Effect site concentrations of remifentanil and pupil response to noxious stimulation.

BACKGROUND: Opioid drugs block reflex pupillary dilatation in response to noxious stimulation. The relationship between the target effect site concentration (Ce(T)) of remifentanil and the pupil diameter and reactivity in response to a standard noxious stimulus were evaluated. METHODS: Anaesthesia was induced with propofol TCI to obtain loss of consciousness (LOC) in 12 ASA I/II patients. Thereafter, remifentanil Ce(T) was titrated by increments of 1 up to 5 ng ml(-1). In the awake state, at LOC and at each plateau level of remifentanil Ce(T), arterial pressure, heart rate, and BIS (A2000) were recorded. Pupil size and dilatation after a 100 Hz tetanic stimulation (T100) were measured at LOC and at each plateau level of remifentanil Ce(T). RESULTS: LOC was observed at a mean propofol Ce(T) of 3.53 (SD 0.43) microg ml(-1). Arterial pressure and heart rate decreased progressively from LOC to 5 ng ml(-1) remifentanil Ce(T) without any statistical difference between each incremental dose of remifentanil. Mean BIS values decreased from 96 (2) in the awake state, to 46 (12) at LOC (P<0.05) and then remained unchanged at all remifentanil Ce(T). Pupil dilatation in response to 100 Hz tetanic stimulation decreased progressively from 1.55 (0.72) to 0.01 (0.03) mm and was more sensitive than pupil diameter measured before and after 100 Hz tetanus. An inverse correlation between pupil dilatation in response to 100 Hz tetanus and an increase in remifentanil Ce(T) from 0 to 5 ng ml(-1) was found (R(2)=0.68). CONCLUSIONS: During propofol TCI in healthy patients, the decrease in pupil response to a painful stimulus is a better measurement of the progressive increase of remifentanil Ce(T) up to 5 ng ml(-1) than haemodynamic or BIS measurements.

Target-controlled infusion of propofol induction with or without plasma concentration constraint in high-risk adult patients undergoing cardiac surgery.

BACKGROUND: Calculated plasma (Cp) and calculated effect site concentrations (Ce) of propofol associated with loss of consciousness (LOC) have been studied in young healthy patients. The aim of the study was to evaluate the calculated propofol concentrations required to induce LOC in ASA III adult patients undergoing cardiac surgery using a smooth target controlled infusion of propofol. METHODS: After informed consent, 44 patients were premedicated with 0.5 mg alprazolam orally. Propofol TCI using the pharmacokinetic set of Marsh et al. incorporated in the Diprifusor (ThalfKeo of 2.6 min) was used. Propofol Ce was progressively increased by 0.5 micro g/ml until LOC was obtained. The constraint on the maximum gradient between Cp and Ce was either 1 micro g/ml in group 1 or not limited in group 2. Hemodynamic variations were assessed. RESULTS: Mean preoperative left ventricular ejection fractions were 44 +/- 15.4% and 56 +/- 11.4% in groups 1 and 2, respectively (P < 0.01). At LOC, mean Cp was 1.9 micro g/ml in both groups but mean Ce was 1.08 +/- 0.31 and 1.43 +/- 0.42 micro g/ml in groups 1 and 2, respectively (P < 0.01). The mean induction time was 12.8 +/- 7.1 min in group 1 and 8.5 +/- 2.7 min in group 2 (P < 0.05). No episode of hypotension has been observed in either group. CONCLUSION: In ASA III patients undergoing cardiac surgery, smooth propofol TCI induction, using the pharmacokinetic set of Marsh et al. incorporated in the Diprifusor, is associated with LOC at a low mean calculated plasma concentration of 1.9 micro g/ml and good hemodynamic stability.

Pharmacokinetic model-driven infusion of sufentanil and midazolam during cardiac surgery: assessment of the prospective predictive accuracy and the quality of anesthesia.

OBJECTIVE: To evaluate the prospective predictive accuracy and the quality of anesthesia of pharmacokinetic model-driven infusion of sufentanil and midazolam designed to establish and maintain a plasma level of drug during cardiac surgery. DESIGN: Prospective analysis. SETTING: Operating room at a university hospital. PARTICIPANTS: Twenty adult patients younger than 75 years old scheduled for valvular or coronary artery bypass graft surgery. INTERVENTIONS: Patients were anesthetized using a variable predicted concentration of sufentanil (1 to 10 ng/mL) combined with a stable predicted concentration of midazolam (100 ng/mL). MEASUREMENTS AND MAIN RESULTS: For each patient, arterial samples were taken before (6 samples), during (2 samples), and after (2 samples) cardiopulmonary bypass (CPB). Plasma sufentanil and midazolam concentrations were measured by specific radioimmunoassay and high-performance liquid chromatography techniques. Predicted sufentanil and midazolam concentrations were derived using the data sets of Gepts et al and Maitre et al. The predictive performance, the percentage prediction error (PE), and the absolute percentage error were calculated for each sample. The bias, inaccuracy, and dispersion were assessed by determining the median of the individual medians of the prediction errors (MDPE), the median of the individual median of the absolute prediction errors (MDAPE), and the 10th and 90th percentiles of PE. For midazolam, the inaccuracy was low (MDAPE < 21%), but CPB was associated with a dilution of the measured concentration associated with a negative bias. For sufentanil, the inaccuracy was also low before CPB (MDAPE = 18%) but increased during and after CPB (MDAPE > 40%). During the whole procedure, the hemodynamic control necessitated only a few interventions. CONCLUSIONS: Pharmacokinetic model-driven infusion of sufentanil and midazolam using the pharmacokinetic sets of Gepts et al and Maitre et al is a safe and accurate anesthetic technique before CPB in adult patients undergoing cardiac surgery when high sufentanil (1 to 10 ng/mL) and low midazolam (100 ng/mL) predicted plasma concentrations are targeted.

Predictive accuracy of target-controlled propofol and sufentanil coinfusion in long-lasting surgery.

BACKGROUND: The predictive accuracy of target concentration infusions of propofol has been documented only for less than 4 h, and no prospective study of sufentanil target controlled infusion is available. The authors investigated the predictive accuracy of pharmacokinetic models for propofol and sufentanil coadministered during long-lasting surgery. METHODS: Ten patients, American Society of Anesthesiologists physical status I and II, were studied during extended cervicofacial surgery. Target controlled infusion of propofol and sufentanil was administered during surgery using decisional algorithms, taking into consideration pain assessment, hemodynamic changes, and peroperative blood losses. Intrasubject data analysis included calculation of performance error, median performance error, median absolute performance error, divergence, and wobble. RESULTS: The range of plasma target concentrations was 2-5 microgram/ml for propofol and 0.2-1 ng/ml for sufentanil. Median performance error was -12.1% for propofol and -10% for sufentanil. The wobble values were 11.6% and 22.3% for propofol and sufentanil, respectively. The pharmacokinetic sets used slightly overpredicted the concentrations, with negative values of divergence of 2.92% and 0.22% units/h for propofol and sufentanil, for a mean infusion period of 762 min. CONCLUSIONS: This prospective study demonstrates the predictive accuracy of the pharmacokinetic model for sufentanil infusion and confirms that for propofol during long-lasting surgery using standardized rules for the management of target controlled infusion and blood loss replacement.

The first object oriented monitor for intravenous anesthesia.

OBJECTIVE: To describe the design and implementation of "INFUSION TOOLBOX," a software tool to control and monitor multiple intravenous drug infusions simultaneously using pharmacokinetic and pharmacodynamic principles. METHODS: INFUSION TOOLBOX has been designed to present a graphical interface. Object Oriented design was used and the software was implemented using Smalltalk, to run on a PC. Basic tools are available to manage patient, drugs, pumps and reports. These tools are the PatientPanel, the DrugPanel, the PumpPanel and the HistoryPanel. The screen is built dynamically. The panels may be collapsed or closed to avoid a crowded display. We also built control panels such as the Target ControlPanel which calculates the best infusion sequence to bring the drug concentration in the plasma compartment to a preset value. Before drug delivery, the user enters the patient's data, selects a drug, enters its dilution factor and chooses a pharmacokinetic model. The calculated plasma concentration is continually displayed and updated. The anesthetist may ask for the history of the delivery to obtain a graphic report or to add events to the logbook. A panel targeting the effect is used when a pharmacodynamic model is known. Data files for drugs, pumps and surgery are upgradable. DISCUSSION: By creating a resizeable ControlPanel we enable the anesthetist to display the information he wishes, when he wishes it. The available panels are diverse enough to meet the anesthetist needs; they may be adapted to the drug used, pumps used and surgery. It is the anesthetist who builds dynamically its different control screens. CONCLUSION: By adopting an evolutionary solution model we have achieved considerable success in building our drug delivery monitor. In addition we have gained valuable insight into the anesthesia information domain that will allow us to further enhance and expand the system.

Integration of a blood pressure controller and an infusion toolbox system using client-server technology.

This paper shortly describes an Infusion Toolbox and a blood pressure (BP) control application. It explains how we applied an agent model and client-server technology to integrate them. We show that by using this framework and object oriented technologies the necessary changes to the existing applications are reduced. Many elements of the tested original systems could be re-used, which enhances safe development.

Effects of target-controlled anesthesia with propofol and sufentanil on the hemodynamic response to Mayfield head holder application.

The effects of target-controlled anesthesia with propofol and sufentanil on the hemodynamic response to Mayfield head holder (MH) application were evaluated in 18 ASA I and II patients undergoing scheduled intracranial surgery. Premedication consisted of hydroxyzine, alprazolam and atropine given orally 1 h before surgery. Anesthesia was provided with propofol and sufentanil using a target-controlled infusion device; constant calculated plasma concentrations of 4 micrograms ml-1 propofol and 0.5 ng ml-1 sufentanil were maintained throughout the study. Muscle relaxation was obtained with atracurium and ventilation was controlled with air/oxygen. The MH was fixed 45 +/- 12 min (mean +/- SD) after induction of anesthesia. Heart rate and systolic, diastolic, and mean non invasive arterial pressure were monitored and recorded 5 min before induction of anesthesia (control), 1 min before MH application (MH-1), at MH application, and 1 and 2 min after MH application. Systolic, diastolic, mean arterial pressure, and heart rate increased significantly during and after MH application when compared with MH-1 values, but remained constantly lower than control. Hemodynamic parameters measured 1 min before MH application were significantly lower than control. The results of the study indicate that target-controlled anesthesia maintained with constant calculated plasma concentrations of 4 micrograms ml-1 propofol and 0.5 ng ml-1 sufentanil prevents the increase in arterial pressure and heart rate beyond control values following MH application but may induce some degree of arterial hypotension in the absence of nociceptive stimulation.

Emergence from target-controlled anesthesia with propofol and sufentanil in patients undergoing intracranial surgery.

The study was designed to characterise the emergence from target-controlled anesthesia assessed by the recovery of spontaneous breathing, eye opening to command, and extubation in 18 adult patients undergoing intracranial surgery. Total intravenous anesthesia was induced and maintained with propofol and sufentanil. Target plasma concentration of propofol ranged between 3.0 and 5.5 micrograms.ml-1 and infusion was stopped after head dressing. The initial target plasma sufentanil concentration of 0.50 ng.ml-1 was decreased to 0.15 ng.ml-1 after craniotomy; sufentanil infusion was discontinued at the dura closure. The time from the end of surgery (head dressing) to recovery of spontaneous breathing was 8.3 +/- 6.5 min, and the time to eye opening and extubation was 14.7 +/- 10.0 min. At the end of surgery, the calculated plasma propofol concentration was 3.42 +/- 0.26 micrograms.ml-1. It significantly decreased to 2.11 +/- 0.51 micrograms.ml-1 at recovery of spontaneous breathing and to 1.81 +/- 0.41 micrograms.ml-1 at eye opening and extubation. The calculated plasma sufentanil concentration was 0.108 +/- 0.019 ng.ml-1 at the end of surgery but did not change significantly between recovery of spontaneous breathing (0.089 +/- 0.013 ng.ml-1), eye opening and extubation (0.087 +/- 0.013 ng.ml-1). The calculated plasma propofol concentrations recorded at emergence were not correlated with patient age, total dose of propofol, and duration of infusion; corresponding calculated sufentanil concentrations were not correlated with age and total dose of sufentanil. An inverse relationship (p < 0.05) was found between the duration of sufentanil infusion and the calculated sufentanil concentrations at emergence. No correlation was observed between calculated concentrations of propofol and sufentanil at emergence.

Predictive accuracy of continuous propofol infusions in neurosurgical patients: comparison of pharmacokinetic models.

The performance of 10 pharmacokinetic models in predicting blood propofol concentrations was evaluated in patients during neurosurgical anesthesia. Eight patients-ASA category I or II, aged 49 +/- 18-years, weighing 71 +/- 20 kg, and scheduled for routine neurosurgery-were anesthetized with propofol and sufentanil using Ohmeda pumps controlled with a personal computer. Sufentanil was administered as a bolus of 0.3 microgram.kg-1, 5 min before induction of anesthesia, and infused at a constant rate of 0.5 microgram.kg-1.h-1 throughout the study. At induction, propofol was administered as a bolus of 1.5 mg.kg-1 followed by a continuous infusion of 6 mg.kg-1.h-1. During surgery, the propofol infusion rate was deliberately increased by 2 mg.kg-1.h-1 every 15 min up to 12 mg.kg-1.h-1. Arterial blood samples were drawn at the end of each infusion step for measurement of propofol concentrations by high-performance liquid chromatography. Measured propofol concentrations were compared with theoretical concentrations derived from 10 published pharmacokinetic models designed in different clinical settings. Each model has been assessed by calculating the median of the performance error, the median of the absolute performance error, and their 10th and 90th percentiles. Models designed for certain categories, such as children, young, or elderly patients who received propofol as a bolus injection, showed a bad predictive accuracy. The models of Gepts et al. (Anesth Analg 1987; 66:1256-1263, Anaesthesia 1988; 43(suppl):8-13), Tackley et al. (Br J Anaesth 1989;62:46-53), and Cockshott (Postgrad Med J 1985;61:55), derived from healthy patients receiving continuous propofol infusions, provided the best agreement between expected and measured propofol concentrations; they showed bias and inaccuracy lower than 17%. In conclusion, the accurate prediction of blood propofol concentrations from different continuous infusion rates in ASA I or II patients requires the selection of appropriate pharmacokinetic models derived from similar categories of patients and using a similar technique of propofol administration. However, in clinical practice, the selection of a specific set among the appropriate models is balanced by the interindividual variability in blood propofol concentrations adjusted to clinical effects.

Management software for a universal device communication controller: application to monitoring and computerized infusions.

We designed a virtual device for a local area network observing, operating and connecting devices to a personal computer. To keep the widest field of application, we proceeded by using abstraction and specification rules of software engineering in the design and implementation of the hardware and software for the Infusion Monitor. We specially built a box of hardware to interface multiple medical instruments with different communication protocols to a PC via a single serial port. We called that box the Universal Device Communication Controller (UDCC). The use of the virtual device driver is illustrated by the Infusion Monitor implemented for the anaesthesia and intensive care workstation.

Safety factors in the remote control of infusion devices.

We have been using computer driven injections in surgery for many years to the benefit of more than thousand patients. Along these years we accumulated extensive experience in remote controlled infusion pumps. Today we have solved many communication problems. Despite the attention and care we brought in our software developments we still meet with some problems.

Predictive accuracy of midazolam in adult patients scheduled for coronary surgery.

STUDY OBJECTIVE: To evaluate the predictive accuracy of midazolam during cardiac anesthesia so as to orient the selection of the most appropriate pharmacokinetic model for use in a computer-assisted continuous-infusion system. DESIGN: Retrospective analysis. SETTING: Operating room at a university hospital. PATIENTS: 66 consecutive middle-aged and elderly coronary patients scheduled for coronary artery bypass graft (CABG) surgery. INTERVENTIONS: Patients were anesthetized using a variable-rate infusion of alfentanil combined with midazolam in an attempt to achieve and maintain target concentrations of 100 ng/ml or 500 ng/ml. MEASUREMENTS AND MAIN RESULTS: A total of 323 arterial blood samples were taken, and serum midazolam concentrations were measured by high-performance liquid chromatography. Predicted midazolam concentrations were calculated using 3 selected data sets. Their bias, inaccuracy, and dispersion were assessed by determining the median performance error, the median absolute performance error (MDAPE), and the 10th and 90th percentiles. Two of the selected data sets of midazolam, with a clearance lower than 5 ml/kg/min, were very accurate (MDAPE less than 20%) in predicting low or high prebypass concentrations of midazolam in adult patients with good left ventricular function. CONCLUSIONS: Two of the 3 pharmacokinetic data sets of midazolam studied may be selected when using a computer-assisted infusion system in adult coronary patients.

Predictive accuracy of alfentanil infusion in coronary artery surgery: a prebypass study in middle-aged and elderly patients.

Twenty-three informed and consenting patients scheduled for CABG were anesthetized using computer-controlled infusions of alfentanil, midazolam, and pancuronium. Thirteen middle-aged patients received a preprogrammed infusion scheme of alfentanil, simulated using the population pharmacokinetic set of Maitre et al (Group M), and 10 elderly patients received a preprogrammed infusion scheme simulated using the model of Helmers et al (Group H). The target alfentanil concentrations in groups M and H for tracheal intubation were: 300-500 ng/mL and for sternotomy: 500-700 ng/mL. Blood alfentanil concentrations were measured at tracheal intubation, skin incision, sternotomy, and aortic cannulation. The bias, inaccuracy, and precision of each pharmacokinetic set were assessed by the median performance error (MDPE), the median absolute performance error (MDAPE), and the 10th and 90th percentiles of the performance errors (P10, P90), respectively. The predictive accuracy of seven other alfentanil pharmacokinetic sets selected from the literature was also evaluated retrospectively. The measured alfentanil concentrations were underpredicted when using all the pharmacokinetic sets, except the set of Scott et al (MDPE: -15.9%). The sets of Maitre et al and Helmers et al were found not to be accurate (MDAPE > 40%) in both groups M and H. The set of Scott et al with the lowest clearance (2.4 mL/kg/min) shows the best accuracy (MDAPE: 19.5%) and precision (P10: -40%, P90: 16%). In conclusion, the set of Scott et al should preferably be selected to predict prebypass alfentanil infusion accurately in either middle aged or elderly patients who have normal myocardial function (LVEF > 50%) and are scheduled for CABG.

Predictive accuracy of continuous alfentanil infusion in volunteers: variability of different pharmacokinetic sets.

To evaluate the variability of the predictive accuracy of alfentanil by using different pharmacokinetic data sets, eight healthy young male adult volunteers were given the same alfentanil infusion for 4 h. Nineteen venous blood samples were taken from each volunteer, and alfentanil concentrations were titrated by radioimmunoassay. For each volunteer, the pharmacokinetic variables of a two-compartment model were calculated, averaged, and considered as a reference set. Based on the infusion profile given to the volunteers, central compartment concentrations were calculated by using the reference set and nine previously published pharmacokinetic sets of alfentanil concentrations in healthy adults. The bias, inaccuracy, and dispersion of each data set were assessed by determining the median performance error, the median absolute performance error (MDAPE) and the 10th and 90th percentiles, respectively. By using the pharmacokinetic variables of the volunteers, the predictive accuracy was excellent (MDAPE, 7.25%). Among the 10 averaged pharmacokinetic sets, there was a significant correlation between their bias and clearance (R2 = 0.996). The reference set had the best predictive accuracy (MDAPE, 23.6%). Five sets from the literature also showed a reliable predictive accuracy but four other sets with a clearance more than 5 mL.kg-1.min-1 and derived from a large bolus injection were inaccurate (MDAPE > 50%) as they underestimated the alfentanil concentrations. We conclude that pharmacokinetic sets derived from large bolus should not be selected to accurately predict alfentanil infusion.

Effect of liposomal content of lipid emulsions on plasma lipid concentrations in low birth weight infants receiving parenteral nutrition.

We studied the effects of phospholipid liposomes present in intravenously administered lipid emulsions on plasma lipid levels in preterm infants given 10% and 20% lipid emulsions. Twenty premature infants (birth weight 1454 +/- 54 gm) on a parenteral nutrition regimen received up to 4 gm triglycerides per kilogram per day in a 20% lipid emulsion for 2 weeks, and then received the 10% emulsion at 2 gm triglycerides per kilogram per day, which delivered the same total phospholipid load but twice the amount of liposomes. Triglyceride, total cholesterol, and phospholipid concentrations increased significantly when the infants were given 2 gm triglycerides per kilogram per day in the 10% emulsion rather than 4 gm/kg per day in the 20% emulsion (44 +/- 4 to 57 +/- 5 mg/dl, 134 +/- 6 to 162 +/- 9 mg/dl, and 204 +/- 8 to 251 +/- 10 mg/dl, respectively). Lipoprotein analysis indicated the presence of lipoprotein X-like particles in the low-density lipoprotein fraction and an increase of the intermediate-density lipoprotein fraction in infants who received the 10% emulsion. The presence of excess phospholipids in the 10% emulsion was associated with greater plasma lipid alterations. Therefore the use of 20% rather than 10% emulsion allows for more efficient triglyceride clearance, even at a higher triglyceride intake. Administration of emulsions that are relatively poor in phospholipid liposomes may allow delivery of > 2 gm triglycerides per kilogram per day to low birth weight infants.

CINA: a software to Compose INfusion sheets for i.v. Anesthetic drugs.

CINA is a software which uses LOTUS 1-2-3 commands and macros and it runs on an IBM PC. It contains an extensive database of three sections. Section 1 includes a list of several models of commercialized infusion devices. Section 2 presents the available IV packagings for a list of IV drugs. Section 3 contains the record of IV standard infusion regimens for each drug. Any other new infusion device, drug, or standard infusion regimen can be added or modified. The software verifies the compatibility of the prescribed infusion device according to the available drug packaging contained in the database. Moreover, it converts the infusion steps into the flow-rate units of the selected infusion device according to the patient's weight and the chosen drug concentration. Finally, the software allows the storage of all the information on a disk file or outputting on a printer.

Rat PHI, PHI-GLY and PHV (1-42) stimulate adenylate cyclase in six rat tissue and cell membranes.

PHI and the two C-terminally extended forms PHI-GLY and PHV(1-42) coexist in rat tissues. We compared the relative potency and efficacy of these three PHI forms and of VIP to stimulate adenylate cyclase activity and, when feasible, to occupy VIP receptors in six rat tissue and cell membranes. With the exception of lung membranes, all three PHI forms were markedly less potent than VIP but all were systematically as efficacious. PHI-GLY and PHV(1-42) were never more potent than PHI itself and their relative potencies revealed four spectra, depending on the membrane preparation tested: 1) PHI = PHI-GLY = PHV(1-42) in hepatic, pulmonary and pancreatic membranes; 2) PHI greater than PHV(1-42) = PHI-GLY in membranes from circulating lymphocytes; 3) PHI = PHV(1-42) greater than PHI-GLY in membranes from the thymocyte cell line 51E; and 4) PHI greater than PHI-GLY = PHV(1-42) in anterior pituitary membranes. These results indicate that the two naturally observed C-terminal extensions of rat PHI variously affected peptide potency on 6 rat membrane preparations.

[Osteosynthesis of lesions of the proximal femur using dynamic screw plates. Multicenter study: 1871 cases]. / Ostéosynthèse des lésions proximales du fémur par vis-plaque dynamisée. Etude multicentrique: 1871 cas.

A series of 1871 lesions of the upper end of the femur were treated in 32 hospitals in Belgium using a dynamic hip screw. Unstable pertrochanteric fractures were present in 34.4%. The remainder were intracapsular, extracapsular and subtrochanteric fractures, or tumour deposits. The patients were elderly, infirm and usually female. A fortnight after operation 89% were sitting, 64% could walk with a frame and 31% with crutches. Failure of fixation occurred in 3.6% of cases overall, with 6.6% in unstable fractures. Perioperative screw compression did not appear helpful, since most fractures settled after operation.

The pharmacokinetics of intravenous anaesthetic drugs given by infusion: SPINA--a software program.

SPINA is a program developed with LOTUS 1-2-3 that simulates the pharmacokinetics of an infusion of intravenous anaesthetic drugs. SPINA incorporates a database which contains records of multiple-compartment pharmacokinetic models. The models have been obtained from the literature. They are directed towards those intravenous drugs that are used frequently during daily clinical anaesthetic practice. The models are classified using keywords for selection criteria (age, biometry, pathology and indication). To perform the pharmacokinetic simulation, the anaesthetist has to choose a pharmacokinetic model in which the program determines the turn-over rates, and displays a sequence of infusion steps. On request, SPINA provides the graphs for the theoretical drug distribution and for the infusion rate required to maintain the target concentration. SPINA therefore allows one to simulate the administration of intravenous anaesthetic drugs and to optimize their delivery.