Ignite Creation Date:
2024-05-05 @ 4:47 PM
Last Modification Date:
2024-10-26 @ 9:24 AM
Study NCT ID:
NCT00314548
Status:
COMPLETED
Last Update Posted:
2010-05-19
First Post:
2006-04-12
Brief Title:
Inhaled Prostacyclin for Adult Respiratory Distress Syndrome ARDS and Pulmonary Hypertension
Sponsor:
Aga Khan University
Organization:
Aga Khan University
Study Overview
Official Title:
Trial of Inhaled Alprostadil to Improve Hypoxia and Pulmonary Hypertension
Status:
COMPLETED
Status Verified Date:
2009-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Summary of the proposed research
The intravenous application of prostacyclin PGE1 or its stable analogue iloprost has been used to cause a decrease not only of the pulmonary but also of the systemic vascular tone Aerosolized prostacyclin on the other hand can result in a selective pulmonary vasodilatation without affecting the systemic blood pressure as shown in preliminary studiescase reports No large trials exist for this type of use of the drug so far Furthermore aerosolized PGI2 can improve gas exchange and pulmonary shunt in clinical settings of impaired ventilationperfusion ratio as it occurs in adult respiratory distress syndrome ARDS due to the redistribution of pulmonary blood flow from non-ventilated to ventilated aerosol accessible lung regions Therefore the investigators propose to carry out a prospective double blinded randomized trial to show that the nebulized iloprost decreases pulmonary hypertension selectively and improves oxygenation in ARDS
The intravenous application of prostacyclin PGE1 or its stable analogue iloprost has been used to cause a decrease not only of the pulmonary but also of the systemic vascular tone Aerosolized prostacyclin on the other hand can result in a selective pulmonary vasodilatation without affecting the systemic blood pressure as shown in preliminary studiescase reports No large trials exist for this type of use of the drug so far Furthermore aerosolized PGI2 can improve gas exchange and pulmonary shunt in clinical settings of impaired ventilationperfusion ratio as it occurs in adult respiratory distress syndrome ARDS due to the redistribution of pulmonary blood flow from non-ventilated to ventilated aerosol accessible lung regions Therefore the investigators propose to carry out a prospective double blinded randomized trial to show that the nebulized iloprost decreases pulmonary hypertension selectively and improves oxygenation in ARDS
Detailed Description:
Introduction
Pulmonary hypertension defined as mean PA pulmonary arterial pressure of 25 mm Hg is an end point of a variety of conditions These include primary pulmonary hypertension post-operative pulmonary hypertension and as a result of increased pulmonary vascular resistance that occurs in ARDS This is an entity distinguished by hypoxemia non-cardiogenic pulmonary edema and bilateral infiltrates on chest X-ray Prostacyclin PGE1 an arachidonic acid metabolite or its stable analogue iloprost has been evaluated for its efficacy in the treatment of pulmonary hypertension and for its use in reducing intra-pulmonary shunting in ARDS While the intravenous application of iloprost can cause a decrease not only of the pulmonary but also of the systemic vascular tone the aerosolized prostacyclin can result in a selective pulmonary vasodilatation without affecting the systemic blood pressure as demonstrated in preliminary studiesreports Furthermore aerosolized iloprost can improve gas exchange and pulmonary shunt in clinical settings of impaired ventilationperfusion ratio as it occurs in ARDS due to the redistribution of pulmonary blood flow from non-ventilated to ventilated aerosol accessible lung regions
Previous case reports and non-randomized studies have indicated that inhalation of aerosolized iloprost may offer a new life saving strategy in intractable pulmonary hypertension and ARDS Further advantages of inhaled iloprost include the lack of adverse reactions and toxic side effects as well as convenient and more cost-effective administration Other available therapies like nitric oxide inhalation costs more around Rs 350liter and a total of 34-45 liters per patient is required It is also associated with additional side effects such as thrombocytopenia Due to the irreversible nature of ARDS associated with high rate of mortality also affecting resource allocation in critically ill patients we suggest carrying out this study in our intensive care unit ICU where the incidence is 10 resulting in almost 90 mortality ICU Quality Indicators Jan-Apr 20048 Iloprost is completely metabolized and excretion of metabolites is primarily via the kidneys the elimination half-life is 30 minutes Inhalation therapy reduces systemic absorption and hence elimination half-life
In a previous study aerosolized iloprost was found effective in improving the functional class of the patient exercise capacity and improved shunting However large randomized trials are needed to prove the efficacy of this cost effective therapy in patients with pulmonary hypertension and ARDS
Objectives
To carry out a prospective double blinded randomized trial to show that the nebulized PGE1 a stable prostacyclin derivative decreases pulmonary hypertension selectively and improves oxygenation in ARDS
ALPROSTADIL 20 mcg ampule manufactured by Schering Pakistan
Importance of work
Prostacyclin PGE1 an arachidonic acid metabolite has been evaluated for its efficacy in the treatment of pulmonary hypertension and for its use in reducing intra-pulmonary shunting in ARDS While the intravenous application PGE1 or alprostadil can cause a decrease not only of the pulmonary but also of the systemic vascular tone the aerosolized PGE1 results in a selective pulmonary vasodilation without affecting the systemic blood pressure Furthermore aerosolized PGE1 can improve gas exchange and pulmonary shunt in clinical settings of impaired ventilationperfusion ratio as it occurs in ARDS due to the redistribution of pulmonary blood flow from non-ventilated to ventilated aerosol accessible lung regions
Critical review of relevant literature on the subject
Previous case reports and non randomized studies have indicated that inhalation of aerosolized alprostadil may offer a new life saving strategy in intractable pulmonary hypertension and ARDS Further advantages of inhaled iloprost include the lack of adverse reactions and toxic side effects as well as convenient and more cost-effective administration Due to the irreversible nature of ARDS associated with high rate of mortality also affecting resource allocation in critically ill patients we suggest carrying out this study in our intensive care unit ICU where the incidence is 10 resulting in almost 90 mortality ICU Quality Indicators Jan-Apr 20048
In a previous study aerosolized alprostadil was effective in improving the functional class of the patient exercise capacity and improved shunting Large randomized trials are needed to prove the efficacy of this cost effective therapy in patients with pulmonary hypertension and ARDS Other available therapies like nitric oxide inhalation costs higher around Rs 350liter and a total of 34-45 liters per patient is required It is also associated with additional side effects such as thrombocytopenia
Resume of any related work carried out by the principal investigator or co-Investigator in this area
The principal investigator and co-investigator have the relevant qualification experience and expertise to conduct this study as is obvious from the list of recent selected publications
Controls
From selected patients included in the study in a random blinded manner Patients will be given a drug or placebo to be determined by pharmacy
Work Up
After enrolling the following tests will be carried out to determine inclusion exclusion criteria
Transthoracic echo - to rule out ejection fraction 30
Pulmonary embolus
Pulmonary hypertension TR jet to be determined by echo
Arterial blood gas
CXR reviewed to determine ARDS criteria
Drug Administration
Drug alprostadilplacebo - normal saline to be nebulized 5 micrograms via standard nebulizer within 4 hours once
Standardization of Critical Care
Standardization of treatment modalities have been incorporated in the methodology with regard to ventilatory support inotropic support and fluid management however as the intensive care unit at the AKUH is an open unit where patients are primarily taken care of by the primary teams and a critical care consultant of which the PI is one strict guidelines cannot be enforced However we have given a general range of parameters keeping in mind the recommendations of the Society of Critical Care medicine and the Acute Respiratory Distress Syndrome Network
Once enrolled the patients will be managed by the ICU consultant and the primary physician may not always include PI The following broad criteria will be followed in order to treat the patient
1 Ventilatory support in ARDSPulmonary hypertension
Any ventilatory mode can be used
Peak airway pressures Pa will be maintained under 35 mm Hg
Peep range to be between 8-14 mm Hg
Tidal volumes of 6 cckg
2 Inotropic Support
Dopamine 5-20 micskgmin as a positive inotrope dopaminergic alpha and beta agonist activity and norepinephrine 01-05 micskgmin as a vasopressor alpha agonist are used for increasing blood pressure The goal will be to maintain a mean arterial pressure DBP plus 13 rd of pulse pressure of 60 mm Hg
3 Fluid management
Keeping a wedge pressure 20 mm Hg will be the goal of fluid management
Sample Size
Assuming total Karachi population of over 150000 1998 Demographic Survey of Pakistan of all age groups and taking incidence of 20 - 105 bound of error of pulmonary hypertension and ARDS at 95 confidence interval we extricated a sample size to be 91 cases with 91 controls Epi-info version 11 was used to calculate sample size Actual sample size 182
Outcome Measures
If met trial will be terminated early in favor of using the drug Positive result will be taken as PA pressures - mean PA pressure decreases by 10 in 4 hours and PaO2FiO2 ratio - increases by 50 or PaO2 increases by 10 in 4 hours
Results will be recorded in a Data Sheet - see Appendix I
Tests done Arterial blood gases Transthoracic echo before and after drug
Ethics Written approval of Aga Khan University Ethics Review Committee ERC has been obtained prior to commencement of the study
Blinding Each patient after enrollment will be assigned a serial number consecutively after meeting inclusion criteria reviewed by the principal investigator and research assistant After the necessary workup and consent drug shall be obtained from the AKUH pharmacy The pharmacy will carry out randomization and deliver either alprostadil or normal saline placebo in an unmarked vial Delivery dose and frequency will be carried out similarly for all patients Data will be collected by the research assistant and nurse At the end of the trial after all cases and controls have been enrolled the serial numbers of the patients will be matched to the delivery chart of the pharmacy to see whether they received the drug or placebo
Year wise plan of work to be used during period
All ICU patients
Inclusion exclusion Pulm HTN ARDS not intubated no swan
echo LVF RVF pulmonary embolus
Swan ganz catheter wedge 20
consent serial and inform pharmacy
Pulmonary hypertension defined as mean PA pulmonary arterial pressure of 25 mm Hg is an end point of a variety of conditions These include primary pulmonary hypertension post-operative pulmonary hypertension and as a result of increased pulmonary vascular resistance that occurs in ARDS This is an entity distinguished by hypoxemia non-cardiogenic pulmonary edema and bilateral infiltrates on chest X-ray Prostacyclin PGE1 an arachidonic acid metabolite or its stable analogue iloprost has been evaluated for its efficacy in the treatment of pulmonary hypertension and for its use in reducing intra-pulmonary shunting in ARDS While the intravenous application of iloprost can cause a decrease not only of the pulmonary but also of the systemic vascular tone the aerosolized prostacyclin can result in a selective pulmonary vasodilatation without affecting the systemic blood pressure as demonstrated in preliminary studiesreports Furthermore aerosolized iloprost can improve gas exchange and pulmonary shunt in clinical settings of impaired ventilationperfusion ratio as it occurs in ARDS due to the redistribution of pulmonary blood flow from non-ventilated to ventilated aerosol accessible lung regions
Previous case reports and non-randomized studies have indicated that inhalation of aerosolized iloprost may offer a new life saving strategy in intractable pulmonary hypertension and ARDS Further advantages of inhaled iloprost include the lack of adverse reactions and toxic side effects as well as convenient and more cost-effective administration Other available therapies like nitric oxide inhalation costs more around Rs 350liter and a total of 34-45 liters per patient is required It is also associated with additional side effects such as thrombocytopenia Due to the irreversible nature of ARDS associated with high rate of mortality also affecting resource allocation in critically ill patients we suggest carrying out this study in our intensive care unit ICU where the incidence is 10 resulting in almost 90 mortality ICU Quality Indicators Jan-Apr 20048 Iloprost is completely metabolized and excretion of metabolites is primarily via the kidneys the elimination half-life is 30 minutes Inhalation therapy reduces systemic absorption and hence elimination half-life
In a previous study aerosolized iloprost was found effective in improving the functional class of the patient exercise capacity and improved shunting However large randomized trials are needed to prove the efficacy of this cost effective therapy in patients with pulmonary hypertension and ARDS
Objectives
To carry out a prospective double blinded randomized trial to show that the nebulized PGE1 a stable prostacyclin derivative decreases pulmonary hypertension selectively and improves oxygenation in ARDS
ALPROSTADIL 20 mcg ampule manufactured by Schering Pakistan
Importance of work
Prostacyclin PGE1 an arachidonic acid metabolite has been evaluated for its efficacy in the treatment of pulmonary hypertension and for its use in reducing intra-pulmonary shunting in ARDS While the intravenous application PGE1 or alprostadil can cause a decrease not only of the pulmonary but also of the systemic vascular tone the aerosolized PGE1 results in a selective pulmonary vasodilation without affecting the systemic blood pressure Furthermore aerosolized PGE1 can improve gas exchange and pulmonary shunt in clinical settings of impaired ventilationperfusion ratio as it occurs in ARDS due to the redistribution of pulmonary blood flow from non-ventilated to ventilated aerosol accessible lung regions
Critical review of relevant literature on the subject
Previous case reports and non randomized studies have indicated that inhalation of aerosolized alprostadil may offer a new life saving strategy in intractable pulmonary hypertension and ARDS Further advantages of inhaled iloprost include the lack of adverse reactions and toxic side effects as well as convenient and more cost-effective administration Due to the irreversible nature of ARDS associated with high rate of mortality also affecting resource allocation in critically ill patients we suggest carrying out this study in our intensive care unit ICU where the incidence is 10 resulting in almost 90 mortality ICU Quality Indicators Jan-Apr 20048
In a previous study aerosolized alprostadil was effective in improving the functional class of the patient exercise capacity and improved shunting Large randomized trials are needed to prove the efficacy of this cost effective therapy in patients with pulmonary hypertension and ARDS Other available therapies like nitric oxide inhalation costs higher around Rs 350liter and a total of 34-45 liters per patient is required It is also associated with additional side effects such as thrombocytopenia
Resume of any related work carried out by the principal investigator or co-Investigator in this area
The principal investigator and co-investigator have the relevant qualification experience and expertise to conduct this study as is obvious from the list of recent selected publications
Controls
From selected patients included in the study in a random blinded manner Patients will be given a drug or placebo to be determined by pharmacy
Work Up
After enrolling the following tests will be carried out to determine inclusion exclusion criteria
Transthoracic echo - to rule out ejection fraction 30
Pulmonary embolus
Pulmonary hypertension TR jet to be determined by echo
Arterial blood gas
CXR reviewed to determine ARDS criteria
Drug Administration
Drug alprostadilplacebo - normal saline to be nebulized 5 micrograms via standard nebulizer within 4 hours once
Standardization of Critical Care
Standardization of treatment modalities have been incorporated in the methodology with regard to ventilatory support inotropic support and fluid management however as the intensive care unit at the AKUH is an open unit where patients are primarily taken care of by the primary teams and a critical care consultant of which the PI is one strict guidelines cannot be enforced However we have given a general range of parameters keeping in mind the recommendations of the Society of Critical Care medicine and the Acute Respiratory Distress Syndrome Network
Once enrolled the patients will be managed by the ICU consultant and the primary physician may not always include PI The following broad criteria will be followed in order to treat the patient
1 Ventilatory support in ARDSPulmonary hypertension
Any ventilatory mode can be used
Peak airway pressures Pa will be maintained under 35 mm Hg
Peep range to be between 8-14 mm Hg
Tidal volumes of 6 cckg
2 Inotropic Support
Dopamine 5-20 micskgmin as a positive inotrope dopaminergic alpha and beta agonist activity and norepinephrine 01-05 micskgmin as a vasopressor alpha agonist are used for increasing blood pressure The goal will be to maintain a mean arterial pressure DBP plus 13 rd of pulse pressure of 60 mm Hg
3 Fluid management
Keeping a wedge pressure 20 mm Hg will be the goal of fluid management
Sample Size
Assuming total Karachi population of over 150000 1998 Demographic Survey of Pakistan of all age groups and taking incidence of 20 - 105 bound of error of pulmonary hypertension and ARDS at 95 confidence interval we extricated a sample size to be 91 cases with 91 controls Epi-info version 11 was used to calculate sample size Actual sample size 182
Outcome Measures
If met trial will be terminated early in favor of using the drug Positive result will be taken as PA pressures - mean PA pressure decreases by 10 in 4 hours and PaO2FiO2 ratio - increases by 50 or PaO2 increases by 10 in 4 hours
Results will be recorded in a Data Sheet - see Appendix I
Tests done Arterial blood gases Transthoracic echo before and after drug
Ethics Written approval of Aga Khan University Ethics Review Committee ERC has been obtained prior to commencement of the study
Blinding Each patient after enrollment will be assigned a serial number consecutively after meeting inclusion criteria reviewed by the principal investigator and research assistant After the necessary workup and consent drug shall be obtained from the AKUH pharmacy The pharmacy will carry out randomization and deliver either alprostadil or normal saline placebo in an unmarked vial Delivery dose and frequency will be carried out similarly for all patients Data will be collected by the research assistant and nurse At the end of the trial after all cases and controls have been enrolled the serial numbers of the patients will be matched to the delivery chart of the pharmacy to see whether they received the drug or placebo
Year wise plan of work to be used during period
All ICU patients
Inclusion exclusion Pulm HTN ARDS not intubated no swan
echo LVF RVF pulmonary embolus
Swan ganz catheter wedge 20
consent serial and inform pharmacy
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None