Acetaminophen Associated Hypotension

1. Acetaminophen Associated Hypotension Presenter: Ri 林志銘 11.20

2. Introduction (1) • Acetaminophen • Analgesic-Antipyretic • Most commonly used drugs • Mechanism • Central nervous system • Weak cyclooxygenase inhibitor • Inhibition of prostaglandin synthesis • Dosage (Adult) • 650~1000 mg PO Q4h, max 4 g/day • 650 mg reatally Q4~6h, max 6 supp./day

3. Introduction (2) • Acetaminophen • Pharmacokinetics • Onset: 0.5 hour • Duration: 4 hours • Metabolism • Liver, first pass 25 % • Metabolite: • Glucuronic acid conjugate • Sulfate conjugate • Excretion: kidney • Contraindication • Hypersensitivity

4. Introduction (3) • Acetaminophen • Common adverse reaction • Hypertension • Addition to an anti-hypertensive regimen • Renal vasodilators (Prostaglandins) were inhibited by cyclooxygenase • Primarily prostaglandins E2, I2, and F2a. • Vasoconstriction -> ↑systemic BP 5 mm Hg • Risk group • Women who took more than 500 mg/day • Hypertensive patients

5. Introduction (4) • Acetaminophen • Common adverse reaction • Acute hepatotoxicity • Allergic reactions • Drug eruption, difficulty breathing • Abdominal pain • Nausea • Unusual bleeding or bruising

6. Hypotension Following Acetaminophen Administration (1) • Mackenzie et al (1999) • Retrospective control study • Topic: • To find associations between AAP administration and Hypotension • Subjects: • 53 patients in ICU stay(29/11/1997~ 29/1/1999) • 191 episodes AAP administration (500 mg PO/rectal)) • Methods: • Chart review • Record T/MAP/HR from 2 hours before administration to 3 hours after • Excluded repeat administrations in recent 6 hours

7. Hypotension Following Acetaminophen Administration (2) • Mackenzie et al (1999) • Comparisons • Baselines: • MAP/HR- 2 hours preceding administration • T- 6 hours preceding administration • Experimental group: • T/MAP/HR in +1,+2, +3 hour • Control group: • The same patient in • 24 hour prior/after administration • 8 hour prior/after administration

8. Hypotension Following Acetaminophen Administration (3) • Mackenzie et al (1999) • Results: • Compared to baseline • Significant fall in T/MAP/HR at +1, +2, +3 hour (p< 0.0001) except HR at +1 • Lowest MAP: 89.0% (48.8~113.3 %), male greater than female (87.1 vs 94.6%) • Compared to control • Significant fall in T/MAP/HR at +1, +2, +3 hour (p< 0.0005) except HR at +1 • Correlation between post-AAP hypotension • Age (p=0.04) • Baseline MAP (p=0.02) Crit Care Med Vol 27 (12) Supp A33

9. Effects of AAP administration • Mackenzie et al (2000) Intensive Care Med 26: 1408

10. Similar study • Boyle M et al (1997) • Prospective observational cohort study • 27 subjects (23 with fever, 12 with vasoactive infusions, 7 with regular anti-hypertensive drugs) • Record SBP/DBP/MAP in all patients taking acetaminophen 1 gm orally • 30 mins prior • 15 mins interval for the first hour • 30 mins interval for the second hour • Results • SBP • Fall significantly in all observation times • 133(4.7) mmHg in -30 mins -> 116(3.8) mmHg in +45 mins • Max fall in 30 mins 36 % • MAP • Fall significantly in 30, 45, 60, 90 mins after AAP administration • 84(2.9) mmHg in -30 mins -> 78(2.5) mmHg in +45 mins • Max fall 34 % in 30/45 mins Aust Crit Care 199710:120-122

11. Case report • Brown G (1996) • #1 53 y/o female • Short of breath , • CXR: RLL, LLL consolidation • Admitted to ICU • Intubation for inadequate arterial oxygenation • APP administration were associated with changes in BP • Increased requirements of vasopressors use • Day 3~8 hypotension with vasopressors use • Erythematous rash rash on the back • DC APP → no further episodes of hypotension Heart & Lung 25 (2); 137~140

13. Case report • Brown G (1996) • #2 21 y/o male • Admitted for Chemotherapy of amyeloblastic leukemia • Day 1~6 cytarabine 1.5 gm/m2 • Day 7~9 daunorubicin • Day 17~22 neutropenic fever • Use gentamycin/ ceftazidine /vancomycin / amphotericin B • Day 23 transfer to ICU • Short of breath, resp. failure,intubation for mechanical support • During ICU course • AAP was administered as an anti-pyretic in an attempt to reduce oxygen demand • The major changes in blood pressure were associated with AAP administration Heart & Lung 25 (2); 137~140

15. Possible Hypothesis • Hypotension could be • Due to acetaminophen related or in acute phase of septic shock or SIRS • Need RCT evidence • APP administration in afebrile condition • Part of delayed hypersensitivity or anaphylactoid reaction • Other unknown mechanism

16. Acetaminophen Hypersensitivity • Vidal et al (1997) • Aspirin and other NSAID may induce urticaria, angioedema, rhinitis, bronchial athma and anaphylactoid reaction • Acetaminophen intolerance can occur less than 5 % of aspirin-sensitive subject • Hypersensitivity to acetaminophen without aspirin sensitivity is rare. • Oral provocation test, specific IgE antibodies • Case report: • 40 y/o female, hypotension (70/40 mmHg), generalized hives • A real allergic mechanism rather than inhibition of prostglandin synthesis Ann Allergy Asthma Immunol 79:320-321

17. Anaphylactoid reaction to AAP • Ayonrinde OT, and Saker BM (2000) • Adverse reaction to AAP, even in therapeutic range can have near fatal consquences Postgrad Med J 2000; 76:501~502

18. Conclusions • Anaphylaxis or anaphylactoid reaction could be one reason of the APP associated hemodynamic change. • Only extremely rarely does AAP result in hypotension. • Further randomized, placebo-controlled trials are necessary to recognize AAP, temperature and SIRS relationships. • Clinician should be vigilant in hypotensive episodes follow administration of AAP • Fluid and vasopressor would be treatment of choice. • Should be mentioned in product information

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