臺灣博碩士論文加值系統

服農藥約佔全球自殺事件的三分之一。為了加快在急診的搶救行動，本研究研發出一種通過熱脫附-電噴灑游離/質譜法（TD-ESI/ MS）來快速鑑定攝取農藥種類的分析方法。本檢測口腔液中農藥的方法其重現性（n = 6）的相對標準偏差（<7％）低。 從四個受試者獲得的口腔液中檢測農藥的極限在1-10 ppb之間，其相對標準偏差為10.7％。五種口腔液中農藥在1 ppb - 1 ppm濃度範圍內其與質譜訊號強度間的線性關係良好（R2在0.9938和0.9988之間）。由於整個分析過程極為快捷，這種技術讓我們能夠在中毒早期幫助因農藥中毒被送到急診室的患者從他們的口腔液中進行快速床邊非侵入性之鑑定工作，提供臨床上重要的毒理學資料，以利急救過程中之關鍵性決策。
誤吞口服藥物常見於兒科年齡層。在急診室裡處理此類急性中毒事件必須講求高效率，以盡量降低中毒造成的傷害和死亡率。無奈詢問病史和理學檢查並非完全可靠。在本項研究中，我們研發出一種質譜技術能早期快速辨識洗胃引流液中患者剛才攝入口服藥物的種類。只需要使用一個金屬取樣探針，直接浸入胃液和誤吞藥物的混合物中。因不必對樣品進行任何前處理，在執行採樣步驟後，隨即通過熱脫附-電噴灑游離和質譜儀分析，在15秒內便能完成誤吞藥物之辨識。四種誤吞口服藥物在洗胃引流液中的檢出量極限可達ppm以下之水平。這項質譜技術，搭配質譜資料庫的快速線上查詢，讓我們能在急診室及早就地鑑定出孩子誤吞口服藥物的種類，在第一時間提供重要的毒理學資料，以確保後續醫療處置之適切性，替傷患對症下藥。

Self-poisoning with pesticides accounts for approximately one-third of all suicides worldwide. To expedite rescue in the emergency department, we developed an analytical method for rapid identification of ingested pesticides by thermal desorption-electrospray ionization mass spectrometry. The reproducibility of this method (n = 6) was shown in the observed low-relative standard deviation (<7%) in the detection of pesticide in oral fluid. The detection limits of the pesticides in oral fluid obtained from four human subjects were between 1–10 ppb with relative standard deviation 10.7%. Linear responses of five pesticides in oral fluid with concentrations between 1 ppb–1 ppm (R2 between 0.9938 and 0.9988) were observed. As the whole analytical process is extremely short, this technique allows for early non-invasive point-of-care identification of pesticides in the oral fluid of self-poisoning patients in the emergency room, providing important toxicological information for decision-making during critical resuscitation.
Mis-swallowing of oral medications is not uncommon in the pediatric group. Acute poisoning should be handled with high efficiency in order to minimize morbidity and mortality in the emergency room. History-taking and physical examination are not always reliable. We developed a rapid point-of-care ambient mass spectrometric method for early identification of ingested oral medications in gastric lavage drainage fluid. A direct metallic sampling probe was dipped into this mixture of gastric juice and medications. Since no pretreatment of the specimen was required, the sampling step, followed by thermal desorption-electrospray ionization and mass spectrometric analysis of the medications were completed within 15 seconds. The limit-of-detection of the four tested oral medications in gastric lavage content is at sub-ppm level. This technique, with informational support provided by online mass spectral database, allows for early point-of-care identification of oral medications in the gastric contents obtained during lavage of mis-swallowing children in the emergency room, and is promising in providing important toxicological information to ensure appropriateness of the succeeding medical management.

Chinese Abstract.............................................................................................................i
English Abstract............................................................................................................iii
Acknowledgments..........................................................................................................v
Table of Contents..........................................................................................................vi
List of Tables..................................................................................................................x
List of Figures................................................................................................................x
List of Abbreviations...................................................................................................xii

Chapter 1: Introduction........................................................................................1
1.1 Intentional pesticide ingestion..................................................................................1
1.1.1 Clinical significance of ingested pesticide identification......................................1
1.1.2 Identification of ingested pesticides in traditional practice ..................................1
1.1.3 Limitations of traditional strategies for pesticide identification...........................2
1.2 Accidental oral medications ingestion.....................................................................3
1.2.1 Clinical significance of mis-swallowed oral medication identification................3
1.2.2 Identification of mis-swallowed oral medication in traditional practice…….......4
1.2.3 Limitations of traditional strategies for medication identification........................4
1.3 Point-of-care tests (PoCT)........................................................................................5

Chapter 2: Ambient mass spectrometry (AMS)..........................................7
2.1 Definition…………….............................................................................................7
2.2 History of development............................................................................................7
2.3 Ionization in AMS....................................................................................................9
2.3.1 Direct desorption ionization……..........................................................................9
2.3.1.1 DESI……...........................................................................................................9
2.3.1.2 DART…….......................................................................................................12
2.3.2 Two-step ionization…….....................................................................................13
2.3.2.1 ELDI…….........................................................................................................13
2.3.2.2 TD-ESI…….....................................................................................................15
2.4 Basic principle of mass spectrometry……….........................................................22
2.4.1 Quadrupole mass filter……….……………………...........................................23
2.4.2 Triple quadrupole…………................................................................................24

Chapter 3: Pesticide identification in oral fluid by TD-ESI/MS..........27
3.1 Aim.........................................................................................................................27
3.2 Material .................................................................................................................27
3.3 Method.…………..….………...............................................................................29
3.3.1 Cotton swab sampling ........................................................................................29
3.3.2 Matrix spiking ....................................................................................................32
3.3.3 Solvent extraction ...............................................................................................33
3.3.4 Analyte transfer...................................................................................................34
3.3.5 Thermal desorption-electrospray ionization........................................................35
3.3.6 Triple quadrupole mass spectrometry……….....................................................36
3.3.7 Pesticide database library matching………........................................................36
3.3.8 Data-guided resuscitation…….………...............................................................36
3.3.8.1 Treatment for paraquat intoxication.................................................................37
3.3.8.2 Treatment for organophosphate intoxication...................................................41
3.3.8.3 Treatment for carbamate intoxication…..........................................................43
3.3.9 Probe cleaning…….………................................................................................43
3.4 Overall procedure……….......................................................................................44
3.5 Results.….………………………….….…………………………………….…...45
3.5.1 Efficiency………................................................................................................47
3.5.1.1 Solvent selection………..................................................................................47
3.5.1.2 Solvent extraction time……….........................................................................48
3.5.1.3 Turnaround time…………………...................................................................49
3.5.2 Sensitivity…….………......................................................................................50
3.5.2.1 Limit-of-detection…….……….......................................................................50
3.5.2.2 Linearity…….………......................................................................................51
3.5.3 Precision………..................................................................................................52
3.5.3.1 Repeatability…….………...............................................................................52
3.6 Discussion………………..…….………...............................................................53
3.6.1 Clinical implications….......................................................................................53

Chapter 4: Medication identification in gastric lavage drainage fluid by TD-ESI/MS........................................................................................................55
4.1 Aim.........................................................................................................................55
4.2 Material .................................................................................................................55
4.3 Method…….………..............................................................................................58
4.3.1 Gastric lavage .....................................................................................................58
4.3.2 Matrix spiking ....................................................................................................59
4.3.3 Analyte transfer...................................................................................................60
4.3.4 Thermal desorption-electrospray ionization........................................................61
4.3.5 Triple quadrupole mass spectrometry……….....................................................61
4.3.6 Medication database library matching………....................................................62
4.3.7 Data-guided resuscitation…….………...............................................................62
4.3.7.1 Treatment for acetaminophen intoxication…...................................................62
4.3.7.2 Treatment for diphenhydramine intoxication…...............................................63
4.3.7.3 Treatment for propranolol intoxication…........................................................65
4.3.7.4 Treatment for doxepin intoxication…..............................................................66
4.3.8 Probe cleaning…….………................................................................................67
4.4 Overall procedure……….......................................................................................68
4.5 Results.….………………………….….…………………………………….…...69
4.5.1 Efficiency………................................................................................................72
4.5.1.1 Turnaround time…………………...................................................................72
4.5.2 Sensitivity…….……….......................................................................................73
4.5.2.1 Limit-of-detection…….……….......................................................................73
4.5.2.2 Linearity…….………......................................................................................75
4.5.3 Precision………..................................................................................................76
4.5.3.1 Repeatability…….………...............................................................................76
4.5.3.2 Reproducibility………………….....................................................................77
4.6 Discussion………………..…….………...............................................................78
4.6.1 Clinical implications….......................................................................................78

Future perspectives…................................................................................................80
Conclusion……………………….….……………………………….………….…...81
Bibliography ……………………….….……………………………………….…...83
Appendix: Reprints of published articles..................................................................100

List of Tables

Table 2.1. Summary of optimal parameters in TD-ESI...............................................22
Table 3.1. Results of MS and MS/MS analyses of pesticides in oral fluid……….....47
Table 3.2. LOD of five different pesticides in four oral fluid samples…...................51
Table 4.1. Clinical data of the providers of the gastric juice matrix...........................57
Table 4.2. Results of MS and MS/MS analyses of oral medications….……..……...72
Table 4.3. LOD of four oral medications in four gastric juice samples......................74

List of Figures

Figure 1. Graphic representation of the geometry of the ELDI set-up........................14
Figure 2. TD-ESI source coupled to a triple quadrupole mass spectrometer..............20
Figure 3. TD-ESI/MS involves four independent analytical steps..............................21
Figure 4. Five tested pesticides and an internal standard............................................28
Figure 5. Cotton swab sampling from the patient’s buccal cavity..............................31
Figure 6. Spiking is used to evaluate the performance of TD-ESI/MS.......................32
Figure 7. Solvent extraction........................................................................................33
Figure 8. Analyte transfer............................................................................................34
Figure 9. Overall TD-ESI/MS analytical processes....................................................44
Figure 10(a-g). Mass spectra of pesticides in oral fluid by TD-ESI/MS....................46
Figure 11. Extraction efficiency of five solvents........................................................48
Figure 12. Minimal extraction time of methanol.........................................................49
Figure 13. Linear responses of pesticides in the 1 ppb–1 ppm range..........................52
Figure 14. Repeatability test for pesticides………….................................................53
Figure 15. Four tested oral medications......................................................................56
Figure 16. Gastric lavage for removing ingested intoxicants......................................58
Figure 17. Spiking is used to evaluate the performance of TD-ESI/MS.....................59
Figure 18. Analyte transfer..........................................................................................60
Figure 19. Overall TD-ESI/MS analytical processes..................................................68
Figure 20. Mass spectra of oral medications in gastric juice………………..............70
Figure 21. MS/MS analysis of four tested medications..............................................71
Figure 22. Linear responses of drugs in 0.5–50 ppm range.....................................75
Figure 23. Within-run test (n = 10) for oral medications by TD-ESI/MS...................76
Figure 24. Between-run test analyzing for oral medication by TD-ESI/MS...............77
Figure 25. TD-ESI/MS brings about timely data-guided resuscitation.......................82

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