Rolf Lauber

Dexmedetomidine Decreases Thiopental Dose Requirement and Alters Distribution Pharmacokinetics

Backgroundα2-Adrenergic agonists such as dexmedetomidine can be used to reduce the dose requirement of intravenous and volatile anesthetics. Whereas dexmedetomidine and volatile anesthetics interact pharmacodynamically (reduction of MAC), the mechanism of interaction between dexmedetomidine and intravenous anesthetics is not known. MethodsFourteen male ASA physical status 1 patients were randomly assigned to serve as control subjects (n = 7) or to be treated with dexmedetomidine (n = 7; 100, 30, and 6 ng. kg−1. min−1 for 10 min, 15 min, and thereafter, respectively). After 35 min, in all patients, thiopental (100 mg/min) was infused until burst suppression appeared in the raw tracing of the electroencephalogram. By using concentrations of thiopental in plasma and the electroencephalogram as a continuous pharmacologic effect measure, the apparent effect site concentrations for thiopental were estimated in both groups. Three-compartment pharmacokinetics were calculated for thiopental. ResultsDexmedetomidine reduced the thiopental dose requirement for electroencephalographic burst suppression by 30%. There was no difference in estimated thiopental effect site concentrations between dexmedetomidine and control patients, suggesting the absence of a major pharmacodynamic interaction. Dexmedetomidine significantly decreased distribution volumes (V2, V3, and Vdss) and distribution clearances (Cl1Z and Cl13) of thiopental. ConclusionsThe thiopental dose-sparing effect of dexmedetomidine on the electroencephalogram is not the result of a pharmacodynamic interaction but rather can be explained by a dexmedetomidlne-lnduced decrease in thiopental distribution volume and distribution clearances. Dexmedetomidine reduces thiopental distribution, most probably by decreasing cardiac output and regional blood flow.

Meperidine and skin surface warming additively reduce the shivering threshold: a volunteer study

IntroductionMild therapeutic hypothermia has been shown to improve outcome for patients after cardiac arrest and may be beneficial for ischaemic stroke and myocardial ischaemia patients. However, in the awake patient, even a small decrease of core temperature provokes vigorous autonomic reactions–vasoconstriction and shivering–which both inhibit efficient core cooling. Meperidine and skin warming each linearly lower vasoconstriction and shivering thresholds. We tested whether a combination of skin warming and a medium dose of meperidine additively would reduce the shivering threshold to below 34°C without producing significant sedation or respiratory depression.MethodsEight healthy volunteers participated on four study days: (1) control, (2) skin warming (with forced air and warming mattress), (3) meperidine (target plasma level: 0.9 μg/ml), and (4) skin warming plus meperidine (target plasma level: 0.9 μg/ml). Volunteers were cooled with 4°C cold Ringer lactate infused over a central venous catheter (rate ≈ 2.4°C/hour core temperature drop). Shivering threshold was identified by an increase of oxygen consumption (+20% of baseline). Sedation was assessed with the Observers Assessment of Alertness/Sedation scale.ResultsControl shivering threshold was 35.5°C ± 0.2°C. Skin warming reduced the shivering threshold to 34.9°C ± 0.5°C (p = 0.01). Meperidine reduced the shivering threshold to 34.2°C ± 0.3°C (p < 0.01). The combination of meperidine and skin warming reduced the shivering threshold to 33.8°C ± 0.2°C (p < 0.01). There were no synergistic or antagonistic effects of meperidine and skin warming (p = 0.59). Only very mild sedation occurred on meperidine days.ConclusionA combination of meperidine and skin surface warming reduced the shivering threshold to 33.8°C ± 0.2°C via an additive interaction and produced only very mild sedation and no respiratory toxicity.

Adding Sodium Bicarbonate to Lidocaine Enhances the Depth of Epidural Blockade

It is controversial whether adding CO2 or sodium bicarbonate to local anesthetics enhances the depth of epidural blockade.Repeated electrical stimulation is a reliable test for assessing epidural analgesia and evokes temporal summation. We used this test to investigate the analgesic effect of lidocaine, with or without CO2 or bicarbonate. Twenty-four patients undergoing epidural blockade with 20 mL lidocaine 2% at L2-3 were randomly divided into three groups: lidocaine hydrochloride, lidocaine CO2, and lidocaine plus 2 mL sodium bicarbonate 8.4%. Pain threshold after repeated electrical stimulation (five impulses at 2 Hz), pinprick, and cold test were performed at S1 and L4. Motor block was assessed. The addition of bicarbonate resulted in higher pain thresholds (P < 0.0001), faster onset of action (P = 0.009), and higher degree of motor block (P = 0.004) compared with lidocaine hydrochloride. We found no significant differences between lidocaine CO2 and hydrochloride. Most of these results were not confirmed by pinprick and cold tests. We conclude that the addition of sodium bicarbonate to lidocaine enhances the depth of epidural blockade, increases inhibition of temporal summation, and hastens the onset of block. Pinprick and cold are inadequate tests for comparing drugs for epidural anesthesia. Implications: We measured pain perception during epidural anesthesia by delivering electrical stimuli to the knee and foot. We found that the addition of sodium bicarbonate to the local anesthetic lidocaine enhances analgesia. We observed no effect of adding carbon dioxide to lidocaine. (Anesth Analg 1998;86:341-7)

Automated determination of midazolam in human plasma by high-performance liquid chromatography using column switching

An automated gradient high-performance liquid chromatographic method using a column-switching technique was developed in order to determine and quantify midazolam (separated from the metabolite alpha-hydroximidazolam) in human plasma. After dilution with an internal standard (flurazepam) solution, containing 20% acetonitrile, 400 microliters of the plasma samples were injected onto a precolumn (17 x 4.6 mm I.D., C18 Corasil 37-53 microns) and retained. Proteins and polar plasma components were washed out using a 0.1 M sodium hydroxide solution, followed by an equilibration with a phosphate buffer of pH 8.0. After column-switching midazolam and flurazepam were eluted and transferred to the analytical column (RP-select B) in the backflush mode, separated by gradient elution and detected at 230 nm by ultraviolet detection. Precision of replicate analyses on the same day was 1.5% for midazolam and 0.7% for flurazepam. Recovery of midazolam was in the range 80-89% and the detection limit was 2 ng/ml plasma.

Carbon dioxide analysers: accuracy, alarm limits and effects of interfering gases

Six mainstream and twelve sidestream infrared carbon dioxide (CO2) analysers were tested for accuracy of the CO2 display value, alarm activation and the effects of nitrous oxide (N2O), oxygen (O2) and water vapour according to the ISO Draft International Standard (DIS) #9918. Mainstream analysers (M-type): Novametrix Capnogard 1265; Hewlett Packard HP M1166A (CO2module HP M1016A); Datascope Passport; Marquette Tramscope 12; Nellcor Ultra Cap N-6000; Heilige Vicom-sm SMU 611/612 ETC. Sidestream analysers: Brüel & Kjaer Type 1304; Datex Capnomac II; Marquette MGA-AS; Datascope Multinex; Ohmeda 4700 OxiCap (all type S1: respiratory cycles not demanded); Biochem BCI 9000; Bruker BCI 9100; Dräger Capnodig and PM 8020; Criticare Poet II; Heilige Vicom-sm SMU 611/612 A-GAS (all type S2: respiratory cycles demanded). The investigations were performed with premixed test gases (2.5, 5, 10 vol%, error ⪯1% rel.). Humidification (37° C) of gases were generated by a Dräger Aquapor. Respiratory cycles were simulated by manually activated valves. All monitors complied with the tolerated accuracy bias in CO2 reading (≤ 12% or 4 mmHg of actual test gas value) for wet and dry test gases at all concentrations, except that the Marquette MGA-AS exceeded this accuracy limit with wet gases at 5 and 10 vol% CO2. Water condensed in the metal airway adapter of the HP M1166A at 37° C gas temperature but not at 3(P C. The Servomex 2500 (nonclinical reference monitor), Passport (M-type), Multinex (S1-type) and Poet II (S2-type) showed the least bias for dry and wet gases. Nitrous oxide and O2 had practically no effect on the Capnodig and the errors in the others were max. 3.4 mmHg, still within the tolerated bias in the DIS (same as above). The difference between the display reading at alarm activation and the set point was in all monitors (except in the Capnodig: bias 1.75 mmHg at 5 vol% CO2) below the tolerated limit of the DIS (difference ≤ 0.2 vol%). The authors conclude that the tested monitors are safe for clinical use (except those failing the DIS limits). The accuracy of the CO2-reading (average of mean absolute bias) is better in the M-type than in the S1- or S2- type analysers although no statistical (nor clinical) significant differences could be detected. Most manufacturers work with stricter limits than those proposed by the DIS.RésuméDes analyseurs de gaz carbonique (CO2 à infrarouge dont six à soutirage latéral et 12 de courant central sont évalués au regard de la précision, de l’activation des alarmes et des effets du protoxyde d’azote (N2O), de l’oxygène (O2 et de la vapeur d’eau conformément à la norme internationale ISO (DIS) 9918. Les analyseurs de courant central sont les suivants: (Type-M): Novametrix Capnogard 1265; Hewlett Packard HP M1166A (CO2module HP M1016A); Datascope Passport; Marquette Tramscope 12; Nellcor Ultra Cap N-6000; Hellige Vicom-sm SMU 611/612 ETC. Les analyseurs à soutirage latéral: Brüel & Kjaer Type 1304; Datex Capnomac II; Marquette MGA-AS; Datascope Multinex; Ohmeda 4700 OxiCap (tous de type S1: sans demande de cycle respiratoire); Biochem BCI 9000; Bruker BCI 9100; Dräger Capnodig et PM 8020; Criticare Poet II; Hellige Vicom-sm SMU 611/612 A-Gas (tous de type S2: avec demande de cycle respiratoire). Les études sont réalisées avec des gaz étalons prémélangés (2,5, 5, 10 vol.%, erreur relative ≤ 1%). Les gaz sont humidifiés (37% C)grâce à un Dräger Aquapor. Les cycles respiratoires sont simulés par des valves actionnées manuellement. Par rapport au biais de tolérance, tous les capnographes sont précis pour la lecture du CO2 (≤ 12% ou 4 mmHg de la valeur du gaz étalon) pour les gaz secs et humidifiés entre 5 et 10% en vol. de CO2. L’eau se condense sur le raccord métallique du HP M1166A à 37° C mais non à 30°C. Le Servomex 2500 (moniteur de référence non clinique), Passport (Type M) Multinex (Type S1) et Poet II (Type S2) sont ceux qui offrent le moins de biais pour les gaz sees et humides. Le protoxyde d’azote et l’O2 n’ont pratiquement pas d’influence sur le Capnodig et les erreurs pour les autres capnographes sont au maximum de 3,4 mmHg, ce qui est toujours en deçà du biais toléré par le DIS. La difference entre l’affichage et l’activation de l’alarme pour un niveau donné est la même pour tous les moniteurs (à l’exception du Capnodig: biais 1,75 mmHg pour un vol. CO2 5%) sous la limite tolérée du DIS (difference ≤0,2 vol%). Les auteurs concluent que les moniteurs mis à l’épreuve sont satisfaisantspour l’usage clinique (excepté ceux qui sont en deçà des limites déterminées par le DIS). La précision de la lecture du CO2 (la moyenne du biais absolu) est supSrieure pour les appareils de type M aux analyseurs de type SI et S2 bien qu’aucune difference statistique (ou clinique) n’ait été décelée. La plupart des manufacturers utilisent des limites plus strides que celle que recommande le DIS.

The Effects of Nefopam on the Gain and Maximum Intensity of Shivering in Healthy Volunteers

BACKGROUND: Mild hypothermia has been shown to improve neurologic outcome after cardiac arrest. Nefopam, a centrally acting, nonsedative analgesic, decreases the threshold of shivering, but not vasoconstriction, and thus might be a suitable drug for induction of therapeutic hypothermia. However, not only the threshold but also the gain and maximum intensity of shivering define the thermoregulatory properties of a drug and thus are clinically important. Therefore, we evaluated the gain and maximum intensity of shivering at 2 different doses of nefopam and placebo. METHODS: Seven healthy volunteers were randomly assigned to 3 study days: (1) control (saline), (2) small-dose nefopam (50 ng/mL), and (3) large-dose nefopam (100 ng/mL). On all study days volunteers were cooled using central venous infusion of cold IV fluid while mean skin temperature was maintained at 31°C. Core temperature was recorded at the tympanic membrane. Threshold, gain, and maximum intensity of shivering were evaluated using oxygen consumption. RESULTS: Both 50 and 100 ng/mL nefopam significantly reduced the shivering threshold as well as the gain of shivering: shivering threshold: 35.6°C ± 0.2°C (control); 35.2°C ± 0.3°C (small dose); 34.9°C ± 0.5°C (large dose), P = 0.004; gain of shivering: 597 ± 235 mL · min−1 · °C−1 (control); 438 ± 178 mL · min−1 · °C−1 (small dose); 301 ± 134 mL · min−1 · °C−1 (large dose), P = 0.028. Maximum intensity of shivering did not differ among the 3 treatments. CONCLUSIONS: Nefopam significantly reduced the gain of shivering. This reduction, in combination with a reduced shivering threshold, will allow clinicians to cool patients even further when therapeutic hypothermia is indicated.

Bispectral index dynamics during propofol hypnosis is similar in red-haired and dark-haired subjects.

BACKGROUND:We have previously shown that red hair is associated with increased desflurane requirement for immobility, compared with dark hair. The effect of red hair on IV anesthetic requirement remains unknown. We tested the hypothesis that the propofol concentration in the effect site associated with half maximal electroencephalogram response, Ce50, is at least 50% higher in subjects with red hair. METHODS:We modeled the propofol concentration versus electroencephalogram response relationship using a 2-step approach in 29 healthy dark- and red-haired volunteers receiving a propofol infusion to produce loss of consciousness. Bispectral Index (BIS) was the measure of drug effect. The parameters of a 3-compartment pharmacokinetic model were fit to measured arterial propofol concentrations. The relationship between effect-site propofol concentration (Ce) and BIS was characterized using a sigmoid Emax model. Model performance and accuracy of the estimated parameters were evaluated using accepted metrics and bootstrap resampling. The effect of hair color on the Ce50 for BIS response in the final model was assessed using a threshold of 6.63 (P < 0.01) in reduction of −2 log likelihood. The influence of body weight on the model was also assessed. RESULTS:The inclusion of hair color as a model covariate did not improve either the pharmacokinetic or the pharmacodynamic model. A separate analysis for the dark- and red-haired subjects estimated a median (95% confidence interval) Ce50 BIS of 2.71 &mgr;g/mL (2.28–3.36 &mgr;g/mL) and 2.57 &mgr;g/mL (1.68–3.60 &mgr;g/mL), respectively. Body weight was a significant covariate for the CL1 and V1. CONCLUSIONS:Red hair phenotype does not affect the pharmacokinetics or pharmacodynamics of propofol.

Nitrous oxide decreases solubility of isoflurane and halothane in blood

This study investigated the effects of carrier gases on the solubility of isoflurane or halothane in blood. The blood/gas partition coefficients (λblood/gas) of 1 minimum alveolar anesthetic concentration of isoflurane or halothane in 100% oxygen, 30% oxygen with 70% nitrous oxide, 100% nitrous oxide or air were measured at 37°C, with blood from four donors. The values of isoflurane or halothane in 100% nitrous oxide (1.42 ± 0.03; 2.59 ± 0.05) were lower (P < 0.05) than those obtained when using 100% oxygen (1.53 ± 0.02; 2.71 ± 0.05) or air (1.54 ± 0.03; 2.74 ± 0.05). To determine the effect of absence of oxygen in the blood containing nitrous oxide on solubility, λblood/gas of 1 minimum alveolar anesthetic concentration of isoflurane or halothane in 100% oxygen, a gas mixture (30% oxygen and 70% nitrous oxide) or 100% nitrous oxide were measured under the same conditions. The values of isoflurane or halothane in 100% nitrous oxide (1.29 ± 0.03; 2.25 ± 0.08) and in a gas mixture of 30% oxygen and 70% nitrous oxide (1.33 ± 0.04; 2.29 ± 0.05) were lower (P < 0.05) than those obtained with 100% oxygen (1.40 ± 0.03; 2.37 ± 0.04). We conclude that nitrous oxide decreases the λblood/gas of isoflurane or halothane, and that this change of solubility, although small, increases the uptake rate of halothane or isoflurane.