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Prostacyclins and analogues for the treatment of pulmonary hypertension in neonates

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Versión publicada: 20 febrero 2018 Historial de versiones

https://doi.org/10.1002/14651858.CD012963

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Abstract

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows:

Primary objective

To determine the efficacy and safety of PGI2 and its analogues (iloprost, treprostinil, and beraprost) in decreasing mortality and need for ECMO in neonates with PH.

Secondary objectives

To determine the efficacy and safety of PGI2 and its analogues (iloprost, treprostinil, and beraprost) in decreasing neonatal morbidity (necrotizing enterocolitis (NEC), chronic lung disease (CLD), retinopathy of prematurity (ROP), neurodevelopmental outcomes, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), length of hospital stay, and duration of mechanical ventilation) in neonates with PH.

Background

Description of the condition

Pulmonary hypertension (PH) in neonates or persistent pulmonary hypertension of newborns (PPHN) is a serious disorder of the pulmonary vasculature that results from the failure of successful postnatal transition of fetal pulmonary circulation. A normal transition includes a decrease in the pulmonary vascular resistance (PVR) to 50% of the systemic vascular resistance (SVR), a 10‐fold increase in the pulmonary blood flow due to expansion and oxygenation of the alveoli, decrease in the ratio of pulmonary vasoconstrictors to vasodilators, and clamping of the umbilical cord (Teitel 1990; Cornfield 1992; Cabral 2013). In PPHN, the PVR is elevated compared to SVR, due to low oxygen tension and an increased ratio of pulmonary vasoconstrictors to vasodilators. This results in a right‐left shunt through the ductus arteriosus or foramen ovale, or both (Lakshminrusimha 1999). PPHN is confirmed by the presence of right‐left shunt through the ductus arteriosus or foramen ovale, or both, without any accompanying heart disease irrespective of the pulmonary artery pressure (Lakshminrusimha 2012; Porta 2012; Cabral 2013; Ivy 2013).

The incidence of PPHN ranges from 0.4 to 2 per 1000 live births with an associated mortality of around 11% (Walsh‐Sukys 2000; Cabral 2013). Pathophysiologically, PPHN may be divided into the following categories:

  • acute pulmonary vasoconstriction as a result of abundance of pulmonary vasoconstrictors compared to vasodilators e.g. maternal diabetes, antenatal exposure to nonsteroidal anti‐inflammatory medications, elective cesarean section delivery, perinatal asphyxia, meconium aspiration syndrome, pneumonia, sepsis, hyaline membrane disease, and metabolic acidosis;

  • pulmonary vascular remodeling, which is characterized by pulmonary artery smooth muscle hyperplasia, adventitial thickening, and muscularization of intra‐acinar arteries e.g. congenital diaphragmatic hernia (CDH), chronic intrauterine hypoxia, and antenatal ductal closure;

  • pulmonary vascular hypoplasia, a condition characterized by decreased pulmonary blood vessels and cross‐sectional area of the pulmonary vascular bed thereby elevating PVR and causing flow restriction e.g. CDH, intrathoracic space occupying lesions, and chronic oligohydramnios; and

  • pulmonary intravascular obstruction that is characterized by blood flow restriction from conditions such as polycythemia and anomalous pulmonary venous drainage (Lakshminrusimha 2012; Cabral 2013; Storme 2013).

The gold standard for the diagnosis of PH is cardiac catheterization. However, this invasive procedure is not performed in most of the neonates and the diagnosis of PH is usually based on one or more of following echocardiography (Echo) findings: right ventricular systolic pressure/systemic systolic blood pressure ratio > 0.5, interventricular septal flattening, cardiac shunt with bidirectional or right‐to‐left blood flow, and right ventricular hypertrophy in the absence of congenital heart disease (Mourani 2008; Bhat 2012; Mourani 2015).

Therapeutic measures for PH in neonates include adequate alveolar recruitment, optimizing cardiac function, and administration of pulmonary vasodilators such as inhaled nitric oxide (iNO), prostacyclin, phosphodiesterase inhibitors such as sildenafil and milrinone, and endothelin antagonists such as bosentan, in addition to general supportive care such as maintenance of temperature and correction of electrolyte and metabolic derangements (Porta 2012; Steinhorn 2012; Cabral 2013; Storme 2013).

Description of the intervention

Prostanoids are metabolites of arachidonic acid that include prostaglandins, prostacyclin (also called prostaglandin I2 or PGI2), and thromboxanes. The enzyme cyclooxygenase converts arachidonic acid to an unstable intermediate, prostaglandin G, and various synthase enzymes then act to form a number of prostanoids including prostacyclin and prostaglandin E (PGE) (Ivy 2010). The prostanoids have numerous actions, and many of them are vasodilators. Thromboxanes are vasoconstrictors and not useful in the treatment of PH. In addition to being a potent pulmonary vasodilator, PGI2 exerts antithrombotic, antiproliferative, antimitogenic, and immunomodulatory activity (Read 1985; Jones 1997; Wharton 2000; Vane 2003). Prostacyclin analogues that can be administered by various routes e.g. intravenous, subcutaneous, by inhalation, or nebulization, are available for clinical use (Keller 2016).

Epoprostenol (Flolan) is the most commonly administered synthetic PGI2 analogue to treat pulmonary arterial hypertension in adults (Dorris 2012). Epoprostenol has a very short half‐life (< five minutes) that necessitates a stable vascular access to administer it as a continuous intravenous infusion. Evidence suggests that epoprostenol improves pulmonary hemodynamics, exercise capacity, quality of life, and survival in children and adults with PH (Barst 1994; Barst 1996; Barst 1999; Rosenzweig 1999; Sitbon 2002; Yung 2004). Children usually require a higher dose of epoprostenol compared to adults to obtain the beneficial vasodilatory effects (Ivy 2010; Steinhorn 2012). Intravenous epoprostenol is initiated at a dose of 1 ng/kg/min and gradually titrated to a dose of up to 50 to 100 ng/kg/min (Ivy 2010; Porta 2012). The most common side effects of intravenous prostacyclin are secondary to systemic vasodilation that leads to systemic hypotension, flushing, diarrhea, headache, jaw pain, alterations in hepatic enzymes, and an erythematous blotchy skin rash (Ivy 2010; Steinhorn 2012). Any interruption of its infusion can result in severe rebound PH and even death (Rubin 1990; Barst 1994; Doran 2008).

Iloprost is also a prostacyclin analogue with a half‐life of 20 to 30 minutes, which can be administered intravenously or by inhalation or nebulization (Ewert 2009). Administration by inhalation or nebulization results in selective pulmonary vasodilation, improved ventilation/perfusion mismatch, and limits the side effects associated with systemic vasodilation. However, the need for repeated nebulizations or inhaled treatments, and side effects such as development of reactive airway disease limits its use (Ivy 2008; Ivy 2010; Dorris 2012).

Treprostinil is a long‐acting tricyclic benzindene prostacyclin analogue (McNulty 1993), with a half‐life of about three hours that can be administered subcutaneously, intravenously, orally, or by inhalation. It is most commonly administered subcutaneously via a microinfusion pump. The main side effect is pain at the site of subcutaneous administration. However, it has fewer side effects when compared to epoprostenol (Ivy 2007; Doran 2008; Ivy 2010).

Beraprost, an oral prostacyclin analogue, which is readily absorbed from the small intestine, and excretion in the urine and feces is rapid and almost complete after oral dosing (Olschewski 2004). A retrospective study reports its use in neonates with PH (Nakwan 2011).

The optimal dose of iloprost and treprostinil to treat neonates and infants with PH is yet to be determined.

How the intervention might work

Prostanoids signal via G‐protein‐coupled cell surface receptors (Gomberg‐Maitland 2008), which, when activated, stimulate the enzyme adenylate cyclase. The resulting increase in intracellular cyclic AMP (cAMP), opening of Ca2+‐activated K+ channels, and membrane hyperpolarization leads to relaxation of vascular smooth muscle and vasodilation (Vane 1995). Pulmonary hypertensive disorders of neonates, children, and adults are associated with a PGI2‐deficient state, which forms the basis for PGI2 therapy in PH (Christman 1992; Majed 2012). In infants, prostacyclins are comparable to iNO in decreasing pulmonary artery pressure and improving oxygenation (Bos 1993; Nakayama 2007). PGE1 is an effective pulmonary vasodilator in adults with ARDS, with an action similar to that of iNO (Putensen 1998). Currently, prostacyclin and its analogues, and PGE1 are increasingly used as an 'add on' therapy for iNO refractory PH (Kelly 2002; Ehlen 2003; Chotigeat 2007; De Luca 2007; Levy 2011).

Why it is important to do this review

Pulmonary hypertension is a serious debilitating illness that is associated with high neonatal mortality and may require extracorporeal membrane oxygenation (ECMO) for survival. Hence, optimal management of PH is critical to improve outcomes in high risk neonates. We aim to systematically review evidence for the use of prostacyclin and analogues in the treatment of PH in neonates and identify gaps in knowledge that will inform future clinical trials.

Objectives

Primary objective

To determine the efficacy and safety of PGI2 and its analogues (iloprost, treprostinil, and beraprost) in decreasing mortality and need for ECMO in neonates with PH.

Secondary objectives

To determine the efficacy and safety of PGI2 and its analogues (iloprost, treprostinil, and beraprost) in decreasing neonatal morbidity (necrotizing enterocolitis (NEC), chronic lung disease (CLD), retinopathy of prematurity (ROP), neurodevelopmental outcomes, intraventricular hemorrhage (IVH), periventricular leukomalacia (PVL), length of hospital stay, and duration of mechanical ventilation) in neonates with PH.

Methods

Criteria for considering studies for this review

Types of studies

Randomized, quasi‐randomized, cluster‐randomized, or cross‐over trials

Types of participants

Term or preterm neonates less than three months of age who are cared for in the neonatal intensive care unit with PH.

Neonates will be diagnosed with PH if they have one or more of the following Echo findings: right ventricular systolic pressure/systemic systolic blood pressure ratio > 0.5, interventricular septal flattening, cardiac, or ductal shunt with bidirectional or right‐to‐left blood flow, and right ventricular hypertrophy in the absence of congenital heart disease (Mourani 2008; Bhat 2012; Mourani 2015).

Types of interventions

Prostacycin (PGI2) or its analogues at any dosage or duration by any route (intravenous, subcutaneous, inhaled, or enteral).

Comparisons

  • Prostacycin (PGI2) or its analogues at any dosage or duration or route of administration used to treat neonatal PH will be compared to no treatment, placebo or iNO therapy;

  • Prostacycin (PGI2) or its analogues at any dosage or duration or route of administration used to treat refractory neonatal PH as an ‘add on’ therapy to iNO compared to iNO alone;

  • head‐to‐head comparison of the different prostacyclin analogues for the treatment of PH.

Types of outcome measures

Primary outcomes

  • 'All‐cause mortality' at 28 days of life, during hospital stay;

  • need for ECMO in infants > 2000 g and > 34 weeks during hospital stay. We will define the need for ECMO according to extracorporeal life support organization (ELSO) guidelines (ELSO 2013):

    • oxygenation index > 40 for > four hours;

    • oxygenation index > 20 with lack of improvement despite prolonged (> 24 hours) maximal medical therapy or persistent episodes of decompensation;

    • severe hypoxic respiratory failure with acute decompensation (PaO2);

    • progressive respiratory failure with or without PPHN with right ventricular dysfunction or continued inotrope.

Secondary outcomes

  • Adverse effects: systemic hypotension (decrease in mean blood pressure lower than the 10th percentile for gestational and postnatal age (Nuntnarumit 1999), worsening oxygenation (oxygen saturations < 10% from before therapy started), rebound PH (increase in pulmonary arterial pressures > 10% as defined by Echo) during treatment;

  • neurodevelopmental outcome assessed by a validated test at ≥ 18 months of age. (Neurodevelopmental impairment defined as one or more of the following outcomes: Bayley Scales of Infant Development‐II Mental Development Index of < 70, Bayley Scales of Infant Development‐II Psychomotor Development Index of < 70, bilateral blindness, bilateral hearing aid use, cerebral palsy, and neurodevelopmental impairment. If Bayley III scales are used then we will use scores equivalent to Bayley II (Payne 2013));

  • decrease in pulmonary arterial pressure (20% from baseline before start of therapy) as demonstrated by Echo or by cardiac catheterization during treatment;

  • decrease in oxygenation index of any duration (20% from baseline before start of therapy) during therapy;

  • NEC (definite NEC and perforated NEC, Bell's stage II or III) (Bell 1978) during hospital stay;

  • CLD defined as oxygen requirement at 36 weeks' postmenstrual age (Jobe 2001);

  • PVL (defined as necrosis of white matter in a characteristic distribution, i.e. in the white matter dorsal and lateral to the external angles of lateral ventricles involving particularly the centrum semi ovale, optic and acoustic radiations and diagnosed by magnetic resonance imaging (MRI) (Volpe 2008) during hospital stay;

  • IVH: severe grade III or IV (Papile 1978) during hospital stay;

  • ROP stages III and IV (CCRP 1984) during hospital stay;

  • use of inotropic agents, dopamine, epinephrine or vasopressin during prostacyclin or its analogue therapy;

  • length of hospital stay in days;

  • duration of mechanical ventilation in days.

Search methods for identification of studies

We will use the search strategy of the Cochrane Neonatal (http://neonatal.cochrane.org/).

Electronic searches

We will search the following databases for relevant trials in any language.

  • Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, current issue);

  • electronic journal reference databases: MEDLINE (1980 to present) and PREMEDLINE, Embase (1980 to present), CINAHL (1982 to present);

  • biological abstracts in the database BIOSIS and conference abstracts from 'Proceedings First' (from 1992 to present).

The MEDLINE search strategy is presented in Appendix 1.

Searching other resources

  • We will search abstracts of conferences: proceedings of Pediatric Academic Societies (American Pediatric Society, Society for Pediatric Research and European Society for Paediatric Research) from 1990 in the 'Pediatric Research' journal and 'Abstracts 2 view' (2000 to present);

  • ongoing trials will be searched with the search engines provided at the web sites: www.clinicaltrials.gov, www.controlled‐trials.com, http://www.who.int/ictrp and http://www.anzctr.org.au/TrialSearch.aspx;

  • authors who published in this field will be contacted for possible unpublished studies;

  • additional searches will be made from the reference lists of identified clinical trials and in the review authors' personal files.

Data collection and analysis

We will use the standardized method of the Cochrane Neonatal Group for conducting a systematic review (http://neonatal.cochrane.org/).

Selection of studies

Two review authors (BS and MP) will independently assess the titles and the abstracts of studies identified by the search strategy for eligibility for inclusion in this review. We will code all studies as either 'exclude' or 'potentially include'. If this cannot be done reliably by title and abstract, then we will obtain the full‐text version for assessment. We will resolve any differences by discussion. We will obtain a full‐text version of all available studies for assessment for inclusion. We will list all studies excluded after full‐text assessment in a 'Characteristics of excluded studies' table. We will illustrate the study selection process in a PRISMA diagram.

Data extraction and management

We will use pre‐designed forms for trial inclusion and exclusion, data extraction, and for requesting additional published information from authors of the original reports. At least two review authors will independently perform data extraction using specifically designed paper forms for identified eligible trials. We will compare the extracted data for differences which we will then resolve by discussion.

Assessment of risk of bias in included studies

Two review authors (BS and SG) will independently assess the risk of bias (low, high, or unclear) of all included trials using the Cochrane ‘Risk of bias’ tool (Higgins 2011) for the following domains:

  • sequence generation (selection bias);

  • allocation concealment (selection bias);

  • blinding of participants and personnel (performance bias);

  • blinding of outcome assessment (detection bias);

  • incomplete outcome data (attrition bias);

  • selective reporting (reporting bias);

  • any other bias.

We will resolve any disagreements by discussion or by consulting a third review author (SG). See Appendix 2 for a more detailed description of risk of bias for each domain.

Measures of treatment effect

We will report relative risk (RR) and risk difference (RD) values with 95% confidence intervals (CIs) for dichotomous outcomes and mean differences for continuous outcomes (MD) when we identify eligible trials. The number needed to treat for an additional beneficial outcome (NNTB) or number needed to treat for an additional harmful outcome (NNTH) will be calculated with 95% CIs if there is a statistically significant reduction or increase in RD.

In cross‐over trials, if neither carry‐over nor period effects are thought to be a problem, then we will use a paired t‐test for continuous data from a two‐period, two‐intervention cross‐over trial (Higgins 2011).

Unit of analysis issues

The unit of analysis will be the participating infant in individually randomized trials, and the cluster (e.g. neonatal unit or subunit) for cluster‐randomized trials. We will use approximate methods of correcting trial results that do not allow for clustering (Higgins 2011).

Dealing with missing data

We will contact the authors of published studies if clarifications are required, or to provide additional information. In the case of missing data, we will describe the number of participants with missing data in the 'Results' section and the 'Characteristics of included studies' table. The results will only be presented for the available participants. We will discuss the implications of the missing data in the 'Discussion' section of the review.

Assessment of heterogeneity

We plan to estimate the treatment effects of individual trials and examine heterogeneity between trials by inspecting the forest plots and by using the Chi² test which assesses whether observed differences in results are compatible with chance alone (Higgins 2011). A low P value < 0.1 (or a large Chi² statistic relative to its degree of freedom) provides evidence of heterogeneity of intervention effects (variation in effect estimates beyond chance). However the Chi² statistic has low power when meta‐analyzed studies have small sample size or are few in number. We will also quantify the impact of heterogeneity using the I2 statistic (which incorporates the Chi² statistic). We will grade the degree of heterogeneity as none if < 25%, low if between 25% to 49%), moderate if between 50% to 74%, or high if > 75%. If we detect statistical heterogeneity, we will explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post‐hoc subgroup analyses.

Assessment of reporting biases

We will attempt to obtain study protocols of all included studies and compare outcomes reported in the protocols to those reported in the included studies. We will investigate reporting and publication bias by examining the degree of asymmetry of a funnel plot if at least 10 studies are included in the meta‐analysis. Where we suspect reporting bias, we will attempt to contact study authors asking them to provide missing outcome data. Where this is not possible, and the missing data are thought to introduce serious bias, we will explore the impact of including such studies in the overall assessment of results by sensitivity analyses.

Data synthesis

We will use Review Manager 5 (RevMan 5) software for statistical analysis and intend to use a fixed‐effect model for meta‐analysis (RevMan 2014). We will perform statistical analyses according to Cochrane Neonatal Group recommendations. For cluster randomized trials, if analyzed appropriately at the level of the cluster and if summary estimates are available, we will synthesize data using the generic inverse variance method. If summary estimates are unavailable or the trials were not analyzed at the cluster level, we will adjust the sample size by using the intracluster co‐efficient (ICC) and design effect (approximate analyses) (Higgins 2011). We will report RR, RD (NNTH and NNTB if the RD value is significant) for dichotomous outcomes, and mean difference (MD) values for continuous outcomes all with 95% CIs.

Quality of the evidence

We will use the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, as outlined in the GRADE handbook for grading quality of evidence and strength of recommendations (Schünemann 2013), to assess the quality of evidence for the following (clinically relevant) outcomes:

  • 'all‐cause mortality' at 28 days of life;

  • need for ECMO;

  • decrease in pulmonary arterial pressure (20% from baseline before start of therapy) as demonstrated by Echo or by cardiac catheterization;

  • adverse effects.

Two review authors will independently assess the quality of the evidence for each of the outcomes above. We will consider evidence from randomized controlled trials as high quality evidence but will downgrade the quality of the evidence by one level for serious (or two levels for very serious) limitations based upon the following: design (risk of bias), consistency across studies, directness of the evidence, precision of estimates, and presence of publication bias.

The GRADE approach results in an assessment of the quality of a body of evidence to one of four grades:

  • high: we are very confident that the true effect lies close to that of the estimate of the effect;

  • moderate: 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: our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect;

  • very low: we have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect.

We will use the GRADEpro Guideline Development Tool to create a ‘Summary of findings’ table to report the quality of the evidence (GRADEpro GDT 2015).

Subgroup analysis and investigation of heterogeneity

We plan to perform the following subgroup analyses:

  • gestational age: term: ≥ 37 completed weeks' gestation; extremely preterm (< 28 weeks); very preterm (28 to < 32 weeks); moderate to late preterm (32 to < 37 weeks);

  • birth weight: ≥ 2500 g; 1000 to 2499 g; < 1000 g;

  • route of administration: Intravenous, subcutaneous; inhalation; enteral;

  • patient subgroups based on etiology of PH: sepsis; meconium aspiration syndrome; perinatal asphyxia; lung hypoplasia; alveolar capillary dysplasia; drug‐induced PH: e.g. Nonsteroidal antiinflammatory drugs (NSAIDs), selective serotonin reuptake inhibitors (SSRIs);

  • responsiveness to iNO (defined as improvement in saturation by 10 points from baseline before start of therapy): iNO responsive PH; iNO‐resistant PH.

Sensitivity analysis

We will explore methodological heterogeneity through the use of sensitivity analyses by excluding studies with high risk of bias.