Infusion Scheme Research Articles

A loading model for ritodrine administration in preterm labour

To develop a ritodrine infusion scheme for preterm labour that avoids plasma levels above those needed for tocolysis, requires only one rate adjustment, and is easy to apply in practice. Prospective study of tocolytic effect and plasma ritodrine concentrations during application of the infusion scheme. High risk labour ward. Consecutive series of 31 women in labour at less than 36 weeks' gestation. Loading dose ritodrine infusion followed, as soon as tocolysis is reached, by a decrease in the infusion rate calculated on the basis of the interval between start of treatment and tocolysis. Overall, steady state ritodrine levels were nearly identical to those at the time of tocolysis and correlated well with levels anticipated on the basis of our calculation (n = 30; r = 0.91; P < 0.001). Adjustments during steady state were made in 12 women (40%), but in only two of them within 12 h after tocolysis had been reached. Delivery was postponed for more than 48 h in 29 women (93.5%) and beyond 37 weeks' gestation in 19 (61.3%). The loading model is easy to apply, avoids relative overdoses, requires few adjustments, is well tolerated, uses smaller quantities of ritodrine, and results in lower plasma ritodrine concentrations than the conventional infusion scheme.

Application of Neural Networks to Pharmacodynamics

Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems. A synopsis is presented of the operational characteristics, structures, and applications of NN. The NN technology has primarily been aimed at recognition science (e.g., handwriting, voice, signal, picture, image, pattern, etc.). It is pointed out that NN may also be particularly suitable to deal with pharmacokinetic (PK) and pharmacodynamic (PD) systems, especially in cases such as multivariate PK/PD population kinetics when the systems are so complex that modeling by a conventional structured model building technique is very troublesome. The main practical advantage of NN is the intrinsic ability to closely emulate virtually any multivariate system, including nonlinear systems, independently of structural/physiologic relevance. Thus, NN are most suitable to model the behavior of complex kinetic systems and unsuitable to model the structure. In a practical sense, this structure limitation may be inconsequential because NN in its multivariate formulation may consider any physiologic, clinical, or population variable that may influence the kinetic behavior. The application of NN in PD is demonstrated in terms of the ability of an NN to predict, by extrapolation, the central nervous system (CNS) activity of alfentanil. The drug was infused by a complex computer-controlled infusion scheme over 180min with simultaneous recording of the CNS effect quantified by a fast Fourier transform power spectrum analysis. The NN was trained to recognize (emulate) the drug input–drug effect behavior of the PD system with the input–effect data for the 180min as a training set. The trained NN was then used to predict, by extrapolation, the CNS effect in the subsequent 120-min period that contained a complex infusion scheme to provide an extra challenge in testing how well the trained NN could predict the effect. The relative prediction performance of the NN was 66% (SD = 32, n = 6), which indicates an excellent prediction considering the intrinsic high degree of fluctuations in the effect variable. The NN was best in predicting the high intensity effects and also learned to recognize an overshoot phenomenon indicative of development of short-term tolerance.

Fentanyl Plasma Concentrations Maintained by a Simple Infusion Scheme in Patients Undergoing Cardiac Surgery

The ability of a simple infusion scheme for fentanyl to achieve and maintain one of two target concentrations of fentanyl in plasma was studied in 17 patients having cardiac surgery that required the use of moderate hypothermic cardiopulmonary bypass (CPB). All patients received preanesthetic medication including morphine, a benzodiazepine, and/or scopolamine. Anesthesia was induced and maintained by one of two fentanyl infusion regimens: HIGH-FEN (n = 6), a priming infusion of 2.4 micrograms.kg-1 x min-1 for 20 min in combination with a continuous infusion of 0.3 microgram.kg-1.min-1 for the duration of the operation to produce a plasma fentanyl concentration of 20-25 ng/mL; or LOW-FEN (n = 11), priming and maintenance infusions of 2.4 and 0.15 micrograms.kg-1 x min-1 designed to produce a fentanyl concentration of 12-15 ng/mL of plasma. The six patients receiving HIGH-FEN had plasma fentanyl concentrations maintained between 20 and 27 ng/mL and none required anesthetic supplementation before CPB; one patient required a single dose of thiopental 50 mg after the termination of CPB. The total fentanyl dose for the operation (3.2 +/- 0.1 h) averaged 107 +/- 2 micrograms/kg (range 100.5-115.5 micrograms/kg). The 11 patients receiving LOW-FEN had a plasma fentanyl concentration maintained below 20 ng/mL (range 13-17 ng/mL). Eight patients before and 10 patients after CPB required anesthetic supplementation for adverse hemodynamic or somatic responses. For comparison purposes, another eight patients received a single 75 micrograms/kg dose of fentanyl during 20 min for induction of anesthesia, and 7 of the 8 required supplemental anesthetic agents before and after CPB.(ABSTRACT TRUNCATED AT 250 WORDS)

A System Approach to Pharmacodynamics. Input-Effect Control System Analysis of Central Nervous System Effect of Alfentanil

Virtually all biological variables, including those affected by drugs, are subject to adaptive self regulation. In the description of the pharmacodynamics (PD) of drugs, it may be necessary to consider the endogenous control system (ECS) as an integral part of the PD. A PDECS model based on system analysis principles is presented and tested on PD data for alfentanil considering the central nervous system activity quantified by a power spectrum analysis of the electroencephalogram. The model was tested in terms of a proposed relative prediction performance criterion that measures the accuracy of future predictions relative to how well the model describes (fits) the past effect data. A mean value of 80% (standard deviation, 28) for relative prediction performance indicates that the model performs well when challenged by the complex multiple infusion scheme used in the test. The overshoot phenomenon observed in the data is considered by the PDECS model as a ECS-based tolerance phenomenon. The proposed development of tolerance is modeled as a variable gain in the ECS processing that influences the effect. Although the development and loss of tolerance is determined by a single rate constant in the tolerance model, the rates of increase and decrease of tolerance may be substantially different. Contrary to other PD tolerance models, the proposed PDECS approach models the tolerance in terms of an effect deviation from an ECS set point. The intrinsic (no tolerance) effect of the drug is isolated in terms of an open loop (no feedback) effect.

Evaluation of sufentanil anesthesia obtained by a computer-controlled infusion for cardiac surgery.

To determine the "therapeutic window" for sufentanil in cardiac surgery, nine hemodynamically stable, lightly premedicated patients were anesthetized with sufentanil to undergo coronary artery bypass grafting. Sufentanil was administered by a computer-controlled infusion pump programmed with an infusion scheme based on average sufentanil pharmacokinetics. The presence of somatic or hemodynamic responses to tracheal intubation, skin incision, sternotomy, and during electrocauterization, to isolate the internal mammary artery were correlated with plasma concentrations of sufentanil. The concentration versus response/no response relationships were analyzed by application of the logistic (Hill) equation. The CP50 of sufentanil to suppress responses to intubation, incision, and sternotomy was 7.1 ng/mL and for mediastinal dissection it was 12.7 ng/mL. Interpatient variability was as much as that reported previously for other opioids in other types of surgical patients. The computer-controlled infusion scheme consistently produced sufentanil plasma concentrations in excess of the target concentrations, but there was a strong correlation between target and actual sufentanil concentrations (r = 0.88, P < 0.05).

A technique for approximately maintaining constant plasma levels of intravenous drugs.

There is increasing interest among anesthesiologists in the use of continuous infusion of intravenous drugs. The therapeutic effect of most drugs is a function of the concentration at the site of drug effect, which in turn is determined by the plasma concentration. Constant plasma concentrations can be maintained by computer-controlled infusion pumps. However, such equipment is not yet widely available and will be expensive. A technique is presented to enable the anesthesiologist to maintain approximately a desired plasma concentration after an arbitrary bolus dose by using a series of infusions with rates decreasing in a stepwise fashion. The algorithm is based on approximating the exact infusion needed to maintain the target plasma concentration by producing this concentration at discrete, specific times. Equations are derived for calculating the sequential rates of the infusion scheme. The equations assume linear pharmacokinetics, and the starting point for derivation of the equations is the assumption that the plasma concentration is given by the convolution of the drug infusion and the unit dose-response function. The accuracy of the technique was assessed by simulating the infusion of fentanyl and midazolam. By using an infusion scheme of three steps, the error was no greater than 38% for fentanyl and no greater than 10% for midazolam. Other than the assumption of linear kinetics, the algorithm is independent of pharmacokinetic models. Implementation does not require computer-based numerical analysis.

PROPOFOL AND ALFENTANIL IN CHILDREN: INFUSION TECHNIQUE AND DOSE REQUIREMENT FOR TOTAL I.V. ANAESTHESIA

We estimated the dose of propofol (initial dose followed by a stepped infusion) when given with two different infusion rates of alfentanil for total i.v. anaesthesia in 59 children aged 3-12 yr. Patients in series 1 (four groups) received an alfentanil loading dose of 85 micrograms kg-1 and an infusion of 65 micrograms kg-1 h-1. Patients in series 2 (groups 5 and 6) received an alfentanil loading dose of 65 micrograms kg-1 and infusion of 50 micrograms kg-1 h-1. Parents gave their informed consent. Premedication comprised temazepam 0.3 mg kg-1. Glycopyrronium 5 micrograms kg-1 was administered and anaesthesia induced and maintained with alfentanil (loading dose and infusion) followed by propofol (loading dose and three-stage manual infusion scheme). Suxamethonium 1 mg kg-1 was used to facilitate tracheal intubation and the lungs were ventilated artificially to normocapnia with 30% oxygen in air. Probit analysis was used to determine the dose requirement of propofol. In series 1, the ED50 was 6.0 mg kg-1 h-1 (95% confidence limits 5.5-6.2 mg kg-1 h-1) and ED95 8.6 (6.8-7.8) mg kg-1 h-1. Corresponding values for series 2 were ED50 7.5 (8.0-9.8) mg kg-1 h-1 and ED95 10.5 (9.6-13.1) mg kg-1 h-1.

Pharmacodynamic System Analysis of the Biophase Level Predictor and the Transduction Function

This work deals with the pharmacodynamic problem of relating a drug effect E(t) to an observable pharmacokinetic (PK) predictor variable r(t), which may be a venous and/or arterial drug level, some other PK variable, or a drug infusion scheme. It is proposed that the relationship between E(t) and r(t) may, in many cases, be appropriately modeled as E(t) = N(F{r(t)}) [for practical analysis reasons, F{r(t)} is denoted the biophase level, c0(t), the operator F{} is accordingly denoted the biophase level predictor (BLP), and N() is denoted the transduction function (TF)]. This work proposes a method for determining the two fundamental components, BLP and TF, that define the E(t)–r(t) relationship. The BLP is determined by a hysteresis minimization (HM) technique with the following features: (1) the method considers errors in both HM variables; (2) the method is suitable for dealing with the important case in which the predictor variable is a drug infusion scheme; (3) the approach is noncompartmental in contrast to the effect‐compartment approaches and it does not require a specific structured modeling of the c0(t)–r(t) relationship when dealing with drugs with linear PKs in a general operational sense; and (4) the method makes use of a dimensionless transformation of the hysteresis variable that eliminates numerical scaling problems so that a complex penalty function optimization approach can be avoided. The TF is determined by a cross validation procedure in conjunction with the BLP determined by HM. The method is demonstrated using pharmacodynamic data for several drugs, considering both concentration‐based and drug input‐based r(t) values. The significance of the information obtained from the determined BLP and TF is discussed, including the concepts of equilibration dynamics and overloading. The limitations and potential problems of the methodology are discussed.

Neural networks in pharmacodynamic modeling. Is current modeling practice of complex kinetic systems at a dead end?

Neural networks (NN) are computational systems implemented in software or hardware that attempt to simulate the neurological processing abilities of biological systems, in particular the brain. Computational NN are classified as parallel distributed processing systems that for many tasks are recognized to have superior processing capability to the classical sequential Von Neuman computer model. NN are recognized mainly in terms of their adaptive learning and self-organization features and their nonlinear processing capability and are considered most suitable to deal with complex multivariate systems that are poorly understood and difficult to model by classical inductive, logically structured modeling techniques. A NN is applied to demonstrate one of the potentially many applications of NN for modeling complex kinetic systems. The NN was used to predict the effect of alfentanil on the heart rate resulting from a complex infusion scheme applied to six rabbits. Drug input-drug effect data resulting from a repeated, triple infusion rate scheme lasting from 30 to 180 min was used to train the NN to recognize and emulate the input-effect behavior of the system. With the NN memory fixed from the 30- to 180-min learning phase the NN was then tested for its ability to predict the effect resulting from a multiple infusion rate scheme applied in the subsequent 180 to 300 min of the experiment. The NN's ability to emulate the system (30-180 min) was excellent and its predictive extrapolation capability (180-300 min) was very good (mean relative prediction accuracy of 78%). The NN was best in predicting the higher intensity effect and was able to identify and predict an overshoot phenomenon likely caused by a withdrawal effect from acute tolerance. Current modeling philosophy and practice is discussed on the basis of the alternative offered by NN in the modeling of complex kinetic systems. In modeling such systems it is questioned whether traditional modeling practice that insists on structure relevance and conceptually pleasing structures has any practical advantages over the empirical NN approach that largely ignores structure relevance but concentrates on the emulation of the behavior of the kinetic system. The traditional searching for appropriate models of complex kinetic systems is a painstakingly slow process. In contrast, the search for empirical models using NN will continue to improve, limited only by technological advances supporting the very promising NN developments.

An approximate model-independent method to maintain constant plasma levels of intravenous drugs

To rapidly achieve and maintain constant plasma concentrations most intravenous drugs must be administered as an initial bolus followed by a combination of exponentially declining plus constant-rate infusions. In the clinical practice of anesthesia and critical care medicine this is often not practical without specialized equipment. In this paper a simpler approach of maintaining approximately constant plasma concentrations is developed using a loading dose with a two-stage infusion scheme (an initial rapid infusion reduced at a given time to a lower rate). Equations are developed for determining the rate of the infusions as well as the duration of the initial infusion by equating moments of the Laplace transform of the approximate infusion to the moments of the Laplace transform of an exact solution. This approach is independent of models and uses as parameters the moments of the curve relating the concentration following a single iv dose of unit magnitude as a function of time. The accuracy of this technique was assessed by computer simulation.

Pharmacokinetic characterization of controlled-release formulations

The development of controlled-release formulations should be based on a clinico-pharmacological rationale such as increased compliance, reduced side effects and improved efficacy. The pharmacokinetic profile of a controlled-release formulation and its dose regimen should be compared under steady-state conditions with that of an immediate-release formulation or that of another controlled-release formulation. Apart from conventional characteristics such as AUC, tmax and Cmax, alternative characteristics are suggested such as residual concentration at the end of the dose interval, peak-through fluctuation in steady state, plateau time, statistical moments, in vivo input functions and intravenous infusion schemes which mimic the concentration/time profile after oral administration of the controlled-release formulation. The pharmacokinetic steady-state profile should be reproduced with and without food, from day to day, and at various dose levels. The in vitro specification should be based on in vivo requirements for "within-product bioequivalence".

Additive benefit of PGI2 and PGE1 (via different mechanisms?) on inhibition of activation of human vascular smooth muscle cells?

It seems likely that the antiplatelet action of antiaggregatory prostaglandins (PGE1, PGI2) is not the pivotal mechanism of action involved in clinical improvement of peripheral vascular disease. Based upon earlier results that both of these agents may have a certain effect on proliferation of vascular smooth muscle cells, we approached that question of an "optimal therapeutic regimen" going one step further. Patients having to undergo amputation were given a randomized "last choice" therapy with either PGI2 (once or twice a day, 6 h, 5 ng/kg/min i.v.), PGE1 (once or twice a day, 1 ng/kg/min i.a.) or a combination of both with a 6 h interval in between for 5 consecutive days. The ones who underwent surgery had a pathomorphological examination of vascular segments removed during amputation. The counting of activated smooth muscle cells indicates a significant drop induced by both of the PG's alone. A second infusion a day with the same compound, however, did not induce a further decrease in the activation state. In contrast administering the complimentary PG caused a comparable, significant decrease (p less than 0.01) in activation of smooth muscle cells in the intima and the media as well. It thus seems, that different mechanisms may be involved inducing additive therapeutic benefit. PGI2 is hypothesised to act predominantly by blocking PDGF-release and interference with PDGF, whereas PGE1 may have a more direct vascular action. From these findings, as well as the beneficial clinical results to be reported elsewhere, a combined therapy by the infusion scheme used may be the optimal one for a PG-therapy at the moment, based upon platelet and smooth muscle cell action.

Induction and maintenance of propofol anaesthesia. A manual infusion scheme.

A simple, manually controlled infusion scheme for continuous administration of propofol was derived by simulation of a computer algorithm designed to achieve a predetermined blood concentration of propofol within 2 minutes and to maintain a constant blood level for the duration of surgery. The manual infusion scheme for a target blood propofol concentration of 3 micrograms/ml, consisted of a loading dose of 1 mg/kg followed immediately by an infusion of 10 mg/kg/hour for 10 minutes, 8 mg/kg/hour for the next 10 minutes and 6 mg/kg/hour thereafter. An overall mean blood propofol concentration of 3.67 micrograms/ml was achieved within 2 minutes and maintained stable for the subsequent 80-90 minutes of surgery. The decrease of systolic and diastolic arterial pressures at induction was much less than that previously described after larger induction doses of propofol and there was a negligible haemodynamic response to laryngoscopy and intubation or to the subsequent surgery. The quality of induction and maintenance of anaesthesia was satisfactory in every patient.

Sufentanil disposition during cardiopulmonary bypass.

In order to investigate the ability of a computer-assisted continuous infusion (CACI) system to maintain constant plasma levels of sufentanil during cardiopulmonary bypass (CPB) using pharmacokinetic data derived from healthy surgical patients to determine the infusion rate, ten patients were anaesthetized with diazepam, enflurane and oxygen until ten minutes prior to the expected time of initiation of CPB. At that point, an infusion of sufentanil, aimed to reach a central compartment concentration of 5 ng.ml-1, was started via CACI. Plasma concentrations of sufentanil, haematocrit, total protein and albumin concentrations, and nasopharyngeal and CPB inflow temperatures were obtained at predetermined intervals before and up to 90 min after the initiation of CPB. Plasma concentrations of sufentanil reached 3.8 +/- 0.4 ng.ml-1 before CPB and approached the 5.0 ng.ml-1 set point (4.7 +/- 0.4 ng.ml-1) over the 90 min of CPB. In conclusion, our results show that it is possible to obtain stable plasma levels of sufentanil on CPB using a pharmacokinetically driven infusion scheme; however, our data suggest that use of such a system may lead to accumulation of drug during CPB.

A loading-dose infusion scheme for intravenous tocolysis with ritodrine: a pilot study

A loading-dose infusion scheme for intravenous ritodrine therapy was tested in twelve patients with preterm labour. We started with a rather high (386 μg/min) infusion rate, but the moment tocolysis was reached this infusion rate was reduced to a level needed to maintain the plasma concentration then found. Plasma samples of ritodrine were taken the moment tocolysis was reached and in the steady state, and compared with each other and with expected and calculated plasma concentrations. In the dynamic loading phase we found a half-life for ritodrine of 1 h. This half-life of 1 h can be explained by cumulation of ritodrine in the central compartment and is therefore called cumulation t 1 2 . In developing an infusion scheme with a loading dose for ritodrine, this cumulation t 1 2 of 1 h should be taken into account.

A new infusion scheme for intravenous tocolysis with ritodrine based on the pharmacokinetic aspects of the drug

A new infusion scheme for intravenous tocolysis with ritodrine based on the pharmacokinetic aspects of the drug

Pharmacokinetics as applied to total intravenous anaesthesia. Practical implications.

In six patients undergoing gynaecological surgery computer assisted total intravenous anaesthesia (CATIA) was performed using etomidate and alfentanil. Constant plasma levels of etomidate (0.3 microgram/ml) from the very beginning onwards were achieved using the so called B.E.T. infusion scheme. Alfentanil plasma concentrations of 0.45 microgram/ml were maintained by the same infusion scheme beginning with skin incision until 20 minutes prior to the end of surgery. The proposed concept of CATIA provided an adequate analgesic and hypnotic effect during anaesthesia for abdominal surgery with a recovery period of short duration.

Rapid achievement of a serum concentration plateau of digoxin through controlled infusion.

Using a volume-controlled infusion pump, a mean serum plateau level of digoxin of 4-5 ng/ml was rapidly achieved and maintained in 6 healthy volunteers. The infusion scheme was calculated on the basis of data published on the pharmacokinetics and pharmacodynamics of digoxin following bolus intravenous injection. The magnitude of the response (change in electromechanical systole) at the end of the plateau phase was comparable to that observed with the concentration in the therapeutic range at steady state.

Verapamil disposition kinetics in chronic atrial fibrillation.

Verapamil disposition was studied in 12 patients with chronic and fibrillation. After an intravenous bolus of 15 mg plasma concentration was determined and the data fit in a three-compartment model. Model independent parameters were calculated and values for half-life (t 1/2), clearance, and steady-state distribution volume were 6.3 +/- 4 hr, 13.3 +/- 7.7 ml/min/kg, and 4.3 +/- 1.9 l/kg. The model was used to design a multistep infusion scheme, which was employed successfully to achieve predetermined plasma concentrations. Following single oral doses of 120 mg, plasma levels of verapamil and norverapamil were determined. The elimination t 1/2 for verapamil and norverapamil were 8.3 +/- 6.1 and 10.5 +/- 5.6 hr, respectively. The bioavailability of oral verapamil was 35 +/- 16%. During long-term oral therapy the mean verapamil plasma concentration was twice the value predicted from the single-dose studies. This suggests that verapamil may have reduced clearance during long-term oral use.

INFUSION MODEL FOR FENTANYL BASED ON PHARMACOKINETIC ANALYSIS

The calculation of pharmacokinetic parameters after a bolus injection of fentanyl allowed an i.v. infusion scheme which guarantees analgesia for the entire duration of surgery, with the advantage of steady plasma concentration and body content. In the initial phase after bolus injection, the serum concentration decreased rapidly for about 10 min, indicating extensive transfer to the peripheral compartment. This was followed by a slower elimination phase with a half-life of about 2 h. The total volume of distribution of 80 litre exceeded the body weight only slightly. The total plasma clearance was 500ml min-1. In developing a model for total i.v. anaesthesia we considered two different consecutive infusion rates. The pharmacokinetic model proved to be valid for all patients. The plasma concentrations duration anaesthesia coincided well with the predicted steady state plasma concentrations and provided continuous analgesia during operation.