title: Effects of critical illness and organ failure on therapeutic argatroban dosage requirements in patients with suspected or confirmed heparin-induced thrombocytopenia.
abstract: BACKGROUND
  Critically ill patients often require therapeutic argatroban dosages lower than those recommended in package labeling. The magnitude of dosage alteration in relation to severity of organ failure is unknown.
  
  
  OBJECTIVE
  To compare therapeutic argatroban dosages between critically ill and noncritically ill patients with confirmed or suspected heparin-induced thrombocytopenia and investigate the relationship between total Sequential Organ Failure Assessment (SOFA) score and therapeutic argatroban dosage.
  
  
  METHODS
  This retrospective cohort study was conducted at an urban academic medical center. Adults without Child-Pugh class C hepatic dysfunction who received argatroban for more than 24 hours over a 3-year period were included. Therapeutic argatroban dosage was that resulting in 2 consecutive activated partial thromboplastin time (aPTT) values 1.5-3 times the patient-specific baseline obtained at least 4 hours apart. Initial argatroban dosages were at the discretion of the managing service.
  
  
  RESULTS
  Fifty-three patients (critically ill, n = 34; noncritically ill, n = 19) were included. Critically ill patients had higher median [interquartile range] Acute Physiology and Chronic Health Evaluation (APACHE II) (17 [12-21] vs 10 [3.25-17.75]; p = 0.007) and SOFA (11 [7-13] vs 2 [0-2.75]; p < 0.001) scores. Critically ill patients required lower mean +/- SD therapeutic argatroban dosage (0.6 +/- 0.5 vs 1.4 +/- 0.9 microg/kg/min; p < 0.001). There was no significant difference in time to therapeutic aPTT or proportion of aPTTs within therapeutic range. Argatroban dosage was inversely related to SOFA score tertiles (<6: 1.34 +/- 0.82 microg/kg/min; 6-9: 0.93 +/- 0.54; > or =10: 0.40 +/- 0.27; p < 0.001). Total SOFA score at the time of argatroban initiation was independently associated with an argatroban dosage less than 0.75 microg/kg/min (OR 1.5, 95% CI 1.2 to 1.8; p < 0.001). Adverse events were similar between groups.
  
  
  CONCLUSIONS
  Critically ill patients with single or multiple organ failure require lower therapeutic argatroban dosages compared with noncritically ill patients. Because of an inverse relationship with SOFA score, initial argatroban dosage in critically ill patients should be based on the presence and magnitude of organ failure.
authors.affiliation: Critical Care, Department of Pharmacy Services, The University Hospital, Cincinnati, OH 45219, USA. Shaun.keegan@healthall.com
authors.forename: Shaun P
authors.initials: SP
authors.lastname: Keegan
authors.forename: Erika M
authors.initials: EM
authors.lastname: Gallagher
authors.forename: Neil E
authors.initials: NE
authors.lastname: Ernst
authors.forename: Emily J
authors.initials: EJ
authors.lastname: Young
authors.forename: Eric W
authors.initials: EW
authors.lastname: Mueller
mesh_terms: D000328:Adult; D000368:Aged; D000925:Anticoagulants / Q000008:administration & dosage*; D001120:Arginine / Q000031:analogs & derivatives; D015331:Cohort Studies; D016638:Critical Illness / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D006493:Heparin / Q000009:adverse effects*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009102:Multiple Organ Failure / Q000097:blood / Q000188:drug therapy*; D010875:Pipecolic Acids / Q000008:administration & dosage*; D012189:Retrospective Studies; D013449:Sulfonamides; D013921:Thrombocytopenia / Q000139:chemically induced* / Q000175:diagnosis
chemical_list: D000925:Anticoagulants; D010875:Pipecolic Acids; D013449:Sulfonamides; D006493:Heparin; D001120:Arginine; C031942:argatroban