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doi: 10.1097/01.anes.0000264752.39511.05
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Every Breath You Take, We’ll Be Watching You

Kharasch, Evan D. M.D., Ph.D.

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MASS spectrometry has enjoyed a prominent place in anesthesiology and critical care, enabling the routine monitoring of anesthetic gases, facilitating our understanding of volatile anesthetic pharmacokinetics and pharmacodynamics, and contributing immeasurably to routine patient care.1–3 Although it is no longer used today for ordinary intraoperative gas monitoring, the legacy of mass spectrometry is the routine quantification of inspired and end-tidal anesthetic and respiratory gas concentrations, albeit by the now more ubiquitous infrared technology.
Shortly after the clinical introduction of propofol (2,6-diisopropylphenol in a lipid emulsion), I purchased a bottle of 2,6-diisopropylphenol from a chemical supply company for resident teaching. The aroma noticeable immediately upon opening the bottle suggested a sufficiently high vapor pressure to portend pulmonary propofol elimination, and hence the possibility of detecting and quantifying propofol in expired gas by the mass spectrometer then in use in the operating room. A proposal to our operating room’s mass spectrometer manufacturer to investigate this possibility was not reviewed favorably, and the idea was soon forgotten.
Harrison et al.,4 in a seminal investigation, gave proof of concept reality to the conjecture of pulmonary propofol elimination and its measurement. They applied a novel technology, proton transfer reaction mass spectrometry, to demonstrate propofol exhalation and its measurement, albeit without absolute quantification. They also demonstrated the feasibility of real-time measurement of propofol and its metabolites in expired breath. They suggested the possibility of defining an alveolar propofol concentration that connotes adequate anesthesia.
In this issue of Anesthesiology are two investigations reporting further evaluation of real-time on-line pulmonary propofol monitoring.5,6 Takita et al.5 administered a propofol infusion and used a proton transfer reaction mass spectrometer to measure absolute propofol concentrations in exhaled gas. These were proportional to propofol blood concentrations in blood simultaneously obtained and measured by conventional techniques. After a propofol bolus, exhaled propofol concentrations rose and fell, expectedly. Hornuss et al.6 used a different but related (both instruments use “soft ionization” techniques) ion–molecule reaction mass spectrometer to also measure, but not absolutely quantify, exhaled propofol. They also measured contemporaneously obtained blood propofol concentrations, and those in the gas phase after a blood sample was placed in a sealed vial. Within a patient, there were correlations between blood propofol concentrations and those in both expired gas and the gas above the blood in the vial. These investigations validate the proof of concept in several patients, and extend it by providing absolute quantification.
While intriguing, both reports leave open questions and limitations to the methods described, presenting challenges for technology refinement. Neither propofol instrument could measure carbon dioxide concentration; hence end-expiration could not be defined. To accomplish this, Takita et al. measured expired gas temperature, and Hornuss et al. used a second mass spectrometer to measure carbon dioxide, so the propofol measurements were “approximately” end-tidal. The proton transfer method required the averaging of 50 breath samples, over 5 min, because of measurement variability. In addition, inspired propofol concentrations were not zero. Although plasma concentrations peak within a few seconds after an intravenous propofol bolus, expired propofol concentrations did not peak for 5 min. Whether this reflects a delay in blood–gas transfer, pulmonary sequestration, or some other factor remains to be determined. Although ion–molecule reaction mass spectrometry found correlations between blood and gas propofol concentrations for any given patient, the slope of this relationship, and that between expired propofol content and that in the gas above the blood in a vial, were highly variable between patients. This might affect robust quantification and requires further evaluation and refinement. Nonetheless, these challenges do not affect the proof of concept.
Other unknown factors may affect propofol exhalation and quantification. What is the influence of the lipids in propofol formulations, or other factors, on the relationship between blood and expired 2,6-diisopropylphenol concentrations? Lipids can alter drug disposition. The presence of lipid in an emulsion of halothane delivered intravenously significantly decreased end-tidal halothane concentrations at blood halothane concentrations identical to those after inhalation.7 Similarly, lipid content in blood markedly altered the isoflurane blood:gas partition coefficient and altered isoflurane elimination from blood to the lungs.8 For propofol, there was a significant influence of lipid and formulation on pharmacodynamics and pharmacokinetics in anesthetized patients, most notably affecting the volume of distribution,9 which might also affect pulmonary elimination. Blood lipid concentrations increase over time with propofol infusions. Not only may exogenous lipids affect propofol, but also endogenous lipids, because propofol is highly bound to serum lipids and proteins, and changes in cholesterol, triglyceride, and lipoprotein concentrations in blood affected the free concentration of 2,6-diisopropylphenol.10 Other endogenous factors, such as pulmonary transfer from blood to alveolar gas, may also affect pulmonary propofol monitoring. Grossherr et al.11 reported a 10-fold difference, between goats and pigs, in expired propofol concentrations at similar plasma concentrations. Whether endogenous or exogenous lipids, pulmonary factors, interindividual variability, or other factors affect either the pulmonary elimination of propofol or its measurement remains to be determined.
In the two reports in this issue of Anesthesiology, exhaled 2,6-diisopropylphenol concentrations were extremely low, typically 2–5 parts per billion (ppb).5 This has (at least) two implications. First, it demonstrates the exquisite sensitivity of the new mass spectrometry techniques. Although Takita et al. did not report their limits of quantification, their calibration curve ranged from 0.4 to 400 ppb. By comparison, exhaled volatile anesthetic concentrations are typically (at maintenance) 1–9% (10–90 million ppb), and an infrared anesthesia monitor with a detection limit of 0.1% has a sensitivity of 1 million ppb. Therefore, the proton transfer reaction mass spectrometer used by Takita et al. is approximately 10 million times more sensitive than conventional infrared anesthesia monitors. This is impressive. Second, elimination in exhaled alveolar gas is not likely to be a quantitatively significant route of the well-described extrahepatic elimination of propofol, in agreement with conclusions reached by measuring central venous and arterial propofol concentrations.12,13
A robust and reliable method to quantify blood 2,6-diisopropylphenol concentrations could have application in research and/or therapeutics. It could have broad applicability in assessing propofol pharmacokinetics. It could replace the frequent use of predicted plasma propofol concentrations as an independent variable in many clinical investigations. It could provide more accurate achievement of desired propofol concentrations than those attained by target-controlled infusions based on population pharmacokinetic parameters. Pulmonary propofol concentrations could be used as a control variable for closed-loop anesthesia.14,15 Whether this would provide a better result (however defined) than electroencephalogram-derived parameters or nociception as the control variable remains to be determined.
The addition of high-sensitivity mass spectrometry for alveolar propofol measurement is an enabling technology, which adds to our armamentarium of medical gas monitoring. With every breath you take, we’ll be watching you.*
Evan D. Kharasch, M.D., Ph.D.
Russell D. and Mary B. Shelden Professor of Anesthesiology, and Director, Division of Clinical and Translational Research, Department of Anesthesiology, Washington University, St. Louis, Missouri.
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2. Blumenfeld W, Wolf S, McCluggage C, Denman R, Turney S: On-line respiratory gas monitoring. Comput Biomed Res 1973; 6:139–49

3. Sodal IE: The medical mass spectrometer. Biomed Instrum Technol 1989; 23:469–76

4. Harrison GR, Critchley AD, Mayhew CA, Thompson JM: Real-time breath monitoring of propofol and its volatile metabolites during surgery using a novel mass spectrometric technique: A feasibility study. Br J Anaesth 2003; 91:797–9

5. Takita A, Masui K, Kazama T: On-line monitoring of end-tidal propofol concentration in anesthetized patients. Anesthesiology 2007; 106:659–64

6. Hornuss C, Praun S, Villinger J, Dornauer A, Moehnle P, Dolch M, Weninger E, Chouker A, Feil C, Briegel J, Thiel M, Schelling G: Real-time monitoring of propofol in expired air in humans undergoing total intravenous anesthesia. Anesthesiology 2007; 106:665–74

7. Musser JB, Fontana JL, Mongan PD: The anesthetic and physiologic effects of an intravenous administration of a halothane lipid emulsion (5% vol/vol). Anesth Analg 1999; 88:671–5

8. Yang XL, Ma HX, Yang ZB, Liu AJ, Luo NF, Zhang WS, Wang L, Jiang XH, Li J, Liu J: Comparison of minimum alveolar concentration between intravenous isoflurane lipid emulsion and inhaled isoflurane in dogs. Anesthesiology 2006; 104:482–7

9. Calvo R, Telletxea S, Leal N, Aguilera L, Suarez E, De La Fuente L, Martin-Suarez A, Lukas JC: Influence of formulation on propofol pharmacokinetics and pharmacodynamics in anesthetized patients. Acta Anaesthesiol Scand 2004; 48:1038–48

10. Zamacona MK, Suarez E, Garcia E, Aguirre C, Calvo R: The significance of lipoproteins in serum binding variations of propofol. Anesth Analg 1998; 87:1147–51

11. Grossherr M, Hengstenberg A, Meier T, Dibbelt L, Gerlach K, Gehring H: Discontinuous monitoring of propofol concentrations in expired alveolar gas and in arterial and venous plasma during artificial ventilation. Anesthesiology 2006; 104:786–90

12. He Y-L, Ueyama H, Tashiro C, Mashimo T, Yoshiya I: Pulmonary disposition of propofol in surgical patients. Anesthesiology 2000; 93:986–91

13. Chen YZ, Zhu SM, He HL, Xu JH, Huang SQ, Chen QL: Do the lungs contribute to propofol elimination in patients during orthotopic liver transplantation without veno-venous bypass? Hepatobiliary Pancreat Dis Int 2006; 5:511–4

14. Struys MM, De Smet T, Versichelen LF, Van De Velde S, Van den Broecke R, Mortier EP: Comparison of closed-loop controlled administration of propofol using Bispectral Index as the controlled variable versus “standard practice” controlled administration. Anesthesiology 2001; 95:6–17

15. Struys MM, Mortier EP, De Smet T: Closed loops in anaesthesia. Best Pract Res Clin Anaesthesiol 2006; 20:211–20

* With homage to the musical group The Police. Cited Here...

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