Inhaled EpoprostenolInhaled Epoprostenol

Considerations for Use Considerations for Use

in Ventilated Patientsin Ventilated PatientsShari McKeown, Practice Leader Respiratory Services VAShari McKeown, Practice Leader Respiratory Services VA

AliasesAliases

Naturally occurring prostaglandinNaturally occurring prostaglandin

Epoprostenol sodiumEpoprostenol sodium

FlolanFlolan

ProstacyclinProstacyclin

PGIPGI22

PGXPGX

……the point…the point…

Inhaled vasodilators can reduce PAP and Inhaled vasodilators can reduce PAP and redistribute pulm blood flow to ventilated redistribute pulm blood flow to ventilated lung regions with little systemic effectlung regions with little systemic effect1,2,3,4,51,2,3,4,5

1. 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.

2. Lowson SM. Inhaled Alternatives to Nitric Oxide. Anesthesiology 2002;96(6):1504-1513

3. 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.

4. 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.

5. 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 ActionsPharmacologic Actions

Selective vasodilation of pulmonary Selective vasodilation of pulmonary vascular bedsvascular beds11

Decreased PVR, PAPDecreased PVR, PAP

Inhibition of platelet aggregation Inhibition of platelet aggregation (but no evidence of platelet dysfunction or (but no evidence of platelet dysfunction or

bleeding noted clinically) bleeding noted clinically)

Increased arterial oxygenation Increased arterial oxygenation Improved V/Q matching in lung (Cochrane Improved V/Q matching in lung (Cochrane

review planned for 2009)review planned for 2009)

1. 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.

IndicationsIndications

Primary and Secondary Pulmonary Primary and Secondary Pulmonary HypertensionHypertension

Cardiac surgery-associated pulmonary Cardiac surgery-associated pulmonary hypertension and RV failurehypertension and RV failure

Lung transplantation-related reperfusion injuryLung transplantation-related reperfusion injury

Liver transplantation portopulmonary Liver transplantation portopulmonary hypertensionhypertension

Hypoxemia due to single-lung ventilation or Hypoxemia due to single-lung ventilation or ARDSARDS

ContraindicationsContraindications

Hypersensitivity to drug or diluentHypersensitivity to drug or diluent

Cost Analysis Cost Analysis (compared with nitric oxide)(compared with nitric oxide)

Average runtime 45.6 hoursAverage runtime 45.6 hours1 1 (for PPH)(for PPH)Flolan (based on average weight 80kg at 31 mcg/kg/min)Flolan (based on average weight 80kg at 31 mcg/kg/min)

Medication - $12.50 hourMedication - $12.50 hour PALL filter unit cost - $4.99 (changes Q2H) = $113.77PALL filter unit cost - $4.99 (changes Q2H) = $113.77 Disposable aeroneb system - $50.00Disposable aeroneb system - $50.00 = $= $733.77 733.77

Nitric OxideNitric Oxide $95.00 hour$95.00 hour = $= $4332.004332.00

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

SetupSetupMust be reconstituted with glycine Must be reconstituted with glycine

Not compatible with any other solutionNot compatible with any other solution Glycine is sticky and viscousGlycine is sticky and viscous

Needs to be shielded from light Needs to be shielded from light Recommended to keep reconstituted solution cold with Recommended to keep reconstituted solution cold with icepacks during administration (2-8 degrees C) (stable for 8 hrs icepacks during administration (2-8 degrees C) (stable for 8 hrs room temp, 24 hours refrigerated) room temp, 24 hours refrigerated) Nebulizer, infusion tubing, connections, changed every 24 hrs Nebulizer, infusion tubing, connections, changed every 24 hrs (refrigerated) or every 8 hrs (unrefrigerated) as drug expires(refrigerated) or every 8 hrs (unrefrigerated) as drug expiresOption AOption A: continuous flow-driven nebulizer (Miniheart) + : continuous flow-driven nebulizer (Miniheart) + infusion pumpinfusion pumpOption BOption B: continuous electronically-driven nebulizer (Aeroneb) : continuous electronically-driven nebulizer (Aeroneb) + infusion pump+ infusion pump

Option A: Miniheart nebOption A: Miniheart neb

Continuous flow-driven nebulizerContinuous flow-driven nebulizer Dose delivery is dependent on flowrateDose delivery is dependent on flowrate

8 ml/hr nebulizer output with 2 Lpm flowrate set on neb8 ml/hr nebulizer output with 2 Lpm flowrate set on nebFluctuating dosing may occur during deliveryFluctuating dosing may occur during deliveryEasy to wean by adjusting neb input from pumpsEasy to wean by adjusting neb input from pumps

Added flow to ventilator circuit affects ventilationAdded flow to ventilator circuit affects ventilationpatient triggering affectedpatient triggering affectedTriggering will be made less sensitive or could cause autocyclingTriggering will be made less sensitive or could cause autocyclingDelivered tidal volumes and pressures increased Delivered tidal volumes and pressures increased Delivered FiO2 changes unless nebulizer connected to blenderDelivered FiO2 changes unless nebulizer connected to blenderAccuracy of monitored values is affected – exhaled tidal and minute Accuracy of monitored values is affected – exhaled tidal and minute volumes will be inaccuratevolumes will be inaccurateAlarm functions may be inaccurate – particularly low tidal Alarm functions may be inaccurate – particularly low tidal volume/low minute volume/leak alarmsvolume/low minute volume/leak alarmsCertain ventilator modes will malfunction (PRVC, CMV with Certain ventilator modes will malfunction (PRVC, CMV with Autoflow, VC+, PAV)Autoflow, VC+, PAV)Safest mode to be on is PSV or PCVSafest mode to be on is PSV or PCV

Option A: Miniheart nebOption A: Miniheart neb

Accidental disconnection of nebulizer tubing is Accidental disconnection of nebulizer tubing is possible due to backpressure from nebulizer possible due to backpressure from nebulizer causing sudden stoppage of dosing (no causing sudden stoppage of dosing (no alarm)alarm)

Accidental disconnection or maladjustment Accidental disconnection or maladjustment from wall flowmeter is possible (causing from wall flowmeter is possible (causing increased or stoppage of dosing) (no alarm)increased or stoppage of dosing) (no alarm)

Nebulizer tipping is possible, causing Nebulizer tipping is possible, causing accidental instillation of entire dose into accidental instillation of entire dose into endotracheal tube or sudden stoppage of endotracheal tube or sudden stoppage of dosing (no alarm)dosing (no alarm)

Option B: AeronebOption B: AeronebContinuous (mesh screen sifter) electronically-driven neb Continuous (mesh screen sifter) electronically-driven neb

Dose delivery is dependent on constant output Dose delivery is dependent on constant output On-off switch only – nebulizer output is set at 30 ml/hrOn-off switch only – nebulizer output is set at 30 ml/hrDosage depends on concentration of medication in nebulizerDosage depends on concentration of medication in nebulizerDifficult to wean – med must be remixedDifficult to wean – med must be remixed

Does not affect ventilator performance – no flow added to circuitDoes not affect ventilator performance – no flow added to circuit Nebulizer dysfunction is likely (no alarm)Nebulizer dysfunction is likely (no alarm)

Unit stops functioning if battery diesUnit stops functioning if battery diesHave had to replace batteries in all of our controllers Have had to replace batteries in all of our controllers Cables can be kinkedCables can be kinkedPowercords malfunction frequently Powercords malfunction frequently Limited number of controllers available – would need backup unit on Limited number of controllers available – would need backup unit on standbystandbyCost of controller unit is $1425. ( we have 3, often all are in use for Cost of controller unit is $1425. ( we have 3, often all are in use for nebulized antibx)nebulized antibx)

Nebulizer tipping is possible. Would not spill dose into Nebulizer tipping is possible. Would not spill dose into endotracheal tube, but may result in sudden stoppage of dose endotracheal tube, but may result in sudden stoppage of dose (no alarm)(no alarm)

BenchmarkingBenchmarkingBarnes Jewish Hospital, St. Louis, MOBarnes Jewish Hospital, St. Louis, MO

126 patients126 patients Miniheart continuous nebulizerMiniheart continuous nebulizer Filter changes Q2 hrsFilter changes Q2 hrs Adverse event – vent exhalation valve became sticky, significant Adverse event – vent exhalation valve became sticky, significant

autopeep/hypotensionautopeep/hypotension

Sudbury Regional Hospital, Sudbury, ONSudbury Regional Hospital, Sudbury, ON Filter changes Q6 hrs and PRNFilter changes Q6 hrs and PRN

Kingston General Hospital, Kingston, ONKingston General Hospital, Kingston, ON Miniheart continuous nebulizerMiniheart continuous nebulizer Filter changes Q4H and PRNFilter changes Q4H and PRN

Harborview Medical Centre, Seattle, WAHarborview Medical Centre, Seattle, WA AeronebAeroneb No filtering?No filtering? Bench test onlyBench test only

St Pauls Hospital, Vancouver, BCSt Pauls Hospital, Vancouver, BC Miniheart nebulizerMiniheart nebulizer Filter changes Q 2-4 hrs and PRNFilter changes Q 2-4 hrs and PRN

Patient SafetyPatient Safety

Neb must run continuously Neb must run continuously Product has biological half-life of 2-3 minutesProduct has biological half-life of 2-3 minutes Rebound pulmonary hypertension may be life-Rebound pulmonary hypertension may be life-

threatening threatening Dyspnea, dizziness, astheniaDyspnea, dizziness, asthenia

Rare reports of death (IV use)Rare reports of death (IV use)1, 2 1, 2

1.1. Augoustides J, Culp K, Smith S. Rebound pulmonary hypertension and cardiogenic Augoustides J, Culp K, Smith S. Rebound pulmonary hypertension and cardiogenic shock after withdrawl of inhaled prostacyclin. (Case Report) Anesthesiology shock after withdrawl of inhaled prostacyclin. (Case Report) Anesthesiology 2004(100):1023-10252004(100):1023-1025

2.2. Barst RJ. Rubin LJ. McGoon MD, et al. Survival in primary pulmonary hypertension 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-with long-term continuous intravenous prostacyclin. Ann Intern Med 1994; 121:409-415.415.

3.3. GlaxoSmithKline Inc. Product Monograph, Flolan for Injection, 2008.GlaxoSmithKline Inc. Product Monograph, Flolan for Injection, 2008.

Patient Safety cont’dPatient Safety cont’d

Filter cloggingFilter clogging Glycine is sticky and viscous; quickly clogs Glycine is sticky and viscous; quickly clogs

filtersfilters Bench testing for filter resistanceBench testing for filter resistance11

1. David Sima, RT Clinical Educator, bench testing data June 20091. David Sima, RT Clinical Educator, bench testing data June 2009

- Standard dose (31 mcg/kg/min, 80 kg)Standard dose (31 mcg/kg/min, 80 kg)- 10 Lpm minute volume- 10 Lpm minute volume- calibrated equipment, reproducible results- calibrated equipment, reproducible results- filter resistance after 1 hour = 18.8 cmH20/Lps- filter resistance after 1 hour = 18.8 cmH20/Lps

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Pre Filter Pressure cm h20

Post Filter Pressure cm h20

Resistance cmh20/L/sec

- Standard dose (31 mcg/kg/min, 80 kg)Standard dose (31 mcg/kg/min, 80 kg)- 20 Lpm minute volume- 20 Lpm minute volume- calibrated equipment, reproducible results- calibrated equipment, reproducible results- filter resistance at 1 hour = 23.09 cmH20/Lps- filter resistance at 1 hour = 23.09 cmH20/Lps

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post filter cmh20

Resistance

Filter CloggingFilter Clogging

↑↑ expiratory resistanceexpiratory resistance↑ ↑ autopeepautopeep↑ ↑ intrathoracic pressureintrathoracic pressure↑ ↑ PVRPVRAffect V/Q matching in lungAffect V/Q matching in lungAffect ventilator performance and safetyAffect ventilator performance and safety Hourly circuit changes may clog vent exp filterHourly circuit changes may clog vent exp filter ‘‘Vent-inop’ at 5 cmH20 transducer differenceVent-inop’ at 5 cmH20 transducer difference Would necessitate immediate manual ventilation and Would necessitate immediate manual ventilation and

vent changevent change

Occupational Health and SafetyOccupational Health and Safety

Would require frequent (Q30min) circuit Would require frequent (Q30min) circuit disconnectionsdisconnections

PPE protection for staff during exposure PPE protection for staff during exposure timestimes

Minimal data on exposure during Minimal data on exposure during pregnancypregnancy

Alternatives?Alternatives?ProstaglandinsProstaglandins

IV EpoprostenolIV Epoprostenol IloprostIloprost TreprostinolTreprostinol BeraprostBeraprost PGEPGE11

NO donorsNO donors Inhaled Nitric OxideInhaled Nitric Oxide Inhaled sodium nitroprussideInhaled sodium nitroprusside Inhaled nitroglycerineInhaled nitroglycerine

Phosphodiesterase InhibitorsPhosphodiesterase Inhibitors SildenafilSildenafil MilrinoneMilrinone

Endothelin AntagonistsEndothelin Antagonists BosentanBosentan

NesiritideNesiritideAdrenomedullinAdrenomedullin

RecommendationsRecommendations

Evaluate risk-benefitsEvaluate risk-benefitsExplore alternativesExplore alternativesIf we must?If we must? Aeroneb recommended as best delivery systemAeroneb recommended as best delivery system Q 30 minute filter changesQ 30 minute filter changes Purchase additional controller setsPurchase additional controller sets Backup equipment on standbyBackup equipment on standby Patient care guideline development, education and Patient care guideline development, education and

vigilance for patient safetyvigilance for patient safety Investigate alarm possibility with manufacturerInvestigate alarm possibility with manufacturer

SummarySummary

Patient benefit for use (PPH, ARDS?)Patient benefit for use (PPH, ARDS?)

Inexpensive in comparison with N.O.Inexpensive in comparison with N.O.

2 delivery systems, both have significant 2 delivery systems, both have significant safety concernssafety concerns

Is it worth it? Or investigate alternatives?Is it worth it? Or investigate alternatives?