Magnesium sulfate for persistent pulmonary hypertension of the newborn

Ho JJ, Rasa G

Background - Methods - Results - References

 

Dates

Date edited: 23/05/2007
Date of last substantive update: 01/03/2007
Date of last minor update: 20/04/2007
Date next stage expected 01/03/2009
Protocol first published: Issue 1, 2006
Review first published: Issue 3, 2007

Contact reviewer

Prof Jacqueline J Ho
Head of Department
Dept Paediatrics
Penang Medical College
4 Sepoy Lines
Penang
MALAYSIA
10450
Telephone 1: +60 4 2263459
Telephone 2: +60 5 2532863
Facsimile: +60 4 2284285
E-mail: jho@pc.jaring.my
Secondary address:
Hospital Ipoh
Ipoh
MALAYSIA
30990
Telephone: +60 5 2533333 extension: 2441
Facsimile: +60 5 2531541

Contribution of reviewers

GR wrote the protocol with input from JJH
JJH performed the search and wrote the review with input from GR

Internal sources of support

Royal College of Medicine, Perak, MALAYSIA
Dept of Paediatrics, Hospital Ipoh, MALAYSIA
University of Kuala Lumpur, MALAYSIA

External sources of support

Centre for Perinatal Health Services Research, University of Sydney, AUSTRALIA

What's new

Dates

Date review re-formatted: / /
Date new studies sought but none found: / /
Date new studies found but not yet included/excluded: / /
Date new studies found and included/excluded: / /
Date reviewers' conclusions section amended: / /
Date comment/criticism added: / /
Date response to comment/criticisms added: / /

Text of review

Synopsis


Pending


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 extra corporeal 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 strategy


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.

Selection criteria


All randomised or quasi-random studies were eligible where one of the treatment groups received magnesium sulfate for PPHN.

Data collection & 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

Reviewers' 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.

Background


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 - 6.82 per 1,000 live births) with half of these newborns having meconium aspiration (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).

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).

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.

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).

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). Two Cochrane protocols are evaluating magnesium sulfate as a potential neuroprotective agent for the fetus and neonate (Crowther 2003; 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:

Subgroup analysis was planned on the basis of diagnosis of PPHN:


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:

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
1. All cause mortality to hospital discharge or 28 days of age
2. Use of inhaled nitric oxide or ECMO
3. Mortality or the use of backup therapy (iNO or ECMO)

Secondary
1. Failure to improve oxygenation within 30 to 60 minutes (dichotomous variable)
2. Short term effect on oxygenation index and arterial PO2 after therapy (both absolute values and change from baseline).
3. Neurodisability (> 2 standard deviation below the mean on a validated assessment tool) in first year of life
4. Neurodisability (> 2 standard deviation below the mean on a validated assessment tool) in childhood and beyond
5. Cerebral palsy on physician assessment
6. Hearing impairment
7. Duration of hospital stay (days)
8. Adverse effects such as hypocalcaemia and hypokalemia, cardiac arrhythmias and severe hypotension

Search strategy for identification of studies


The standard search strategy of the Cochrane Neonatal Review Group (CNRG) was used. 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. In addition we reviewed the reference lists of retrieved articles and to obtain unpublished data contacted known experts. 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.

Methods of the review


The standard methods of the CNRG were used. The searches were done by JJH. 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. For any study that was located agreement about trial inclusion would be reached by consensus. Data extraction was independently by two review authors was planned.

Data synthesis using the standard methods of the CNRG was planned. This included the use of relative risk (RR), risk difference (RD), number needed to treat (NNT) or
number needed to harm (NNH) derived from 1/RD, and mean difference for continuous outcomes. For each estimate of effect the 95% confidence intervals would be given in brackets. We planned to use a fixed effects model, Q or I2, or both, to estimate heterogeneity. If heterogeneity was observed, it was planned to be explored using a sensitivity analysis. A sensitivity analysis was planned based on trial quality.

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. Besides these studies, 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.

Methodological quality of included studies


No randomized controlled trials were found for inclusion in the review.

Results


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 - 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.

Reviewers' 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.

Acknowledgements



Potential conflict of interest


None

Characteristics of excluded studies

StudyReason for exclusion
Abu-Osba 1992Uncontrolled study
Baquero 2006Sildenafil was not compared with magnesium sulfate
Chandran 2004Uncontrolled study
Daffa 2002Uncontrolled study
Konduri 1996Trial of adenosine compared with normal saline. No comparison with magnesium sulfate
Tolsa 1995Uncontrolled study
Wu 1995Uncontrolled study on preterm infants

Characteristics of ongoing studies

StudyTrial name or titleParticipantsInterventionsOutcomesStarting dateContact informationNotes
Boo 2004

References to studies

References to excluded studies

Abu-Osba 1992 {published data only}

Abu-Osba YK, Galal O, Manasra K, Rejjal A. Treatment of severe persistent pulmonary hypertension of the newborn with magnesium sulphate. Archives of Disease in Childhood 1992;67:31-5.

Baquero 2006 {published data only}

Baquero H, Soliz A, Neira F, Venegas ME, Sola A. Oral sildenafil in infants with persisitent pulmonary hypertension of the newborn: a pilot randomized blinded study. Pediatrics 2006;117:1077-83.

Chandran 2004 {published data only}

Chandran S, Haque ME, Wickramasinghe HR, Wint Z. Use of magnesium sulphate in severe persistent pulmonary hypertension of the newborn. Journal of Tropical Pediatrics 2004;50:219-23.

Daffa 2002 {published data only}

Daffa SH, Milaat WA. Role of magnesium sulphate in treatmet of severe persistent pulmonary hypertension of the newborn. Saudi Medical Journal 2002;23:1266-9.

Konduri 1996 {published data only}

Konduri GG, Garcia DC, Kazzi NJ, Shankaran S. Adenosine infusion improves oxygenation in term infants with respiratory failure. Pediatrics 1996;97:295-300.

Tolsa 1995 {published data only}

Tolsa JF, Cotting J, Sekarski N, Payot M, Micheli JL, Calame A. Magnesium sulphate as an alternative and sage treatment for severe persistent pulmonary hypertension of the newborn. Archives of Disease in Childhood 1995;72:F184-7.

Wu 1995 {published data only}

Wu TJ, Teng RJ, Tsou KI. Persistent pulmonary hypertension of the newborn treated with magnesium sulfate in premature neonates. Pediatrics 1995;96:472-4.

References to ongoing studies

Boo 2004 {unpublished data only}

* indicates the primary reference for the study

Other references

Additional references

Ali 2003

Ali A, Walentik C, Mantych GJ, Sadiq F, Keenan WJ, Noguchi A. Iatrogenic acute hypermagnesemia after total parenteral nutrition infusion mimicking septic shock syndrome: two case reports. Pediatrics 2003;112:e70-2. URL: http://www.pediatrics.org/cgi/content/full/112/1/e70.

Andrews 1965

Andrews BF, Campbell DR, Thomas P. Effects of hypertonic magnesium-sulphate enemas on newborn and young lambs. Lancet 1965;ii:64-5.

Bhuta 2005

Bhuta T, Clark RH, Henderson-Smart DJ. Rescue high frequency oscillatory ventilation vs conventional ventilation for infants with severe pulmonary dysfunction born at or near term. In: Cochrane Database of Systematic Reviews, Issue 1, 2001.

Bigal 2002

Bigal ME, Bordini CA, Tepper SJ, Speciali JG. Intravenous magnesium sulphate in the acute treatment of migraine without aura and migraine with aura. A randomized, double-blind, placebo-controlled study. Cephalalgia 2002;22:345-53.

Born 1954

Born GV, Dawes GS, Mott JC, Widdicomb JG. Changes in the heart and lungs at birth. Cold Spring Harbor Symposium on Quantitative Biology 1954;19:102.

Brady 1967

Brady JP, Williams HC. Magnesium intoxication in a premature infant. Pediatrics 1967;40:100-3.

Clark 2000

Clark RH, Slutsky AS, Gerstmann DR. Lung protective strategies of ventilation in the neonate: what are they? Pediatrics 2000;105:112-4.

Costello 1994

Costello AM, Manandhar DS. Perinatal asphyxia in less developed countries. Archives of Disease in Childhood Fetal and Neonatal Edition 1994;71:F1-3.

Crowther 2003

Crowther CA, Hiller JE, Doyle LW, Haslam RR, Australasian Collaborative Trial of Magnesium Sulphate (ACTOMg SO4) Collaborative Group. Effect of magnesium sulfate given for neuroprotection before preterm birth: a randomized controlled trial. JAMA 2003;290:2669-76.

Crowther 2003a

Crowther CA, Hiller JE, Doyle LW. Magnesium sulphate for preventing preterm birth in threatened preterm labour. In: Cochrane Database of Systematic Reviews, Issue 4, 2002.

Crowther 2004

Crowther CA, Doyle LW. Magnesium sulphate prior to preterm birth for neuroprotection of the fetus [Protocol]. In: Cochrane Database of Systematic Reviews, Issue 1, 2004.

Davidson 1998

Davidson D, Barefield ES, Kattwinkel J, Dudell G, Damask M, Straube R et al. Inhaled nitric oxide for the early treatment of persistent pulmonary hypertension of the term newborn: a randomized, double-masked, placebo-controlled, dose-response, multicenter study. The I-NO/PPHN Study Group. Pediatrics 1998;101:325-34.

Ellis 2000

Ellis M, Manandhar DS, Manandhar N, Wyatt J, Bolam AJ, Costello AM. Stillbirths and neonatal encephalopathy in Kathmandu, Nepal: an estimate of the contribution of birth asphyxia to perinatal mortality in a low-income urban population. Paediatric and Perinatal Epidemiology 2000;14:39-52.

Finer 2004

Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. In: Cochrane Database of Systematic Reviews, Issue 4, 2001.

Heiden 1999

Heiden A, Frey R, Presslich O, Blasbichler T, Smetana R, Kasper S. Treatment of severe mania with intravenous magnesium sulphate as a supplementary therapy. Psychiatry Research 1999;89:239-46.

Kent 2003

Kent A, Kecskes Z. Magnesium sulfate for term infants following perinatal asphyxia. [Protocol]. In: Cochrane Database of Systematic Reviews, Issue 2, 2003.

Kuo 2001

Kuo S, Camerini V, Boyle R, Griffin MP, Kaufman D, Kattwinkel J. Pulmonary hypertension-hyperventilation versus alkali infusion. [comment]. Pediatrics 2001;107:452.

Lipitz 1971

Lipitz JP. The clinical and biochemical effects of excess magnesium in the newborn. Pediatrics 1971;47:501-9.

MAGIC 2002

Magnesium in Coronaries (MAGIC) Trial Investigators. Early administration of intravenous magnesium to high-risk patients with acute myocardial infarction in the Magnesium in Coronaries (MAGIC) Trial: a randomised controlled trial. Lancet 2002;360:1189-96.

Mofenson 1991

Mofenson HC, Caraccio TR. Magnesium intoxication in a neonate from oral magnesium hydroxide laxative. Clinical Toxicology 1991;29:215-22.

Moodley 1998

Moodley J, Matchaba P, Payne AJ. Intrapartum amnioinfusion for meconium-stained liquor in developing countries. Tropical Doctor 1998;28:31-4.

Nasheit 2003

Nasheit NA. Perinatal and neonatal mortality and morbidity in Iraq. Journal of Maternal-Fetal & Neonatal Medicine 2003;13:64-7.

Ng 2004

Ng C, Franklin O, Vaidya M, Pierce C, Petros A. Adenosine infusion for the management of persistent pulmonary hypertension of the newborn. Pediatric Critical Care Medicine 2004;5:10-3.

Parida 1997

Parida SK, Baker S, Kuhn R, Desai N, Pauly TH. Endotracheal tolazoline administration in neonates with persistent pulmonary hypertension. Journal of Perinatology 1997;17:461–4.

Patole 1995

Patole SK, Finer NN. Experimental and clinical effects of magnesium infusion in the treatment of neonatal pulmonary hypertension. Magnesium Research 1995;8:373-88.

Ranieri 1999

Ranieri VM, Suter PM, Tortorella C, De Tullio R, Dayer JM, Brienza A et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome: a randomized controlled trial. JAMA 1999;282:54-61.

Rowe 2005

Rowe BH, Bretzlaff JA, Bourdon C, Bota GW, Camargo CA Jr. Magnesium sulfate for treating exacerbations of acute asthma in the emergency department. In: Cochrane Database of Systematic Reviews, Issue 1, 2000.

Shekerdemian 2002

Shekerdemian LS, Ravn HB, Penny DJ. Intravenous sildenafil lowers pulmonary vascular resistance in a model of neonatal pulmonary hypertension. American Journal of Respiratory & Critical Care Medicine 2002;165:1098-102.

Skinner 1993

Skinner JR, Stuart AG, O'Sullivan J, Heads A, Boys RJ, Hunter S. Right heart pressure determination by Doppler in infants with tricuspid regurgitation. Archives of Disease in Childhood 1993;69:216-20.

Sullivan 2000

Sullivan JE, Berman BW. The pediatric forum; hypermagnesemia with lethargy and hypotonia due to administration of magnesium hydroxide to a 4-week old infant. Archives of Pediatric and Adolescent Medicine 2000;154:1272-4.

Turlapaty 1978

Turlapaty PD, Altura BM. Extracellular magnesium ions control calcium exchange and content of vascular smooth muscle. European Journal of Pharmacology 1978;52:421-3.

Walsh-Sukys 2000

Walsh-Sukys MC, Tyson JE, Wright LL, Bauer CR, Korones SB, Stevenson DK et al. Persistent pulmonary hypertension of the newborn in the era before nitric oxide: practice variation and outcomes. Pediatrics 2000;105:14-20.

Welch 1995

Welch JC, Bridson JM, Gibbs B. Endotracheal tolazoline for severe persistent pulmonary hypertension of the newborn. British Heart Journal 1995;73:99–100.


Contact details for co-reviewers

Dr Ganesa Rasa
Lecturer
Paediatrics
Perak College of Medicine
Greentown
Perak MALAYSIA
30450
Telephone 1: 605 2432635 extension: 161
Facsimile: 605 2432636
E-mail: grasa@perakmed.edu.my

 

This review is published as a Cochrane review in The Cochrane Library, Issue 3, 2007 (see http://www.thecochranelibrary.com for information). Cochrane reviews are regularly updated as new evidence emerges and in response to feedback. The Cochrane Library should be consulted for the most recent version of the review.