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

  • Review
  • Intervention

Authors

  • Arash Afshari,

    Corresponding author
    1. Rigshospitalet, The Cochrane Anaesthesia Review Group & Copenhagen Trial Unit and Department of Paediatric and Obstetric Anaesthesia, 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.

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  • Jesper Brok,

    1. Rigshospitalet, Paediatric Department 4072, Copenhagen, Denmark
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  • Ann Merete Møller,

    1. Herlev University Hospital, The Cochrane Anaesthesia Review Group, Rigshospitalet & Department of Anaesthesiology, Herlev, Denmark
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  • Jørn Wetterslev

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

Background

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical conditions that are associated with high mortality and morbidity. Aerosolized prostacyclin has been used to improve oxygenation despite the limited evidence available so far.

Objectives

To systematically assess the benefits and harms of aerosolized prostacyclin in critically ill patients with ALI and ARDS.

Search methods

We identified randomized clinical trials (RCTs) from electronic databases: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 1); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; and the Chinese Biomedical Literature Database (to 31st January 2010). We contacted trial authors and manufacturers in the field.

Selection criteria

We included all RCTs, irrespective of blinding or language, that compared aerosolized prostacyclin with no intervention or placebo in either children or adults with ALI or ARDS.

Data collection and analysis

Two authors independently abstracted data and resolved any disagreements by discussion. We presented pooled estimates of the intervention effects as relative risks (RR) with 95% confidence intervals (CI) for dichotomous outcomes. Our primary outcome measure was all cause mortality. We planned to perform subgroup and sensitivity analyses to assess the effect of aerosolized prostacyclin in adults and children, and on various clinical and physiological outcomes. We assessed the risk of bias through assessment of methodological trial components and the risk of random error through trial sequential analysis.

Main results

We included one paediatric RCT with low risk of bias and involving a total of 14 critically ill children with ALI or ARDS. Aersosolized prostacyclin over less than 24 hours did not reduce overall mortality at 28 days (RR 1.50, 95% CI 0.17 to 12.94) compared with aerosolized saline (a total of three deaths). The authors did not encounter any adverse events such as bleeding or organ dysfunction. We were unable to perform the prespecified subgroups and sensitivity analyses or trial sequential analysis due to the limited number of RCTs. We were also not able to assess the safety and efficacy of aerosolized prostacyclin for ALI and ARDS. We found two ongoing trials, one involving adults and the other paediatric participants. The adult trial has been finalized but the data are not yet available.

Authors' conclusions

There is no current evidence to support or refute the routine use of aerosolized prostacyclin for patients with ALI and ARDS. There is an urgent need for more randomized clinical trials.

Résumé scientifique

Prostacycline administrée en aérosol en cas de lésion pulmonaire aigüe (LPA) et de syndrome de détresse respiratoire aigüe (SDRA)

Contexte

La lésion pulmonaire aigüe (LPA) et le syndrome de détresse respiratoire aigüe (SDRA) sont des affections graves qui sont associées à des taux de mortalité et de morbidité élevés. La prostacycline administrée en aérosol a été utilisée pour améliorer l'oxygénation en dépit des preuves limitées disponibles à ce jour.

Objectifs

Evaluer systématiquement les bénéfices et les préjudices de la prostacycline administrée en aérosol chez les patients gravement malades avec une LPA et un SDRA.

Stratégie de recherche documentaire

Nous avons identifié les essais cliniques randomisés (ECR) à partir des bases de données électroniques : le registre Cochrane des essais contrôlés - Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Numéro 1); MEDLINE; EMBASE; Science Citation Index Expanded; International Web of Science; CINAHL; LILACS; et le Chinese Biomedical Literature Database (jusqu'au 31 janvier 2010). Nous avons contacté des auteurs et des fabricants du domaine.

Critères de sélection

Nous avons inclus tous les ECR, quelque soit la mise en aveugle ou la langue, qui comparaient la prostacycline administrée en aérosol à l'absence d'intervention ou à un placebo soit chez les enfants, soit chez les adultes avec une LPA ou un SDRA.

Recueil et analyse des données

Deux auteurs ont indépendamment extrait les données et résolu les désaccords par la discussion. Nous avons présenté les estimations regroupées des effets de l'intervention en tant que risques relatifs (RR) avec des intervalles de confiance (IC) à 95 % pour les critères des jugements dichotomiques. Notre principal critère de jugement était la mortalité toutes causes. Nous avons prévu de réaliser des analyses de sous-groupes et de sensibilité afin d'évaluer l'effet de la prostacycline administrée par aérosol chez les adultes et les enfants, et sur différents critères de jugement cliniques et physiologiques. Nous avons évalué le risque de biais par l'évaluation des composants méthodologiques des essais et le risque d'erreur randomisée par une analyse séquentielle des essais.

Résultats principaux

Nous avons inclus un ECR pédiatrique à faible risque de biais qui impliquait un total de 14 enfants gravement malades avec une LPA ou un SDRA. La prostacycline administrée par aérosol sur une période inférieure à 24 heures n'a pas réduit la mortalité globale à 28 jours (RR 1,50, IC à 95 % 0,17 à 12,94) par rapport à une solution saline aérosolisée (un total de trois décès). Les auteurs n'ont pas signalé d'évènements indésirables comme des saignements ou un dysfonctionnement des organes. Nous n'avons pas été capables de réaliser les analyses de sous-groupes et de sensibilité pré-spécifiées ou l'analyse séquentielle des essais en raison du nombre limité d'ECR. Nous n'avons pas non plus été capables d'évaluer l'innocuité et l'efficacité de la prostacycline administrée en aérosol pour la LPA ou le SDRA. Nous avons trouvé deux essais en cours, un impliquant des adultes et l'autre des participants pédiatriques. L'essai sur les adultes a été finalisé mais les données ne sont pas encore disponibles.

Conclusions des auteurs

Il n'existe actuellement aucune preuve permettant de soutenir ou de réfuter l'utilisation de routine de la prostacycline administrée en aérosol pour les patients avec une LPA ou un SDRA. Il est urgent de réaliser d'autres essais cliniques randomisés.

Plain language summary

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

The clinical research is insufficient to support the routine use of inhaled prostacyclin for acute lung injury and acute respiratory distress syndrome in critically ill children or adults with low blood oxygen levels. Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are critical respiratory conditions that are triggered by respiratory viral infections or develop following burns, massive transfusions, multiple trauma, aspiration of gastric contents, pancreatitis, inhalation injury, sepsis, drug overdose and near drowning.

Prostacyclin is a naturally occurring short acting prostaglandin that can improve blood flow and oxygenation in the lungs and reduce inflammation. Prostaglandins are lipid mediators that are derived from essential fatty acids and have important functions. They have important effects on the endothelium of blood vessels, platelets, uterine and mast cells and are found in virtually all tissues and organs. Administration of inhalable prostacyclins requires continuous aerosols over a period of hours to several days, usually during mechanical ventilation. Little of the inhaled prostacyclin reaches the systemic blood circulation although the drug solution may act as a potential irritant due to its very alkaline pH.

We identified one randomized clinical trial with low risk of bias that involved a total of 14 critically ill children with ALI or ARDS. Aerosolized prostacyclin over less than 24 hours did not reduce deaths at 28 days when compared with giving aerosols of saline (a total of three deaths occurred). The authors reported no bleeding or organ dysfunction adverse events. Two trials, one involving adults and the other children, are still to be completed.

Résumé simplifié

Prostacycline administrée en aérosol en cas de lésion pulmonaire aigüe (LPA) et de syndrome de détresse respiratoire aigüe (SDRA)

Les recherches cliniques sont insuffisantes pour pouvoir soutenir l'utilisation de routine de la prostacycline inhalée en cas de lésion pulmonaire aigüe et de syndrome de détresse respiratoire aigüe chez les enfants ou les adultes gravement malades avec des niveaux bas d'oxygène dans le sang. La lésion pulmonaire aigüe (LPA) et le syndrome de détresse respiratoire aigüe (SDRA) sont des affections respiratoires graves qui sont déclenchées par des infections virales respiratoires et qui se développent après des brûlures, des transfusions massives, des traumatismes multiples, une aspiration du contenu gastrique, une pancréatite, une lésion d'inhalation, une septicémie, une overdose de drogue ou une quasi-noyade.

La prostacycline est une prostaglandine à action rapide naturelle qui peut améliorer le flux sanguin et l'oxygénation dans les poumons et réduire l'inflammation. Les prostaglandines sont des médiateurs lipidiques dérivés des acides gras essentiels qui ont des fonctions importantes. Ils ont des effets importants sur l'endothélium des vaisseaux sanguins, les plaquettes, les cellules utérines et les mastocytes, on les retrouve dans quasiment tous les tissus et tous les organes. L'administration des prostacyclines inhalables requiert l'utilisation d'aérosols en continu pendant une période pouvant aller de quelques heures à plusieurs jours, généralement pendant une ventilation mécanique. Une quantité infime de prostacycline inhalée atteint la circulation sanguine systémique bien que la solution médicamenteuse puisse agir comme un irritant potentiel en raison de son pH alcalin très élevé.

Nous avons identifié un essai clinique randomisé à faible risque de biais qui impliquait un total de 14 enfants gravement malades avec une LPA ou un SDRA. La prostacycline administrée en aérosol pendant moins de 24 heures n'a pas réduit la mortalité à 28 jours par rapport aux aérosols de solution saline (un total de trois décès a été signalé). Les auteurs n'ont mentionné aucun saignement ou dysfonctionnement d'organes dans les évènements indésirables. Deux essais, un impliquant des adultes et l'autre des enfants, doivent toujours être complétés.

Notes de traduction

Traduit par: French Cochrane Centre 5th March, 2013
Traduction financée par: Instituts de Recherche en Sant� du Canada, Minist�re de la Sant� et des Services Sociaux du Qu�bec, Fonds de recherche du Qu�bec Sant� et Institut National d'Excellence en Sant� et en Services Sociaux

Summary of findings(Explanation)

Summary of findings for the main comparison. Mortality for patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS)
  1. 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%).

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)
⊕⊕⊝⊝
low 1,2,3,4
 
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.

Background

Description of the condition

Acute respiratory distress syndrome (ARDS) affects both children and adults. it is the result of an inflammatory process where the end-organ affected by the inflammatory cascade is the lung and its alveolar-capillary units (Anderson 2003). ARDS is a complication of a direct (primary) or indirect (secondary) lung injury caused by burns, massive transfusions, multiple trauma, aspiration of gastric contents, pancreatitis, inhalation injury, nosocomial pneumonia, sepsis, drug overdose and near drowning (Jain 2006; Ware 2000) (Table 1). Various definitions of ARDS exist (Murray 1988) in the literature, with the most recent established in 1994 (Bernard 1994). ARDS is defined by non-cardiogenic pulmonary oedema, severe acute hypoxaemia (P/F ratio < 200 (ratio of partial pressure of oxygen in arterial blood (PaO2) to fraction of inspired oxygen (FiO2)) and bilateral infiltrates on chest radiography without evidence of congestive heart failure including a pulmonary artery occlusion pressure (PAOP) ≤ 18 mm Hg (Bernard 1994). Acute lung injury (ALI) is a more benign form of ARDS with a P/F ratio < 300. The incidence of ALI and ARDS is reported to be between 14 and 86 persons per 10,0000 per year in the general population (Luhr 1999; Rubenfeld 2005); but a recent report from Finland indicates a smaller incidence of ALI and ARDS of 10.6 and 5.0 per 100,000 per year, respectively (Linko 2009). Previously mortality was very high (80% to 90%) but has dropped to 25% to 58%, depending on the underlying health status of the patient, due to improved treatment regimens (Anderson 2003; MacCallum 2005). A recent systematic review indicated a mortality rate of 44.0% (95% confidence interval (CI) 40.1 to 47.5) from observational studies, and 36.2% (95% CI 32.1 to 40.5) from randomized clinical trials (Phua 2009).

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)

In paediatric settings, recent evidence indicates that the incidence of ARDS and ALI is around 12 cases per 100,000 per year (Zimmerman 2009). In-hospital mortality is reported to be around 18% to 23%, with pneumonia, aspiration and sepsis as the primary cause of the condition (Dahlem 2003; Dahlem 2007; Flori 2005; Zimmerman 2009).

Inflammatory injuries (Table 1) disrupt the capillary endothelium and alveolar epithelia leading to neutrophil invasion and alveolar oedema and collapse (exudative phase). The next stage (the proliferative stage) occurs at days 7 to 21 with initiation of lung repair and increased surfactant production. Patients experience dyspnoea and hypoxaemia at this stage, with or without ventilatory support. Some patients may then proceed to the fibrotic stage with a long-term need for ventilatory assist or oxygen therapy.

The worst prognosis is seen among patients with sepsis, multiple organ failure, are immunocompromised, and in whom oxygenation fails to improve after six days (TenHoor 2001; Ware 2000). Survivors tend to be young and their pulmonary function recovers gradually over a year (Piantadosi 2004). Many adult survivors have long-term abnormalities in pulmonary function and impaired quality of life (Anderson 2003; Angus 2001).

Description of the intervention

Prostaglandins are lipid mediators that are synthesized from essential fatty acids by cellular enzymes and have strong physiological properties. They have important effects on endothelium, platelet, uterine and mast cells and are found in virtually all tissues and organs.

Prostacyclin (PGI2), generic name epoprostenol (brand name Flolan) is a member of the family of lipid molecules known as eicosanoids. PGI2 is a naturally occurring prostaglandin that has vascular smooth muscle relaxant and has anti-inflammatory properties (it inhibits platelet aggregation and neutrophil adhesion). It is synthesized by vascular endothelial and smooth muscle cells within the lung and has an in vivo half-life of three to six minutes (Jain 2006). PGI2 is a potent vasodilator of the systemic and pulmonary vasculature resulting in reduction of right and left heart afterload (Siobal 2004) and can be administered by different routes such as: intravenous for pulmonary hypertension, and inhalational preparations for ALI and ARDS. Inhaled PGI2 appears to improve oxygenation; lower pulmonary vascular resistance (PVR) and mean pulmonary arterial pressure (MPAP); and reduce pulmonary shunt fraction (Siobal 2004). It might have potential benefits in resolving hypoxaemia from ALI or ARDS and in the treatment of pulmonary hypertension and right heart failure, similar to the indications for inhaled nitric oxide (Siobal 2004).

Iloprost is a stable, synthetic analogue of PGI2. It has a plasma half-life of 20 to 30 minutes, similar pulmonary and haemodynamic properties as PGI2 and can be administered as an intravenous or inhalable solution (Hoeper 2000).

During mechanical ventilation lasting from hours to several days, Inhalable prostacyclins require continuous aerosolization with specific nebulizers or periodic nebuliziation for example several times a day using long-acting prostacyclin (for example iloprost) (Siobal 2003).

Prostaglandin E1 (PGE1), generic name alprostadil (brand name Prostin) is a naturally occurring prostaglandin with anti-inflammatory capabilities. PGE1 is an arterial vasodilator, a platelet aggregation inhibitor and stimulates intestinal and uterine smooth muscle (Siobal 2004). It is mainly used to treat sexual dysfunction or as an intravenous treatment for neonates with congenital heart defects, in order to maintain patency of ductus arteriosus until surgery. Its half-life is 5 to 10 minutes and it is primarily removed by the pulmonary vascular bed. PGE1 leads to a decrease in MPAP, mean arterial pressure (MAP), PVR and systemic vascular resistance (SVR). It can also be used as an inhalable solution with the potential to improve oxygenation in patients with severe ARDS (Schuster 2008).

How the intervention might work

Aerosolized prostacyclins are potent vasodilators which reduce pulmonary arterial hypertension, improve right-heart function, redistribute pulmonary blood flow to ventilated segments of the lung with matching improvements in ventilation and perfusion to result in better oxygenation.

PGE1 and PGI2 seem to reduce obstruction of pulmonary microcirculation in ALI and ARDS and modulate the underlying inflammation due to their ability to reduce leukocyte adhesion, and antithrombotic and platelet disaggregation properties (Wetzel 1995). Inhaled prostacyclins cause minimal systemic vasodilation and, due to minor transfer to the vascular system, they may even have systemic anti-inflammatory and antithrombotic features and improve splanchnic oxygenation (Eichelbrönner 1996; Siobal 2004). However, the principle action of aerosolized prostacyclins is their property of selective vasodilation to reduce hypoxaemia.

Inhaled prostacyclins may result in an increased ventilation/perfusion mismatch, decreased oxygenation, systemic hypotension, bleeding, flushing, headache, nausea, vomiting and chest pain. However, there appear to be very few reported side effects from inhaled prostacyclins (Siobal 2004). PGI2 solution may act as a potential irritant due to its very alkaline pH. Prostacyclins have no known toxic metabolites.

Why it is important to do this review

ALI and ARDS are characterized by severe hypoxaemia from intrapulmonary shunting, pulmonary hypertension due to elevated PVR and areas with a low ventilation/perfusion ratio (Schuster 2008). Pulmonary hypertension is believed to be caused by mechanical obstruction of the pulmonary microcirculation by microthromboemboli (composed of platelets and leukocytes) and hypoxic pulmonary vasoconstriction due to alveolar and interstitial oedema triggered by inflammatory mediators (Moloney 2003).

Although patients with ALI or ARDS are a heterogeneous population, they are all characterized by having local and systemic inflammation that causes lung damage and fluid leakage across the alveolar-capillary barrier (Piantadosi 2004). This inflammation can result in multiple organ failure and death. Aerosolized prostacyclins are used because of the potential benefit of modifying the process of inflammation, preserving or restoring oxygen delivery and decreasing mortality in ALI and ARDS patients (Siobal 2004). Aerosolized prostacyclins are used as an alternative to inhaled nitric oxide (INO) due to various advantages (cost, setup and administration) but this strategy is controversial as the evidence for using prostacyclins is unclear. There are indications of harmful effects of INO in ARDS or ALI (Adhikari 2007; Afshari 2010; Barrington 2007).

There are no previous systematic reviews on this topic and, being a very costly treatment, the benefit and efficacy of aerosolized prostacyclin in patients with ALI or ARDS is still controversial and debated. The aim of this review is to assess whether aerosolized prostacyclin therapy is beneficial for patients with ALI and ARDS.

All abbreviations are explained in Table 2.

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

Objectives

We assessed the benefits and harms of aerosolized prostacyclin in adults and children with ALI or ARDS. Furthermore, we planned to look at various primary and secondary outcomes, conduct subgroup and sensitivity analyses, examine the role of bias and apply trial sequential analyses (TSA) to examine the level of evidence.

Methods

Criteria for considering studies for this review

Types of studies

We included parallel group, randomized clinical trials irrespective of publication status, blinding status or language. We contacted the investigators and the authors in order to retrieve relevant data. We planned to only include unpublished trials if trial data and methodological descriptions were either provided in written form or could be retrieved from the authors. We planned to exclude trials using quasi-randomization and observational studies.

Intravenous PGI2 and PGE1 are potent systemic and pulmonary vasodilators that act as potent platelet aggregation inhibitors. They increase the risk of bleeding and adversely affect ventilation to perfusion matching and oxygenation (Siobal 2004). Since aerosolized prostacylins are believed to have more selective properties with little systemic spillover, we chose not to include intravenous trials. Additionally, a recent updated systematic review failed to show any beneficial effect of intravenous PGE1 in patients with ARDS (Adhikari 2004).

Types of participants

We included patients defined as having ALI or ARDS according to the various definitions presented in the literature. We chose to accept the terms standard treatment of ALI and ARDS and critically ill patients as reported by many authors, despite ongoing controversy. We excluded neonatal patients with 'bronchopulmonary dysplasia' or 'chronic lung disease' due to the different pathophysiology, treatment, prognosis and progression of the disease.

Types of interventions

We included trials comparing aerosolized prostacyclins with placebo or no intervention in adults and children with ALI or ARDS. We chose to include any type or dose of aerosolized prostacyclin for any duration of administration. Any co-intervention was allowed if it was administered in both groups. We excluded trials if the only aim was to compare the efficacy of different doses or types of prostacyclins and which did not have a control group without prostacyclin administration.

We did not intend to compare aerosolized prostacyclin with INO since, in our view, this comparison justifies the need for a separate systematic review in light of the current controversy surrounding the use of INO for ARDS and ALI (Adhikari 2007; Afshari 2010 ). Indeed, we did not identify RCTs comparing aerosolized prostacyclin and INO.

Types of outcome measures

Primary outcomes

1.1 Overall mortality. We used the longest follow-up data from each trial regardless of the period of follow up.

1.2 Overall 28 day mortality. We planned to include data provided as 30 day mortality in the same analysis.

Secondary outcomes

2.1 Resolution of multiple organ failure (according to different organ dysfunction scores).

2.2 Bleeding events. We defined bleeding events as pulmonary or systemic bleeding requiring transfusion. We planned to count repeated transfusions in the same participant as a singular event.

2.3 Complications during the in-patient stay, e.g. hypotensive episodes, direct irritation on administration, thrombosis, congestive cardiac failure, myocardial infarction, renal failure, cerebrovascular accident.

2.4 Quality of life assessment, as defined by the authors in the included studies.

2.5 Duration of mechanical ventilation.

2.6 Improvement of respiratory failure (ventilator-free days).

2.7 Improvement in mean pulmonary arterial pressure (mm Hg).

2.8 PaO2/FiO2 ratio.

2.9 Oxygenation index defined as [100 x mean airway pressure/(PaO2/FiO2)] or [(mean airway pressure x FiO2 X 100)/systemic arterial oxygen tension].

2.10 Number of days in hospital.

2.11 Mean length of stay in an intensive care unit (ICU).

2.12 Cost benefit analyses.

Search methods for identification of studies

Electronic searches

We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2010, Issue 1); SilverPlatter MEDLINE (WebSPIRS) (1950 to 31 January 2010); SilverPlatter EMBASE (WebSPIRS) (1980 to 31 January 2010); SilverPlatter BIOSIS (WebSPIRS) (1993 to 31 January 2010); International Web of Science (1964 to 31 January 2010); Latin American Caribbean Health Sciences Literature (LILACS) (via BIREME) (1982 to 31 January 2010); the Chinese Biomedical Literature Database; and Cumulative Index to Nursing & Allied Health Literature (CINAHL) (via EBSCO host) (1980 to 31 January 2010).

We performed a systematic and sensitive search strategy to identify relevant randomized clinical trials with no language or date restrictions.

For specific information regarding our search strategies please see Appendix 1.

We searched for ongoing clinical trials and unpublished studies on the following Internet sites:

  1. Current Controlled Trials;

  2. ClinicalTrials.gov;

  3. http://www.centerwatch.com.

Searching other resources

We handsearched the reference lists of reviews, randomized and non-randomized studies, and editorials for additional studies. We contacted the main authors of studies and experts in this field to ask for any missed, unreported, or ongoing studies. We contacted pharmaceutical companies for any unpublished trials.

Data collection and analysis

Selection of studies

Two authors (AFSH and JB) independently evaluated all relevant trials and provided detailed descriptions of the included, excluded and ongoing studies under the sections 'Characteristics of included studies, Characteristics of excluded studies and Characteristics of ongoing studies'. We also provided a detailed description of our search results (Figure 1).

Figure 1.

Search results.

Data extraction and management

We screened the titles and abstracts in order to identify studies that were eligible. AFSH and JB independently extracted and collected the data on a standardized paper form (data extraction sheet). We were not blinded to the author, source institution or the publication source of trials. We resolved disagreements by discussion and approached all first authors of the included trials for additional information on a trial's outcome measures and risks of bias. For more specific information please see the 'Contributions of authors' section.

Assessment of risk of bias in included studies

We evaluated the validity and design characteristics of each trial. To draw conclusions about the overall risk of bias for an outcome it is necessary to evaluate the trials for major sources of bias, also defined as domains (random sequence generation, allocation concealment, blinding, incomplete outcome data, selective outcome reporting and other sources of bias). The Cochrane Collaboration’s recommended tool for assessing risk of bias is neither a scale nor a checklist but rather the domain-based evaluation. Any assessment of the overall risk of bias involves consideration of the relative importance of the different domains (Higgins 2008).

Even the most realistic assessment of the validity of a study may involve subjectivity since it is impossible to know the extent of bias (or even the true risk of bias) in a given study. Some domains affect the risk of bias across outcomes in a study, for example sequence generation and allocation sequence concealment, while others such as blinding and incomplete outcome data may have different risks of bias for the different outcomes within a study. Thus, the risk of bias is not the same for all outcomes in a study. When examining blinding as a component of the risk of bias we planned to perform separate sensitivity analyses for patient-reported outcomes (subjective outcomes) and for mortality (Higgins 2008).

We defined the trials as having low risk of bias only if they adequately fulfilled the criteria listed in the Cochrane Handbook, determined by performing summary assessments of the risk of bias for each important outcome (across domains) within and across studies. We applied a 'Risk of bias' graph and a 'Risk of bias' summary figure (Higgins 2008) (Figure 2; Figure 3).

Figure 2.

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

Figure 3.

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

As there is no sufficiently well-designed formal statistical method to combine the results of different studies at high and low risk of bias, the Cochrane Handbook provides three major approaches to incorporating risk of bias assessments in Cochrane reviews:

  1. presenting all studies and providing a narrative discussion of risk of bias;

  2. conducting primary analysis restricted to studies at low (or low and unclear) risk of bias;

  3. presenting multiple analyses (Higgins 2008).

We planned to include high and low risk studies and to present multiple analyses.

Random sequence generation

Adequate: the method used generated random sequences, e.g. random number generation, toss of coin.

Unclear: no information on random sequence generation available.

Inadequate: alternate medical record numbers or other non-random sequence generation.

Allocation concealment

Adequate: allocation method prevented investigators or participants from knowing the next allocation, e.g. central allocation; sealed opaque envelopes; serially or sequentially-numbered but otherwise identical vehicles, including their contents; or other descriptions of convincing concealment of allocation.

Unclear: no information on allocation method available or the description did not allow a clear determination.

Inadequate: allocation method allowed the investigators or participants to know the next allocation, e.g. alternate medical record numbers; reference to case record numbers or date of birth; an open allocation sequence or unsealed envelopes.

Blinding

Adequate: we considered blinding as adequate if blinding of participants and key study personnel was ensured without likelihood of blinding being broken, or participants; some key study personnel were not blinded but outcome assessment was blinded and the non-blinding of the others was unlikely to introduce bias (Higgins 2008).

Unclear: either insufficient information to permit judgement of the adequacy of blinding or the the study did not address this methodological component (Higgins 2008).

Inadequate: lack of blinding or incomplete blinding and when the outcome or outcome measurement was likely to be influenced by lack of blinding; blinding of key study participants and personnel attempted but likely that the blinding could have been broken; either participants or some key study personnel were not blinded and the non-blinding was likely to introduce bias (Higgins 2008).

Follow up

Adequate: the numbers of and reasons for dropouts and withdrawals in the intervention groups were described or if it was specified that there were no dropouts or withdrawals.
Unclear: if the report gave the impression that there had been no dropouts or withdrawals but this was not specifically stated.
Inadequate: the number of or reasons for dropouts and withdrawals not described.

Dealing with missing data

We contacted the first authors and contact person of the trials with missing data (Dahlem 2004; Siddiqui 2009; Yung 2010) in order to retrieve the relevant data.

Intention-to-treat analysis (ITT) is recommended in order to minimize bias in design, follow up and analysis of the efficacy of randomized clinical trials. It gives a pragmatic estimate of the benefit from a change in treatment policy rather than potential benefit in patients who receive treatment exactly as planned (Hollis 1999). Full application of ITT is possible only when complete outcome data are available for all randomized participants. Despite the fact that about half of all published reports of randomized clinical trials state that ITT is used, handling of deviations from randomized allocation varies widely and many trials have missing data on the primary outcome variables. Methods used to deal with this are generally inadequate and potentially lead to bias (Hollis 1999).

Performing an ITT in a systematic review is not straightforward in practice since review authors must decide how to handle missing outcome data in the contributing trials (Gamble 2005). No consensus exists about how missing data should be handled in ITT, and different approaches may be appropriate in different situations (Higgins 2008; Hollis 1999). In cases of missing data, we planned to apply 'complete-case analysis' for primary and secondary outcomes, which simply excludes all participants with the missing outcome from the analysis.

Selective outcome reporting occurs when non-significant results are selectively withheld from publication (Chan 2004), and is defined as selection on the basis of results of a subset of the original variables recorded for inclusion in trial publications (Hutton 2000). The most important types of selective outcome reporting are: selective omission of outcomes from reports; selective choice of data for an outcome; selective reporting of analyses using the same data; selective reporting of subsets of the data and selective under-reporting of data (Higgins 2008). Statistical methods to detect within-study selective reporting are still in development. We planned to explore selective outcome reporting by comparing publications with their protocols, if the latter are available.

Assessment of reporting biases

Publication bias occurs when the publication of research results depends on their nature and direction (Dickersin 1990). We planned to provide a funnel plot in order to detect either publication bias or a difference between smaller and larger studies ('small study effects') expressed by asymmetry (Egger 1997). In order to quantify this asymmetry in meta-analyses with binary outcomes we also intended to apply the arcsine test as proposed by Rücker 2008. This test has the advantage of including trials with no events.

Funding bias is defined as the bias in the design, outcome and reporting of industry sponsored research in order to show that a drug shows a favourable outcome (Bekelman 2003). Relationships between industry, scientific investigators and academic institutions are widespread and often result in conflicts of interest (Bekelman 2003). We planned to conduct a sensitivity analysis in order to examine the role of funding bias.

According to the Cochrane Handbook a minimum of 10 trials has to be included before a statistical test is applied, to detect possible reporting bias, and results from tests for funnel plot asymmetry should be interpreted cautiously (Higgins 2008).

Data synthesis

The degree of heterogeneity observed in the results is quantified using the I² statistic, which can be interpreted as the proportion of the total variation observed between studies that is attributable to differences between studies rather than sampling error (chance) (Higgins 2002). Suggested threshold values for the I² statistic are: low (25% to 49%), moderate (50% to 74%), and high (≥ 75%) (Higgins 2003). If I² = 0, we planned to report only the results from the fixed-effect model; in the case of I² > 0 we planned to report only the results from the random-effects model unless one or two trials comprised more than 60% (weight %) of the total evidence provided, in which case the random-effects model may be biased. The latter is to make the review more readable. We believe that there is little value in using a fixed-effect model in cases of substantial heterogeneity possibly due to the various reasons leading to ARDS. Additionally, in the case of I² > 0 (mortality outcome) we planned to determine the cause of heterogeneity by performing relevant subgroup analyses. We intended to pool trial results only in the case of low clinical heterogeneity.

We used Review Manager software (RevMan 5.0). We calculated the relative risks (RR) and risk differences (RD) with 95% confidence intervals (CI) for dichotomous variables (binary outcomes). However, with identical conclusions we planned only to provide the RR. We chose mean difference (MD), the measure of absolute change, with 95% CI for continuous outcomes (Keus 2009). We used the Chi2 test to provide an indication of heterogeneity between studies, with P ≤ 0.1 considered significant heterogeneity. We used GRADEpro software to create a summary of findings table (GRADEpro).

Meta-analyses may result in type I errors due to systematic errors (bias) or random errors due to repeated significance testing when updating meta-analyses with new trials (Brok 2008; Wetterslev 2008). Bias from trials with low methodological quality, outcome measure bias, publication bias, early stopping for benefit and small trial bias may result in spurious P values (Brok 2008; Wetterslev 2008).

In a single trial, interim analysis increases the risk of type I errors. To avoid type I errors, group sequential monitoring boundaries (Lan 1983) are applied to decide whether a trial could be terminated early because of a sufficiently small P value, that is the cumulative z-curve crosses the monitoring boundaries. Sequential monitoring boundaries can be applied to meta-analysis as well, called trial sequential monitoring boundaries. In trial sequential analysis (TSA) the addition of each trial in a cumulative meta-analysis is regarded as an interim meta-analysis and helps to decide whether additional trials are needed.

The idea in TSA is that if the cumulative z-curve crosses the boundary a sufficient level of evidence is reached and no further trials are needed. If the z-curve does not cross the boundary then there is insufficient evidence to reach a conclusion. To construct the trial sequential monitoring boundaries the information size is needed and is calculated as the least number of participants needed in a well-powered single trial (Brok 2008; Pogue 1997; Pogue 1998; Wetterslev 2008). We applied TSA since it prevents an increase of the risk of type I error (< 5%) due to potential multiple updating in a cumulative meta-analysis and provides us with important information in order to estimate the level of evidence of the experimental intervention. Additionally, TSA provides us with important information regarding the need for additional trials and the required information size. We applied trial sequential monitoring boundaries according to an information size suggested by the low bias risk trials and a 10% relative risk reduction (RRR). We used Trial Sequential Analysis software, version 0.8 (TSA 2010).

Subgroup analysis and investigation of heterogeneity

We planned the following subgroup analyses.

1. Assessment of the benefits and harms of prostacyclins in participants with ALI or ARDS based on the cause (primary lung injury versus secondary lung injury).

2. Assessment of the benefits and harms of prostacyclins in paediatrics (paediatric, age less than 18 years, versus adults).

3. Assessment of the benefits and harms of prostacyclins based on the duration of drug administration.

If analyses of various subgroups were significant, we planned to perform a test of interaction (Altman 2003). We considered P < 0.05 as indicating significant interaction between the prostacyclin effect on mortality and subgroup category (Higgins 2008) (Chapters 9.6.1 and 9.7).

Sensitivity analysis

We planned the following sensitivity analyses.

1. Comparing estimates of the pooled intervention effect in trials with low risk of bias to estimates from trials with high risk of bias (i.e. trials having at least one inadequate risk of bias component).

2. Comparing estimates of the pooled intervention effect in trials based on different components of risk of bias (random sequence generation, allocation concealment, blinding, follow up, intention to treat).

3. Comparing estimates of the pooled intervention effect in trials based on American European Consensus Conference criteria for ARDS/ALI (AECC).

4. Assessment of the benefits and harms of prostacyclins in participants with ALI and ARDS versus participants given placebo or usual care when excluding data from studies only published as abstracts.

5. Assessment of the benefits and harms of aerosolized prostacyclin in participants with ALI and ARDS versus participants given placebo or usual care when excluding trials with zero events.

6. Examining the role of funding bias when excluding trials that were exclusively sponsored by pharmaceutical companies.

We planned to calculate RR with 95% CI and apply complete case analysis, if possible, for our sensitivity and subgroup analyses based on our primary outcome measure (mortality).

Results

Description of studies

Results of the search

Through electronic searches and from references of potentially relevant articles, we identified 2556 publications. We excluded 2532 publications as they were either duplicates or were clearly irrelevant. A total of 24 potentially relevant publications were retrieved for further assessment. From these, we excluded 21 trials, included one trial which randomized a total of 14 children (Dahlem 2004) and found two ongoing trials (Siddiqui 2009; Yung 2010). The two review authors (AA, JB) completely agreed on the selection of the included study. We obtained additional information from the lead author and from the principal investigator of the ongoing trials.

Included studies

Only one study met entry criteria for this systematic review (Dahlem 2004), see Included studies. The authors of this paediatric trial used the ARDS definition based on the European-American consensus statement as an entry criterion. The trial had a sample size of 14 children with ALI or ARDS and reported on mortality. The duration of intervention was less than 24 hours. Length of follow up was 28 days. The agent used as placebo was aerosolized saline. No other co-intervention was applied beside standard critical care treatment. There was no predefined protocol for mechanical ventilation. All patients were tapered after a prespecified time period (see Characteristics of included studies).

Excluded studies

We excluded 23 potentially relevant publications (see Characteristics of excluded studies). Five of the publications referred to two trials and were duplicates or reported on different outcomes based on the same trial data (Bone 1989; Holcroft 1986). One RCT was excluded since the intervention was a comparison of inhaled nitric oxide and inhaled prostacyclin among a septic population and where very few of the patients fulfilled the criteria for ALI and ARDS (Eichelbrönner 1996).

We excluded 10 trials because they were case reports or non-randomized observational studies (Bein 1994; Domenighetti 2001; Meyer 1998; Pappert 1995; Putensen 1998; Shoemaker 1986; Van Heerden 1996; Van Heerden 2000; Walmrath 1995; Zwissler 1996). We excluded nine RCTs because they either used intravenous PGE1 (Abraham 1996; Abraham 1999; Bone 1989; Holcroft 1986; Rossignon 1990; Shoemaker 1986; Vincent 2001) or intravenous PGI2 (Archer 1996; Eichelbrönner 1996) as the active intervention and did not use any form of aerosolized prostacyclin as an intervention.

Risk of bias in included studies

The overall quality of Dahlem 2004 was evaluated based on the major sources of bias (domains) as described above. It was classified as a trial with overall low risk of bias. For a more detailed description of individual trial methodology see the table Characteristics of included studies. The various bias domains are presented in the 'Risk of bias' graph and 'Risk of bias' summary (Figure 2; Figure 3).

Allocation

Random sequence generation was adequately reported, as was allocation concealment (Dahlem 2004).

Blinding

The included trial was categorized as double blinded (Dahlem 2004).

Incomplete outcome data

There appeared to be complete follow up for the primary outcome but only for the length of follow up, which was 28 days (Dahlem 2004). The authors performed analysis according to the ITT method.

Selective reporting

We were unable to retrieve the original protocol of the included trial and thus were unable to examine selective outcome reporting as described above.

Other potential sources of bias

The trial was not industry funded. Sample size calculation was not reported and the trial was not powered to show a statistically significant benefit in primary outcome measures. We were unable to conduct analyses such as the funnel plot, the arcsine-Thompson test as proposed by Rücker (Rücker 2008) or the Egger's regression intercept test as only one RCT was included.

Effects of interventions

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

Primary outcomes

Based on the data provided in Dahlem 2004, and applying complete-case analysis, there was no statistically significant effect of inhaled prostacyclin on longest follow-up mortality: 2/8 deaths (25%) in the inhaled prostacyclin group compared with 1/6 deaths (16.7%) in the control group (RR 1.50, 95% CI 0.17 to 12.94) (Table 3).

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]

Sensitivity and subgroup analyses

As previously mentioned we were unable to conduct our prespecified sensitivity and subgroup analyses due to lack of included RCTs. Additionally, the authors of the included trial conducted very few analyses relevant to our systematic review (Dahlem 2004) (Table 3).

Bias assessment: we were unable to conduct any relevant estimate of the intervention effect based on random sequence generation, allocation concealment, blinding, follow up, sample size calculation, early stopping, funding bias and the overall risk of bias since we only managed to find one relevant RCT (Table 3).

Respiratory outcomes: the authors did not measure any other respiratory outcome relevant to our review than oxygenation index. The authors reported a 26% improvement in oxygenation index at 30 ng/kg/min compared with placebo but there was no information on the oxygenation index based on different days (Dahlem 2004).

Outcomes such as severity of illness, differences in mean pulmonary arterial pressure, resolution of organ dysfunction, length of stay in ICU or hospital, quality of life assessment and cost benefit analyses were not conducted by the authors.

Adverse events and complications: the authors did not encounter any adverse events such as bleeding, organ dysfunction, airway reactivity or adverse events unrelated to the intervention (Dahlem 2004).

Quality of life: the authors did not conduct any quality of life assessment or cost benefit analysis.

TSA: trial sequential analysis was meaningless as only one trial has been conducted so far, and thus the proportion of the required information size is probably less than 1%. However, we tried to estimate the required information size for a conclusive meta-analysis considering a type 1 error risk of 5%; a type 2 error risk of 20%; an anticipated relative risk reduction of 20%; a mortality rate in the control group of a paediatric population of about 20% and 40% in the adult population.

The required information size for a paediatric population, depending on the level of heterogeneity adjustment, is between 2897 (I2 = 0) and 3862 (I2 = 25%). The required information size for the adult population with the same level of heterogeneity is between 1132 (I2 = 0) and 1508 (I2 = 25%).

Discussion

In this systematic review, we were only able to include one trial with 14 critically ill children with ALI and ARDS that assessed the effect of aerosolized prostacyclin (Dahlem 2004). This is insufficient to demonstrate any benefits or harms of inhaled prostacyclin therapy. We found two ongoing trials (Siddiqui 2009; Yung 2010) but were not able to retrieve any data from the authors of these studies since they were not at a stage where they could disclose data. Based on the very limited data available, we were unable to show any benefits of aerosolized prostacyclin on survival or other clinical outcomes. The sparse data on mortality is not promising but are not evidence of the absence of a beneficial effect; nor do the data suggest the degree of a potentially beneficial or detrimental effect of inhaled prostacyclin.

In contrast to mortality, the oxygenation index significantly improved in the prostacyclin group. This is only a surrogate outcome and it is uncertain whether it predicts any clinical benefits, as previously illustrated by trials examining the role of inhaled nitric oxide (INO). INO has similar effects as inhaled prostacyclin on oxygenation and pulmonary vascular pressure (Adhikari 2007; Afshari 2010; Eichelbrönner 1996). This result must therefore be interpreted with caution. Additionally, it is very important to distinguish between adult and paediatric patients since the incidence of ALI and ARDS and outcomes seems to differ.

The evidence for inhaled prostacyclin in adult ALI and ARDS is currently based on observational studies and case reports examining the role of inhaled prostacyclin as a single intervention, compared to INO or in conjunction with INO, all indicating improved oxygenation but with little data on survival (Domenighetti 2001; Meyer 1998; Putensen 1998; Van Heerden 1996; Van Heerden 2000; Walmrath 1996; Zwissler 1996).

A recent systematic review identified seven RCTs which applied intravenous prostaglandin E1 (PGE1) for treatment of ALI and ARDS (Adhikari 2004). The authors found no evidence to support the routine administration of PGE1. However, there are important pharmacological differences that might not justify a direct comparison of intravenous and aerosolized treatment of PGE1. Intravenous PGE1 is a vasodilator that decreases both pulmonary and systemic blood pressure and at the same time increases the venous admixture. Inhaled prostacyclin is believed to selectively dilate the pulmonary vasculature in ventilated lung areas, thus improving the ventilation/perfusion ratio and oxygenation (Meyer 1998).

Summary of main results

This systematic review is unable to show any beneficial effect of aerosolized prostacyclin despite indications of improved oxygenation index, due to the limited number of randomized clinical trials at this stage. We were unable to conduct our prespecified multiple subgroup and sensitivity analyses. There is currently a lack of evidence to support the routine use of aerosolized prostacyclin for ALI and ARDS.

Quality of the evidence

We planned to apply several statistical methods in order to explore and reduce the risk of bias and risk of random error, such as complete case analysis, trial sequential analysis, overall methodological bias assessment and analyses of various relevant clinical and physiological outcomes. However, since only one trial was included in this review (Dahlem 2004) we were unable to carry out the analyses. Thus, we tried to estimate the required information for a conclusive meta-analysis on this intervention in both paediatric and adult populations, with and without a 25% heterogeneity adjustment.

Our systematic review has several potential limitations The findings and interpretations are limited by the quality and quantity of the available evidence. The risk of bias of the included trial was mainly assessed by using the published data, which ultimately may not reflect the truth. Also, our estimation of a required information size makes it possible to conclude that the risk of random error in the meta-analysis is both imminent and manifest, as less than 1% of the required information size is actually randomized. The lead author was contacted but he was only able to provide a limited amount of relevant information (Dahlem 2004). We were unable to retrieve the original protocol of Dahlem 2004 and thus were unable to compare the published outcomes to the proposed outcomes for this trial.

Potential biases in the review process

Since there is no previous systematic review on this topic, we were unaware of the number of existing trials. Most of the review authors were familiar with this intervention from their experience in various ICU settings. However, this did not influence our assessment of the existing data and to our knowledge there was no other additional bias in the review process.

Agreements and disagreements with other studies or reviews

Our findings do not contradict the existing controversy surrounding the treatment of patients with ALI and ARDS.

Authors' conclusions

Implications for practice

There is insufficient evidence to support the routine use of aerosolized prostacyclin in ALI and ARDS patients. Despite signs of improved oxygenation, there is no statistically significant effect on mortality or other clinical outcomes since only one small paediatric RCT has been carried out (Dahlem 2004).

Implications for research

There is a need for large randomized trials with low risk of bias and an information size of up to several thousand participants (children as well as adults) to evaluate aerosolized prostacyclin before this intervention can be definitely rejected or accepted for use in critically ill patients with ALI and ARDS. However, more light will be shed on this matter when the data from the two ongoing RCTs are published (Siddiqui 2009; Yung 2010) enabling us to evaluate more evidence and providing more information regarding the need for future large RCTs with low risk of bias.

Acknowledgements

We would like to thank Karen Hovhannisyan (CARG) for his assistance in providing our different search strategies and results and by facilitating contact with various authors. We would like to thank Jane Cracknell for her extensive support during the entire editorial process. Additionally we like to thank Dr Peter Dahlem, Mark Siobal and Janet Wale (Consumer Editor) for their peer review contribution and constructive criticism. Finally, special thanks to Prof Harald Herkner and Prof Nathan L Pace for their great editorial criticism and assistance, enabling us to improve the overall quality of this paper.

Data and analyses

Download statistical data

This review has no analyses.

Appendices

Appendix 1. Search strategies

DatabaseSearch strategy
Biosis Previews (Ovid SP)1. (prostaglandin*or Iloprost or Prostin or Flolan or Epoprostenol or Beraprost or Treprostinil or prostacyclin*).af.
2. (PROSTAGLANDIN or PROSTACYCLIN).ti,ab.
3. 2 or 1
4. ARDS.af.
5. (respirator* or distress).ti,ab.
6. (distress adj3 syndrome).mp.
7. 5 or 4 or 6
8. 3 and 7
9. (RANDOM* or CROSS?OVER* or FACTORIAL* or PLACEBO* or VOLUNTEER*).ti,ab.
10. ((SINGL* or DOUBL* or TREBL* or TRIPL*) adj6 (BLIND* or MASK*)).ti,ab.
11. 10 or 9
12. 8 and 11
CENTRAL, The Cochrane Library,

#1 MeSH descriptor Epoprostenol explode all trees

#2 MeSH descriptor Prostaglandins explode all trees

#3 prostaglandin*or Iloprost or Prostin or Flolan or Epoprostenol or Beraprost or Treprostinil or prostacyclin*

#4 (#1 OR #2 OR #3)

#5 MeSH descriptor Respiratory Distress Syndrome, Adult explode all trees

#6 ARDS

#7 respirator* or distress

#8 distress and syndrome

#9 (#5 OR #6 OR #7 OR #8)

#10 (#9 AND #4)

EMBASE (Ovid SP)1. exp prostacyclin/ or exp prostaglandin/
2. (prostaglandin*or Iloprost or Prostin or Flolan or Epoprostenol or Beraprost or Treprostinil or prostacyclin*).mp.
3. 1 or 2
4. exp adult-respiratory-distress-syndrome/
5. ARDS.mp. or (respirator* or distress).ti,ab. or (distress adj6 syndrome).mp.
6. 4 or 5
7. 6 and 3
8. (RANDOMIZED-CONTROLLED-TRIAL/ or RANDOMIZATION/ or CONTROLLED-STUDY/ or MULTICENTER-STUDY/ or PHASE-3-CLINICAL-TRIAL/ or PHASE-4-CLINICAL-TRIAL/ or DOUBLE-BLIND-PROCEDURE/ or SINGLE-BLIND-PROCEDURE/ or (RANDOM* or CROSS?OVER* or FACTORIAL* or PLACEBO* or VOLUNTEER* or ((SINGL* or DOUBL* or TREBL* or TRIPL*) adj3 (BLIND* or MASK*))).ti,ab.) not (animals not (humans and animals)).sh.
9. 8 and 7
ISI Web of Science

#1 TS = (prostacyclin*) or TS = prostaglandin* or TS = Iloprost or TS = Prostin or TS = Flolan or TS = Epoprostenol or TS = Beraprost or TS = Treprostinil

#2 TS = ARDS

#3 TS = (respirator* SAME distress)

#4 TS = (distress SAME syndrome)

#5 #2 or #3 or #4

#6 #1 and #5

LILACS (via BIREME)("EPOPROSTENOL" or "EPOPROSTENOL/" or "PROSTAGLANDINS" or "prostaglandin$" or "Iloprost" or "Prostin" or "Flolan" or "Epoprostenol" or "Beraprost" or "Treprostinil" or "prostacyclin$") and ("RESPIRATORY DISTRESS SYNDROME, ACUTE/" or "RESPIRATORY DISTRESS SYNDROME, ADULT/" or "respirator$" or "distress")
MEDLINE (Ovid SP)1. exp Epoprostenol/ or exp Prostaglandins/
2. (prostaglandin*or Iloprost or Prostin or Flolan or Epoprostenol or Beraprost or Treprostinil or prostacyclin*).mp.
3. #1 or #2
4. exp Respiratory Distress Syndrome, Adult/
5. (ARDS or (respirator* or distress) or (distress adj6 syndrome)).mp.
6. 5 or 4
7. 6 and 3
8. ((randomized controlled trial or controlled clinical trial).pt. or randomized.ab. or placebo.ab. or clinical trials as topic.sh. or randomly.ab. or trial.ti.) not (animals not (humans and animals)).sh.
9. 8 and 7
CINAHL (EBSCOhost)((MM "Respiratory Distress Syndrome, Acute") or (MH "Respiratory Distress Syndrome+") or ARDS or respirator* or distress ) and ( prostaglandin*or Iloprost or Prostin or Flolan or Epoprostenol or Beraprost or Treprostinil or prostacyclin*)

What's new

DateEventDescription
11 February 2013AmendedContact details updated

History

DateEventDescription
12 October 2010AmendedContact details updated.
11 August 2009AmendedKeus 2009: no longer in press; page numbers added

Contributions of authors

Conceiving the review: Arash Afshari (AFSH), Ann Merete Møller (AMM), Jørn Wetterslev (JW), Jesper Brok (JB)
Co-ordinating the review: AFSH
Undertaking manual searches: AFSH
Screening search results: AFSH, JB
Organizing retrieval of papers: AFSH
Screening retrieved papers against inclusion criteria: AFSH, JW, AMM, JB
Appraising quality of papers: AFSH, JW, AMM, JB
Abstracting data from papers: AFSH, JB
Writing to authors of papers for additional information: AFSH, JB
Providing additional data about papers: AFSH
Obtaining and screening data on unpublished studies: AFSH
Data management for the review: AFSH, JW, JB
Entering data into Review Manager (RevMan 5.0): AFSH, JW, JB
RevMan statistical data: JW, AFSH
Other statistical analysis not using RevMan: JW
Double entry of data: (data entered by person one: AFSH; data entered by person two: JB)
Interpretation of data: AFSH, JW, AMM, JB
Statistical analysis: JW, AFSH
Writing the review: AFSH, JW, AMM, JB
Securing funding for the review: AMM
Performing previous work that was the foundation of the present study: AFSH
Guarantor for the review (one author): AFSH
Person responsible for reading and checking review before submission: AFSH

Declarations of interest

None known

Sources of support

Internal sources

  • Cochrane Anaesthesia Review Group (CARG), Denmark.

    Support from TSC (Karen Hovhannisyan) in designing search strategy

External sources

  • New Source of support, Not specified.

Differences between protocol and review

January 2010

There are minor changes compared to the protocol. We have decided to exclude the following analyses: uncertainty method, empirical continuity correction and the analyses based on the median duration of the intervention due to some ongoing controversy surrounding these analyses. Thus, the sections in the protocol describing these analyses have been revised. We have added the following analysis for the future update of our review: "Comparing estimates of the pooled intervention effect in trials based on American European Consensus Conference criteria for ARDS/ALI".

Characteristics of studies

Characteristics of included studies [ordered by study ID]

Dahlem 2004

Methods

Two-group parallel RCT, one centre
ITT: Yes

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

Participants

14 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.

Interventions

Intervention 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.

Outcomes

Primary 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.

Notes

Country: 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 information

Dr. 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
Outcomes

Primary: 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 information

Delphine 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.

Ancillary