Mass spectrometers have been developed for the needs of industry. Powerful bench-top instruments with a high level of reliability and sensitivity were developed for routine analysis. Real-time breath analysis is a small field and is not recognized by the big mass spectrometer producing companies. The needs for an instrument for real-time breath analysis are in fact a bit different. In addition to sensitivity, reliability, scan speed, resolution and mass accuracy, the capability of measuring on-site also needs to be considered. For PTR-MS and SIFT-MS, custom-made mass spectrometers are used, which provide some ability to be used on-site. For SESI/EESI and APCI every mass spectrometer that incorporates an ambient ion source can be used. However, most of the investigations published were performed on standard bench top instruments. This is very feasible for research projects where the patients and healthy controls are able to move to the instrument. However, for real-time medical applications the mass spectrometer needs to be used on site, next to the patient. Most instruments used in research are big and noisy and are not made for this purpose.
The development of small, mobile, and even portable mass spectrometers is a separate field that is directly connected with the task of real-time monitoring (not exclusively for drugs in breath). Therefore it is necessary to discuss this aspect in some detail, especially since many developments in this field are limited to academic research. The main challenge of miniaturizing mass spectrometers is the need for sufficiently strong pumps to maintain the high vacuum. One way to reduce the pump size is to reduce the gas volume transported in to the mass spectrometer. This is realized, for example, with the use of separation systems (e.g., GC) and sub-ambient ionization techniques such as electron impact ionization (EI). Mobile quadrupole mass spectrometer in combination with miniaturized GC systems have been shown by Smith et al. to be useful for the detection of chemical warfare agents (Smith et al., 2004). Such GC-MS systems have a limited gas load, which allows to maintain the vacuum in relatively pressure tolerant quadrupoles (Shortt et al., 2005) or ion traps (Contreras et al., 2008). A portable quadrupole mass spectrometer equipped with an electron impact ion source was used for the detection of halothane, isoflurane, and servoflurane (Turner et al., 2008). The system used in this approach is displayed in Figure 11. This system, which has the size of a suitcase, was used to monitor anesthetized horses on-site. The size of this system is suitable for mass spectrometers for on-site use. A different approach is the suitcase time of flight (TOF) mass spectrometer (Ecelberger et al., 2004). This system is based on a membrane inlet system to maintain the vacuum (Kotiaho et al., 1991; Johnson et al., 2000; Ketola et al., 2002). This strategy is very effective, although the membrane is selective and limited to VOCs. Other mobile devices for breath analysis such as the proton transfer reaction mass spectrometer (PTR-MS) reduce the delivered volume through the use of a smaller inlet and an intermediate pressure region (80 mbar). Such mobile quadrupole (Lindinger et al., 1998, 376) or TOF spectrometers are on wheels (Jordan et al., 2009b, 88) and have been commercialized (Ionicon/Ionimed, Innsbruck, AT). For ambient ionization methods such as APCI, SESI, and EESI, mobile systems have to be constructed in a different way (Badman & Cooks, 2000). There are series of mobile and portable instruments introduced by the Cooks group (Gao et al., 2006; Fico et al., 2007; Keil et al., 2007; Janfelt et al., 2008; Yang et al., 2008; Ouyang et al., 2009; Huang et al., 2010), which enable the use of ambient ion sources. These small ion traps use a pulsed gas inlet to run with very small pumps and still maintain the vacuum (Emary et al., 1990). The pulsed gas inlet allows the connection to ambient ionization techniques (Collings & Romaschin, 2009). Nevertheless, the performance of these rectilinear ion traps is quite limited. The systems have to be considered as prototypes although they are already partially commercialized (Aston Labs, West Lafayette, IN). The sensitivity is only in the range of ppm, and mass accuracy and mass resolution are not anywhere close to these of bench top instruments (Berchtold et al., 2011). Nevertheless, the development of portable ion traps is an important step towards truly mobile mass spectrometers for patient monitoring. For ambient mass spectrometry, there is no mass spectrometer available yet that delivers the required sensitivity and reliability for on-site operation. Bench-top instruments could be modified for on-site application without significant loss of performance.
Every ambient inlet instrument on the market could theoretically be used for on-site breath analysis in combination with an ambient ionization technique (EESI, SESI, APCI). As a compromise for the targeted detection of exhaled drugs, ion traps seem to best fit the needs. Traps may be quite slow in terms of scanning speed (0.1–1 sec), but they allow the accumulation of specific ions. In the single ion monitoring (SIM) mode, only ions of a certain mass-to-charge ratio are trapped. Ion traps also allow fragmenting the trapped ions (MSn), which enhances selectivity and sensitivity. The selectivity is enhanced due to specific fragments and sensitivity by reducing the observed background. Finally, ion trap mass spectrometers can be converted into mobile devices since they are able to operate at relatively high pressure, thus allowing to reduce the pump size.
Many types of mass spectrometers are suitable to be modified for mobile use/breath analysis. A system as big as a bench-top instrument, which may be placed on a movable cart is already sufficient for on-site experiments. For targeted analysis, ion-trap or triple quadrupole instruments are very beneficial, and they can be made quite small, too. Triple quadrupoles are fast and sensitive, whereas ion traps are slower, but allow the accumulation of ions for a longer time period. The use of Q-ToF instruments as mobile devices is less likely, since they need a better vacuum. However, their scan speed and high resolution is very appealing, especially in studies where several m/z values must be monitored in parallel, or if unknown drug metabolites are analyzed. FT-ICR instruments are unfortunately by far too large for mobile applications.