Design of a pharmacokinetic/pharmacodynamic model for administration of low dose peripheral norepinephrine during general anaesthesia.

AIMS: Intraoperative hypotension is a risk factor for kidney, heart and cognitive postoperative complications. Literature suggests that the use of low-dose peripheral norepinephrine (NOR) reduces organ dysfunction, yet its administration remains unstandardized. In this work we develop a pharmacokinetic (PK)/pharmacodynamic (PD) model of NOR and its effect on mean arterial pressure (MAP). METHODS: From June 2018 to December 2021, we included patients scheduled for elective neurosurgery and requiring vasopressors for intraoperative hypotension management at Lariboisière Hospital, Paris. Low doses of NOR were administered peripherally, and successive arterial blood samples were collected to track its plasmatic concentration. We used a compartmental modelling approach for NOR PK. We developed and compared 2 models for NOR PD on MAP. Model comparison was done using Bayes information criteria. The resulting PK/PD model parameters were fitted over the entire population and linked to age, weight, height and sex. RESULTS: We included 29 patients (age 52 [46-64] years, 69% female). NOR median time to peak effect on MAP was 74 [53-94] s. After bolus administration, MAP increased by 24% (15-31%). A 2-comparment model with depot best captured NOR PK. NOR PD effect on MAP was well represented by both Emax and Windkessel models, with better results for the former. We found that age, height and weight as well as history of smoking and hypertension were correlated with model parameters. CONCLUSION: We have developed a PK/PD model to accurately track norepinephrine plasma concentration and its effect on MAP over time, which could serve for target-controlled infusion.

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.

Pharmacokinetics of propofol in severely obese surgical patients.

BACKGROUND: Existing PK models of propofol include sparse data from very obese patients. The aim of this study was to develop a PK model based on standardised surgical conditions and spanning from normal-weight up to, and including, a high number of very obese patients. METHODS: Adult patients scheduled for laparoscopic cholecystectomy or bariatric surgery were studied. Anaesthesia was induced with propofol 2 mg/kg adjusted body weight over 2 min followed by 6 mg/kg/h adjusted body weight over 30 min. For the remainder of the operation anaesthesia was maintained with sevoflurane. Remifentanil was dosed according to clinical need. Eight arterial samples were drawn in a randomised block sampling regimen over a span of 24 h. Time-concentration data were analysed by population PK modelling using non-linear mixed-effects modelling. RESULTS: Four hundred and seventy four serum propofol concentrations were collected from 69 patients aged 19-60 years with a BMI 21.6-67.3 kg/m2. Twenty one patients had a BMI above 50 kg/m2. A 3-compartment PK model was produced wherein three different body weight descriptors and sex were included as covariates in the final model. Total body weight was found to be a covariate for clearance and Q3; lean body weight for V1, V2 and Q2; predicted normal weight for V3 and sex for V1. The fixed allometric exponent of 0.75 applied to all clearance parameters improved the performance of the model. Accuracy and precision were 1.4% and 21.7% respectively in post-hoc performance evaluation. CONCLUSION: We have developed a new PK model of propofol that is suitable for all adult weight classes. Specifically, it is based on data from an unprecedented number of individuals with very high BMI.

External validation of the modified Marsh and Schnider models for medium-chain triglyceride propofol in target-controlled infusion anesthesia.

BACKGROUND: Propofol formulated with medium- and long-chain triglycerides (MCT/LCT propofol) has rapidly replaced propofol formulated with long-chain triglycerides (LCT propofol). Despite this shift, the modified Marsh and Schnider pharmacokinetic models developed using LCT propofol are still widely used for target-controlled infusion (TCI) of propofol. This study aimed to validate the external applicability of these models by evaluating their predictive performance during TCI of MCT/LCT propofol in general anesthesia. METHODS: Adult patients (n = 48) undergoing elective surgery received MCT/LCT propofol via a TCI system using either the modified Marsh or Schnider models. Blood samples were collected at various target propofol concentrations and at specific time points, including the loss of consciousness and the recovery of consciousness (13 samples per patient). The actual plasma concentration of propofol was determined using high-performance liquid chromatography. The predictive performance of each pharmacokinetic model was assessed by calculating four parameters: inaccuracy, bias, divergence, and wobble. RESULTS: Both the modified Marsh and Schnider models demonstrated predictive performances within clinically acceptable ranges for MCT/LCT propofol. The inaccuracy values were 24.4% for the modified Marsh model and 26.9% for the Schnider model. Both models showed an overall positive bias, 16.4% for the modified Marsh model and 16.6% for the Schnider model. The predictive performance of MCT/LCT propofol was comparable to that of LCT propofol, suggesting formulation changes might exert only a minor impact on the reliability of the TCI system during general anesthesia. Additionally, both models exhibited higher bias and inaccuracy at target concentrations ranging from 3.5 ~ 5 ug/ml than at concentrations between 2 ~ 3 ug/ml. CONCLUSIONS: The modified Marsh and Schnider models, initially developed for LCT propofol, remain clinically acceptable for TCI with MCT/LCT propofol. TRIAL REGISTRATION: This study was registered at the Clinical Research Information Service of the Korean National Institute of Health ( https://cris.nih.go.kr ; registration number: KCT0002191; 06/01/2017).

Evaluating inter-individual variability captured by the Eleveld pharmacokinetics model.

Inter-individual variability in Pharmacokinetic (PK) and Pharmacodynamic (PD) models significantly affects the accuracy of Target Controlled Infusion and closed-loop control of anesthesia. We hypothesize that the novel Eleveld PK model captures more inter-individual variability relevant to both open-loop and closed-loop control design, resulting in reduced variability in PD models identified using the Eleveld PK model's plasma prediction compared to the Schuttler or Schnider PK model. We used a dataset of propofol infusion rates and Depth of Hypnosis measurements across three demographic groups: elderly, obese, and adult. PD models are identified based on plasma concentration prediction using three PK models (Schuttler, Schnider, and Eleveld). Validation methods are presented to confirm acceptable predictive performance and comparable PK-PD model variability within each demographic group. To test our hypothesis, we compared coefficient variations in step responses for open-loop control and multiplicative uncertainty of PD model sets for closed-loop control. Validated PKPD models using the Schuttler and Schnider PK model showed no significant differences in predictive response and multiplicative uncertainty compared to the Eleveld PK model. The coefficient variations in step responses of PD model sets and the frequency ranges, corresponding to uncertainty below one, were comparable for all three PK models. The comparison of the accumulated coefficient of variation in the step-response and the uncertainty of the PD model sets indicated that the Eleveld PK model does not offer any advantage for the design of open-loop or closed-loop control of anesthesia.

General purpose propofol target-controlled infusion using the marsh model with adjusted weight input.

We report a simple method for adjusting the weight input of the Marsh target-controlled infusion (TCI) model such that the resulting infusion regime closely mimics the behaviour of the Eleveld model, thereby making the Marsh model more precise for patients at the extremes of age and body mass index. To assess the performance of our method, we simulated 2768 subjects with diverse combinations of age, weight, height and sex undergoing a hypothetical four-hour propofol TCI using both the Marsh model with our weight adjustment and the Eleveld model. The weight adjusted Marsh model produced infusion regimes and corresponding effect site concentrations closely mimicking that of the Eleveld model at all time points, with median and maximum absolute performance errors less than 8.1% and 20.3%, respectively, across the entire cohort. Our weight adjustment method is a simple and robust way of improving the precision of the Marsh model in patients at extremes of age and body mass index, until general purpose TCI models for propofol, such as the Eleveld model, become more widely available in commercial infusion pumps.

Study of Two Sedative Protocols for Drug-Induced Sleep Endoscopy: Propofol versus Propofol-Remifentanil Combination, Delivered in Target-Controlled Infusion Mode.

Background and Objectives: Obstructive sleep apnea (OSA) is a prevalent sleep-disordered breathing pathology with significant clinical consequences, including increased cardiovascular risk and cognitive decline. Continuous positive airway pressure (CPAP) is the gold-standard treatment, but alternative strategies are sometimes needed for patients intolerant to CPAP. Drug-induced sleep endoscopy (DISE) is a key diagnostic tool for assessing upper airway obstruction in OSA patients and subsequently tailoring a surgical approach, with sedation protocols playing a crucial role in its efficacy and results accuracy. This study aimed to investigate the effect of adding remifentanil to a propofol target-controlled infusion (TCI) regimen on the sedation parameters and procedural outcomes of DISE. Materials and Methods: The study was conducted at the Central University and Emergency Military Hospital "Dr. Carol Davila" and Ria Clinic in Bucharest between July 2021 and October 2023. Thirty-one patients were enrolled and randomised into two groups: a propofol group (P group, n= 11) and a remifentanil-propofol group (R-P group, n = 20). DISE was performed using standardised protocols, sedative drugs were administered in TCI mode, and data on sedation levels, respiratory and cardiovascular parameters, and procedural incidents were collected. Results: The addition of remifentanil at 1 ng/mL effect-site concentration significantly reduced the effect-site concentration of propofol required for adequate sedation (3.4 ± 0.7 µg/mL in the P group vs. 2.8 ± 0.6 µg/mL in the R-P group, p = 0.035). The time to achieve adequate sedation was also shorter in the R-P group (7.1 ± 2.5 min vs. 9.5 ± 2.7 min, p = 0.017). The incidence of cough, hypoxemia, and cardiovascular events did not significantly differ between the two groups. Conclusions: Adding remifentanil to a propofol TCI regimen for DISE effectively reduces the required propofol effect-site concentration and shortens sedation time without increasing the risk of adverse events. This combination may enhance the safety and efficiency of DISE, offering a promising alternative for patients undergoing this procedure.

Is target-controlled infusion better than manual controlled infusion during TIVA for elective neurosurgery? Results of a single-centre pilot study.

INTRODUCTION: Maintaining optimal systemic circulatory parameters is essential to ensure adequate cerebral perfusion (CPP) during neurosurgery, especially when autoregulation is impaired. AIM OF STUDY: To compare two types of total intravenous anaesthesia i.e. target controlled infusion (TCI) and manually controlled infusion (MCI) with propofol and remifentanil in terms of their control of cardiovascular parameters during neurosurgical resection of intracranial pathology. MATERIAL AND METHODS: Patients with supratentorial intracranial pathology were selected for the study. Patients in ASA grades III and IV and those with diseases of the circulatory system were excluded. Patients were randomly divided into two equal groups according to the method of general anaesthesia used i.e. TCI or MCI. During the neurosurgery, the values of mean arterial pressure (MAP), heart rate (HR), bispectral index (BIS) and central venous pressure were monitored and recorded at the designated 14 relevant (i.e. critical from the anaesthetist's and neurosurgeon's points of view) measurement points. RESULTS: Fifty patients (25 TCI and 25 MCI) were enrolled in the study. The groups did not differ with respect to sex, age and BMI, operation time or volume of removed lesions. TCI-anaesthetised patients had better MAP stability at the respective time points. CONCLUSIONS: Due to the greater stability of MAP, which has a direct effect on CPP, TCI appears to be the method of choice in anaesthesia for intracranial surgery.

Target-controlled infusion: A comparative, prospective, observational study of the conventional TCI pump and the novel smartphone-based application iTIVA.

Background and Aims: Empirically adjusted, standard drug doses fail to address interindividual pharmacokinetic and pharmacodynamics variability. Target-controlled infusion (TCI) delivers drugs in calibrated boluses to achieve and maintain a selected target plateau drug level (plasma or effect site). Interactive total intravenous anesthesia (iTIVA™) smartphone software simulates TCI and employs 31 established pharmacokinetic models for 11 different intravenous agents and is coupled with standard volumetric infusion pumps for administering TCI. Material and Methods: This prospective, observational, study investigates the degree of agreement between iTIVA and a conventional TCI pump (CTP) for the volume of propofol infused using the Schnider pharmacokinetic model in adult patients of either sex undergoing oncosurgery lasting 1-3 h under total intravenous anesthesia. Bland-Altman analysis of 124 data pairs from 30 patients provided bias, precision, and limits of agreement between the volumes infused by CTP and iTIVA (V-CTP and V-iTIVA) during specific identical time periods. Spearman's rho and Kendall's tau rank correlation coefficients provided the degree of association between V-CTP and V-iTIVA. Results: Spearman's rho and Kendall's tau were 0.996 and 0.964, respectively. Bias or the mean of differences was -0.02, while the limits of agreement were 0.58 and -0.63, respectively (Bland-Altman plot). The maximum allowed difference of 2 ml was much larger than the 95% confidence intervals for the limits of agreement. The Mountain plot was short tailed (-1.28 to 1.55) and centred over zero (0.01). Conclusion: The volume of propofol infused using TCI pump was similar to that calculated by iTIVA in identical time periods, confirming the clinical applicability of iTIVA.

Comparison of hemodynamics during induction of general anesthesia with remimazolam and target-controlled propofol in middle-aged and elderly patients: a single-center, randomized, controlled trial.

BACKGROUND: Remimazolam confers a lower risk of hypotension than propofol. However, no studies have compared the efficacy of remimazolam and propofol administered using target-controlled infusion (TCI). This study aimed to investigate hemodynamic effects of remimazolam and target-controlled propofol in middle-aged and elderly patients during the induction of anesthesia. METHODS: Forty adults aged 45-80 years with the American Society of Anesthesiologists Physical Status 1-2 were randomly assigned to remimazolam or propofol group (n = 20 each). Patients received either remimazolam (12 mg/kg/h) or propofol (3 µg/mL, TCI), along with remifentanil for inducing anesthesia. We recorded the blood pressure, heart rate (HR), and estimated continuous cardiac output (esCCO) using the pulse wave transit time. The primary outcome was the maximum change in mean arterial pressure (MAP) after induction. Secondary outcomes included changes in HR, cardiac output (CO), and stroke volume (SV). RESULTS: MAP decreased after induction of anesthesia in both groups, without significant differences between the groups (- 41.1 [16.4] mmHg and - 42.8 [10.8] mmHg in remimazolam and propofol groups, respectively; mean difference: 1.7 [95% confidence interval: - 8.2 to 4.9]; p = 0.613). Furthermore, HR, CO, and SV decreased after induction in both groups, without significant differences between the groups. Remimazolam group had significantly shorter time until loss of consciousness than propofol group (1.7 [0.7] min and 3.5 [1.7] min, respectively; p < 0.001). However, MAP, HR, CO, and SV were not significantly different between the groups despite adjusting time until loss of consciousness as a covariate. Seven (35%) and 11 (55%) patients in the remimazolam and propofol groups, respectively, experienced hypotension (MAP < 65 mmHg over 2.5 min), without significant differences between the groups (p = 0.341). CONCLUSIONS: Hemodynamics were not significantly different between remimazolam and target-controlled propofol groups during induction of anesthesia. Thus, not only the choice but also the dose and usage of anesthetics are important for hemodynamic stability while inducing anesthesia. Clinicians should monitor hypotension while inducing anesthesia with remimazolam as well as propofol. TRIAL REGISTRATION: UMIN-CTR (UMIN000045612).

A Deep Learning Framework for Anesthesia Depth Prediction from Drug Infusion History.

In the target-controlled infusion (TCI) of propofol and remifentanil intravenous anesthesia, accurate prediction of the depth of anesthesia (DOA) is very challenging. Patients with different physiological characteristics have inconsistent pharmacodynamic responses during different stages of anesthesia. For example, in TCI, older adults transition smoothly from the induction period to the maintenance period, while younger adults are more prone to anesthetic awareness, resulting in different DOA data distributions among patients. To address these problems, a deep learning framework that incorporates domain adaptation and knowledge distillation and uses propofol and remifentanil doses at historical moments to continuously predict the bispectral index (BIS) is proposed in this paper. Specifically, a modified adaptive recurrent neural network (AdaRNN) is adopted to address data distribution differences among patients. Moreover, a knowledge distillation pipeline is developed to train the prediction network by enabling it to learn intermediate feature representations of the teacher network. The experimental results show that our method exhibits better performance than existing approaches during all anesthetic phases in the TCI of propofol and remifentanil intravenous anesthesia. In particular, our method outperforms some state-of-the-art methods in terms of root mean square error and mean absolute error by 1 and 0.8, respectively, in the internal dataset as well as in the publicly available dataset.

Comparison between continuous rate infusion and target-controlled infusion of propofol in dogs: a randomized clinical trial.

OBJECTIVE: To compare a propofol continuous rate infusion (CRI) with a target-controlled infusion (TCI) in dogs. STUDY DESIGN: Randomized prospective double-blinded clinical study. ANIMALS: A total of 38 healthy client-owned dogs. METHODS: Dogs premedicated intramuscularly with acepromazine (0.03 mg kg-1) and an opioid (pethidine 3 mg kg-1, morphine 0.2 mg kg-1 or methadone 0.2 mg kg-1) were allocated to P-CRI group (propofol 4 mg kg-1 intravenously followed by CRI at 0.2 mg kg-1 minute-1), or P-TCI group [propofol predicted plasma concentration (Cp) of 3.5 µg mL-1 for induction and maintenance of anaesthesia via TCI]. Plane of anaesthesia, heart rate, respiratory rate, invasive blood pressure, oxygen haemoglobin saturation, end-tidal carbon dioxide and body temperature were monitored by an anaesthetist blinded to the group. Numerical data were analysed by unpaired t test or Mann-Whitney U test, one-way analysis of variance and Dunnett's post hoc test. Categorical data were analysed with Fisher's exact test. Significance was set for p < 0.005. RESULTS: Overall, propofol induced a significant incidence of relative hypotension (mean arterial pressure 20% below baseline, 45%), apnoea (71%) and haemoglobin desaturation (65%) at induction of anaesthesia, with a higher incidence of hypotension and apnoea in the P-CRI than P-TCI group (68% versus 21%, p = 0.008; 84% versus 58%, p = 0.0151, respectively). Propofol Cp was significantly higher at intubation in the P-CRI than P-TCI group (4.83 versus 3.5 µg mL-1, p < 0.0001), but decreased during infusion, while Cp remained steady in the P-TCI group. Total propofol administered was similar between groups. CONCLUSIONS AND CLINICAL RELEVANCE: Both techniques provided a smooth induction of anaesthesia but caused a high incidence of side effects. Titration of anaesthesia with TCI caused fewer fluctuations in Cp and lower risk of hypotension compared with CRI.

Development and optimization of a fentanyl pharmacokinetic model for target-controlled infusion in anaesthetized dogs.

OBJECTIVE: To investigate pharmacokinetics (PK) of fentanyl administered by target-controlled infusion (TCI), and to develop a PK model optimized by covariates for TCI in anaesthetized dogs. STUDY DESIGN: Prospective clinical study. ANIMALS: A group of 20 client-owned dogs with spinal pain undergoing anaesthesia for magnetic resonance imaging. METHODS: Fentanyl was administered as an infusion to 20 anaesthetized dogs using a TCI system incorporating a previously described fentanyl two-compartment PK. Arterial blood samples were collected at specific time points during the infusion and over 60 minutes post-infusion for measurement of fentanyl plasma concentrations. The predictive performance of the Sano PK model was assessed by comparing predicted and measured plasma concentrations. A population PK analysis was then performed using a nonlinear mixed-effect modelling approach, allowing inter- and intra-individual variability estimation. Finally, a quantitative stepwise evaluation of the influence of various covariates such as weight, body condition score, size, size-related age, sex and type of premedication on the PK model was considered. RESULTS: Overall predictive performance of the Sano PK set of variables was not clinically acceptable in anaesthetized dogs. Fentanyl PK was best described by a three-compartment model. Weight and sex were found to affect the volume of distribution of the central compartment. Addition of these two covariate/variable associations resulted in a reduction of the objective function value (OFV) from -340.18 to -448.34, and of the median population weighted residual and the median population absolute weighted residual from 16.1% and 38.6% to 3.9% and 20.3%, respectively. Fentanyl infusions at measured concentrations up to 5.4 ng mL-1 in sevoflurane-anaesthetized dogs resulted in stable anaesthesia and smooth recoveries without complications. CONCLUSIONS AND CLINICAL RELEVANCE: A population three-compartment PK model for fentanyl TCI in anaesthetized dogs was developed. Weight and sex have been detected and incorporated as significant covariates.

The requirement of propofol for induction of anesthesia in patients with traumatic brain injury determined using bilateral bispectral index and target controlled infusion - An observational cohort study.

Background and Aims: Patients with traumatic brain injury (TBI) frequently require emergency surgery. There is a paucity of literature with regard to anesthetic requirements in these patients. The aim of the study was to compare the dose of propofol required for induction of anesthesia in patients with different grades of TBI. Material and Methods: This prospective, observational study included patients with mild, moderate, and severe grades of TBI undergoing emergency surgery within 48 h of injury. Bispectral Index (BIS) values were recorded using a bilateral BIS sensor. Anesthesia was induced with a target controlled infusion (TCI) pump. Once BIS reached 40, plasma (Cp) and effect-site (Ce) concentration and total dose of propofol required were noted from the TCI pump. Results: Of the 96 patients recruited, 27, 36, and 33 patients belonged to mild, moderate, and severe TBI (sTBI) groups, respectively. The Ce of propofol in mild, moderate, and sTBI groups was 6 ± 0.9, 5.82 ± 0.98, and 4.48 ± 1.5 µg/mL (P < 0.001), and the dose of propofol required was 1.9 ± 0.2, 1.8 ± 0.4, 1.41 ± 0.5 mg/kg, respectively (P < 0.001). Baseline BIS on the injured side was 80 ± 7.8, 71 ± 9.4, 55 ± 11.6, and on the uninjured side was 89 ± 5.5, 81 ± 8.4, and 65 ± 12 in mild, moderate, and sTBI groups, respectively. Conclusions: The requirement of propofol was reduced in patients with sTBI. The dose of propofol required for induction of anesthesia as determined using Ce was significantly lower only between sTBI and mild TBI and not between patients with sTBI and moderate TBI or between mild and moderate head injury. BIS values were significantly different between the groups (highest in mild TBI and lowest in sTBI) and between normal and injured sides within each group.

Remifentanil pharmacodynamics during conscious sedation using algometry: a more clinically relevant pharmacodynamical model.

BACKGROUND: The Minto remifentanil pharmacokinetic/pharmacodynamic (PK/PD) model is used in target-controlled infusion (TCI) devices. The endpoint used to calculate the PD parameters, including the ke0, was the electroencephalogram (EEG), which only changes at high remifentanil concentrations. As the ke0 should adequately predict the time course of drug effects at clinically relevant concentrations, we evaluated the temporal agreement between effect-site concentrations estimated with the Minto model and pressure pain thresholds during conscious sedation. METHODS: We enrolled 100 patients scheduled for gynaecological surgery. The first group (35 subjects) received an effect site targeted remifentanil infusion (target 1.5 ng ml-1); the second group (35 subjects) received the same infusion and a 1 mg bolus of midazolam to evaluate anxiolytic effects; the control group (30 subjects) received a saline infusion. Algometry and vital signs were measured at different time points. RESULTS: The Minto model predicted stable effect-site concentrations within 1.5 min of starting the infusion. Haemodynamic variables stabilised within 5 min, whereas there was a significant increase in pressure pain threshold for up to 15 min in both remifentanil groups. Midazolam had no effect on pressure pain threshold. A PD model based on algometry and Minto PK model was developed. CONCLUSIONS: Our results demonstrate the limitation of the Minto PD model at low target remifentanil concentrations, with a discrepancy in the time course between EEG and pressure pain threshold changes. Clinicians should be aware that the time course of onset of analgesic effects is slower than the estimates of the Minto model. Investigators should consider using algometry data in future opioid PD modelling studies.

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.

Reliability of the Minto model for target-controlled infusion of remifentanil during cardiac surgery with cardiopulmonary bypass.

BACKGROUND: The Minto pharmacokinetic model is used for target-controlled infusion of remifentanil. The reliability of this model has never been evaluated during normothermic cardiac surgery with cardiopulmonary bypass (CPB). The aim of this study was to assess the predictive performance of the model during CPB to determine its reliability during cardiac surgery. METHODS: This was a single-centre observational study. Arterial blood samples were drawn at five time points: T1, after tracheal intubation; T2, immediately before CPB; T3, 10 min after starting CPB; T4, 45 min after starting CPB; T5, 10 min after weaning off CPB. Prediction error (PE) and absolute prediction error (APE) were calculated for each sample and used to determine median prediction error (MDPE) and median absolute prediction error (MDAPE) per patient. Risk factors for APE >30% were assessed using multivariable analysis. Results are presented as medians with inter-quartile ranges. RESULTS: Fifty-eight patients with 283 blood samples (110 during CPB) were included. In the pre-CPB period, MDPE and MDAPE were -17.3 [-32.9 to 2.3] and 24.6 [12-37.7]%, whereas during CPB, they were -1.8 [-15.6 to 11.1] and 14.0 [6.74-27.1]%, respectively. There was no statistically significant difference between measured and predicted remifentanil plasma concentrations during CPB. Age, preoperative albumin concentrations, temperature, and haemodilution were not independently associated with MDAPE >30%. CONCLUSIONS: The Minto model accurately predicts plasma remifentanil concentrations during cardiac surgery with CPB. CLINICAL TRIAL REGISTRATION: 2017-A03153-50.

Patient-maintained versus anaesthetist-controlled propofol sedation during elective primary lower-limb arthroplasty performed under spinal anaesthesia: a randomised controlled trial.

BACKGROUND: Patient-maintained propofol TCI sedation (PMPS) allows patients to titrate their own target-controlled infusion (TCI) delivery of propofol sedation using a handheld button. The aim of this RCT was to compare PMPS with anaesthetist-controlled propofol TCI sedation (ACPS) in patients undergoing elective primary lower-limb arthroplasty surgery under spinal anaesthesia. METHODS: In this single-centre open-label investigator-led study, adult patients were randomly assigned to either PMPS or ACPS during their surgery. Both sedation regimes used Schnider effect-site TCI modelling. The primary outcome measure was infusion rate adjusted for weight (expressed as mg kg-1 h-1). Secondary outcomes measures included depth of sedation, occurrence of sedation-related adverse events and time to medical readiness for discharge from the postanaesthsia care unit (PACU). RESULTS: Eighty patients (48 female) were randomised. Subjects using PMPS used 39.3% less propofol during the sedation period compared with subjects in group ACPS (1.56 [0.57] vs 2.57 [1.33] mg kg-1 h-1; P<0.001), experienced fewer discrete episodes of deep sedation (0 vs 6; P=0.0256), fewer airway/breathing adverse events (odds ratio [95% confidence interval]: 2.94 [1.31-6.64]; P=0.009) and were ready for discharge from PACU more quickly (8.94 [5.5] vs 13.51 [7.2] min; P=0.0027). CONCLUSIONS: Patient-maintained propofol sedation during lower-limb arthroplasty under spinal anaesthesia results in reduced drug exposure and fewer episodes of sedation-related adverse events compared with anaesthetist-controlled propofol TCI sedation. To facilitate further investigation of this procedural sedation technique, PMPS-capable TCI infusion devices should be submitted for regulatory approval for clinical use. CLINICAL TRIAL REGISTRATION: ISRCTN29129799.

Efficacy and safety of remifentanil for endoscopic ultrasound-guided tissue acquisition: a single center retrospective study.

BACKGROUND: Remifentanil is a rapid onset and rapid recovery opioid. The combination of remifentanil and propofol for deep sedation decreases the incidents of movement, cough, and hiccup. We evaluated the efficacy and safety of remifentanil during endoscopic ultrasound-guided tissue acquisition. METHODS: We retrospectively reviewed patients in whom endoscopic ultrasound-guided tissue acquisition was performed for solid mass lesions of the upper gastrointestinal tract and adjacent organs. All patients were premedicated with midazolam (2 mg), and target-controlled infusion of propofol, opioid, and Bispectral Index (BIS) monitoring were administered as necessary to maintain moderate-to-deep sedation. The opioids used were a bolus of alfentanil or remifentanil infusion. The discharge time, consumption of propofol and opioid, adverse events, diagnostic accuracy, and sensitivity and specificity for malignancy, were compared. RESULTS: Tissue acquisition was achieved in 123 patients (alfentanil group, n = 64; remifentanil group, n = 59). The discharge time of the remifentanil group (16.5 ± 3.2 min) was significantly shorter than that of the alfentanil group (19.0 ± 4.9 min, P = 0.001). The consumption of propofol, adverse events, diagnostic accuracy, sensitivity, and specificity for malignancy in the alfentanil group were not significantly different from those in the remifentanil group. CONCLUSIONS: Use of alfentanil or remifentanil for target-controlled infusion of propofol-BIS monitoring can provide good sedative and diagnostic quality for endoscopic ultrasound-guided tissue acquisition. However, remifentanil resulted in faster recovery than alfentanil.

Body mass index and pharmacodynamics of target-controlled infusion of propofol: A prospective non-randomized controlled study.

WHAT IS KNOWN AND OBJECTIVE: In our preliminary study, there were large individual variations at sedation levels during propofol target-controlled infusion (TCI). The present study aimed to assess the effects of body mass index (BMI) on the pharmacodynamic index of propofol TCI. METHODS: This prospective, non-randomized controlled trial evaluated 175 female patients undergoing breast lumpectomy. Anesthesia was induced with propofol using the TCI system embedded Schnider model. The effect compartment concentration was set to 3 µg/ml, and the start time of infusion was recorded. When the target concentration reached 3 µg/ml, the patient could not be awakened (Ramsay sedation score ≥4), and when the Bispectral Index (BIS) was <60, the infusion was discontinued, and the time point was recorded. The observation end-point was set at the Observer's Assessment of Alertness/Sedation (OAA/S) score of <4. The correlation between the BMI and the pharmacodynamic index of propofol was evaluated. RESULTS AND DISCUSSION: Propofol induction time was significantly correlated with the BMI (p < 0.001). The induction time of the underweight subjects was 10.14 ± 2.19 min, which was remarkably higher than that of normal weight (6.48 ± 3.44 min) and overweight (4.75 ± 2.53 min) individuals (p < 0.001). There were still significant differences after multivariable-adjusted regressions (p < 0.001). There were no significant differences in recovery time and sedative effect indicators, such as Ramsay score, BIS value, and effect compartment concentration, between the three groups (p > 0.05 for all). WHAT IS NEW AND CONCLUSION: These results suggest that the BMI is one of the critical factors affecting the pharmacodynamic index of propofol TCI, and the induction time decreased progressively with increasing BMI. The Schnider model might underpredict doses of propofol for underweight individuals.