A Review of Inhaled Nitric Oxide and Aerosolized Epoprostenol in Acute Lung Injury or Acute Respiratory Distress Syndrome

A Review of Inhaled Nitric Oxide and Aerosolized

Epoprostenol in Acute Lung Injury or Acute Respiratory

Distress Syndrome

Amy L. Dzierba,1,* Erik E. Abel,2 Mitchell S. Buckley,3 and Ishaq Lat4

1Department of Pharmacy, NewYork-Presbyterian Hospital, New York, New York; 2Department of Pharmacy,

The Ohio State University Wexner Medical Center, Columbus, Ohio; 3Department of Pharmacy, Banner Good

Samaritan Medical Center, Phoenix, Arizona; 4Department of Pharmaceutical Services, University of Chicago

Medical Center, Chicago, Illinois

Acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) are conditions associated withan estimated mortality of 40–50%. The use of inhaled vasodilators can help to improve oxygenationwithout hemodynamic effects. This article reviews relevant studies addressing the safety and efficacy ofinhaled nitric oxide (iNO) and aerosolized epoprostenol (aEPO) in the treatment of life-threateninghypoxemia associated with ARDS and ALI. In addition, the article also provides a practicable guide tothe clinical application of these therapies. Nine prospective randomized controlled trials were includedfor iNO reporting on changes in oxygenation or clinical outcomes. Seven reports of aEPO were exam-ined for changes in oxygenation. Based on currently available data, the use of either iNO or aEPO issafe to use in patients with ALI or ARDS to transiently improve oxygenation. No differences have beenobserved in survival, ventilator-free days, or attenuation in disease severity. Further studies with con-sistent end points using standard delivery devices and standard modes of mechanical ventilation areneeded to determine the overall benefit with iNO or aEPO.KEY WORDS acute respiratory distress syndrome, critical care, pulmonary.(Pharmacotherapy 2014;34(3):279–290) doi: 10.1002/phar.1365

Acute respiratory distress syndrome (ARDS) isa devastating form of acute lung injury (ALI)estimated to affect 200,000 individuals annuallyin the United States with an estimated mortalityof 40–50%.1 In 1994, the American-EuropeanConsensus Conference on ARDS developed astandardized definition: acute onset; bilateralinfiltrates on chest radiograph due to noncardio-genic causes; pulmonary artery wedge pressure18 mm Hg or lower or the absence of left atrialhypertension; and a partial arterial oxygen pres-sure to fraction of inspired oxygen ratio (PaO2:

FIO2) of 200 mm Hg or lower (PaO2:FIO2 of300 mm Hg or lower in ALI).2 More recently,the Berlin definition for ARDS offered a spec-trum of disease severity by defining three mutu-ally exclusive categories intending to provide amore reliable definition for case recognition andimproved predictive validity for mortality.3 Thenew definition classifies ARDS based on thedegree of hypoxemia including mild (PaO2:FIO2 of 300 mm Hg or lower but greater than200 mm Hg), moderate (PaO2:FIO2 of 200 mmHg or lower but greater than 100 mm Hg), andsevere (PaO2:FIO2 of 100 mm Hg or lower).3

Treatment of ARDS consists of supportivemeasures aimed at minimizing pulmonary edemaand preventing ventilator-induced lung injurywhile managing and/or attenuating severe oxy-gen-exchange abnormalities.4–9 Overall, there isa paucity of successful therapeutic strategies to

Disclosures: None for all authors.*Address for correspondence: Amy L. Dzierba, Clinical

Pharmacy Manager, Department of Pharmacy, NewYork-Presbyterian Hospital, 622 West 168th Street, VC Base-ment, New York, NY 10032, e-mail: [email protected].� 2013 American College of Clinical Pharmacy

R E V I E W S O F T H E R A P E U T I C S

manage ARDS. Mechanical ventilation with low-tidal volumes remains the only intervention witha significant survival benefit when comparedwith conventional tidal volumes.5 Several phar-macologic therapies have been evaluated for themanagement of ARDS including ketoconazole,corticosteroids, surfactant, lisofylline, acetylcys-teine, and fish oil.10 Although none of thesetherapies have been shown to improve out-comes, cisatracurium use for 48 hours from thetime of diagnosis was associated with an increasein ventilator-free days and survival in patientswith severe ARDS after statistical adjustment forboth the baseline PaO2:FIO2, plateau pressure,and the Simplified Acute Physiology II score.11

Although refractory respiratory failure is anuncommon cause of death in patients withARDS, rescue treatment with inhaled vasodila-tors may attenuate severe hypoxemia while otherdefinitive therapies are established.12 Inhaledvasodilators, such as nitric oxide (iNO) andprostacyclins, produce selective pulmonary vaso-dilation leading to improvements in ventilation-perfusion mismatch and oxygenation withoutsystemic hemodynamic effects. Additional bene-fits obtained from pulmonary vasodilation mayinclude decreased pulmonary vascular resistance(PVR), reduced right ventricular afterload, andincreased right ventricular stroke volume.Our primary objective was to systematically

review the literature on the clinical safety andefficacy of inhaled vasodilators, focusing on iNOand aerosolized epoprostenol (aEPO), for thetreatment of ALI or ARDS in critically ill adults.Short-term efficacy end points included oxygen-ation reported as either changes in PaO2 or PaO2:FIO2; long-term efficacy outcomes included mor-tality and ventilator-free days. Secondary objec-tives included a brief review of thepharmacology of iNO and aEPO and a practica-ble guide to the clinical application of thesetherapies.

Methods

For the primary objective, articles were identi-fied through an English-language PubMed searchbetween January 1966 and June 2013 using theterms acute respiratory distress syndrome, acutelung injury, respiratory failure, nitric oxide, pros-tacyclin, epoprostenol, oxygenation, inhalation,nebulized, and aerosolized. This review includedclinical studies that met the following criteria:adult population 18 years of age or older withARDS or ALI accepting various definitions, iNO

or aEPO therapy administered, and documentedeffects of therapy on indices of oxygenation ortoxicity when delivered by inhalation. Only pro-spective randomized controlled clinical trialswere included for iNO; however, case series andcase reports for aEPO were permitted. Animalinvestigations of aEPO toxicities were alsoincluded because of otherwise limited clinicaldata. Trials evaluating iNO with other drug ther-apies were excluded because this was beyondthe scope of this review article. For the purposeof the secondary objective, articles were identi-fied through an English-language PubMed searchusing the same search terms and time period asthe primary objective; however, only articles,case reports, and reviews addressing the deliverysystem, dosage form, or cost evaluation for iNOor aEPO were included.

Pharmacology

Inhaled nitric oxide readily diffuses throughthe alveolar epithelial cells into the pulmonaryvascular smooth muscle cells.13, 14 Upon deliv-ery, iNO exerts selective pulmonary vasodilationby stimulating a cascade of intracellular pathwayswithin the pulmonary vasculature.15 Nitric oxideis responsible for activating the enzyme solubleguanylyl cyclase that converts guanosine-5-tri-phosphate to cyclic guanosine monophosphate(cGMP), subsequently causing vascular smoothmuscle relaxation.13–15 Ultimately, activation ofthese intracellular pathways produces clinicaleffects including a reduction in PVR, pulmonaryarterial pressure and intrapulmonary shuntingand improvement in ventilation-perfusion match-ing, arterial oxygenation, and right ventricularoutput.13, 14 Other physiologic effects induced bycGMP include inhibition of leukocyte and plate-let aggregation, reduction or prevention ofinflammation, and antimicrobial activity.13, 14

Nitric oxide is rapidly inactivated after binding tohemoglobin in the pulmonary capillaries contrib-uting to its short half-life of a few seconds; there-fore, systemic effects are not typically observed.Prostacyclins possess significant vasodilating

properties through complex intracellular pro-cesses within the vasculature.16 However, intra-venous administration is not selective andspecific to the pulmonary circulation and mayresult in systemic hypotension. Systemic effectshave not been observed following inhalation ofprostacyclins, indicating pulmonary selectivity.17

The primary mechanism of action of prostacyc-lins is interaction with the prostaglandin I (IP)

280 PHARMACOTHERAPY Volume 34, Number 3, 2014

receptor, which is readily expressed on bloodvessels, leukocytes, and platelets.16 Stimulationof IP receptors increases production of intracel-lular cyclic adenosine monophosphate (cAMP)through enhanced enzymatic activity of adenyl-ate cyclase within these target cells. Alterna-tively, cAMP can be increased through asecondary mechanism by prostacyclin-inducedactivity on prostaglandin E (EP) receptors. Irre-spective of the pathway, the primary physio-logic effect of prostacyclin is smooth musclerelaxation within the systemic and pulmonaryvasculature through increased cAMP genera-tion.16 Intravenous prostacyclin administrationcauses IP receptor downregulation; thus moder-ate dose escalations are required over prolongeduse to produce an equivalent vasodilatingeffect.18 This finding suggests the primary pros-tacyclin-induced vasodilating effect could shiftfrom the IP- to the EP-receptor pathway withchronic exposure. However, this phenomenonhas not been observed with prolonged inhaleduse.19–21

Inhaled Nitric Oxide

Effects on Oxygenation and Clinical Outcomes

Nine randomized controlled trials describingthe effects of iNO on indexes of oxygenationand clinical outcomes in patients with ALI orARDS were identified (Table 1).22–30 Seven ofthese studies evaluated the effects of iNO inARDS; two studies investigated its use in ALI.Most studies compared iNO with standard ofcare; three trials were placebo controlled.In patients with ARDS, five trials reported the

effects of iNO on oxygenation.24, 27–30 A multi-center prospective, randomized placebo-con-trolled phase II study investigated thephysiologic effects of iNO in immunocompetentpatients with nonseptic ARDS.24 Increases inPaO2 of 20% or higher above baseline wereobserved in 60% of patients receiving iNO ascompared with only 24% of patients receivingplacebo within the first 4 hours of iNO treat-ment. In addition, the mean PaO2:FIO2 was sig-nificantly higher in the iNO group comparedwith placebo on study day 1; however, theseimprovements were not sustained throughoutthe duration of the study. Results from a posthoc analysis indicated that significantly morepatients receiving 5 ppm of iNO were alive andoff the ventilator at day 28 compared with pla-cebo. Using this subgroup analysis, another large

randomized controlled trial evaluated low-doseiNO compared with placebo in adults withARDS.29 Despite improvements in PaO2 duringthe initial 24 hours in patients receiving iNO,the primary end point, days alive without theneed for mechanical ventilation at day 28, wasnot significantly different between the twogroups. Small single-center studies comparingiNO with conventional or usual care also dem-onstrated an initial improvement in oxygenation;however, these effects were not sustainedbeyond the study period.27, 28, 30

In adults with ALI, iNO had similar effects onoxygenation as observed in ARDS. A prospectivemulticenter randomized controlled trial includedpatients with ALI experiencing at least a 20%increase in PaO2 from iNO during the initialdose-response component.26 Only if the patientfulfilled the criteria previously described werethey included and randomized to iNO or conven-tional therapy.26 Reversal of ALI within 30 daysafter randomization to either iNO or conven-tional therapy was not significantly differentbetween the groups (61% vs 54%, respectively;p = NS). However, fewer patients experiencedworsening respiratory failure, FIO2 higher than0.9 and a PaO2 lower than 8 kPa, in the iNOgroup compared with the conventional therapygroup (2.2% vs 10.3%, respectively; p<0.05). Asmaller study with a similar design found 60%of patients in both the iNO and control grouphad resolution of ALI at 30 days; however,patients randomized to iNO had a significantlyshorter time to resolution of ALI compared withthe control group (median 7.5 vs 12.4 days,respectively; p=0.006).23 This study prospec-tively defined ALI resolution as a PaO2 of 11 orhigher or 12 kPa (depending on patient age)with an FIO2 less than 0.35 and peak end-expira-tory pressures (PEEP) of 5 cm H2O or lower inthe absence of iNO.23

Despite the acute improvements in oxygena-tion observed with iNO, improvements in mor-tality have not been observed (Table 1).22–30 Ofnote, these trials did not have sufficient powerto detect differences in long-term outcomes, andeven when pooled together, differences in mor-tality and ventilator-free days are notobserved.31, 32 A phase III study assessed thelong-term outcomes associated with low-doseiNO in ARDS.22 The 1-year survival rate was notsignificantly different between the iNO and pla-cebo arms. This was the first report of long-termoutcomes associated with iNO in ARDS; how-ever, it corroborated the findings from short-

A REVIEW OF INHALED NITRIC OXIDE AND AEROSOLIZED EPOPROSTENOL IN ALI OR ARDS Dzierba et al 281

Table

1.Ran

domized

Controlled

TrialsofInhaled

NitricOxidein

AdultPatients

WithALI/ARDS

Study

No.of

patients

ALI/ARDSdefinition

Inhaled

nitric

oxideregimen

Durationofinhaled

nitricoxide

Controlregimen

Change

inoxygenation

Mortality

24

177with

ARDS

AECC;onset<72hrs

1.25,5,20,40,or

80ppm

Day

28oruntiladequate

oxygenationat

predetermined

ventilator

settings

from

baseline

Nitrogengas

(placebo)

Increase

inPaO

2by≥20%:

60%

iNO

vs24%

control

(p<0.001)at

4hrs

30%

poolediN

Ovs

30%

control(p=NS)

28

40with

ARDS

ModifiedAECC:

P:F

≤150mm

Hg,

FIO

2≥0.8

forat

least

12,orFIO

2≥0.65for

atleast24hrs

5,10,15,or

20ppm

titrated

toresponse

72hrs

Conventional

therapy

Nodifference

inPa O

2at

72hrs

from

baseline

55%

iNO

vs45%

control

30

30with

ARDS

Lunginjury

score

≥2.5

2.5,5,10,20,30

or40ppm

titrated

toresponse

Meanduration:

8.1

�1.3

days(range:

28–4

53hrs)

Usual

care

Meanchange

inPaO

2:

+23.3

�6.9

mm

HgiN

Ovs

�6.2

�10.7

mm

Hg

control(p=0.03)at

24hrs

from

baseline

60%

iNO

vs53%

controlat

30days

26

268with

ALI

Lunginfiltrate

with

P:F

<165mm

Hg,

PEEP≥5cm

H2O,and

MVfor18–9

6hrs

2,10,or40ppm

titrated

toresponse

Day

30,reversal

ofALI,

orprogressionto

severe

respiratory

failure

Conventional

therapy

Notreported

44%

iNO

vs40%

controlat

30days

23

30with

ALI

Bilateral

lunginfiltrates,

P:F

≤165mm

Hg,

PEEP≥5cm

H2O,

meanairw

aypressure

>10cm

H2O,and

PAOP<18mm

Hg

0,2,10,or

40ppm

Medianduration:10.6

(1.6–3

0)days

Usual

care

Notreported

53%

iNO

vs47%

controlat

30days

27

14with

ARDS

AECC

5,10,15,or

20ppm

titrated

toresponse

96hrs

Conventional

therapy

Meanchange

inPaO

2:

130�

25mm

HgiN

Ovs

81�

14mm

Hgcontrol

(p=0.057)

50%

inboth

groups

25

30with

ARDS

ModifiedAECC:

MV≥48hrs

with

FIO

2≥0.6,PEEP

≥10cm

H2O

leading

toaPaO

2≤150mm

Hg,

andPCWP

≤18mm

Hg

10ppm

96hrs

Usual

care

Notreported

15%

iNO

vs20%

control

29

385with

ARDS

ModifiedAECC:

P:F

≤250mm

Hg;

onset<72hrs

5ppm

Day

28,death,oruntil

adequateoxygenation

Nitrogengas

(placebo)

Statisticallysign

ificant

increase

inPaO

2withiN

Oduringinitial24hrs

ascompared

(p<0.05)

23%

iNO

vs20%

controlat

28days

22

385with

ARDS

ModifiedAECC:

P:F

≤250mm

Hg;

onset<72hrs

5ppm

Day

28,death,oruntil

adequateoxygenation

Nitrogengas

(placebo)

Notreported

33%

iNO

vs32%

controlat

1year

(p=0.71)

iNO

=inhaled

nitricoxide;

ARDS=acute

respiratory

distresssyndrome;

NS=notsign

ificant;AECC

=American-EuropeanConsensusConference;PaO

2=partial

pressure

ofarterial

oxygen;

FIO2=fraction

ofinspired

oxygen;PEEP=positive

end-expiratory

pressure;ALI=acute

lunginjury;MV

=mechanical

ventilation;P:F

=partial

pressure

ofarterial

oxygen

tofraction

of

inspired

oxygen

ratio;PAOP=pulm

onaryartery

occluded

pressure;PCWP=pulm

onarycapillary

wedge

pressure.


term studies suggesting iNO does not improveclinical outcomes in ARDS.Extensive research has been conducted with

iNO in ARDS; however, the published studieshave several limitations. The use of inconsistentdefinitions combined with an exceedingly heter-ogeneous patient population may have contrib-uted to the variable response seen with iNO.Perhaps more importantly, mechanical ventila-tion practices varied among the studies rangingfrom no adjustments during iNO inhalation toaggressive measures such as extracorporealmembrane oxygenation. Finally, all studies hadsubstantial differences in dosing and duration ofiNO. Only two studies used fixed-dose iNO ver-sus placebo in patients with ARDS over adefined period of time.24, 29 Most trials useddoses of iNO at 40 ppm or less without demon-strating a dose-response relationship. One studyobserved a decline in oxygenation parameters inselect patients receiving 10 ppm or more ofiNO.25 In addition, none of the trials reporteddata on concomitant corticosteroids, sedation, orparalytic agents that may be potential confound-ers in evaluating changes in oxygenation.The optimal dose of iNO to produce maximal

effects on oxygenation in patients with ARDShas yielded mixed results in clinical stud-ies.33, 34 One small nonrandomized trialobserved an increase in PaO2 with iNO doseescalation, plateauing at 10 ppm.33 In contrast, asmall nonrandomized study demonstrated dose-dependent improvements in PaO2 with increasingiNO doses.34 In a larger prospective study, time-dependent effects on the individual response toiNO were studied through dose-response assess-ments.25 At 96 hours of sustained iNO adminis-tration, patients developed tolerance leading to adecrease in mean effective iNO dose from10 ppm to 1 ppm. Furthermore, iNO doses of10 ppm or higher lead to oxygenation deteriora-tion in some patients. This suggests a routineindividualized titration of iNO to a defined ther-apeutic goal in efforts to minimize the loss oftherapeutic effect and potential for deteriorationin oxygenation.

Safety

Inhaled nitric oxide administered at therapeu-tic concentrations rarely causes toxicity. Nitro-gen dioxide (NO2) and peroxynitrite are toxicproducts produced from the spontaneous con-version of iNO in the presence of oxygen or thereaction of iNO in the presence of free radicals,

respectively.13 Clinical trials have establishedlow levels of exhaled NO2 when iNO is adminis-tered at doses of 40 ppm or lower to patientswith ARDS.25, 27 However, unmeasured concen-trations of NO2 within poorly perfused areas ofthe lung may accumulate and cause unknowndeleterious effects.Methemoglobinemia occurs from the reaction

of NO with hemoglobin. Clinically significantmethemoglobinemia from iNO administered atdoses of 20 ppm or less to patients with ARDS isuncommon (incidence less than 1%) and morelikely to occur at doses greater than 80 ppm.24–30

Guidelines recommend the routine measurementof methemoglobin at initiation, 1 and 6 hoursafter initiation, and daily thereafter during iNOadministration.35

Inhaled nitric oxide attenuates platelet adhe-sion and aggregation. Platelet aggregation andagglutination were significantly decreased in sixadult patients with ARDS receiving iNO withoutany effects on bleeding times.36 In clinical trials,significant increases in bleeding events were notobserved in patients receiving iNO comparedwith controls; however, bleeding events may bemore likely to occur in patients with an underly-ing bleeding diathesis or concomitant antithrom-botics.37

One study reported an increased rate of kid-ney injury, managed with renal replacementtherapy, over the study period in patients receiv-ing iNO compared with conventional therapy(24.7% vs 10%, respectively; p<0.025).26 Inaddition, when data from four adult trials werecombined, a significant increase in risk of kid-ney injury with the use of iNO was noted (rela-tive risk 1.59, 95% confidence interval 1.17–2.16).37 The mechanisms of toxic renal effectsdue to iNO are not known but are thought toinvolve damage to mitochondria complexes anddeoxyribonucleic acid.38

Aerosolized Epoprostenol

Effects on Oxygenation and Clinical Outcomes

There are no randomized controlled trialsassessing the clinical effects of aEPO on oxygen-ation in patients with ARDS or ALI. Six of theseven case series report the effects of aEPO onoxygenation (Table 2).39–44 The first case seriesusing aEPO in patients with severe ARDS dem-onstrated an improvement in PaO2:FIO2 and adecrease in shunt fraction in three patients.42

The effects of aEPO on primary and secondary


Table

2.TrialsofAerosolizedEpoprosten

olin

AdultPatients

withARDS

Study

No.ofpatients

ARDSdefinition

Aerosolizedepoprostenol

regimen

Durationof

aerosolized

epoprostenol

Controlregimen

Change

inoxygenation

Mortality

42

3withARDS

P:F

ratio<150

despiteoptimal

MVfor>24hrs

5ng/kg/min

titrated

up

to50ng/kg/min

30min

Glycinediluent

(placebo)

Change

inP:F:119.5

�19.3

to173�

17.7

(reported

asmean�

SEM)from

baseline

Notreported

42

12withARDS;

group

A=nolungdisease;

groupB=preexisting

lungdisease

Severe

CAPand

P:F

<150mm

Hg

despiteoptimal

MVfor24–4

8hrs

1ng/kg/min

and

increaseduntilPa O

2

increasedby10mm

Hg

ordecreased

by

>5mm

Hgto

80ng/kg/min

~1hr

Glycinediluent

(placebo)

Change

inPa O

2:(groupA)

74.0

�7.6

to96�

9.2

mm

Hg;

p<0.05and(groupB)

64.3

�4.2

to56.5

�3.3

mm

Hg;

p<0.05from

baseline

33%

groupAvs

83%

groupB

46

9withARDS

Lunginjury

score

≥2.5

Increaseddose

every

30min

by

10–5

0ng/kg/min

4hrs

Notreported

Sign

ificantdose-dependent

increase

inP:F

ratio

(p=0.003)from

baseline

Notreported

40

15withARDS

AECC

2ng/kg/min,titrated

every15min

based

on

Pa O

2to

40ng/kg/min

~1hr

Notreported

Change

inPaO

2:11.6

�0.3

to10.5

�0.3

kPa;

p<0.02

primaryARDSand

10.2

�0.5

to11.2

�0.5

kPa;

p<0.1

secondaryARDSfrom

baseline

43%

primary

ARDSvs

44%

secondaryARDS

39

27withARDS

AECC

17.4

�12.5

ng/kg/min

upto

34.3

�13.2

5.9

�7.6

days

Notreported

Nochange

inP:F

orPaO

2from

baseline

53%

45

4withARDS

Notreported

20ng/kg/min

upto

40ng/kg/min

Meanduration:

72hrs

Notreported

Nochange

inPaO

2from

baseline

75%

44

16withARDS

AECC

Meanstartingdose:

30�

10ng/kg/min

Meanduration:

4.8

�6days

Notreported

63%

experienceda10%

increase

inPa O

2within

4hrs

56%

ARDS=acute

respiratory

distresssyndrome;

MV

=mechanical

ventilation;P:F

=partial

pressure

ofarterial

oxygen

tofractionofinspired

oxygen

ratio;SE

M=standarderrorofthemean;

CAP=community-acquired

pneumonia;PaO

2=partial

pressure

ofarterial

oxygen;AECC

=American-EuropeanConsensusConference.


ARDS were evaluated in a prospective interven-tional study.40 Fifteen consecutive patients wereexposed to aEPO starting at 2 ng/kg/minute andescalated every 15 minutes to a maximum of40 ng/kg/minute based on PaO2 improvement.Patients with primary lung injury had a signifi-cant decrease in PaO2:FIO2 with the initiation ofaEPO, whereas patients with secondary lunginjury had a significant increase in PaO2:FIO2

with the addition of aEPO. The findings of thiscase series conflict with those of a study inwhich patients with severe pneumonia withoutunderlying interstitial disease had a significantimprovement in PaO2 with the addition ofaEPO.43 A small retrospective review demon-strated no significant changes in PaO2 or PaO2:FIO2 in patients with ARDS with the addition ofaEPO.39 The use of aEPO was described in fourpatients with H1N1 influenza and correspondingARDS.45 All of these patients had severe hypoxiarequiring 100% FIO2 before initiating aEPO at adose of 20 ng/kg/minute titrated up to 40 ng/kg/minute. In this case series, there were nochanges in oxygen requirements or plateau pres-sures at the cessation of aEPO therapy. Of note,in all of these patients, antiviral therapy was notinitiated for ~4–10 days after symptom onset,possibly mitigating the effect of any subsequenttherapy. The most recent case series describes theuse of aEPO in 17 patients with ARDS.44 Morethan half of the patients demonstrated in increasein PaO2 during the initial 4 hours of therapy.Similar to studies of iNO, these trials are lim-

ited by small sample sizes and heterogeneousclinical end points. There have been no placebo-controlled studies of aEPO. This is partially dueto the complexity of the patient population andthe drug delivery system. Theoretical equipoisewould be challenged in the ability to maintainan even selection and enrollment of studypatients. To date, no studies have assessed theeffects of aEPO therapy on mortality or otheroutcomes in adult patients with ALI or ARDS.When considering aEPO for ARDS, adminis-

tration is challenged by selecting the optimaldosing strategy to derive maximal benefit:weight based versus fixed dose. One dose-response study administered aEPO over a doserange of 0 to 50 ng/kg/minute to determine theassociation between dose and the effect onindexes of oxygenation such as PaO2:FIO2 andalveolar-arterial oxygen partial pressure differ-ence [P(A-a)O2], while also accounting for hemo-dynamic effects such as cardiac index, meanarterial pressure, and mean pulmonary arterial

pressure (MPAP). The dose of aEPO wasadjusted every 30 minutes in increments of10 ng/kg/minute, in a dose range of 0 to 50 ng/kg/minute, with a correlating arterial blood gasto determine the effect of each dose titration.Aerosolized epoprostenol significantly improvedPaO2:FIO2 and P(A-a)O2 in a dose-dependentmanner. The greatest impact on oxygenationparameters was observed at a dose of 10 ng/kg/minute, whereas dose increases in aEPO from 10to 50 ng/kg/min provided incremental improve-ment in oxygenation parameters. No significantchanges in oxygenation were observed withdoses exceeding 50 ng/kg/minute. Interestingly,indexes of oxygenation reverted to baselinewhen aEPO was discontinued. Overall, therewere no significant changes in hemodynamiceffects with increased doses.

Safety

Published data about aEPO toxicity is onlyavailable from small studies and case series,which makes it difficult to distinguish betweendrug toxicity and the nature of the disease. Theprimary concerns with aEPO revolve aroundinhibition of platelet aggregation and the local-ized effect of the highly alkaline glycine diluent(pH ~10.5) required for drug stability.36 A studyin piglets investigated the effects of administra-tion of aEPO in glycine diluent versus glycinediluent alone at a nebulization rate of 15 ml/hour (mean aEPO dose 200 ng/kg/min) for upto 8 hours.46 Mild acute tracheitis that involvedthe superficial layers of the trachea wereobserved after exposure to ~2-fold the hourlydose of diluent and 4-fold the hourly dose ofaEPO commonly administered in humans.46

Additionally, no supporting evidence of pulmo-nary toxicity was identified. In vitro plateletfunction can be impaired by aEPO; however, itis of little consequence in patients undergoingcardiothoracic surgery.47

Practicable Applications of iNO and aEPO

Delivery Systems

Only one commercially available iNO deliverysystem exists in North America, which is aclosed-loop delivery system that connects to theinspiratory limb.48 Nitric oxide is delivered inproportion to the flow signal from the ventilator,allowing for a constant concentration of NO.This system is universally compatible with


nearly any conventional mechanical ventilator inNorth America.No aEPO delivery system is approved for use

in mechanically ventilated patients. Variability indrug delivery through nebulization is a majorconcern because less than 20% of the medicationreaches the site of action with most conventionalnebulizers.49–53 The glycine buffer solution usedas the diluent for aEPO is a highly viscous solu-tion potentially leading to ventilator malfunc-tions (e.g., clogging), inducing unintendedelevations in PEEP and dysfunction of carbondioxide analyzers.54

Despite these challenges, several deliverymethods have been developed.54–56 Several fac-tors are relevant when putting aEPO therapyinto practice. A multidisciplinary gap analysisshould outline the role of each team member inthe care, delivery, administration, and monitor-ing of the patient receiving this therapy to

ensure a consistent, safe method of delivery andrapid turnaround from the pharmacy (Table 3).Figure 1 depicts a nebulizer and ventilator

setup. The nebulizer is connected to the inspira-tory limb of the ventilator circuit. If using a heatand moisture exchange filter, the nebulizershould be placed proximal to the patient to pre-vent filtering of the drug. If using the Mini-HEART Lo-Flo nebulizer (Westmed, Tucson,AZ), it should be primed with 15 ml of theepoprostenol dilution and infused at a rate of8 ml/hour into the nebulizer. To match the FIO2

being delivered via the ventilator and deliver thenebulized solution continuously, an air/oxygenblender should be used to deliver 2 to 3 L/min-ute through the nebulizer. The expiratory filtershould be checked routinely (as often as every2–4 hours) to identify clogging and inadvertentauto-PEEP due to the diluent.54 Additionally, aheated wire circuit should be considered to

Table 3. Points to Consider Before Implementation of Aerosolized Epoprostenol

� Weight-based vs non–weight-based dosage regimen� Nebulizer type and limitations� Syringe pump vs infusion pump: consider keeping this on the ventilator side of the patient while keeping the intravenous

medications on the other side if room permits� Limitations to use (compatibility with ventilators/ventilation modes, metered-dose inhaler administration, use during

transport, procedural plans, use in nonintubated patients)� Restrictions to use by certain prescribers and/or intensive care units� Avoidance of potential errors (auxiliary labeling, 8-hour expiration, light protection, Luer-lock connection concerns,

limiting prostacyclin administration responsibilities to respiratory therapists, frequency of ventilator filter checks and/orchanges)

� Education and reinforcement of communication� Development of a weaning protocol and establishing requirements for monitoring

Figure 1. Aerosolized epoprostenol setup and administration.


maintain humidification of the ventilator circuitat approximately 34–36°C. Minor adjustments tothe desired tidal volume through the ventilatormay be required because additional gas flow isbeing introduced to the circuit beyond what theventilator is delivering.Dosing schemes can be best described as

fixed-dose or weight-based dosing regimens.When using a fixed-dose regimen, it should benoted that changing the infusion rate to the neb-ulizer does not alter the amount of drug deliv-ered; this can only be affected by modifyingnebulizer delivery (gas flow to nebulizer) or bychanging the concentration of epoprostenoldelivered to the nebulizer. A fixed-dose regimenallows for ease of preparation and setup. Alter-natively, a weight-based regimen can be used todeliver aEPO via a dual infusion pump with asingle drug concentration. Because lung volumeis best reflected by height, dosing should bebased on ideal body weight. A weight-based regi-men can be administered by setting the appro-priate rate of aEPO and normal saline for acombined rate of 8 ml/hour, which allows doseadjustments by changing the rates of bothepoprostenol and normal saline. Weight-basedadministration has the advantage of not requir-ing a new concentration of epoprostenol fordose titrations; however, it introduces risk fromdosing calculation errors as well as a more labo-rious and intensive setup.Several differences in patient exposure have

not yet been accounted for with aEPO and iNO.Comparing outcomes of specific dosing regimensbecomes rather abstract if ventilator managementand minute ventilation generate different drugexposure per minute despite equivalent ordereddoses of aEPO or iNO. For example, if twopatients are ordered aEPO at 10 ng/kg/minuteand patient “A” has a set respiratory rate of 15breaths per min (BPM), whereas patient “B” hasa respiratory rate of 20 BPM, patient “A” willreceive 25% less aEPO/minute. Ventilator gassampling of iNO can measure delivered iNO perbreath, but no such technology exists for aEPO.Without regard to dosing scheme, accurate

aEPO dose delivery can be highly dependent onnebulizer type, drug/solution characteristics, vol-ume of solution in the nebulizer, circuit temper-ature and humidification, driving pressure anddensity of the carrier gas, respiratory rate, tidalvolume, PEEP, length of ventilator tubing, andpotentially the type of ventilator and tubing.Given these multiple confounding factors, it isimportant to recognize that when the solution is

backing up into the nebulizer, it is not alwaysan indication to decrease the infusion rate of thenebulizer. Most often, this indicates the medica-tion is not being delivered adequately; a firststep is to increase gas flow to the nebulizer(from 2 to 3 L/min of gas flow). If solution con-tinues to back up in the nebulizer after increas-ing gas flow (more than 15–20 ml in theMiniHEART nebulizer), the infusion rate of theepoprostenol dilution (and normal saline ifusing the weight-based regimen) will need to bedecreased to a total of 4 to 6 ml/hour. AlthoughaEPO has been used with various ventilationmodes, it has not been studied for use withhigh-frequency oscillatory ventilation, a therapysometimes considered in ARDS.

Dosage Forms

Nitric oxide gas is commercially manufacturedin cylinders holding up to 800 ppm. Epoproste-nol is currently commercially available in twoformulations: epoprostenol sodium suppliedwith the glycine diluent Flolan (GlaxoSmithK-line, Research Triangle Park, NC) and epopros-tenol sodium supplied with arginine, mannitol,and sodium hydroxide, Veletri (Actelion Phar-maceuticals US, San Francisco, CA).57, 58 Theelevated pH of the Veletri formulation shouldwarrant concern when considering this for off-label use by nebulization because this has notbeen tested in human or animal models for riskof toxicity. Likewise, administration methodsrequiring delivery of the glycine diluent in Flo-lan above 15 ml/hour are beyond the rates thathave been evaluated for toxicity.

Cost of Therapy

In the current setting of health care cost con-tainment, institutions have adapted less costlyalternatives to iNO. Current trends in acquisi-tion cost of iNO have changed considerably inthe last few years as the patent approaches expi-ration. Formerly, many institutions were billedbased on use up through the first 96 hours in a28-day cycle at ~$150/hour (more than $3500/day). However, billing is now based on anhourly rate that will charge institutions for thepatients’ entire duration of therapy (hourly costdetermined by a price plan based on the institu-tion’s estimated annual hours of use; similar tocellular phone plans). In contrast, aEPO isapproximately $300/day, making it an attractivealternative. Selection of dosing strategy and


nebulizer may influence this cost to some extent;however, direct acquisition costs of aEPOremain less than iNO.A phase III clinical study assessed the cost

associated with low-dose iNO in patients withARDS.22 Overall, the in-hospital use of resourcesand hospital charges were similar in patientsreceiving iNO or placebo. Intensive care costswere also comparable between both groups($50,200 vs $48,200; p=NS). Interestingly, iNOhad no impact on resource use during thepatient’s hospital stay or postdischarge costs. Amore recent retrospective study compared thecost of iNO and aEPO in 105 mechanically ven-tilated patients, ~60% of whom had ARDS.59

When using a low- or high-contract price foriNO, the use of iNO was 4.5–17 times morecostly than aEPO.

Conclusion

The clinical benefits of inhaled vasodilators inpatients with ALI or ARDS have been studied inlarge clinical trials with iNO and limited trialswith aEPO. These agents produce localized pul-monary vasodilatation resulting in short-termoxygenation improvements without systemic he-modynamic compromise. In clinical trials, up to60% of patients with ARDS had an increase inoxygenation with iNO or aEPO.24, 26, 27, 29, 30, 60

The temporary improvement in oxygenation maynot be observed in all patients due to preexistingpulmonary disease, concomitant use of systemicvasopressors, or lack of dose-response curves todefine treatment doses.40, 43, 61, 62

The optimal dose of iNO and aEPO to maxi-mize oxygenation is unknown. It appears thatincreasing the dose of iNO beyond 40 ppm doesnot provide further clinical benefits; rather,higher doses may increase the risk of toxiceffects.24 In addition, the sustained use of iNOmay lead to a loss of therapeutic effect.25 Dose-dependent effects of aEPO have been observedwith maximal effects seen at 50 ng/kg/minute.41

Direct comparisons of iNO and aEPO are lim-ited; however, aEPO at 10 ng/kg/minuteimproves gas exchange and decreases MPAP inpatients with ARDS comparable with iNO at 1,4, and 8 ppm.63 In some cases the reductions inMPAP and PVR were greater with aEPO as com-pared with iNO.63, 64

Despite the transient improvement in oxygen-ation, no significant differences have beenobserved for mortality, ventilator-free days, orattenuation in disease severity.22–24, 26, 29 These

data are limited by the small sample sizes, lackof appropriate control subjects, varying doses ofgas/drug, timing of therapy, different modes ofgas/drug delivery, and variable definitions of ALIand ARDS used in clinical trials. Only a limitednumber of well-designed trials have comparedthe effects of iNO and aEPO for the treatment ofARDS.59, 60, 63, 64 Any improvements in mortal-ity may be offset by known toxicities and thefailure of other organ systems in these criticallyill patients. Finally, trials of inhaled vasodilatorsdo not account for advances in clinical practicethat affect the ability to interpret the magnitudeof benefit of aEPO therapy correctly. If clinicalpractices can be standardized, dose-related out-comes of inhaled vasodilator therapy might bebetter represented by accounting for drug expo-sure as measured by the ordered dose and min-ute ventilation.The incidence of toxic effects of iNO and

aEPO are minimal at the doses used in the treat-ment of ARDS. The extent to which these toxici-ties obscure the beneficial effects on oxygenationremains elusive.Overall, evidence is insufficient to support the

routine use of inhaled vasodilators in patientswith ARDS or ALI; however, it may be consid-ered as a rescue therapy in severe refractoryhypoxemia after optimal adjustments to mechan-ical ventilation. Current data are lacking on sub-groups of patients with ARDS that would benefitfrom inhaled vasodilators.

References

1. Zambon M, Vincent JL. Mortality rates for patients with acutelung injury/ARDS have decreased over time. Chest2008;133:1120–7.

2. Bernard GR, Artigas A, Brigham KL, et al. The American-European Consensus Conference on ARDS. Definitions, mech-anisms, relevant outcomes, and clinical trial coordination. AmJ Respir Crit Care Med 1994;149:818–24.

3. Ranieri VM, Rubenfeld GD, Thompson BT, et al. Acute respi-ratory distress syndrome: the Berlin Definition. JAMA2012;307:2526–33.

4. Kollef MH, Schuster DP. The acute respiratory distress syn-drome. N Engl J Med 1995;332:27–37.

5. Ventilation with lower tidal volumes as compared with tradi-tional tidal volumes for acute lung injury and the acute respi-ratory distress syndrome. The Acute Respiratory DistressSyndrome Network. N Engl J Med 2000;342:1301–8.

6. Silversides JA, Ferguson ND. Clinical review: acute respira-tory distress syndrome—clinical ventilator management andadjunct therapy. Crit Care 2012;29:225.

7. Ware LB, Matthay MA. The acute respiratory distress syn-drome. N Engl J Med 2000;342:1334–49.

8. Murphy CV, Schramm GE, Doherty JA, et al. The importanceof fluid management in acute lung injury secondary to septicshock. Chest 2009;136:102–9.

9. Wiedemann HP, Wheeler AP, Bernard GR, et al., NationalHeart Lung and Blood Institute Acute Respiratory DistressSyndrome Clinical Trials Network. Comparison of two


fluid-management strategies in acute lung injury. N Engl JMed 2006;354:2564–75.

10. Shafeeq H, Lat I. Pharmacotherapy for acute respiratory dis-tress syndrome. Pharmacotherapy 2012;32:943–57.

11. Papazian L, Forel JM, Gacouin A, et al. Neuromuscular block-ers in early acute respiratory distress syndrome. N Engl J Med2010;363:1107–16.

12. Stapleton RD, Wang BM, Hudson LD, et al. Causes and tim-ing of death in patients with ARDS. Chest 2005;128:525–32.

13. Griffiths MJ, Evans TW. Inhaled nitric oxide therapy inadults. N Engl J Med 2005;353:2683–95.

14. Steudel W, Hurford WE, Zapol WM. Inhaled nitric oxide:basic biology and clinical applications. Anesthesiology1999;91:1090–121.

15. Bloch KD, Ichinose F, Roberts JD Jr, et al. Inhaled NO as atherapeutic agent. Cardiovasc Res 2007;75:339–48.

16. Gomberg-Maitland M, Olschewski H. Prostacyclin therapiesfor the treatment of pulmonary arterial hypertension. EurRespir J 2008;31:891–901.

17. Buckley MS, Feldman JP. Inhaled epoprostenol for the treat-ment of pulmonary arterial hypertension in critically ill adults.Pharmacotherapy 2010;30:728–40.

18. Schermuly RT, Pullamsetti SS, Breitenbach SC, et al. Ilo-prost-induced desensitization of the prostacyclin receptor inisolated rabbit lungs. Respir Res 2007;8:4.

19. Olschewski H, Ghofrani HA, Schmehl T, et al. Inhaled iloprostto treat severe pulmonary hypertension. An uncontrolled trial.German PPH Study Group. Ann Intern Med 2000;132:435–43.

20. Olschewski H, Rohde B, Behr J, et al. Pharmacodynamics andpharmacokinetics of inhaled iloprost, aerosolized by three dif-ferent devices, in severe pulmonary hypertension. Chest 2003;124:1294–304.

21. Olschewski H, Walmrath D, Schermuly R, et al. Aerosolizedprostacyclin and iloprost in severe pulmonary hypertension.Ann Intern Med 1996;124:820–4.

22. Angus DC, Clermont G, Linde-Zwirble WT, et al. Healthcarecosts and long-term outcomes after acute respiratory distresssyndrome: a phase III trial of inhaled nitric oxide. Crit CareMed 2006;34:2883–90.

23. Cuthbertson BH, Galley HF, Webster NR. Effect of inhalednitric oxide on key mediators of the inflammatory response inpatients with acute lung injury. Crit Care Med 2000;28:1736–41.

24. Dellinger RP, Zimmerman JL, Taylor RW, et al. Effects ofinhaled nitric oxide in patients with acute respiratory distresssyndrome: results of a randomized phase II trial. InhaledNitric Oxide in ARDS Study Group. Crit Care Med 1998;26:15–23.

25. Gerlach H, Keh D, Semmerow A, et al. Dose-response charac-teristics during long-term inhalation of nitric oxide in patientswith severe acute respiratory distress syndrome: a prospective,randomized, controlled study. Am J Respir Crit Care Med2003;167:1008–15.

26. Lundin S, Mang H, Smithies M, et al. Inhalation of nitricoxide in acute lung injury: results of a European multicentrestudy. The European Study Group of Inhaled Nitric Oxide.Intensive Care Med 1999;25:911–9.

27. Mehta S, Simms HH, Levy MM, et al. Inhaled nitric oxideimproves oxygenation acutely but not chronically in acuterespiratory distress syndrome: a randomized, control trial.J Appl Res 2001;1:73–84.

28. Michael JR, Barton RG, Saffle JR, et al. Inhaled nitric oxideversus conventional therapy: effect on oxygenation in ARDS.Am J Respir Crit Care Med 1998;157:1372–80.

29. Taylor RW, Zimmerman JL, Dellinger RP, et al. Low-doseinhaled nitric oxide in patients with acute lung injury: a ran-domized controlled trial. JAMA 2004;291:1603–9.

30. Troncy E, Collet JP, Shapiro S, et al. Inhaled nitric oxide inacute respiratory distress syndrome: a pilot randomized con-trolled study. Am J Respir Crit Care Med 1998;157:1483–8.

31. Adhikari NK, Burns KE, Friedrich JO, et al. Effect of nitricoxide on oxygenation and mortality in acute lung injury: sys-tematic review and meta-analysis. BMJ 2007;334:779.

32. Sokol J, Jacobs SE, Bohn D. Inhaled nitric oxide for acutehypoxemic respiratory failure in children and adults. CochraneDatabase Syst Rev 2003; CD002787.

33. Gerlach H, Rossaint R, Pappert D, et al. Time-course anddose-response of nitric oxide inhalation for systemic oxygena-tion and pulmonary hypertension in patients with adult respi-ratory distress syndrome. Eur J Clin Invest 1993;23:499–502.

34. Puybasset L, Rouby JJ, Mourgeon E, et al. Inhaled nitric oxidein acute respiratory failure: dose-response curves. IntensiveCare Med 1994;20:319–27.

35. Cuthbertson BH, Dellinger P, Dyar OJ, et al. UK guidelinesfor the use of inhaled nitric oxide therapy in adult ICUs.American-European Consensus Conference on ALI/ARDS.Intensive Care Med 1997;23:1212–8.

36. Samama CM, Diaby M, Fellahi JL, et al. Inhibition of plateletaggregation by inhaled nitric oxide in patients with acuterespiratory distress syndrome. Anesthesiology 1995;83:56–65.

37. Afshari A, Brok J, Moller AM, et al. Inhaled nitric oxide foracute respiratory distress syndrome (ARDS) and acute lunginjury in children and adults. Cochrane Database Syst Rev2010;7:CD002787.

38. Brown GC. Nitric oxide regulates mitochondrial respirationand cell functions by inhibiting cytochrome oxidase. FEBS Lett1995;369:136–9.

39. Camamo JM, McCoy RH, Erstad BL. Retrospective evaluationof inhaled prostaglandins in patients with acute respiratorydistress syndrome. Pharmacotherapy 2005;25:184–90.

40. Domenighetti G, Stricker H, Waldispuehl B. Nebulized pros-tacyclin (PGI2) in acute respiratory distress syndrome: impactof primary (pulmonary injury) and secondary (extrapulmonaryinjury) disease on gas exchange response. Crit Care Med2001;29:57–62.

41. van Heerden PV, Barden A, Michalopoulos N, et al. Dose-response to inhaled aerosolized prostacyclin for hypoxemiadue to ARDS. Chest 2000;117:819–27.

42. Walmrath D, Schneider T, Pilch J, et al. Aerosolised prostacy-clin in adult respiratory distress syndrome. Lancet 1993;342:961–2.

43. Walmrath D, Schneider T, Pilch J, et al. Effects of aerosolizedprostacyclin in severe pneumonia. Impact of fibrosis. Am JRespir Crit Care Med 1995;151:724–30.

44. ley KA, Louzon PR, Lee J, et al. Efficacy, safety, and medica-tion errors associated with the use of inhaled epoprostenol foradults with acute respiratory distress syndrome: a pilot study.Ann Pharmacother 2013;47:790–6.

45. McMillen JC, Burke CF, Dhingra A, et al. Use of inhaledepoprostenol in patients with H1N1 influenza-associated acuterespiratory distress syndrome: a case series. Ann Pharmacother2011;45:e26.

46. van Heerden PV, Caterina P, Filion P, et al. Pulmonary toxic-ity of inhaled aerosolized prostacyclin therapy—an observa-tional study. Anaesth Intensive Care 2000;28:161–6.

47. Haraldsson A, Kieler-Jensen N, Wadenvik H, et al. Inhaledprostacyclin and platelet function after cardiac surgery andcardiopulmonary bypass. Intensive Care Med 2000;26:188–94.

48. Datex-Ohmeda I. INOvent delivery system operational and main-tenance manual CGA variant (2000). Publication 1605-0014-000.

49. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part II:the role of inhalant delivery devices and drug formulations intherapeutic effectiveness of aerosolized medications. Br J ClinPharmacol 2003;56:600–12.

50. Labiris NR, Dolovich MB. Pulmonary drug delivery. Part I:physiological factors affecting therapeutic effectiveness of aero-solized medications. Br J Clin Pharmacol 2003;56:588–99.

51. O’Riordan TG, Greco MJ, Perry RJ, et al. Nebulizer functionduring mechanical ventilation. Am Rev Respir Dis 1992;145:1117–22.

52. O’Riordan TG, Palmer LB, Smaldone GC. Aerosol depositionin mechanically ventilated patients. Optimizing nebulizerdelivery. Am J Respir Crit Care Med 1994;149:214–9.

53. Thomas SH, O’Doherty MJ, Fidler HM, et al. Pulmonarydeposition of a nebulised aerosol during mechanical ventila-tion. Thorax 1993;48:154–9.


54. De Wet CJ, Affleck DG, Jacobsohn E, et al. Inhaled prostacy-clin is safe, effective, and affordable in patients with pulmo-nary hypertension, right heart dysfunction, and refractoryhypoxemia after cardiothoracic surgery. J Thorac CardiovascSurg 2004;127:1058–67.

55. Siobal MS, Kallet RH, Pittet JF, et al. Description and evalua-tion of a delivery system for aerosolized prostacyclin. RespirCare 2003;48:742–53.

56. Sutcliffe N, McCluskey A. Simple apparatus for continuousnebulisation of prostacyclin. Anaesthesia 2000;55:405.

57. Flolan� (epoprostenol sodium) for injection. Prescribinginformation. Research Triangle Park, NC: GlaxoSmithKline,March 2011.

58. Veletri� (epoprostenol sodium) for injection. Prescribinginformation. South San Francisco, CA: Actelion Pharmaceuti-cals, March 2011.

59. Torbic H, Szumita PM, Anger KE, et al. Inhaled epoprostenolvs inhaled nitric oxide for refractory hypoxemia in critically illpatients. J Crit Care 2013;28:844–8.

60. Walmrath D, Schneider T, Schermuly R, et al. Direct compar-ison of inhaled nitric oxide and aerosolized prostacyclin inacute respiratory distress syndrome. Am J Respir Crit CareMed 1996;153:991–6.

61. Bigatello LM, Hurford WE, Kacmarek RM, et al. Prolongedinhalation of low concentrations of nitric oxide in patientswith severe adult respiratory distress syndrome. Effects on pul-monary hemodynamics and oxygenation. Anesthesiology1994;80:761–70.

62. Krafft P, Fridrich P, Fitzgerald RD, et al. Effectiveness ofnitric oxide inhalation in septic ARDS. Chest 1996;109:486–93.

63. Zwissler B, Kemming G, Habler O, et al. Inhaled prostacyclin(PGI2) versus inhaled nitric oxide in adult respiratory distresssyndrome. Am J Respir Crit Care Med 1996;154:1671–7.

64. Van Heerden PV, Blythe D, Webb SA. Inhaled aerosolizedprostacyclin and nitric oxide as selective pulmonary vasodila-tors in ARDS—a pilot study. Anaesth Intensive Care 1996;24:564–8.


Documents

A Review of Inhaled Nitric Oxide and Aerosolized Epoprostenol in Acute Lung Injury or Acute Respiratory Distress Syndrome