Pulmonary Hypertension Clinical Trial
Official title:
Trial of Inhaled Alprostadil to Improve Hypoxia and Pulmonary Hypertension
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
studies/case 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 ventilation/perfusion 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.
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 studies/reports. Furthermore,
aerosolized iloprost can improve gas exchange and pulmonary shunt in clinical settings of
impaired ventilation/perfusion 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
350/liter 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 ventilation/perfusion 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
350/liter 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 (alprostadil/placebo - 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 ARDS/Pulmonary 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 cc/kg
2. Inotropic Support:
Dopamine (5-20 mics/kg/min) as a positive inotrope (dopaminergic, alpha and beta
agonist activity) and norepinephrine (0.1-0.5 mics/kg/min) as a vasopressor (alpha
agonist) are used for increasing blood pressure. The goal will be to maintain a mean
arterial pressure (DBP plus 1/3 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 150,000 (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 1.1 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 PaO2/FiO2
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)
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment
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