Computer-controlled Infusion Pump Research Articles

Pharmacokinetics and pharmacodynamics of dexmedetomidine-induced vasoconstriction in healthy volunteers.

Alpha-2 agonists are direct peripheral vasoconstrictors, which achieve these effects by activating vascular smooth muscle alpha-2 adrenoceptors. The impact of this response during dexmedetomidine infusion remains poorly quantified. Our goal was to investigate the pharmacokinetic (PK) and pharmacodynamic (PD, vasoconstriction) effects of a computer-controlled dexmedetomidine infusion in healthy volunteers. After local ethics committee approval, we studied 10 healthy volunteers. To study the peripheral vasoconstrictive effect of dexmedetomidine without concurrent sympatholytic effects, sympathetic fibres were blocked with a brachial plexus block. Volunteers received a dexmedetomidine target-controlled infusion for 15min, to a target concentration of 0.3ng ml-1 . Arterial blood samples were collected during and for 60min after dexmedetomidine infusion for PK analysis. Peripheral vasoconstriction (PD) was assessed using finger photoelectric plethysmography. PK/PD analysis was carried out using nonlinear mixed-effect models. We found that the computer-controlled infusion pump delivered mean concentrations greater than 0.3ng ml-1 over the 15-min infusion duration. The peripheral vasoconstrictive effect correlated with dexmedetomidine plasma concentrations during and after the infusion. A three-compartment model provided a better fit to the data than a two-compartment model. We found that dexmedetomidine-induced vasoconstriction is concentration dependent over time. Dexmedetomidine PK were best estimated by a three-compartment model with allometric scaling. Our results may contribute to future modelling of dexmedetomidine-induced haemodynamic effects.

In vitro delivery accuracy of Computer Controlled Infusion Pump (CCIP) software linked to an Alaris® GH syringe pump for propofol target-controlled infusion in dogs

We calculated the in vitro delivery accuracy of a computer software (CCIP) linked to an Alaris® GH syringe pump to deliver propofol by target-controlled infusion in dogs. This was studied by simulating an infusion of propofol at two target concentrations (2 and 6 g ml-1) in a 6 and 22 kg dog, each for 10, 60 and 240 minutes in a crossover design. Each infusion was replicated three times (36 infusions). The total volume of propofol delivered at the end of each infusion was measured using a high precision scales and compared with the volume predicted by the software and that displayed by the syringe driver. Median prediction error (MDPE), median absolute performance error (MDAPE), divergence and intraclass correlation coefficient (ICC) were calculated as indexes of bias, accuracy, time-related changes in accuracy and reliability, respectively. The ranges of MDPA and MDAPE for all the infusions were -2.08 – 4.28% and 1.85 – 4.28%. respectively and the median (95% CI) was -1.75% (-1.84 – 1.02%) and 2.18% (2.23 – 4.13%), respectively. The divergence was 0.010 ± 0.004% h-1. The ICC was 1.00% (0.99-1.00%; P<0.0001). The volume of propofol infused by the CCIP linked to an Alaris® GH syringe pump is accurate and has a small tendency to overestimate the real volume delivered. The prediction error fell in the ± 5% range of delivery performance considered clinically acceptable. The performance of the CCIP ameliorates with time and the error will decrease for long infusions, reducing the risk of administering an excessive dose of propofol and increasing the safety of CCIP. The CCIP had also an excellent index of reliability for all the targets, animal body weight and length of infusions tested. In conclusion, CCIP linked to an Alaris® GH syringe pump is precise, reliable and suitable for clinical practice. .

Effect of Intravenous Alfentanil on Nonpainful Thermally Induced Hyperalgesia in Healthy Volunteers.

Experimental interventions that activate specific components of clinical pain are necessary for characterization of underlying mechanisms and pharmacology. Cutaneous hyperalgesia has been described that uses nonpainful heat to induce secondary hyperalgesia. This study evaluated the effect of intravenous alfentanil on experimental cutaneous hyperalgesia created using this method. Eighteen subjects participated in a randomized, double-blinded, placebo-controlled crossover study consisting of 2 sessions, 1 with alfentanil and 1 with placebo. Using a computer-controlled infusion pump, alfentanil or matching placebo was maintained at a constant plasma level of 75 ng/mL for 1 hour followed by the application of a 40°C heat stimulus to the right thenar eminence for 15 minutes. The temperature was raised by 1°C every 15 minutes until the subject reported pain or 45°C was reached. After the end point was reached, the temperature was maintained, and repeat testing was performed. The nonpainful heat created an area of secondary cutaneous hyperalgesia and significant decrease in mechanical pain threshold on heat-treated right vs untreated left during placebo administration. Alfentanil prevented the hypersensitivity when compared to placebo (P < .05) but failed to reduce the area of secondary hyperalgesia created by nonpainful heat when compared to placebo (P = .06). Neither alfentanil nor the heat lamp treatment showed any significant effect on other neurosensory measures. This study demonstrated a reliable production of cutaneous hyperalgesia using a nonpainful stimulus that is affected by the systemic delivery of alfentanil. This model for human cutaneous experimental pain may be a useful method for scientific characterization of analgesics.

Evaluation and optimisation of propofol pharmacokinetic parameters in cats for target-controlled infusion

The aim of this study was to develop and evaluate a pharmacokinetic model-driven infusion of propofol in premedicated cats. In a first step, propofol (10 mg/kg) was administered intravenously over...

Effects of mild to moderate sedation on saccadic eye movements

Sedatives alter the metrics of saccadic eye movements. If these effects are nonspecific consequences of sedation, like drowsiness and loss of attention to the task, or differ between sedatives is still unresolved. A placebo-controlled multi-step infusion of one of three sedatives, propofol or midazolam, both GABA-A agonists, or dexmedetedomidine, an α2-adrenergic agonist, was adopted to compare the effects of these three drugs in exactly the same experimental conditions. 60 healthy human volunteers, randomly divided in 4 groups, participated in the study. Each infusion step, delivered by a computer-controlled infusion pump, lasted 20min. During the last 10min of each step, the subject executed a saccadic task. Target concentration was doubled at each step. This block was repeated until the subject was too sedated to continue or for a maximum of 6 blocks. Subjects were unaware which infusion they were receiving. A video eye tracker was used to record the movements of the right eye. Saccadic parameters were modeled as a function of block number, estimated sedative plasma concentration, and subjective evaluation of sedation. Propofol and midazolam had strong effects on the dynamics and latency of the saccades. Midazolam, and to a less extent, propofol, caused saccades to become increasingly hypometric. Dexmedetedomidine had less impact on saccadic metrics and presented no changes in saccadic gain. Suppression of the sympathetic system associated with dexmedetomidine has different effects on eye movements from the increased activity of the inhibitory GABA-A receptors by propofol and midazolam even when the subjects reported similar sedation level.

Airway management of an ankylosing spondylitis patient with severe temporomandibular joint ankylosis and impossible mouth opening

Airway management of an ankylosing spondylitis patient with severe temporomandibular joint ankylosis and impossible mouth opening

Dexmedetomidine reduces emergence agitation after tonsillectomy in children by sevoflurane anesthesia: A case-control study

ObjectiveTo evaluate the efficacy and safety of dexmedetomidine for emergence agitation after tonsillectomy in children. Methods120 ASA physical status I and II children, aged 5–14 years, undergoing anesthesia for tonsillectomy, were randomly divided into 3 groups: Placebo group, the low dexmedetomidine concentration group and the high dexmedetomidine concentration group. Before the entrance of the operating room (OR), all of the children received intravenous injection 40μgkg−1 midazolam to reduce anxiety at first, and then dexmedetomidine was given intravenously at an initial loading dose of 0.5μgkg−1 or 1μg/kg over a 10-min period via a computer controlled infusion pump followed by a maintenance infusion of 0.2μgkg−1h−1 or 0.4μgkg−1h−1over the surgery. The heart rate, SpO2 and mean arterial blood pressure were recorded for each patient in both operation room and PACU. The designated time points: at the start of the anesthetic induction, at the discontinuation of inhalational agents, at first opening of eyes, at time to remove endotracheal tube were recorded. After patient arrival at the PACU, VAS score, RSS, the occurrence of emergence agitation were recorded every 5min for the first 30min and every 10min for the next 30min after endotracheal tube was removed. ResultsThere was significant difference in the incidence of emergence agitation between Placebo group and the high concentration group when endotracheal tube was removed (P<0.05). There was significant difference in the VAS pain scores and in the RSS between three groups at the time of extubation, as well as 5min and 10min after extubation (P<0.05). ConclusionsDexmedetomidine appears to be safe and effective to reduce the incidence of early emergence agitation in children after tonsillectomy. Initial loading dose of 1.0μgkg−1 followed by a maintenance infusion of 0.4μgkg−1h−1 is better choice for children received tonsillectomy.

Pharmacokinetic–pharmacodynamic modeling of the hypotensive effect of remifentanil in infants undergoing cranioplasty

Although remifentanil has been used to induce hypotension during surgery in infants, no pharmacokinetic-pharmacodynamic (PKPD) model exists for its quantitative analysis. Our aim was to determine the quantitative relationship between whole blood remifentanil concentration and its hypotensive effect during surgery in infants. We studied seven infants (age 0.3-1 year) who underwent cranioplasty surgery and received remifentanil delivered by a computer-controlled infusion pump during the maintenance of anesthesia. Arterial blood samples to determine remifentanil concentration and mean arterial blood pressure (MAP) measurements were collected. A simultaneous PKPD mixed-effects model was built in NONMEM. A total of 77 remifentanil concentrations and 185 MAP measurements were collected. Remifentanil pharmacokinetics was described with a two-compartment model, parameter estimates were 2.99 l x min(-1) x 70 kg(-1) for clearance and 16.23 l x 70 kg(-1) for steady state volume of distribution. Mean baseline MAP was 69.7 mmHg and was decreased as per clinical requirements. A sigmoidal E(max) model driven by an effect compartment described the decrease in MAP, with an estimated concentration to decrease MAP by half (EC(50)) being 17.1 ng x ml(-1). Remifentanil is effective in causing hypotension. The final model predicts that a steady state remifentanil concentration of 14 ng.ml(-1) would typically achieve a 30% decrease in MAP.

Population pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery

BackgroundThe aim of this study was to provide a model-based analysis of the pharmacokinetics of remifentanil in infants and children undergoing cardiac surgery with cardiopulmonary bypass (CPB).MethodsWe studied nine patients aged 0.5 to 4 years who received a continuous remifentanil infusion via a computer-controlled infusion pump during cardiac surgery with mildly hypothermic CPB were studied. Arterial blood samples taken prior to, during and after CPB were analyzed for remifentanil concentrations using a validated gas-chromatographic mass-spectrophotometric assay. We used population mixed-effects modeling to characterize remifentanil pharmacokinetics. The final model was evaluated by its predictive performance.ResultsThe pharmacokinetics of remifentanil was described by a 1-compartment model with adjustments for CPB. Population mean parameter estimates were 1.41 L for volume of distribution (V) and 0.244 L/min for clearance. V was increased during CPB and post-CPB to 2.41 times the pre-CPB value. The median prediction error and the median of individual median absolute prediction error were 2.44% and 21.6%, respectively.ConclusionRemifentanil dosage adjustments are required during and after CPB due to marked changes in the V of the drug. Simulations indicate that a targeted blood concentration of 14 ng/mL is achieved and maintained in 50% of typical patients by administration of an initial dose of 18 μg remifentanil followed by an infusion of 3.7 μg/min before, during and post-CPB, supplemented with a bolus dose of 25 μg given at the start of CPB.

A computerized infusion pump for control of tissue tracer concentration during positron emission tomography in vivo pharmacokinetic/pharmacodynamic measurements.

BackgroundA computer controlled infusion pump (UIPump) for regulation of target tissue concentration of radioactive compounds was developed for use in biological research and tracer development for PET.MethodsBased on observed tissue or plasma kinetics after a bolus injection of the tracer an algorithm calculates the infusion needed to obtain a specified target kinetic curve. A computer feeds this infusion scheme into an infusion pump connected to an animal via a venous catheter. The concept was validated using [11C]Flumazenil administrated to Sprague-Dawley rats where the whole brain distribution and kinetic of the tracer was measured over time using a microPET-scanner. The accuracy and precision of the system was assessed by producing steady-state levels of the tracer and by mimicking kinetics after oral administration.ResultsVarious kinetic profiles could be generated, including rapid achievement of constant levels, or step-wise increased levels. The resulting tissue curves had low deviation from the target curves according to the specified criteria: AUC (%): 4.2 ± 2.8, Maximal deviation (%): 13.6 ± 5.0 and R2: 0.95 ± 0.02.ConclusionThe UIPump-system is suitable for use in PET-research for assessment of PK/PD properties by simulation of different tracer tissue kinetics in vivo.

Sympathetic and Hemodynamic Effects of Moderate and Deep Sedation with Propofol in Humans

The objective of this study was to determine the mechanisms involved in the hypotension associated with sedative doses of propofol in humans. Ten healthy volunteers (aged 21-37 yr) participated on two occasions and in random order received placebo or propofol infusions. Standard monitoring and radial artery blood pressure were combined with measurement of forearm blood flow (plethysmography) and derivation of forearm vascular resistance, recording of peroneal nerve sympathetic activity, and blood sampling for norepinephrine concentrations. A computer-controlled infusion pump delivered placebo or two concentrations of propofol, adjusted to achieve moderate and deep sedation based on the Observer Assessment of Alertness/Sedation score (responsiveness component) of 4 and 3. Level of sedation was quantitated using bispectral analysis of the electroencephalogram. Baroreflexes were assessed with a hypotensive challenge via administration of sodium nitroprusside. Baseline neurocirculatory and respiratory parameters did not differ between sessions. Progressive infusions to achieve moderate and deep sedation resulted in average Bispectral Index values of 70 and 54, respectively. Propofol significantly reduced sympathetic nerve activity at both levels of sedation and decreased norepinephrine and forearm vascular resistance at deep sedation. These effects resulted in significant decreases in mean blood pressure of 9% and 18% at moderate and deep sedation, respectively. Propofol also reduced reflex increases in sympathetic nerve activity. These data from healthy subjects indicate that sedation doses of propofol, which did not compromise respiratory function, had substantial inhibitory effects on sympathetic nerve activity and reflex responses to hypotension resulting in vasodilation and significant decreases in mean blood pressure.

Brain processing of tonic muscle pain induced by infusion of hypertonic saline

Most of the previous studies on the effects of pain on Regional Cerebral Blood Flow (rCBF) had been done with brief cutaneous or intramuscular painful stimuli. The aim of the present study was to investigate the effect on rCBF of long lasting tonic experimental muscle pain. To this end we performed PET investigations of rCBF following tonic experimental low back pain induced by continuous intramuscular infusion of hypertonic (5%) saline (HS) with computer controlled infusion pump into the right erector spinae on L 3 level in 19 healthy volunteers. Changes in rCBF were measured with the use of 15O labelled water during four conditions: Baseline (before start of infusion), Early Pain (4 min after start of infusion), Late Pain (20 min after start of infusion) and Post-Pain (>15 min after stop of infusion) conditions. Results of SPM analysis showed relative rCBF increase in the right insula and bilateral decrease in the temporo-parieto-occipital cortex during initial phase of painful stimulation (Early Pain) followed by activation of the medial prefrontal region and bilateral inhibition of insula, anterior cingulate and dorso-lateral prefrontal cortex mainly in ipsilateral hemisphere during Late Pain conditions. The results show that longer lasting tonic experimental muscle pain elicited by i.m infusion of HS results in decreases rather than increases in rCBF. Possible explanations for differences found in rCBF during tonic hypertonic saline-induced experimental muscle pain as compared with previous findings are discussed.

A model of the ventilatory depressant potency of remifentanil in the non-steady state.

The C50 of remifentanil for ventilatory depression has been previously determined using inspired carbon dioxide and stimulated ventilation, which may not describe the clinically relevant situation in which ventilatory depression occurs in the absence of inspired carbon dioxide. The authors applied indirect effect modeling to non-steady state Paco2 data in the absence of inspired carbon dioxide during and after administration of remifentanil. Ten volunteers underwent determination of carbon dioxide responsiveness using a rebreathing design, and a model was fit to the end-expiratory carbon dioxide and minute ventilation. Afterwards, the volunteers received remifentanil in a stepwise ascending pattern using a computer-controlled infusion pump until significant ventilatory depression occurred (end-tidal carbon dioxide [Peco2] > 65 mmHg and/or imminent apnea). Thereafter, the concentration was reduced to 1 ng/ml. Remifentanil pharmacokinetics and Paco2 were determined from frequent arterial blood samples. An indirect response model was used to describe the Paco2 time course as a function of remifentanil concentration. The time course of hypercarbia after administration of remifentanil was well described by the following pharmacodynamic parameters: F (gain of the carbon dioxide response), 4.30; ke0 carbon dioxide, 0.92 min-1; baseline Paco2, 42.4 mmHg; baseline minute ventilation, 7.06 l/min; kel,CO2, 0.08 min-1; C50 for ventilatory depression, 0.92 ng/ml; Hill coefficient, 1.25. Remifentanil is a potent ventilatory depressant. Simulations demonstrated that remifentanil concentrations well tolerated in the steady state will cause a clinically significant hypoventilation following bolus administration, confirming the acute risk of bolus administration of fast-acting opioids in spontaneously breathing patients.

Intracranial delivery of proteins and peptides as a therapy for neurodegenerative diseases.

Parkinson's disease is characterized by a progressive degeneration of the substantia nigra pars compacta dopamine neurons that innervate the striatum. Unlike current treatments for PD, GDNF administration could potentially slow or halt the continued degeneration of nigral dopaminergic neurons. GDNF does not cross the blood-brain barrier and needs to be administered directly into the brain. Due to the progressive nature of PD, sustained delivery of trophic factors may be necessary for optimal, long-term neuronal effects. Novel methods for sustained delivery of GDNF into the nigrostriatal pathway are currently being studied in non-human primates, including computer-controlled infusion pumps. Using this approach, we have demonstrated that chronic infusions of nominally 7.5 or 22.5 microg/day GDNF into the lateral ventricle, the putamen or the substantia nigra, using programmable pumps, promotes restoration of the nigrostriatal dopaminergic system and significantly improves motor functions in MPTP-lesioned rhesus monkeys with neural deficits modeling the terminal stages of PD and in aged rhesus monkeys modeling the early stages of PD. Based on the promising studies of the chronic effects of GDNF in non-human primate models of PD, a study was recently conducted in England on five advanced PD patients. Chronic GDNF infusion into the dorsal putamen, via programmable pumps, resulted in improved motor function in all patients and limited side effects were observed. However, while the data from this intraparenchymal clinical trial in humans look encouraging, extensive blinded efficacy trials will need to be conducted before it can be determined if chronic treatment with GDNF or other trophic molecules will prove useful in treating patients with PD.

A new paradigm for the closed-loop intraoperative administration of analgesics in humans.

We present a new paradigm for the closed-loop administration of analgesics during general anesthesia. The manipulated variable in the control system is the infusion rate of the opiate alfentanil, administered intravenously through a computer-controlled infusion pump (CCIP). The outputs to be controlled are the patient's mean arterial pressure (MAP) and the drug concentration in the plasma. Maintaining MAP within appropriate ranges provides optimal treatment of the patient's reactions to surgical stimuli. Maintaining plasma drug concentrations close to a reference value specified by the anesthesiologist allows to titrate analgesic administration to qualitative clinical end-points of insufficient analgesia. MAP is acquired invasively through a catheter cannula. Since plasma drug concentrations cannot be measured on-line, they are estimated via a pharmacokinetic model. We describe an explicit model-predictive controller which achieves the above-mentioned objectives. An upper constraint on drug concentrations is maintained to avoid overdosing. Constraints on the MAP are introduced to trigger a prompt controller reaction during hypertensive and hypotensive periods. Measurement artifacts in the MAP signal are rejected to prevent harmful misbehavior of the controller. We discuss the results of the clinical validation of the controller on humans.

A system-approach method for the adjustment of time-varying continuous drug infusion in individual patients: a simulation study.

The aim of this simulation study was to present a system-approach method for adjustment of continuous drug infusions at time-varying rates, aimed at achieving and then maintaining required drug concentration-time profiles in patients. The method presented can be used for safe and cost-effective individualization of drug dosing by computer-controlled infusion pumps. Utilization of this method is exemplified by simulation experiments, aimed at adjusting continuous infusions of Factor VIII (FVIII) at time-varying rates, which would theoretically yield required concentration-time profiles of FVIII in hemophilia A patients over several days.

Predicting Drug-induced Memory and Sedation Changes Using Auditory Event-related Potentials.

Predicting Drug-induced Memory and Sedation Changes Using Auditory Event-related Potentials. Veselis et al. (page 896)Building on the work of researchers who have used specific components of event-related potentials (ERPs) to discriminate between the memory and sedative effects of drugs such as lorazepam and scopolamine, Veselis et al. present a new analysis of memory effects using ERPs obtained in a previous study. That placebo-controlled study used 65 healthy volunteers who randomly received intravenously placebo, midazolam, propofol, thiopental, fentanyl with ondansetron, or ondansetron alone in five different stable target concentrations. The concentrations (three increasing, two decreasing) were achieved using a computer-controlled infusion pump to produce mild, moderate, and maximal sedation levels without loss of consciousness. At each target concentration, volunteers were given a list of 16 words to learn. In addition, ERPs were recorded while participants were asked to give a button-press response to a deviant auditory stimulus (target tone, standard oddball paradigm, 80:20 ratio, to elicit a P3 response). Then the researchers determined the predictive probabilities of various ERP components for memory (recognition of the words at the end of the day) and sedation (log reaction time to the deviant stimulus).Results showed that the N2 latency of the ERP consistently predicted log reaction time in all groups. The N2P3 amplitude of the ERP was most predictive of memory performance for subjects to whom midazolam, propofol, and thiopental were administered. Midazolam and propofol affect memory differentially from their sedative effects, as indexed by specific components of the auditory ERP. Relating electrophysiologic changes to the memory and sedative effects of drugs allows researchers to independently measure these effects without the confounding subjective perceptions of the participants. These changes can then be related to brain images from positron emission tomography or magnetic resonance imaging to more accurately localize and quantify the neuroanatomic regions mediating these drug effects.

Concentration–effect relationship of intravenous alfentanil and ketamine on peripheral neurosensory thresholds, allodynia and hyperalgesia of neuropathic pain

Both μ opioid agonists and N-methyl- d-aspartate (NMDA) receptor antagonists are implicated in the regulation of neuropathic pain in post-nerve injury preclinical pain models. This study characterizes the effects of intravenously infused alfentanil (a μ-receptor agonist) and ketamine (an NMDA-receptor antagonist) on human neuropathic pain states, characterized by allodynia and hyperalgesia. Using diphenhydramine as the placebo, alfentanil and ketamine infusions were given in a randomized double-blind fashion 1 week apart via a computer-controlled infusion (CCI) pump that was programmed to target plasma levels of alfentanil at 25, 50 and 75 ng/ml and ketamine at 50, 100 and 150 ng/ml. At the beginning of each infusion and each targeted plasma level, baseline vital signs, neurosensory testing that included thermal thresholds, thermal pain and von Frey filament thresholds, and spontaneous and evoked pain scores were obtained. Moreover, the areas of allodynia or hyperalgesia to stroking and a 5.18 von Frey filament were mapped at the beginning and the end of each infusion. A total of seven males and five females with post-nerve injury allodynia and hyperalgesia were enrolled in the study. Elevations of cold, warm, hot pain and von Frey tactile thresholds were noted. Dose-dependent increases in cold and cold pain thresholds, and reductions in stroking pain scores were noted in both the alfentanil and the ketamine infusions. In addition, alfentanil showed a statistically significant dose-dependent reduction in both spontaneous and von Frey pain scores. Both the alfentanil and ketamine infusions showed a reduction in the stroking hyperalgesic area and ketamine showed a significant reduction in the von Frey hyperalgesia area. No significant CNS side effects and changes in vital signs were noted. A partial deafferentation state was found in the post-nerve injury patients who presented with allodynia and hyperalgesia. The effects of alfentanil on cold and cold pain thresholds and spontaneous pain scores correlates with previous studies suggesting an opiate central analgesic effect. In addition, the reduction of the hyperalgesic area and evoked pain scores with the alfentanil infusion suggests that opioids may have some peripheral effects in the post-nerve injury patients. Therefore, clinical utilization of opioids with careful titration may be beneficial in post-nerve injury patients with partial deafferentation. With the absence of significant CNS side effects, the ketamine infusion not only demonstrated the well-documented spinal cord mechanism of the NMDA receptor, but the result of the current study also suggests that a peripheral mechanism of NMDA receptor may exist. The relationship between central sensitization and regulation of peripheral NMDA-receptor expression requires further investigation.

Effect of dexmedetomidine on propofol requirements in healthy subjects

Dexmedetomidine–propofol pharmacodynamic interaction was evaluated in nine healthy subjects in a crossover design. Dexmedetomidine/placebo was infused using a computer‐controlled infusion pump (CCIP) to maintain a pseudo‐steady‐state plasma concentration of 0.66 ± 0.080 or 0 ng/mL, respectively. Forty‐five minutes after the dexmedetomidine/placebo infusion was started, propofol was infused using a second CCIP to achieve a stepwise logarithmically ascending propofol concentration (1.00 to 13.8 μg/mL) profile. Each propofol step lasted 10 min. Blood was sampled for plasma concentration determination, and pharmacodynamic endpoint assessments were made during the study. Propofol and dexmedetomidine/placebo infusions were terminated when three endpoints (subjects were too sedated to hold a syringe, followed by loss of eyelash reflex, followed by loss of motor response to electrical stimulation) were achieved sequentially. The concentration of propofol associated with 50% probability of achieving a pharmacodynamic endpoint in the absence of dexmedetomidine (EC50; placebo treatment) was 6.63 μg/mL for motor response to electrical stimulation and ranged from 1.14 to 1.98 μg/mL for the ability to hold a syringe, eyelash reflex, and sedation scores. The apparent EC50 values of propofol (EC50APP; concentration of propofol at which the probability of achieving a pharmacodynamic endpoint is 50% in the presence of dexmedetomidine concentrations observed in the current study; dexmedetomidine treatment) were 0.273, 0.544–0.643, and 3.89 μg/mL for the ability to hold a syringe, sedation scores, and motor response, respectively. Dexmedetomidine reduced propofol concentrations required for sedation and suppression of motor response. Therefore, the propofol dose required for sedation and induction of anesthesia may have to be reduced in the presence of dexmedetomidine. © 2001 Wiley‐Liss, Inc. and the American Pharmaceutical Association J Pharm Sci 90:172–181, 2001

Bispectral index (BIS) and burst suppression: revealing a part of the BIS algorithm.

The bispectral index (BIS) is a complex EEG parameter which integrates several disparate descriptors of the EEG into a single variable. One of the subparameters incorporated in the BIS is the suppression ratio, quantifying the percentage of suppression during burst suppression pattern. The exact algorithm used to synthetize the information to the BIS value is unpublished and still unknown. This study provides insight into the integration of the suppression ratio into the BIS algorithm. EEG data of 10 healthy volunteers during propofol infusion were analyzed. Propofol concentrations were ramped up to 4 predetermined concentrations (1, 2, 3, 4, 6, 8, 9, or 12 microg/ml) using a computer controlled infusion pump (STANPUMP). EEG recordings were performed with an Aspect A-1000 EEG monitor (Version 3.22). The relationship of the processed EEG variables bispectral index and suppression ratio, calculated by the Aspect A-1000 monitor, was analyzed. Up to 40% suppression ratio the average BIS values remained constant regardless of suppression ratios (r = 0.13). Beyond a suppression ratio of 40%, BIS and suppression ratio were invariably linearly correlated (r = -1). At a suppression ratio > or = 40% the BIS value could be calculated as BIS = 50 - suppression ratio/2. Suppression ratio values > 40% are linearly correlated with BIS values from 30 to 0. An increasing anesthetic drug effect resulting in an increase of the duration of suppression to a suppression ratio up to 40% is not adequately reflected by the BIS value.