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Aerosolized prostacyclin for acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)

  1. Arash Afshari1,*,
  2. Jesper Brok2,
  3. Ann Merete Møller3,
  4. Jørn Wetterslev4

Editorial Group: Cochrane Anaesthesia Group

Published Online: 4 AUG 2010

Assessed as up-to-date: 23 JUN 2010

DOI: 10.1002/14651858.CD007733.pub2


How to Cite

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. Art. No.: CD007733. DOI: 10.1002/14651858.CD007733.pub2.

Author Information

  1. 1

    Rigshospitalet, The Cochrane Anaesthesia Review Group & Copenhagen Trial Unit and Department of Paediatric and Obstetric Anaesthesia, Copenhagen, Denmark

  2. 2

    Rigshospitalet, Paediatric Department 4072, Copenhagen, Denmark

  3. 3

    Herlev University Hospital, The Cochrane Anaesthesia Review Group, Rigshospitalet & Department of Anaesthesiology, Herlev, Denmark

  4. 4

    Rigshospitalet, Copenhagen University Hospital, Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7812, Copenhagen, Denmark

*Arash Afshari, The Cochrane Anaesthesia Review Group & Copenhagen Trial Unit and Department of Paediatric and Obstetric Anaesthesia, Rigshospitalet, Blegdamsvej 9, Afsnit 3342, rum 52, Copenhagen, 2100, Denmark. arriba.a@gmail.com. afshari@rocketmail.com.

Publication History

  1. Publication Status: Edited (no change to conclusions)
  2. Published Online: 4 AUG 2010

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Characteristics of included studies [ordered by study ID]
Dahlem 2004

MethodsTwo-group parallel RCT, one centre
ITT: Yes

Funding: not for profit
Overall study quality: low risk of bias
Sample size calculation was not reported.


Participants14 children included first after 24 hours of admission with acute lung injury defined by the criteria of the American-European consensus conference in 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 was classified as either primary (intrapulmonary) or secondary (extrapulmonary) lung injury.

Exclusion criteria: congenital heart disease, decreased cardiac shortening fraction < 30%, mitral regurgitation, and/or 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 hrs.


InterventionsIntervention group: 8 patients, first treated with aerosolized prostacyclin (epoprostenol sodium), stepwise increase of doses (10, 20, 30, 40 and 50 ng/kg/min) followed by normal saline (designated as placebo). Each dose was administered during a 20-min period, followed by a 5-min period between each dose increment. In order to achieve washout, there was a 30-min period between the prostacyclin and the placebo nebulization.

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

Ventilation strategy and weaning standardized. no crossover of treatment failures. Standard critical care therapy to both groups.


OutcomesPrimary outcomes: improved oxygenation

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


NotesCountry: the Netherlands

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."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Low riskAdequate

Allocation concealment (selection bias)Low riskAdequate, sequentially numbered envelopes following a crossover randomization procedure

Blinding (performance bias and detection bias)
All outcomes
Low riskAdequate, Investigators and caregivers were blinded to the assignment of the patients

Incomplete outcome data (attrition bias)
All outcomes
Low risk

Selective reporting (reporting bias)Low risk

Other biasLow risk

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Abraham 1996Randomized, prospective, multicentre, double-blind, placebo-controlled, phase II clinical trial of intravenous liposomal prostaglandin E-1 versus placebo for patients with ARDS. No inhalational therapy of prostacyclin.

Abraham 1999Prospective, multicentre, double-blind, placebo-controlled, phase III clinical trial. 350 patients with ARDS were randomized to receive either liposomal prostaglandin E1 or placebo. No inhalational therapy of prostacyclin.

Archer 1996A randomized, prospective, placebo-controlled trial of intravenous prostacyclin (PGI-2) in acute respiratory failure in COPD patients. No inhalational therapy of prostacyclin.

Bein 1994Case report. No randomization.

Bone 1989Randomized double-blind, multicentre study of intravenous prostaglandin E(1) in patients with the ARDS versus placebo. No inhalational therapy of prostacyclin. There are multiple publications in different journals based on this trial.

Domenighetti 2001Prospective, non-randomized interventional study examining the effect of inhaled prostacyclin (PGI(2)) in 15 consecutive, mechanically ventilated patients with ARDS and severe hypoxaemia.

Eichelbrönner 1996Prospective, randomized, interventional clinical study comparing the effects of inhaled nitric oxide and aerosolized prostacyclin (PGI(2)) on haemodynamics and gas exchange in patients with septic shock and pulmonary hypertension. Excluded since majority of the patients did not have ARDS or ALI.

Holcroft 1986A prospective, randomized, placebo-controlled, double-blinded trial of intravenous prostaglandin E1 (PGE(1)) in surgical patients with ARDS. No inhalational therapy of prostacyclin.

Meyer 1998Fifteen patients with ALI were treated with PGE1 inhalation in addition to standard intensive care. No randomization.

Pappert 1995Case report. No randomization.

Putensen 1998Ten patients with ARDS received in random order: nitric oxide (NO) inhalation, aerosolized prostaglandin E1 (PGE1), infusion of PGE1, or no intervention. No control group and thus not a RCT.

Rossignon 1990Randomized double-blind placebo-controlled study on the activity of intravenous administration of prostaglandin E1 (PGE1) in patients with ARDS. No inhalational therapy with prostacyclin.

Shoemaker 1986Case report. Prostaglandin E1 (PGE(1)) infusion. No randomization.

Van Heerden 1996Case report. Comparison of Inhaled nitric oxide and Inhaled prostacyclin. No randomization.

Van Heerden 2000Unblinded, non-randomized interventional, prospective clinical study of inhaled aerosolized prostacyclin in ARDS.

Vassar 1991Prospective, double-blind, placebo-controlled trial evaluating the efficacy of early infusion of PGE(1) for reducing the incidence of severe respiratory failure and mortality. No inhalational prostacyclin therapy.

Vincent 2001A multi-centre, randomized, double-blind, placebo-controlled clinical study evaluating the safety of intravenous liposomal PGE1 (TLC C-53) in patients with ARDS. No inhalational therapy of prostacyclin.

Walmrath 1995A trial examining the effects of aerosolized prostaglandin (PGI 2) on gas exchange and haemodynamics in patients ventilated mechanically because of severe community-acquired pneumonia. Both groups received active treatment of inhalational prostacyclin. No control group.

Walmrath 199616 patients with ARDS were randomized to receive either first inhaled nitric oxide and then inhaled PGI-2, or vice versa for very short period of time. Not a RCT.

Zwissler 1996Case report of eight patients receiving both inhaled prostacyclin (PGI2) and inhaled nitric oxide at various concentration. Not a RCT.

 
Characteristics of ongoing studies [ordered by study ID]
Siddiqui 2009

Trial name or titleInhaled Prostacyclin for Adult Respiratory Distress Syndrome (ARDS) and pulmonary hypertension

MethodsRandomized, double blind (subject, caregiver, investigator, outcome assessor), placebo control, parallel assignment, safety/efficacy study

ParticipantsAll patients with ARDS (PaO2/FiO2 < 200 - arterial hypoxaemia, bilateral infiltrates on chest x-ray, wedge pressure < 20 on swan ganz parameters) or signs of heart failure; all patients admitted to ICU with pulmonary hypertension (mean pulmonary artery pressure > 35 mmHg). Age > 16 years

InterventionsInhaled prostacyclin (Iloprost) versus inhaled saline. Standard critical care according to various protocols applied to both groups

OutcomesImproved respiratory outcome, decreased pulmonary artery pressure

Starting dateMay 2006

Contact informationDr. Shahla Siddiqui, MBBS, DABA, principal investigator, Aga Khan University hospital, Karachi, Pakistan

E-mail: shahla.siddiqui@aku.edu

NotesLetter sent to authors in December 2009. Authors replied in December 2009. Study is completed and data is being analysed. No data have been published at this stage.

Yung 2010

Trial name or titleA randomized, double blind, placebo-controlled pilot study of the safety and effective dosing of inhaled Iloprost in Pediatric Critical Care Patients with pulmonary hypertension treated with inhaled nitric oxide

MethodsRandomized, double blind (subject, caregiver, investigator), placebo control, parallel assignment, safety/efficacy study

ParticipantsPatients with pulmonary hypertension, ARDS, neonatal hypoxic respiratory failure, persistent pulmonary hypertension of newborn, congenital heart defects

InterventionsInhaled Iloprost versus placebo

OutcomesPrimary: safety and effective dosing of inhaled iloprost in mechanically ventilated paediatric patients with pulmonary hypertension. Duration of time that the subject is receiving study drug

Secondary: Time to wean off INO, time to extubation, total cost of INO, incidence of rebound phenomenon, time to ICU discharge

Starting dateSeptember 2009

Contact informationDelphine Yung, MD, Principal investigator, Seattle Children's Hospital, USA

E-mail: delphine.yung@seattlechildrens.org

Michelle L. Russo, RN

E-mail: michelle.russo@seattlechildrens.org

NotesLetter sent to authors in December 2009. Reply received in January 2010. The trial is ongoing.

 
Summary of findings for the main comparison. Mortality for patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)

Mortality for Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)

Patient or population: patients with Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
Settings: Critical Care
Intervention: Mortality

OutcomesIllustrative comparative risks* (95% CI)Relative effect
(95% CI)
No of Participants
(studies)
Quality of the evidence
(GRADE)
Comments

Assumed riskCorresponding risk

ControlMortality

28 days mortality, paediatric, low bias trialStudy populationRR 1.5
(0.17 to 12.94)
14
(1 study)
⊕⊕⊝⊝
low1,2,3,4

167 per 1000251 per 1000
(28 to 1000)

Medium risk population

167 per 1000251 per 1000
(28 to 1000)

*The basis for the assumed risk (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (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; RR: Risk ratio;

GRADE Working Group grades of evidence
High quality: Further research is very unlikely to change our confidence in the estimate of effect.
Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate.
Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate.
Very low quality: We are very uncertain about the estimate.

 1 Only one small paediatric trial was found. There are two ongoing RCTs (one adult and one paediatric).
2 There is insufficient evidence to demonstrate any benefits or harms of inhaled prostacyclin therapy
3 The required information size for paediatric population depending on the level of heterogeneity adjustment is between 2897 (I2=0) and 3862 (I2=25%)
4 The required information size for the adult population depending on the same level of heterogeneity is between 1132 (I2=0) and1508 (I2=25%).
 
Table 1. Causes of ALI and ARDS

Most common causes of ALI and ARDS

Burns, massive transfusions, multiple trauma, aspiration of gastric contents, pancreatitis, inhalation injury, nosocomial pneumonia, sepsis, drug overdose and near drowning (Ware 2000)

 
Table 2. Abbreviations

Abbreviations

ARDS = acute respiratory distress syndrome; ALI = acute lung injury; CI = confidence interval; cm = centimetre; CINAHL = Cumulative Index to Nursing & Allied Health Literature; CMV = conventional mechanical ventilation; COPD = chronic obstructive lung disease; ECMO = extracorporeal membrane oxygenation; FiO2 = fraction of inspired oxygen; ICU = intensive care unit; INO = inhaled nitric oxide; ITT = intention to treat analysis; LBHIS = low bias heterogeneity adjusted information size; LILACS = Latin American Caribbean Health Sciences Literature; MAP = mean arterial pressure; ml/kg = millilitres per kilogram; MPAP = mean arterial pulmonary pressure; ng: nanograms; PaCO2 = partial pressure of carbon dioxide in arterial blood; PaO2 = partial pressure of oxygen in arterial blood; PAOP = pulmonary artery occlusion pressure; PEEP = positive end expiratory pressure; P/F ratio = PaO2/FiO2; ppm: parts per million; PGE1 = prostaglandin E1; PGI2 = prostacyclin or epoprostenol or Flolan; PVR = pulmonary vascular resistance; RCT = randomized controlled trial; RD = risk difference; RR = relative risk; RRI = relative risk increase; RRR = relative risk reduction; SVR = systemic vascular resistance; TSA = trial sequential analysis; WMD = weighted mean difference

 
Table 3. Mortality: inhaled prostacyclin versus placebo, single study analyses

Subgroup analysisStudyParticipantsStatistical MethodEffect Estimate

28-day mortality (complete case analysis)Dahlem 200414Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.17, 12.94]

Primary lung injuryDahlem 20046Risk Ratio (M-H, Fixed, 95% CI)Not estimable

Secondary lung injuryDahlem 20048Risk Ratio (M-H, Fixed, 95% CI)1.20 [0.17, 8.24]

Random sequence generation (adequate)Dahlem 200414Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.17, 12.94]

Allocation concealment (adequate)Dahlem 200414Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.17, 12.94]

Blinding (adequate)Dahlem 200414Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.17, 12.94]

Follow up (complete)Dahlem 200414Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.17, 12.94]

Sample size calculation (inadequate)Dahlem 200414Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.17, 12.94]

Funding bias (not for profit)Dahlem 200414Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.17, 12.94]

Overall risk of bias (low)Dahlem 200414Risk Ratio (M-H, Fixed, 95% CI)1.50 [0.17, 12.94]