Mortality and morbidity after total intravenous anaesthesia versus inhalational anaesthesia: a systematic review and meta-analysis.

Background: General anaesthesia is provided to more than 300 million surgical patients worldwide, every year. It is administered either through total intravenous anaesthesia, using only intravenous agents, or through inhalational anaesthesia, using volatile anaesthetic agents. The debate on how this affects postoperative patient outcome is ongoing, despite an abundance of published trials. The relevance of this topic has grown by the increasing concern about the contribution of anaesthetic gases to the environmental impact of surgery. We aimed to summarise all available evidence on relevant patient outcomes with total intravenous anaesthesia versus inhalational anaesthesia. Methods: In this systematic review and meta-analysis, we searched PubMed/Medline, Embase and Cochrane Central Register of Controlled trials for works published from January 1, 1985 to August 1, 2023 for randomised controlled trials comparing total intravenous anaesthesia using propofol versus inhalational anaesthesia using the volatile anaesthetics sevoflurane, desflurane or isoflurane. Two reviewers independently screened titles, abstracts and full text articles, and assessed risk of bias using the Cochrane Collaboration tool. Outcomes were derived from a recent series of publications on consensus definitions for Standardised Endpoints for Perioperative trials (StEP). Primary outcomes covered mortality and organ-related morbidity. Secondary outcomes were related to anaesthetic and surgical morbidity. This study is registered with PROSPERO (CRD42023430492). Findings: We included 317 randomised controlled trials, comprising 51,107 patients. No difference between total intravenous and inhalational anaesthesia was seen in the primary outcomes of in-hospital mortality (RR 1.05, 95% CI 0.67-1.66, 27 trials, 3846 patients), 30-day mortality (RR 0.97, 95% CI 0.70-1.36, 23 trials, 9667 patients) and one-year mortality (RR 1.14, 95% CI 0.88-1.48, 13 trials, 9317 patients). Organ-related morbidity was similar between groups except for the subgroup of elderly patients, in which total intravenous anaesthesia was associated with a lower incidence of postoperative cognitive dysfunction (RR 0.62, 95% CI 0.40-0.97, 11 trials, 3834 patients) and a better score on postoperative cognitive dysfunction tests (standardised mean difference 1.68, 95% CI 0.47-2.88, 9 trials, 4917 patients). In the secondary outcomes, total intravenous anaesthesia resulted in a lower incidence of postoperative nausea and vomiting (RR 0.61, 95% CI 0.56-0.67, 145 trials, 23,172 patients), less emergence delirium (RR 0.40, 95% CI 0.29-0.56, 32 trials, 4203 patients) and a higher quality of recovery score (QoR-40 mean difference 6.45, 95% CI 3.64-9.25, 17 trials, 1835 patients). Interpretation: The results indicate that postoperative mortality and organ-related morbidity was similar for intravenous and inhalational anaesthesia. Total intravenous anaesthesia offered advantages in postoperative recovery. Funding: Dutch Society for Anaesthesiology (NVA).

Dynamic Prediction of Patient Outcomes in the Intensive Care Unit: A Scoping Review of the State-of-the-Art.

INTRODUCTION: Intensive care units (ICUs) are high-pressure, complex, technology-intensive medical environments where patient physiological data are generated continuously. Due to the complexity of interpreting multiple signals at speed, there are substantial opportunities and significant potential benefits in providing ICU staff with additional decision support and predictive modeling tools that can support and aid decision-making in real-time.This scoping review aims to synthesize the state-of-the-art dynamic prediction models of patient outcomes developed for use in the ICU. We define "dynamic" models as those where predictions are regularly computed and updated over time in response to updated physiological signals. METHODS: Studies describing the development of predictive models for use in the ICU were searched, using PubMed. The studies were screened as per Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines, and the data regarding predicted outcomes, methods used to develop the predictive models, preprocessing the data and dealing with missing values, and performance measures were extracted and analyzed. RESULTS: A total of n = 36 studies were included for synthesis in our review. The included studies focused on the prediction of various outcomes, including mortality (n = 17), sepsis-related complications (n = 12), cardiovascular complications (n = 5), and other complications (respiratory, renal complications, and bleeding, n = 5). The most common classification methods include logistic regression, random forest, support vector machine, and neural networks. CONCLUSION: The included studies demonstrated that there is a strong interest in developing dynamic prediction models for various ICU patient outcomes. Most models reported focus on mortality. As such, the development of further models focusing on a range of other serious and well-defined complications-such as acute kidney injury-would be beneficial. Furthermore, studies should improve the reporting of key aspects of model development challenges.

Development and validation of a digital biomarker predicting acute kidney injury following cardiac surgery on an hourly basis.

Objectives: To develop and validate a digital biomarker for predicting the onset of acute kidney injury (AKI) on an hourly basis up to 24 hours in advance in the intensive care unit after cardiac surgery. Methods: The study analyzed data from 6056 adult patients undergoing coronary artery bypass graft and/or valve surgery between April 1, 2012, and December 31, 2018 (development phase, training, and testing) and 3572 patients between January 1, 2019, and June 30, 2022 (validation phase). The study used 2 dynamic predictive modeling approaches, namely logistic regression and bootstrap aggregated regression trees machine (BARTm), to predict AKI. The mean area under the receiver operating characteristic curve (AUC), sensitivity, specificity, and positive and negative predictive values across all lead times before the occurrence of AKI were reported. The clinical practicality was assessed using calibration. Results: Of all included patients, 8.45% and 16.66% had AKI in the development and validation phases, respectively. When applied to testing data, AKI was predicted with the mean AUC of 0.850 and 0.802 by BARTm and logistic regression, respectively. When applied to validation data, BARTm and LR resulted in a mean AUC of 0.844 and 0.786, respectively. Conclusions: This study demonstrated the successful prediction of AKI on an hourly basis up to 24 hours in advance. The digital biomarkers developed and validated in this study have the potential to assist clinicians in optimizing treatment and implementing preventive strategies for patients at risk of developing AKI after cardiac surgery in the intensive care unit.

Definition and Classification of Postoperative Complications After Cardiac Surgery: Pilot Delphi Study.

BACKGROUND: Postoperative complications following cardiac surgery are common and represent a serious burden to health services and society. However, there is a lack of consensus among experts on what events should be considered as a "complication" and how to assess their severity. OBJECTIVE: This study aimed to consult domain experts to pilot the development of a definition and classification system for complications following cardiac surgery with the goal to allow the progression of standardized clinical processes and systems in cardiac surgery. METHODS: We conducted a Delphi study, which is a well-established method to reach expert consensus on complex topics. We sent 2 rounds of surveys to domain experts, including cardiac surgeons and anesthetists, to define and classify postoperative complications following cardiac surgery. The responses to open-ended questions were analyzed using a thematic analysis framework. RESULTS: In total, 71 and 37 experts' opinions were included in the analysis in Round 1 and Round 2 of the study, respectively. Cardiac anesthetists and cardiac critical care specialists took part in the study. Cardiac surgeons did not participate. Experts agreed that a classification for postoperative complications for cardiac surgery is useful, and consensus was reached for the generic definition of a postoperative complication in cardiac surgery. Consensus was also reached on classification of complications according to the following 4 levels: "Mild," "Moderate," "Severe," and "Death." Consensus was also reached on definitions for "Mild" and "Severe" categories of complications. CONCLUSIONS: Domain experts agreed on the definition and classification of complications in cardiac surgery for "Mild" and "Severe" complications. The standardization of complication identification, recording, and reporting in cardiac surgery should help the development of quality benchmarks, clinical audit, care quality assessment, resource planning, risk management, communication, and research.

Clinical Validation of the Covariates Pharmacokinetic Model for Propofol in an Adult Population.

BACKGROUND AND OBJECTIVE: Pharmacokinetic or pharmacokinetic-pharmacodynamic models have been instrumental in facilitating the clinical use of propofol in target-controlled infusion systems in anaesthetic practice. There has been debate over which model should be recommended for practice. The covariates model is an updated pharmacokinetic model for propofol. The aim of this study was to prospectively validate this model in an adult population. METHODS: Twenty-nine patients were included, with a range of ages to assess model performance in younger and older individuals. Subjects received propofol through a target-controlled infusion device programmed with the covariates model. Subjects were randomised to one of two increasing/decreasing regimes of propofol plasma target concentrations between 2 and 5 µg.mL-1. After the start of the infusion, arterial and venous blood samples were drawn at pre-specified timepoints between 1.5 and 20 min and between 1.5 and 45 min, respectively. Predictive performance was assessed using established methodology. RESULTS: The model achieved a bias of 9 (- 45 to 82) and precision of 24 (9-82) for arterial samples and bias of - 8 (- 64 to 70) and precision of 23 (9-70) for venous samples. Predicted concentrations tended to be higher than the measured concentrations in female individuals but lower in male individuals. There was no clear systematic difference in the bias between younger and older patients. CONCLUSIONS: The covariates propofol pharmacokinetic model achieved an acceptable level of predictive performance, as assessed by both arterial and venous sampling, for use in target-controlled infusion in clinical practice. CLINICAL TRIAL REGISTRATION: NCT01492712 (15 December, 2011).

Pharmacokinetic models can estimate the changes in the concentration of a drug in the body over time. These have been instrumental in facilitating the clinical use of anaesthetic agents such as propofol in target-controlled infusions, which aim to achieve a set concentration in either plasma or the brain to achieve anaesthesia. The covariates model is a previously described pharmacokinetic model for propofol. The aim of the described study was to validate the performance of the model in an independent adult population. Participants received anaesthesia with propofol through a target-controlled infusion device programmed with the covariates model. The concentration of propofol in the blood was measured at various timepoints and compared to the target concentration specified by the target-controlled infusion device. The analysis showed that overall, the covariates model performed to a level acceptable for use in clinical practice and compared favourably to other pharmacokinetic models.

The Use of Intravenous Lidocaine in Perioperative Medicine: Anaesthetic, Analgesic and Immune-Modulatory Aspects.

This narrative review provides an update on the applied pharmacology of lidocaine, its clinical scope in anaesthesia, novel concepts of analgesic and immune-modulatory effects as well as the current controversy around its use in perioperative opioid-sparing multi-modal strategies. Potential benefits of intravenous lidocaine in the context of cancer, inflammation and chronic pain are discussed against concerns of safety, toxicity and medico-legal constraints.

Robotic-assisted Versus Video-assisted Thoracoscopic Lobectomy: Short-term Results of a Randomized Clinical Trial (RVlob Trial).

OBJECTIVE: To determine whether RAL affects perioperative outcomes and long-term efficacy in NSCLC patients, compared with traditional VAL. SUMMARY OF BACKGROUND DATA: RAL is a promising treatment for NSCLC. However, its efficacy has not been fully evaluated. METHODS: A single-center, open-labeled prospective randomized clinical trial was launched in May 2017 to compare the efficacy of RAL and VAL. By May 2020, 320 patients were enrolled. The perioperative results of RAL and VAL were compared. RESULTS: The 320 enrolled patients were randomly assigned to the RAL group (n = 157) and the VAL group (n = 163). Perioperative outcomes were comparable between the 2 groups, including the length of hospital stay (P = 0.76) and the rate of postoperative complications (P = 0.45). No perioperative mortality occurred in either group. The total amount of chest tube drainage {830 mL [interquartile range (IQR), 550-1130 mL] vs 685 mL [IQR, 367.5-1160 mL], P = 0.007} and hospitalization costs [$12821 (IQR, $12145-$13924) vs $8009 (IQR, $7014-$9003), P < 0.001] were significantly higher in the RAL group. RAL group had a significantly higher number of LNs harvested [11 (IQR, 8-15) vs 10 (IQR, 8-13), P = 0.02], higher number of N1 LNs [6 (IQR, 4-8) vs 5 (IQR, 3-7), P = 0.005], and more LN stations examined [6 (IQR, 5-7) vs 5 (IQR, 4-6), P < 0.001]. CONCLUSIONS: Both RAL and VAL are safe and feasible for the treatment of NSCLC. RAL achieved similar perioperative outcomes, together with higher LN yield. Further follow-up investigations are required to evaluate the long-term efficacy of RAL. (ClinicalTrials.gov identifier: NCT03134534).

Cost-Effectiveness of Propofol (Diprivan) Versus Inhalational Anesthetics to Maintain General Anesthesia in Noncardiac Surgery in the United States.

OBJECTIVES: It is not known whether using propofol total intravenous anaesthesia (TIVA) to reduce incidence of postoperative nausea and vomiting (PONV) is cost-effective. We assessed the economic impact of propofol TIVA versus inhalational anesthesia in adult patients for ambulatory and inpatient procedures relevant to the US healthcare system. METHODS: Two models simulate individual patient pathways through inpatient and ambulatory surgery with propofol TIVA or inhalational anesthesia with economic inputs from studies on adult surgical US patients. Efficacy inputs were obtained from a meta-analysis of randomized controlled trials. Probabilistic and deterministic sensitivity analyses assessed the robustness of the model estimates. RESULTS: Lower PONV rate, shorter stay in the post-anesthesia care unit, and reduced need for rescue antiemetics offset the higher costs for anesthetics, analgesics, and muscle relaxants with propofol TIVA and reduced cost by 11.41 ± 10.73 USD per patient in the inpatient model and 11.25 ± 9.81 USD in the ambulatory patient model. Sensitivity analyses demonstrated strong robustness of the results. CONCLUSIONS: Maintenance of general anesthesia with propofol was cost-saving compared to inhalational anesthesia in both inpatient and ambulatory surgical settings in the United States. These economic results support current guideline recommendations, which endorse propofol TIVA to reduce PONV risk and enhance postoperative recovery.

The quantification and monitoring of intraoperative nociception levels in thoracic surgery: a review.

Nociception is the unconscious perception of a stimulus applied by trauma or surgery and expressed through a response of the autonomous nervous system. Local anaesthetics (LAs), opioids and other modulating agents such as ketamine are usually utilised to blunt nociception as a component during general anaesthesia (GA) and surgery. The effectiveness of these measures, however, are still difficult to quantify and monitoring of anti-nociception has been confined to assess variation of heart rate (HR) or blood pressure (BP). Recently, various monitoring concepts have been introduced to quantify nociception more systematically and on the other hand guide anti-nociceptive interventions more appropriately. This review describes the various technologies, their performance in clinical studies and provides a critical appraisal with particular application to thoracic anaesthesia and surgery and their relevance in the context of chronic pain after surgery.

Combined Monitoring-Brain Function Monitoring and Cerebral Oximetry.

Peri-operative brain function monitoring is still seen by most clinicians as complex, difficult to interpret and is therefore adopted very slowly. Current available technology mainly focusses on either a processed parameter based on the electroencephalogram to titrate anesthetics and central acting agents or on cerebral oximetry, a wider term to obtain information on the cerebral oxygen balance. There is still a lack of technological offerings that allow to monitor both entities in one device. However, there is scientific evidence that it is possible to combine measurements in an algorithmic approach that allows to better manage brain function in the surgical setting. Such integrated solutions should be made available to clinicians as they are likely to optimize patient care dependent on a sound health technology assessment.

Propofol vs. inhalational agents to maintain general anaesthesia in ambulatory and in-patient surgery: a systematic review and meta-analysis.

BACKGROUND: It is unclear if anaesthesia maintenance with propofol is advantageous or beneficial over inhalational agents. This study is intended to compare the effects of propofol vs. inhalational agents in maintaining general anaesthesia on patient-relevant outcomes and patient satisfaction. METHODS: Studies were identified by electronic database searches in PubMed™, EMBASE™ and the Cochrane™ library between 01/01/1985 and 01/08/2016. Randomized controlled trials (RCTs) of peer-reviewed journals were studied. Of 6688 studies identified, 229 RCTs were included with a total of 20,991 patients. Quality control, assessment of risk of bias, meta-bias, meta-regression and certainty in evidence were performed according to Cochrane. Common estimates were derived from fixed or random-effects models depending on the presence of heterogeneity. Post-operative nausea and vomiting (PONV) was the primary outcome. Post-operative pain, emergence agitation, time to recovery, hospital length of stay, post-anaesthetic shivering and haemodynamic instability were considered key secondary outcomes. RESULTS: The risk for PONV was lower with propofol than with inhalational agents (relative risk (RR) 0.61 [0.53, 0.69], p < 0.00001). Additionally, pain score after extubation and time in the post-operative anaesthesia care unit (PACU) were reduced with propofol (mean difference (MD) - 0.51 [- 0.81, - 0.20], p = 0.001; MD - 2.91 min [- 5.47, - 0.35], p = 0.03). In turn, time to respiratory recovery and tracheal extubation were longer with propofol than with inhalational agents (MD 0.82 min [0.20, 1.45], p = 0.01; MD 0.70 min [0.03, 1.38], p = 0.04, respectively). Notably, patient satisfaction, as reported by the number of satisfied patients and scores, was higher with propofol (RR 1.06 [1.01, 1.10], p = 0.02; MD 0.13 [0.00, 0.26], p = 0.05). Secondary analyses supported the primary results. CONCLUSIONS: Based on the present meta-analysis there are several advantages of anaesthesia maintenance with propofol over inhalational agents. While these benefits result in an increased patient satisfaction, the clinical and economic relevance of these findings still need to be addressed in adequately powered prospective clinical trials.

The role of local anaesthetic techniques in ERAS protocols for thoracic surgery.

The use of enhanced recovery after surgery (ERAS), as in other surgical specialties, is an emerging concept in cardio-thoracic surgery but there is still a lack of effective protocols to reduce the burden of surgery on the patient, shorten the period of postoperative recovery, and reduce the likelihood of chronic pain developing. The use of local anaesthetic (LA) techniques, such as thoracic epidural analgesia (TEA) and paravertebral blocks (PVB), as an adjunct to anaesthesia are considered key components, though there is little data for direct comparison of the techniques. This review aims to evaluate the role of LA techniques in a thoracic ERAS program through evidence from literature and considering aspects of clinical practice. We discuss how ERAS is adapting and evolving with the increasing use of video-assisted thoracoscopic surgery (VATS) is thoracic surgery. It also examines the advantages of multimodal, opioid-sparing analgesia in the post-operative period to minimise the inflammatory response and improve functional recovery. LA techniques within ERAS protocols have the potential to hasten recovery when managed appropriately and to their full potential.

Postoperative management.

Most patients undergoing major aortic surgery have multiple comorbidities and are at high risk of postoperative complications that affect multiple organ systems. Different aortic pathologies and surgical repair techniques have specific impact on the postoperative course. Ischemia-reperfusion injury is the common denominator in aortic surgery and influences the integrity of end-organ function. Common postoperative problems include hemodynamic instability due to the immediate inflammatory response, renal impairment, spinal cord ischemia, respiratory failure with prolonged mechanical ventilation, and gastrointestinal symptoms such as ileus or mesenteric ischemia. Focused care bundles to establish homeostasis and a team working toward an early functional recovery determine the success of effective rehabilitation and outcomes after aortic surgery.

Interoperator and intraoperator variability of whole blood coagulation assays: a comparison of thromboelastography and rotational thromboelastometry.

OBJECTIVES: Near-patient viscoelastic tests have proved useful in decreasing blood and blood product use in cardiac surgery. Two different analyzers are available, TEG and ROTEM. Many different individuals operate these devices, which raises concern that this factor may significantly affect results. The present study sought to objectively assess variability in results between operators. DESIGN: Prospective study. SETTING: Regional cardiac center. PARTICIPANTS: Adult patients undergoing elective cardiac surgery. INTERVENTIONS: Thirty-six mL of blood were taken from each of 21 patients. TEG kaolin and functional fibrinogen (FF) analyses and the equivalent ROTEM INTEM S and FIBTEM S analyses were performed. Six operators performed one of each test per patient to assess interoperator variability. One further operator performed 6 of each test per patient to assess intraoperator variability. MEASUREMENTS AND MAIN RESULTS: All routine measurement parameters were noted and the coefficient of variation (CV) calculated, analyzing comparable parameters. All inter-operator CVs were significantly lower for ROTEM analyses compared with TEG. CV for INTEM S CT/ kaolin r time was 4.7 versus 16.3 and MCF/MA was 2.6 versus 4.3 (p < 0.01). Similarly, FIBTEM S MCF/ FF MA was 8.3 versus 12.2. All intraoperator CVs were significantly lower for ROTEM analyses compared with TEG (p<0.01). CV for INTEM S CT/kaolin r time was 3.1 versus 9.8 and MCF/ MA was 1.6 versus 4. Similarly, FIBTEM S MCF/ MA was 6.9 versus 12.1. CONCLUSIONS: This series of results suggested ROTEM analyses are more reproducible than TEG and, consequently, that ROTEM may be better suited for use in a multiuser environment.

Limitations of anaesthesia depth monitoring.

PURPOSE OF REVIEW: We critically review brain function monitors based on the processed electroencephalogram with regards to signal quality, artefacts and other limitations in clinical performance. RECENT FINDINGS: Several studies have been showing that depth of anaesthesia monitors based on processed electroencephalogram has limitations that can lead to a wrong interpretation of the level of anaesthesia. Processed electroencephalogram indices can be altered by nonanaesthetic influences ranging from artefacts that affect signal quality and signal processing, adverse effects of some anaesthetic and nonanaesthetic drugs, neuromuscular blocking agents to conditions inherent to the patient such as cerebral tumours, brain ischemia and temperature. SUMMARY: Clinicians should be aware of the several limitations of the commercial devices intending to monitor the depth of anaesthesia, which may not reflect the real underlying level of unconsciousness.

The effective concentration 50 (EC50) for propofol with 70% xenon versus 70% nitrous oxide.

BACKGROUND: Xenon anesthesia has many favorable properties, such as pain modulation and organ protection. However, due to its MAC of 70%, it cannot be used as a sole anesthetic. We estimated the amount of propofol required to supplement xenon to produce adequate anesthesia in 50% and 95% of patients in comparison with nitrous oxide. METHODS: We randomized 75 premedicated female patients to receive either 70% xenon or 70% nitrous oxide in oxygen supplemented by propofol target-controlled infusion anesthesia starting with 4.5 microg/mL for the first patient in each group. Dixon's up and down method was used to determine the propofol concentration for subsequent patients. After induction of anesthesia with propofol, patients breathed 70% xenon or 70% nitrous oxide in oxygen via a facemask for 15 min. They were then observed for movement in response to skin incision for 60 s after the incision and assigned as movers or nonmovers. Probit analysis was used to estimate the effective concentration 50% and 95% (EC50 and EC95) for propofol in both groups. RESULTS: The EC50 for propofol with 70% xenon was 1.5 microg/mL and the EC95 was 2.3 microg/mL. The EC50 and EC95 values for propofol with nitrous oxide were 2.2 and 8.2 microg/mL, respectively. This implies a reduction of propofol requirements between 32% (EC50) and 72% (EC95) by xenon compared with nitrous oxide. The suppression of auditory evoked potentials was more pronounced with xenon than with nitrous oxide. CONCLUSION: Xenon seems to be clinically more potent than nitrous oxide, but still requires minimal supplement of a hypnotic anesthetic to suppress noxious stimulation during and after skin incision.

Use of target controlled infusion to derive age and gender covariates for propofol clearance.

BACKGROUND AND OBJECTIVE: Attempts to describe the variability of propofol pharmacokinetics in adults and to derive population covariates have been sparse and limited mainly to experiments based on bolus doses or infusions in healthy volunteers. This study aimed to identify age and gender covariates for propofol when given as an infusion in anaesthetized patients. STUDY DESIGN AND SETTING: One hundred and thirteen patients (American Society of Anesthesiologists class I or II and aged 14-92 years) were anaesthetized for elective surgical procedures with propofol using a target controlled infusion (TCI) system and with alfentanil as a baseline analgesic infusion. Frequent venous blood samples were obtained for measurement of propofol plasma concentrations. PHARMACOKINETIC AND STATISTICAL ANALYSIS: Pharmacokinetic accuracy was determined by the percentage prediction error, bias and precision, as were wobble and divergence. The clearance of propofol from the central compartment was determined for each patient using the computerized record of the infusion profile delivered to each patient, together with relevant blood propofol concentration estimations. For each patient, the nonlinear mixed-effects modelling (NONMEM) objective function was employed to determine the goodness of fit. RESULTS: The population distribution of propofol clearance was subsequently found to have a Gaussian distribution only in the log domain (mean value equivalent to 26.1 mL/kg/min). The distribution in the normal domain was consequently asymmetric, with a slight predominance of patients with high values of clearance (5% and 95% confidence limits 17.7 and 42.1 mL/kg/min, respectively). Using regression analysis, gender and age covariates were derived that optimized the performance of the target controlled infusion system. The clearance (CL) of propofol in male patients changed little with age (CL [mL/kg/min]=26.88-0.029xAge; r2=0.006) whereas that in female patients had a higher initial value but decreased progressively with age (CL [mL/kg/min]=37.87-0.198xAge; r2=0.246). CONCLUSION: We achieved a relatively simple and practical covariate model in which the variability of pharmacokinetics within the study population could be ascribed principally to variability in clearance from the central compartment. Pharmacokinetic simulation predicted an improved performance of the TCI system when employing the derived covariates model, especially in elderly female patients.