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.

The drug titration paradox: something obvious finally understood.

The drug titration paradox is an emerging concept in clinical pharmacology. The paradox refers to the observation that when drug is titrated to a specified level of effect in a population of patients, the expected positive correlation between dose and effect is reversed. That is, when titration rather than fixed dosing is used, greater drug exposure is associated with lesser effect, and vice versa. The drug titration paradox may have important implications for study design and data interpretation in anaesthesiology investigations, particularly in big data studies.

Raw and processed electroencephalography in modern anesthesia practice: a brief primer on select clinical applications.

The evidence supporting the intraoperative use of processed electroencephalography (pEEG) monitoring to guide anesthetic delivery is growing rapidly. This article reviews the key features of electroencephalography (EEG) waveforms and their clinical implications in select patient populations and anesthetic techniques. The first patient topic reviewed is the vulnerable brain. This term has emerged as a description of patients who may exhibit increased sensitivity to anesthetics and/or may develop adverse neurocognitive effects following anesthesia. pEEG monitoring of patients who are known to have or are suspected of having vulnerable brains, with focused attention on the suppression ratio, alpha band power, and pEEG indices, may prove useful. Second, pEEG monitoring along with vigilant attention to anesthetic delivery may minimize the risk of intraoperative awareness when administering a total intravenous anesthesia in combination with a neuromuscular blockade. Third, we suggest that processed EEG monitoring may play a role in anesthetic and resuscitative management when adverse changes in blood pressure occur. Fourth, pEEG monitoring can be used to better identify anesthesia requirements and guide anesthetic titration in patients with known or suspected substance use.

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

OBJECTIVES: Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. DESIGN: A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. PARTICIPANTS: Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. MEASUREMENTS AND MAIN RESULTS: The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. CONCLUSIONS: These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

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.

A pharmacokinetic-pharmacodynamic real-time display may change anesthesiologists' behavior.

We have developed a real-time graphical display that presents anesthetic pharmacology data (drug effect site concentrations (Ce) and probability of anesthetic effects including hypnosis, loss of response to tracheal intubation), improving a previous prototype. We hypothesized that the use of the display alters (1) clinical behavior of anesthesiologists (i.e., Ce of isoflurane and fentanyl at the end of anesthesia), (2) fentanyl dose during the first 30 min of recovery in the post anesthesia care unit (PACU), and that the response of clinicians to the display in terms of workload and utility is favorable. The display was evaluated in a two-group, non-randomized prospective observational study of 30 patients undergoing general anesthesia using isoflurane and fentanyl. The isoflurane-predicted Ce was lower in the display group (without-display: 0.64% ± 0.06%; with-display: 0.42 ± 0.04%; t23.9 = 3.17, P = 0.004 < adjusted alpha 0.05/2). The difference in fentanyl-predicted Ce did not achieve statistical significance (without-display: 1.5 ± 0.1 ng/ml; with-display: 2.0 ± 0.2 ng/ml; t25.5 = 2.26, P = 0.03 > adjusted alpha 0.05/2) (means ± standard error). A joint test of isoflurane and fentanyl Ce with respect to the display condition rejected the null hypothesis of no differences (Hotelling T2, P = 0.01), supporting our primary hypothesis. The total fentanyl per patient during the first 30 min in the PACU with the display was 75.0 ± 62.7 µg and that without the display was 83.0 ± 74.7 µg. There was no significant difference between the groups (means ± standard deviation, P = 0.75). There were no differences in perceived workload. Use of the display does not appear to be cognitively burdensome and may change the anesthesiologist's dosing regimen.

Soft drugs in anesthesia: remifentanil as prototype to modern anesthetic drug development.

PURPOSE OF REVIEW: The unique demands of modern anesthesia practice require that medications be effective, well tolerated, and efficient. These attributes are increasingly achieved with the soft drug approach, wherein novel active compounds are specifically designed to be susceptible to rapid biotransformation to inactive metabolites. The present review summarizes the historical background and recent trends in soft drug development in anesthesiology. RECENT FINDINGS: Soft drug development programs for propranadid, etomidate, and benzodiazepine analogues have been undertaken in recent years. Although all three drugs advanced into human trials, neuro-excitatory adverse effects hampered the propranadid and etomidate analogue projects. Remimazolam, the soft benzodiazepine analogue, is at an advanced stage of development, having already received regulatory approval or review in several countries. SUMMARY: With succinylcholine as the historical forerunner and remifentanil as the modern prototype, the soft drug paradigm continues to hold promise for the future of anesthesia drug development.

An Automated Algorithm Incorporating Poincaré Analysis Can Quantify the Severity of Opioid-Induced Ataxic Breathing.

BACKGROUND: Opioid-induced respiratory depression (OIRD) is traditionally recognized by assessment of respiratory rate, arterial oxygen saturation, end-tidal CO2, and mental status. Although an irregular or ataxic breathing pattern is widely recognized as a manifestation of opioid effects, there is no standardized method for assessing ataxic breathing severity. The purpose of this study was to explore using a machine-learning algorithm for quantifying the severity of opioid-induced ataxic breathing. We hypothesized that domain experts would have high interrater agreement with each other and that a machine-learning algorithm would have high interrater agreement with the domain experts for ataxic breathing severity assessment. METHODS: We administered target-controlled infusions of propofol and remifentanil to 26 healthy volunteers to simulate light sleep and OIRD. Respiration data were collected from respiratory inductance plethysmography (RIP) bands and an intranasal pressure transducer. Three domain experts quantified the severity of ataxic breathing in accordance with a visual scoring template. The Krippendorff alpha, which reports the extent of interrater agreement among N raters, was used to assess agreement among the 3 domain experts. A multiclass support vector machine (SVM) was trained on a subset of the domain expert-labeled data and then used to quantify ataxic breathing severity on the remaining data. The Vanbelle kappa was used to assess the interrater agreement of the machine-learning algorithm with the grouped domain experts. The Vanbelle kappa expands on the Krippendorff alpha by isolating a single rater-in this case, the machine-learning algorithm-and comparing it to a group of raters. Acceptance criteria for both statistical measures were set at >0.8. The SVM was trained and tested using 2 sensor inputs for the breath marks: RIP and intranasal pressure. RESULTS: Krippendorff alpha was 0.93 (95% confidence interval [CI], 0.91-0.95) for the 3 domain experts. Vanbelle kappa was 0.98 (95% CI, 0.96-0.99) for the RIP SVM and 0.96 (0.92-0.98) for the intranasal pressure SVM compared to the domain experts. CONCLUSIONS: We concluded it may be feasible for a machine-learning algorithm to quantify ataxic breathing severity in a manner consistent with a panel of domain experts. This methodology may be helpful in conjunction with traditional measures to identify patients experiencing OIRD.

Michael K. Cahalan: In Celebration of His Life and Contributions to Cardiac Anesthesiology.

Dr. Michael K. Cahalan, former chair of the Department of Anesthesiology at the University of Utah School of Medicine, died March 9, 2019, at the age of 69 after a brief illness. He was a giant in anesthesiology and a pioneer in the development of transesophageal echocardiography applications in anesthesia. He made many other important contributions to the specialty of anesthesiology, having achieved a notable measure of success in all the traditional missions of academics, including research, teaching, clinical care, and administration. In this summary, his early life, education, and the contributions he made to the practice of anesthesiology in general and to cardiac anesthesia and echocardiography in particular are reviewed. The attributes that made Cahalan a model in the profession of anesthesiology that all can strive to emulate also are described.

American Society for Enhanced Recovery and Perioperative Quality Initiative Joint Consensus Statement on the Role of Neuromonitoring in Perioperative Outcomes: Electroencephalography.

Electroencephalographic (EEG) monitoring to indicate brain state during anesthesia has become widely available. It remains unclear whether EEG-guided anesthesia influences perioperative outcomes. The sixth Perioperative Quality Initiative (POQI-6) brought together an international team of multidisciplinary experts from anesthesiology, biomedical engineering, neurology, and surgery to review the current literature and to develop consensus recommendations on the utility of EEG monitoring during anesthesia. We retrieved a total of 1023 articles addressing the use of EEG monitoring during anesthesia and conducted meta-analyses from 15 trials to determine the effect of EEG-guided anesthesia on the rate of unintentional awareness, postoperative delirium, neurocognitive disorder, and long-term mortality after surgery. After considering current evidence, the working group recommends that EEG monitoring should be considered as part of the vital organ monitors to guide anesthetic management. In addition, we encourage anesthesiologists to be knowledgeable in basic EEG interpretation, such as raw waveform, spectrogram, and processed indices, when using these devices. Current evidence suggests that EEG-guided anesthesia reduces the rate of awareness during total intravenous anesthesia and has similar efficacy in preventing awareness as compared with end-tidal anesthetic gas monitoring. There is, however, insufficient evidence to recommend the use of EEG monitoring for preventing postoperative delirium, neurocognitive disorder, or postoperative mortality.

Are opioids indispensable for general anaesthesia?

The drug-induced, reversible coma of anaesthesia requires three clinical outcomes: unconsciousness, immobility, and the control of autonomic nervous system (ANS) responses to surgical stimulation. Producing the anaesthetised state with a single anaesthetic agent, such as an inhaled vapour or propofol, is challenging, primarily because suppressing ANS responses requires very high anaesthetic concentrations, resulting in haemodynamic depression and prolonged recovery. The antinociceptive effects of opioids (i.e. minimum alveolar concentration reduction) are thus central to the well-entrenched 'balanced anaesthesia' concept. In recent years, the notion of 'multimodal general anaesthesia' has extended the concept of balanced anaesthesia to include more drugs that target different neuroanatomical circuits and multiple neurophysiologic mechanisms. The opioid epidemic has provided some of the motivation to move away from opioids toward other adjunct drugs. Persistent opioid use after surgery is a component of the opioid epidemic and is a major concern for perioperative physicians. Potential solutions to the problem of persistent opioid use after surgery have focused on proper 'opioid stewardship' after operation, wherein opioids are used conservatively in combination with other analgesic adjuncts, and excessive opioid prescribing for home use is avoided. But there is a paucity of data on how intraoperative opioid usage patterns may be contributing to persistent opioid use after surgery. There are cogent reasons to moderate perioperative opioid use, including intraoperative opioids, but whether these changes in practice integral to the multimodal general anaesthesia concept will improve anaesthesia outcomes, including persistent opioid use after surgery, is unknown. Studies investigating these issues are an important research priority.