提示: 手机请竖屏浏览!

醇中毒
Toxic Alcohols


Jeffrey A. Kraut ... 其他 • 2018.01.18

毒性醇包括甲醇、乙二醇、异丙醇、二甘醇和丙二醇等,醇中毒会引起细胞功能障碍和死亡1,但症状并无特异性。诊断延误会增加器官不可逆损伤和死亡的风险2。在这篇综述中,我们将讨论醇中毒的机制、诊断方法以及目前的治疗建议。

 

醇中毒的机制


毒性醇会引起迷醉,但除异丙醇外,其他醇并没有直接毒性,其毒性效应是由代谢物引起。图1A简要描绘了这几种醇的主要代谢途径。

 

图1. 毒性醇的代谢途径,以及合并或不合并乙醇摄入情况下渗透压间隙和阴离子间隙随时间的变化

图A显示了毒性醇的代谢途径。醇脱氢酶和醛脱氢酶依次氧化毒性醇及其代谢物。毒性醇的首次氧化由醇脱氢酶催化完成,该过程是解毒治疗的重要目标。加框突出显示了推定的毒性代谢物。甲醇代谢为甲酸,乙二醇代谢为草酸和甘醇酸,二甘醇代谢为2-羟基乙氧基乙酸和羟基乙酸,丙二醇则代谢为D-乳酸和L-乳酸。图B显示了合并和不合并乙醇摄入的情况下,渗透压间隙和阴离子间隙随时间的变化。由于非离子化醇的蓄积,早期渗透压间隙增加较为明显。随着代谢进行,渗透压间隙随离子化代谢物的形成而下降。相反,在醇代谢之前,血清阴离子间隙处于最低值,而后会随着离子化代谢物的形成而升高。对于不同的醇,这两种参数随时间的变化是不同的。通常情况下,它们会在几小时至1天内逐渐变化。合并乙醇摄入会阻碍代谢(如虚线所示)并延迟高阴离子间隙酸中毒的发生。

 

毒性醇的第一次氧化经由醇脱氢酶催化进行,产生的醛(异丙醇氧化产生的丙酮除外)经醛脱氢酶催化进一步氧化形成羧酸代谢物:甲醇代谢为甲酸3,乙二醇代谢为草酸和甘醇酸3,二甘醇代谢为2-羟基乙氧基乙酸和羟基乙酸4,丙二醇则代谢为D-乳酸和L-乳酸5。醇脱氢酶是控制毒性代谢物产生的关键酶。同时摄入的乙醇是醇脱氢酶的竞争性底物,会延迟毒性代谢物的产生6。暴露于甲醇或乙二醇的代谢物可导致乳酸生成增多3,7,但暴露于乙二醇代谢物时,血液乳酸水平可能会出现假性升高,这是由于甘醇酸酯会干扰床边乳酸测量工具的准确性。





作者信息

Jeffrey A. Kraut, M.D., and Michael E. Mullins, M.D.
From Medical and Research Services and Division of Nephrology, Veterans Health Administration Greater Los Angeles (VHAGLA) Healthcare System, and Membrane Biology Laboratory, David Geffen School of Medicine, University of California, Los Angeles — both in Los Angeles (J.A.K.); and the Division of Emergency Medicine, Washington University School of Medicine, St. Louis (M.E.M.). Address reprint requests to Dr. Kraut at the Division of Nephrology, VHAGLA Healthcare System, 11301 Wilshire Blvd., Bldg. 500, Rm. 6018, Los Angeles, CA 90073, or at jkraut@ucla.edu.

 

参考文献

1. Kraut JA, Kurtz I. Toxic alcohol ingestions: clinical features, diagnosis, and management. Clin J Am Soc Nephrol 2008;3:208-225

2. Mahieu P, Hassoun A, Lauwerys R. Predictors of methanol intoxication with unfavourable outcome. Hum Toxicol 1989;8:135-137

3. Jacobsen D, McMartin KE. Methanol and ethylene glycol poisonings: mechanism of toxicity, clinical course, diagnosis and treatment. Med Toxicol 1986;1:309-334

4. Robinson CN, Latimer B, Abreo F, Broussard K, McMartin KE. In-vivo evidence of nephrotoxicity and altered hepatic function in rats following administration of diglycolic acid, a metabolite of diethylene glycol. Clin Toxicol (Phila) 2017;55:196-205

5. Zar T, Graeber C, Perazella MA. Recognition, treatment, and prevention of propylene glycol toxicity. Semin Dial 2007;20:217-219

6. Ammar KA, Heckerling PS. Ethylene glycol poisoning with a normal anion gap caused by concurrent ethanol ingestion: importance of the osmolal gap. Am J Kidney Dis 1996;27:130-133

7. Latus J, Kimmel M, Alscher MD, Braun N. Ethylene glycol poisoning: a rare but life-threatening cause of metabolic acidosis — a single-centre experience. Clin Kidney J 2012;5:120-123

8. Verelst S, Vermeersch P, Desmet K. Ethylene glycol poisoning presenting with a falsely elevated lactate level. Clin Toxicol (Phila) 2009;47:236-238

9. Bennett IL Jr, Cary FH, Mitchell GL Jr, Cooper MN. Acute methyl alcohol poisoning: a review based on experiences in an outbreak of 323 cases. Medicine (Baltimore) 1953;32:431-463

10. Ghannoum M, Hoffman RS, Mowry JB, Lavergne V. Trends in toxic alcohol exposures in the United States from 2000 to 2013: a focus on the use of antidotes and extracorporeal treatments. Semin Dial 2014;27:395-401

11. Slaughter RJ, Mason RW, Beasley DM, Vale JA, Schep LJ. Isopropanol poisoning. Clin Toxicol (Phila) 2014;52:470-478

12. Cantarell MC, Fort J, Camps J, Sans M, Piera L, Rodamilans M. Acute intoxication due to topical application of diethylene glycol. Ann Intern Med 1987;106:478-479

13. Devoti E, Marta E, Belotti E, et al. Diethylene glycol poisoning from transcutaneous absorption. Am J Kidney Dis 2015;65:603-606

14. Schep LJ, Slaughter RJ, Temple WA, Beasley DM. Diethylene glycol poisoning. Clin Toxicol (Phila) 2009;47:525-535

15. Kapitein BS, Biesmans RS, van der Sijs HS, de Wildt SS. Propylene glycol-related delirium after esmolol infusion. Ann Pharmacother 2014;48:940-942

16. Hovda KE, Hunderi OH, Tafjord AB, Dunlop O, Rudberg N, Jacobsen D. Methanol outbreak in Norway 2002-2004: epidemiology, clinical features and prognostic signs. J Intern Med 2005;258:181-190

17. Karayel F, Turan AA, Sav A, Pakis I, Akyildiz EU, Ersoy G. Methanol intoxication: pathological changes of central nervous system (17 cases). Am J Forensic Med Pathol 2010;31:34-36

18. Haviv YS, Rubinger D, Zamir E, Safadi R. Pseudo-normal osmolal and anion gaps following simultaneous ethanol and methanol ingestion. Am J Nephrol 1998;18:436-438

19. Reddy NJ, Sudini M, Lewis LD. Delayed neurological sequelae from ethylene glycol, diethylene glycol and methanol poisonings. Clin Toxicol (Phila) 2010;48:967-973

20. Alhamad T, Blandon J, Meza AT, Bilbao JE, Hernandez GT. Acute kidney injury with oxalate deposition in a patient with a high anion gap metabolic acidosis and a normal osmolal gap. J Nephropathol 2013;2:139-143

21. McMartin K. Are calcium oxalate crystals involved in the mechanism of acute renal failure in ethylene glycol poisoning? Clin Toxicol (Phila) 2009;47:859-869

22. McQuade DJ, Dargan PI, Wood DM. Challenges in the diagnosis of ethylene glycol poisoning. Ann Clin Biochem 2014;51:167-178

23. Pappas AA, Ackerman BH, Olsen KM, Taylor EH. Isopropanol ingestion: a report of six episodes with isopropanol and acetone serum concentration time data. J Toxicol Clin Toxicol 1991;29:11-21

24. Sosa NR, Rodriguez GM, Schier JG, Sejvar JJ. Clinical, laboratory, diagnostic, and histopathologic features of diethylene glycol poisoning — Panama, 2006. Ann Emerg Med 2014;64:38-47

25. Landry GM, Martin S, McMartin KE. Diglycolic acid is the nephrotoxic metabolite in diethylene glycol poisoning inducing necrosis in human proximal tubule cells in vitro. Toxicol Sci 2011;124:35-44

26. Dorwart WV, Chalmers L. Comparison of methods for calculating serum osmolality form chemical concentrations, and the prognostic value of such calculations. Clin Chem 1975;21:190-194

27. Kraut JA. Diagnosis of toxic alcohols: limitations of present methods. Clin Toxicol (Phila) 2015;53:589-595

28. Krasowski MD, Wilcoxon RM, Miron J. A retrospective analysis of glycol and toxic alcohol ingestion: utility of anion and osmolal gaps. BMC Clin Pathol 2012;12:1-1

29. Hovda KE, Hunderi OH, Rudberg N, Froyshov S, Jacobsen D. Anion and osmolal gaps in the diagnosis of methanol poisoning: clinical study in 28 patients. Intensive Care Med 2004;30:1842-1846

30. Ku E, Cheung EL, Khan A, Yu ASL. Anion and osmolal gaps after alcohol intoxication. Am J Kidney Dis 2009;54:385-388

31. Hovda KE, Froyshov S, Gudmundsdottir H, Rudberg N, Jacobsen D. Fomepizole may change indication for hemodialysis in methanol poisoning: prospective study in seven cases. Clin Nephrol 2005;64:190-197

32. Brent J, McMartin K, Phillips S, et al. Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med 1999;340:832-838

33. Kraut JA, Nagami GT. The serum anion gap in the evaluation of acid-base disorders: what are its limitations and can its effectiveness be improved? Clin J Am Soc Nephrol 2013;8:2018-2024

34. Iberti TJ, Leibowitz AB, Papadakos PJ, Fischer EP. Low sensitivity of the anion gap as a screen to detect hyperlactatemia in critically ill patients. Crit Care Med 1990;18:275-277

35. Roberts DM, Yates C, Megarbane B, et al. Recommendations for the role of extracorporeal treatments in the management of acute methanol poisoning: a systematic review and consensus statement. Crit Care Med 2015;43:461-472

36. Kraut JA, Xing SX. Approach to the evaluation of a patient with an increased serum osmolal gap and high-anion-gap metabolic acidosis. Am J Kidney Dis 2011;58:480-484

37. Rastogi A, Itagaki B, Bajwa M, Kraut JA. Spurious elevation in serum creatinine caused by ingestion of nitromethane: implication for the diagnosis and treatment of methanol intoxication. Am J Kidney Dis 2008;52:181-187

38. Mullins ME, Hammett-Stabler CA. Intoxication with nitromethane-containing fuels: don’t be “fueled” by the creatinine. J Toxicol Clin Toxicol 1998;36:315-320

39. Guo C, Cenac TA, Li Y, McMartin KE. Calcium oxalate, and not other metabolites, is responsible for the renal toxicity of ethylene glycol. Toxicol Lett 2007;173:8-16

40. Hodgman M, Marraffa JM, Wojcik S, Grant W. Serum calcium concentration in ethylene glycol poisoning. J Med Toxicol 2017;13:153-157

41. Jorens PG, Demey HE, Schepens PJC, et al. Unusual D-lactic acid acidosis from propylene glycol metabolism in overdose. J Toxicol Clin Toxicol 2004;42:163-169

42. Van Hee P, Neels H, De Doncker M, et al. Analysis of gamma-hydroxybutyric acid, DL-lactic acid, glycolic acid, ethylene glycol and other glycols in body fluids by a direct injection gas chromatography-mass spectrometry assay for wide. Clin Chem Lab Med 2004;42:1341-1345

43. Parsa T, Cunningham SJ, Wall SP, Almo SC, Crain EF. The usefulness of urine fluorescence for suspected antifreeze ingestion in children. Am J Emerg Med 2005;23:787-792

44. Hack JB, Early J, Brewer KL. An alcohol oxidase dipstick rapidly detects methanol in the serum of mice. Acad Emerg Med 2007;14:1130-1134

45. Hovda KE, Urdal P, Jacobsen D. Increased serum formate in the diagnosis of methanol poisoning. J Anal Toxicol 2005;29:586-588

46. Juenke JM, Hardy L, McMillin GA, Horowitz GL. Rapid and specific quantification of ethylene glycol levels: adaptation of a commercial enzymatic assay to automated chemistry analyzers. Am J Clin Pathol 2011;136:318-324

47. Rooney SL, Ehlers A, Morris C, et al. Use of a rapid ethylene glycol assay: a 4-year retrospective study at an academic medical center. J Med Toxicol 2016;12:172-179

48. Shin JM, Sachs G, Kraut JA. Simple diagnostic tests to detect toxic alcohol intoxications. Transl Res 2008;152:194-201

49. Eder AF, McGrath CM, Dowdy YG, et al. Ethylene glycol poisoning: toxicokinetic and analytical factors affecting laboratory diagnosis. Clin Chem 1998;44:168-177

50. Casavant MJ, Shah MN, Battels R. Does fluorescent urine indicate antifreeze ingestion by children? Pediatrics 2001;107:113-114

51. Barceloux DG, Bond GR, Krenzelok EP, Cooper H, Vale JA. American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol 2002;40:415-446

52. Brent J. Fomepizole for ethylene glycol and methanol poisoning. N Engl J Med 2009;360:2216-2223

53. Barceloux DG, Krenzelok EP, Olson K, Watson W. American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol poisoning. J Toxicol Clin Toxicol 1999;37:537-560

54. Abramson S, Singh AK. Treatment of the alcohol intoxications: ethylene glycol, methanol and isopropanol. Curr Opin Nephrol Hypertens 2000;9:695-701

55. Zakharov S, Pelclova D, Navratil T, et al. Fomepizole versus ethanol in the treatment of acute methanol poisoning: comparison of clinical effectiveness in a mass poisoning outbreak. Clin Toxicol (Phila) 2015;53:797-806

56. Jacobsen D, Webb R, Collins TD, McMartin KE. Methanol and formate kinetics in late diagnosed methanol intoxication. Med Toxicol Adverse Drug Exp 1988;3:418-423

57. Wacker WE, Haynes H, Druyan R, Fisher W, Coleman JE. Treatment of ethylene glycol poisoning with ethyl alcohol. JAMA 1965;194:1231-1233

58. McMartin K, Jacobsen D, Hovda KE. Antidotes for poisoning by alcohols that form toxic metabolites. Br J Clin Pharmacol 2016;81:505-515

59. Beatty L, Green R, Magee K, Zed P.. A systematic review of ethanol and fomepizole use in toxic alcohol ingestions. Emerg Med Int 2013;2013:638057-638057

60. Antizol (fomepizole): highlights of prescribing information. Montreal: Paladin Labs, 2009.

61. Mowry JB, Spyker DA, Brooks DE, Zimmerman A, Schauben JL. 2015 Annual Report of the American Association of Poison Control Centers’ National Poison Data System (NPDS): 33rd Annual Report. Clin Toxicol (Phila) 2016;54:924-1109

62. Thanacoody RH, Gilfillan C, Bradberry SM, et al. Management of poisoning with ethylene glycol and methanol in the UK: a prospective study conducted by the National Poisons Information Service (NPIS). Clin Toxicol (Phila) 2016;54:134-140

63. Rietjens SJ, de Lange DW, Meulenbelt J. Ethylene glycol or methanol intoxication: which antidote should be used, fomepizole or ethanol? Neth J Med 2014;72:73-79

64. Zakharov S, Pelclova D, Urban P, et al. Use of out-of-hospital ethanol administration to improve outcome in mass methanol outbreaks. Ann Emerg Med 2016;68:52-61

65. WHO model list of essential medicines: 18th list. Geneva: World Health Organization, 2013.

66. Lepik KJ, Levy AR, Sobolev BG, et al. Adverse drug events associated with the antidotes for methanol and ethylene glycol poisoning: a comparison of ethanol and fomepizole. Ann Emerg Med 2009;53:439-450.e10

67. Anseeuw K, Sabbe MB, Legrand A. Methanol poisoning: the duality between ‘fast and cheap’ and ‘slow and expensive.’ Eur J Emerg Med 2008;15:107-109

68. Zakharov S, Pelclova D, Navratil T, et al. Intermittent hemodialysis is superior to continuous veno-venous hemodialysis/hemodiafiltration to eliminate methanol and formate during treatment for methanol poisoning. Kidney Int 2014;86:199-207

69. Peces R, Fernández R, Peces C, et al. Effectiveness of pre-emptive hemodialysis with high-flux membranes for the treatment of life-threatening alcohol poisoning Nefrologia 2008;28:413-418

70. Borron SW, Mégarbane B, Baud FJ. Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet 1999;354:831-831

71. Mégarbane B, Borron SW, Trout H, et al. Treatment of acute methanol poisoning with fomepizole. Intensive Care Med 2001;27:1370-1378

72. Mégarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe toxic alcohol poisonings. Intensive Care Med 2005;31:189-195

73. Hovda KE, Mundal H, Urdal P, McMartin K, Jacobsen D. Extremely slow formate elimination in severe methanol poisoning: a fatal case report. Clin Toxicol (Phila) 2007;45:516-521

74. Wiles D, Tzeng J, Russell J, Casavant MJ. Comment on treatment methods for ethylene glycol intoxication. Neth J Med 2014;72:383-384

75. Brent J. Fomepizole for the treatment of pediatric ethylene and diethylene glycol, butoxyethanol, and methanol poisonings. Clin Toxicol (Phila) 2010;48:401-406

76. Hirsch DJ, Jindal KK, Wong P, Fraser AD. A simple method to estimate the required dialysis time for cases of alcohol poisoning. Kidney Int 2001;60:2021-2024

77. Borron SW, Baud FJ, Garnier R. Intravenous 4-methylpyrazole as an antidote for diethylene glycol and triethylene glycol poisoning: a case report. Vet Hum Toxicol 1997;39:26-28

78. Brophy PD, Tenenbein M, Gardner J, Bunchman TE, Smoyer WE. Childhood diethylene glycol poisoning treated with alcohol dehydrogenase inhibitor fomepizole and hemodialysis. Am J Kidney Dis 2000;35:958-962

79. Pillai U, Hothi JC, Bhat ZY. Severe propylene glycol toxicity secondary to use of anti-epileptics. Am J Ther 2014;21:e106-e109

80. Hunderi OH, Hovda KE, Jacobsen D. Use of the osmolal gap to guide the start and duration of dialysis in methanol poisoning. Scand J Urol Nephrol 2006;40:70-74

服务条款 | 隐私政策 | 联系我们