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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 6  |  Issue : 1  |  Page : 10-14

Melatonin administration as an adjuvant therapy in neonatal necrotizing enterocolitis


1 Department of Pediatrics, Faculty of Medicine, Tanta University, Tanta, Egypt
2 Department of Medical Biochemstry, Faculty of Medicine, Tanta University, Tanta, Egypt

Date of Web Publication8-Feb-2017

Correspondence Address:
Prof. Mohamed Shawky Elfrargy
El Nahas Street, Tanta
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/2249-4847.199761

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  Abstract 

Objective: Determine the value of melatonin as an adjuvant therapy in treating necrotizing enterocolitis (NEC) in neonates. Patients and Methods: A prospective clinical trial study was conducted on 50 neonates which suffer from picture like NEC to detect cases with evident NEC diagnosed on the basis of both clinical and laboratory criteria. Enrolled neonates were divided into two groups: Studied group (G I) (n = 25) received melatonin and antibiotics, while the control group (G II) (n = 25) was treated with antibiotics only. Melatonin was administered as 20 mg for 3 consecutive days and antibiotics were administered according to a standard protocol. Results: Showed comparison between Group I and Group II according to incidence of NEC at the onset of the research and after 1 week of onset wherein Group I there were 6 neonates out of 25 neonates at the onset of research suffering from NEC and became 1 neonate only after 1 week showing significant difference in Group I (P < 0.05) while in Group II there were 4 neonates at the onset of research suffering from NEC and became 3 neonates after 1 week showing nonsignificant difference P > 0.05. Conclusion: Melatonin administration as an adjuvant therapy in neonatal NEC treatment is associated with improvement of clinical and laboratory outcome.

Keywords: Melatonin, necrotizing enterocolitis, neonates


How to cite this article:
Elfrargy MS, Soliman NA. Melatonin administration as an adjuvant therapy in neonatal necrotizing enterocolitis. J Clin Neonatol 2017;6:10-4

How to cite this URL:
Elfrargy MS, Soliman NA. Melatonin administration as an adjuvant therapy in neonatal necrotizing enterocolitis. J Clin Neonatol [serial online] 2017 [cited 2019 Dec 9];6:10-4. Available from: http://www.jcnonweb.com/text.asp?2017/6/1/10/199761


  Introduction Top


Neonatal period is defined as the first 4 weeks of life or the first 28 days of life. Necrotizing enterocolitis (NEC) is one of the most dangerous gastrointestinal diseases that affects the neonates especially preterm neonates. This disease is fatal and could be misdiagnosed with other neonatal diseases like sepsis and some surgical neonatal diseases like Hirsh sprung disease. It can lead to severe morbidity and even mortality, so early detection of NEC would give us good chance for early prevention and treatment with better prognosis.[1],[2],[3],[4]

Free radicals play a significant role in the pathogenesis of neonatal sepsis and NEC. It has been suggested that melatonin as an antioxidant can be used to counteract the toxicity of oxygen radicals that are released during neonatal illness.[5],[6],[7],[8]

Melatonin, an endogenously produced indoleamine, is a highly effective antioxidant and free radicals scavenger and it works directly through the detoxification of toxic radicals. Beside these scavenging actions, melatonin also stimulates several antioxidative enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase.[9],[10],[11],[12],[13] Melatonin can reduce the peroxidative breakdown of lipids in cell membranes secondary to NEC and sepsis.[14]

Neonatal sepsis and NEC is associated with release of endotoxins that activate inflammatory cells as macrophages and monocytes, which in turn secrete cytokines such as interlenkin-1 (IL-1) and tumor necrosis factor (TNF)-alpha which activate more inflammatory cells (neutrophils, macrophages/monocytes, mastocytes) which lead to tissue ischemia, and intense systemic inflammatory response which modify serum inflammatory parameters.[6],[7],[8]

Melatonin showed to be effective in neonatal disorders characterized by the excessive inflammatory reaction and oxidative damage including sepsis and sepsis-related conditions like NEC through its anti-oxidant and anti-inflammatory effect.[15] We hypothized that using melatonin in neonatal NEC will be associated with improvement in clinical course of newborns suffering from NEC.

The objective of this study is to evaluate the therapeutic efficacy of melatonin as an adjuvant therapy in treating of neonatal NEC.


  Patients and Methods Top


This is a prospective clinical trial after informed consent; we enrolled 50 neonates with suspected NEC. Abdominal distension, blood in stool, and pneumatosis intestinalis on X-ray are considered the classical features of NEC in neonates.[16]

Exclusion criteria

Exclusion criteria were major congenital anomalies, hypoxic ischemic encephalopathy, intracranial hemorrhage, and respiratory distress syndrome.

Enrolled neonates were divided into two groups: Studied group (G I) (n = 25) received melatonin and antibiotics, while the control group (G II) (n = 25) was treated with antibiotics only. Melatonin was administered as 20 mg for 3 consecutive days and antibiotics were administered according to a standard protocol. Patients were enrolled from the Neonatal Intensive Care Unit of Tanta University Hospital from June 2013 to July 2016.

Evaluation

All cases were subjected to careful history taking, clinical examination, and laboratory investigations. Both groups had laboratory investigations in the form of complete blood count including (total leukocyte count, absolute neutrophil count, platelet count, and C-reactive protein), Na, K levels, blood gasses and abdominal X-ray. NEC is evaluated according to modified bell staging.[17]

Stage I (A, B) or suspected NEC, includes neonates who present with the mildest of symptoms. Systemic manifestations include lethargy, apnea, and bradycardia. The infant may feed poorly, have increasing gastrointestinal residuals, vomit, present with a mildly distended abdomen, or pass stool with occult blood. Stage II (A, B) or proven NEC show the classic radiological sign of pneumatosis intestinalis. Abdominal distention in these patients is marked, and persistent occult or frank blood in the stool may be present. Stage III (A, B) or advanced NEC, infants show a deterioration of vital signs or marked gastrointestinal bleeding. Pneumoperitoneum may be present.[17]

Intervention

Enrolled neonates were divided into two groups: Studied group (Group I) (n = 25) received melatonin and antibiotics, while the control group (Group II) (n = 25) was treated with antibiotics only. Melatonin was given in a dose (20 mg) dissolved in a distilled water and given through the oro/nasogastric tube for 3 consecutive days. The standard antibiotics protocol is ampicillin plus gentamycin.

This study was approved by the Ethics Committee of Faculty of Medicine, Tanta University. Written informed consents were obtained from the parents of all subjects of the study. The duration of the study was 10 months.

Statistical analysis was performed using SPSS for Windows, version 20. Data were expressed as range and mean ± standard deviation. Differences between groups in continuous variables were tested for significance with independent t-test while Chi-square test used to compare categorical variables. For all statistical tests done, P < 0.05 was considered significant.


  Results Top


Fifty patients were enrolled, 25 in Group I and 25 in Group II. There was no difference between the intervention and control group as regards gestational age (weeks), weight in (kg), mode of delivery and sex (P > 0.05) [Table 1].
Table 1: Comparison between intervention group and control group as regard gestational age (weeks), weight in (kg), mode of delivery and sex

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[Table 2] shows a comparison between both groups according to abdominal distension showing a significant difference in Group I between neonates at the onset of the research and after 1 week of onset (P < 0.05).
Table 2: Comparison between both groups according to abdominal distension showing significant difference in Group I between neonates at the onset of the research and after 1 week of onset (P<0.05)

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[Table 3] shows a comparison between both groups according to blood in stool showing significant difference in Group I between neonates at the onset of the research and after 1 weeks of onset (P < 0.05).
Table 3: Comparison between both groups according to blood in stool showing significant difference in Group I between neonates at the onset of the research and after 1 week of onset (P<0.05)

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[Table 4] shows Comparison between both groups according to metabolic acidosis showing a significant difference in Group I between neonates at the onset of the research and after 1 week of onset (P < 0.05).
Table 4: Comparison between both groups according to metabolic acidosis showing significant difference in Group I between neonates at the onset of the research and after 1 week of onset (P<0.05)

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[Table 5] shows Comparison between both groups according to the presence of thrombocytopenia showing a significant difference in Group I between neonates at the onset of the research and after 1 weeks of onset (P < 0.05).
Table 5: Comparison between both groups according to the presence of thrombocytopenia showing significant difference in Group I between neonates at the onset of the research and after 1 week of onset (P<0.05)

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[Table 6] shows Comparison between both groups according to the presence of hyponatremia showing significant difference in group I between neonates at the onset of the research and after 1 weeks of onset (P < 0.05).
Table 6: Comparison between both groups according to the presence of hyponatremia showing significant difference in Group I between neonates at the onset of the research and after 1 week of onset (P<0.05)

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[Table 7] shows Comparison between both groups according to the presence of pneumatosis intestinalis (proven NEC) showing significant difference in Group I between neonates at the onset of the research and after 1 weeks of onset (P < 0.05).
Table 7: Comparison according to incidence of necrotizing enterocolitis at the onset of the research and after 1 week of onset showing significant difference in Group I (P<0.05)

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[Table 8]shows prognosis of patients after follow-up for 4 weeks showing decrease in rate of death in neonates of Group I where 3 neonates died in Group II (12%) while 1 neonate only died in Group I (4%).
Table 8: Prognosis of patients after follow up for 4 weeks showing decrease in rate of death in neonates of Group I

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  Discussion Top


NEC in neonates is a serious condition in neonatal period with high morbidity and mortality rates despite the progress in neonatal intensive care and antibiotics. The immunity against infections is immature in the newborn infant especially in premature neonates, and this makes the premature neonate more susceptible to multiple recurrent infections.[18]

NEC is a gastrointestinal surgical emergency in premature neonates. Free radicals have been linked to the development of the disease in infants.[19] Melatonin, a hormone secreted by the pineal gland in the brain, has been shown to function as a direct free radical scavenger and an indirect antioxidant through its stimulatory actions on antioxidative enzymes.[20],[21]

Melatonin, an endogenously produced indoleamine, is a highly effective antioxidant and free radicals scavenger and it works directly via the detoxification of toxic radicals. Beside these scavenging actions, melatonin also stimulates several antioxidative enzymes including superoxide dismutase, glutathione peroxidase, and glutathione reductase.[9],[10],[11],[12],[13] Melatonin can reduce the peroxidative breakdown of lipids in cell membranes secondary to NEC and sepsis.[14]

Melatonin showed to be effective in neonatal disorders characterized by excessive inflammatory reaction and oxidative damage including sepsis and sepsis-related conditions like NEC through its anti-oxidant and anti-inflammatory effect through inhibition of inflammatory cells as macrophages and monocytes, which in turn secrete cytokines such as IL-1 and TNF-alpha which activate more inflammatory cells (neutrophils, macrophages/monocytes, mastocytes) which lead to tissue ischemia, and intense systemic inflammatory response.[6],[7],[8]

The present study showed significant difference in the presence of blood in the stool of the neonates in Group I between neonates at the onset of the research and after 1 weeks of onset This was in agreement with Gitto et al., who had shown that melatonin has anti-inflammatory effect in neonates suffering from neonatal sepsis or NEC if it is added as an adjuvant therapy.[15]

The present study found significant difference in abdominal distension between neonates at the onset of the research and after 1 weeks of onset and in agreement with this study with Marseglia et al., who found that melatonin could be considered as a potentially safe approach to prevent and treat NEC in premature infants.[22]

The present study found significant difference in metabolic acidosis, hyponatremia, and thrombocytopenia between neonates at the onset of the research and after 1 weeks of onset and in agreement with this study some studies who found that melatonin has a cytoprotection effect includes free radical scavenging activity exerting cytoprotective and anti-inflammatory activities on gastrointestinal system mucosa.[14],[23]

The present study found significant difference in the incidence of presence of pneumatosis intestinalis on X-ray between neonates at the onset of the research and after 1 weeks of onset and in agreement with this study some studies who stated that melatonin are potent antioxidants which synthesized in the gastrointestinal tract, especially after feeding and the concentration of melatonin in the gastrointestinal system surpasses blood levels by several times, and there is melatonin in the gastrointestinal tract more than in the pineal gland.[24],[25]

Administration of melatonin as an adjuvant therapy in the treatment of neonatal sepsis is associated with improvement of clinical and laboratory outcome.


  Conclusion Top


Melatonin administration as an adjuvant therapy in neonatal NEC treatment is associated with improvement of clinical and laboratory outcome.

Acknowledgment

The authors would like to acknowledge Dr. Walaa Keshk who contributed toward the study by making substantial contributions to conception, design, analysis, and interpretation of data.

The source of funding for authors: Are their private money.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
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    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]


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