On-line determination of serum propofol concentrations by expired air analysis
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Propofol (2,6-diisopropylphenol)—an intravenous anaesthetic—can be identified and quantified in expired air directly. For the first time, a β-radiation ion mobility spectrometer operated in the positive mode and coupled to a multi-capillary column for rapid (seconds–minutes) pre-separation (MCC/IMS) was used for the quantification of Propofol in expired air. The comparison of the concentrations in exhaled air (300 pptV–5 ppbV) and in serum (0.3–5 μg/mL) showed satisfying agreement affirmed by a correlation coefficient of 0.73. Therefore, MCC/IMS is an adequate method to determine Propofol concentrations in exhaled air and may be applied for the prediction of venous concentrations or for automatic anaesthesia control.
KeywordsPropofol 2,6-diisopropylphenol Anaesthesia Serum TIVA Breath analysis Ion mobility spectrometry GC/MS GC/IMS
The monitoring of volatile anaesthetics in end-tidal breath is a standard procedure to improve safety of the patient and to adjust anaesthetic depth. Presently, this is not easy to perform for intravenous anaesthetics such as Propofol. Complex and time consuming off-line analyses of blood samples are required. Therefore, an on-line method for the determination of the serum anaesthetics concentration is desirable to improve safety and adjust anaesthetic depth or the level of sedation in intensive care units (ICU).
The on-line measurement of Propofol in exhaled air has already been demonstrated using different techniques like proton transfer reaction mass spectrometry (PTR-MS) [1, 2], thermal desorption gas chromatography  and ion molecule reaction-mass spectrometry (IMR-MS) . Those investigations showed close relations of Propofol concentrations in exhaled air and in blood [2, 3, 4]. However, those instruments are expensive and in general not commercially available as validated medical instrumentation.
For the present study, an ion mobility spectrometer in combination with a multi-capillary column (MCC/IMS) was applied for the quantification of Propofol in exhaled air for the first time as presented in  for the medical community, in particular with regard to the possible routine application. Here, the technical aspects will come to the fore. The results were compared to serum concentrations of Propofol determined by GC/MS. The MCC/IMS has already been applied successfully for medical purpose [6, 7, 8]. It is a suitable tool to analyse human breath as it provides high sensitivity (down to pptV) and selectivity combined with high-speed data acquisition (single spectra 0.1s / complete breath analysis ∼5 min) and relatively low technical expenditure.
The bi-directional β-radiation MCC/IMS operated with synthetic air under ambient pressure and temperature used for the study was custom designed at ISAS and has been described in detail in literature as well as the software used for data acquisition and evaluation [6, 7, 8]. For pre-separation, a 20 cm un-polar multi-capillary chromatographic column (OV-5, MULTICHROM, Novosibirsk, Russia) was operated isothermal at 40 °C. Sampling was controlled by a CO2 sensor (IRMA, Fa. PhaseIn, Danderyd, Sweden), which was used to flush the sample loop (8 mL volume) only if carbon dioxide exceeded 25 mmHg, thus sampling only end-tidal breath. The volume of the sample loop was then introduced directly into the MCC without any pre-treatment of the sample.
Demographics of the study population: Median (Min.⬄Max.)
Anaesthesia and sample acquisition
The patients received a standard total intravenous anaesthesia (TIVA) with Propofol (Disoprivan 1%; Astra Zeneca, Wedel, Germany) as hypnotic agent, Remifentanil for analgesia and optional Rocuronium as muscle relaxant. Anaesthesia was induced with intravenous application of 2.1 (±0.7) mg/kg Propofol bolus and 30 μg/kg/h Remifentanil. After tracheal intubation, the lung was ventilated with a standard anaesthesia respirator (Cato, Dräger, Lübeck, Germany). Propofol (3.9 (±1.8) mg/kg/h) and Remifentanil (30 μg/kg/h) were applied continuously to maintain anaesthesia adjusted to clinical parameters. Sampling was performed as described above and in Total Intravenous Anaesthesia in analogy to Schubert et al.  measuring CO2 in breath with mainstream capnography (IRMA, Fa. PhaseIn, Danderyd, Sweden). Breath samples were drawn when the CO2 level exceeded 25 mmHg and venous blood samples were obtained via a separate venous access at the opposite site of the drug infusion simultaneously. All samples were collected at steady state conditions (achieved by administration of Propofol and Remifentanil for 15 min). Depending on the duration of surgery, one or two sample pairs of breath and serum were taken per patient.
Determination of propofol concentrations by GC/MS
Breath samples have been adsorbed on Tenax tubes (1 L of breath, controlled by the sampling control of the MCC/IMS) and were thermally desorbed and analysed just as the blood samples (injected in one bolus at 250 °C) using a GC/MS with EI-ionisation (70 eV) by Agilent Technologies 6,890 N GC-system connected to an Agilent Technologies 5,973 mass selective detector (MSD; Gerstel, Mülheim, Germany). The operating parameters were: SSL-injector 180 °C; column DB-5: 30 m; 0,25 mm ID; 0,25 μm FD; 1 mL/min He const.; T-program 40 °C/5 °C/min–100 °C/20 °C/min–200 °C (5 min). Integrated signals from the internal standard Thymol (m/z 135,150) and from Propofol (m/z 163,178) were evaluated by AMDIS/NIST (Automated Mass Spectral Deconvolution and Identification System; version 2.62, 2005; NIST version 2.0, 2005).
Simultaneously to breath sampling, venous blood was from the arm that was not used for the infusion. All samples were collected under steady-state conditions (Achieved by administration of Propofol and Remifentanil for 15 min). Depending on the duration of surgery, 1–2 samples were obtained from each patient.
Results and discussion
The correlation between exhaled air concentrations and serum concentrations of Propofol was described for the first time using a MCC/IMS. The system obtains a point of care measurement with non-invasive sampling and reliable prediction of venous Propofol concentrations without pre-concentration. The on-line determination (5–10 s after sample acquisition) of serum Propofol concentrations via breath analysis with regard to safety factors is feasible for infusion control at ICU and for Total Intravenous Anaesthesia (TIVA).
The financial support of the Bundesministerium für Bildung und Forschung and the Ministerium für Wissenschaft und Forschung des Landes Nordrhein-Westfalen is gratefully acknowledged. The dedicated work of Luzia Seifert, Susanne Krois, Stefanie Güssgen, Sandra Stelzer and Jacqueline Friedrich, technicians at ISAS, was indispensable for the successful investigations. Furthermore, the valuable contribution of Bertram Boedeker related to data evaluation is acknowledged as well as the general support of B&S Analytik, Dortmund, Germany.
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