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Protamine Induced Pulmonary Hypertension

Protamine Induced Pulmonary Hypertension. Presented by Ri 陸尊惠 /Ri 黃崧溪 Supervised by CR 林子富. Basic Data. Name: 王嚴 Age: 45 Gender: Male Chart number: 4221159 Date of admission: 3/28. Chief complaint. Intermittent fever for more than 2 months. Present Illness.

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Protamine Induced Pulmonary Hypertension

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  1. Protamine Induced Pulmonary Hypertension Presented by Ri陸尊惠/Ri黃崧溪 Supervised by CR林子富

  2. Basic Data • Name: 王嚴 • Age: 45 • Gender: Male • Chart number: 4221159 • Date of admission: 3/28

  3. Chief complaint • Intermittent fever for more than 2 months

  4. Present Illness • Intermittent fever for more than 2 months • Hematuria • Poor appetite, general weakness in recent weeks • Body weight loss (10 kg in recent 7 months) • Mild cough

  5. Past History • ESRD (drug abuse related) s/p renal transplantation in Feb 2004 with graft failure s/p T1W hemodialysis since Aug 2004 • No immunosuppressant or steroid use since August 2004 • DM (-), hypertension (+) • HBV (+), HCV (+)

  6. Physical Examination • Conscious: clear • Vital signs: BT 37.1°C, PR 105, BP 100/45 mmHg, SpO2 98% • HEENT: pink conjunctiva, anicteric sclera • Chest: symmetric expansion, clear breathing sound • Heart: regular heart beat, grade 3/6 diastolic murmur at apex noted at ward • Abdomen: flat and soft, no tenderness, no shifting dullness, no rebound pain • Extremities: Right forearm AVF

  7. Laboratory Data

  8. Initial Impression • R/O intraabdominal infection • R/O chronic rejection • R/O occult infection • ESRD under hemodialysis TIW • FUO

  9. Cardiac echo (4/1) • AV vegetation (a shaggy mass 6x10mm at LCC of AV) • Normal mitral valve morphology • Severe AR • Concentric LVH • Small amount of pericardial effusion • LVEF: 68% • Pulmonary hypertension • Suspect infective endocarditis

  10. Treatment Course • Blood cultures were negative for pathogens • CVS consultation: antibiotic treatment for at least 2 weeks then elective surgery for AVR; emergent operation indicated if heart failure s/s flare-up or uncontrolled infection • Fever (up to 39°C+) noted despite antibiotics since 3/31 (Penicillin + Gentamicin -> Rocephin -> Cravit + Amikin)

  11. TEE (4/29) • An oscillating hyperechoic nodule (0.50 x 0.55cm) was seen on LCC of AV; a vegetation cannot be ruled out • Peri-aortic root space with fluid accumulation and extension to aorto-mitral intervalvular fibrosa • AR, moderate-severe • MR, moderate • TR, moderate • PR, moderate • Impression: IE with disease progression

  12. Preoperative Evaluation • Basic Data • 45 year-old male • BW: 61.8 kg • BH: 161 cm • Past History • Hypertension, HBV carrier, ESRD s/p renal transplantation and graft failure, under H/D, cigarette smoking 1 ppd • Laboratory Data • WBC 11970, Hb 8.8, BUN/Cr 37.1/4.0 • Clinical Diagnosis: Infective endocarditis • Operation proposed: AVR • Operator: 許榮彬 • Date of operation: 94/5/1 • ASA Class: 4E

  13. Peri-operative Anesthesiology Note • ASA Class: 4E • General anesthesia (ET tube: 7.5# at 22cm) • Induction at 14:35 with Fentanyl 250 ug, Esmeron 50 mg, Etomidate 20 mg • Maintenance: O2 + Desflurane • Monitors: • Right hand arterial line • Right neck Swan-Ganz • Left neck CVP • Foley catheter

  14. Op Note (5/1) • Pre-op diagnosis: IE, AR, MR, uremia • Post-op diagnosis:IE, AR, MR, uremia • Op method: AVR • Op finding: • Cardiomegaly • Bloody pericardial effusion • Aortic valve: perforation in LCC and RCC, vegetation in NCC ventricular side • No paraaortic abscess, aortic annulus intact • No mitral valve vegetation • Hypertrophy of LV muscle

  15. Duration of anesthesia: 14:35 to 20:35 • Duration of operation: 16:00 to 20:25 • Partial bypass on at 17:02, off at 19:06 • Total bypass on at 17:11, off at 18:53 • Aorta x-clamp on at 17:12, off at 18:37 • ACT: 177 • PRBC 7U, PLT 12U

  16. 體外循環記錄表 • Heparin • To patient: 4.8 cc • To pump: 1.6 cc • Protamine: 6.5ml • Added during CPB • N/S: 1000cc • Blood: 2+2+2 • Vitacal: 20cc • Xylocaine: 8ml+7ml

  17. Heparin Reversal With Protamine • Transient drop in BP and near asystole was noted after initial protamine infusion at 19:10 (BP <50/30 mmHg) • Transient elevation of PAP (>70 mmHg) was also noted • Protamine was held and Epinephrine (Bosmin) 1mg was administered • BP 70/50 mmHg, HR 130 after epinephrine administration

  18. Heparin reversal with protamine continued • Transient drop in BP, HR, and elevation of PAP was noted again • Protamine infusion discontinued • At end of surgery: • ACT: 117 • BT: 37.1 • SpO2: 100 • ETCO2: 34 • PAP: 38/23 • CVP: 10

  19. Post-operative Course • Patient was admitted to 4A2 on 5/1 • Post-op inotropic agents: Dopamine 2amp/250ml, Bosmin 1amp/20ml, Levophed 0.5amp/50ml IVD titration • Smooth extubation on 5/2 • Transferred to 8A ward on 5/4 • Inotropic agents gradually tapered off at ward • Currently, intermittent low grade fever is still noted with mild leukocytosis (WBC 10750) and elevated CRP (5.21), under Vancomycin 500mg Q3D and Amikin 250mg QOD • Hemodialysis T1W

  20. DISCUSSION

  21. Pharmacological Properties of Protamine • Protamine is a polycationic, alkaline protein molecule, and is made up of rich arginine residues. • Heads of the sperm of the salmonidae or clupeidae family as well as man are rich in protamine and salmon milt is the commercial source of protamine. • International Anesthesiology Clinics. 42(3):135-145, Summer 2004

  22. Clinical uses of protamine • Neutralization of heparin use • It forms a stable complex with negatively charged heparin. • Heparin-protamine complex is devoid of anticoagulant activities. • Retardation of insulin absorption in intermediate- and long-acting insulin preparations. • Protamine also exerts a mild anticoagulant activity. • International Anesthesiology Clinics. 42(3):135-145, Summer 2004

  23. 1000X • - Chest. 2001;119(1 suppl):64S–94S

  24. Protamine Reactions • 3 main different categories: • Transient systemic hypotension • Anaphylaxis or anaphylactoid reactions • Catastrophic pulmonary vasoconstriction (0.6%) • Major adverse responses related to protamine administration occur during 2.6% of cardiac surgery procedure. • Hemodynamic perturbations after protamine administration are independently related to in-hospital mortality. • Chest. 2002; 122(3):1061-1066 • Anesthesiology. 2005; 102:308-314

  25. Represent “AUC”: time * ×Δ PAP/ΔSBP • Anesthesiology. 2005; 102:308-314

  26. How does this happen?(1) • Systemic hypotension • Transient systemic hypotension often associated with rapid administration of protamine. • Protamine decreases peripheral vascular resistance rather than depressing myocardial function • Compensatory increased cardiac output • Proposed mechanism: protamine, free or complexed with heparin, acts on endothelial receptors • Chest. 2002, 122(3):1061-1066 • Anesthesia & Analgesia. 1985; 64: 348-361

  27. Chest. 2002, 122(3):1061-1066

  28. How does this happen? (2) • Anaphylaxis or anaphylactoid reaction • As a nonhuman protein, protamine can be antigenic. • It is manifested with decreased SVR, flushing, edema, and bronchospasm. • It is mediated by Ag-specific B-cell (IgE-mediated, anaphylaxis) or direct activation of complement system (non-IgE-mediated, anaphylactoid reaction) • Anesthesia & Analgesia. 1985; 64: 348-361

  29. - From website of University of Sussex, UK

  30. How does this happen?(3) • Catastrophic pulmonary vasoconstriction • Patient presented with pulmonary arterial hypertension, dilated RV, decreased LV filling pressure, and systemic hypotension. • It can occur under various dosage (even low dose at 10 mg) and usually develops in 10 minutes. • The reaction was not seen if protamine was given alone without heparin • International Anesthesiology Clinics. 42(3):135-145, Summer 2004

  31. How does this happen? (4) • Catastrophic pulmonary vasoconstriction • Large increase in plasma C5a and TXB2, but not histamine, in these patients • Proposed mechanism: protamine-heparin complex ￫ complement activation ￫ generation of TXA2 ￫ platelet aggregation and vasoconstriction • Jour of Cardiothoracic and Vascular Anesthesia. 2003, 17(3): 309-313

  32. Who is more susceptible to protamine reactions? • Suspected risk factors: • Fish allergy, not shellfish • Vasectomy and infertility • Prior protamine exposure, eg. DM, vascular surgery • History of pulmonary hypertension • The site of venous protamine administration does not influence incidence of protamine-induced pulmonary vasoconstriction. • Jour of Cardiothoracic and Vascular Anesthesia. 2003, 17(3): 309-313

  33. How to deal with protamine reaction?(1) • Systemic hypotension • Use slow-rate injection • Methylene blue as a NO blocker in refractory cases • Acute anaphylactoid reactions • Diphenhydramine 50 mg IV • Fluid repletion • Epinephrine • Bronchodilators • International Anesthesiology Clinics. 42(3):135-145, Summer 2004 • Chest. 2002, 122(3):1061-1066

  34. How to deal with protamine reaction?(2) • Catastrophic pulmonary vasoconstriction • iNO may be effective • Inodilator such as isoproterenol or milrinone • In patient with known hypersensitivity • Hexadimethrine or heparin removal device as alternative to protamine? • Pretreat with steroid or antihistamine? • The use of aspirin? • Chest. 2002, 122(3):1061-1066 • International Anesthesiology Clinics. 42(3):135-145, Summer 2004

  35. Summary • Protamine reactions appeared with different presentation and can be categorized into 3 main groups: systemic hypotension, anaphylaxis or anaphylactoid reactions, and catastrophic pulmonary hypertension. • These reactions can be associated with adverse outcome of the patients and thus prompt recognition and treatment are important.

  36. Thanks For Your Attention!!

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