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Prostacyclin uses and setup for hypoxic respiratory failure

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Prostacyclin uses and setup for hypoxic respiratory failure

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    1. Prostacyclin uses and setup for hypoxic respiratory failure Alex Yartsev, 30/11/2011

    2. Prostacyclin: Prostaglandin I2 (PG I2) Endogenous eicosanoid Released by endothelial cells A paracrine signaling molecule Targets neighboring endothelial cells and platelets

    3. Prostacyclin: Prostaglandin I2 (PG I2)

    4. Epoprostenol: a synthetic prostacyclin analogue

    5. Epoprostenol: a synthetic prostacyclin analogue Essentially identical molecule

    6. Pharmacokinetics Highly unstable at any normal pH

    7. Pharmacokinetics Small volume of distribution, 357 ml/kg Undergoes spontaneous non-enzymatic hydrolysis in the blood at normal physiological pH Half-life 40-180 seconds Vascular effects disappear within 30 minutes of infusion/nebulizer cessation Metabolite has less than 5% of parent activity

    8. Prostacyclin receptors Found on the surface of platelets and endothelial cells GS protein coupled receptors Increase cAMP cAMP inhibits platelet aggregation by counteracting increases in cytosolic Ca++ cAMP also activates protein kinase A PKA inhibits myosin light-chain kinase, which causes smooth muscle relaxation.

    9. In summary, the effects of prostacyclin: Vasodilation Decreased platelet aggregation also Antiinflammatory effects Decreased fibroblast proliferation Increased fibroblast apoptosis Increased nociceptor sensitivity to pain Inhibition of gastric acid secretion

    10. Indications for prostacyclin Pulmonary hypertension (as infusion) Specifically, pulmonary hypertension associated with scleroderma Hypoxia with PHT in ARDS (nebulised) Alternative to heparin in dialysis circuit

    11. Indications for prostacyclin Pulmonary hypertension (as infusion) Specifically, pulmonary hypertension associated with scleroderma Hypoxia with PHT in ARDS (nebulised) Alternative to heparin in dialysis circuit

    12. Precautions and Contraindications for Prostacyclin Contraindicated in severe LV dysfunction (increases mortality) Hypotension Bleeding diathesis Extravasation (highly alkaline) Abrupt cessation of chronic treatment

    13. Administration of continuous nebulised prostacyclin

    14. The Aerogen continuous nebuliser

    15. The Aerogen continuous nebuliser

    16. The Aerogen continuous nebuliser

    17. Whats the point? Hypoxia in ARDS is due to Intrapulmonary shunting: much of the lung is unventilated Pulmonary microcirculation is obstructed by microthrombi Pulmonary vascular resistance is elevated; Pulmonary hypoxic vasoconstriction occurs but NOT the areas where the hypoxia is greatest (otherwise, it would be helpful)

    18. Whats the point? Pulmonary arteries constrict in presence of hypoxia, to direct flow to better oxygenated areas of the lung This response is impaired in ARDS Inhaled prostacyclin vasodilates pulmonary arteries in well-aerated regions of the lung, directing flow to these regions. Thus, the shunt is decreased The decreased right ventricular afterload can also improve right ventricular function.

    19. Whats the expected effect? Bein (1994) case report 65 yr old man Klebsiella pneumonia and ARDS O2 sensor in his left radial artery 5 ng / kg / min aerosolized prostacyclin PA pressure also decreased from 49 to 38 mmHg

    20. Whats the best evidence? Cochrane: 2010 systematic review Only one trial qualified: 14 paediatric patients. In those kids, no mortality benefit at 28 days. Unsurprisingly, There is no current evidence to support or refute the routine use of aerosolized prostacyclin for patients with ALI and ARDS.

    21. Whats the next best evidence? Shoemaker 1986 PGE1, given IV. RCT - 15 patients, PO2 / PAP improved. Bein 1994 - single case report; PGI neb = PO2 improved Pappert 1995 pediatric population, comparison with NO (no difference) Walmrath 1995 - 16 patients, PGI nebs vs NO. No difference. Zwissler 1996 PGI nebs vs NO; no difference Van Heerden 1996 5 patients, PGI nebs vs NO. No difference. Meyer 1998 PGE1, given IV. 15 patients, no controls. ICU mortality 40%. Putensen 1998 10 patients, PGE vs NO no difference Van Heerden 2000 9 patients, PGI nebs = oxygenation improvement is dose -related Domenighetti 2001- 15 patients, PGI -PO2 improved more in extrapulmonary ARDS Siddiqui et al : ongoing trial since 2009, data not yet available. Inhaled Prostacyclin for Adult Respiratory Distress Syndrome (ARDS) and Pulmonary Hypertension

    22. Why is everyone comparing it to Nitric Oxide? Better studied Similar mechanism of action Incidentally, large systematic review of NO in ARDS = no mortality benefit

    23. Why not just use Nitric Oxide? More expensive (hundreds of litres required per patient) INOMax (from Ikaria Australia Pty Ltd) $125 per hr Wheras, Flolan is yours for only $52.11 per 500mcg pack, hence ~ $5.21 per hour of neb. NO Side effects include Thrombocytopenia Methaemoglobinaemia DNA damage (genotoxicity) According to manufacturer, not indicated for use in the adult population

    24. In summary; Epoprostenol Cheap Sound mechanism Few side effects Improves the numbers As for survival jury is out

    25. No further questions, please.

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