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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.