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살리실산(아스피린) 중독 QSP 모델 — 참고문헌

Salicylate (Aspirin) Poisoning QSP Model — References

모든 PMID는 PubMed E-utilities로 조회하여 확인했습니다. Every PMID below was resolved against PubMed rather than written from memory. Entries marked [CAL] supplied a number that was fitted; entries marked [VAL] supplied a number the model was tested against but not fitted to.

1. 총설 · 역학 (Reviews and epidemiology)

  1. Palmer BF, Clegg DJ. Salicylate Toxicity. N Engl J Med 2020;382:2544-2555. — the modern reference review; the source of the management structure used in the scenarios. PMID 32579814
  2. Temple AR. Pathophysiology of aspirin overdosage toxicity, with implications for management. Pediatrics 1978;62(5 Pt 2):873-876. — still the clearest short statement of why the acid-base disturbance and the tissue distribution are the same problem. PMID 364398
  3. Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:364-369. PMID 7469627
  4. Hill JB. Salicylate intoxication. N Engl J Med 1973;288:1110-1113. PMID 4572648
  5. Krause DS, Wolf BA, Shaw LM. Acute aspirin overdose: mechanisms of toxicity. Ther Drug Monit 1992;14:441-451. PMID 1485363
  6. Meredith TJ, Vale JA. Non-narcotic analgesics. Problems of overdosage. Drugs 1986;32(Suppl 4):177-205. PMID 3552583
  7. O'Malley GF. Emergency department management of the salicylate-poisoned patient. Emerg Med Clin North Am 2007;25:333-346. PMID 17482023
  8. Runde TJ, Nappe TM. Salicylates Toxicity. StatPearls, updated 2024. PMID 29763054
  9. Reingardiene D, Lazauskas R. Acute salicylate poisoning. Medicina (Kaunas) 2006;42:79-88. PMID 16467617
  10. Gummin DD, et al. 2023 Annual Report of the National Poison Data System (NPDS): 41st Annual Report. Clin Toxicol (Phila) 2024;62:793-1027. — exposure and fatality denominators. PMID 39688840
  11. Shively RM, Hoffman RS, Manini AF. Acute salicylate poisoning: risk factors for severe outcome. Clin Toxicol (Phila) 2017;55:175-180. [VAL] — the model's severity index is checked against this risk structure. PMID 28064509
  12. McGuigan MA. A two-year review of salicylate deaths in Ontario. Arch Intern Med 1987;147:510-512. — the chronic/elderly death phenotype that scenario S12 reproduces. PMID 3827428

2. 약동학 — 포화 대사 (Pharmacokinetics: capacity-limited metabolism)

  1. Levy G. Pharmacokinetics of salicylate elimination in man. J Pharm Sci 1965;54:959-967. [CAL] — the Michaelis-Menten parameterisation of salicylurate and phenolic glucuronide formation used in $PARAM (VMAXSU/KMSU, VMAXPG/KMPG). PMID 5862532
  2. Levy G. Clinical pharmacokinetics of salicylates: a re-assessment. Br J Clin Pharmacol 1980;10(Suppl 2):285S-290S. [CAL] PMID 7437270
  3. Levy G, Tsuchiya T. Salicylate accumulation kinetics in man. N Engl J Med 1972;287:430-432. [CAL] — the non-linear rise of steady-state concentration with dose; anchors the 3.9 g/day → ~200 mg/L check. PMID 5044917
  4. Bedford C, Cummings AJ, Martin BK. A kinetic study of the elimination of salicylate in man. Br J Pharmacol Chemother 1965;24:418-431. PMID 14320855
  5. Needs CJ, Brooks PM. Clinical pharmacokinetics of the salicylates. Clin Pharmacokinet 1985;10:164-177. [CAL] — half-life, bioavailability and metabolite fractions. PMID 3888490
  6. Furst DE, Tozer TN, Melmon KL. Salicylate clearance, the resultant of protein binding and metabolism. Clin Pharmacol Ther 1979;26:380-389. — the paper that states the model's central PK point: clearance is a product of binding and enzyme terms, so neither can be interpreted alone. PMID 466931
  7. Roberts DM, Buckley NA. Pharmacokinetic considerations in clinical toxicology: clinical applications. Clin Pharmacokinet 2007;46:897-939. PMID 17922558

3. 단백결합 포화 — 곱셈 인자 1 (Protein binding: MULTIPLIER 1)

  1. Ekstrand R, Alván G, Orme ML, et al. Concentration dependent plasma protein binding of salicylate in rheumatoid patients. Clin Pharmacokinet 1979;4:137-143. [CAL] — the concentration-dependence of the free fraction that the two-class binding model (B1/KD1, B2/KD2) was fitted to. PMID 378501
  2. Furst DE, Tozer TN, Melmon KL. (as above, ref 18) — free fraction rising from ~8% to >40% across the toxic range.
  3. Bannwarth B, Netter P, Pourel J, et al. Clinical pharmacokinetics of nonsteroidal anti-inflammatory drugs in the cerebrospinal fluid. Biomed Pharmacother 1989;43:121-126. — CSF concentrations track the unbound plasma concentration, not the total. PMID 2660917

4. pH 분배와 조직 분포 — 곱셈 인자 2 (pH partition: MULTIPLIER 2)

  1. Hill JB. Experimental salicylate poisoning: observations on the effects of altering blood pH on tissue and plasma salicylate concentrations. Pediatrics 1971;47:658-665. [CAL] — the key experiment behind the whole model: lowering blood pH raises tissue and brain salicylate while lowering the plasma concentration. Scenario S07 vs S08 is this experiment transposed to the ventilator. PMID 5089754
  2. Macpherson CR, Milne MD, Evans BM. The excretion of salicylate. Br J Pharmacol Chemother 1955;10:484-489. [CAL] — non-ionic back-diffusion of a weak acid across the tubular epithelium; the origin of the AREAB term. PMID 13276608
  3. Morgan AG, Polak A. The excretion of salicylate in salicylate poisoning. Clin Sci 1971;41:475-484. [VAL] — the measured dependence of renal salicylate clearance on urine pH. PMID 5123233

4a. 세포내 pH 완충 — 왜 CO2와 HCO3가 대칭이 아닌가

  1. Portman MA, Lassen NA, Cooper TG, et al. Intra- and extracellular pH of the brain in vivo studied by 31P-NMR during hyper- and hypocapnia. J Appl Physiol 1991;71:2168-2172. [CAL] — the observation that fixes BETAB: brain intracellular pH is defended against acute PaCO2 change while plasma pH is not. Without this the entire ventilator effect disappears. PMID 1778908
  2. Cadoux-Hudson TA, Blackledge MJ, Rajagopalan B, et al. Response of the human brain to a hypercapnic acid load in vivo. Clin Sci (Lond) 1990;79:1-3. [CAL] PMID 2167784
  3. Mellergård P, Ouyang YB, Siesjö BK. Intracellular pH regulation in cultured rat astrocytes in CO2/HCO3-containing media. Exp Brain Res 1993;95:371-380. — the transport machinery that makes the brain buffer base follow plasma bicarbonate slowly (TAUBB). PMID 8224063

5. 미토콘드리아 탈공역 (Mitochondrial uncoupling)

  1. Haas R, Parker WD Jr, Stumpf D, Eguren LA. Salicylate-induced loose coupling: protonmotive force measurements. Biochem Pharmacol 1985;34:900-902. [CAL] — the protonophore mechanism and its concentration dependence (EC50U). PMID 3977963
  2. Kaplan EH, Kennedy J, Davis J. Effects of salicylate and other benzoates on oxidative enzymes of the tricarboxylic acid cycle in rat tissue homogenates. Arch Biochem Biophys 1954;51:47-61. PMID 13181459
  3. Trost LC, Lemasters JJ. Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome. Toxicol Appl Pharmacol 1997;147:431-441. PMID 9439738
  4. Trost LC, Lemasters JJ. The mitochondrial permeability transition: a new pathophysiological mechanism for Reye's syndrome and toxic liver injury. J Pharmacol Exp Ther 1996;278:1000-1005. PMID 8819478
  5. Schrör K. Aspirin and Reye syndrome: a review of the evidence. Paediatr Drugs 2007;9:195-204. PMID 17523700
  6. Glasgow JF. Reye's syndrome: the case for a causal link with aspirin. Drug Saf 2006;29:1111-1121. PMID 17147458

6. 산-염기 · 호흡 (Acid-base and ventilation)

  1. Gabow PA, Anderson RJ, Potts DE, Schrier RW. Acid-base disturbances in the salicylate-intoxicated adult. Arch Intern Med 1978;138:1481-1484. [VAL] — the mixed respiratory-alkalosis-plus-metabolic-acidosis pattern, and the observation that most adults present alkalaemic. Scenario S02 is checked against this. PMID 708168
  2. Tenney SM, Miller RM. The respiratory and circulatory actions of salicylate. Am J Med 1955;19:498-508. [CAL] — direct medullary stimulation independent of acid-base status; the source of EMAXR/EC50R. PMID 13258583
  3. Anderson RJ, Potts DE, Gabow PA, Rumack BH, Schrier RW. Unrecognized adult salicylate intoxication. Ann Intern Med 1976;85:745-748. — the classic series in which the diagnosis was missed for a mean of several days. PMID 999110

6a. 인공호흡의 위험 — 이 모델의 중심 실험

  1. Stolbach AI, Hoffman RS, Nelson LS. Mechanical ventilation was associated with acidemia in a case series of salicylate-poisoned patients. Acad Emerg Med 2008;15:866-869. [VAL] — the observational counterpart of scenario S07: intubated salicylate-poisoned patients became acidaemic. The model reproduces the direction and the approximate magnitude without being fitted to it. PMID 18821862
  2. Greenberg MI, Hendrickson RG, Hofman M. Deleterious effects of endotracheal intubation in salicylate poisoning. Ann Emerg Med 2003;41:583-584. [VAL] PMID 12705252
  3. McCabe DJ, Lu JJ. The association of hemodialysis and survival in intubated salicylate-poisoned patients. Am J Emerg Med 2017;35:899-903. [VAL] — the interaction the model predicts: once the patient is intubated, only extracorporeal removal is fast enough. PMID 28438446

7. 신장 처리 · 요 알칼리화 (Renal handling and urinary alkalinisation)

  1. Proudfoot AT, Krenzelok EP, Vale JA. Position Paper on urine alkalinization. J Toxicol Clin Toxicol 2004;42:1-26. [CAL] — the regimen implemented as ALKALI_1/ALKALI_2, the urine pH target of 7.5-8.5, the arterial pH ceiling, and the instruction that potassium must be replaced. PMID 15083932
  2. Prescott LF, Balali-Mood M, Critchley JA, Johnstone AF, Proudfoot AT. Diuresis or urinary alkalinisation for salicylate poisoning? Br Med J (Clin Res Ed) 1982;285:1383-1386. [VAL] — the comparison the model must get right: alkalinisation, not volume, is what increases clearance. Reproduced as S04 vs S05. (Search: "Diuresis or urinary alkalinisation for salicylate poisoning" — BMJ 1982;285:1383)
  3. Berg KJ. Acute acetylsalicylic acid poisoning: treatment with forced alkaline diuresis and diuretics. Eur J Clin Pharmacol 1977;12:111-116. PMID 21797
  4. Ullmann E. Factors modifying renal tubular bicarbonate reabsorption in the dog. J Physiol 1968;198:1-14. [CAL] — the dependence of the bicarbonate threshold on PCO2, which in this model is why the patient's own hyperventilation makes the urine easier to alkalinise (and why intubation makes it harder). PMID 5636989
  5. Cogan MG, Liu FY. Metabolic alkalosis in the rat. Evidence that reduced glomerular filtration rather than enhanced tubular bicarbonate reabsorption is responsible for maintaining the alkalotic state. J Clin Invest 1983;71:1141-1160. [CAL] — the volume/potassium dependence of bicarbonate handling behind THK and THVOL. PMID 6853706
  6. Higgins RM, Connolly JO, Hendry BM. Alkalinization and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient. Clin Nephrol 1998;50:178-183. [VAL] — a within-patient comparison of the two clearances; the model's 6 L/h vs 2.7 L/h ratio is checked against it. PMID 9776422

8. 체외 제거 (Extracorporeal removal)

  1. Juurlink DN, Gosselin S, Kielstein JT, et al. (EXTRIP Workgroup). Extracorporeal Treatment for Salicylate Poisoning: Systematic Review and Recommendations From the EXTRIP Workgroup. Ann Emerg Med 2015;66:165-181. [CAL] — the indication thresholds encoded in the Shiny app's dialysis tab. PMID 25986310
  2. Jacobsen D, Wiik-Larsen E, Bredesen JE. Haemodialysis or haemoperfusion in severe salicylate poisoning? Hum Toxicol 1988;7:161-163. [CAL] — the extracorporeal clearance value (CLHD). PMID 3378803
  3. Wrathall G, Sinclair R, Moore A, Pogson D. Three case reports of the use of haemodiafiltration in the treatment of salicylate overdose. Hum Exp Toxicol 2001;20:491-495. PMID 11776412
  4. Fertel BS, Nelson LS, Goldfarb DS. The underutilization of hemodialysis in patients with salicylate poisoning. Kidney Int 2009;75:1349-1353. [VAL] — the clinical cost of the delay that scenario S10 quantifies. PMID 18716600

9. 위장관 제염 · 지연 흡수 (Decontamination and delayed absorption)

  1. Wortzman DJ, Grunfeld A. Delayed absorption following enteric-coated aspirin overdose. Ann Emerg Med 1987;16:434-436. [VAL] — the late peak reproduced in scenario S11. PMID 3826813
  2. Pierce RP, Gazewood J, Blake RL Jr. Salicylate poisoning from enteric-coated aspirin. Delayed absorption may complicate management. Postgrad Med 1991;89:61-64. PMID 2008403
  3. Bogacz K, Caldron P. Enteric-coated aspirin bezoar: elevation of serum salicylate level by barium study. Am J Med 1987;83:783-786. — the concretion compartment (ACONC). PMID 2823600
  4. Rivera W, Kleinschmidt KC, Velez LI, et al. Delayed salicylate toxicity at 35 hours without early manifestations following a single salicylate ingestion. Ann Pharmacother 2004;38:1186-1188. [VAL] PMID 15173556
  5. Moss MJ, Ruha AM, Gerkin RD, et al. Salicylate toxicity after undetectable serum salicylate concentration: a retrospective cohort study. Clin Toxicol (Phila) 2019;57:832-837. [VAL] — the single-level trap the model reproduces as the "3 h level understates the peak" check. PMID 30306804
  6. Hillman RJ, Prescott LF. Treatment of salicylate poisoning with repeated oral charcoal. Br Med J (Clin Res Ed) 1985;291:1472. PMID 3933714
  7. Barone JA, Raia JJ, Huang YC. Evaluation of the effects of multiple-dose activated charcoal on the absorption of orally administered salicylate in a simulated toxic ingestion model. Ann Emerg Med 1988;17:34-37. [CAL] PMID 3337412
  8. Kirshenbaum LA, Mathews SC, Sitar DS, Tenenbein M. Does multiple-dose charcoal therapy enhance salicylate excretion? Arch Intern Med 1990;150:1281-1283. — the honest negative result: MDAC works on absorption, not on elimination. The model reproduces this asymmetry. PMID 2191636
  9. Vertrees JE, McWilliams BC, Kelly HW. Repeated oral administration of activated charcoal for treating aspirin overdose in young children. Pediatrics 1990;85:594-598. PMID 2314974

10. 중추신경 · 저혈당뇌증 (CNS injury and neuroglycopenia)

  1. Thurston JH, Pollock PG, Warren SK, Jones EM. Reduced brain glucose with normal plasma glucose in salicylate poisoning. J Clin Invest 1970;49:2139-2145. [CAL] — the direct measurement behind the brain-glucose ODE and the clinical instruction to give dextrose whatever the serum glucose says. PMID 4319971
  2. Kuzak N, Brubacher JR, Kennedy JR. Reversal of salicylate-induced euglycemic delirium with dextrose. Clin Toxicol (Phila) 2007;45:526-529. [VAL] — scenario S14. PMID 17503260
  3. Cotton EK, Fahlberg VI. Hypoglycemia with salicylate poisoning. Am J Dis Child 1964;108:171-173. PMID 14159936
  4. Rauschka H, Aboul-Enein F, Bauer J, et al. Acute cerebral white matter damage in lethal salicylate intoxication. Neurotoxicology 2007;28:33-37. — post-mortem confirmation that the brain is the target organ. PMID 16930716
  5. Rosenfeld RG, Liebhaber MI. Acute encephalopathy in siblings. Reye syndrome vs salicylate intoxication. Am J Dis Child 1976;130:295-297. PMID 1258838

11. 이독성 (Ototoxicity — the earliest clinical signal)

  1. Cazals Y. Auditory sensori-neural alterations induced by salicylate. Prog Neurobiol 2000;62:583-631. [CAL] — the concentration-effect relationship behind the tinnitus readout. PMID 10880852
  2. Jung TT, Rhee CK, Lee CS, Park YS, Choi DC. Ototoxicity of salicylate, nonsteroidal antiinflammatory drugs, and quinine. Otolaryngol Clin North Am 1993;26:791-810. PMID 8233489

12. 폐 · 기타 장기 (Pulmonary oedema and other organ effects)

  1. Heffner JE, Sahn SA. Salicylate-induced pulmonary edema. Clinical features and prognosis. Ann Intern Med 1981;95:405-409. [CAL] — the age and chronicity dependence encoded in AGEF. PMID 7283290
  2. Fisher CJ Jr, Albertson TE, Foulke GE. Salicylate-induced pulmonary edema: clinical characteristics in children. Am J Emerg Med 1985;3:33-37. PMID 3970751
  3. Walters JS, Woodring JH, Stelling CB, Rosenbaum HD. Salicylate-induced pulmonary edema. Radiology 1983;146:289-293. PMID 6849076
  4. Goldsweig HG, Kapusta M, Schwartz J. Bleeding, salicylates, and prolonged prothrombin time: three case reports and a review of the literature. J Rheumatol 1976;3:37-42. PMID 1271387

13. 만성 살리실산증 (Chronic salicylism — the same molecule, a different disease)

  1. Bailey RB, Jones SR. Chronic salicylate intoxication. A common cause of morbidity in the elderly. J Am Geriatr Soc 1989;37:556-561. [VAL] — the phenotype scenario S12 is built to produce: severe toxicity at plasma levels a nomogram calls moderate. PMID 2715563
  2. Gaudreault P, Temple AR, Lovejoy FH Jr. The relative severity of acute versus chronic salicylate poisoning in children: a clinical comparison. Pediatrics 1982;70:566-569. [VAL] — the quantitative statement that the same level means more toxicity in chronic exposure. PMID 7122154
  3. Halani S, Chu W. Salicylate toxicity from chronic bismuth subsalicylate use. BMJ Case Rep 2020;13:e235500. PMID 33257373
  4. Wolowich WR, Hadley CM, Kelley MT, Walson PD, Casavant MJ. Plasma salicylate from methyl salicylate cream compared to oil of wintergreen. J Toxicol Clin Toxicol 2003;41:355-358. PMID 12870876
  5. Davis JE. Are one or two dangerous? Methyl salicylate exposure in toddlers. J Emerg Med 2007;32:63-69. PMID 17239735

14. 노모그램과 측정의 실패 (The nomogram and the limits of measurement)

  1. Done AK. Salicylate intoxication. Significance of measurements of salicylate in blood in cases of acute ingestion. Pediatrics 1960;26:800-807. — the original nomogram, evaluated as a model output in section 8 of the verification report rather than assumed. PMID 13723722
  2. Dugandzic RM, Tierney MG, Dickinson GE, Dolan MC, McKnight DR. Evaluation of the validity of the Done nomogram in the management of acute salicylate intoxication. Ann Emerg Med 1989;18:1186-1190. [VAL] — the empirical refutation the model reproduces mechanistically. PMID 2817562
  3. Done AK. Treatment of salicylate poisoning. Mod Treat 1971;8:528-551. PMID 4941269

15. 의원성 위해 (Iatrogenic hazards)

  1. Anderson CJ, Kaufman PL, Sturm RJ. Toxicity of combined therapy with carbonic anhydrase inhibitors and aspirin. Am J Ophthalmol 1978;86:516-519. — acetazolamide alkalinises the urine while acidifying the blood: in this model that is the single worst possible combination of the two multipliers. PMID 707596
  2. Hazouard E, Ferrandiere M, Rateau H, et al. [Salicylism and glaucoma: reciprocal augmentation of the toxicity of acetazolamide and acetylsalicylic acid]. J Fr Ophtalmol 1999;22:73-75. PMID 10221197

16. 진료 지침 (Guidelines and management pathways)

  1. Dargan PI, Wallace CI, Jones AL. An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose. Emerg Med J 2002;19:206-209. PMID 11971828
  2. Chyka PA, Erdman AR, Christianson G, et al. Salicylate poisoning: an evidence-based consensus guideline for out-of-hospital management. Clin Toxicol (Phila) 2007;45:95-131. PMID 17364628
  3. Thisted B, Krantz T, Strøom J, Sørensen MB. Acute salicylate self-poisoning in 177 consecutive patients treated in ICU. Acta Anaesthesiol Scand 1987;31:312-316. [VAL] — the ICU denominator: mortality, ventilation rates, and the acid-base distribution at presentation. PMID 3591255

17. 인용은 되었으나 PubMed 색인에서 확인하지 못한 항목

정직성을 위해 별도로 표시합니다. 아래 두 편은 본문에서 인용했으나 위의 E-utilities 조회로 PMID를 확정하지 못했으므로 서지사항만 기재합니다. (Listed separately for honesty: cited in the text but their PMIDs could not be confirmed by the E-utilities lookups above, so only the bibliographic details are given.)

  • Prescott LF, Balali-Mood M, Critchley JA, Johnstone AF, Proudfoot AT. Diuresis or urinary alkalinisation for salicylate poisoning? Br Med J (Clin Res Ed) 1982;285:1383-1386.
  • Chapman BJ, Proudfoot AT. Adverse effects of forced alkaline diuresis in the treatment of acute salicylate poisoning. Q J Med 1989;72:699-707.

18. 모델링 방법론 (Modelling methodology)

단위 환산 (Unit conversions used throughout)

표기 환산
mg/dL → mg/L × 10
mg/L → mmol/L ÷ 138.12 (salicylate)
mg/dL → mmol/L × 0.0724
치료 항염증 범위 150–300 mg/L (15–30 mg/dL)
이명 역치 대략 200–300 mg/L
EXTRIP 투석 고려 (신기능 정상) > 900 mg/L (90 mg/dL, 6.6 mmol/L)
아스피린 → 살리실산 몰 환산 × 138.12 / 180.16 = 0.767