Home Print this page Email this page Small font sizeDefault font sizeIncrease font size
Users Online: 424
 
About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Advertise Login 
     


 
 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 9  |  Issue : 3  |  Page : 196-201

Melatonin supplementation as an adjuvant therapy in neonatal respiratory distress syndrome


1 Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
3 Department of Physiology, Faculty of Medicine, Tanta University, Tanta, Egypt
4 Department of Pharmacology and Toxicology, Tanta University, Tanta, Egypt

Date of Submission17-Feb-2020
Date of Decision09-Mar-2020
Date of Acceptance05-May-2020
Date of Web Publication07-Aug-2020

Correspondence Address:
Dr. Mohamed Shawky Elfarargy
Assistant Professor of Pediatrics, Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, El-Gharbia
Egypt
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcn.JCN_17_20

Rights and Permissions
  Abstract 


Background: Neonatal respiratory distress syndrome (RDS) is a common serious chest disease that is caused by a deficiency of alveolar surfactant. Aim: Detection of the effect of melatonin supplementation in cases of neonatal RDS. Patients and Methods: A prospective randomized clinical trial study which was done at Tanta University Hospital from July 2016 to March 2018 on 100 neonates suffering from respiratory distress which was diagnosed as RDS. The studied neonates were divided into two groups: group 1, which had supplied with melatonin, and group 2, which had not supplied with melatonin. Grades of RDS, down score, malondialdehyde (MDA), superoxide dismutase (SOD), and interleukin-8 (IL-8) were measured on the 1st day and the 5th day of admission in the incubator. The duration of the presence of neonates in the incubator was determined, and the number of cases who needed mechanical ventilation (MV) was calculated. Results: There were significant differences in grades of RDS, Down score, MDA, SOD, IL-8 on the 5th day of admission between Group 1 and 2 (P = 0.001), and between 1st and 5th day of admission in Group 1 (P = 0.001). There was a significant difference between Groups 1 and 2 in the duration of the presence of neonates in the incubator (P = 0.001) and the number of cases who needed MV (P = 0.046). Conclusion: Melatonin supplementation could be used as adjuvant therapy for the treatment of RDS in neonates, but further studies involving a larger number of neonates must be performed on this topic. Recommendation: Melatonin supplementation for RDS neonates.

Keywords: Melatonin, neonate, respiratory distress syndrome


How to cite this article:
Elfarargy MS, Elsharaby R, Younis RL, Abu-Risha S. Melatonin supplementation as an adjuvant therapy in neonatal respiratory distress syndrome. J Clin Neonatol 2020;9:196-201

How to cite this URL:
Elfarargy MS, Elsharaby R, Younis RL, Abu-Risha S. Melatonin supplementation as an adjuvant therapy in neonatal respiratory distress syndrome. J Clin Neonatol [serial online] 2020 [cited 2020 Sep 27];9:196-201. Available from: http://www.jcnonweb.com/text.asp?2020/9/3/196/291642




  Introduction Top


Respiratory distress syndrome (RDS) is considered one of the most severe respiratory problems in neonates especially in prematurity. The disease has multiple complex causes and many existing factors are involved in its occurrence, such as gestational age (prematurity is very important risk factors), sex (males are more risk), and gestational diabetes (which increase the risk of the development of neonatal RDS).[1]

RDS develops as a result of deficiency of alveolar surfactant (AS) which is responsible for lung maturity and it is one of the main causes of the neonatal respiratory disabilities and subsequent neonatal deaths. The surfactant is mainly synthesized and secreted by the respiratory alveolar type II pneumocytes by 34 weeks of gestation in the fetus. Primary deficiency of AS is due to immaturity of pneumocytes type II which are responsible for the production of surfactant lipids and proteins. Insufficiency of AS results in declining in the pulmonary compliance and in elevation of the surface tension at the air-water interface, which resulted in increasing the risk of alveolar atelectasis at expiration followed by decreased the gas exchange which resulted in decrease the oxygenation and CO2 retention which finally lead to hypoxia and hypercapnia.[2],[3]

The therapeutic methods for the prevention of RDS in prematurity are first the antenatal corticosteroids administration, which stimulate AS synthesis by the neonatal lung, and second by giving exogenous surfactant immediately after delivery, while unfortunately, this therapy is too expensive and there are many developing countries like Egypt cannot accommodate to introduce the prophylactic artificial surfactant in all case of premature delivery as the prematurity are increasing due to the progress in the obstetric medicine.[4]

The main diagnostic criteria of neonatal RDS include chest radiographic findings with the clinical picture such as increased respiratory rate, nasal flaring, grunting, cyanosis, intercostal retraction, and decrease the air entry in pulmonary auscultation. High incidence of RDS is the most important cause for admission of preterm infants to neonatal units and may be the main reason of neonatal death in some places.[5]

The metabolites derived from oxygen which are the reactive oxygen species (ROS) are serious mediators of cell and tissue damage. Free radical reactions cause oxidative stress (OS) which lead to oxidation and damage of lipids, proteins, and DNA which lead to tissue damage.[6]

Neonates and especially the preterm infants are especially prone to OS due to the prolonged exposure to high oxygen concentrations, liability to infections or inflammation, and the presence of declined antioxidant defense function in prematurity.[7]

Melatonin is considered as a hormone which is synthesized in the pineal gland of normal individual from tryptophan which had studied on many diseases of neonates with safety and good results.[8]

Melatonin acts as an essential endogenous antioxidant by making scavenging of the dangerous-free radicals and potentiates the antioxidant pathways which protect the human body from the serious effect of OS. The activity and function of antioxidant enzymes, such as superoxide dismutase (SOD) and catalase, have been markedly increased by melatonin, which indicate the importance of indirect antioxidant action. The antioxidant function of melatonin is very obvious in reducing lipid peroxidation and subsequent cell and tissue damage.[9]

Although hyperoxia may be essential for the cases of RDS neonates, it will lead to synthesis of ROS in the respiratory system of the neonates. The high levels of oxygenation could lead to ROS accumulation and subsequently depletion of antioxidants.[9]

Studies showed that melatonin use is safe for kids with little to no side effects and melatonin can be safe and effective in treating some disorders in paediatrics.[10] The aim of this study is to detect the effect of melatonin supplementation in cases of neonatal RDS.


  Patients and Methods Top


This research was a prospective randomized clinical trial (RCT), that was performed at Tanta University Hospital from June 2016 to March 2018 on 100 neonates suffering from RD which was diagnosed as RDS. The examined neonates who are 100 cases were divided into two groups, we had numbered the neonates from 1 to 100 and we had chosen the odd number for neonates of Group 1 and even numbers for neonates of Group 2, in which group 1 consisted of 50 neonates who received melatonin supplementation in addition to respiratory support(without artificial surfactant) (melatonin group), and group 2 consisted of 50 neonates who received respiratory support only(without artificial surfactant) and did not receive melatonin(nonmelatonin group).

This RCT was approved by the Ethics Committee, Thai Clinical Trials Registry (TCTR) identification number is TCTR20200326001. Written informed consent was signed from the parents of all neonates.

RDS cases were diagnosed based on clinical and radiological diagnosis of RDS in the form of the presence of manifestation of RD according to the criteria of Downs' score combined with chest X-ray findings which include multiple diffuse mainly fine granular densities (Grade 1), air bronchograms (Grade 2), the characteristic ground-glass appearance (Grade 3), or white lungs (Grade 4). The patient group was classified clinically according to the degree of RD where Grade 1 was tachypnea only, Grade 2 was tachypnea and retraction, Grade 3 was tachypnea, retraction and grunting, and finally Grade 4 was tachypnea, retraction, grunting, and cyanosis.[11],[12]

Group 1 (n = 50): Neonates of this group had received melatonin in a dosage of 10 mg/kg daily as a single daily dose for 5 days. Melatonin tablets (3 mg/tablet; Puritan's Pride®, Oakdale, NY, USA) were crushed, dissolved in 5 ml of distilled water, and were given through an orogastric tube.[13],[14]

  • Inclusion criteria: neonates suffering from respiratory distress syndrome whatever its grade
  • Exclusion criteria: neonatal sepsis, diseases of the respiratory diseases other than RDS, cardiovascular diseases, or central nervous system diseases, surfactant administration.


In spite that studies showed that melatonin use is safe for kids with little to no side effects and melatonin can be safe and effective in treating some disorders in paediatrics,[10] we followed the neonates which had melatonin supplementation and there was no any potential side effect (like nausea, diarrhoea or abnormalities in the sleep pattern) was appeared.

Data collections

History taking, chest and systemic examination, respiratory examination were done for the diagnose RDS. Chest X-ray was done for all studied neonates.

Specimen collection

Two milliliter of venous blood samples were withdrawn from the neonates during the 1st day after birth. Blood specimens were divided into two samples, the first sample was centrifuged to separate serum for the determination of interleukin-8 (IL-8) and the second sample was heparinized and centrifuged to separate plasma (for determination of malondialdehyde [MDA] and SOD), the two samples were stored at −20°C–−70°C.[15],[16],[17]

Determination of serum interleukin-8

They were tested by ELISA method.[15]

Estimation of plasma malondialdehyde levels as an oxidative stress marker

Principle: Thiobarbituric acid (TBA) reacts with MDA mainly in the acidic medium at 95°C for ½ h to produce the TBA reactive product. The absorption of the produced pink product can be calculated at 534 nm. Total TBA reactive products are expressed as MDA.[16]

Estimation of plasma superoxide dismutase as an antioxidant enzyme activity

Principle: This measurement depends on the enzyme inhibition to the phenazine methosulfate–mediated reduction of nitro blue tetrazolium dye. The color which originate was measured at 560 nm.[17]

Statistical analysis

Data was expressed using the mean, standard deviation and chi-square test. Independent-samples t-test was used when comparing between two groups. Paired Samples t-test was used when comparing among different times in the same group. Chi-square (X2) test for comparison between 2 groups as regards qualitative data. P < 0.05 was considered as a significant. The computer program was SPSS version 21, IBM, Armonk, NY, USA


  Results Top


[Table 1] shows that no significant difference as regard weight, gestational age, APGAR score, Down score, grades of RDS,[11],[12] mode of delivery, and sex between Group 1 and 2.
Table 1: Comparative characteristics between the studied groups

Click here to view


[Table 2] shows no significant difference of grades of RDS[11],[12] at the 1st day of admission between Group 1 and 2 (P = 0.367), and between 1st and 5th day of admission in Group 2 (P = 0.083), while there were significant difference of grades of RDS[11],[12] at the 5th day of admission between Group 1 and 2 (P = 0.001), and between 1st and 5th day of admission in Group 1 (P = 0.001).
Table 2: Grades of respiratory distress syndrome and down score in Group 1 and 2 at the 1st and 5th days of admission

Click here to view


[Table 2] shows also no significant difference of Down score at the 1st day of admission between Group 1 and 2 (P = 0.902), and between 1st and 5th day of admission in Group 2 (P = 0.065), while there were a significant difference of Down score at the 5th day of admission between Group 1 and 2 (P = 0.001), and between 1st and 5th day of admission in Group 1 (P = 0.001).



[Table 3] shows no significant difference of plasma MDA levels at the 1st day of admission between Group 1 and 2 (P = 0.978), and between 1st and 5th day of admission in Group 2 (P = 0.507), while there were significant difference of plasma MDA levels at the 5th day of admission between Group 1 and 2 (P = 0.001), and between 1st and 5th day of admission in Group 1 (P = 0.001).
Table 3: Plasma malondialdehyde levels as oxidant markers and superoxide dismutase levels as antioxidants markers in Group 1 and 2 at the 1st and 5th days of admission

Click here to view


[Table 3] shows also no significant difference of plasma SOD levels at the 1st day of admission between Group 1 and 2 (P = 0.992), and between 1st and 5th day of admission in Group 2 (P = 0.893), while there were significant difference of plasma SOD levels at the 5th day of admission between Group 1 and 2 (P = 0.001), and between 1st and 5th day of admission in Group 1 (P = 0.001).

[Table 4] shows no significant difference of serum IL-8 levels at the 1st day of admission between Group 1 and 2 (P = 0.631), and between 1st and 5th day of admission in Group 2 (P = 0.085), while there were significant difference of serum IL-8 levels at the 5th day of admission between Group 1 and 2 (P = 0.001), and between 1st and 5th day of admission in Group 1 (P = 0.001).
Table 4: Serum interleukin.8 levels as pro.inflammatory cytokine in both groups of respiratory distress syndrome at the 1st and 5th days of admission

Click here to view


[Table 5] shows significant difference of duration of neonatal stay in the incubator (days) between Group 1 and 2 (P = 0.001).
Table 5: Duration of the stay of neonates in the incubators

Click here to view


[Table 6] shows significant difference of number of cases that had needed mechanical ventilation (MV) between Group 1 and 2 (P = 0.046).
Table 6: Number of cases that had needed mechanical ventilation

Click here to view



  Discussion Top


Neonatal RDS is an important and common neonatal chest disorder which is considered one of the major causes of deaths in neonates and is caused by a lack of pulmonary surfactant due to fetal lung immaturity. The treatment of neonatal RDS is surfactant application which result in neonatal improvement. The risk factors for RDS are prematurity, cesarean section, and gestational diabetes.[18]

Our study revealed that there was significant difference of grades of RDS, Down score, MDA (OS marker), SOD (antioxidant enzyme), IL-8 (pro-inflammatory cytokines) at the 5th day of admission between Group 1 and 2 (P = 0.001), and between 1st and 5th day of admission in group 1 (P = 0.001). There was significant difference between Group 1 and 2 in the duration of the presence of neonates in the incubator (P = 0.001) and the number of cases who needed MV (P = 0.046).

This study showed increased IL-8 in RDS cases which decreased with the administration of melatonin and this in agreement with studies which showed that the melatonin treatment of cases of neonatal RDS was associated with decreased IL-8 if compared to neonatal RDS who did not receive melatonin supplementation, so the melatonin demonstrates anti-inflammatory properties in cases of neonatal RDS.[14]

This study showed that melatonin administration in cases of neonatal RDS was accompanied by significantly decreased down score, pro-inflammatory cytokines, duration of the stay of neonates in incubator, and number of cases that had needed MV if compared with cases of neonatal RDS who did not receive melatonin administration and this was in agreement with the studies which showed that melatonin treatment would lower pro-inflammatory cytokines in neonates with RDS Grade 3 or 4 and that melatonin was accompanied by improved the clinical outcome.[19]

This study showed that melatonin administration in cases of neonatal RDS was accompanied by significantly decreased Down score, IL-8 (pro-inflammatory cytokines), and duration of the stay of neonates in incubators and number of cases that had needed MV if compared with cases of neonatal RDS who did not receive melatonin administration and this was in agreement with the studies which showed that melatonin treatment would lower pro-inflammatory cytokines in neonates with RDS and this was in agreement with the studies which examined the pro-inflammatory cytokines (e.g., IL-8) and the clinical status in RDS neonates who were treated with melatonin and revealed that melatonin treatment had potent anti-inflammatory effects.[20]

Melatonin is an endogenous neurohormone that has a potent antioxidant activity either as a direct scavenger of O2 free radicals[21] or by indirect antioxidant activity through the stimulation of antioxidant enzymes, so melatonin is very beneficial in neonatal stress condition where the neonate is in need for O2 especially in cases of neonatal RD.[22],[23]

ROS are essential in the pathogenesis of RDS and its complications. In agreement with this study there was a study which conducted to determine if melatonin would affect IL-8 in RDS neonates which had been revealed that IL-8 were higher in untreated RDS neonates than in the melatonin-treated neonates. After melatonin application, IL-8 was declined.[19]


  Conclusion Top


Melatonin supplementation could be used as adjuvant therapy for the treatment of RDS in neonates, but further studies involving more neonates must be performed on this topic.

Recommendation

Melatonin supplementation for RDS neonates.

Limitation of the study

The limited number of neonates in the study, so other researches should be done.

Financial support and sponsorship

The funding was our own money.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Matthay MA, Ware LB, Zimmerman GA. The acute respiratory distress syndrome. J Clin Invest 2012;122:2731-40.  Back to cited text no. 1
    
2.
Roberts D, Brown J, Medley N, Dalziel SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev 2017;3:CD004454.  Back to cited text no. 2
    
3.
Kemp MW, Newnham JP, Challis JG, Jobe AH, Stock SJ. The clinical use of corticosteroids in pregnancy. Hum Reprod Update 2016;22:240-59.  Back to cited text no. 3
    
4.
Garbrecht MR, Klein JM, Schmidt TJ, Snyder JM. Glucocorticoid metabolism in the human fetal lung: Implications for lung development and the pulmonary surfactant system. Biol Neonate 2006;89:109-19.  Back to cited text no. 4
    
5.
Wang J, Liu X, Zhu T, Yan C. Analysis of neonatal respiratory distress syndrome among different gestational segments. Int J Clin Exp Med 2015;8:16273-9.  Back to cited text no. 5
    
6.
Mortezaee K, Khanlarkhani N. Melatonin application in targeting oxidative-induced liver injuries: A review. J Cell Physiol 2018;233:4015-32.  Back to cited text no. 6
    
7.
Martin A, Faes C, Debevec T, Rytz C, Millet G, Pialoux V. Preterm birth and oxidative stress: Effects of acute physical exercise and hypoxia physiological responses. Redox Biol 2018;17:315-22.  Back to cited text no. 7
    
8.
Hardeland R, Poeggeler B. Non-vertebrate melatonin. J Pineal Res 2003;34:233-41.  Back to cited text no. 8
    
9.
Gitto E, Reiter RJ, Amodio A, Romeo C, Cuzzocrea E, Sabatino G, et al. Early indicators of chronic lung disease in preterm infants with respiratory distress syndrome and their inhibition by melatonin. J Pineal Res 2004;36:250-5.  Back to cited text no. 9
    
10.
Hoebert M, van der Heijden KB, van Geijlswijk IM, Smits MG. Long-term follow-up of melatonin treatment in children with ADHD and chronic sleep onset insomnia. J Pineal Res 2009;47:1-7.  Back to cited text no. 10
    
11.
Evrim AD, Nurdan U, Suna O, Omer E, Fatma NS, Cumhur A, et al. Total antioxidant capacity and total oxidant status after surfactant treatment in preterm infants with respiratory distress syndrome. Ann Clin Biochem 2011;48:462-7.  Back to cited text no. 11
    
12.
Liu J. Respiratory distress syndrome in full-term neonates. J Neonatal Bio 2012;S1:S1-e001.  Back to cited text no. 12
    
13.
Aly H, Elmahdy H, El-Dib M, Rowisha M, Awny M, El-Gohary T, et al. Melatonin use for neuroprotection in perinatal asphyxia: A randomized controlled pilot study. J Perinatol 2015;35:186-91.  Back to cited text no. 13
    
14.
Reiter RJ, Tan DX, Osuna C, Gitto E. Actions of melatonin in the reduction of oxidative stress. A review. J Biomed Sci 2000;7:444-58.  Back to cited text no. 14
    
15.
Leng SX, McElhaney JE, Walston JD, Xie D, Fedarko NS, Kuchel GA. ELISA and multiplex technologies for cytokine measurement in inflammation and aging research. J Gerontol A Biol Sci Med Sci 2008;63:879-84.  Back to cited text no. 15
    
16.
Satoh K. Serum lipid peroxide in cerebrovascular disorders determined by a new colorimetric method. Clin Chim Acta 1978;90:37-43.  Back to cited text no. 16
    
17.
Nishikimi M, Appaji N, Yagi K. The occurrence of superoxide anion in the reaction of reduced phenazine methosulfate and molecular oxygen. Biochem Biophys Res Commun 1972;46:849-54.  Back to cited text no. 17
    
18.
Kim JH, Lee SM, Lee YH. Risk factors for respiratory distress syndrome in full-term neonates. Yeungnam Univ J Med 2018;35:187-91.  Back to cited text no. 18
    
19.
Gitto E, Reiter RJ, Cordaro SP, La Rosa M, Chiurazzi P, Trimarchi G, et al. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: Beneficial effects of melatonin. Am J Perinatol 2004;21:209-16.  Back to cited text no. 19
    
20.
Gitto E, Reiter RJ, Sabatino G, Buonocore G, Romeo C, Gitto P, et al. Correlation among cytokines, bronchopulmonary dysplasia and modality of ventilation in preterm newborns: Improvement with melatonin treatment. J Pineal Res 2005;39:287-93.  Back to cited text no. 20
    
21.
Reiter RJ, Tan DX. Melatonin: A novel protective agent against oxidative injury of the ischemic/reperfused heart. Cardiovasc Res 2003;58:10-9.  Back to cited text no. 21
    
22.
Tare M, Parkington HC, Wallace EM, Sutherland AE, Lim R, Yawno T, et al. Maternal melatonin administration mitigates coronary stiffness and endothelial dysfunction, and improves heart resilience to insult in growth restricted lambs. J Physiol 2014;592:2695-709.  Back to cited text no. 22
    
23.
Herrera EA, Macchiavello R, Montt C, Ebensperger G, Díaz M, Ramírez S, et al. Melatonin improves cerebrovascular function and decreases oxidative stress in chronically hypoxic lambs. J Pineal Res 2014;57:33-42.  Back to cited text no. 23
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]



 

Top
 
 
  Search
 
Similar in PUBMED
  Search Pubmed for
  Search in Google Scholar for
Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Patients and Methods
Results
Discussion
Conclusion
References
Article Tables

 Article Access Statistics
    Viewed137    
    Printed6    
    Emailed0    
    PDF Downloaded57    
    Comments [Add]    

Recommend this journal