Target-controlled Infusion Device Research Articles

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

BackgroundThe 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. MethodsWe 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. ResultsThe 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. ConclusionsOur 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.

To ascertain the plasma concentration of propofol to achieve bispectral index-guided sedation using a target-controlled infusion in patients undergoing elective surgeries under neuraxial anaesthesia.

Sedation improves patient satisfaction, comfort and acceptance of regional anaesthesia. Propofol using bispectral index (BIS)/target-controlled infusion (TCI) system can be an optimal method of sedation, as it combines objective measurement of sedation using BIS along with maintenance of a steady plasma concentration of propofol with the TCI device. The aim of this study was to ascertain the dose and safety of propofol using BIS/TCI system for sedation in patients undergoing surgeries under neuraxial anaesthesia. One hundred and seven adult patients, undergoing elective surgical procedures under spinal or combined spinal epidural anaesthesia, were recruited. Propofol infusion was started with TCI at an initial target plasma concentration (Cpt) of 1.2 μg/mL, and after equilibration between Cpt and effect site concentration (Ce), propofol was then adjusted in increments and/or decrements of 0.2 μg/mL in order to maintain a BIS value between 60 and 80. The average time to reach BIS = 80 after starting infusion was 7.32 ± 3.13 minutes. The objective was to calculate mean Cpt value maintaining BIS between 60 and 80 and to observe recovery time and complications. Mean Cpt value was 1.13 ± 0.17 mg/mL with 95% confidence interval (1.10-1.16 μg/mL). In 85% of patients, a BIS value of 60-80 was maintained at Cpt ≤ 1.2 μg/mL. No patient had severe complications requiring stoppage of infusion. Propofol sedation using BIS/TCI system can provide safe and convenient sedation during neuraxial anaesthesia at very low plasma concentration, Cpt ≤ 1.2 μg/mL in majority of patients. There were no periprocedural complications, and recovery was rapid.

Thyroidectomy and uncontrolled graves' disease - Multidisciplinary approach prevents unnecessary cancellation.

Dear Editor, Thyroidectomy is the definitive treatment for thyrotoxicosis for patients resistant to medical treatment and performed preferably when the patient is euthyroid.[1] Sometimes it may not be possible to render a patient euthyroid for various reasons leading to postponement or deferment of surgery.[2] A 35-year-old woman, was suffering from Graves’ disease, confirmed by a low thyroid-stimulating hormone (<0.005 miliunits/L), markedly elevated free thyroxine (>100 nanograms/dL), and positive thyroid receptor antibodies. Thionamide (carbimazole) therapy was started to lower the circulating thyroid hormone levels and beta-blockers added to reduce her hyper-adrenergic symptoms. She developed adverse drug effects resulting in agranulocytosis which necessitated discontinuing thionamide therapy. A multidisciplinary team consisting of an endocrinologist, endocrine surgeon, and anaesthetist was convened and a consensus view emerged for urgent total thyroidectomy. In preparation for surgery Lugol’s iodine and oral propranolol 20 mg 8 hourly administered to control tachycardia. Intravenous hydrocortisone 100 mg 8 hourly was started 1 week prior to planned operation to reduce peripheral conversion of free thyroxine to free triiodothyronine. General anaesthesia was administered with target-controlled infusion (TCI) of propofol and remifentanil with intubating dose of atracurium. Neural integrity monitor (NIM) electromyogram tracheal tube was used for intraoperative recurrent laryngeal nerve function monitoring. No further dose of atracurium was used. Anaesthesia was maintained with total intravenous anaesthesia (TIVA) using TCI devices and depth of anaesthesia was monitored with bispectral index (BIS monitor). Total thyroidectomy with parathyroid preservation was uneventful. After a brief observation in the post-anaesthesia recovery unit, she was transferred to the high dependency unit for monitoring. The postoperative course was complicated by severe hypocalcaemia (0.82 mg/dL) due to transient postsurgical hypoparathyroidism. This was confirmed by inappropriately normal parathyroid hormone levels post-surgery despite severe hypocalcaemia. Prolonged and severe stimulation of thyroid hormone is known to induce a high bone turnover state described as thyrotoxic osteodystrophy.[34] The high incidence of hypocalcaemia after thyroidectomy in thyrotoxic patients suggests that rapid loss and sudden removal of T3 and T4 hormone stimulation and inadequate parathyroid hormone response resulting in transient post-thyroidectomy hypocalcaemia. The calcium levels stabilized over the next 3 days with intravenous calcium replacement; subsequently, she was discharged with oral calcium and vitamin D supplements. Thyroidectomy may be the last option in some patients with Graves’ thyrotoxicosis refractory to medical treatment who cannot be optimized by medical treatment. A multidisciplinary team approach may help in appropriate preparation of patients prior to thyroidectomy avoiding unnecessary cancellation or postponement of surgery. Close postoperative monitoring of serum-ionized calcium is also recommended. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

A Prototype Patient-Maintained Propofol Sedation System Using Target Controlled Infusion for Primary Lower-Limb Arthroplasty

Each year, many operations in the UK are performed with the patient awake, without the use of general anaesthesia. These include joint replacement procedures, and in order to reduce patient anxiety, the supervising anaesthetist delivers the sedative propofol intravenously using a target-controlled infusion (TCI) device. However, it is clinically challenging to judge the required effect-site concentration of sedative for an individual patient, resulting in patient care issues related to over or under-sedation. To improve the process, patient-maintained propofol sedation (PMPS), where the patient can request an increase in concentration through a hand-held button, has been considered as an alternative. However, due to the proprietary nature of modern TCI pumps, the majority of PMPS research has been conducted using prototypes in research studies. In this work, a PMPS system is presented that effectively converts a standard infusion pump into a TCI device using a laptop with TCI software. Functionally, the system delivers sedation analogous to a modern TCI pump, with the differences in propofol consumption and dosage within the tolerance of clinically approved devices. Therefore, the Medicines and Healthcare products Regulatory Agency (MHRA) has approved the system as a safe alternative to anaesthetist-controlled TCI procedures. It represents a step forward in the consideration of PMPS as a sedation method as viable alternative, allowing further assessment in clinical trials.

Pharmacokinetic Analysis of Propofol Target-Controlled Infusion Models in Chinese Patients with Hepatic Insufficiency.

BackgroundEffects of liver dysfunction on target-controlled infusion (TCI) with Marsh parameters of propofol remain poorly documented. The purpose of this study was to evaluate the performance of propofol TCI in a cohort of Chinese patients with severe hepatic insufficiency.Material/MethodsWe assigned 32 patients who underwent liver transplantation to 3 groups according to Child-Turcotte-Pugh (CTP) score. Anesthesia, preceding liver transplantation, was induced and maintained with TCI of 3 μg/mL propofol. Plasma propofol concentration was assessed. Propofol TCI system performance was analyzed in terms of error size, bias, and divergence. Data on plasma propofol concentrations were analyzed, and population pharmacokinetic parameters of propofol were fitted by NONMEM software.ResultsIn the CTP C group, measured concentrations of propofol were much higher than those of predictive concentrations, with significantly higher overshoots compared to CTP A patients. Overall, TCI system performance was significantly lower in CTP C patients. Linear regression equations of Cm vs. Cp and a regression model of pharmacokinetics were obtained.ConclusionsPropofol TCI device performance with Marsh parameters was clinically acceptable in CTP A patients but may not be suitable for patients with severe hepatic impairment.

Clinical Pharmacokinetics and Pharmacodynamics of Propofol.

Propofol is an intravenous hypnotic drug that is used for induction and maintenance of sedation and general anaesthesia. It exerts its effects through potentiation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) at the GABAA receptor, and has gained widespread use due to its favourable drug effect profile. The main adverse effects are disturbances in cardiopulmonary physiology. Due to its narrow therapeutic margin, propofol should only be administered by practitioners trained and experienced in providing general anaesthesia. Many pharmacokinetic (PK) and pharmacodynamic (PD) models for propofol exist. Some are used to inform drug dosing guidelines, and some are also implemented in so-called target-controlled infusion devices, to calculate the infusion rates required for user-defined target plasma or effect-site concentrations. Most of the models were designed for use in a specific and well-defined patient category. However, models applicable in a more general population have recently been developed and published. The most recent example is the general purpose propofol model developed by Eleveld and colleagues. Retrospective predictive performance evaluations show that this model performs as well as, or even better than, PK models developed for specific populations, such as adults, children or the obese; however, prospective evaluation of the model is still required. Propofol undergoes extensive PK and PD interactions with both other hypnotic drugs and opioids. PD interactions are the most clinically significant, and, with other hypnotics, tend to be additive, whereas interactions with opioids tend to be highly synergistic. Response surface modelling provides a tool to gain understanding and explore these complex interactions. Visual displays illustrating the effect of these interactions in real time can aid clinicians in optimal drug dosing while minimizing adverse effects. In this review, we provide an overview of the PK and PD of propofol in order to refresh readers’ knowledge of its clinical applications, while discussing the main avenues of research where significant recent advances have been made.

Anesthetic considerations during surgical intervention in Woake’s syndrome -a case report

BackgroundWoake’s syndrome (WS) is a recurrent nasal polyposis, accompanied by broadening of the nose, frontal sinus aplasia, dyscrinia, and bronchiectasis. There has been no previous report on anesthetic management in patients with WS.CaseWe describe a case involving a 13-year-old male patient with WS who was scheduled for septorhinoplasty for necrotic ethmoiditis. Anesthesia was induced and maintained with propofol and remifentanil using a target-controlled infusion device. The anesthetic considerations of this rare syndrome and the advantages of an intravenous infusion method over local and volatile anesthesia for these patients are discussed. We report on caveats, such as pulmonary dysfunction during the anesthetic management, and nasal structural problems encountered in WS patients.ConclusionsGiven that conventional inhaled anesthesia reduces ciliary movement and that local anesthesia with sedative has several disadvantages, perioperative control and precautions against respiratory infections by using antibiotics, and preventing cilio-depressant actions, are important for anesthetic management.

Anomalies in target-controlled infusion: an analysis after 20years of clinical use.

Although target-controlled infusion has been in use for more than two decades, its benefits are being obscured by anomalies in clinical practice caused by a number of important problems. These include: a variety of pharmacokinetic models available in open target-controlled infusion systems, which often confuse the user; the extrapolation of anthropomorphic data which provokes anomalous adjustments of dosing by such systems; and the uncertainty of regulatory requirements for the application of target-controlled infusion which causes uncontrolled exploitation of drugs and pharmacokinetic models in target-controlled infusion devices. Comparison of performance of pharmacokinetic models is complex and mostly inconclusive. However, a specific behaviour of a model in a target-controlled infusion system that is neither intended nor supported by scientific data can be considered an artefact or anomaly. Several of these anomalies can be identified in the current commercially available target-controlled infusion systems and are discussed in this review.

Best anaesthetic drug strategy for morbidly obese patients.

The purpose of this review is to describe an evidence-based drug strategy applicable to any obese patient, rather than to present one standard 'ideal' anaesthetic drug combination. The ultimate choice of specific drugs in any given situation will depend upon clinician experience, patient specifics, and drug availability. The fundamental principle in anaesthesia for the obese patient is to use the shortest acting, least fat soluble agents to ensure rapid recovery to safe levels of alertness and mobility. No new drugs have been introduced over the past few years, but we have seen an introduction of enhanced recovery after surgery-based protocols into bariatric surgery. Our understanding of how obesity affects pharmacokinetics/dynamics of our drugs is improving, with new and better use of established drugs. Allometric scaling is being tested in the different pharmacokinetic/dynamic models used in target controlled infusion devices, with improved performance as a result. Obstructive sleep apnoea has a significant impact upon outcome and utilization of clinical resources, including critical care beds. If an improved drug dosing strategy will reduce this impact, then this would be a step forward. This review introduces newer findings to help us use anaesthetic and analgesic drugs more safely in the morbidly obese. However, there remain many areas of uncertainty with a lack of consensus on many issues.

Modelling of the Sedative Effects of Propofol in Patients undergoing Spinal Anaesthesia: A Pharmacodynamic Analysis.

Sedation can increase patient comfort during spinal anaesthesia. Understanding the relationship between the propofol effect-site concentration (Ce) and patient sedation level could help clinicians achieve the desired sedation level with minimal side effects. We aimed to model the relationship between the propofol Ce and adequate and deep sedation and also incorporate covariates. Thirty patients scheduled for orthopaedic surgery received spinal anaesthesia with 0.5% bupivacaine. Propofol was administered via an effect-site target-controlled infusion device using the Schnider pharmacokinetic model. The pharmacodynamic models for both adequate sedation [Observer's Assessment of Alertness/Sedation (OAA/S) scores of 3-4] and deep sedation (OAA/S scores of 1-2) were developed using nonlinear mixed-effects modelling. Increments in the propofol Ce were associated with increased depths of sedation. In the basic model, the estimated population Ce50 values for adequate and deep sedation were 0.94 and 1.52 μg/ml, respectively. The inclusion of the patient's age and sensory block level for adequate sedation and of age for deep sedation as covariates significantly improved the basic model by decreasing the objective function's minimum value from 10696.72 to 10677.92 (p = 0.0003). The simulated Ce50 values for adequate sedation in 20-year-old patients with a T12 sensory level and in 80-year-old patients with a T4 level were 1.63 and 0.53 μg/ml, respectively. Both age and sensory block level should be considered for adequate sedation, and the propofol concentration should be reduced for elderly patients with a high spinal block to avoid unnecessarily deep levels of sedation.

Variations of the Analgesia Nociception Index During Propofol Anesthesia for Total Knee Replacement

The Analgesia Nociception Index (ANI) monitor measures the relative parasympathetic tone as a surrogate for the antinociception/nociception balance during general anesthesia. The aims of this observational study were to test whether ANI could early detect hemodynamic reactivity (HemodR) during propofol anesthesia, measure pain in conscious patients after surgery, and determine ANI predictive thresholds. After institutional approval and informed consent, adult patients scheduled for total knee replacement were included. Propofol was administered using a target-controlled infusion device, and sufentanil was administered at induction and in case of "HemodR," defined as a 20% increase in heart rate or systolic blood pressure. Data were collected before the start of surgery (NoStim), in case of "HemodR," and after awakening before and after the pain had been treated by truncular analgesia. Nonparametric tests were conducted. Thresholds were determined using an receiver operating characteristic analysis. Results are presented as median (interquartile range). A total of 27 patients have been analysed. ANI decreased from 82 (30) at "NoStim" to 47 (22) at "HemodR," whereas heart rate increased moderately from 61 (14) to 65 (18) and systolic blood pressure increased significantly from 91 mm Hg (16 mm Hg) to 151 mm Hg (25 mm Hg). Receiver operating characteristic analysis led to a threshold of 63 for "HemodR" detection (sensitivity=80%, specificity=88%, area under the curve=0.92), whereas ANI performance in awake patients was lower. ANI measures during propofol anesthesia are coherent with the evolution of the analgesia/nociception balance, although its performance decreases in awake patients. Further clinical validation should focus on demonstrating the benefit of maintaining ANI over 63 during surgery.

Monitoring and delivery of sedation

Sedation for medical procedures is provided in a variety of clinical settings by medical personnel with differing levels of education and training. Although generally a safe practice, there is a degree of morbidity and mortality associated with sedation practice. Monitoring standards continue to be refined by professional societies with the goal of improving care. The depth of sedation should be monitored with clinical criteria. Processed electroencephalographic monitors currently do not contribute significantly to sedation care. Monitoring ventilation using pulse oximetry should be abandoned for more direct methods, such as capnography-transcutaneous carbon dioxide, respiratory acoustical and thoracic impedance monitoring could also play a role. Propofol has become widely utilized for sedation, although there are concerns about its margin of safety and synergistic interactions with other agents. Dexmedetomidine and propofol/ketamine also have utility. Patient-controlled sedation pumps and target-controlled infusion devices have been developed to improve patient care and satisfaction. A computer-assisted propofol sedation device to be used by non-anaesthesiologists has been approved in the USA by the Food and Drug Administration. More computer-assisted sedation delivery devices are likely to be developed, but their clinical utility is unclear.

Desempeño predictivo y clínico de un dispositivo target-controlled infusion para sevofluorano en una estación de trabajo convencional: correlación farmacocinética del modelo empleado

IntroductionGood governance of resources and global warming has attracted interest on minimal flow (0.3–0.5 l/min) inhalation anesthesia. ObjectivesTo evaluate the predictive and clinical performance of a TCI (Target-controlled infusion) device, and its pharmacokinetic correlation for sevoflurane. MethodsProspective, longitudinal, and analytical study on 25 adult patients. Fresh gas flow used 0.5 l/min. Target concentration of 1.2% (v/v). Continuous and variable infusion into the circuit of the anesthesia workstation. Controller developed with LABVIEW 6.1. Hemodynamic, respiratory and anesthetic depth data collected every 5 s using the anesthesia workstation software. Bias (MDPE%), inaccuracy (MDAPE%), wobble, and divergence of the TCI device were determined in the first hour. STATA-12 pk collapse was used to analyze the area under the curve of the target and expired concentrations. The results are expressed as Mean (CI 95%) and Median [IQR]*. ResultsTarget concentration used 1.22 [1.14–1.37] %*, reached in 04:07 [03:15–06:15]* min:s (expiratory branch). Anesthetic duration 1:10:50 (00:56:57–1:24: 43) h:min:s. Sevoflurane consumption 6.9 (5.7–8.0) ml. MDPE% −12.8 (−17.6 to −8.1) %; MDAPE% 15.9 (11.9–19.8) %; wobble 6.9 (5.0–8.7)% and divergence 0.89% (−5.96 to 7.7)%h-1. Interactions per hour on the TCI of 3 (2–4). Correlation of the area under the curve, Spearman's rho = 0.8577, p < 0.00001. ≥15% inaccuracy was associated with age >65 years and obesity. ConclusionsThe TCI sevoflurane© showed good performance, and the target concentration was rapidly reached and remained stable, with few interactions with the device needed during the first hour. There were neither overdosing nor clinically significant alterations.

Predictive and clinical performance of a TCI device for sevoflurane at a conventional workstation: Pharmacokinetic correlation of the model used

IntroductionGood governance of resources and global warming has attracted interest on minimal flow (0.3–0.5l/min) inhalation anesthesia. ObjectivesTo evaluate the predictive and clinical performance of a TCI (Target-controlled infusion) device, and its pharmacokinetic correlation for sevoflurane. MethodsProspective, longitudinal, and analytical study on 25 adult patients. Fresh gas flow used 0.5l/min. Target concentration of 1.2% (v/v). Continuous and variable infusion into the circuit of the anesthesia workstation. Controller developed with LABVIEW 6.1. Hemodynamic, respiratory and anesthetic depth data collected every 5s using the anesthesia workstation software. Bias (Median of Predictive Error, MDPE%), inaccuracy (Absolute Mean of Predictive Error, MDAPE%), wobble, and divergence of the TCI device were determined in the first hour. STATA-12 pk collapse was used to analyze the area under the curve of the target and expired concentrations. The results are expressed as mean (95% CI) and median [IQR]*. ResultsTarget concentration used 1.22 [1.14–1.37]%*, reached in 04:07 [03:15–06:15]* min:s (expiratory branch). Anesthetic duration 1:10:50 (00:56:57–1:24: 43) h:min:s. Sevoflurane consumption 6.9 (5.7–8.0) ml. MDPE% −12.8 (−17.6 to −8.1) %; MDAPE% 15.9 (11.9–19.8) %; wobble 6.9 (5.0–8.7)% and divergence 0.89% (−5.96 to 7.7)%h-1. Interactions per hour on the TCI of 3 (2–4). Correlation of the area under the curve, Spearman's rho=0.8577, p<0.00001. ≥15% inaccuracy was associated with age >65 years and obesity. ConclusionsThe TCI sevoflurane© showed good performance, and the target concentration was rapidly reached and remained stable, with few interactions with the device needed during the first hour. There were neither overdosing nor clinically significant alterations.

TIKSLINIS INFUZINIS REŽIMAS ANESTEZIOLOGIJOJE

Target controlled infusion is a relatively new technique which enables the anaesthesiologist to target a constant blood concentration during total intravenous anaesthesia. The objective of this review is to take a look into the principles of target controlled infusion and the results of novel research comparing this technique with manually controlled infusion.We reviewed articles describing general pharmacokinetics of intravenous drugs and pharmacokinetic models used in target controlled infusion devices. We also reviewed the most recent research papers published between 2008 and 2013 investigating the efficiency of this method. Studies performed before 2007 had some controversial results, but this seems to be because of their high heterogeneity. More recent research, especially those using closed-loop systems, show many advantages of target controlled infusion in comparison with manually controlled infusion for total intravenous anaesthesia: increased satisfaction of anaesthesiologists and surgeons, less interventions during the anaesthesia, smaller doses of drugs used, increased stability of patient’s condition during the operation and less side effects after the operation. In conclusion, it is safe to say that target controlled infusion is a very promising technique and its usage in clinical practice will continue to increase.

Effect of palonosetron on postanesthetic shivering after propofol–remifentanil total intravenous anesthesia

The authors conducted a prospective, randomized, double-blind study to evaluate the anti-shivering efficacy of palonosetron for patients after gynecological laparoscopy under total intravenous propofol-remifentanil anesthesia. Sixty female patients were randomly assigned to one of two groups and administered palonosetron 0.075 mg (palonosetron group, n = 30) or the same volume of normal saline (control group, n = 30) immediately after anesthesia induction. Anesthesia was induced and maintained with propofol and remifentanil, using a target-controlled infusion device. Esophageal and index finger temperatures were measured immediately after anesthesia induction (baseline) and at 15-min intervals until the end of the surgery. Postanesthetic shivering and side effects were assessed in a postanesthetic care unit. Incidence of shivering was comparable in the control and palonosetron groups (10/30 vs. 8/30, respectively, P = 0.779). No significant intergroup differences were observed between esophageal and index finger temperatures. Compared with baseline values, esophageal temperatures decreased immediately after pneumoperitoneum in the control group and from 30 min after pneumoperitoneum in the palonosetron group. Use of palonosetron (0.075 mg) did not reduce the incidence of postanesthetic shivering after gynecological laparoscopy under propofol-remifentanil anesthesia. Further study including other 5-HT3 antagonists or male patients would elucidate the effect of palonosetron on shivering after propofol-remifentanil anesthesia.

Torsades de pointes observed in the early postoperative period in a patient with long QT syndrome

Torsades de pointes observed in the early postoperative period in a patient with long QT syndrome

Pharmacokinetics and pharmacodynamics – is there anything new?

Pharmacokinetics and pharmacodynamics – is there anything new?

Target-controlled infusion devices: are we missing much?

Total intravenous anesthesia is probably less popular in North America than in other parts of the world, perhaps because of limited access in Canada and the United States to target-controlled infusion (TCI) devices to deliver intravenous drugs, such as propofol and remifentanil. The principle of operation of commercially available TCI devices, such as the Diprifusor , (Astra-Zeneca Pharmaceuticals, Macclesfield, UK) is rather simple. The operator selects a target plasma concentration of drug (e.g., propofol) that the patient requires for a specified procedure, and the TCI device automatically administers a small bolus loading dose followed by a kinetically driven infusion rate to rapidly attain and then maintain that drug concentration until a new drug concentration is selected. The TCI device informs the anesthesiologist in real time of the population-based theoretical drug plasma concentration attained and the quantity of drug delivered. It is also possible to set TCI devices to target effect-site concentrations. In this case, the infusion rate takes into account the time lag between the plasma and the site of action (e.g., the brain in the case of hypnotics and opioids). In the United States, the Food and Drug Administration did not deem TCI devices sufficiently advantageous in anesthesia to approve their commercial use, and the devices are also not currently available in Canada. Are we being deprived of a truly useful tool to improve delivery of intravenous anesthetics, or are these devices merely gadgets that are useful in the research arena but much less so in the clinical setting? At first glance, the concept of the TCI device is clinically appealing. The anesthesiologist enters the patient’s covariates (age, weight, and height) with a population kinetic data set from a selection menu; the TCI device then calculates and delivers in real time the correct amount of drug that will rapidly achieve the desired target plasma or effect-site drug concentration. Whenever a new drug concentration is selected, the TCI calculations consider all drug history to achieve the new target concentration as soon as possible. There is no need to adjust the infusion rate to take into consideration complex pharmacokinetic redistribution and elimination processes or effect site time lag – the machine does all of this for you! Users of TCI devices do not think in terms of bolus doses and infusion rates, but rather in terms of target concentrations. Some users have pushed the concept even one step further and used TCI devices in their research to explore relationships between a concentration and a desired effect, such as loss of consciousness or specific bispectral index (BIS) targets. In this issue of the Journal, Austrian and Chinese groups collaborated to examine the responses to propofol when using this technology in two different patient populations. Their findings suggest that Chinese patients were more sensitive to propofol than Austrian patients. Their study can be viewed as an example of the advantages and limitations of TCI devices. The authors administered propofol to all patients in the same manner, but instead of giving a certain dose or a certain dose per kilogram, they programmed the TCI device, in this case the Diprifusor , to achieve a target F. Donati, MD, PhD (&) Departement d’anesthesiologie, Hopital MaisonneuveRosemont, Universite de Montreal, 5415, boul l’Assomption, Montreal, QC H1T 2M4, Canada e-mail: francois.donati@umontreal.ca

Half-time or Half-life

Elimination half-life is the pharmacokinetic parameter used most commonly to describe duration of pharmacologic action, including that expected of intravenous anesthetic drugs administered by continuous infusion. Little consideration has been given, however, to the relevance of elimination half-life in describing plasma (central compartment) drug concentrations in the context of relevant infusion durations. Therefore, simulations were performed with multicompartment pharmacokinetic models for six intravenous anesthetic drugs. These models had elimination half-lives ranging from 111 to 577 min. The input in each simulation was in infusion regimen designed to maintain a constant plasma drug concentration for durations ranging from 1 min to 8 h and until steady state. The time required for the plasma drug concentration to decrease by 50% after terminating each infusion in each of the models was determined and was designated the "context-sensitive half-time," where "context" refers to infusion duration. The context-sensitive half-times were markedly different from their respective elimination half-lives and ranged from 1 to 306 min. The half-times were explained by posing each pharmacokinetic model in the form of a hydraulic model. These simulations demonstrate that elimination half-life is of no value in characterizing disposition of intravenous anesthetic drugs during dosing periods relevant to anesthesia. We propose that context-sensitive half-times are a useful descriptor of postinfusion central compartment kinetics.