Inhaled Epoprostenol Considerations for Use in Ventilated Patients Shari McKeown, Practice Leader Respiratory Services VA
Aliases • Naturally occurring prostaglandin • Epoprostenol sodium • Flolan • Prostacyclin • PGI2 • PGX
…the point… • Inhaled vasodilators can reduce PAP and redistribute pulm blood flow to ventilated lung regions with little systemic effect1,2,3,4,5 • Della Rocca G., Coccia C, Pompei L. et al. Inhaled aerosolized prostacyclin and pulmonary hypertension during anesthesia for lung transplantation. 2001 Transplant Proc, 33, 1634-1636. • Lowson SM. Inhaled Alternatives to Nitric Oxide. Anesthesiology 2002;96(6):1504-1513 • Mikhail G, Gibbs S, Richardson G, Wright G, Khaghani A, Banner N, Yacoub M. An evaluation of nebulized prostacyclin in patients with primary and secondary pulmonary hypertension. Eur Heart J 1997, 18;1499-1504. • Olschewski H. et al. Inhaled prostacycin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Respiratory and Critical Care Medicine 160(2) 1999:600-607. • Walmrath D, Schneider T, Schermuly R, et al. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. Am J Respir Crit Care Med 1996; 153:991-996.
Pharmacologic Actions • Selective vasodilation of pulmonary vascular beds1 • Decreased PVR, PAP • Inhibition of platelet aggregation • (but no evidence of platelet dysfunction or bleeding noted clinically) • Increased arterial oxygenation • Improved V/Q matching in lung (Cochrane review planned for 2009) • Olschewski H. et al. Inhaled prostacycin and iloprost in severe pulmonary hypertension secondary to lung fibrosis. Respiratory and Critical Care Medicine 160(2) 1999:600-607.
Indications • Primary and Secondary Pulmonary Hypertension • Cardiac surgery-associated pulmonary hypertension and RV failure • Lung transplantation-related reperfusion injury • Liver transplantation portopulmonary hypertension • Hypoxemia due to single-lung ventilation or ARDS
Contraindications • Hypersensitivity to drug or diluent
Cost Analysis (compared with nitric oxide) • Average runtime 45.6 hours1 (for PPH) • Flolan (based on average weight 80kg at 31 mcg/kg/min) • Medication - $12.50 hour • PALL filter unit cost - $4.99 (changes Q2H) = $113.77 • Disposable aeroneb system - $50.00 • = $733.77 • Nitric Oxide • $95.00 hour • = $4332.00 1. De Wet CJ. Inhaled prostacyclin is safe, effective and affordable in patients with pulmonary hypertension, right heart dysfunction, and refractory hypoxemia after cardiothoracic surgery. J Thoracic and Cardiovascular Surgery 2006;127:1058-67
Setup • Must be reconstituted with glycine • Not compatible with any other solution • Glycine is sticky and viscous • Needs to be shielded from light • Recommended to keep reconstituted solution cold with icepacks during administration (2-8 degrees C) (stable for 8 hrs room temp, 24 hours refrigerated) • Nebulizer, infusion tubing, connections, changed every 24 hrs (refrigerated) or every 8 hrs (unrefrigerated) as drug expires • Option A: continuous flow-driven nebulizer (Miniheart) + infusion pump • Option B: continuous electronically-driven nebulizer (Aeroneb) + infusion pump
Option A: Miniheart neb • Continuous flow-driven nebulizer • Dose delivery is dependent on flowrate • 8 ml/hr nebulizer output with 2 Lpm flowrate set on neb • Fluctuating dosing may occur during delivery • Easy to wean by adjusting neb input from pumps • Added flow to ventilator circuit affects ventilation • patient triggering affected • Triggering will be made less sensitive or could cause autocycling • Delivered tidal volumes and pressures increased • Delivered FiO2 changes unless nebulizer connected to blender • Accuracy of monitored values is affected – exhaled tidal and minute volumes will be inaccurate • Alarm functions may be inaccurate – particularly low tidal volume/low minute volume/leak alarms • Certain ventilator modes will malfunction (PRVC, CMV with Autoflow, VC+, PAV) • Safest mode to be on is PSV or PCV
Option A: Miniheart neb • Accidental disconnection of nebulizer tubing is possible due to backpressure from nebulizer causing sudden stoppage of dosing (no alarm) • Accidental disconnection or maladjustment from wall flowmeter is possible (causing increased or stoppage of dosing) (no alarm) • Nebulizer tipping is possible, causing accidental instillation of entire dose into endotracheal tube or sudden stoppage of dosing (no alarm)
Option B: Aeroneb • Continuous (mesh screen sifter) electronically-driven neb • Dose delivery is dependent on constant output • On-off switch only – nebulizer output is set at 30 ml/hr • Dosage depends on concentration of medication in nebulizer • Difficult to wean – med must be remixed • Does not affect ventilator performance – no flow added to circuit • Nebulizer dysfunction is likely (no alarm) • Unit stops functioning if battery dies • Have had to replace batteries in all of our controllers • Cables can be kinked • Powercords malfunction frequently • Limited number of controllers available – would need backup unit on standby • Cost of controller unit is $1425. ( we have 3, often all are in use for nebulized antibx) • Nebulizer tipping is possible. Would not spill dose into endotracheal tube, but may result in sudden stoppage of dose (no alarm)
Benchmarking • Barnes Jewish Hospital, St. Louis, MO • 126 patients • Miniheart continuous nebulizer • Filter changes Q2 hrs • Adverse event – vent exhalation valve became sticky, significant autopeep/hypotension • Sudbury Regional Hospital, Sudbury, ON • Filter changes Q6 hrs and PRN • Kingston General Hospital, Kingston, ON • Miniheart continuous nebulizer • Filter changes Q4H and PRN • Harborview Medical Centre, Seattle, WA • Aeroneb • No filtering? • Bench test only • St Pauls Hospital, Vancouver, BC • Miniheart nebulizer • Filter changes Q 2-4 hrs and PRN
Patient Safety • Neb must run continuously • Product has biological half-life of 2-3 minutes • Rebound pulmonary hypertension may be life-threatening • Dyspnea, dizziness, asthenia • Rare reports of death (IV use)1, 2 • Augoustides J, Culp K, Smith S. Rebound pulmonary hypertension and cardiogenic shock after withdrawl of inhaled prostacyclin. (Case Report) Anesthesiology 2004(100):1023-1025 • Barst RJ. Rubin LJ. McGoon MD, et al. Survival in primary pulmonary hypertension with long-term continuous intravenous prostacyclin. Ann Intern Med 1994; 121:409-415. • GlaxoSmithKline Inc. Product Monograph, Flolan for Injection, 2008.
Patient Safety cont’d • Filter clogging • Glycine is sticky and viscous; quickly clogs filters • Bench testing for filter resistance1 1. David Sima, RT Clinical Educator, bench testing data June 2009
Standard dose (31 mcg/kg/min, 80 kg)- 10 Lpm minute volume- calibrated equipment, reproducible results- filter resistance after 1 hour = 18.8 cmH20/Lps
Standard dose (31 mcg/kg/min, 80 kg)- 20 Lpm minute volume- calibrated equipment, reproducible results- filter resistance at 1 hour = 23.09 cmH20/Lps
Filter Clogging • ↑expiratory resistance • ↑ autopeep • ↑ intrathoracic pressure • ↑ PVR • Affect V/Q matching in lung • Affect ventilator performance and safety • Hourly circuit changes may clog vent exp filter • ‘Vent-inop’ at 5 cmH20 transducer difference • Would necessitate immediate manual ventilation and vent change
Occupational Health and Safety • Would require frequent (Q30min) circuit disconnections • PPE protection for staff during exposure times • Minimal data on exposure during pregnancy
Alternatives? • Prostaglandins • IV Epoprostenol • Iloprost • Treprostinol • Beraprost • PGE1 • NO donors • Inhaled Nitric Oxide • Inhaled sodium nitroprusside • Inhaled nitroglycerine • Phosphodiesterase Inhibitors • Sildenafil • Milrinone • Endothelin Antagonists • Bosentan • Nesiritide • Adrenomedullin
Recommendations • Evaluate risk-benefits • Explore alternatives • If we must? • Aeroneb recommended as best delivery system • Q 30 minute filter changes • Purchase additional controller sets • Backup equipment on standby • Patient care guideline development, education and vigilance for patient safety • Investigate alarm possibility with manufacturer
Summary • Patient benefit for use (PPH, ARDS?) • Inexpensive in comparison with N.O. • 2 delivery systems, both have significant safety concerns • Is it worth it? Or investigate alternatives?