Jürgen Schüttler

Selenium in Intensive Care (SIC): results of a prospective randomized, placebo-controlled, multiple-center study in patients with severe systemic inflammatory response syndrome, sepsis, and septic shock.

Objective: Sepsis is associated with an increase in reactive oxygen species and low endogenous antioxidative capacity. We postulated that high‐dose supplementation of sodium‐selenite would improve the outcome of patients with severe sepsis and septic shock. Design: Prospective randomized, placebo‐controlled, multiple‐center trial. Setting: Eleven intensive care units in Germany. Patients: Patients were 249 patients with severe systemic inflammatory response syndrome, sepsis, and septic shock and an Acute Physiology and Chronic Health Evaluation (APACHE) III score >70. Interventions: Patients received 1000 &mgr;g of sodium‐selenite as a 30‐min bolus injection, followed by 14 daily continuous infusions of 1000 &mgr;g intravenously, or placebo. Measurements and Main Results: The primary end point was 28‐day mortality; secondary end points were survival time and clinical course of APACHE III and logistic organ dysfunction system scores. In addition, selenium levels in serum, whole blood, and urine as well as serum gluthation‐peroxidase‐3 activity were measured. From 249 patients included, 11 patients had to be excluded. The intention‐to‐treat analysis of the remaining 238 patients revealed a mortality rate of 50.0% in the placebo group and 39.7% in the selenium‐treated group (p = .109; odds ratio, 0.66; confidence interval, 0.39–1.1). A further 49 patients had to be excluded before the final analysis because of severe violations of the study protocol. In the remaining 92 patients of the study group, the 28‐day mortality rate was significantly reduced to 42.4% compared with 56.7% in 97 patients of the placebo group (p = .049, odds ratio, 0.56; confidence interval, 0.32–1.00). In predefined subgroup analyses, the mortality rate was significantly reduced in patients with septic shock with disseminated intravascular coagulation (n = 82, p = .018) as well as in the most critically ill patients with an APACHE III score ≥102 (>75% quartile, n = 54, p = .040) or in patients with more than three organ dysfunctions (n = 83, p = .039). Whole blood selenium concentrations and glutathione peroxidase‐3 activity were within the upper normal range during selenium treatment, whereas they remained significantly low in the placebo group. There were no side effects observed due to high‐dose sodium‐selenite treatment. Conclusions: The adjuvant treatment of patients with high‐dose sodium‐selenite reduces mortality rate in patients with severe sepsis or septic shock.

Population pharmacokinetics of propofol: a multicenter study.

Background: Target-controlled infusion is an increasingly common type of administration for propofol. This method requires accurate knowledge of pharmacokinetics, including the effects of age and weight. The authors performed a multicenter population analysis to quantitate the effects of covariates. Methods: The authors analyzed 4,112 samples of 270 individuals (150 men, 120 women, aged 2–88 yr, weighing 12–100 kg). Population pharmacokinetic modeling was performed using NONMEM (NONMEM Project Group, University of California, San Francisco, CA). Inter- and intraindividual variability was estimated for clearances and volumes. The effects of age, weight, type of administration and sampling site were investigated. Results: The pharmacokinetics of propofol were best described by a three-compartment model. Weight was found to be a significant covariate for elimination clearance, the two intercompartmental clearances, and the volumes of the central compartment, the shallow peripheral compartment, and the deep peripheral compartment; power functions with exponents smaller than 1 yielded the best results. The estimates of these parameters for a 70-kg adult were 1.44 l/min, 2.25 l/min, 0.92 l/min, 9.3 l, 44.2 l, and 266 l, respectively. For patients older than 60 yr the elimination clearance decreased linearly. The volume of the central compartment decreased with age. For children, all parameters were increased when normalized to body weight. Venous data showed a decreased elimination clearance; bolus data were characterized by increases in the volumes of the central and shallow peripheral compartments and in the rapid distribution clearance (Cl2) and a decrease in the slow distribution clearance (Cl3). Conclusions: Pharmacokinetics of propofol can be well described by a three-compartment model. Inclusion of age and weight as covariates significantly improved the model. Adjusting pharmacokinetics to the individual patient should improve the precision of target-controlled infusion and may help to broaden the field of application for target-controlled infusion systems.

Different profiles of buprenorphine-induced analgesia and antihyperalgesia in a human pain model

&NA; Different mechanisms were proposed for opioid‐induced analgesia and antihyperalgesia, which might result in different pharmacodynamics. To address this issue, the time course of analgesic and antihyperalgesic effects of intravenous (i.v.) and sublingual (s.l.) buprenorphine was assessed in an experimental human pain model. Fifteen volunteers were enrolled in this randomized, double‐blind, and placebo controlled cross‐over study. The magnitude of pain and the area of secondary hyperalgesia following transcutaneous stimulation were repetitively assessed before and up to 150 min after administration of (1) 0.15 mg buprenorphine i.v. and placebo pill s.l., (2) 0.2 mg buprenorphine s.l. and saline 0.9% i.v. or (3) saline 0.9% i.v. and placebo pill s.l. as a control. The sessions were separated by 2 week wash‐out periods. For both applications of buprenorphine the antihyperalgesic effects were more pronounced as compared to the analgesic effects (66±9 vs. 26±5% and 43±10 vs. 10±6%, for i.v. and s.l. application, respectively). This contrasts the pattern for the intravenous administration of pure μ‐receptor agonists in the same model in which the antihyperalgesic effects are weaker. The apparent bioavailability of buprenorphine s.l. as compared to buprenorphine i.v. was 58% with a 15.8 min later onset of antinociceptive effects. The half‐life of buprenorphine‐induced analgesic and antihyperalgesic effects were 171 and 288 min, respectively. In contrast to pure μ‐receptor agonists, buprenorphine exerts a lasting antihyperalgesic effect in our model. It will be of major clinical interest whether this difference will translate into improved treatment of pain states dominated by central sensitization.

Closed-loop feedback control of methohexital anesthesia by quantitative EEG analysis in humans.

A combined pharmacokinetic and pharmacodynamic model of methohexital was used to establish and evaluate feedback control of methohexital anesthesia in 13 volunteers. The median frequency of the EEG power spectrum served as the pharmacodynamic variable constituting feedback. Median frequency values from 2–3 Hz were chosen as the desired EEG level (set-point). In 11 volunteers, the feedback system succeeded in maintaining a satisfactory depth of anesthesia (i.e., unresponsiveness to verbal commands and tactile stimuli). During feedback control, 75% of all measured median frequency values were in the preset range of 2–3 Hz. This distribution of median frequency was obtained by applying random stimulation (six different acoustic and tactile stimuli) to the volunteers approximately every 1.5 min. The decrease of median frequency from baseline to anesthetic values was primarily induced by increasing the fractional power in the frequency band of 0.5–2 Hz from 12.6 ± 4.5% (mean ± SD) to 46.0 ± 2.5%. The median time to recovery (as defined by opening eyes on command) after cessation of the feedback control period was 20.6 min (10.7–44.5 min) when median EEG frequency was 5.2 Hz (4.7–8.4 Hz). The average requirement of methohexital (mean ± SD) during the 2 h was 1.02 ± 0.16 g. It is concluded that pharmacokinetic-pharmacodynamic models of intravenous anesthetics established previously may be used to form a suitable background for model-based feedback control of anesthesia by quantitative EEG analysis. This approach gives a possible solution to the problem of adapting pharmacokinetic and pharmacodynamic data to individuals when using population mean data as starting values for drug therapy.

Coincidence of pro- and anti-inflammatory responses in the early phase of severe sepsis: Longitudinal study of mononuclear histocompatibility leukocyte antigen-DR expression, procalcitonin, C-reactive protein, and changes in T-cell subsets in septic and postoperative patients.

ObjectiveTo determine the time course of histocompatibility leukocyte antigen (HLA)-DR expression in peripheral blood mononuclear cells and their relationship to markers of inflammation, organ function, and outcome during severe sepsis. DesignProspective, longitudinal study. SettingUniversity hospital intensive care unit. PatientsTwenty-three postoperative patients with severe sepsis and 26 patients with uneventful postoperative course as well as 24 healthy, age-matched subjects. InterventionsSerum procalcitonin was determined by using an immunochemiluminescence assay, and C-reactive protein and leukocyte antigens were determined by using flow cytometry over 14 days in parallel with clinical data collection. Measurements and Main ResultsDespite a relative lymphopenia, absolute lymphocyte counts and CD4+/CD8+ T-cell ratio in septic patients were significantly elevated above normal. Particularly, CD4+ and CD8+ T-cell counts in nonsurvivors of sepsis were approximately twice as high as those of survivors. Significantly decreased monocytic HLA-DR expression was observed in both survivors and nonsurvivors at the onset of severe sepsis. Percentages of HLA-DR+ lymphocytes, however, were significantly increased during sepsis, especially in nonsurvivors. Whereas survivors of sepsis showed a continuous recovery of monocytic HLA-DR expression to ≥70% within 10 days, nonsurvivors were characterized by a second decrease in monocytic HLA-DR expression after day 7 or a permanent suppression (<40%). Peak of systemic inflammatory reaction, documented by maximum serum concentrations of procalcitonin and C-reactive protein, coincided with the nadir of monocytic HLA-DR expression. Moreover, procalcitonin and C-reactive protein as well as scores on the Acute Physiology and Chronic Health Evaluation II and Sepsis Organ Failure Assessment were inversely correlated with the monocytic HLA-DR expression. ConclusionsDecreases in monocytic HLA-DR expression occurred simultaneously with signs of hyperinflammation as early as the onset of severe sepsis and usually developed in opposite directions than inflammatory markers and sepsis severity scores.

Pharmacodynamic modeling of the EEG effects of ketamine and its enantiomers in man

The pharmacodynamics of a racemic mixture of ketamine R,S (±)-ketamine and of each enantiomer, S(+)-ketamine and R(−)-ketamine, were studied in five volunteers. The median frequency of the electroencephalogram (EEG) power spectrum, a continuous noninvasive measure of the degree of central nervous system (CNS) depression (pharmacodynamics), was related to measured serum concentrations of drug (pharmacokinetics). The concentration-effect relationship was described by an inhibitory sigmoid Emax pharmacodynamic model, yielding estimates of both maximal effect (Emax) and sensitivity (IC50) to the racemic and enantiomeric forms of ketamine. R(−)-ketamine was not as effective as R,S(±)-ketamine or S(+)-ketamine in causing EEG slowing. The maximal decrease (mean±SD) of the median frequency (Emax)for R(−)-ketamine was 4.4±0.5 Hz and was significantly different fromR,S (±)-ketamine (7.6 ±1.7 Hz) and S(+)-ketamine (8.3±1.9Hz). The ketamine serum concentration that caused one-half of the maximal median frequency decrease (IC50) was 1.8±0.5Μg/mL for R(−)-ketamine; 2.0±0.5 Μg/mL for R,S(±)-ketamine; and 0.8±0.4 Μg/mL for S(+)-ketamine. Because the maximal effect (Emax) of the R(−)-ketamine was different from that of S(+)-ketamine and R,S(±)-ketamine, it was not possible to directly compare the potency (i.e., IC50) of these compounds. Accordingly, a classical agonist/partial-agonist interaction model was examined, using the separate enantiomer results to predict racemate results. Although the model did not predict racemate results well, its failure was not so great as to provide clear evidence of synergism (or excess antagonism) of the enantiomers.

Pharmacokinetics and clinical pharmacodynamics of the new propofol prodrug GPI 15715 in volunteers.

BACKGROUND GPI 15715 (AQUAVAN injection) is a new water-soluble prodrug which is hydrolyzed to release propofol. The objectives of this first study in humans were to investigate the safety, tolerability, pharmacokinetics, and clinical pharmacodynamics of GPI 15715. METHODS Three groups of three healthy male volunteers (aged 19-35 y, 67-102 kg) received 290, 580, and 1,160 mg GPI 15715 as a constant rate infusion over 10 min. The plasma concentrations of GPI 15715 and propofol were measured from arterial and venous blood samples up to 24 h. Pharmacokinetics were analyzed with compartment models. Pharmacodynamics were assessed by clinical signs. RESULTS GPI 15715 was well tolerated without pain on injection. Two subjects reported a transient unpleasant sensation of burning or tingling at start of infusion. Loss of consciousness was achieved in none with 290 mg and in one subject with 580 mg. After 1,160 mg, all subjects experienced loss of consciousness at propofol concentrations of 2.1 +/- 0.6 microg/ml. A two-compartment model for GPI 15715 (central volume of distribution, 0.07 l/kg; clearance, 7 ml. kg-1 min-1; terminal half-life, 46 min) and a three-compartment model for propofol (half-lives: 2.2, 20, 477 min) best described the data. The maximum decrease of blood pressure was 25%; the heart rate increased by approximately 35%. There were no significant laboratory abnormalities. CONCLUSIONS Compared with propofol lipid emulsion, the potency seemed to be higher with respect to plasma concentration but was apparently less with respect to dose. Pharmacokinetic simulations showed a longer time to peak propofol concentration after a bolus dose and a longer context-sensitive half-time.

Endobronchial instillation of epinephrine during cardiopulmonary resuscitation

We used a standard animal CPR model to study the effectiveness and hemodynamic response of 100 micrograms/kg epinephrine administered endobronchially and to compare the findings after conventional iv administration. Results showed that the endobronchial and iv epinephrine medication improved the survival rate by 100% compared to that of a control group receiving no medication. Although the hemodynamic conditions during cardiac compression were not significantly different after both routes of drug administration, endobronchial instillation produced a prolonged drug action during the first hour of restored spontaneous circulation. A more extensive use of this type of drug administration, especially in out-of-hospital resuscitation, is suggested.

Modulation of Remifentanil-induced Postinfusion Hyperalgesia by Propofol

BACKGROUND:Experimental and clinical studies suggest that brief opioid exposure can enhance pain sensitivity. During anesthesia, however, opioids are commonly administered in combination with either IV or inhaled hypnotic drugs. In this investigation we sought to determine the analgesic and antihyperalgesic properties of propofol in subhypnotic concentrations on remifentanil-induced postinfusion hypersensitivity in an experimental human pain model. METHODS:Fifteen healthy volunteers were included in this randomized, double-blind, and placebo-controlled study in a cross-over design. Transcutaneous electrical stimulation at high current densities (41.7 ± 14.3 mA) induced spontaneous acute pain (numerical rating scale = 6 of 10) and stable areas of hyperalgesia. Pain intensities and areas of hyperalgesia were assessed before, during and after a 30 min target-controlled infusion of propofol (1.5 &mgr;g/mL) and remifentanil (0.05 &mgr;g · kg−1 · min−1), either alone or in combination (propofol 1.5 &mgr;g/mL with remifentanil 0.025 or 0.05 &mgr;g · kg−1 · min−1). RESULTS:During infusion, propofol significantly reduced the electrically evoked pain to 72% ± 21% of control. Subhypnotic concentrations of propofol did not lead to any hyperalgesic effects. Coadministration of remifentanil led to synergistic analgesic effects (to 62% ± 26% and 58% ± 25% of control, for 0.025 or 0.05 &mgr;g · kg−1 · min−1, respectively), but upon withdrawal, pain and hyperalgesia increased above control level. CONCLUSIONS:The results suggest clinically relevant interactions of propofol and remifentanil in humans, since propofol led to a delay and a weakening of remifentanil-induced postinfusion anti-analgesia in humans. Nevertheless, pronociceptive effects were not completely antagonized by propofol, which may account for the increased demand for analgesics after remifentanil-based anesthesia in clinical practice.

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

&NA; 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 37.5 mg 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.