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Prostaciclinas en aerosol para el síndrome de dificultad respiratoria aguda (SDRA)

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References

Referencias de los estudios incluidos en esta revisión

Dahlem 2004 {published and unpublished data}

Dahlem P, van Aalderen WM, de Neef M, Dijkgraaf MG, Bos AP. Randomized controlled trial of aerosolized prostacyclin therapy in children with acute lung injury. Critical Care Medicine 2004;32(4):1055‐60. [PUBMED: 15071401]CENTRAL

Siddiqui 2013 {published and unpublished data}

Siddiqui S, Salahuddin N, Zubair S, Yousuf M, Azam I, Gilani AH. Use of inhaled PGE1 to improve diastolic dysfunction, LVEDP, pulmonary hypertension and hypoxia in ARDS ‐ a randomised clinical trial. Open Journal of Anesthesiology 2013;3(2):109‐15. [DOI: 10.4236/ojanes.2013.32027]CENTRAL

Referencias de los estudios excluidos de esta revisión

Abraham 1996 {published data only}

Abraham E, Park YC, Covington P, Conrad SA, Schwartz M. Liposomal prostaglandin E1 in acute respiratory distress syndrome: a placebo‐controlled, randomized, double‐blind, multicenter clinical trial. Critical Care Medicine 1996;24(1):10‐5. [PUBMED: 8565513]CENTRAL

Abraham 1999 {published data only}

Abraham E, Baughman R, Fletcher E, Heard S, Lamberti J, Levy HN, et al. Liposomal prostaglandin E1 (TLC C‐53) in acute respiratory distress syndrome: a controlled, randomized, double‐blind, multicenter clinical trial. TLC C‐53 ARDS Study Group. Critical Care Medicine 1999;27(8):1478‐85. [PUBMED: 10470753 ]CENTRAL

Ammar 2015 {published data only}

Ammar MA, Bauer SR, Bass SN, Sasidhar M, Mullin R, Lam SW. Noninferiority of inhaled epoprostenol to inhaled nitric oxide for the treatment of ARDS. Annals of Pharmacotherapy 2015;49(10):1105‐12. [PUBMED: 26187741]CENTRAL

Archer 1996 {published data only}

Archer SL, Mike D, Crow J, Long W, Weir EK. A placebo‐controlled trial of prostacyclin in acute respiratory failure in COPD. Chest 1996;109(3):750‐5. [PUBMED: 8617086]CENTRAL

Bein 1994 {published data only}

Bein T, Pfeifer M, Riegger GA, Taeger K. Continuous intraarterial measurement of oxygenation during aerosolized prostacyclin administration in severe respiratory failure. New England Journal of Medicine 1994;331(5):335‐6. [PUBMED: 8022461]CENTRAL

Boeck 2012 {published data only}

Boeck L, Tamm M, Grendelmeier P, Stolz D. Acute effects of aerosolized iloprost in COPD related pulmonary hypertension ‐ a randomized controlled crossover trial. PloS One 2012;7(12):e52248. [PUBMED: 23300624 ]CENTRAL

Bone 1989 {published data only}

Bone RC, Slotman G, Maunder R, Silverman H, Hyers TM, Kerstein MD, et al. Randomized double‐blind, multicenter study of prostaglandin E1 in patients with the adult respiratory distress syndrome. Prostaglandin E1 Study Group. Chest 1989;96(1):114‐9. [PUBMED: 2661155]CENTRAL
Silverman HJ, Slotman G, Bone RC, Maunder R, Hyers TM, Kerstein MD, et al. Effects of prostaglandin E1 on oxygen delivery and consumption in patients with the adult respiratory distress syndrome. Results from the prostaglandin E1 multicenter trial. The Prostaglandin E1 Study Group. Chest 1990;98(2):405‐10. [PUBMED: 2198140]CENTRAL
Slotman GJ, Kerstein MD, Bone RC, Silverman H, Maunder R, Hyers TM, et al. The effects of prostaglandin E1 on non‐pulmonary organ function during clinical acute respiratory failure. The Prostaglandin E1 Study Group. Journal of Trauma 1992;32(4):480‐8. [PUBMED: 1569622]CENTRAL

Domenighetti 2001 {published data only}

Domenighetti G, Stricker H, Waldispuehl B. Nebulized prostacyclin (PGI2) in acute respiratory distress syndrome: impact of primary (pulmonary injury) and secondary (extrapulmonary injury) disease on gas exchange response. Critical Care Medicine 2001;29(1):57‐62. [PUBMED: 11176161]CENTRAL

Dunkley 2013 {published data only}

Dunkley KA, Louzon PR, Lee J, Vu S. Efficacy, safety, and medication errors associated with the use of inhaled epoprostenol for adults with acute respiratory distress syndrome: a pilot study. Annals of Pharmacotherapy 2013;47(6):790‐6. [PUBMED: 23656748 ]CENTRAL

Eichelbrönner 1996 {published data only}

Eichelbrönner O, Reinelt H, Wiedeck H, Mezödy M, Rossaint R, Georgieff M, et al. Aerosolized prostacyclin and inhaled nitric oxide in septic shock ‐ different effects on splanchnic oxygenation?. Intensive Care Medicine 1996;22(9):880‐7. [PUBMED: 8905421]CENTRAL

Holcroft 1986 {published data only}

Holcroft JW, Vassar MJ, Weber CJ. Prostaglandin E(1) and survival in patients with the adult respiratory distress syndrome: a prospective trial. Seminars in Respiratory Medicine 1986;8 Suppl:40‐7. CENTRAL
Holcroft JW, Vassar MJ, Weber CJ. Prostaglandin E1 and survival in patients with the adult respiratory distress syndrome. A prospective trial. Annals of Surgery 1986;203(4):371‐8. [PUBMED: 3516085]CENTRAL

Liu 2015 {published data only}

Liu D, Luo G, Luo C, Wang T, Sun G, Hei Z. Changes in the concentrations of mediators of inflammation and oxidative stress in exhaled breath condensate during liver transplantation and their relations with postoperative ARDS. Respiratory Care 2015;60(5):679‐88. [PUBMED: 25628453 ]CENTRAL

Meyer 1998 {published data only}

Meyer J, Theilmeier G, Van Aken H, Bone HG, Busse H, Waurick R, et al. Inhaled prostaglandin E1 for treatment of acute lung injury in severe multiple organ failure. Anesthesia and Analgesia 1998;86(4):753‐8. [PUBMED: 9539597]CENTRAL

NCT00981591 {published and unpublished data}

NCT00981591. Inhaled iloprost as an adjunct to inhaled nitric oxide in pediatric critical care patients. clinicaltrials.gov/ct2/show/NCT00981591 Date first received: 18 September 2009. CENTRAL

Pappert 1995 {published data only}

Pappert D, Busch T, Gerlach H, Lewandowski K, Radermacher P, Rossaint R. Aerosolized prostacyclin versus inhaled nitric oxide in children with severe acute respiratory distress syndrome. Anesthesiology 1995;82(6):1507‐11. [PUBMED: 7793662]CENTRAL

Putensen 1998 {published data only}

Putensen C, Hörmann C, Kleinsasser A, Putensen‐Himmer G. Cardiopulmonary effects of aerosolized prostaglandin E1 and nitric oxide inhalation in patients with acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 1998;157(6 Pt 1):1743‐7. [PUBMED: 9620900]CENTRAL

Rossignon 1990 {published data only}

Rossignon MD, Khayat D, Royer C, Rouby JJ, Jacquillat C, Viars P. Functional and metabolic activity of polymorphonuclear leukocytes from patients with adult respiratory distress syndrome: results of a randomized double‐blind placebo‐controlled study on the activity of prostaglandin E1. Anesthesiology 1990;72(2):276‐81. [PUBMED: 2405741]CENTRAL

Sawheny 2013 {published data only}

Sawheny E, Ellis AL, Kinasewitz GT. Iloprost improves gas exchange in patients with pulmonary hypertension and ARDS. Chest 2013;144(1):55‐62. [PUBMED: 23370599]CENTRAL

Shoemaker 1986 {published data only}

Shoemaker WC, Appel PL. Effects of prostaglandin E1 in adult respiratory distress syndrome. Surgery 1986;99(3):275‐83. [PUBMED: 3513357]CENTRAL

Sood 2014 {published and unpublished data}

Sood B, Keszler M, Garg M, Klein JM, Ohls R, Ambalavanan N, et al. Inhaled PGE1 in neonates with hypoxemic respiratory failure: two pilot feasibility randomized clinical trials. Trials 2014;15:486. [PUBMED: 25496504]CENTRAL

Torbic 2013 {published data only}

Torbic H, Szumita PM, Anger KE, Nuccio P, LaGambina S, Weinhouse G. Inhaled epoprostenol vs inhaled nitric oxide for refractory hypoxemia in critically ill patients. Journal of Critical Care 2013;28(5):844‐8. [PUBMED: 23683572]CENTRAL

Torbic 2016 {published data only}

Torbic H, Szumita PM, Anger KE, Nuccio P, Lagambina S, Weinhouse G. Clinical and economic impact of formulary conversion from inhaled Flolan to inhaled veletri for refractory hypoxemia in critically ill patients. Annals of Pharmacotherapy 2016;50(2):106‐12. [PUBMED: 26668204]CENTRAL

Van Heerden 1996 {published data only}

Van Heerden PV, Blythe D, Webb SA. Inhaled aerosolized prostacyclin and nitric oxide as selective pulmonary vasodilators in ARDS ‐ a pilot study. Anaesthesia and Intensive Care 1996;24(5):564‐8. [PUBMED: 8909667]CENTRAL

Van Heerden 2000 {published data only}

Van Heerden PV, Barden A, Michalopoulos N, Bulsara MK, Roberts BL. Dose‐response to inhaled aerosolized prostacyclin for hypoxemia due to ARDS. Chest 2000;117(3):819‐27. [PUBMED: 10713012]CENTRAL

Vassar 1991 {published data only}

Vassar MJ, Fletcher MP, Perry CA, Holcroft JW. Evaluation of prostaglandin E1 for prevention of respiratory failure in high risk trauma patients: a prospective clinical trial and correlation with plasma suppressive factors for neutrophil activation. Prostaglandins, Leukotrienes and Essential Fatty Acids 1991;44(4):223‐31. [PUBMED: 1667693]CENTRAL

Vincent 2001 {published data only}

Vincent JL, Brase R, Santman F, Suter PM, McLuckie A, Dhainaut JF, et al. A multi‐centre, double‐blind, placebo‐controlled study of liposomal prostaglandin E1 (TLC C‐53) in patients with acute respiratory distress syndrome. Intensive Care Medicine 2001;27(10):1578‐83. [PUBMED: 11685297]CENTRAL

Walmrath 1995 {published data only}

Walmrath D, Schneider T, Pilch J, Schermuly R, Grimminger F, Seeger W. Effects of aerosolized prostacyclin in severe pneumonia. Impact of fibrosis. American Journal of Respiratory and Critical Care Medicine 1995;151(3 Pt 1):724‐30. [PUBMED: 7881662]CENTRAL

Walmrath 1996 {published data only}

Walmrath D, Schneider T, Schermuly R, Olschewski H, Grimminger F, Seeger W. Direct comparison of inhaled nitric oxide and aerosolized prostacyclin in acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 1996;153(3):991‐6. [PUBMED: 8630585]CENTRAL

Zwissler 1996 {published data only}

Zwissler B, Kemming G, Habler O, Kleen M, Merkel M, Haller M, et al. Inhaled prostacyclin (PGI2) versus inhaled nitric oxide in adult respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 1996;154(6 Pt 1):1671‐7. [PUBMED: 8970353]CENTRAL

Adhikari 2004

Adhikari N, Burns KE, Meade MO. Pharmacologic therapies for adults with acute lung injury and acute respiratory distress syndrome. Cochrane Database of Systematic Reviews 2004, Issue 4. [DOI: 10.1002/14651858.CD004477.pub2]

Adhikari 2007

Adhikari NK, Burns KE, Friedrich JO, Granton JT, Cook DJ, Meade MO. Effect of nitric oxide on oxygenation and mortality in acute lung injury: systematic review and meta‐analysis. BMJ 2007;334(7597):779. [PUBMED: 17383982]

Altman 2003

Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ 2003;326(7382):219. [PUBMED: 12543843]

Anderson 2003

Anderson MR. Update on pediatric acute respiratory distress syndrome. Respiratory Care 2003;48(3):261‐76. [PUBMED: 12667276]

Angus 2001

Angus DC, Musthafa AA, Clermont G, Griffin MF, Linde‐Zwirble WT, Dremsizov TT, et al. Quality‐adjusted survival in the first year after the acute respiratory distress syndrome. American Journal of Respiratory and Critical Care Medicine 2001;163(6):1389‐94. [PUBMED: 11371406]

Barrington 2007

Barrington KJ, Finer NN. Inhaled nitric oxide for respiratory failure in preterm infants. Cochrane Database of Systematic Reviews 2007, Issue 3. [DOI: 10.1002/14651858.CD000509.pub3]

Bernard 1994

Bernard GR, Artigas A, Brigham KL, Carlet J, Falke K, Hudson L, et al. The American‐European Consensus Conference on ARDS. Definitions, mechanisms, relevant outcomes, and clinical trial coordination. American Journal of Respiratory and Critical Care Medicine 1994;149(3 Pt 1):818‐24. [PUBMED: 7509706]

Brok 2009

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Dahlem 2003

Dahlem P, van Aalderen WM, Hamaker ME, Dijkgraaf MG, Bos AP. Incidence and short‐term outcome of acute lung injury in mechanically ventilated children. European Respiratory Journal 2003;22(6):980‐5. [PUBMED: 14680089]

Dahlem 2007

Dahlem P, van Aalderen WM, Bos AP. Pediatric acute lung injury. Paediatric Respiratory Reviews 2007;8(4):348‐62. [PUBMED: 18005903]

Dickersin 1990

Dickersin K. The existence of publication bias and risk factors for its occurrence. JAMA 1990;263(10):1385‐9. [PUBMED: 2406472]

Egger 1997

Egger M, Davey Smith G, Schneider M, Minder C. Bias in metaanalysis detected by a simple, graphical test. BMJ 1997;315(7109):629‐34. [PUBMED: 9310563]

Flori 2005

Flori HR, Glidden DV, Rutherford GW, Matthay MA. Pediatric acute lung injury: prospective evaluation of risk factors associated with mortality. American Journal of Respiratory and Critical Care Medicine 2005;171(9):995‐1001. [PUBMED: 15618461]

Fröhlich 2013

Fröhlich S, Murphy N, Ryan D, Boylan J. Acute respiratory distress syndrome: current concepts and future directions. Anaesthesia and Intensive Care 2013;41(4):463‐72. [PUBMED: 23808504]

Fuller 2015

Fuller BM, Mohr NM, Skrupky L, Fowler S, Kollef MH, Carpenter CR. The use of inhaled prostaglandins in patients with ARDS: a systematic review and meta‐analysis. Chest 2015;147(6):1510‐22. [PUBMED: 25742022]

Gebistorf 2016

Gebistorf F, Karam O, Wetterslev J, Afshari A. Inhaled nitric oxide for acute respiratory distress syndrome (ARDS) in children and adults. Cochrane Database of Systematic Reviews 2016, Issue 6. [DOI: 10.1002/14651858.CD002787.pub3]

GRADEpro [Computer program]

GRADE Working Group, McMaster University. GRADEpro GDT. Hamilton (ON): GRADE Working Group, McMaster University, 2015.

Higgins 2003

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Higgins 2011

Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from handbook.cochrane.org.

Hill 2015

Hill NS, Preston IR, Roberts KE. Inhaled therapies for pulmonary hypertension. Respiratory Care 2015;60(6):794‐802. [PUBMED: 26070575 ]

Hutton 2000

Hutton JL, Williamson PR. Bias in meta‐analysis due to outcome variable selection within studies. Journal of the Royal Statistical Society. Series C, Applied Statistics 2000;49(3):359‐70. [DOI: 10.1111/1467‐9876.00197]

Jain 2006

Jain R, DalNogare A. Pharmacological therapy for acute respiratory distress syndrome. Mayo Clinic Proceedings 2006;81(2):205‐12. [PUBMED: 16471076]

Keus 2009

Keus F, Wetterslev J, Gluud C, Gooszen HG, van Laarhoven CJ. Robustness assessments are needed to reduce bias in meta‐analyses including zero‐event randomized trials. American Journal of Gastroenterology 2009;104(3):546‐51. [PUBMED: 19262513 ]

Lan 1983

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Linko R, Okkonen M, Pettilä V, Perttilä J, Parviainen I, Ruokonen E, et al. Acute respiratory failure in intensive care units. FINNALI: a prospective cohort study. Intensive Care Medicine 2009;35(8):1352‐61. [PUBMED: 19526218]

Luhr 1999

Luhr OR, Antonsen K, Karlsson M, Aardal S, Thorsteinsson A, Frostell CG, et al. Incidence and mortality after acute respiratory failure and acute respiratory distress syndrome in Sweden, Denmark, and Iceland. The ARF Study Group. American Journal of Respiratory and Critical Care Medicine 1999;159(6):1849‐61. [PUBMED: 10351930]

MacCallum 2005

MacCallum NS, Evans TW. Epidemiology of acute lung injury. Current Opinion in Critical Care 2005;11(1):43‐9. [PUBMED: 15659944]

Moloney 2003

Moloney ED, Evans TW. Pathophysiology and pharmacological treatment of pulmonary hypertension in acute respiratory distress syndrome. European Respiratory Journal 2003;21(4):720‐7. [PUBMED: 12762363]

Phua 2009

Phua J, Badia JR, Adhikari NK, Friedrich JO, Fowler RA, Singh JM, et al. Has mortality from acute respiratory distress syndrome decreased over time? A systematic review. American Journal of Respiratory and Critical Care Medicine 2009;179(3):220‐7. [PUBMED: 19011152]

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Referencias de otras versiones publicadas de esta revisión

Afshari 2009

Afshari A, Brok J, Møller AM, Wetterslev J. Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Cochrane Database of Systematic Reviews 2009, Issue 2. [DOI: 10.1002/14651858.CD007733]

Afshari 2010

Afshari A, Brok J, Møller AM, Wetterslev J. Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). Cochrane Database of Systematic Reviews 2010, Issue 8. [DOI: 10.1002/14651858.CD007733; PUBMED: 20687093]

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Jump to:

Dahlem 2004

Methods

2‐group cross‐over RCT, 1 centre.

ITT: yes.

Overall study quality: low risk of bias.

Sample size calculation: not reported.

Country: the Netherlands.

Participants

14 children included first after 24 hours of admission with ALI defined by the criteria of the American‐European Consensus Conference in 1994 (Bernard 1994).

Inclusion criteria: acute onset of respiratory failure; PaO2/FIO2 ratio ≤ 300 torr; no clinical signs of atrial hypertension (suspected clinically); bilateral infiltrates on chest radiographs, children intubated with endotracheal tubes with an internal diameter > 3.5 mm. ALI classified as either primary (intrapulmonary) or secondary (extrapulmonary) lung injury.

Exclusion criteria: congenital heart disease, decreased cardiac shortening fraction < 30%, mitral regurgitation, enlarged left atrium suspected to have raised left atrial pressure and cardiogenic pulmonary oedema, thrombocytopenia (< 50,000/L), bleeding diathesis, activated partial thromboplastin time > 43 seconds, intracranial haemorrhage, acute renal failure, chronic lung disease or poor prognosis with the probability of death, or withdrawal of therapy within the following 24 hours.

Interventions

Intervention group: 8 children, first treated with aerosolized prostacyclin (epoprostenol sodium), stepwise increase of doses (10, 20, 30, 40 and 50 ng/kg/minute) followed by normal saline (designated as placebo). Each dose administered over 20‐minute period, followed by 5‐minute period between each dose increment. To achieve washout, there was 30‐minute period between prostacyclin and placebo nebulization.

Control group: 6 children, initially treated with 5 doses of normal saline followed by aerosolized prostacyclin.

Ventilation strategy and weaning standardized. No cross‐over of treatment failures. Standard critical care therapy to both groups.

Outcomes

Primary outcomes: improved oxygenation.

Secondary outcomes: mortality, adverse effects, oxygenation index, FiO2, improved ventilation and respiratory variables, primary versus secondary lung injury, changes in haemodynamics, bleeding.

Notes

Aerosolized prostacyclin over < 24 hours did not reduce overall mortality at 28 days (RR 1.50, 95% CI 0.17 to 12.94, 14 participants) compared with aerosolized saline (total of 3 deaths).

Letter sent to authors in December 2009. Authors replied in December 2009. The authors were unable to provide additional information except data for the analysis of mortality based on origin of the lesion (primary versus secondary lung injury) without finding statistical significance. Length of longest follow‐up: 28 days.

Authors conclusion: "Aerosolized prostacyclin improves oxygenation in children with acute lung injury. Future trials should investigate whether this treatment will positively affect outcome."

Funding: not for profit.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Randomized by numbered envelopes, following a cross‐over randomization procedure.

Allocation concealment (selection bias)

Low risk

Sequentially numbered envelopes.

Blinding (performance bias and detection bias)
All outcomes

Low risk

Investigators and carers blinded to assignment of participants.

Incomplete outcome data (attrition bias)
All outcomes

Low risk

No withdrawals specified.

Selective reporting (reporting bias)

Unclear risk

Unable to assess based on available information.

Other bias

Low risk

Appeared free of such biases.

Siddiqui 2013

Methods

Single‐centre, RCT.

Country: Pakistan.

Participants

67 adults aged ≥ 18 years with ARDS.

Interventions

Intervention group: PGE1 (alprostadil) 20 μg in 5 mL normal saline in a nebulizer continuously over 30 minutes.

Control group: 5 mL normal saline in a nebulizer continuously over saline over 30 minutes.

Used concealed syringes.

Outcomes

Primary endpoint: proportion of participants achieving 25% improvement in diastolic dysfunction, left ventricular end diastolic pressure, pulmonary artery systolic pressures and PaO2/FiO2 ratio from baseline as measured by repeat transthoracic echo and arterial blood gas analysis 30 minutes after treatment.

No secondary outcomes.

Notes

Participant enrolment from May 2006 to February 2008. Contacted study author twice, 20 June 2016 and 24 March 2017 and received relevant response.

Study took place in an adult, multidisciplinary, "open‐policy," 11 bed ICU in a tertiary care hospital of Karachi, Pakistan. The authors stated that measurement of pulmonary artery pressure was carried out with the application of echocardiography instead of pulmonary artery catheterization with the inherent risk of inaccuracies and bias in regards to measurements and inter‐observer variability. However, we were advised to approach the authors due to some questions in regards to the accuracy of the reported values of the pulmonary artery pressures in the publication (> 80 mmHg in both the intervention and control group). It became apparent that the authors had mistakenly reported on the systemic vascular mean systolic pressure and not the mean pulmonary artery systolic pressure. Furthermore, the authors provided additional information on lack of mortality data during the trial follow‐up. The trial was funded by the Pakistan Medical Research Council.

Risk of bias

Bias

Authors' judgement

Support for judgement

Random sequence generation (selection bias)

Low risk

Parallel‐group study with balanced randomizations from a computer‐generated randomization list.

Allocation concealment (selection bias)

Low risk

Independent pharmacists dispensed either the intervention or the control from pharmacy in a syringe form concealed with aluminium foil.

Blinding (performance bias and detection bias)
All outcomes

Low risk

All investigators, staff and participants were masked to outcome measurements and allocation.

Incomplete outcome data (attrition bias)
All outcomes

Unclear risk

All randomized participants seemed to be accounted for in the tables. However, the authors were unable to report data on mean artery pulmonary pressure and had provided data on systemic artery pressure instead in the manuscript.

Selective reporting (reporting bias)

Low risk

Trial registration available on ClinicalTrials.gov: NCT00314548.

Other bias

Low risk

Appeared free of other bias.

For explanation of acronyms and abbreviations used in this table, see Appendix 1.

Characteristics of excluded studies [ordered by study ID]

Jump to:

Study

Reason for exclusion

Abraham 1996

Randomized, multicentre, double‐blind, placebo‐controlled, phase II clinical trial of intravenous liposomal PGE1 versus placebo for people with ARDS. No inhalational therapy of prostacyclin.

Abraham 1999

Multicentre, double‐blind, placebo‐controlled, phase III clinical trial; 350 people with ARDS randomized to receive either liposomal PGE1 or placebo. No inhalational therapy of prostacyclin.

Ammar 2015

Retrospective, non‐interventional cohort study. 94 participants included, with 47 participants receiving prostacyclin and 47 receiving placebo. Reason for exclusion: retrospective study.

Archer 1996

Randomized, placebo‐controlled trial of intravenous prostacyclin in acute respiratory failure in people with COPD. No inhalational therapy of prostacyclin.

Bein 1994

Case report. No randomization.

Boeck 2012

Randomized, double‐blind, cross‐over study; 16 people with COPD randomized to either a single dose of iloprost 10 mg (low dose), iloprost 20 mg (high dose) or placebo. All participants excluded because of chronic lung disease.

Bone 1989

Randomized double‐blind, multicentre study of intravenous PGE1 in people with the ARDS versus placebo. No inhalational therapy of prostacyclin. There are multiple publications in different journals based on this trial.

Domenighetti 2001

Prospective, non‐randomized interventional study examining the effect of inhaled prostacyclin in 15 consecutive, mechanically ventilated people with ARDS and severe hypoxaemia.

Dunkley 2013

16 participants in an observational study. Reason for exclusion: retrospective study.

Eichelbrönner 1996

Randomized, interventional clinical study comparing INO and aerosolized prostacyclin on haemodynamics and gas exchange in people with septic shock and pulmonary hypertension. Excluded since majority of participants did not have ARDS or ALI.

Holcroft 1986

Randomized, placebo‐controlled, double‐blind trial of intravenous PGE1 in surgical participants with ARDS. No inhalational therapy of prostacyclin.

Liu 2015

28 adults with end‐stage cirrhosis (18 men and 10 women) underwent modified piggyback liver transplantations. Reason for exclusion: observational study on elective patients.

Meyer 1998

15 people with ALI treated with PGE1 inhalation in addition to standard intensive care. No randomization.

NCT00981591

Trial terminated prior to enrolment. Accessed 26 April 2016.

Pappert 1995

Case report. No randomization.

Putensen 1998

10 people with ARDS received in random order: nitric oxide inhalation, aerosolized PGE1, infusion of PGE1 or no intervention. No control group and thus not an RCT.

Rossignon 1990

Randomized double‐blind placebo‐controlled study on the activity of intravenous PGE1 in people with ARDS. No inhalational therapy with prostacyclin.

Sawheny 2013

Prospective, non‐randomized interventional study examining the effect of nebulized iloprost in 20 people admitted to medical and surgical ICUs. No control group.

Shoemaker 1986

Case report. PGE1 infusion. No randomization.

Sood 2014

RCT enrolling only neonates and therefore excluded. All 7 participants INO prior to enrolment. 4 participants received pulmonary vasodilators (milrinone, sildenafil), 1 participant, randomized to high‐dose inhaled PGE1 received low‐dose inhaled PGE1 for the first 24 hours, thereafter high‐dose inhaled PGE1. 5/7 participants received surfactant. 5/7 received neuromuscular blockade and 4/7 received steroids before randomization. 6 participants received extracorporeal membrane oxygenation.

Torbic 2013

Retrospective, single‐centre analysis of mechanically ventilated adults receiving INO or PGI2 for improvement in oxygenation; 105 mechanically ventilated people evaluated. Retrospective analysis and thus not an RCT.

Torbic 2016

Same cohort as Torbic 2013.

Van Heerden 1996

Case report. Comparison of INO and inhaled prostacyclin. No randomization.

Van Heerden 2000

Unblinded, non‐randomized interventional, prospective clinical study of inhaled aerosolized prostacyclin in people with ARDS.

Vassar 1991

Double‐blind, placebo‐controlled trial evaluating the efficacy of early infusion of PGE1 for reducing the incidence of severe respiratory failure and mortality. No inhalational prostacyclin therapy.

Vincent 2001

Multicentre, randomized, double‐blind, placebo‐controlled clinical study evaluating the safety of intravenous liposomal PGE1 (TLC C‐53) in people with ARDS. No inhalational therapy of prostacyclin.

Walmrath 1995

Trial examining the effects of aerosolized PGI2 on gas exchange and haemodynamics in mechanically ventilated people with severe community‐acquired pneumonia. Both groups received active treatment of inhalational prostacyclin. No control group.

Walmrath 1996

16 people with ARDS selected to receive initially either INO and then inhaled PGI2, or vice versa for very short period of time. No control group.

Zwissler 1996

Case report of 8 participants receiving both inhaled prostacyclin and INO at various concentration. Not an RCT.

For explanation of acronyms and abbreviations used in this table, see Appendix 1.

Study flow diagram.
Figures and Tables -
Figure 1

Study flow diagram.

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.
Figures and Tables -
Figure 2

Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies.

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.
Figures and Tables -
Figure 3

Methodological quality summary: review authors' judgements about each methodological quality item for each included study.

Summary of findings for the main comparison. Aerosolized prostacyclin compared to placebo for acute respiratory distress syndrome (ARDS)

Aerosolized prostacyclin compared to placebo for acute respiratory distress syndrome (ARDS)

Patient or population: people with ARDS

Setting: intensive care unit in the Netherlands and Pakistan

Intervention: aerosolized prostacyclin

Comparison: placebo

Outcomes

Anticipated absolute effects* (95% CI)

Relative effect
(95% CI)

No of participants
(studies)

Quality of the evidence
(GRADE)

Comments

Risk with control

Risk with aerosolized prostacyclin

Mortality

Study population

RR 1.50
(0.17 to 12.94)

14
(1 study)

⊕⊝⊝⊝
Very low1,2,3,4

Only 1 small paediatric trial with cross‐over design provided mortality data (Dahlem 2004). Thus, no meta‐analysis carried out.

167 per 1000

250 per 1000
(28 to 1000)

PaO2/FiO2 ratio5

MD 25.35 lower
(60.48 lower to 9.78 higher)

67
(1 study)

⊕⊝⊝⊝
Very low6

Only 1 trial provided data (Siddiqui 2013). Thus, no meta‐analysis was carried out.

Improvement in mean pulmonary arterial pressure

No data is available for meta‐analysis (Characteristics of included studies, Siddiqui 2013)

Adverse events7

81

(2 studies)

⊕⊝⊝⊝
Very low8

Only descriptive assessment of safety with no available data to carry out meaningful analyses (Dahlem 2004; Siddiqui 2013).

*The risk in the intervention group (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI).

CI: confidence interval; FiO2: fraction of inspired oxygen; MD: mean difference; PaO2: partial pressure of oxygen in arterial blood; RR: risk ratio.

GRADE Working Group grades of evidence
High quality: we are very confident that the true effect lies close to that of the estimate of the effect.
Moderate quality: we are moderately confident in the effect estimate: The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different.
Low quality: our confidence in the effect estimate is limited: The true effect may be substantially different from the estimate of the effect.
Very low quality: we have very little confidence in the effect estimate: The true effect is likely to be substantially different from the estimate of effect.

1Mortality at 28 to 30 days.

2Required information size for paediatric population depending on the level of heterogeneity adjustment was between 2897 (I2 = 0) and 3862 (I2 = 25%).
3Required information size for the adult population depending on the same level of heterogeneity was between 1132 (I2 = 0) and 1508 (I2 = 25%).

4This outcome was downgraded from high to low quality of evidence due to limitations in design (small sample size, few events, cross‐over design) suggesting high likelihood of bias, indirectness of evidence and high probability of publication bias. (Dahlem 2004).

5Despite the fact that biochemical markers of clinical outcomes are often not included in SoF tables, we have chosen to include this outcomes since it is widely used in clinical practice to guide treatment.

6The outcome was downgraded two levels (from high to very low quality of evidence) for very serious imprecision due to small sample size, few events and wide 95% CI suggesting high likelihood of bias and indirectness of evidence. (Siddiqui 2013).

7Adverse events such as bleeding or organ dysfunction

8The outcome was downgraded two levels (from high to very low quality of evidence) for very serious imprecision due to small sample size and few events and since only descriptive assessment of safety and adverse events were provided in the included trials with no data being available for meta‐analyses.

Figures and Tables -
Summary of findings for the main comparison. Aerosolized prostacyclin compared to placebo for acute respiratory distress syndrome (ARDS)