Patient-controlled Analgesia with Target-controlled Infusion of Hydromorphone in Postoperative Pain Therapy.

BACKGROUND: Patient-controlled analgesia (PCA) is a common method for postoperative pain therapy, but it is characterized by large variation of plasma concentrations. PCA with target-controlled infusion (TCI-PCA) may be an alternative. In a previous analysis, the authors developed a pharmacokinetic model for hydromorphone. In this secondary analysis, the authors investigated the feasibility and efficacy of TCI-PCA for postoperative pain therapy with hydromorphone. METHODS: Fifty adult patients undergoing cardiac surgery were enrolled in this study. Postoperatively, hydromorphone was applied intravenously during three sequential periods: (1) as TCI with plasma target concentrations of 1 to 2 ng/ml until extubation; (2) as TCI-PCA with plasma target concentrations between 0.8 and 10 ng/ml during the following 6 to 8 h; and (3) thereafter as PCA with a bolus dose of 0.2 mg until the next morning. During TCI-PCA, pain was regularly assessed using the 11-point numerical rating scale (NRS). A pharmacokinetic/pharmacodynamic model was developed using ordinal logistic regression based on measured plasma concentrations. RESULTS: Data of 43 patients aged 40 to 81 yr were analyzed. The hydromorphone dose during TCI-PCA was 0.26 mg/h (0.07 to 0.93 mg/h). The maximum plasma target concentration during TCI-PCA was 2.3 ng/ml (0.9 to 7.0 ng/ml). The NRS score under deep inspiration was less than 5 in 83% of the ratings. Nausea was present in 30%, vomiting in 9%, and respiratory insufficiency in 5% of the patients. The EC50 of hydromorphone for NRS of 4 or less was 4.1 ng/ml (0.6 to 12.8 ng/ml). CONCLUSION: TCI-PCA with hydromorphone offered satisfactory postoperative pain therapy with moderate side effects.

Influence of disease progression on the neuromuscular blocking effect of mivacurium in children and adolescents with Duchenne muscular dystrophy.

BACKGROUND: Studies with nondepolarizing neuromuscular blocking agents showed a delayed onset and prolonged recovery in patients with Duchenne muscular dystrophy. The objective of this study was to investigate if these alterations depend on disease progression. METHODS: The authors studied 11 children (6-9 yr) with moderate Duchenne muscular dystrophy, 11 adolescents (12-16 yr) with advanced Duchenne muscular dystrophy, and 2 age-matched control groups of 8 patients each (5-9 and 10-17 yr). Anesthesia was performed with propofol and remifentanil. Patients received a single intravenous dose of 0.2 mg/kg mivacurium. Neuromuscular transmission was monitored by acceleromyography. The time course of neuromuscular blockade was characterized by the onset time and the times to different levels of recovery. RESULTS: Onset and duration of neuromuscular blockade were significantly prolonged in adolescent Duchenne muscular dystrophy patients (onset time, 4.0 min; recovery index, 12.3 min; median), as compared with Duchenne muscular dystrophy children (onset time, 2.3 min; recovery index, 6.8 min), and also as compared with young controls (onset time, 2.0 min; recovery index, 4.4 min) and adolescent controls (onset time, 2.5 min; recovery index, 4.8 min). Within the Duchenne muscular dystrophy patients, onset time and recovery index increased significantly with age. In the control group, age had no effect. CONCLUSIONS: The neuromuscular blocking effects of mivacurium showed a significant age dependency in Duchenne muscular dystrophy patients, which was most probably caused by the progression of the disease.

Pharmacodynamic modelling of rocuronium in adolescents with Duchenne muscular dystrophy.

BACKGROUND AND OBJECTIVE: Studies with rocuronium showed a delayed onset and prolonged recovery in patients with Duchenne muscular dystrophy (DMD). The objective of this study was to identify the pharmacokinetic and/or pharmacodynamic origin of these alterations. METHODS: Twenty-five male patients (15 with DMD, 10 controls, aged 10-18 years) were studied. Patients were anaesthetized with propofol and sufentanil. Neuromuscular transmission was monitored by acceleromyography. Patients received a single intravenous dose of 0.3 mg kg(-1) rocuronium. In five patients of the DMD group, pharmacokinetic modelling was performed from arterial rocuronium concentrations. The time course of neuromuscular block was analysed with a sigmoid E(max) model including an effect compartment. RESULTS: The pharmacokinetics of rocuronium in DMD patients were Vc 63 +/- 14 ml kg(-1), Cl 3.0 +/- 1.0 ml min(-1) kg(-1), half-lives 2.0 +/- 0.6, 20 +/- 10 and 129 +/- 98 min, SE. For both the DMD and the control group, the time course of neuromuscular block could be described by a sigmoid E(max) model using the estimated pharmacokinetic parameters of the DMD group. In patients with DMD, the equilibration between the central and effect compartment was significantly slower (T(1/2)ke0: 9.7 +/- 0.3 vs. 1.3 +/- 0.1 min) and the EC(50) was significantly smaller (512 +/- 20 vs. 1170 +/- 64 ng ml(-1)), whereas the ED(50) was 0.16 +/- 0.02 mg kg(-1) in both groups. CONCLUSION: The pharmacodynamics of rocuronium were significantly altered in patients with DMD, whereas the pharmacokinetics seemed to be similar to those in healthy adults. Patients with DMD were more sensitive with respect to effect site concentration but not with respect to dose.

Concentration-effect relations, prediction probabilities (Pk), and signal-to-noise ratios of different electroencephalographic parameters during administration of desflurane, isoflurane, and sevoflurane in rats.

BACKGROUND: The authors investigated the suitability of different electroencephalographic parameters to quantify the anesthetic effect of desflurane, isoflurane, and sevoflurane in rats. METHODS: Ten male Sprague-Dawley rats were anesthetized in a randomized crossover design with maximum values of 11% desflurane, 2.1% isoflurane, and 3.5% sevoflurane. The electroencephalogram was recorded with implanted electrodes and a wireless telemetry system. Concentration-effect relations and signal-to-noise ratios were determined for the approximate entropy and for the median frequency and the spectral edge frequency, which were modified to account for spikes and burst suppression. The prediction probability Pk with respect to the response to a painful stimulus was determined. RESULTS: All drugs produced deep anesthesia with burst suppression and no response at the highest concentrations. The occurrence of spikes and burst suppression made a modification of median frequency and spectral edge frequency necessary to obtain Pk values greater than 0.5 and monotonic sigmoid concentration-effect relations. The Pk values were between 0.89 and 0.98, with significantly higher values for modified median frequency and spectral edge frequency during desflurane and sevoflurane. The signal-to-noise ratios were between 3.0 and 6.4 dB, with significantly better values for modified spectral edge frequency and approximate entropy during sevoflurane. CONCLUSIONS: If modified for spikes and burst suppression, median frequency and spectral edge frequency as well as the unmodified approximate entropy were able to assess the anesthetic effect of desflurane, isoflurane, and sevoflurane in rats. For sevoflurane, the modified spectral edge frequency was best with regard to signal-to-noise ratio and prediction probability.

The discriminant power of simultaneous monitoring of spontaneous electroencephalogram and evoked potentials as a predictor of different clinical states of general anesthesia.

Spontaneous or evoked electrical brain activity is increasingly used to monitor general anesthesia. Previous studies investigated the variables from spontaneous electroencephalogram (EEG), acoustic (AEP), or somatosensory evoked potentials (SSEP). But, by monitoring them separately, the available information from simultaneous gathering could be missed. We investigated whether the combination of simultaneous information from EEG, AEP, and SSEP shows a more discriminant power to differentiate between anesthesia states than from information derived from each measurement alone. Therefore, we assessed changes of 30 EEG, 21 SSEP, and 29 AEP variables recorded from 59 patients during four clinical states of general anesthesia: "awake," "light anesthesia," "surgical anesthesia," and "deep surgical anesthesia." The single and combined discriminant powers of EEG, AEP, and SSEP variables as predictors of these states were investigated by discriminant analysis. EEG variables showed a higher discriminant power than AEP or SSEP variables: 85%, 46%, and 32% correctly classified cases, respectively. The frequency of correctly classified cases increased to 90% and 91% with information from EEG + AEP and EEG + AEP + SSEP, respectively. Thus, future anesthesia monitoring should consider combined information simultaneously distributed on different electrophysiological measurements, rather than single variables or their combination from EEG or AEP or SSEP.

The orofacial formalin test in mice revisited--effects of formalin concentration, age, morphine and analysis method.

UNLABELLED: The orofacial formalin test is established in rats and was recently transferred to mice. The aim of this study was to determine the ideal formalin concentration for testing analgesic drugs, to examine alternatives for the assessment of nociceptive and non-nociceptive behavior as well as the effects of morphine and age on formalin-induced nociception. Formalin (.5, 1, 2.5, 5, 7.5, 10, and 15%) was injected into the vibrissa of mice. The cumulative nociceptive behavior was measured as well as nociceptive and non-nociceptive behavior based on a score that was recorded over a 5-second observation period once per minute. We also examined the effects of morphine on the nociceptive response induced by 2.5% formalin. Age-dependent differences were tested in the third part of the experiment. NONMEM was used to model the pharmacodynamic effects of formalin and morphine. Injection of formalin lead to a concentration-dependent increase in cumulative nociceptive behavior ratings as well as the specific nociceptive behavior 3 of scratching injection site with hindpaw (score 3). The formalin concentrations that lead to 50% of the maximum effect were 2.6 and 3.3%, respectively, for the continuous rating method and the scoring method. Morphine dose dependently suppressed the nociceptive behavior and the number of score 3 ratings of the nociceptive behavior. Age differences in behavior could not be detected by either analytic method. PERSPECTIVE: To improve the existing behavioral nociceptive assay for pain processed by the trigeminal system, we determined an ideal formalin concentration for the orofacial formalin test in mice, evaluated alternative timesaving analysis approaches, and investigated effects of morphine and age on formalin-induced nociception.

Supra-additive effects of tramadol and acetaminophen in a human pain model.

The combination of analgesic drugs with different pharmacological properties may show better efficacy with less side effects. Aim of this study was to examine the analgesic and antihyperalgesic properties of the weak opioid tramadol and the non-opioid acetaminophen, alone as well as in combination, in an experimental pain model in humans. After approval of the local Ethics Committee, 17 healthy volunteers were enrolled in this double-blind and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (29.6+/-16.2 mA) induced spontaneous acute pain (NRS=6 of 10) and distinct areas of hyperalgesia for painful mechanical stimuli (pinprick-hyperalgesia). Pain intensities as well as the extent of the areas of hyperalgesia were assessed before, during and 150 min after a 15 min lasting intravenous infusion of acetaminophen (650 mg), tramadol (75 mg), a combination of both (325 mg acetaminophen and 37.5mg tramadol), or saline 0.9%. Tramadol led to a maximum pain reduction of 11.7+/-4.2% with negligible antihyperalgesic properties. In contrast, acetaminophen led to a similar pain reduction (9.8+/-4.4%), but a sustained antihyperalgesic effect (34.5+/-14.0% reduction of hyperalgesic area). The combination of both analgesics at half doses led to a supra-additive pain reduction of 15.2+/-5.7% and an enhanced antihyperalgesic effect (41.1+/-14.3% reduction of hyperalgesic areas) as compared to single administration of acetaminophen. Our study provides first results on interactions of tramadol and acetaminophen on experimental pain and hyperalgesia in humans. Pharmacodynamic modeling combined with the isobolographic technique showed supra-additive effects of the combination of acetaminophen and tramadol concerning both, analgesia and antihyperalgesia. The results might act as a rationale for combining both analgesics.

Impact of the CYP3A5 genotype on midazolam pharmacokinetics and pharmacodynamics during intensive care sedation.

OBJECTIVE: Information is lacking on whether the CYP3A5 genotype affects the disposition and effects of midazolam during the long-term intensive care sedation of patients. This study was undertaken to estimate whether the CYP3A5 genotype can explain a relevant portion of pharmacokinetic interindividual variability. METHODS: We determined the CYP3A5 genotype in 71 Caucasian patients who underwent long-term sedation during intensive care treatment. We then assessed the relation between the genotype and both the plasma concentrations of midazolam and 1'-OH-midazolam in 645 plasma samples and the simultaneously estimated Ramsay sedation score, both of which were recorded during routine midazolam drug monitoring. RESULTS: Eight patients had the CYP3A5*1/*3 genotype and 63 patients the CYP3A5*3/*3 genotype. The concentration-dose ratio [C/D; plasma concentration of midazolam (ng/ml) divided by the rate of infusion (mg/h); expressed as the mean (95% confidence interval)] was 87.4 (70.8, 108.9) for the *3/*3 patients and 79.0 (48.9, 129.0) for *1/*3 patients. The corresponding data for infusion rate (IR; in mg/h), Ramsay score (RS) and the ratio 1'-OH-midazolam concentration/midazolam concentration (ROH) for *3/*3 and *1/*3 patients were IR 7.4 (6.2, 8.6) vs. 11.4 (4.9, 17.9), RS 5.4 (5.2, 5.6) vs. 5.3 (4.2, 6.0) and ROH 0.11 (0.09, 0.13) vs. 0.17 (0.11, 0.26), respectively. CONCLUSIONS: The CYP3A5*1/*3 genotype did not lead to an apparently lower midazolam concentration/dose ratio or Ramsay score values. As the present sedation procedure during intensive care therapy may be described as a physician closed-loop titration towards Ramsay scores of 4 +/- 1, our data do not indicate that prior determination of the genotype will result in better care or economic savings.

Concepts of EEG processing: from power spectrum to bispectrum, fractals, entropies and all that.

Over the past two decades, methods of processing the EEG for monitoring anaesthesia have greatly expanded. Whereas power spectral analysis was once the most important tool for extracting EEG monitoring variables, higher-order spectra, wavelet decomposition and especially methods used in the analysis of complex dynamical systems such as non-linear dissipative systems are nowadays attracting much attention. This chapter reviews some of these methods in brief. However, a comparison of some of the newer approaches with the more traditional ones with respect to clinical end-points by association measures and to the signal-to-noise ratio raises some doubt over whether the newer EEG-processing techniques really do better than the more traditional ones.

Electroencephalogram monitoring during anesthesia with propofol and alfentanil: the impact of second order spectral analysis.

Bispectral analysis of the electroencephalogram (EEG) has been used for monitoring anesthesia. The estimation of bicoherence allows us to determine whether a given time series represents a linear random process in cases where the bicoherence is trivial, i.e., a mere constant independent of frequency. In this study, we investigated the proportion of EEG epochs with nontrivial bicoherence during surgical anesthesia with propofol and alfentanil as an indicator for the degree of nonlinearity in the EEG. We reanalyzed 90 h of EEG recorded from 20 patients undergoing abdominal surgery using the Hinich procedure, which provides a statistical test for the following hypothesis: the EEG is a linear random process. In approximately 90% of all artifact-free, stationary EEG epochs, the bicoherence was found to be zero or a mere constant. Under these conditions, the EEG can be considered as a linear random process. Our findings suggest that the spectral information in the frequency domain delivered by the EEG monitoring during anesthesia is largely contained in the power spectrum of the signal. This calls into question the benefit of EEG bispectral analysis for monitoring anesthesia effect.

Binding of propofol to human serum albumin.

The binding properties of the short-acting hypnotic agent propofol (CAS 2078-54-8) to human serum albumin were studied in vitro. Using centrifugation through ultrafiltration membranes the ratio of free and bound propofol as a function of the human serum albumin concentration was determined. In addition, a biomathematical approach was tested that allowed the determination of the number of binding sites from the measured binding profile. At a total propofol concentration of 8.81 +/- 0.25 microg/mL the concentration of the free fraction of propofol ranged from 338 +/- 11 ng/mL (mean +/- SE) at an albumin concentration of 0.5% to 15 +/- 2 ng/ mL at an albumin concentration of 8.0%. The corresponding percentage of propofol binding ranged from 96.07 +/- 0.14% to 99.83 +/- 0.02%. From this binding profile the binding site was estimated to be n(0) = 2. The measured influence of the albumin concentration on propofol binding might be of relevance in states of hypo- or hyperalbuminaemia which could result in an altered demand of propofol.

Sedation with GPI 15715, a water-soluble prodrug of propofol, using target-controlled infusion in volunteers.

GPI 15715 is the first water-soluble propofol prodrug that has been studied in humans. Present propofol lipid formulations have well known undesirable properties, for example, pain on injection and increased triglyceride concentrations. We investigated whether GPI 15715 is suitable to achieve and maintain moderate sedation for 2 h. Six male and six female volunteers received a target-controlled infusion of GPI 15715, with an initial propofol target concentration of 1.8 microg/mL and the possibility to adjust the propofol target once after 1 h. Propofol concentrations, the bispectral index, and modified Observer's Assessment of Alertness/Sedation Scale (MOAA/S) scores were monitored. The median MOAA/S score was 4 during the first hour and was 3 during the second hour of infusion. The propofol target had to be changed to 2.4 microg/mL in seven volunteers and to 3.0 microg/mL in two volunteers. A propofol concentration of 1.9 microg/mL had the highest probability to result in an MOAA/S score of 3, which corresponds with moderate sedation. We observed no serious side effects. We conclude that GPI 15715 produces excellent sedation.

Does the EEG during isoflurane/alfentanil anesthesia differ from linear random data?

OBJECTIVE: Bispectral analysis of the electroencephalogram (EEG) has been used to monitor depth of anesthesia. In the majority of publications this has been done using the so called Bispectral (BIS) Index. The exact relation of this index to bispectral quantities like the bispectrum and its normalized version the bicoherence has not yet been published. In case the EEG is a linear random process the bicoherence is trivial. It is a mere constant independent of the EEG frequency. If the signal is a linear Gaussian random process this constant is zero. In this case both the bispectrum and bicoherence are zero. The aim of this study was to determine the proportion of EEG epochs with non-trivial bicoherence during anesthesia with isoflurane/nitrous oxide. METHODS: We reanalyzed 26.4 hr of EEG signal recorded in 8 patients during anesthesia for general abdominal surgery which were stored in digitized form on CD-Rom. The test developed by Hinich for Gaussianity and linearity was applied to these data. The test was validated with various kinds of surrogate data; especially the phase randomized (pr) EEG, synthetic Gaussian random data and the z-component of the Lorenz attractor and its pr version. RESULTS: The proportion of epochs for which a non-trivial bicoherence was detected by the test was as follows: Lorenz data 95%, pr Lorenz data 5%, synthetic Gaussian data 13.8%, pr EEG 5.4%, original EEG 6.2%. CONCLUSION: As expected the test procedure correctly identified for the Lorenz data for 95% of all epochs a non-trivial bicoherence. For the original EEG data we could not find a significant greater percentage of epochs with non-trivial bicoherence than for the pr data and the synthetic Gaussian data. We conclude that the EEG during anesthesia with isoflurane/alfentanil appears to be largely a linear random process.

Midazolam therapeutic drug monitoring in intensive care sedation: a 5-year survey.

During a 5-year period, 1997 to 2002, therapeutic drug monitoring of midazolam plasma concentrations in combination with the level of sedation as assessed by the Ramsay sedation scale was performed in 648 critically ill patients requiring artificial ventilation. In a subgroup of 189 patients sepsis-related organ failure assessment procedure was additionally performed. A total number of 3354 samples were analyzed. Significantly reduced clearance of midazolam was observed within the first 4 days of midazolam treatment of critically ill patients. As a result, accumulation of midazolam and its metabolites occurred within the first week of treatment. In contrast, parameters such as serum bilirubin or creatinine, which are commonly used to adapt drug therapy to organ dysfunction, showed significant changes with a delay of more than 10 days as compared with the findings of midazolam monitoring. Midazolam plasma concentrations showed a good correlation with the sedative capacity of the drug (r2 = 0.906). However, a great variability of the drug effect between patients could be demonstrated, which, as a consequence, may complicate the development of dosing strategies based on midazolam plasma concentrations to better control sedation in critically ill patients. Furthermore, patient age seems to be an important factor for the considerable variability of the sedative effect of midazolam. To achieve a certain levels of sedation, significantly lower midazolam infusion rates as well as plasma concentrations were required as the patients age increased. No significant sex-related differences could be observed for any pharmacologic parameter obtained in this study. Our findings suggest that midazolam therapeutic drug monitoring might be a useful tool to individualize midazolam therapy, especially in critically ill patients developing organ dysfunction and requiring long-term sedation to minimize the risk of drug accumulation and excessive sedation.

Modelling acute tolerance to the EEG effect of two benzodiazepines.

AIMS: We studied the development of acute tolerance to the EEG effect of midazolam and the new benzodiazepine Ro 48-6791. METHODS: Nine young (24-28 years) and nine elderly (67-81 years) male volunteers received midazolam and Ro 48-6791 computer-controlled, targeting linearly increasing plasma concentrations for 30 min (targeted slopes: 40 and 20 ng ml-1 min-1 for midazolam, 3 and 1.5 ng ml-1 min-1 for Ro 48-6791, for young and elderly, respectively) and a constant concentration for the following 15 min. After recovery, the same infusion scheme was repeated. Plasma concentrations of midazolam, Ro 48-6791 and its metabolite Ro 48-6792 were determined from arterial blood samples. The hypnotic effect was assessed using the median frequency of the EEG power spectrum. RESULTS: The concentration-effect relationship in each infusion cycle could be described by a sigmoid Emax model. The half-maximum concentration EC50 was higher in the second infusion cycle compared with the first one (midazolam, 47% (2.3-91.6%) and 37% (5.3-69.5%); Ro 48-6791, 22% (-2.8% to 44.6%) and 43% (3.4-82.4%) for young and elderly; mean and 95% confidence interval). The complete time course of the EEG median frequency could be described by an interaction between the parent drug in an effect compartment and a hypothetical competitive drug in an additional tolerance compartment. For Ro 48-6791, the use of its metabolite Ro 48-6792 as competitive compound also gave appropriate results. CONCLUSION: Midzolam and Ro 48-6791 showed acute tolerance to the EEG effect which might be caused by competitive interaction with the metabolite.

Comparative pharmacokinetics and pharmacodynamics of the new propofol prodrug GPI 15715 and propofol emulsion.

BACKGROUND: GPI 15715 is a new water-soluble prodrug that is hydrolyzed to release propofol. The objectives of this crossover study in volunteers were to investigate the pharmacokinetics and pharmacodynamics of GPI 15715 in comparison with propofol emulsion. METHODS: In two separate sessions, nine healthy male volunteers (19-35 yr, 70-86 kg) received GPI 15715 and propofol emulsion as a target controlled infusion over 60 min. In the first 20 min, the propofol target concentration increased linearly to 5 microg/ml. Subsequently, the targets were reduced to 3 microg/ml and 1.5 microg/ml for 20 min each. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h and pharmacokinetics were analyzed. The pharmacodynamic effect was measured by the median frequency of the power spectrum of the electroencephalogram, and a sigmoid model with effect compartment was fitted to the data. RESULTS: Compared with propofol emulsion, propofol from GPI 15715 showed a different disposition function and especially larger volumes of distribution. The propofol effect site concentration for half maximum effect was 2.0 +/- 0.5 microg/ml for GPI 15715 and 3.0 +/- 0.7 microg/ml for propofol emulsion (P < 0.05). Propofol from GPI 15715 did not show a hysteresis between plasma concentration and effect. CONCLUSIONS: Compared with propofol emulsion, propofol from GPI 15715 showed different pharmacokinetics and pharmacodynamics, particularly a higher potency with respect to concentration. These differences may indicate an influence of the formulation.