Abstract
Background
Persistent pulmonary hypertension of the newborn (PPHN) occurs in approximately 1.9 per 1000 newborns and may be more frequent in developing countries. There is strong evidence for the use of inhaled nitric oxide (iNO) and extracorporeal membrane oxygenation (ECMO) in the treatment of PPHN. However, many developing countries do not have access or the technical expertise required for these expensive therapies. Magnesium sulfate is a potent vasodilator and hence has the potential to reduce the high pulmonary arterial pressures associated with PPHN. If magnesium sulfate were found to be effective in the treatment of PPHN, this could be a cost effective and potentially life‐saving therapy.
Objectives
To evaluate the use of magnesium sulfate compared with placebo or standard ventilator management alone, sildenafil infusion, adenosine infusion, or inhaled nitric oxide on mortality or the use of backup iNO or ECMO in term and near‐term newborns (> 34 weeks gestational age) with PPHN.
Search methods
The standard search strategy of the Cochrane Neonatal Review Group (CNRG) was used. No language restrictions was applied. The Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006) and MEDLINE (1966 to April 20, 2007) were searched for relevant randomized and quasi‐randomized trials. In addition the reference lists of retrieved articles were reviewed and known experts were contacted to obtain unpublished data. This search was updated in December 2009.
Selection criteria
All randomised or quasi‐random studies were eligible where one of the treatment groups received magnesium sulfate for PPHN.
Data collection and analysis
Standard methods of the Cochrane Collaboration and the CNRG were used, including independent assessment of trial quality and extraction of data by each author.
Main results
No eligible trials were found
Authors' conclusions
On the basis of the current lack of evidence, the use of magnesium sulphate cannot be recommended in the treatment of PPHN. Randomised controlled trials are recommended.
Plain language summary
Magnesium sulfate for persistent pulmonary hypertension of the newborn
The blood pressure in the arteries of the lungs (pulmonary arteries) is normally much lower than the blood pressure in the rest of the body. Before a baby is born the muscle surrounding the pulmonary arteries is tightly constricted resulting in a very high pressure in these arteries. After birth the arteries dilate and the pressure drops. In persistent pulmonary hypertension of the newborn this drop in pulmonary blood pressure, for a variety of reasons, fails to occur.
Magnesium sulfate is able to dilate constricted muscles of the type in the pulmonary arteries. However, its action is not specific and when given via an intravenous infusion, it will act on other muscles in the body including other arteries. This means that even if it were found to be effective in pulmonary hypertension, unwanted actions in other parts of the body might be a problem.
This review found that the use of magnesium sulfate for persistent pulmonary hypertension of the newborn has not been tested by randomized controlled trials. Evidence from uncontrolled studies is extremely limited but since the little evidence that does exist suggests a potential benefit, randomized controlled trials are recommended.
Background
Description of the condition
The incidence of persistent pulmonary hypertension of the newborn (PPHN) varies widely depending on the center. Walsh‐Sukys estimated the incidence of PPHN to be 1.9/1000 live births (0.43 to 6.82 per 1,000 live births)(Walsh‐Sukys 2000). PPHN can occur as a primary condition or be secondary to meconium aspiration, respiratory distress syndrome, infection or congenital diaphragmatic hernia (Finer 2004). Approximately half of infants with PPHN have meconium aspiration syndrome.
There are no data on the incidence of PPHN in developing countries, but since birth asphyxia and meconium aspiration occur more frequently in this setting (Ellis 2000; Nasheit 2003; Moodley 1998; Costello 1994), it is likely PPHN also occurs more frequently.
There is no universally agreed upon definition for PPHN. The diagnosis is usually based on clinical features; the patient is hypoxic in spite of maximal ventilation and oxygen supplementation (Tolsa 1995). Echocardiography is used to confirm the diagnosis by demonstrating right to left shunting at the ductal or atrial level with posterior systolic bowing of the interventricular septum or systolic pulmonary artery pressure (PAP) greater than or equal to 75% of systolic aortic pressure (Davidson 1998). PAP is estimated by measuring the tricuspid regurgitant jet gradient (Skinner 1993); however, facilities for these measurements may not always be available. An alternative method for establishing the diagnosis is the measurement of a preductal versus postductal transcutaneous oxygen saturation gradient of 10% or greater (Davidson 1998). However, the outcome is similar whether the diagnosis is based on clinical criteria or on the presence of echocardiographic evidence of PPHN (Finer 2004).
Generally, newborns with PPHN are paralyzed or sedated and placed on intermittent positive pressure ventilation (IPPV). High frequency oscillatory ventilation has been used, but there is little data from randomized controlled trials to support its efficacy (Bhuta 2005). Inhaled nitric oxide (iNO) is the only known selective pulmonary vasodilator, by virtue of being directly delivered to the airways. Inhaled nitric oxide improves oxygenation in 50% of treated infants and reduces the requirement for ECMO (Finer 2004). ECMO is considered the last line of management. Besides iNO and ECMO, other treatments described include intravenous or nebulized tolazoline (Parida 1997; Welch 1995), intravenous adenosine (Konduri 1996; Ng 2004) and intravenous sildenafil (Shekerdemian 2002).
Description of the intervention
The drawback with many of the conventional therapies (iNO, ECMO) is the expense and required technical expertise. Many neonatal units in developing countries do not have the resources for these interventions. If magnesium sulfate were shown to be effective in the treatment of PPHN, then perhaps some lives could be saved in the developing world.
How the intervention might work
The use of magnesium sulfate for the treatment of PPHN has been described. Non‐randomized studies using magnesium sulfate in doses of 20 ‐ 100 mg/kg/hour (preceded by a loading dose of 200 mg/kg) suggest it may be effective (Abu‐Osba 1992; Tolsa 1995; Daffa 2002). It is a potent vasodilator. The exact mechanism of action of magnesium sulfate in PPHN is only partially understood. Animal studies have established that magnesium sulfate is a modulator of vascular contraction. It activates many cellular processes, including cation transport, and modulates membrane excitability. It is also a physiological calcium antagonist. Magnesium decreases the frequency of depolarization of smooth muscle by modulating calcium uptake, binding and distribution in smooth muscle cells, thereby promoting vasodilatation (Turlapaty 1978). Magnesium sulfate may help in PPHN due to its sedative, muscle relaxant and bronchodilator effects, or by its associated alkalosis (Patole 1995). It has been used in a variety of other conditions including myocardial infarction, severe bronchial asthma, migraine and mania. (MAGIC 2002; Rowe 2005; Bigal 2002; Heiden 1999). Excessive magnesium causes hypotonia, hypotension, and cardiorespiratory failure (Andrews 1965; Brady 1967; Lipitz 1971; Mofenson 1991; Sullivan 2000; Ali 2003).
Why it is important to do this review
Magnesium sulfate has been extensively used in the management of preeclampsia. A systematic review of magnesium sulfate as a tocolytic agent found an association between use of magnesium sulfate and increased mortality in the infant, raising concern for its use (Crowther 2003a). However, other research has suggested that magnesium sulfate is neuroprotective (Crowther 2003). A Cochrane review has shown that magnesium sulfate is neuroprotective to the fetus (Doyle 2009). A further Cochrane protocol is evaluating its potential neuroprotective effect on the neonate following perinatal asphyxia (Kent 2003).
This systematic review compares magnesium sulfate with either with placebo or no treatment or with other active treatment in infants with PPHN.
Objectives
To determine the effect of magnesium sulfate on mortality, the use of backup iNO or ECMO, and neurodevelopmental outcome in term and near‐term newborns (> 34 weeks gestational age) with PPHN. Treatment with magnesium sulfate will be compared to:
placebo or standard ventilator management alone;
sildenafil infusion;
adenosine infusion;
inhaled nitric oxide.
Subgroup analysis was planned on the basis of diagnosis of PPHN:
echocardiographic diagnosis vs. criteria defining severity of the hypoxia or pre and postductal gradient;
ventilator support vs. no ventilator support.
Methods
Criteria for considering studies for this review
Types of studies
Randomized or quasi‐randomized studies.
Types of participants
Term and near term neonates (> 34 weeks gestation at birth and < 1 month of age) with PPHN diagnosed by degree of hypoxia [such as PaO2 of less than 50 mm Hg or 6.67 kPa or Oxygenation Index (OI) > 25] or echocardiographic criteria.
Types of interventions
Magnesium sulfate infusion of any dose or duration.
The comparison group would be:
placebo or standard ventilator management alone;
sildenafil infusion;
adenosine infusion;
inhaled nitric oxide.
Both groups may or may not be on assisted ventilation. Treatment backup with iNO and ECMO was allowed in either group.
Types of outcome measures
Primary outcomes
All cause mortality to hospital discharge or 28 days of age.
Use of inhaled nitric oxide or ECMO.
Mortality or the use of backup therapy (iNO or ECMO).
Secondary outcomes
Failure to improve oxygenation within 30 to 60 minutes (dichotomous variable).
Short term effect on oxygenation index and arterial PO2 after therapy (both absolute values and change from baseline).
Neurodisability (> 2 standard deviation below the mean on a validated assessment tool) in first year of life.
Neurodisability (> 2 standard deviation below the mean on a validated assessment tool) in childhood and beyond.
Cerebral palsy on physician assessment.
Hearing impairment.
Duration of hospital stay (days).
Adverse effects such as hypocalcaemia and hypokalemia, cardiac arrhythmias and severe hypotension.
Search methods for identification of studies
The standard search strategy of the Cochrane Neonatal Review Group (CNRG) was used.
Electronic searches
We searched the latest issue of the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library, Issue 1, 2006) and MEDLINE from 1966 up to April 20, 2007 for all reports of relevant randomized and quasi‐randomized trials. The search strategy for CENTRAL and MEDLINE used the MeSH terms infant newborn, AND magnesium sulfate, AND (persistent fetal circulation OR the keywords pulmonary hypertension OR persistent pulmonary hypertension of the newborn). No language restrictions were applied.
In December 2009, we updated the search as follows: MEDLINE (search via PubMed), CINAHL, EMBASE and CENTRAL (The Cochrane Library) were searched from 1999 to 2009. Search terms: magnesium sulfate AND persistent fetal circulation OR pulmonary hypertension OR persistent pulmonary hypertension of the newborn. Limits: human, infant and clinical trial. No language restrictions were applied.
Searching other resources
In addition to the electronic search, we reviewed the reference lists of retrieved articles and to obtain unpublished data contacted known experts.
Data collection and analysis
The standard methods of the CNRG were used.
Selection of studies
All randomized and quasi‐randomized controlled trials fulfilling the selection criteria described in the previous section were to be included. Two investigators reviewed the results of the search separately for selection of the studies for inclusion. The review authors resolved any disagreement by discussion.
Data extraction and management
If studies were deemed eligible for inclusion, two review authors planned to separately extract, assess and code all data for each study using a form that was designed specifically for this review.
Assessment of risk of bias in included studies
Independent assessment of retrieved reports for methodological quality and eligibility by each review author was planned. If trials were found evaluation of the quality of these trials would include blinding of randomization, completion of follow up and blinding of outcome assessment.If available, this information would be entered into the "Characteristics of Included Studies" table.
If studies were located for the 2009 update, we planned to complete the Risk of Bias table. If studies were deemed appropriate for inclusion, two authors planned to independently assess the risk of bias for each study using the criteria outlined in the Cochrane Handbook for Systematic Reviews of Interventions.
Measures of treatment effect
Statistical analyses were to be performed using Review Manager software. If available, categorical data were to be analyzed using relative risk (RR), risk difference (RD) and the number needed to treat (NNT). Continuous data were to be analyzed using weighted mean difference (WMD). The 95% Confidence interval (CI) was to be reported on all estimates as a measure of uncertainty.
Assessment of heterogeneity
We planned to estimate the treatment effects of individual trials and examine heterogeneity between trials by inspecting the forest plots and quantifying the impact of heterogeneity using the I2 statistic. If we detected statistical heterogeneity, we planned to explore the possible causes (for example, differences in study quality, participants, intervention regimens, or outcome assessments) using post hoc subgroup analyses.
Data synthesis
If multiple studies were identified and meta‐analysis was judged to be appropriate, the analysis would have been performed using Review Manager software (RevMan 5), supplied by the Cochrane Collaboration. For estimates of typical relative risk and risk difference, we planned to use the Mantel‐Haenszel method. For measured quantities, we planned to use the inverse variance method. All meta‐analyses were to be done using the fixed effect model.
Subgroup analysis and investigation of heterogeneity
A sensitivity analysis was planned based on trial quality.
Results
Description of studies
Five clinical trials of magnesium sulfate were identified (Abu‐Osba 1992; Chandran 2004; Daffa 2002; Tolsa 1995; Wu 1995). All were uncontrolled trials. In addition, one randomised controlled trial using adenosine (Konduri 1996) and one using sildenafil (Baquero 2006) for PPHN was found. Neither study compared the intervention to magnesium sulfate. The reasons for exclusion are given in the table of excluded studies. No studies that met the inclusion criteria of the review were found.
Risk of bias in included studies
No randomized controlled trials were found for inclusion in the review.
Effects of interventions
No randomized controlled trials were found for inclusion in the review.
Discussion
There is extremely limited information on the use of magnesium sulfate for PPHN. Of the five uncontrolled clinical studies identified, four were on term infants (Abu‐Osba 1992; Chandran 2004; Daffa 2002; Wu 1995) and included a total of only 40 patients. One further study included seven preterm infants (Wu 1995). In all studies, the diagnosis was made on clinical grounds. In one study, the investigators did echocardiogram on all infants prior to starting magnesium sulfate. All patients were on mechanical ventilation prior to magnesium sulfate infusion. In all studies, a loading dose of 200 mg/kg was used and was followed by a continuous infusion of 20 to 150 mg/kg/hr. Magnesium levels were measured and the dose was adjusted to maintain a normal blood level. All studies showed a significant improvement in oxygenation measured by changes in partial oxygen pressure, alveolar‐arterial oxygen index, oxygen index or change in ventilatory requirement. In three of the studies inotropes were given to all or most patients. Only one study did not use inotropic agents. In this study, there was a transient fall in blood pressure two hours after commencing the infusion that normalized by eight hours. One study reported a transient bradycardia that was corrected by dobutamine infusion. No other adverse effects were reported. Of the 40 infants, 35 survived. Two were reported to have bronchopulmonary dysplasia, one of whom died. Most studies reported the one year outcome. None had formal neurological assessment, but all reported that all survivors were developing normally. One study did formal hearing assessment and reported no hearing loss.
Given the consistent improvement noted in these four observational studies involving term infants, randomized controlled trials should be performed. As high income countries have access to the expensive but effective treatment iNO, such studies would have to be done in this setting. PPHN is not a common condition and developing countries may consider it a low priority, preferring to channel scarce manpower and resources into areas likely to result in greater reductions in mortality. The low incidence of this condition would also mean that any studies would have to be multicenter, posing further difficulties for resource poor countries wishing to tackle this question.
Although these studies suggested an improvement in oxygenation following infusion of magnesium sulphate, there is no evidence from randomized controlled trials to support its use. Given the absence of evidence, magnesium sulfate cannot be recommended as a treatment for PPHN.
Authors' conclusions
Implications for practice.
There is no evidence of benefit or harm in the use of magnesium sulfate for PPHN.
Implications for research.
Uncontrolled clinical trials suggest a potential benefit of magnesium sulfate in infants with PPHN. Since magnesium sulfate is inexpensive and potentially beneficial, randomized controlled trials are recommended. Such trials could be carried out in settings where iNO or ECMO are not available. Besides mortality, outcome measures should include adverse effects such as the incidence of hypotension, hypocalcaemia, apnea and cardiac arrhythmias. Survivors should be followed up for neurodevelopmental outcome.
What's new
| Date | Event | Description |
|---|---|---|
| 22 December 2009 | New search has been performed | This review updates the existing review "Magnesium sulfate for persistent pulmonary hypertension of the newborn" published in the Cochrane Database of Systematic Reviews (Ho 2007). Updated search found no new trials. No changes to conclusions. |
History
Protocol first published: Issue 1, 2006 Review first published: Issue 3, 2007
| Date | Event | Description |
|---|---|---|
| 22 August 2008 | Amended | Converted to new review format. |
| 1 March 2007 | New citation required and conclusions have changed | Substantive amendment |
Acknowledgements
The Cochrane Neonatal Review Group has been funded in part with Federal funds from the Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Department of Health and Human Services, USA, under Contract No. HHSN267200603418C.
Characteristics of studies
Characteristics of excluded studies [ordered by study ID]
| Study | Reason for exclusion |
|---|---|
| Abu‐Osba 1992 | Uncontrolled study |
| Baquero 2006 | Sildenafil was not compared with magnesium sulfate |
| Chandran 2004 | Uncontrolled study |
| Daffa 2002 | Uncontrolled study |
| Konduri 1996 | Trial of adenosine compared with normal saline. No comparison with magnesium sulfate |
| Tolsa 1995 | Uncontrolled study |
| Wu 1995 | Uncontrolled study on preterm infants |
Contributions of authors
GR wrote the protocol with input from JJH JJH performed the search and wrote the review with input from GR
The recent update (December 2009) was conducted centrally by the Cochrane Neonatal Review Group staff (Yolanda Montagne, Diane Haughton and Roger Soll) and reviewed and approved by JJH.
Sources of support
Internal sources
Royal College of Medicine, Perak, Malaysia.
Dept of Paediatrics, Hospital Ipoh, Malaysia.
University of Kuala Lumpur, Malaysia.
External sources
Centre for Perinatal Health Services Research, University of Sydney, Australia.
Declarations of interest
None
New search for studies and content updated (no change to conclusions)
References
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