Target controlled infusion: TCI

Progress in computing technology has allowed the development of target controlled infusion devices, with drugs delivered to achieve specific predicted target blood drug concentrations. Target controlled infusion (TCI) system has been developed as a standardised infusion system for the administration of opioids, propofol and other anaesthetics by target controlled infusion. A set of pharmacokinetic parameters has been selected using computer simulation of a known infusion scheme. The selected model is incorporated into a computer-compatible infusion pump. Clinical trials with such systems have provided appropriate target concentrations for the administration of target controlled infusion of anaesthetic drugs. The technique of TCI strongly influences the development of intravenous anaesthesia and opens a scenario of new and exciting applications in peri-operative anaesthetic management. The launch of 'Diprifusor' as the first commercially available TCI system for propofol was the cornerstone of a successful research period within the last decade, which evaluated the pharmacokinetic foundations of computer assisted intravenous drug delivery. Nowadays TCI technology is becoming a part of routine anaesthesia technique for the practitioner rather than a research tool for specialists and those who are enthusiasts of intravenous anaesthesia. Besides clinical application in anaesthesia, target controlled systems will play a significant role as research tools in the evaluation of drug interactions in anaesthesia and in the development of new control techniques for the administration of sedative and analgesic drugs in the peri-operative period.     

Effect site concentration during propofol TCI sedation: a comparison of sedation score with two pharmacokinetic models

Target controlled infusion (TCI) pumps function using a programme based on a pharmacokinetic/pharmacodynamic model. We compared the Marsh and Schnider models to find out which better correlates with the clinically observed effect of propofol as assessed by the Observer Assessment of Alertness/Sedation (OAAS) score and the Bispectral index. We assessed the sedation score and Bispectral index score in 40 un-premedicated patients undergoing surgical procedures under spinal anaesthesia with propofol sedation to a target concentration of 2 microg.ml(-1). Half of the patients received TCI propofol driven by the Schnider model in effect site control, the other half were sedated with TCI propofol driven by the Marsh model in plasma control. We calculated the effect site concentration predicted by both models for all the patients. Changes in the sedation score and Bispectral index correlated better with the Marsh than with the Schnider effect site prediction in both study groups.     

Simulation analysis of estimated effect-site concentrations of propofol and fentanyl administered by a TCI system for other drugs

BACKGROUND: We experienced a case of inadequate sedation because of inappropriate use of TCI system for fentanyl. METHODS: We evaluated the blood and effect-site concentrations of propofol and fentanyl calculated by a pharmacokinetic simulation model in which the administration of one drug was managed with target-controlled infusion pump set for another drug. RESULTS: In case propofol was administered with an effect-site-steering TCI system for fentanyl, the blood concentration of propofol increased within the first few minutes, especially immediately after starting the infusion, decreased for the next 10 minutes, and then was stabilized at a level of 0.7 times the target concentration. When fentanyl was administered with a blood-steering TCI for propofol, the calculated blood concentration of fentanyl was almost equal to the target concentration in the first few minutes, and then gradually increased until reaching 2.21 times the target concentration, at 240 minutes. Furthermore, the propofol concentration and the fentanyl concentration showed small differences between the target and calculated concentrations when the infusion time was not so long. CONCLUSIONS: When the administration time is short, the anesthesiologist must be aware of the difficulty in distinguishing the human error of choosing one drug for the TCI system for another drug.     

Target controlled infusion (TCI)--status and clinical perspectives

The technique of target controlled infusion (TCI) has influenced the development of intravenous anaesthesia substantially and opens the possibility of many new and exciting applications in peri-operative anaesthetic care. The launch of "Diprifusor" as the first commercially available TCI system for propofol was the cornerstone of a successful research period within the last decade, which evaluated the pharmacokinetic foundations of computer assisted intravenous drug delivery. We are now in a period where TCI technology is becoming a part of routine anaesthesia technique for the practitioner rather than a research tool for specialists and enthusiasts. This review gives an update on the rational pharmacokinetic basis of TCI development, the preliminary clinical experience with the new technique, the performance and accuracy of TCI devices and potential technical pitfalls in clinical routine. Besides clinical application in anaesthesia with "Diprifusor" TCI, target controlled systems are expected to play a significant role as research tools in the evaluation of drug interactions in anaesthesia and in the development of novel control techniques for the administration of sedative and analgesic drugs in the peri-operative period.     

Pharmacokinetics of propofol during conscious sedation using target- controlled infusion in anxious patients undergoing dental treatment

Infusion of propofol by a target-controlled infusion (TCI) system is effective in achieving conscious sedation for anxious patients presenting for dental surgery. It is a common clinical observation that anxious patients require more anaesthetic drugs than non-anxious individuals. In study 1 we have defined blood propofol concentrations necessary for conscious sedation in both anxious (n = 23) and non- anxious (n = 18) patients. The pump performance of the TCI system, using Gepts' pharmacokinetic model, was evaluated in these two patient groups. Subsequently, clearance of propofol was compared in the two groups. Mean measured venous serum propofol concentrations obtained between 20 and 35 min after the optimal sedation level was reached were 1.6 (SD 0.2) micrograms ml-1 in the anxious patients compared with 1.7 (0.3) micrograms ml-1 in the control group (study 1) and 1.4 (0.27) micrograms ml-1 in study 2. The pump systematically overpredicted measured propofol concentrations in both groups (study 1). There was no significant difference in propofol clearance between the two groups. In study 2, an optimized set of microconstants was derived which should more accurately predict the pharmacokinetic profile of the anxious population and this set was tested prospectively in another group of 12 anxious dental patients. Bias and precision with the optimized kinetic set were significantly less than the values obtained in study 1. We conclude that there was no significant pharmacokinetic differences between anxious and non-anxious subjects receiving subanaesthetic doses of propofol for conscious sedation.      

Isoflurane and propofol for long-term sedation in the intensive care unit

Propofol and isoflurane have been reported recently to offer better sedation than alternative agents in patients who require long-term ventilation in the Intensive Care Unit. This is the first report of a direct comparison between propofol and isoflurane. Twenty-four patients predicted to require artificial ventilation for at least 48 h were entered into a randomised crossover study to monitor sedation quality and time to recovery from sedation. There were no significant differences between the two agents in either end-point, with over 95% optimal sedation achieved by the use of each drug. Few adverse events were noted. Technological advances in the administration of volatile agents as long-term sedatives in the Intensive Care Unit may facilitate their more widespread use.     

Randomized controlled trial of patient‐controlled sedation for colonoscopy: Entonox vs modified patient‐maintained target‐controlled propofol

Aim Propofol sedation is often associated with deep sedation and decreased manoeuvrability. Patient‐maintained sedation has been used in such patients with minimal side‐effects. We aimed to compare novel modified patient‐maintained target‐controlled infusion (TCI) of propofol with patient‐controlled Entonox inhalation for colonoscopy in terms of analgesic efficacy (primary outcome), depth of sedation, manoeuvrability and patient and endoscopist satisfaction (secondary outcomes). Method One hundred patients undergoing elective colonoscopy were randomized to receive either TCI propofol or Entonox. Patients in the propofol group were administered propofol initially to achieve a target concentration of 1.2 μg/ml and then allowed to self‐administer a bolus of propofol (200 μg/kg/ml) using a patient‐controlled analgesia pump with a handset. Entonox group patients inhaled the gas through a mouthpiece until caecum was reached and then as required. Sedation was initially given by an anaesthetist to achieve a score of 4 (Modified Observer’s Assessment of Alertness and Sedation Scale), and colonoscopy was then started. Patients completed an anxiety score (Hospital Anxiety and Depression questionnaire), a baseline letter cancellation test and a pain score on a 100‐mm visual analogue scale before and after the procedure. All patients completed a satisfaction survey at discharge and 24 h postprocedure. Results The median dose of propofol was 174 mg, and the median number of propofol boluses was four. There was no difference between the two groups in terms of pain recorded (95% confidence interval of the difference ?0.809, 5.02) and patient/endoscopist satisfaction. There was no difference between the two groups in either depth of sedation or manoeuvrability. Conclusion Both Entonox and the modified TCI propofol provide equally effective sedation and pain relief, simultaneously allowing patients to be easily manoeuvred during the procedures.     

The use of propofol and remifentanil for the anaesthetic management of a super-obese patient

Morbid obesity is defined as body mass index (BMI) > 35 kg.m(-2), and super-obesity as BMI > 55 kg.m(-2). We report the case of a 290-kg super-obese patient scheduled for open bariatric surgery. A propofol-remifentanil TCI (target controlled infusion) was chosen as the anaesthetic technique both for sedation during awake fibreoptic nasotracheal intubation and for maintenance of anaesthesia during surgery. Servin's weight correction formula was used for propofol. Arterial blood samples were taken at fixed time points to assess the predictive performance of the TCI system. A significant difference between measured and predicted plasma propofol concentrations was found. After performing a computer simulation, we found that predictive performance would have improved significantly if we had used an unadjusted pharmacokinetic set. However, in conclusion (despite the differences between measured and predicted plasma propofol concentrations), the use of a propofol-remifentanil TCI technique both for sedation during awake fibreoptic intubation and for Bispectral Index-guided propofol-remifentanil anaesthesia resulted in a rapid and effective induction, and operative stability and a rapid emergence, allowing rapid extubation in the operating room and an uneventful recovery.     

Predictive capability of the TCI Diprifusor system in patients with terminal chronic renal insufficiency

OBJECTIVE: To evaluate the predictive capability of a target-controlled infusion (TCI) system in patients with terminal chronic renal failure by comparing real drug concentrations with predicted concentrations. METHODS: Forty ASA II-III patients undergoing kidney transplants were enrolled and grouped by age: group A 18-54 years old and group B 55-80 years old. Propofol was administered through the Diprifusor TCI system (Astra Zeneca) with the target concentration of propofol for induction set at 3 micrograms/mL for group A patients and 2.5 micrograms/mL for group B patients. Arterial blood samples were taken for analysis of drug concentrations at the following times: 2 and 5 minutes after starting the infusion; immediately after the incision; before and 5 minutes after increasing or decreasing the target concentration > 25%; before and 5 minutes after switching off the perfusion for surgery; upon eye opening; and 30 minutes after switching off the infusion pump. The predictive capability of the system was determined by performance error (PE). We calculated bias (%, median PE) and accuracy (%, median absolute PE). RESULTS: Twenty group A and 20 group B patients were studied. The median PEs in groups A and B, respectively, were -3.45 (-20.3-28.4) and -1.1 (-19.7-15.4). Median absolute PEs were 21.2 (11.9-45.1) and 16.3 (11.5-27.4), respectively. CONCLUSIONS: The results indicate that the predictive capability of the Diprifusor pharmacokinetic model is acceptable in patients with terminal kidney failure, given the minor bias of 10% to 20% and the degree of accuracy between 20% and 40%.     

Propofol anaesthesia via target controlled infusion or manually controlled infusion: effects on the bispectral index as a measure of anaesthetic depth.

Target controlled infusions (TCI) of propofol allow anaesthetists to target constant blood concentrations and respond promptly to signs of inappropriate anaesthetic depth. Studies comparing propofol TCI with manually controlled infusion (MCI) reported similar control of anaesthesia, but did not use an objective measure of anaesthetic depth. We therefore tested whether the Bispectral Index (BIS), an electroencephalographic (EEG) variable, is more stable during propofol TCI or MCI. Forty patients received midazolam and fentanyl before induction and were randomized to TCI or MCI. Target propofol concentrations in the TCI group were 3 to 8 microg/ml. The MCI group received propofol bolus (approximately 2 mg/kg) and infusion (3 to 10 mg/kg/h). Neuromuscular blockade was achieved with rocuronium. Following endotracheal intubation, nitrous oxide (66%) in oxygen was delivered and propofol infusion and fentanyl boluses were titrated against clinical signs. Blood pressure, heart rate and EEG were recorded, although the anaesthetist was blind to BIS values. The ideal BIS for general anaesthesia was defined as 50. Performance error, absolute performance error, wobble and divergence of BIS, and maximum changes in blood pressure and heart rate were compared using two-sample t-tests or rank-sum tests where appropriate. There was no difference in absolute performance errors during maintenance of anaesthesia with propofol TCI or MCI (23 +/- 11% vs 23 +/- 9%; P=0.97). The two groups did not differ significantly in performance error, wobble, divergence on haemodynamic changes. We conclude that TCI and MCI result in similar depth of anaesthesia and haemodynamic stability when titrated against traditional clinical signs.     

Intravenous sedation with target-controlled infusion (TCI) in patients with difficult airways

Tracheal intubation was facilitated with an intubating laryngeal mask (ILM) in two patients with difficult airways. Target-controlled infusion (TCI) of propofol and fentanyl was used for sedation during placement of an ILM. An ILM was inserted smoothly. Spontaneous ventilation and oxygenation were well maintained throughout the induction. Both patients were satisfied with intravenous sedation using TCI for awake instrumentation of their airways.     

ZURÜCKGEZOGEN: Propofolapplikationssysteme

Background

During anaesthesia propofol is administered either by manual controlled infusion (MCI) or by target controlled infusion (TCI) techniques. In this study two different TCI systems for propofol administration were evaluated with regard to handling, patient safety, and costs and compared to administration of propofol by the MCI technique.

Methods

In a prospective study, 90 patients scheduled for elective surgery of the nose or nasal sinuses were randomly enrolled in three groups. The two TCI systems were examined in two groups of 30 patients: one group received propofol following the pharmacokinetic TCI model of Schnider (TCI-Schnider) and the other group received propofol following the TCI model of Marsh (TCI-Marsh). A manual perfusion technique (MCI, n=30) was used in the control group. Depth of anesthesia was controlled using the bispectral index (BSI) which was adjusted to fall within the range of 40–55. Hemodynamics, extubation times and time of awaking, rate and quality of propofol dose adjustment, total drug requirements, costs, and quality of recovery were documented. The incidence of postoperative nausea and vomiting (PONV) as well as shivering and patient satisfaction were also documented.

Results

Demographics, hemodynamics and perioperative data did not differ between the groups. Propofol consumption within the first 60 min also showed no significant differences. In the course of extended anaesthesia, propofol consumption was significantly less in both TCI groups compared to the control group (MCI) and the TCI-Schnider group also showed less episodes of bradycardia. The necessity of propofol dose adjustment did not differ significantly between the TCI groups. Administration and consumption of anaesthesia co-medication (fentanyl, remifentanil, cisatracurium) did not differ between the groups.

Conclusion

The investigated propofol administration procedures using the MCI or TCI techniques were safe and easy to handle under BIS monitoring. No differences were found concerning extubation times and time of awaking. During extended anaesthesia procedures (>60 min), propofol consumption was lower with both TCI techniques and thus costs could be saved.     

Fentanyl-induced hemodynamic changes after esophagectomy or cardiac surgery

STUDY OBJECTIVE: The goal of this study was to characterize the hemodynamic response to propofol vs propofol with fentanyl when used for sedation after esophagectomy or cardiac surgery. DESIGN: Prospective, randomized, controlled study. SETTING: University Hospital, Intensive Care Unit. PATIENTS: Thirty patients undergoing elective cardiac surgery and 26 patients undergoing esophagectomy were examined. INTERVENTION: Patients were randomized to receive propofol (0.5 mg/kg bolus over 10 minutes, followed by continuous infusion at 1 mg/kg per hour) with or without fentanyl (2.0 microg/kg per hour) to achieve sedation overnight while in the intensive care unit. Randomization was performed in a double-blind manner. MEASUREMENT: Mean arterial pressure (MAP) was monitored throughout the treatment period, and sedation level was measured. Sedation level was targeted to achieve a Ramsay score of 4. MAIN RESULTS: The number of patients experiencing a greater than 20% drop in baseline MAP was higher in cardiac patients receiving propofol alone (11 of 15 patients, 73%) than in cardiac patients receiving propofol with fentanyl (4 of 15 patients, 27%). Furthermore, the time of optimal sedation was lower in the cardiac patients who received propofol than in cardiac patients who received propofol with fentanyl group (propofol alone, 79%; propofol with fentanyl, 88%). In contrast, there was no difference in the number of esophagectomy patients experiencing a greater than 20% drop in baseline MAP or in the mean time of optimal sedation when comparing the 2 treatment regimens. CONCLUSIONS: Propofol has a differential effect on hemodynamics and sedation when comparing patients after cardiac surgery and esophagectomy.     

Prolonged sedation with propofol in the rat does not result in sleep deprivation

The use of propofol provides sedation without prolonging emergence in patients in the Intensive Care Unit. When prolonged, however, continuous sedation may overlap with naturally occurring sleep periods and potentially increase the risk of sleep deprivation. We modified an established rat model of sleep to determine whether prolonged, continuous sedation results in sleep deprivation. Rats were continuously sedated for a 12-h period overlapping completely with their normal sleep phase. Electroencephalogram (EEG) and movement data were collected before and after the sedation period. Rats were evaluated for EEG and movement evidence of sleep deprivation after sedation. When compared with baseline, the time spent in rapid eye movement (REM) and non-REM sleep was decreased during the first 4 h after sedation. The duration of non-REM sleep bouts was not altered. Power in the delta band (0.5-4 Hz) during non-REM sleep was diminished during the first 2 h only. Movements were reduced during the first hour after emergence from sedation only. In summary, no EEG or behavioral evidence of sleep deprivation was observed on emergence from sedation. These results imply that sedation is associated with a restorative process reversing the natural accumulation of sleep need that occurs during wakefulness. IMPLICATIONS: Prolonged sedation in the Intensive Care Unit may alter the restorative effects of naturally occurring sleep. We sedated rats during their sleep phase to determine whether sedation interferes with sleep. Upon emergence, no evidence of sleep deprivation was observed. Sedation may thus be associated with a restorative effect similar to sleep.     

Programación errónea de una bomba de TCI. Caso SENSAR del trimestre

We report the case of a patient who underwent surgical aortic valve replacement. During general anaesthesia maintenance, the patient received a remifentanyl infusion via a target controlled infusion (TCI) system. The infusion pump that was prepared to deliver the infusion showed malfunction at the beginning of the surgery, so it was quickly replaced with a second pump. After a few minutes into the surgery, the patient presented with hypotension refractory to treatment. The remifentanyl syringe also emptied faster than expected. On reviewing the TCI pump, it was found that it was erroneously programmed for propofol instead of remifentanyl, thus the patient had received a very high dose of remifentanyl that was probably the cause of the haemodynamic disturbances. The incident was an error in equipment use, facilitated by hurry, lack of checking of the equipment prior to its use, and the complex and unclear design of the devices’ screens. After analysis of this incident, all TCI pumps were reviewed, and all the programs for infrequently used drugs were deleted. Furthermore, 2 pumps were selected for exclusive use in the cardiac surgery theatre, one with propofol-only programming, and the other with remifentanyl-only programming, both clearly marked and situated in fixed places in that theatre.     

A combined technique utilising regional anaesthesia and target-controlled sedation in a patient with myotonic dystrophy

Myotonic dystrophy presents several problems to the anaesthetist. We describe what we believe to be the first report of target-controlled sedation combined with regional anaesthesia in a patient with myotonic dystrophy. Precise control of propofol levels and titration to patient satisfaction avoided the problem of delayed recovery which has been described with propofol anaesthesia.     

Safety and performance of TCI pumps in a magnetic resonance imaging environment

Target controlled infusion (TCI) devices can be associated with significant safety concerns when used during magnetic resonance imaging (MRI). We tested the safety and compatibility of newer TCI systems in a 3‐Tesla MRI environment. Two Asena PK and two Agilia TCI pumps were used to administer TCI propofol (at target blood concentrations of 0.5 and 6.0 μg.ml^?1) using the Marsh model under magnetic fields of up to 50 G with a T2‐weighted sequence. We assessed the devices for projectile risk, accuracy of drug delivery, alarm function and effects on MR image quality. Both devices did not demonstrate any significant deflection at the tested field strengths, and performed within acceptable limits (cumulative error in total delivered volume < 3%; maximum 10‐min interval error < 10%). The Asena pump caused minor artefacts on MR images. The TCI pumps tested perform well and safely implement pharmacokinetic software in a high magnetic field.     

Hypoglycaemia secondary to labetalol infusion

A 42-year-old multigravida with severe pre-eclampsia had an emergency caesarean section under spinal anaesthesia. Peri-operatively, her arterial pressure was controlled with oral methyldopa and an intravenous infusion of labetalol. Postoperatively, in the Intensive Care Unit, she had recurrent episodes of hypoglycaemia which required treatment with intravenous glucose. These episodes resolved when the labetalol infusion was stopped. Clinicians should be aware of the potential of labetalol to cause hypoglycaemia.     

Structured sedation programme for magnetic resonance imaging examination in children

One thousand, eight hundred and fifty-seven patients underwent magnetic resonance imaging following the establishment of a structured sedation programme. Forty-eight of these patients came from the intensive care unit with a secure airway and were therefore excluded from any further analysis. Oral sedation was to be given to children aged 5 years and below. For children >/= 6 years old, oral sedation could be given only if their level of co-operation was judged to be inadequate by the referring physician. Oral sedation consisted of chloral hydrate 90 mg x kg-1 (maximum 2.0 g) orally with or without rectal paraldehyde 0.3 ml x kg-1. All magnetic resonance imaging requests for children who failed oral sedation as well as those referred for general anaesthesia from the outset were reviewed by a consultant anaesthetist who then allocated patients to undergo the procedure with either general anaesthesia or intravenous sedation. Scans requiring intravenous sedation or general anaesthesia were performed in the presence of a consultant anaesthetist. Intravenous sedation consisted of either a propofol 0.5 mg x kg-1 bolus followed by an infusion (maximum 3 mg x kg-1 x h-1) or midazolam 0.2-0.5 mg x kg-1 boluses. General anaesthesia was given using spontaneous ventilation with a mixture of 66% nitrous oxide in oxygen and isoflurane following either inhalation (sevoflurane) or intravenous (propofol) induction. One thousand and thirty-nine (57.4%) of the scans were done without sedation whereas 93 scans were performed during the consultant anaesthetist supervised sessions. Oral sedation failed in 50 out of 727 patients (6.9%). Eighty-seven per cent of children aged 5 years and below needed sedation compared with 4.5% of those aged over 10 years. Two patients who had only received chloral hydrate developed significant respiratory depression. This structured sedation programme has provided a safe, effective and efficient use of limited resources.     

Electroencephalograph variables, drug concentrations and sedation scores in children emerging from propofol infusion anaesthesia

BACKGROUND: Inadequate sedation or oversedation are common problems in Paediatric Intensive Care because of wide variations in drug response and the lack of objective tests for sedative depth. We undertook a pilot study to try to identify correlates of propofol drug concentration, electroencephalographic (EEG) variables and observed behaviour during a stepwise reduction in propofol infusion after paediatric cardiac surgery. METHODS: This was a prospective pilot study with 10 children (5 months to 8 years) emerging from propofol anaesthesia following cardiac surgery with cardiopulmonary bypass (CPB). Patients underwent a stepped wake-up from propofol anaesthesia during which the propofol infusion rate was decreased from 4 mg.kg(-1).h(-1) in 1 mg.kg(-1).h(-1) steps at 30 min intervals. EEG variables, propofol blood concentrations and clinical sedation scores (COMFORT scale) were recorded during the stepped wakeup. Analgesia was maintained with a standardized continuous infusion of fentanyl. RESULTS: : Mean (SD) whole blood propofol concentrations at arousal varied considerably [973 ng.ml(-1) (SD 523 ng.ml(-1))]. The summed ratio (SR) of high frequency to low frequency bands correlated with both propofol infusion rate (R2 value=0.47) and propofol blood concentrations (R2 value=0.64). The mean SR in deeply sedated patients was significantly different from that in the 5 min prior to wakening (6.84 vs 1.55, P=0.00002). There was no relationship between COMFORT scores and SR. CONCLUSIONS: In this group of patients receiving opioid analgesia and relatively high doses of propofol, sedation scores were unhelpful in predicting arousal. The SR correlated with propofol blood concentrations and clinical arousal and may have potential as a predictive tool for arousal in children.