Computer-controlled Infusion Research Articles

Pain sensitivity and opioid analgesia: A pharmacogenomic twin study

Opioids are the cornerstone medication for the management of moderate to severe pain. Unfortunately, vast inter-individual differences in dose requirements complicate their effective and safe clinical use. Mechanisms underlying such differences are incompletely understood, are likely multifactorial, and include genetic and environmental contributions. While accumulating evidence suggests that variants of several genes account for some of the observed response variance, the relative contribution of these factors remains unknown. This study used a twin paradigm to provide a global estimate of the genetic and environmental contributions to inter-individual differences in pain sensitivity and analgesic opioid effects. Eighty one monozygotic and 31 dizygotic twin pairs successfully underwent a computer-controlled infusion with the μ-opioid agonist alfentanil in a single occasion, randomized, double-blind and placebo-controlled study design. Pain sensitivity and analgesic effects were assessed with experimental heat and cold pressor pain models along with important covariates including demographic factors, depression, anxiety, and sleep quality. Significant heritability was detected for cold pressor pain tolerance and opioid-mediated elevations in heat and cold pressor pain thresholds. Genetic effects accounted for 12–60% of the observed response variance. Significant familial effects accounting for 24–32% of observed variance were detected for heat and cold pressor pain thresholds and opioid-mediated elevation in cold pressor pain tolerance. Significant covariates included age, gender, race, education, and anxiety. Results provide a strong rationale for more detailed molecular genetic studies to elucidate mechanisms underlying inter-individual differences in pain sensitivity and analgesic opioid responses. Such studies will require careful consideration of the studied pain phenotype.

Evaluation of doripenem in an experimental model of resistant Pseudomonas aeruginosa pneumonia

Sir, In a previous study we demonstrated that doripenem, the most recently approved carbapenem, exhibited antimicrobial activity similar to that of imipenem or meropenem in an experimental rabbit model of susceptible Pseudomonas aeruginosa pneumonia. Mutational inactivation of oprD is known to be the main mechanism of imipenem resistance in the absence of acquired carbapenemase. Although oprD inactivation also increases the MICs of meropenem and doripenem, clinical resistance to these drugs is thought to require additional mechanisms. In this work we compared the efficacy of doripenem versus imipenem or meropenem against a resistant oprD-inactive strain of P. aeruginosa in an experimental model. The experimental rabbit model of pneumonia has been described previously. The bacterial strain was a DoprD PAO1, which is resistant to carbapenems after inactivation of OprD porin, a carbapenem-specific transport porin. This strain was provided by courtesy of Professor P. Plesiat, Besancon, France. MICs of meropenem, doripenem and imipenem were 8, 1 and 16 mg/L, respectively. Antibiotics were delivered through a venous catheter, with changing infusion rates determined by computer-controlled electric pumps, in order to simulate the pharmacokinetics observed in human serum. Animals were randomly assigned to four groups: (i) controls (no treatment); (ii) meropenem group [computer-controlled syringe-pump infusion to simulate a human equivalent (HE) dosage of meropenem of 1 g three times daily]; (iii) doripenem group (simulating an HE dosage of doripenem of 0.5 g three times daily); and (iv) imipenem group (simulating an HE dosage of imipenem of 1 g three times daily). Evaluation of infection was performed at the end of treatment (2 days). The spleen and both lungs from each animal were weighed and homogenized in 1 mL of saline buffer and used for quantitative cultures on agar for 24 h at 378C. Viable counts after 24 h of incubation were expressed as the mean+SD log10 cfu/g of lung. Spleen culture results were expressed quantitatively (positive or negative). From each animal, plasma antibiotic concentrations were determined by a microbioassay to obtain a pharmacokinetic analysis. Selection of variants resistant in vivo to doripenem, meropenem or imipenem was evaluated by spreading undiluted homogenates on agar plates that contained the appropriate antibiotic at a concentration of 4-fold the MIC. Bacterial counts were determined after 48 h of incubation at 378C. Quantitative variables were compared using one-way analysis of variance. This analysis was completed with a post hoc Bonferroni test. Proportions (percentages) were compared using Fisher’s exact test. P,0.05 was considered statistically significant. Animals were treated in accordance with institutional policies and the guidelines stipulated by the animal welfare committee. The Committee of Animal Ethics of the University of Nantes approved all animal experimentation in this study. Mean pulmonary bacterial loads were 3.1+1.3, 2.6+0.4 and 2.8+0.7 log10 cfu/g for meropenem, doripenem and imipenem, respectively, compared with 5.9+0.8 log10 cfu/g for control animals. The results of these pulmonary bacterial counts are shown in Figure 1; they were significantly lower in the treated animals compared with the controls (P,0.05), but were similar between the different antibiotic regimens. The proportions of positive versus negative spleen cultures for controls, meropenem, doripenem and imipenem were 4/3, 3/4, 1/6 and 2/7, respectively; they were not statistically different. No resistant mutants were isolated from any of the post-treatment biological samples.

Tracking brain states under general anesthesia by using global coherence analysis

Time and frequency domain analyses of scalp EEG recordings are widely used to track changes in brain states under general anesthesia. Although these analyses have suggested that different spatial patterns are associated with changes in the state of general anesthesia, the extent to which these patterns are spatially coordinated has not been systematically characterized. Global coherence, the ratio of the largest eigenvalue to the sum of the eigenvalues of the cross-spectral matrix at a given frequency and time, has been used to analyze the spatiotemporal dynamics of multivariate time-series. Using 64-lead EEG recorded from human subjects receiving computer-controlled infusions of the anesthetic propofol, we used surface Laplacian referencing combined with spectral and global coherence analyses to track the spatiotemporal dynamics of the brain's anesthetic state. During unconsciousness the spectrograms in the frontal leads showed increasing α (8-12 Hz) and δ power (0-4 Hz) and in the occipital leads δ power greater than α power. The global coherence detected strong coordinated α activity in the occipital leads in the awake state that shifted to the frontal leads during unconsciousness. It revealed a lack of coordinated δ activity during both the awake and unconscious states. Although strong frontal power during general anesthesia-induced unconsciousness--termed anteriorization--is well known, its possible association with strong α range global coherence suggests highly coordinated spatial activity. Our findings suggest that combined spectral and global coherence analyses may offer a new approach to tracking brain states under general anesthesia.

Ephedrine and Phenylephrine Use during Cesarean Delivery

Ephedrine and Phenylephrine Use during Cesarean Delivery

Optimal Control of Blood Glucose: The Diabetic Patient or the Machine?

In this issue of Science Translational Medicine, El-Khatib et al. describe a "closed-loop" bihormonal artificial pancreas, designed to avert episodes of low blood sugar in patients with insulin-dependent diabetes. We discuss the benefits and challenges of therapy directed at tight control of blood glucose and ask whether this and similar technological breakthroughs can address as yet unanswered questions in the biology of diabetes.

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.

The Correlation Between Bispectral Index and Observational Sedation Scale in Volunteers Sedated with Dexmedetomidine and Propofol

Bispectral index (BIS) is a widely used quantitative parameter for evaluating anesthesia and sedation levels. Dexmedetomidine is a novel sedative, providing sedation while patients remain cooperative and can be easily aroused; as a consequence, BIS used with dexmedetomidine may poorly characterize sedation. Thus, we tested the hypothesis that BIS values are lower with dexmedetomidine than with propofol at comparable Observer's Assessment of Alertness and Sedation (OAA/S) scores. This was a randomized, 2-day, crossover study. On the first study day, healthy volunteers were randomly allocated to either propofol or dexmedetomidine sedation. Drugs were administered using computer-controlled infusions targeting an effect-site concentration of 1, 2, and 4 microg/mL for propofol or a plasma concentration of 0.6, 1.2, and 2.4 ng/mL for dexmedetomidine. The relationship between BIS and OAA/S score was obtained 20 and 40 min after changing each drug concentration. BIS values at each OAA/S score were compared between drugs. The cutoff values of BIS for OAA/S score of < or =2 were obtained by analysis of receiver operating characteristic curves. Nine volunteers were included in our analysis. Heart rates decreased significantly with dexmedetomidine sedation. ETco(2) was significantly increased with high doses of propofol but did not increase with high doses of dexmedetomidine. BIS values at OAA/S scores of 1, 2, 3, 4, and 5 during propofol sedation were 95.5 (90-97), 78 (71-84.5), 67 (64-70), 57 (51.5-60), and 34 (30-37), respectively. BIS values at OAA/S scores of 1, 2, 3, 4, and 5 during dexmedetomidine sedation were 95 (79-98), 62 (53.5-68.5), 45.5 (45.3-52), 39.5 (34.3-41.8), and 24.5 (22.5-30.5), respectively. BIS values were significantly less with dexmedetomidine than propofol at OAA/S responsiveness scores of 2, 3, and 4. The calculated cutoff BIS values for OAA/S scores of < or =2 were 67 (sensitivity of 86%, specificity of 97%, and area under the curve of 0.98) for propofol and 46 (sensitivity of 84%, specificity of 91%, and area under the curve of 0.96) for dexmedetomidine. The combination of both BIS and sedative scales could provide different and complementary data to the clinician evaluating the patient's response to sedation than would either tool alone, especially when dexmedetomidine is used.

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.

Closed‐loop feedback computer‐controlled infusion of phenylephrine for maintaining blood pressure during spinal anaesthesia for caesarean section: a preliminary descriptive study*

We describe the novel use of a closed-loop feedback computer-controlled infusion of phenylephrine for maintaining blood pressure in 53 patients having spinal anaesthesia for elective caesarean section. A simple on-off algorithm was used that activated an intravenous phenylephrine infusion at 100 microg.min(-1) when systolic blood pressure was less than or equal to baseline and stopped the infusion when systolic blood pressure exceeded baseline. Up to uterine incision, 94.6% of all systolic blood pressure measurements were within the range (baseline +/- 20%). Seven patients (13.2%) had one or more episodes of hypotension (systolic blood pressure < 80% of baseline) and 23 patients (37.7%) had one or more episodes of hypertension (systolic blood pressure > 120% of baseline). No patient had nausea or vomiting and in no case was umbilical arterial blood pH < 7.2. Calculated system performance parameters were comparable with those of previously published closed-loop systems and provide a reference for the potential development and comparison of more advanced algorithms.

The Effect of Dexmedetomidine on Electrocorticography in Patients with Temporal Lobe Epilepsy Under Sevoflurane Anesthesia

Although dexmedetomidine is often used in neuroanesthesia and neuronal critical care practice, its effect on cerebral electrical activity in those with an abnormal electroencephalogram is not known. The electrocorticogram (ECoG), a sensitive method for examining the effect of drugs on cerebral electrical activity and surgical treatment for epilepsy, is usually guided by monitoring of the ECoG. We investigated the effect of dexmedetomidine on ECoG in patients with epilepsy undergoing surgery with sevoflurane. Patients with medically intractable temporal lobe epilepsy undergoing resection of the epileptic foci (n = 11) were enrolled. Under general anesthesia with 2.5% sevoflurane and end-tidal carbon dioxide tension at 30 mm Hg, ECoG was recorded by strip electrodes with eight contacts placed on the mesial temporal lobe ipsilateral to the epilepsy foci. Dexmedetomidine was given as a computer-controlled infusion to achieve target plasma concentrations of 0.5 and 1.5 ng/mL. Each concentration was maintained for 20 min and ECoG was recorded before infusion of dexmedetomidine and between the 10th and 20th min after starting infusion. The median frequency of ECoG, spectral power density of each spectral band, and number of spikes at each concentration of dexmedetomidine were compared by Kruskal-Wallis test, followed by Student-Newman-Keuls test. The median frequency of ECoG in 88 leads from all leads from all patients was significantly decreased by 1.5 ng/mL of dexmedetomidine compared with those at baseline and 0.5 ng/mL (P = 0.003 and 0.03, respectively); however, spectral power densities in the frequency bands: delta (<4 Hz), theta (> or =4 and <8 Hz), alpha (> or =8 and <13 Hz), and beta (> or =13 Hz), were not changed. Neither the number of leads with spikes nor the number of spikes in all leads and in the lead with highest number of spikes at baseline was affected by dexmedetomidine. Dexmedetomidine at plasma concentrations of 0.48 and 1.60 ng/mL decreased the median frequency of ECoG, but did not affect spike activity in patients with temporal lobe epilepsy anesthetized with 2.5% sevoflurane.

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.

Regional anaesthesia and propofol sedation for carotid endarterectomy

Many surgeons now perform carotid endarterectomy under regional anaesthesia. The aim of the present study was to review a sedation technique using a computer-controlled infusion of propofol. A consecutive series of 84 carotid endarterectomies done by a single surgeon and commenced under regional anaesthesia with sedation was studied. There were 54 men and 27 women (three bilateral procedures), with a median age of 71 years (range 48-87 years). All patients had carotid stenosis > 70% 80 procedures were done for symptomatic disease and three asymptomatic patients were treated before cardiac surgery (one bilateral). Seventy-seven procedures were completed under regional anaesthesia and sedation alone; seven required conversion to general anaesthetic, usually for intolerance of the operation. An intraoperative shunt was required on only four occasions (5%). Postoperatively eight patients required critical care monitoring, usually for blood pressure control. The remainder were nursed on the vascular ward, and 68% were discharged home on the day after surgery. No patient died, but there were two neurological complications. One patient had a cerebellar stroke 10 days after surgery, but recovered fully after 4 months. A second developed cerebral oedema due to severe intraoperative hypertension and required intensive care for 15 days. He too recovered fully. Five patients had a further episode of transient cerebral ischaemia within 1 month of operation, but in all cases duplex imaging showed a widely patent carotid and there were no sequelae. Target controlled propofol infusion is an effective method of sedation in patients undergoing carotid endarterectomy.

Modern concepts in pharmacokinetics of intravenous anesthetics

From a pharmacological perspective, anesthesia is concerned with controlling the time course of drug effect. Mathematical models are commonly used to relate the administered drug dose to the measured drug concentration (a pharmacokinetic model) and to relate the measured drug concentrations to the measured drug effects (a pharmacodynamic model). With such models, the time course of the drug effect for different drug regimens can be predicted. Although the conventional pharmacokinetic parameters such as the volume of distribution, clearance, distribution and elimination half-lives can be used to accurately describe the time course of the plasma concentration, the plasma is usually not the site of drug effect. An understanding of the "effect compartment concept" and the "time of the peak effect site concentration," together with the concepts of" context sensitive"half-time and "relevant decrement time,' contribute substantially to the anesthetist's understanding of the principles governing the onset and offset of drug effect. As part of a computer-controlled infusion system, the pharmacokinetic model facilitates optimized and rational dosing. These systems, also called target-controlled infusion systems (TCI), calculate the infusion rates for rapidly achieving and then maintaining a target concentration.

Proper Target Concentration of Fentanyl during Endotracheal Intubation with a CACI (Computer Assisted Continuous Infusion) in Patients Undergoing Coronary Artery Bypass Graft Surgery

Background: The computer-assisted continuous infusion (CACI) system was developed to more rapidly attain and to maintain stable effect-site fentanyl concentrations as compared with the intermittent injection method. The CACI system allows the anesthesiologist to control effect-site fentanyl concentrations during various surgical stimuli during cardiac anesthesia. This system can rapidly control the depth of anesthesia and compensate for the disadvantages of IV anesthesia. Early patient recovery also enables early tracheal extubation, which is an important component of the “fast track” cardiac surgery pathway. In this study, the use of a target-controlled infusion of low-dose propofol was combined with the target-controlled infusion of fentanyl for patients undergoing coronary artery bypass graft surgery. The purpose of this study was to evaluate the proper effect-site concentration of fentanyl for the tracheal intubation of patients undergoing coronary artery bypass graft surgery. Methods: Fifty patients scheduled for elective coronary artery bypass graft surgery were included, and randomly allocated to group L (effect-site fentanyl concentration = 5 ng/ml, n = 25) or group H (effect-site fentanyl concentration = 7.5 ng/ml, n = 25). Anesthesia was induced and maintained by the computer-controlled infusions of propofol and fentanyl. Hemodynamics and other variables were recorded preinduction, and before and 1 minute after intubation. Results: The two groups were compared with regard to demographic and perioperative data. The two groups were similar demographically, and no significant differences was found in any hemodynamic parameter at any time between the two groups. Conclusions: Both fentanyl regimens provided stable hemodynamics and adequate anesthesia in patients during endotracheal intubation. It is reasonable to say that the lower dose of fentanyl (5 ng/ml) may be the better choice, because it provides the same level of anesthesia during endotracheal intubation during coronary artery bypass graft surgery.

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.

The μ-opioid agonist remifentanil attenuates hyperalgesia evoked by blunt and punctuated stimuli with different potency: a pharmacological evaluation of the freeze lesion in humans

Experimental pain models inducing hyperalgesia, i.e. an increased sensitivity to noxious stimuli often present in clinical pain, are important tools for studying antinociceptive drug profiles. The correct interpretation of results obtained in these models necessitates their mechanistic understanding. This study evaluated the freeze lesion, an experimental model of hyperalgesia, in humans. Twelve healthy subjects were tested with mechanical (brush, punctuated and blunt) and electrical (5, 250, and 2000 Hz sine wave current) stimuli before and after freezing the skin, and during a computer-controlled infusion of the μ-opioid agonist remifentanil targeting five different plasma concentrations between 0 and 6 ng/ml in a two-staged, single occasion, randomized, and double blind study design. Pharmacodynamic modeling techniques were used to describe the effect of freezing and drug administration on the mechanical and electrical pain thresholds. Freezing the skin resulted in hyperalgesia to blunt and punctuated stimuli and lowered the respective pain threshold by 29 and 73%. Hyperalgesia to brushing or electrical stimuli was not detected. Remifentanil attenuated hyperalgesia to blunt stimuli about twice as potently as hyperalgesia to punctuated stimuli, as indicated by a significantly steeper linear relationship between the remifentanil plasma concentration and the increase of the pain threshold to blunt stimuli. Remifentanil attenuated electrical pain with greater potency for low frequency stimulation. The potency difference of remifentanil suggests that different neuronal mechanisms mediate hyperalgesia to blunt and punctuated stimulation. Absence of brush-evoked and electrical hyperalgesia is compatible with the view that mechanical hyperalgesia to blunt and punctuated stimulation of the freeze lesion is predominantly caused by a peripheral mechanism.

Predictive performance of computer-controlled infusion of remifentanil during propofol/remifentanil anaesthesia

The predictive performance of the available pharmacokinetic parameter sets for remifentanil, when used for target-controlled infusion (TCI) during total i.v. anaesthesia, has not been determined in a clinical setting. We studied the predictive performance of five parameter sets of remifentanil when used for TCI of remifentanil during propofol anaesthesia in surgical patients. Remifentanil concentration-time data that had been collected during a previous pharmacodynamic interaction study in 30 female patients (ASA physical status I, aged 20-65 yr) who received a TCI of remifentanil and propofol during lower abdominal surgery were used in this evaluation. The remifentanil concentrations predicted by the five parameter sets were calculated on the basis of the TCI device record of the infusion rate-time profile that had actually been administered to each individual. The individual and pooled bias [median performance error (MDPE)], inaccuracy [median absolute performance error (MDAPE)], divergence and wobble of the remifentanil TCI device were determined from the pooled and intrasubject performance errors. A total of 444 remifentanil blood samples were analysed. Blood propofol and remifentanil concentrations ranged from 0.5 to 11 micro g ml(-1) and 0.1 to 19.6 ng ml(-1) respectively. Pooled MDPE and MDAPE of the remifentanil TCI device were -15 and 20% for the parameter set of Minto and colleagues (Anesthesiology 1997; 86: 10-23), 1 and 21%, -6 and 21%, and -6 and 19% for the three parameter sets described by Egan and colleagues (Anesthesiology 1996; 84: 821-33, Anesthesiology 1993; 79: 881-92, Anesthesiology 1998; 89: 562-73), and -24 and 30% for the parameter set described by Drover and Lemmens (Anesthesiology 1998; 89: 869-77). Remifentanil can be administered by TCI with acceptable bias and inaccuracy. The three pharmacokinetic parameter sets described by Egan and colleagues resulted in the least bias and best accuracy.

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.

Prediction of the haemodynamic response to tracheal intubation: comparison of laser-Doppler skin vasomotor reflex and pulse wave reflex

The laser-Doppler skin vasomotor reflex (SVmR) caused by tetanic stimulation of the ulnar nerve may be a test that can predict the haemodynamic response to tracheal intubation. A decrease in pulse wave amplitude (pulse wave reflex, PWR) may be an alternative index of this response. We compared the abilities of PWR and SVmR to predict the haemodynamic response to tracheal intubation and studied how alfentanil, muscle relaxation, stimulation site and stimulation pattern affected the two reflexes. Anaesthesia was induced and maintained with 2% sevoflurane and 50% nitrous oxide in two groups of 10 ASA status 1 patients. Tetanic stimuli were applied to the flexor muscles of the forearm and the ulnar nerve before and after administration of vecuronium. The change in skin blood flow (laser-Doppler) and pulse wave amplitude (pulse oximetry) after a 5 and 10 s stimulation was measured on the opposite hand. If skin blood flow (laser-Doppler) decreased by more than 10%, a computer-controlled infusion of alfentanil was started and the target plasma concentration was increased in steps until this response was suppressed (< 10%). The trachea was intubated and arterial pressure and heart rate responses were recorded. Plasma alfentanil concentration was measured. When PWR and SVmR were suppressed, the haemodynamic response to tracheal intubation was reduced in 100 and 53% of patients respectively. PWR and SVmR responses decreased with increasing plasma alfentanil concentration. The SVmR response to muscle stimulation was reduced by muscle relaxants. The pulse wave response to both muscle and neural stimulation was reduced by relaxants. The responses to 5 and 10 s stimulations were similar. An absent SVmR does not predict a blunted arterial pressure or heart rate response to tracheal intubation. The PWR may be a better predictor.

Propofol Reduces Spinal Motor Neuron Excitability in Humans

Propofol Reduces Spinal Motor Neuron Excitability in Humans