摘要
全氟异丁烯(Perfluoroisobutylene，PFIB)是一种低分子氟碳化合物，常温下气态，无色并近于无味。其有极强的呼吸道毒性，属光气类毒气，而毒性达到光气的十倍，吸入后可致严重肺损伤。PFIB是聚氟工业常见的副产物，含氟塑料Teflon加热至300℃以上亦可产生。由于Teflon有化学性质稳定、摩擦系数小、绝缘、耐热等优点，被广泛用于民间各个方面，屡有报道在火灾事故中发生人吸入PFIB中毒事件。鉴于PFIB来源广、毒性大，已成为威胁人民健康和公共环境卫生的隐患。此外，PFIB还能穿透普通防毒面具的滤毒罐，难以防护，被各国有关部门认为是潜在的军用毒剂和恐怖攻击手段。因此，研究PFIB的毒性作用特点，探索有效的防护、治疗方法，于军于民都有着迫切的现实意义。
目前对PFIB的毒理机制未完全搞清，因此缺乏针对性的防
军医进修学院硕士毕业论文
中文摘要
护、治疗措施。我们从临床医学的角度出发，首次选用大动
物(杂种犬)进行PFIB染毒，完成了以下工作:
1.通过改造建立犬PFIB染毒系统，保证其吸入浓度稳定
均一(p>0.05)的pFIB。经摸索确定吸入0.30一o.32mg/L的
PFIB3omin后，实验犬在22h内PaOZ压10:均降至ARDS水平。
考察了犬吸入PFIB后临床表现、肺及其他脏器的病理改变。
认为所造成肺损伤属严重的ARDS。
2.检测了犬吸入PFIB前后循环TNF一a、IL一6、IL一8变化。
发现其中IL一8水平持续显著升高(p<0 .05)，而，I’NF一a、IL一6无
明显变化印>.05)，认为严重肺损伤很可能是潜伏期肺内大量
PMN扣押、激活后造成。
3.对所建立ARDS模型进行动脉一静脉无泵型ECMO治
疗的研究:作为对照，呼吸机辅助能提高犬模型SaO2，但随着
肺实变加重，逐渐难以保障基本氧需求;ECMO组，对ARDS
模型先行呼吸机辅助，当无法维持sao:在90%以上，立即开
始颈动脉一颈静脉无泵ECMO由于犬肺气体交换面积明显减
小，而所用膜肺表面积有限(lmZ)，所行ECMO难以达到完
全氧合。但与呼吸机辅助协同氧合，可维持SaO:在90%以上，
第4公乏
军医进修学院硕圣毕业论文
中文摘要
paCO:在20一3ommHg。此外，A一v无泵EeMo可显著降低模
型队P(p<0.05)，从而改善右心功能。转流40h结束，处死
取肺病检，肺损伤变化改善。
Perfluoroisobutelene(PFIB) is a kind of low-molecular-weight fluorocarbon compound, which exists as colorless gas with almost no smell at normal tempetature. PFIB is of the same kind of toxic gas as phosgene, but ten times as toxic as phosgene, and inhalation of PFIB can induce severe lung injury . PFIB can be generated as a commom byproduct in fluoropolymer industry, and also by pyrolysis of Teflon with temperature above 300 C . As Teflon is of many benifitial properties, it is widely used in people life, so poisoning cases by inhalation of PFIB often happen during fire accidents .
Up to now, the specific mechamisms of PFIB' s toxic funtion has not been thoroughly interpreted, correspondingly we can take little anti-measures to protect and treat. From view of clinical medicine, we for the 1st time chose big animal(mongrel) as poisoned object, several work has been finished as follows:
1. Constructed inhalation system fit for mongrel to ensure that concentration of PFIB during inhalation by mongrel kept stable and constant (p>0.05)o We established that PaO2/FiO2 of mongrel invariably reached level of
ARDS 22 hours after inhalation of PFIB with concentration of 0.30-0.32
mg/L for 30 minutes, and by observation of clinical signs and pathologic
changes we concluded that inhalation of PFIB induced severe ARDS.
2. We measured levels of TNF-a, IL-6, IL-8 in mongrel blood circulation before and after inhalation of PFIB, and found level of IL-8 elevated significantly after inhalation, whereas the other two cytokines did not change significantly. Thereby we speculated that lung injury after inhalation of PFIB may be result of PMN recruitment and activation in lung during latency.
3. We studied therapeutic effect of artery-vein pumpless ECMO: as control, assist by ventilator is capable of increase mongrel' s SaO2, but as the lung gradually became solid, basic oxygen intake of mongrel could hardly be provided by ventilator; as for ECMO group, we began ventilator assist on ARDS model first. As soon as it can not keep SaO2 above 90%, we start A-V pumpless ECMO using jugular vessels,, As lung area capable of air exchange reduced significantly and area of the oxygenator used is also limited, the ECMO is not capable of complete oxygenation by itself . When combined with mechanical ventilation, SaO2 kept above 90%, and PaCO2 kept between 20 and 30mmHg. Moreover A-V pumpless ECMO is capable of reducing model ' s PAP ( p<0.05 ) , thereby improve right ventricular function. After 40 hours ECMO were ended, and pathologic examination of lung show signs of improvement.
引文
1．张宪成．全氟异丁烯的理化性质及侦检防护．国外医学军事医学分册，1995，12(3)：113-118．
2. Tsai PJ,Guo YL,Chen JL,et al.An integrated approach to initiate preventive strategies for workers exposed to Teflon pyrolytic gases in a plastic industuy. J Occup Health,2000,42:297-303.
3. Makulova ID.Clinical picture of acute poisoning with perfluoroisobutylene. Gig.Tr.Prof.Zabol, 1965,9:20-23.
4. Smith LW, Gardner RJ, Kennedy GL Jr, et al.Short-term inhalation toxicity of perfluoroisobutylene. Drug Chem Toxicol, 1982,5:295-303.
5. Nold JB,Petrali JP, Wall HG,et al.Progressive pulmonary pathology of two organofluorine compounds in rats. Inhal Toxicol ,1991,3:123-137.
6. Brown RFR,Rice P.Electron microscopy of rat lung following a single acute exposure to perfluoroisobutylene(PFIB).A sequential study of the first 24 hours following exposure.Int.J.Exp.Path,1991,72:437-450.
7. Onyefuru LC,Upshall DG,Rice P.Effects of Furosemide,Torasemide and controlled fluid intake on perfluoroisobutylene induced lung oedema and mortality. Arzneim Forsch./Drug Res,1996,46(1):283-287.
8. Lailey AF, Hill L,Lawston LW, ea al.Protection by cysteine esters against chemically induced pulmonary oedema. Biochem Pharmacol, 1991,42 (suppl):s47-s54.
9. Arroyo CM.The chemistuy of perfluoroisobutelene(PFIB) with nitrone and nitroso spin traps:an EPR/Spin trapping study.Chem Biol Interact, 1997, 105: 119-129.
10. Lehnert BE,Archuleta D,Behr MJ,et al.Lung injury after acute inhalation of perfluoroisobutylene:exposure-response relationships. Inhal Toxicol, 1993,5:1-32.
11. Alpard SK,Zwischenberger JB.Extraorporeal membrane oxygenation for severe respiratory failure.Chest Surg Clin N Am,2002,12:355-378.
12．张宪成，孙晓红，侯廷奎等．PFIB的吸入染毒装置及大鼠吸入毒性．防化学报，2002，1：27-29．
13. Heyder J,Beck-Speier I,Busch B,et al.Health effects of sulfur- related environmental air pollution. Ⅰ. Executive summary. Inhal Toxicol, 1999, 11: 343-359.
14. Kreyling WG,Dirscherl P, Ferron GA,et al.Health effects of sulfur- related environmental air pollution. Ⅲ .Nonspecific respiratory defense capacities. Inhal Toxicol, 1999,11 ;391-422.
15. Azar A,Trochimowicz HJ,Terrill JB,et al.Blood levels of fluorocarbon related to cardiac sensitization.Am Ind Hyg Assoc J, 1973,34:102-109.
16. Frei FJ,Thomson DA,Zbinden AM.Influence of ventilatory and circulatory changes on the pharmacokinetics of halothane and isoflurane.Experientia, 1988, 44: 178-181.
17. Davies CN.Absorption of gases in the respiratory tract. Ann.Occup.Hyg, 1985,29:13-25.
18. Morrison RJ, Bidani A.Acute respiratory distress synduome epidemiology and pathophysiolohy.Chest Surg Clin N Am,2002,12:301-323.
19. Miller EJ,Cohen AB,Nagao S,et al.Elevated levels of NAP-l/interleukin-8 are present in the airspaces of patients with the adult respiratory distress
syndrome and are associated with increased mortality.Am Rev Respir Dis, 1992,146:427-432.
20. Stricter RM,Kunkel SL,Keane MP, et al.Chemokines in lung injury: Thomas A.Neff Lecture.Chest, 1999,116(1 suppl): 103s-110s.
21. Shames BD,Zallen Gs,Mcintyre RC,et al.Chemokines as mediators of diseases related to surgical conditions.Shock,2000,14(1): 1-7.
22. Weiss SJ,Lobuglio AF.Phagocyte-generated oxygen metabolites and cellular injury. Lab Invest, 1982,47:5-18.
23. Nelson S,Bagby GJ,Bainton BG,et al.Compartmentalization of intra-alveolar and systemic lipopolysaccharide-induced tumor necrosis factor and the pulmonary inflam-matory response. J Infec Dis, 1989,159:189-194.
24．童善庆．细胞因子．见：陆德源主编．现代免疫学．第一版．上海，上海科学技术出版社，1995，61．
25. Buford TH, Burbank B.Traumatic wet lung. J thoarac surg, 1945, 14:415-24.
26. Aschbaugh DG,Bigelow DB,Petty TL,et al.Acute respiratory distress in adults. Lancet,1967:319-323.
27. Bernard GR, Artigas A,Brigham KL,Carlet J,et al.Report of the American -European Consensus conference on ARDS: definitions, mechanisms, relevant outcomes and clinical trial coordination.Intensive Care Med, 1994,20:225-232.
28. Conrad SA,Bidani A.Management of the acute respiratory distress syndrome.Chest Surg Clin N Am,2002,12:325-354.
29. Gattinoni L,Pesenti A,Avalli L,et al.Pressure-volume curve of total respiratory system in acute respiratory failure:computed tomographic scan
study.Am Rev Respir Dis, 1987,136:730-6.
30. Gattinoni L,D'Andrea L,Pelosi P,et al.Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome. JAMA, 1993,269:2122-7.
31. Bendixen HH,Hedley WJ,Laver MB,et al.Impaired oxygenation in surgical patients during general anesthesia with controlled ventilation:a concept of atelectasis. N Engl J Med, 1963,269:991-6.
30. Webb HH,Tierney DF.Experimental pulmonary edema due to intermittent positive pressure ventilation with high inflation pressures:protection by positive end-expiratory pressure. Am Rev Respir Dis, 1974,110:556-65.
31. Dreyfuss D,Bassed G,Soler P, et al.Intermittent intermittent positive-pressure hyperventilation with high inflation pressures produces pulmonary microvascular injury in rats. Am Rev Respir Dis, 1985,132:880-4.
32. Dreyfuss D,Soler P, Basset G,et al.High inflation pressure pulmonary edema:respective effects of high airway pressure,high tidal volume,and positive end-expiratory pressure. Am Rev Respir Dis, 1988,137:1159-64.
33. Hickling KG,Wright T, Laubsecher K,et al.Extreme hypoventilation reduces ventilator-induced lung injury during ventilation with low positive end-expiratory pressure in saline-lavaged rabbits.Crit Care Med, 1998,26: 1690-7.
34. Muscedere JG,Mullen JB,Gan K,et al.Tidal ventilation at low airway pressures can augment lung injury.Am J Respir Crit Care Med, 1994,149: 1327-34.
35. Hotchkiss JR, Blanch L,Murias G,Adams AB,et al.Effects of decreased
respiratory frequency on ventilator-induced lung injury.Am J Respir Crit Care Med,2000,161: 463-8.
36. Gattinoni L,D"Andrea L,Pelosi P, et al.Regional effects and mechanism of positive end-expiratory pressure in early adult respiratory distress syndrome.JAMA, 1993,269: 2122-7.
37. The Acute Respiratory Distress Syndrome Network:ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.N Engl J Med,2000,342:1301-8.
38. Hickling KG,Henderson SJ,Jackson R.Low motality associated with low volume pressure limited ventilation with permissive hypercapnia in severe adult respiratory distress syndrome.Intens Care Med, 1990,16:372-377.
39. Briegel J,Hummel T, Lenhart A,et al.Complications during long-term extracorporeal lung assist(ECLA).Acta Anaesthes Scand, 1996,109(suppl): 121-122.
40. Michaels AJ,Schriener RJ,Kolla S,et al.Extracorporeal life support in pulmonary failure after trauma.J Trauma, 1999,638-645.
41. Bartlett RH,Gazzaniga AB,Jeffries MR,et al.Extracorporeal membrane oxygenation(ECMO) in neonatal respiratory failure. 100 cases.Ann Surg,1986, 204:236-45.
42. Zapol WM,Snider MT, Hill JD,et al.Extracorporeal membrane oxygenation in severe acute respiratory failure:a randomized prospective study. JAMA, 1979,2422193-6.
43. Mols G,Loop T,Geiger K,et al.Extracorporeal membrane oxygenation:a ten-year experience.AmJ Surg,2000,180:144-154.
44. Peek G,Jaffe W, Ward D,et al.Extracorporeal membrane oxygenation in the treatment of inhaliation injuries.Burns, 1998,24:562-565.
45. Sasadeusz KJ,Long WB,Kemalyan N,et al.Successful treatment of a patient with multiple injuries using extracorporeal membrane oxygenation and inhaled nitric oxide.J Trauma,2000,49:1126-1128.
46. Zapol WM,Snider MT.Pulmonary hypertension in severe acute respiratory failure.N Engl J, 1977,296:476-80.