010, and 91 from 2011 to 2015. Thirty-one (34%) survived until hospital discharge in the first time period, 44 (48%) in the second time period (p = 0.071); 26/31 (83%) and 40/44 (91%) respectively had a CPC score of 1–2. Between 2011 and 2015, the 1-year survival rate of the patients discharged from hospital was 36/44 (82%). All of these 36 patients (100%) had a favourable neurological outcome (CPC 1–2). These results were well within the range reported in the literature, although this range is wide (11 to 52% for survival at discharge and 6 to 47% for survival at 1 year). CONCLUSIONS: Survival was found to be at the upper range of the results retrieved by the systematic literature review. However, we found no significant improvements over time. The neurological outcomes of the survivors were favourable. The generalisability of this study is limited by its small sample size. To further improve outcomes, more public health measures, such as a functioning chain of survival, are required (e.g. an effective first responder network).