Salvatore Aversa

Update on the use of melatonin in pediatrics

Abstract:  Melatonin, an endogenously produced indoleamine, is a highly effective antioxidant, free radical scavenger, and a primary circadian regulator. Melatonin has important antioxidant properties owing to direct and indirect effects. It directly scavenges reactive oxygen and reactive nitrogen species, prevents molecular oxidation, improves mitochondrial physiology, and restores glutathione homeostasis. Its indirect antioxidant effects stem from its ability to stimulate the activities of the enzymes involved in the glutathione cycling and production. Melatonin, by reducing free radical damage, may be an effective protective agent for the fetus as it is in adults. Several clinical studies on melatonin have shown that it reduces oxidative stress in human newborns with sepsis, hypoxic distress, or other conditions, where there is excessive free radical generation. A role of melatonin in infant development has also been suggested. Pineal dysfunction may be associated with deleterious outcomes in infants and may contribute to an increased prevalence of sudden infant death syndrome. Delayed melatonin production is evident in infants who had experienced an apparent life‐threatening event. Melatonin has been used as a pharmacologic treatment for insomnias associated with shift work, jet lag, and delayed sleep onset in adults for decades. In children as well, melatonin has value as a sleep‐promoting agent. Evidence suggests that melatonin has utility as an analgesic agent presumably related to its ability to release β‐endorphin. The data support the notion that melatonin, or one of its analogs, might find use as an anesthetic agent in children.

Potential utility of melatonin as an antioxidant during pregnancy and in the perinatal period

Reactive oxygen species (ROS) play a critical role in the pathogenesis of various diseases during pregnancy and the perinatal period. Newborns are more prone to oxidative stress than individuals later in life. During pregnancy, increased oxygen demand augments the rate of production of ROS and women, even during normal pregnancies, experience elevated oxidative stress compared with non-pregnant women. ROS generation is also increased in the placenta during preeclampsia. Melatonin is a highly effective direct free-radical scavenger, indirect antioxidant, and cytoprotective agent in human pregnancy and it appears to be essential for successful pregnancy. This suggests a role for melatonin in human reproduction and in neonatal pathologies (asphyxia, respiratory distress syndrome, sepsis, etc.). This review summarizes current knowledge concerning the role for melatonin in human pregnancy and in the newborn. Numerous studies agree that short-term melatonin therapy is highly effective in reducing complications during pregnancy and in the neonatal period. No significant toxicity or treatment-related side effects with long-term melatonin therapy in children and adults have been reported. Treatment with melatonin might result in a wide range of health benefits, including improved quality of life and reduced healthcare costs.

Pain in neonatal intensive care: role of melatonin as an analgesic antioxidant

Abstract:  Endotracheal intubation is a common painful procedure in newborn care. Neonates are more sensitive to pain than older infants, children, and adults, and this hypersensitivity is further exacerbated in preterm neonates. The aim of this study was to evaluate the analgesic activity of melatonin during endotracheal intubation of the newborn by using the Neonatal Infant Pain Scale (NIPS) and Premature Infant Pain Profile (PIPP) score. Secondary outcome was an evaluation of melatonin as inflammatory responses. This was performed by measuring the levels of pro‐ and anti‐inflammatory cytokines implicated in the pain. Sixty preterm infants were enrolled in the study and were randomly divided into two groups: 30 infants treated with melatonin plus common sedation and analgesia recommended by Italian Society of Neonatology (group 1) and 30 infants treated with only common sedation and analgesia. The sedative and analgesic drugs included atropine, fentanyl, and vecuronium. The reduction in pain score (NIPS) was similar in both groups at an early phase, while it (PIPP score) was lower in melatonin‐treated group infants than the other newborns at a late phase, during intubation and mechanical ventilation. The differences were statistically significant at 12, 24, 48, and 72 hr (P < 0.001). Pro‐inflammatory and anti‐inflammatory cytokines (IL‐6, IL‐8, IL‐10 and IL‐12) were higher in the common sedation and analgesia group than in melatonin‐treated infants at 24, 48, 72 hr and 7 days (P < 0.001). This study suggests the use of melatonin as an adjunct analgesic therapy during procedural pain, especially when an inflammatory component is involved.

Analgesic, Anxiolytic and Anaesthetic Effects of Melatonin: New Potential Uses in Pediatrics

Exogenous melatonin is used in a number of situations, first and foremost in the treatment of sleep disorders and jet leg. However, the hypnotic, antinociceptive, and anticonvulsant properties of melatonin endow this neurohormone with the profile of a drug that modulates effects of anesthetic agents, supporting its potential use at different stages during anesthetic procedures, in both adults and children. In light of these properties, melatonin has been administered to children undergoing diagnostic procedures requiring sedation or general anesthesia, such as magnetic resonance imaging, auditory brainstem response tests and electroencephalogram. Controversial data support the use of melatonin as anxiolytic and antinociceptive agents in pediatric patients undergoing surgery. The aim of this review was to evaluate available evidence relating to efficacy and safety of melatonin as an analgesic and as a sedative agent in children. Melatonin and its analogs may have a role in antinociceptive therapies and as an alternative to midazolam in premedication of adults and children, although its effectiveness is still controversial and available data are clearly incomplete.

Oxidative Stress-Mediated Damage in Newborns with Necrotizing Enterocolitis: A Possible Role of Melatonin.

BACKGROUND Necrotizing enterocolitis is a gastrointestinal surgical emergency in premature neonates. Free radicals have been linked to the development of the disease in infants. Ischemia, hypoxia-reperfusion, infection, and inflammation produce elevated levels of reactive oxygen species, impairing the redox balance and shifting cells into a state of oxidative stress. Melatonin, an effective direct free-radical scavenger and indirect antioxidant agent, exerts pleiotropic action on the human body. Several studies have tested the efficacy of melatonin in counteracting oxidative injury in diseases of newborns. Melatonin has been widely used in newborns including cases of asphyxia, respiratory distress syndrome, and sepsis, and no significant toxicity or treatment-related side effects with long-term melatonin therapy have been reported. CONCLUSION Therefore, melatonin, besides standard therapies, could be considered as a potentially safe approach to prevent and treat necrotizing enterocolitis in premature infants. This review summarizes what is known about the role of oxidative stress, and potentially beneficial effects of antioxidants, such as melatonin, in necrotizing enterocolitis.

Iatrogenic Cushing syndrome caused by ocular glucocorticoids in a child

A boy aged 7.6 years presented to our Unit of Paediatric Endocrinology for evaluation of obesity. Progressive weight gain (10 kg) started 6 months earlier after an accidental penetrating orbital injury on the right eye. During this period the child has been treated with oral betamethasone (0.5 mg/day) for 1 month and dexamethasone 2% ocular drops (2 hourly by day) for 6 months. Physical examination showed he was 113.5 cm in height (−1.5 SD), weight 36.0 kg, blood pressure 110/90 mmHg (90th centile), body mass index 28 (+5 SD), truncal obesity, buffalo hump, “moon-face”, increased lanugo hair and supraclavicular fullness. Endocrinological work-up revealed undetectable levels of basal adrenocorticotropic hormone (ACTH), basal and ACTH-stimulated cortisol and 24 h urine excretion cortisol, confirming the diagnosis of iatrogenic Cushing syndrome. The abrupt withdrawal of ocular glucocorticoids by the parents evoked two adrenal crises; 4 months later the patient recovered. In conclusion, we would alert doctors that every formulation of glucocorticoids, no ocular drops excluded, can determine severe systemic side effects and iatrogenic Cushing syndrome.

Visfatin: New marker of oxidative stress in preterm newborns

Background: Oxidative stress is involved in several neonatal conditions characterized by an upregulation in the production of oxidative or nitrative free radicals and a concomitant decrease in the availability of antioxidant species. Oxygen, which is obviously vital to survival, can be highly damaging to neonatal tissue which is known to be poorly equipped to neutralize toxic derivatives. Thus, exposure of the newborn infant to high oxygen concentrations during resuscitation at birth increases oxidative damage. Visfatin is an adipocytokine involved in oxidative stress and an important mediator of inflammation that induces dose-dependent production of both pro-inflammatory and anti-inflammatory cytokines. To our knowledge, the diagnostic value of visfatin as a marker of oxidative stress in preterm newborns has not been investigated. Objective: The aim of this study was to evaluate visfatin levels in preterm neonates resuscitated with different concentrations of oxygen in the delivery room. Patients: Fifty-two preterm newborns with gestational age less than 32 weeks, resuscitated randomly with different oxygen concentrations (40%, 60%, or 100%) were enrolled at the University Hospital of Messina, over a 12-month period to evaluate serum visfatin levels at T0 (within 1 h after birth), T24 h, T72 h, and T168 h of life. Results: At T72 h and T168 h, higher serum visfatin values in the high-oxygen group compared to the low- and mild-oxygen subjects (P = 0.002 and P <0.001, respectively) were noted. Conclusion: The results of this study suggest that visfatin could be a new marker of oxidative stress in preterm newborns.

Oxidative stress and persistent pulmonary hypertension of the newborn treated with inhaled nitric oxide and different oxygen concentrations

Objectives: The aim of this study was to determine the effects of inhaled NO with different oxygen concentrations on the inflammatory cascade in newborns with hypoxic respiratory failure secondary to persistent pulmonary hypertension. Methods: 60 newborns received iNO and 30 of them received an initial oxygen concentration of 45% (group 1), while the other 30 newborns received an initial oxygen concentration of 80% (group 2). The levels of inflammatory cytokines (IL-6, IL-8, TNF-α) were measured. The clinical outcome was also recorded. Results: The findings show that interleukin concentrations (IL-6, IL-8, TNF-α) were significantly decreased between 0 and 72 hours (p < 0.01) in the newborns exposed to initial oxygen concentration of 45% and significantly increased in the other group. Conclusions: When inhaled, NO was co-administered with concentration of O2 <45%, anti-inflammatory responses occurred, in accord with evidence in the published literature. The benefits of iNO on the clinical outcome in the current study demonstrate that inhaled NO in both groups was associated with improved short-term oxygenation.

Ventilation strategies for preventing oxidative stress-induced injury in preterm infants with respiratory disease: an update

Reactive oxygen and nitrogen species are produced by several inflammatory and structural cells of the airways. The lungs of preterm newborns are susceptible to oxidative injury induced by both reactive oxygen and nitrogen species. Increased oxidative stress and imbalance in antioxidant enzymes may play a role in the pathogenesis of inflammatory pulmonary diseases. Preterm infants are frequently exposed to high oxygen concentrations, infections or inflammation; they have reduced antioxidant defense and high free iron levels which enhance toxic radical generation. Multiple ventilation strategies have been studied to reduce injury and improve outcomes in preterm infants. Using lung protective strategies, there is the need to reach a compromise between satisfaction of gas exchange and potential toxicities related to over-distension, derecruitment of lung units and high oxygen concentrations. In this review, the authors summarize scientific evidence concerning oxidative stress as it relates to resuscitation in the delivery room and to the strategies of ventilation.

Transient natural killer deficiency in a boy with herpes simplex virus-associated recurrent erythema multiforme

Abstract Erythema multiforme is characterized by itching macules, papules and bullae, symmetrically distributed on the dorsum of the hands. They can follow the administration of several drugs or infections with various agents, and in particular with herpes simplex virus. The recurrent variant is very rare, especially in the paediatric age group. We describe the case of a male adolescent with recurrent erythema multiforme caused by herpes virus and transient natural killer deficiency.