annals of routine warfarin follow up

1. Annals of �Routine� Warfarin Follow Up Paul R. Chelminski, MD, MPH Associate Residency Program Director

7. GSK Double Dip

9. Case Laboratory Data combined respiratory alkalosis and metabolic acidosis ? Na, ? Cl, ? K, ? HCO3, ? anion gap ? pCO2, ? pO2, ~ ? LA, ? Ca coagulopathy ? PT, ? PTT ? Hct salicylate 41.1 ?g/mL Labs from this patient: Na 146 (135-145) BUN 11 (7-21) PO4 4.3 (2.4-4.5) K 3.5 (3.5-5.8) CR 1 (0.8-1.4) Mg 2.0 (1.6-2.2) Cl 116 (98-107) glu 87 (65-110) AST 26 ( 19-55) HCO3 9 (22-30) OSMO 309 ALT 22 (19-72) Anion gap 25 (<14) OG 8 (<10) alk phos 107 (38-126) Ca 8.2 (8.5-10.2) GGT 27 (13-126) bili 0.3 (0-1.2) UA NH4 27 (15-45) SG 1.005 pH 5.5 HCT 35.3 (37-51) PT 15 (12-14.4) ABG INR 1.65 pH 7.39 (7.35-7.45) PTT 38.3 (20.7-27.7) pCO2 17 (35-45) pO2 108 (80-110)Labs from this patient: Na 146 (135-145) BUN 11 (7-21) PO4 4.3 (2.4-4.5) K 3.5 (3.5-5.8) CR 1 (0.8-1.4) Mg 2.0 (1.6-2.2) Cl 116 (98-107) glu 87 (65-110) AST 26 ( 19-55) HCO3 9 (22-30) OSMO 309 ALT 22 (19-72) Anion gap 25 (<14) OG 8 (<10) alk phos 107 (38-126) Ca 8.2 (8.5-10.2) GGT 27 (13-126) bili 0.3 (0-1.2) UA NH4 27 (15-45) SG 1.005 pH 5.5 HCT 35.3 (37-51) PT 15 (12-14.4) ABG INR 1.65 pH 7.39 (7.35-7.45) PTT 38.3 (20.7-27.7) pCO2 17 (35-45) pO2 108 (80-110)

10. Aspirin At therapeutic doses, ASA rapidly hydrolyzes to salicylate (t1/2 ~15 m). All of the other pharmacological and toxicological actions of aspirin are contributed by salicylate. A number of enzymes are involved in the metabolism of salicylate. A key point here is that these pathways may become saturated even at high therapeutic doses. Consequently, serum salicylate levels may increase disproportionately with dosage. At high therapeutic or toxic doses, the salicylate elimination half-life is prolonged (15-30 h VS 2-3h at low dose). While we�re on delays, remember too, that while the absorption of normal doses of regular aspirin from the GI tract is generally rapid, with peak serum concentrations achieved within 2h. This peak value may be delayed for 12 h or longer for enteric-coated or slow-release formulations. Toxic doses may produce pylorospasm and delay absorption. In these cases, levels may not reach max concentrations for 6h or longer. Finally, excretion is pH dependant with alkaline urine enhancing excretion. At therapeutic doses, ASA rapidly hydrolyzes to salicylate (t1/2 ~15 m). All of the other pharmacological and toxicological actions of aspirin are contributed by salicylate. A number of enzymes are involved in the metabolism of salicylate. A key point here is that these pathways may become saturated even at high therapeutic doses. Consequently, serum salicylate levels may increase disproportionately with dosage. At high therapeutic or toxic doses, the salicylate elimination half-life is prolonged (15-30 h VS 2-3h at low dose). While we�re on delays, remember too, that while the absorption of normal doses of regular aspirin from the GI tract is generally rapid, with peak serum concentrations achieved within 2h. This peak value may be delayed for 12 h or longer for enteric-coated or slow-release formulations. Toxic doses may produce pylorospasm and delay absorption. In these cases, levels may not reach max concentrations for 6h or longer. Finally, excretion is pH dependant with alkaline urine enhancing excretion.

11. Aspirin Intoxication Acute ingestion ~20000 incidents reported yearly 25% adults Chronic ingestion salicylism frequency unknown doses - 2-6 g/d Aspirin intoxications can be divided into those that occur from a single ingestion and those resulting from long-term use. About 20000 acute ingestions are reported each year to the Poison Control Centers with only about 1/4 of these being adults. These doses have varied considerably from single tablets to over 100g. Long-term ingestion of 2-6 g/d can result in salicylism - which is defined as mild, chronic salicylate intoxication. Aspirin intoxications can be divided into those that occur from a single ingestion and those resulting from long-term use. About 20000 acute ingestions are reported each year to the Poison Control Centers with only about 1/4 of these being adults. These doses have varied considerably from single tablets to over 100g. Long-term ingestion of 2-6 g/d can result in salicylism - which is defined as mild, chronic salicylate intoxication.

12. Acute Salicylate Toxicity Direct CNS respiratory stimulant hyperventilation and respiratory alkalosis Direct uncoupling of oxidative phosphorylation hyperthermia, inc�d O2 consumption and metabolic rate Impairment of Krebs cycle metabolic acidosis Even at low to moderate doses, salicylates directly stimulate the central respiratory center and thereby cause hyperventilation and respiratory alkalosis. Sali cause uncoupling of oxidative phosphorylation. As a result, heat production (hyperthermia), oxygen consumption, and metabolic rate may be increased. In addition, salicylates enhance anaerobic glycolysis, but inhibit Krebs cycle and transaminase enzymes, all of which lead to accumulation or organic acids and thus to metabolic acidosis. The primary acid-base disturbance observed with sali overdosage depends on age and severity of intoxication. Respiratory alkalosis initially predominates in children over age 4 y and in adults, and this often progresses thru a mixed respiratory alkalosis-metabolic acidosis to metabolic acidosis. In 97 patients who had plasma sali conc greater than 70 mg/dL, 19% were found to have respiratory alkalosis, 61% had combined RA/MA and 15% had metabolic acidosis. Mortality was associated with acidemia. The symptoms of salicylate intoxication include tinnits, diaphoresis, hyperthermia, hyperventilation, nausea, vomiting, and acid-base disturbances. CNS effects include lethargy, disorientation, and in severe cases, coma and seizures. Tinnitus may occur at [S] > 20 mg/dL but more serious toxic manifestations are generally not evident unless the [S] > 30 mg/dL.Even at low to moderate doses, salicylates directly stimulate the central respiratory center and thereby cause hyperventilation and respiratory alkalosis. Sali cause uncoupling of oxidative phosphorylation. As a result, heat production (hyperthermia), oxygen consumption, and metabolic rate may be increased. In addition, salicylates enhance anaerobic glycolysis, but inhibit Krebs cycle and transaminase enzymes, all of which lead to accumulation or organic acids and thus to metabolic acidosis. The primary acid-base disturbance observed with sali overdosage depends on age and severity of intoxication. Respiratory alkalosis initially predominates in children over age 4 y and in adults, and this often progresses thru a mixed respiratory alkalosis-metabolic acidosis to metabolic acidosis. In 97 patients who had plasma sali conc greater than 70 mg/dL, 19% were found to have respiratory alkalosis, 61% had combined RA/MA and 15% had metabolic acidosis. Mortality was associated with acidemia. The symptoms of salicylate intoxication include tinnits, diaphoresis, hyperthermia, hyperventilation, nausea, vomiting, and acid-base disturbances. CNS effects include lethargy, disorientation, and in severe cases, coma and seizures. Tinnitus may occur at [S] > 20 mg/dL but more serious toxic manifestations are generally not evident unless the [S] > 30 mg/dL.

13. Salicylism No history of overdose Nonfocal neurological abnormalities Noncardiogenic pulmonary edema Laboratory: acid-base and electrolyte abnormalities, ketosis, prolonged prothrombin time These patients may be difficult to diagnose - first, because there is no history of overdose. Toxicity is often the result of their therapeutic regimen and again these patients typically take 2-6 g of aspirin daily for pain or inflammation. The earliest symptoms are typically dizziness, tinnitus, hearing loss with progression to headache, dimness in vision, lethargy, drowsiness, sweating, thirst, hyperventilation, nausea, vomiting and mental confusion which includes restlessness, confusion, talkativeness. Some may present with a noncardiogenic pulmonary edema [the plasma volume is increased about 20%, the hematocrit falls and cardiac output and work are increased] Lab studies will show acid-base and electrolyte abnormalities, prolonged coagulation studies, decreased hematocrit, and possibly ketosis.These patients may be difficult to diagnose - first, because there is no history of overdose. Toxicity is often the result of their therapeutic regimen and again these patients typically take 2-6 g of aspirin daily for pain or inflammation. The earliest symptoms are typically dizziness, tinnitus, hearing loss with progression to headache, dimness in vision, lethargy, drowsiness, sweating, thirst, hyperventilation, nausea, vomiting and mental confusion which includes restlessness, confusion, talkativeness. Some may present with a noncardiogenic pulmonary edema [the plasma volume is increased about 20%, the hematocrit falls and cardiac output and work are increased] Lab studies will show acid-base and electrolyte abnormalities, prolonged coagulation studies, decreased hematocrit, and possibly ketosis.

14. Salicylate concentrations

15. Salicylate concentrations

16. Treatment: Acute Intoxication Supportive: 02, IVF Decontamination with AC Dextrose (D50) d/t low CNS glucose if ?MS Alkalinization of plasma & urine (pH 7.5 to 8.0) (alkalemia not a contraindication but pH should not exceed 7.6) Hemodialysis in severely ill patients Acetazolamide contraindicated

17. Alkalinization Promotes efflux of salicylate from tissues Promotes renal excretion Bicarb pushes the equation to the �left�: H+�� +�� sal-����<�>���� HS

18. Hemodialysis Indications ?MS Pulmonary or cerebral edema Renal insufficiency impeding salicylate excretion Fluid overload preventing sodium bicard administration