The place for short-acting opioids: special emphasis on remifentanil

Pain is among the worst possible experiences for the critically ill. Therefore, nearly all intensive care patients receive some kind of pain relief, and opioids are most frequently administered. Morphine has a number of important adverse effects, including histamine release, pruritus, constipation, and, in particular, accumulation of morphine-6-glucuronide in patients with renal impairment. Hence, it is not an ideal analgesic for use in critically ill patients. Although the synthetic opioids fentanyl, alfentanil, and sufentanil have better profiles, they undergo hepatic metabolism and their continuous infusion also leads to accumulation and prolonged drug effects. Various attempts have been made to limit these adverse effects, including daily interruption of infusion of sedatives and analgesics, intermittent bolus injections rather than continuous infusions, and selection of a ventilatory support pattern that allows more spontaneous ventilation. However, these techniques at best only limit the effects of drug accumulation, but they do not solve the problem. Another type of approach is to use remifentanil in critically ill patients. Remifentanil is metabolized by unspecific blood and tissue esterases and undergoes rapid metabolism, independent of the duration of infusion or any organ insufficiency. There are data indicating that remifentanil can be used for analgesia and sedation in all kinds of adult intensive care unit patients, and that its use will result in rapid and predictable offset of effect. This may permit both a significant reduction in weaning and extubation times, and clear differentiation between over-sedation and brain dysfunction. This article provides an overview of the use of short-acting opioids in the intensive care unit, with special emphasis on remifentanil. It summarizes the currently available study data regarding remifentanil and provides recommendations for clinical use of this agent

Plasma Disappearance Rate of Indocyanine Green for Determination of Liver Function in Three Different Models of Shock

The measurement of the liver function via the plasma disappearance rate of indocyanine green (PDRICG) is a sensitive bed-side tool in critical care. Yet, recent evidence has questioned the value of this method for hyperdynamic conditions. To evaluate this technique in different hemodynamic settings, we analyzed the PDRICG and corresponding pharmacokinetic models after endotoxemia or hemorrhagic shock in rats. Male anesthetized Sprague-Dawley rats underwent hemorrhage (mean arterial pressure 35 ± 5 mmHg, 90 min) and 2 h of reperfusion, or lipopolysaccharide (LPS) induced moderate or severe (1.0 vs. 10 mg/kg) endotoxemia for 6 h (each n = 6). Afterwards, PDRICG was measured, and pharmacokinetic models were analyzed using nonlinear mixed effects modeling (NONMEM®). Hemorrhagic shock resulted in a significant decrease of PDRICG, compared with sham controls, and a corresponding attenuation of the calculated ICG clearance in 1- and 2-compartment models, with the same log-likelihood. The induction of severe, but not moderate endotoxemia, led to a significant reduction of PDRICG. The calculated ICG blood clearance was reduced in 1-compartment models for both septic conditions. 2-compartment models performed with a significantly better log likelihood, and the calculated clearance of ICG did not correspond well with PDRICG in both LPS groups. 3-compartment models did not improve the log likelihood in any experiment. These results demonstrate that PDRICG correlates well with ICG clearance in 1- and 2-compartment models after hemorrhage. In endotoxemia, best described by a 2-compartment model, PDRICG may not truly reflect the ICG clearance

Quantification of Volatile Acetone Oligomers Using Ion-Mobility Spectrometry

Background. Volatile acetone is a potential biomarker that is elevated in various disease states. Measuring acetone in exhaled breath is complicated by the fact that the molecule might be present as both monomers and dimers, but in inconsistent ratios. Ignoring the molecular form leads to incorrect measured concentrations. Our first goal was to evaluate the monomer-dimer ratio in ambient air, critically ill patients, and rats. Our second goal was to confirm the accuracy of the combined (monomer and dimer) analysis by comparison to a reference calibration system. Methods. Volatile acetone intensities from exhaled air of ten intubated, critically ill patients, and ten ventilated Sprague-Dawley rats were recorded using ion-mobility spectrometry. Acetone concentrations in ambient air in an intensive care unit and in a laboratory were determined over 24 hours. )e calibration reference was pure acetone vaporized by a gas generator at concentrations from 5 to 45 ppbv (parts per billion by volume). Results. Acetone concentrations in ambient laboratory air were only slightly greater (5.6 ppbv; 95% CI 5.1–6.2) than in ambient air in an intensive care unit (5.1 ppbv; 95% CI 4.4–5.5; p < 0.001). Exhaled acetone concentrations were only slightly greater in rats (10.3 ppbv; 95% CI 9.7–10.9) than in critically ill patients (9.5 ppbv; 95% CI 7.9–11.1; p < 0.001). Vaporization yielded acetone monomers (1.3–5.3 mV) and dimers (1.4–621 mV). Acetone concentrations (ppbv) and corresponding acetone monomer and dimer intensities (mV) revealed a high coefficient of determination (R2 � 0.96). )e calibration curve for acetone concentration (ppbv) and total acetone (monomers added to twice the dimers; mV) was described by the exponential growth 3-parameter model, with an R2 � 0.98. Conclusion. )e ratio of acetone monomer and dimer is inconsistent and varies in ambient air from place-to-place and across individual humans and rats. Monomers and dimers must therefore be considered when quantifying acetone. Combining the two accurately assesses total volatile acetone

Stability of Propofol (2,6-Diisopropylphenol) in Thermal Desorption Tubes during Air Transport

The anesthetic propofol and other exhaled organic compounds can be sampled in Tenax sorbent tubes and analyzed by gas chromatography coupled with mass spectrometry. The aim of this study was to evaluate the stability of propofol in Tenax sorbent tubes during overseas shipping. This is relevant for international pharmacokinetic studies on propofol in exhaled air. Tenax sorbent tube propofol samples with concentrations between 10 and 100 ng were prepared by liquid injection and with a calibration gas generator. For each preparation method, one reference set was analyzed immediately after preparation, a second set was stored at room temperature, and a third one was stored refrigerated. The fourth set was sent from Germany by airmail to USA and back. The shipped set of tubes was analyzed when it returned after 55 days elapsed. Then, the room temperature samples and the refrigerated stored samples were also analyzed. To evaluate the stability of propofol in the stored and shipped tubes, we calculated the recovery rates of each sample set. The mean recovery in the stored samples was 101.2% for the liquid preparation and 134.6% for the gaseous preparation at 4°C. At 22°C, the recovery was 96.1% for liquid preparation and 92.1% for gaseous preparation, whereas the shipped samples had a recovery of 85.3% and 111.3%. Thus, the deviation of the shipped samples is within a range of 15%, which is analytically acceptable. However, the individual values show significantly larger deviations of up to -32.1% (liquid) and 30.9% (gaseous). We conclude that storage of propofol on Tenax tubes at room temperature for 55 days is possible to obtain acceptable results. However, it appears that due to severe temperature and pressure variations air shipment of propofol samples in Tenax tubes without cooling shows severe deviations from the initial concentration. Although it was not tested in this study, we assume that refrigerated transport might be necessary to obtain comparable results as in the stored samples

Stability of Propofol (2,6-Diisopropylphenol) in Thermal Desorption Tubes during Air Transport

The anesthetic propofol and other exhaled organic compounds can be sampled in Tenax sorbent tubes and analyzed by gas chromatography coupled with mass spectrometry. The aim of this study was to evaluate the stability of propofol in Tenax sorbent tubes during overseas shipping. This is relevant for international pharmacokinetic studies on propofol in exhaled air. Tenax sorbent tube propofol samples with concentrations between 10 and 100 ng were prepared by liquid injection and with a calibration gas generator. For each preparation method, one reference set was analyzed immediately after preparation, a second set was stored at room temperature, and a third one was stored refrigerated. The fourth set was sent from Germany by airmail to USA and back. The shipped set of tubes was analyzed when it returned after 55 days elapsed. Then, the room temperature samples and the refrigerated stored samples were also analyzed. To evaluate the stability of propofol in the stored and shipped tubes, we calculated the recovery rates of each sample set. The mean recovery in the stored samples was 101.2% for the liquid preparation and 134.6% for the gaseous preparation at 4°C. At 22°C, the recovery was 96.1% for liquid preparation and 92.1% for gaseous preparation, whereas the shipped samples had a recovery of 85.3% and 111.3%. Thus, the deviation of the shipped samples is within a range of 15%, which is analytically acceptable. However, the individual values show significantly larger deviations of up to -32.1% (liquid) and 30.9% (gaseous). We conclude that storage of propofol on Tenax tubes at room temperature for 55 days is possible to obtain acceptable results. However, it appears that due to severe temperature and pressure variations air shipment of propofol samples in Tenax tubes without cooling shows severe deviations from the initial concentration. Although it was not tested in this study, we assume that refrigerated transport might be necessary to obtain comparable results as in the stored samples

Exhaled Aldehydes as Biomarkers for Lung Diseases : A Narrative Review

Breath analysis provides great potential as a fast and non-invasive diagnostic tool for several diseases. Straight-chain aliphatic aldehydes were repeatedly detected in the breath of patients suffering from lung diseases using a variety of methods, such as mass spectrometry, ion mobility spectrometry, or electro-chemical sensors. Several studies found increased concentrations of exhaled aldehydes in patients suffering from lung cancer, inflammatory and infectious lung diseases, and mechanical lung injury. This article reviews the origin of exhaled straight-chain aliphatic aldehydes, available detection methods, and studies that found increased aldehyde exhalation in lung diseases

Residual volatile anesthetics after workstation preparation and activated charcoal filtration

Background Volatile anesthetics potentially trigger malignant hyperthermia crises in susceptible patients. We therefore aimed to identify preparation procedures for the Draeger Primus that minimize residual concentrations of desflurane and sevoflurane with and without activated charcoal filtration. Methods A Draeger Primus test workstation was primed with 7% desflurane or 2.5% sevoflurane for 2 hours. Residual anesthetic concentrations were evaluated with five preparation procedures, three fresh gas flow rates, and three distinct applications of activated charcoal filters. Finally, non‐exchangeable and autoclaved parts of the workstation were tested for residual emission of volatile anesthetics. Concentrations were measured by multicapillary column–ion mobility spectrometry with limits of detection/quantification being <1 part per billion (ppb) for desflurane and <2.5 ppb for sevoflurane. Results The best preparation procedure included a flushing period of 10 minutes between removal and replacement of all parts of the ventilator circuit which immediately produced residual concentrations <5 ppm. A fresh gas flow of 10 L/minute reduced residual concentration as effectively as 18 L/minute, whereas flows of 1 or 5 L/minute slowed washout. Use of activated charcoal filters immediately reduced and maintained residual concentrations <5 ppm for up to 24 hours irrespective of previous workstation preparation. The fresh gas hose, circle system, and ventilator diaphragm emitted traces of volatile anesthetics. Conclusion In elective cases, presumably safe concentrations can be obtained by a 10‐minute flush at ≥10 L/minute between removal and replacement all components of the airway circuit. For emergencies, we recommend using an activated charcoal filter

Stability of Propofol (2,6-Diisopropylphenol) in Thermal Desorption Tubes during Air Transport

The anesthetic propofol and other exhaled organic compounds can be sampled in Tenax sorbent tubes and analyzed by gas chromatography coupled with mass spectrometry. The aim of this study was to evaluate the stability of propofol in Tenax sorbent tubes during overseas shipping. This is relevant for international pharmacokinetic studies on propofol in exhaled air. Tenax sorbent tube propofol samples with concentrations between 10 and 100 ng were prepared by liquid injection and with a calibration gas generator. For each preparation method, one reference set was analyzed immediately after preparation, a second set was stored at room temperature, and a third one was stored refrigerated. The fourth set was sent from Germany by airmail to USA and back. The shipped set of tubes was analyzed when it returned after 55 days elapsed. Then, the room temperature samples and the refrigerated stored samples were also analyzed. To evaluate the stability of propofol in the stored and shipped tubes, we calculated the recovery rates of each sample set. The mean recovery in the stored samples was 101.2% for the liquid preparation and 134.6% for the gaseous preparation at 4°C. At 22°C, the recovery was 96.1% for liquid preparation and 92.1% for gaseous preparation, whereas the shipped samples had a recovery of 85.3% and 111.3%. Thus, the deviation of the shipped samples is within a range of 15%, which is analytically acceptable. However, the individual values show significantly larger deviations of up to -32.1% (liquid) and 30.9% (gaseous). We conclude that storage of propofol on Tenax tubes at room temperature for 55 days is possible to obtain acceptable results. However, it appears that due to severe temperature and pressure variations air shipment of propofol samples in Tenax tubes without cooling shows severe deviations from the initial concentration. Although it was not tested in this study, we assume that refrigerated transport might be necessary to obtain comparable results as in the stored samples. Document type: Articl

Population pharmacokinetic modeling of multiple-dose intravenous fosfomycin in critically ill patients during continuous venovenous hemodialysis

The aim of this study was to investigate the pharmacokinetics of multiple-dose intravenous (i.v.) fosfomycin in critically ill patients during continuous venovenous hemodialysis (CVVHD). Noncompartmental analysis and population pharmacokinetic modeling were used to simulate diferent dosing regimens. We evaluated 15 critically ill patients with renal insufciency and CVVHD undergoing anti-infective treatment with fosfomycin in our ICU. Five grams of fosfomycin were administered for 120 min every 6 h. Plasma concentrations were determined with and without CVVHD. Pharmacokinetic analysis and simulations were performed using non-linear mixed efects modelling (NONMEM). A two-compartment model with renal and dialysis clearance was most accurate in describing the pharmacokinetics of i.v. fosfomycin during CVVHD. Population parameter estimates were 18.20 L and 20.80 L for the central and peripheral compartment volumes, and 0.26 L/h and 5.08 L/h for renal and intercompartmental clearance, respectively. Urinary creatinine clearance (CLCR) represented a considerable component of renal clearance. Central compartment volume increased over time after the frst dose. For patients with CLCR > 50 (90) mL/min and CVVHD, dosage should be increased to≥ 15 (16) grams of i.v. fosfomycin across three (four) daily doses. Individual CLCR must be considered when dosing i.v. fosfomycin in critically ill patients during CVVHD

Quantification of Volatile Aldehydes Deriving from In Vitro Lipid Peroxidation in the Breath of Ventilated Patients

Exhaled aliphatic aldehydes were proposed as non-invasive biomarkers to detect increased lipid peroxidation in various diseases. As a prelude to clinical application of the multicapillary column–ion mobility spectrometry for the evaluation of aldehyde exhalation, we, therefore: (1) identified the most abundant volatile aliphatic aldehydes originating from in vitro oxidation of various polyunsaturated fatty acids; (2) evaluated emittance of aldehydes from plastic parts of the breathing circuit; (3) conducted a pilot study for in vivo quantification of exhaled aldehydes in mechanically ventilated patients. Pentanal, hexanal, heptanal, and nonanal were quantifiable in the headspace of oxidizing polyunsaturated fatty acids, with pentanal and hexanal predominating. Plastic parts of the breathing circuit emitted hexanal, octanal, nonanal, and decanal, whereby nonanal and decanal were ubiquitous and pentanal or heptanal not being detected. Only pentanal was quantifiable in breath of mechanically ventilated surgical patients with a mean exhaled concentration of 13 ± 5 ppb. An explorative analysis suggested that pentanal exhalation is associated with mechanical power—a measure for the invasiveness of mechanical ventilation. In conclusion, exhaled pentanal is a promising non-invasive biomarker for lipid peroxidation inducing pathologies, and should be evaluated in future clinical studies, particularly for detection of lung injury