Melatonin in Critically Ill Children

Abstract

Melatonin, while best known for its chronobiologic functions, has multiple effects that may be relevant in critical illness. It has been used for circadian rhythm maintenance, analgesia, and sedation, and has antihypertensive, anti-inflammatory, antioxidant, antiapoptotic, and antiexcitatory effects. This review examines melatonin physiology in health, the current state of knowledge regarding endogenous melatonin production in pediatric critical illness, and the potential uses of exogenous melatonin in this population, including relevant information from basic sciences and other fields of medicine. Pineal melatonin production and secretion appears to be altered in critical illness, though understanding in pediatric critical illness is in early stages, with only 102 children reported in the current literature. Exogenous melatonin may be used for circadian rhythm disturbances and, within the critically ill population, holds promise for diseases involving oxidant stress. There are no studies of exogenous melatonin administration to critically ill children beyond the neonatal period.

Keywords

melatonin - pineal gland - intensive care units - pediatric - critical care - circadian rhythm - antioxidants

• References

• 1 Hardeland R, Poeggeler B. Non-vertebrate melatonin. J Pineal Res 2003; 34 (4) 233-241
• 2 Hardeland R, Pandi-Perumal SR, Cardinali DP. Melatonin. Int J Biochem Cell Biol 2006; 38 (3) 313-316
• 3 Bojkowski CJ, Arendt J, Shih MC, Markey SP. Melatonin secretion in humans assessed by measuring its metabolite, 6-sulfatoxymelatonin. Clin Chem 1987; 33 (8) 1343-1348
• 4 Reppert SM, Godson C, Mahle CD, Weaver DR, Slaugenhaupt SA, Gusella JF. Molecular characterization of a second melatonin receptor expressed in human retina and brain: the Mel1b melatonin receptor. Proc Natl Acad Sci U S A 1995; 92 (19) 8734-8738
• 5 Reppert SM, Weaver DR, Ebisawa T. Cloning and characterization of a mammalian melatonin receptor that mediates reproductive and circadian responses. Neuron 1994; 13 (5) 1177-1185
• 6 Lewy AJ, Wehr TA, Goodwin FK, Newsome DA, Markey SP. Light suppresses melatonin secretion in humans. Science 1980; 210 (4475) 1267-1269
• 7 Hardeland R, Cardinali DP, Srinivasan V, Spence DW, Brown GM, Pandi-Perumal SR. Melatonin—a pleiotropic, orchestrating regulator molecule. Prog Neurobiol 2011; 93 (3) 350-384
• 8 Hardeland R. Chronobiology of melatonin beyond the feedback to the suprachiasmatic nucleus—consequences to melatonin dysfunction. Int J Mol Sci 2013; 14 (3) 5817-5841
• 9 Tricoire H, Locatelli A, Chemineau P, Malpaux B. Melatonin enters the cerebrospinal fluid through the pineal recess. Endocrinology 2002; 143 (1) 84-90
• 10 Reiter RJ. Pineal melatonin: cell biology of its synthesis and of its physiological interactions. Endocr Rev 1991; 12 (2) 151-180
• 11 Bagci S, Mueller A, Reinsberg J, Heep A, Bartmann P, Franz AR. Saliva as a valid alternative in monitoring melatonin concentrations in newborn infants. Early Hum Dev 2009; 85 (9) 595-598
• 12 Hardeland R. Antioxidative protection by melatonin: multiplicity of mechanisms from radical detoxification to radical avoidance. Endocrine 2005; 27 (2) 119-130
• 13 Bubenik GA. Gastrointestinal melatonin: localization, function, and clinical relevance. Dig Dis Sci 2002; 47 (10) 2336-2348
• 14 Bourne RS, Mills GH. Melatonin: possible implications for the postoperative and critically ill patient. Intensive Care Med 2006; 32 (3) 371-379
• 15 Brzezinski A. Melatonin in humans. N Engl J Med 1997; 336 (3) 186-195
• 16 Claustrat B, Brun J, Chazot G. The basic physiology and pathophysiology of melatonin. Sleep Med Rev 2005; 9 (1) 11-24
• 17 Webley GE, Leidenberger F. The circadian pattern of melatonin and its positive relationship with progesterone in women. J Clin Endocrinol Metab 1986; 63 (2) 323-328
• 18 Commentz JC, Henke A, Dammann O, Hellwege HH, Willig RP. Decreasing melatonin and 6-hydroxymelatonin sulfate excretion with advancing gestational age in preterm and term newborn male infants. Eur J Endocrinol 1996; 135 (2) 184-187
• 19 Hartmann L, Roger M, Lemaitre BJ, Massias JF, Chaussain JL. Plasma and urinary melatonin in male infants during the first 12 months of life. Clin Chim Acta 1982; 121 (1) 37-42
• 20 Gitto E, Pellegrino S, Gitto P, Barberi I, Reiter RJ. Oxidative stress of the newborn in the pre- and postnatal period and the clinical utility of melatonin. J Pineal Res 2009; 46 (2) 128-139
• 21 Ardura J, Gutierrez R, Andres J, Agapito T. Emergence and evolution of the circadian rhythm of melatonin in children. Horm Res 2003; 59 (2) 66-72
• 22 Kennaway DJ, Stamp GE, Goble FC. Development of melatonin production in infants and the impact of prematurity. J Clin Endocrinol Metab 1992; 75 (2) 367-369
• 23 Sivan Y, Laudon M, Tauman R, Zisapel N. Melatonin production in healthy infants: evidence for seasonal variations. Pediatr Res 2001; 49 (1) 63-68
• 24 Wetterberg L, Bratlid T, von Knorring L, Eberhard G, Yuwiler A. A multinational study of the relationships between nighttime urinary melatonin production, age, gender, body size, and latitude. Eur Arch Psychiatry Clin Neurosci 1999; 249 (5) 256-262
• 25 Griefahn B, Bröde P, Blaszkewicz M, Remer T. Melatonin production during childhood and adolescence: a longitudinal study on the excretion of urinary 6-hydroxymelatonin sulfate. J Pineal Res 2003; 34 (1) 26-31
• 26 Young IM, Francis PL, Leone AM, Stovell P, Silman RE. Constant pineal output and increasing body mass account for declining melatonin levels during human growth and sexual maturation. J Pineal Res 1988; 5 (1) 71-85
• 27 Bojkowski CJ, Arendt J. Factors influencing urinary 6-sulphatoxymelatonin, a major melatonin metabolite, in normal human subjects. Clin Endocrinol (Oxf) 1990; 33 (4) 435-444
• 28 Tetsuo M, Poth M, Markey SP. Melatonin metabolite excretion during childhood and puberty. J Clin Endocrinol Metab 1982; 55 (2) 311-313
• 29 Attanasio A, Borrelli P, Gupta D. Circadian rhythms in serum melatonin from infancy to adolescence. J Clin Endocrinol Metab 1985; 61 (2) 388-390
• 30 Waldhauser F, Weiszenbacher G, Tatzer E , et al. Alterations in nocturnal serum melatonin levels in humans with growth and aging. J Clin Endocrinol Metab 1988; 66 (3) 648-652
• 31 Waldhauser F, Weiszenbacher G, Frisch H, Zeitlhuber U, Waldhauser M, Wurtman RJ. Fall in nocturnal serum melatonin during prepuberty and pubescence. Lancet 1984; 1 (8373) 362-365
• 32 Touitou Y, Auzéby A, Camus F, Djeridane Y. Daily profiles of salivary and urinary melatonin and steroids in healthy prepubertal boys. J Pediatr Endocrinol Metab 2009; 22 (11) 1009-1015
• 33 Tauman R, Zisapel N, Laudon M, Nehama H, Sivan Y. Melatonin production in infants. Pediatr Neurol 2002; 26 (5) 379-382
• 34 Cardinali DP, Srinivasan V, Brzezinski A, Brown GM. Melatonin and its analogs in insomnia and depression. J Pineal Res 2012; 52 (4) 365-375
• 35 Gehlbach BK, Chapotot F, Leproult R , et al. Temporal disorganization of circadian rhythmicity and sleep-wake regulation in mechanically ventilated patients receiving continuous intravenous sedation. Sleep 2012; 35 (8) 1105-1114
• 36 Jan JE, Reiter RJ, Wong PK, Bax MC, Ribary U, Wasdell MB. Melatonin has membrane receptor-independent hypnotic action on neurons: an hypothesis. J Pineal Res 2011; 50 (3) 233-240
• 37 Lipton J, Megerian JT, Kothare SV , et al. Melatonin deficiency and disrupted circadian rhythms in pediatric survivors of craniopharyngioma. Neurology 2009; 73 (4) 323-325
• 38 Kocher L, Brun J, Borson-Chazot F, Gonnaud PM, Claustrat B. Increased REM sleep associated with melatonin deficiency after pinealectomy: a case study. Chronobiol Int 2006; 23 (4) 889-901
• 39 Holmes SW, Sugden D. Proceedings: The effect of melatonin on pinealectomy-induced hypertension in the rat. Br J Pharmacol 1976; 56 (3) 360P-361P
• 40 Carrillo-Vico A, Guerrero JM, Lardone PJ, Reiter RJ. A review of the multiple actions of melatonin on the immune system. Endocrine 2005; 27 (2) 189-200
• 41 Karaaslan C, Suzen S. Antioxidant properties of melatonin and its potential action in diseases. Curr Top Med Chem 2015; 15 (9) 894-903
• 42 Jimenez-Jorge S, Jimenez-Caliani AJ, Guerrero JM , et al. Melatonin synthesis and melatonin-membrane receptor (MT1) expression during rat thymus development: role of the pineal gland. J Pineal Res 2005; 39 (1) 77-83
• 43 Valero N, Bonilla E, Pons H , et al. Melatonin induces changes to serum cytokines in mice infected with the Venezuelan equine encephalomyelitis virus. Trans R Soc Trop Med Hyg 2002; 96 (3) 348-351
• 44 Morrey KM, McLachlan JA, Serkin CD, Bakouche O. Activation of human monocytes by the pineal hormone melatonin. J Immunol 1994; 153 (6) 2671-2680
• 45 Srinivasan V, Mohamed M, Kato H. Melatonin in bacterial and viral infections with focus on sepsis: a review. Recent Pat Endocr Metab Immune Drug Discov 2012; 6 (1) 30-39
• 46 Reiter RJ, Paredes SD, Korkmaz A, Jou MJ, Tan DX. Melatonin combats molecular terrorism at the mitochondrial level. Interdiscip Toxicol 2008; 1 (2) 137-149
• 47 Reiter RJ, Paredes SD, Manchester LC, Tan DX. Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin. Crit Rev Biochem Mol Biol 2009; 44 (4) 175-200
• 48 Joo JY, Uz T, Manev H. Opposite effects of pinealectomy and melatonin administration on brain damage following cerebral focal ischemia in rat. Restor Neurol Neurosci 1998; 13 (3–4) 185-191
• 49 Cavallo A, Dolan LM. 6-Hydroxymelatonin sulfate excretion in human puberty. J Pineal Res 1996; 21 (4) 225-230
• 50 Olofsson K, Alling C, Lundberg D, Malmros C. Abolished circadian rhythm of melatonin secretion in sedated and artificially ventilated intensive care patients. Acta Anaesthesiol Scand 2004; 48 (6) 679-684
• 51 Müller HL, Handwerker G, Wollny B, Faldum A, Sörensen N. Melatonin secretion and increased daytime sleepiness in childhood craniopharyngioma patients. J Clin Endocrinol Metab 2002; 87 (8) 3993-3996
• 52 Frisk U, Olsson J, Nylén P, Hahn RG. Low melatonin excretion during mechanical ventilation in the intensive care unit. Clin Sci (Lond) 2004; 107 (1) 47-53
• 53 Esposti D, Esposti G, Lissoni P, Parravicini L, Fraschini F. Action of morphine on melatonin release in the rat. J Pineal Res 1988; 5 (1) 35-39
• 54 Govitrapong P, Pariyanonth M, Ebadi M. The presence and actions of opioid receptors in bovine pineal gland. J Pineal Res 1992; 13 (3) 124-132
• 55 Hajak G, Rodenbeck A, Bandelow B, Friedrichs S, Huether G, Rüther E. Nocturnal plasma melatonin levels after flunitrazepam administration in healthy subjects. Eur Neuropsychopharmacol 1996; 6 (2) 149-153
• 56 Gupta M, Kohli K, Gupta YK. Modulation of serum concentrations of melatonin by carbamazepine and valproate. Indian J Physiol Pharmacol 2006; 50 (1) 79-82
• 57 Hallam KT, Olver JS, Norman TR. Effect of sodium valproate on nocturnal melatonin sensitivity to light in healthy volunteers. Neuropsychopharmacology 2005; 30 (7) 1400-1404
• 58 Paul T, Lemmer B. Disturbance of circadian rhythms in analgosedated intensive care unit patients with and without craniocerebral injury. Chronobiol Int 2007; 24 (1) 45-61
• 59 Mundigler G, Delle-Karth G, Koreny M , et al. Impaired circadian rhythm of melatonin secretion in sedated critically ill patients with severe sepsis. Crit Care Med 2002; 30 (3) 536-540
• 60 Miyazaki T, Kuwano H, Kato H , et al. Correlation between serum melatonin circadian rhythm and intensive care unit psychosis after thoracic esophagectomy. Surgery 2003; 133 (6) 662-668
• 61 Gottschlich MM, Jenkins ME, Mayes T , et al. The 1994 Clinical Research Award. A prospective clinical study of the polysomnographic stages of sleep after burn injury. J Burn Care Rehabil 1994; 15 (6) 486-492
• 62 Riutta A, Ylitalo P, Kaukinen S. Diurnal variation of melatonin and cortisol is maintained in non-septic intensive care patients. Intensive Care Med 2009; 35 (10) 1720-1727
• 63 Bagci S, Yildizdas D, Horoz OO, Reinsberg J, Bartmann P, Mueller A. Use of nocturnal melatonin concentration and urinary 6-sulfatoxymelatonin excretion to evaluate melatonin status in children with severe sepsis. J Pediatr Endocrinol Metab 2011; 24 (11–12) 1025-1030
• 64 Bagci S, Horoz ÖÖ, Yildizdas D, Reinsberg J, Bartmann P, Müller A. Melatonin status in pediatric intensive care patients with sepsis. Pediatr Crit Care Med 2012; 13 (2) e120-e123
• 65 Marseglia L, Aversa S, Barberi I , et al. High endogenous melatonin levels in critically ill children: a pilot study. J Pediatr 2013; 162 (2) 357-360
• 66 Gitto E, Aversa S, Reiter RJ, Barberi I, Pellegrino S. Update on the use of melatonin in pediatrics. J Pineal Res 2011; 50 (1) 21-28
• 67 Bruni O, Alonso-Alconada D, Besag F , et al. Paediatric use of melatonin [Author reply to D. J. Kennaway]. Eur J Paediatr Neurol 2015; 19 (4) 491-493
• 68 Fourtillan JB, Brisson AM, Gobin P, Ingrand I, Decourt JP, Girault J. Bioavailability of melatonin in humans after day-time administration of D(7) melatonin. Biopharm Drug Dispos 2000; 21 (1) 15-22
• 69 Mistraletti G, Sabbatini G, Taverna M , et al. Pharmacokinetics of orally administered melatonin in critically ill patients. J Pineal Res 2010; 48 (2) 142-147
• 70 Cavallo A, Ritschel WA. Pharmacokinetics of melatonin in human sexual maturation. J Clin Endocrinol Metab 1996; 81 (5) 1882-1886
• 71 Bourne RS, Minelli C, Mills GH, Kandler R. Clinical review: sleep measurement in critical care patients: research and clinical implications. Crit Care 2007; 11 (4) 226
• 72 Hardin KA. Sleep in the ICU: potential mechanisms and clinical implications. Chest 2009; 136 (1) 284-294
• 73 Nelson AB, Faraguna U, Tononi G, Cirelli C. Effects of anesthesia on the response to sleep deprivation. Sleep 2010; 33 (12) 1659-1667
• 74 Wyatt JK, Dijk DJ, Ritz-de Cecco A, Ronda JM, Czeisler CA. Sleep-facilitating effect of exogenous melatonin in healthy young men and women is circadian-phase dependent. Sleep 2006; 29 (5) 609-618
• 75 Braam W, Smits MG, Didden R, Korzilius H, Van Geijlswijk IM, Curfs LM. Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis. Dev Med Child Neurol 2009; 51 (5) 340-349
• 76 Carr R, Wasdell MB, Hamilton D , et al. Long-term effectiveness outcome of melatonin therapy in children with treatment-resistant circadian rhythm sleep disorders. J Pineal Res 2007; 43 (4) 351-359
• 77 Gupta M, Aneja S, Kohli K. Add-on melatonin improves sleep behavior in children with epilepsy: randomized, double-blind, placebo-controlled trial. J Child Neurol 2005; 20 (2) 112-115
• 78 Kemp S, Biswas R, Neumann V, Coughlan A. The value of melatonin for sleep disorders occurring post-head injury: a pilot RCT. Brain Inj 2004; 18 (9) 911-919
• 79 Huang HW, Zheng BL, Jiang L , et al. Effect of oral melatonin and wearing earplugs and eye masks on nocturnal sleep in healthy subjects in a simulated intensive care unit environment: which might be a more promising strategy for ICU sleep deprivation?. Crit Care 2015; 19 (1) 124
• 80 Saugstad OD. Oxidative stress in the newborn—a 30-year perspective. Biol Neonate 2005; 88 (3) 228-236
• 81 Shilo L, Dagan Y, Smorjik Y , et al. Effect of melatonin on sleep quality of COPD intensive care patients: a pilot study. Chronobiol Int 2000; 17 (1) 71-76
• 82 Ibrahim MG, Bellomo R, Hart GK , et al. A double-blind placebo-controlled randomised pilot study of nocturnal melatonin in tracheostomised patients. Crit Care Resusc 2006; 8 (3) 187-191
• 83 Bourne RS, Mills GH, Minelli C. Melatonin therapy to improve nocturnal sleep in critically ill patients: encouraging results from a small randomised controlled trial. Crit Care 2008; 12 (2) R52
• 84 Mistraletti G, Umbrello M, Sabbatini G , et al. Melatonin reduces the need for sedation in ICU patients: a randomized controlled trial. Minerva Anestesiol 2015; 81 (12) 1298-1310
• 85 Huang H, Jiang L, Shen L , et al. Impact of oral melatonin on critically ill adult patients with ICU sleep deprivation: study protocol for a randomized controlled trial. Trials 2014; 15: 327
• 86 Tan DX, Reiter RJ, Manchester LC , et al. Chemical and physical properties and potential mechanisms: melatonin as a broad spectrum antioxidant and free radical scavenger. Curr Top Med Chem 2002; 2 (2) 181-197
• 87 Tan DX, Manchester LC, Terron MP, Flores LJ, Reiter RJ. One molecule, many derivatives: a never-ending interaction of melatonin with reactive oxygen and nitrogen species?. J Pineal Res 2007; 42 (1) 28-42
• 88 Longoni B, Salgo MG, Pryor WA, Marchiafava PL. Effects of melatonin on lipid peroxidation induced by oxygen radicals. Life Sci 1998; 62 (10) 853-859
• 89 Rodriguez C, Mayo JC, Sainz RM , et al. Regulation of antioxidant enzymes: a significant role for melatonin. J Pineal Res 2004; 36 (1) 1-9
• 90 Fulia F, Gitto E, Cuzzocrea S , et al. Increased levels of malondialdehyde and nitrite/nitrate in the blood of asphyxiated newborns: reduction by melatonin. J Pineal Res 2001; 31 (4) 343-349
• 91 Gitto E, Romeo C, Reiter RJ , et al. Melatonin reduces oxidative stress in surgical neonates. J Pediatr Surg 2004; 39 (2) 184-189 , discussion 184–189
• 92 Gitto E, Reiter RJ, Cordaro SP , et al. Oxidative and inflammatory parameters in respiratory distress syndrome of preterm newborns: beneficial effects of melatonin. Am J Perinatol 2004; 21 (4) 209-216
• 93 Gitto E, Reiter RJ, Amodio A , 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 (4) 250-255
• 94 Gitto E, Reiter RJ, Sabatino G , et al. Correlation among cytokines, bronchopulmonary dysplasia and modality of ventilation in preterm newborns: improvement with melatonin treatment. J Pineal Res 2005; 39 (3) 287-293
• 95 Wu JY, Tsou MY, Chen TH, Chen SJ, Tsao CM, Wu CC. Therapeutic effects of melatonin on peritonitis-induced septic shock with multiple organ dysfunction syndrome in rats. J Pineal Res 2008; 45 (1) 106-116
• 96 Erbaş O, Ergenoglu AM, Akdemir A, Yeniel AO, Taskiran D. Comparison of melatonin and oxytocin in the prevention of critical illness polyneuropathy in rats with experimentally induced sepsis. J Surg Res 2013; 183 (1) 313-320
• 97 Shang Y, Xu SP, Wu Y , et al. Melatonin reduces acute lung injury in endotoxemic rats. Chin Med J (Engl) 2009; 122 (12) 1388-1393
• 98 Ozdemir D, Uysal N, Tugyan K , et al. The effect of melatonin on endotoxemia-induced intestinal apoptosis and oxidative stress in infant rats. Intensive Care Med 2007; 33 (3) 511-516
• 99 Escames G, López LC, Ortiz F , et al. Attenuation of cardiac mitochondrial dysfunction by melatonin in septic mice. FEBS J 2007; 274 (8) 2135-2147
• 100 Tekbas OF, Ogur R, Korkmaz A, Kilic A, Reiter RJ. Melatonin as an antibiotic: new insights into the actions of this ubiquitous molecule. J Pineal Res 2008; 44 (2) 222-226
• 101 Rahman MA, Azuma Y, Fukunaga H , et al. Serotonin and melatonin, neurohormones for homeostasis, as novel inhibitors of infections by the intracellular parasite chlamydia. J Antimicrob Chemother 2005; 56 (5) 861-868
• 102 Wiid I, Hoal-van Helden E, Hon D, Lombard C, van Helden P. Potentiation of isoniazid activity against Mycobacterium tuberculosis by melatonin. Antimicrob Agents Chemother 1999; 43 (4) 975-977
• 103 Ben-Nathan D, Maestroni GJ, Lustig S, Conti A. Protective effects of melatonin in mice infected with encephalitis viruses. Arch Virol 1995; 140 (2) 223-230
• 104 Tan DX, Korkmaz A, Reiter RJ, Manchester LC. Ebola virus disease: potential use of melatonin as a treatment. J Pineal Res 2014; 57 (4) 381-384
• 105 Gitto E, Karbownik M, Reiter RJ , et al. Effects of melatonin treatment in septic newborns. Pediatr Res 2001; 50 (6) 756-760
• 106 Galley HF, Lowes DA, Allen L, Cameron G, Aucott LS, Webster NR. Melatonin as a potential therapy for sepsis: a phase I dose escalation study and an ex vivo whole blood model under conditions of sepsis. J Pineal Res 2014; 56 (4) 427-438
• 107 Ochoa JJ, Vílchez MJ, Palacios MA, García JJ, Reiter RJ, Muñoz-Hoyos A. Melatonin protects against lipid peroxidation and membrane rigidity in erythrocytes from patients undergoing cardiopulmonary bypass surgery. J Pineal Res 2003; 35 (2) 104-108
• 108 Dobsak P, Siegelova J, Eicher JC , et al. Melatonin protects against ischemia-reperfusion injury and inhibits apoptosis in isolated working rat heart. Pathophysiology 2003; 9 (3) 179-187
• 109 Wang Z, Zhang J, Liu H , et al. Melatonin, a potent regulator of hemeoxygenase-1, reduces cardiopulmonary bypass-induced renal damage in rats. J Pineal Res 2009; 46 (3) 248-254
• 110 Huang H, Yin R, Zhu J , et al. Exogenous melatonin ameliorates hepatic injury in a rat cardiopulmonary bypass model. Eur J Pharmacol 2008; 580 (3) 416-424
• 111 Sokullu O, Sanioğlu S, Kurç E , et al. Does the circadian rhythm of melatonin affect ischemia-reperfusion injury after coronary artery bypass grafting?. Heart Surg Forum 2009; 12 (2) E95-E99
• 112 Maldonado MD, Murillo-Cabezas F, Calvo JR , et al. Melatonin as pharmacologic support in burn patients: a proposed solution to thermal injury-related lymphocytopenia and oxidative damage. Crit Care Med 2007; 35 (4) 1177-1185
• 113 Wiggins-Dohlvik K, Han MS, Stagg HW , et al. Melatonin inhibits thermal injury-induced hyperpermeability in microvascular endothelial cells. J Trauma Acute Care Surg 2014; 77 (6) 899-905 , discussion 905
• 114 Bekyarova G, Apostolova M, Kotzev I. Melatonin protection against burn-induced hepatic injury by down-regulation of nuclear factor kappa B activation. Int J Immunopathol Pharmacol 2012; 25 (3) 591-596
• 115 Bekyarova G, Tancheva S, Hristova M. The effects of melatonin on burn-induced inflammatory responses and coagulation disorders in rats. Methods Find Exp Clin Pharmacol 2010; 32 (5) 299-303
• 116 Görgülü A, Palaoğlu S, Ismailoğlu O , et al. Effect of melatonin on cerebral edema in rats. Neurosurgery 2001; 49 (6) 1434-1441 , discussion 1441–1442
• 117 Sarrafzadeh AS, Thomale UW, Kroppenstedt SN, Unterberg AW. Neuroprotective effect of melatonin on cortical impact injury in the rat. Acta Neurochir (Wien) 2000; 142 (11) 1293-1299
• 118 Beni SM, Kohen R, Reiter RJ, Tan DX, Shohami E. Melatonin-induced neuroprotection after closed head injury is associated with increased brain antioxidants and attenuated late-phase activation of NF-kappaB and AP-1. FASEB J 2004; 18 (1) 149-151
• 119 Uchida K, Aoki T, Ishizuka B. Postoperative delirium and plasma melatonin. Med Hypotheses 1999; 53 (2) 103-106
• 120 Shigeta H, Yasui A, Nimura Y , et al. Postoperative delirium and melatonin levels in elderly patients. Am J Surg 2001; 182 (5) 449-454
• 121 Yoshitaka S, Egi M, Morimatsu H, Kanazawa T, Toda Y, Morita K. Perioperative plasma melatonin concentration in postoperative critically ill patients: its association with delirium. J Crit Care 2013; 28 (3) 236-242
• 122 Al-Aama T, Brymer C, Gutmanis I, Woolmore-Goodwin SM, Esbaugh J, Dasgupta M. Melatonin decreases delirium in elderly patients: a randomized, placebo-controlled trial. Int J Geriatr Psychiatry 2011; 26 (7) 687-694
• 123 Sultan SS. Assessment of role of perioperative melatonin in prevention and treatment of postoperative delirium after hip arthroplasty under spinal anesthesia in the elderly. Saudi J Anaesth 2010; 4 (3) 169-173
• 124 Kain ZN, MacLaren JE, Herrmann L , et al. Preoperative melatonin and its effects on induction and emergence in children undergoing anesthesia and surgery. Anesthesiology 2009; 111 (1) 44-49
• 125 Daoud A, Duff JP, Joffe AR, Alberta Sepsis N ; Alberta Sepsis Network. Diagnostic accuracy of delirium diagnosis in pediatric intensive care: a systematic review. Crit Care 2014; 18 (5) 489
• 126 Papp M, Litwa E, Gruca P, Mocaër E. Anxiolytic-like activity of agomelatine and melatonin in three animal models of anxiety. Behav Pharmacol 2006; 17 (1) 9-18
• 127 Yousaf F, Seet E, Venkatraghavan L, Abrishami A, Chung F. Efficacy and safety of melatonin as an anxiolytic and analgesic in the perioperative period: a qualitative systematic review of randomized trials. Anesthesiology 2010; 113 (4) 968-976
• 128 Ismail SA, Mowafi HA. Melatonin provides anxiolysis, enhances analgesia, decreases intraocular pressure, and promotes better operating conditions during cataract surgery under topical anesthesia. Anesth Analg 2009; 108 (4) 1146-1151
• 129 Schmidt CM, Knief A, Deuster D, Matulat P. am Zehnhoff-Dinnesen AG. Melatonin is a useful alternative to sedation in children undergoing brainstem audiometry with an age dependent success rate—a field report of 250 investigations. Neuropediatrics 2007; 38 (1) 2-4
• 130 Ashrafi MR, Mohammadi M, Tafarroji J, Shabanian R, Salamati P, Zamani GR. Melatonin versus chloral hydrate for recording sleep EEG. Eur J Paediatr Neurol 2010; 14 (3) 235-238
• 131 Almenrader N, Haiberger R, Passariello M. Steal induction in preschool children: is melatonin as good as clonidine? A prospective, randomized study. Paediatr Anaesth 2013; 23 (4) 328-333
• 132 Samarkandi A, Naguib M, Riad W , et al. Melatonin vs. midazolam premedication in children: a double-blind, placebo-controlled study. Eur J Anaesthesiol 2005; 22 (3) 189-196
• 133 Sury MR, Fairweather K. The effect of melatonin on sedation of children undergoing magnetic resonance imaging. Br J Anaesth 2006; 97 (2) 220-225
• 134 Isik B, Baygin O, Bodur H. Premedication with melatonin vs midazolam in anxious children. Paediatr Anaesth 2008; 18 (7) 635-641
• 135 Naguib M, Samarkandi AH, Moniem MA , et al. The effects of melatonin premedication on propofol and thiopental induction dose-response curves: a prospective, randomized, double-blind study. Anesth Analg 2006; 103 (6) 1448-1452
• 136 Turkistani A, Abdullah KM, Al-Shaer AA, Mazen KF, Alkatheri K. Melatonin premedication and the induction dose of propofol. Eur J Anaesthesiol 2007; 24 (5) 399-402
• 137 Borazan H, Tuncer S, Yalcin N, Erol A, Otelcioglu S. Effects of preoperative oral melatonin medication on postoperative analgesia, sleep quality, and sedation in patients undergoing elective prostatectomy: a randomized clinical trial. J Anesth 2010; 24 (2) 155-160
• 138 Mistraletti G, Mantovani ES, Cadringher P , et al; SedaEN investigators. Enteral vs. intravenous ICU sedation management: study protocol for a randomized controlled trial. Trials 2013; 14: 92
• 139 Wilhelmsen M, Amirian I, Reiter RJ, Rosenberg J, Gögenur I. Analgesic effects of melatonin: a review of current evidence from experimental and clinical studies. J Pineal Res 2011; 51 (3) 270-277
• 140 Caumo W, Levandovski R, Hidalgo MP. Preoperative anxiolytic effect of melatonin and clonidine on postoperative pain and morphine consumption in patients undergoing abdominal hysterectomy: a double-blind, randomized, placebo-controlled study. J Pain 2009; 10 (1) 100-108
• 141 Shavali S, Ho B, Govitrapong P , et al. Melatonin exerts its analgesic actions not by binding to opioid receptor subtypes but by increasing the release of beta-endorphin an endogenous opioid. Brain Res Bull 2005; 64 (6) 471-479
• 142 Pang CS, Tsang SF, Yang JC. Effects of melatonin, morphine and diazepam on formalin-induced nociception in mice. Life Sci 2001; 68 (8) 943-951
• 143 Zahn PK, Lansmann T, Berger E, Speckmann EJ, Musshoff U. Gene expression and functional characterization of melatonin receptors in the spinal cord of the rat: implications for pain modulation. J Pineal Res 2003; 35 (1) 24-31
• 144 Aydin ON, Ugur B, Kir E, Ozkan SB. Effect of single-dose fentanyl on the cardiorespiratory system in elderly patients undergoing cataract surgery. J Clin Anesth 2004; 16 (2) 98-103
• 145 Mantovani M, Kaster MP, Pertile R, Calixto JB, Rodrigues AL, Santos AR. Mechanisms involved in the antinociception caused by melatonin in mice. J Pineal Res 2006; 41 (4) 382-389
• 146 Yu CX, Zhu CB, Xu SF, Cao XD, Wu GC. Selective MT(2) melatonin receptor antagonist blocks melatonin-induced antinociception in rats. Neurosci Lett 2000; 282 (3) 161-164
• 147 Gitto E, Aversa S, Salpietro CD , et al. Pain in neonatal intensive care: role of melatonin as an analgesic antioxidant. J Pineal Res 2012; 52 (3) 291-295
• 148 Jonas M, Garfinkel D, Zisapel N, Laudon M, Grossman E. Impaired nocturnal melatonin secretion in non-dipper hypertensive patients. Blood Press 2003; 12 (1) 19-24
• 149 Cavallo A, Daniels SR, Dolan LM, Bean JA, Khoury JC. Blood pressure-lowering effect of melatonin in type 1 diabetes. J Pineal Res 2004; 36 (4) 262-266
• 150 Scheer FA, Van Montfrans GA, van Someren EJ, Mairuhu G, Buijs RM. Daily nighttime melatonin reduces blood pressure in male patients with essential hypertension. Hypertension 2004; 43 (2) 192-197
• 151 Muñoz-Hoyos A, Sánchez-Forte M, Molina-Carballo A , et al. Melatonin's role as an anticonvulsant and neuronal protector: experimental and clinical evidence. J Child Neurol 1998; 13 (10) 501-509
• 152 Brigo F, Del Felice A. Melatonin as add-on treatment for epilepsy. Cochrane Database Syst Rev 2012; 6: CD006967
• 153 Jain S, Besag FM. Does melatonin affect epileptic seizures?. Drug Saf 2013; 36 (4) 207-215
• 154 Goldberg-Stern H, Oren H, Peled N, Garty BZ. Effect of melatonin on seizure frequency in intractable epilepsy: a pilot study. J Child Neurol 2012; 27 (12) 1524-1528
• 155 Cummings C ; Canadian Paediatric Society, Community Paediatrics Committee. Melatonin for the management of sleep disorders in children and adolescents. Paediatr Child Health (Oxford) 2012; 17 (6) 331-336
• 156 Kennaway DJ. Potential safety issues in the use of the hormone melatonin in paediatrics. J Paediatr Child Health 2015; 51 (6) 584-589
• 157 Nickkholgh A, Schneider H, Sobirey M , et al. The use of high-dose melatonin in liver resection is safe: first clinical experience. J Pineal Res 2011; 50 (4) 381-388
• 158 Seabra ML, Bignotto M, Pinto Jr LR, Tufik S. Randomized, double-blind clinical trial, controlled with placebo, of the toxicology of chronic melatonin treatment. J Pineal Res 2000; 29 (4) 193-200
• 159 Weishaupt JH, Bartels C, Pölking E , et al. Reduced oxidative damage in ALS by high-dose enteral melatonin treatment. J Pineal Res 2006; 41 (4) 313-323
• 160 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) 1-7
• 161 Aversa S, Marseglia L, Arco A, D'Angelo G, Cusumano E, Barberi I. Efficacy and safety of melatonin in neonates. Arch Dis Child 2012; 97 (Suppl2): A464
• 162 Buscemi N, Vandermeer B, Hooton N , et al. Efficacy and safety of exogenous melatonin for secondary sleep disorders and sleep disorders accompanying sleep restriction: meta-analysis. BMJ 2006; 332 (7538) 385-393