Вопросы анальгезии и седации новорожденных детей при длительной искусственной вентиляции легких

Представлена актуальная информация о медикаментозных препаратах, применяемых для анальгезии и седации новорожденных детей в условиях отделения реанимации при проведении искусственной вентиляции легких. Приведен обзор исследований наиболее часто используемых седативных и анальгетических средств — опиоидов, ацетаминофена, кетамина, мидазолама, дексмедетомидина, пропофола. Представлен анализ их эффективности и риска развития краткосрочных и отдаленных нежелательных эффектов, в том числе связанных с формированием нервной системы ребенка. Обсуждается применение препаратов как в монотерапии, так и в сочетании с другими лекарственными средствами для анальгезии и седации.

1. Simons SH, Tibboel D. Pain perception development and maturation. Semin Fetal Neonatal Med. 2006;11(4):227–231. doi: https://doi.org/10.1016/j.siny.2006.02.010

2. Andrews K, Fitzgerald M. Cutaneous flexion reflex in human neonates: a quantitative study of threshold and stimulus-response characteristics after single and repeated stimuli. Dev Med Child Neurol. 1999;41(10):696–703. doi: https://doi.org/10.1017/s0012162299001425

3. Carbajal R, Rousset A, Danan C, et al. Epidemiology and treatment of painful procedures in neonates in intensive care units. JAMA. 2008;300(1):60–70. doi: https://doi.org/10.1001/jama.300.1.60

4. Porter FL, Wolf CM, Miller JP. Procedural pain in newborn infants: the influence of intensity and development. Pediatrics. 1999; 104(1):e13. doi: https://doi.org/10.1542/peds.104.1.e13

5. Guinsburg R, Kopelman BI, Anand KJ, et al. Physiological, hormonal, and behavioral responses to a single fentanyl dose in intubated and ventilated preterm neonates. J Pediatr. 1998;132(6):954–959. doi: https://doi.org/10.1016/s0022-3476(98)70390-7

6. Craig KD, Whitfield MF, Grunau RVE, et al. Pain in the preterm neonate: behavioural and physiological indices. Pain. 1993;52(3): 287–299. doi: https://doi.org/10.1016/0304-3959(93)90162-I

7. Lago P, Boccuzzo G, Garetti E, et al. Pain management during invasive procedures at Italian NICUs: has anything changed in the last five years? J Matern Fetal Neonatal Med. 2013;26(3):303–305. doi: https://doi.org/10.3109/14767058.2012.733783

8. Roofthooft DW, Simons SH, Anand KJ, et al. Eight years later, are we still hurting newborn infants? Neonatology. 2014;105(3): 218–226. doi: https://doi.org/10.1159/000357207

9. COMMITTEE ON FETUS AND NEWBORN and SECTION ON ANESTHESIOLOGY AND PAIN MEDICINE. Prevention and Management of Procedural Pain in the Neonate: An Update. Pediatrics. 2016;137(2):e20154271. doi: https://doi.org/10.1542/peds.2015-4271

10. Barker DP, Rutter N. Stress, severity of illness, and outcome in ventilated preterm infants. Arch Dis Child Fetal Neonatal Ed. 1996; 75(3):F187–F190. doi: https://doi.org/10.1136/fn.75.3.f187

11. Hall RW, Boyle E, Young T. Do ventilated neonates require pain management? Semin Perinatol. 2007;31(5):289–297. doi: https://doi.org/10.1053/j.semperi.2007.07.002

12. Saarenmaa E, Huttunen P, Leppäluoto J, Fellman V. Alfentanil as procedural pain relief in newborn infants. Arch Dis Child Fetal Neonatal Ed. 1996;75(2):F103–F107. doi: https://doi.org/10.1136/fn.75.2.f103

13. Behnke J, Lemyre B, Czernik C, et al. Non-Invasive Ventilation in Neonatology. Dtsch Arztebl Int. 2019;116(11):177–183. doi: https://doi.org/10.3238/arztebl.2019.0177

14. Sand L, Szatkowski L, Kwok TC, et al. Observational cohort study of changing trends in non-invasive ventilation in very preterm infants and associations with clinical outcomes. Arch Dis Child Fetal Neonatal Ed. 2022;107(2):150–155. doi: https://doi.org/10.1136/archdischild-2021-322390

15. Walsh MC, Morris BH, Wrage LA, et al. Extremely low birthweight neonates with protracted ventilation: mortality and 18-month neurodevelopmental outcomes. J Pediatr. 2005;146(6):798–804. doi: https://doi.org/10.1016/j.jpeds.2005.01.047

16. Зиганшин И.М., Баялиева А.Ж., Бабинцева А.А., Шай марданова Г.Р. Эффективность искусственной вентиляции легких с гарантированным объемом у новорожденных // Российский вестник детской хирургии, анестезиологии и реаниматологии. — 2020. — Т. 10. — № 2. — С. 165–172. — doi: https://doi.org/10.17816/psaic611

17. Greco P, Nencini G, Piva I, et al. Pathophysiology of hypoxic-ischemic encephalopathy: a review of the past and a view on the future. Acta Neurol Belg. 2020;120(2):277–288. doi: https://doi.org/10.1007/s13760-020-01308-3

18. Williams EE, Greenough A. Lung Protection During Mechanical Ventilation in the Premature Infant. Clin Perinatol. 2021;48(4): 869–880. doi: https://doi.org/10.1016/j.clp.2021.08.006

19. Hummler H, Schulze A. New and alternative modes of mechanical ventilation in neonates. Semin Fetal Neonatal Med. 2009;14(1): 42–48. doi: https://doi.org/10.1016/j.siny.2008.08.006

20. Ancora G, Lago P, Garetti E, et al. Evidence-based clinical guidelines on analgesia and sedation in newborn infants undergoing assisted ventilation and endotracheal intubation. Acta Paediatr. 2019;108(2):208–217. doi: https://doi.org/10.1111/apa.14606

21. American Academy of Pediatrics Committee on Fetus and Newborn; American Academy of Pediatrics Section on Surgery; Canadian Paediatric Society Fetus and Newborn Committee, Batton DG, Barrington KJ, Wallman C. Prevention and management of pain in the neonate: an update. Pediatrics. 2006;118(5): 2231–2241. doi: https://doi.org/10.1542/peds.2006-2277

22. Vittinghoff M, Lönnqvist PA, Mossetti V, et al. Postoperative pain management in children: Guidance from the pain committee of the European Society for Paediatric Anaesthesiology (ESPA Pain Management Ladder Initiative). Paediatr Anaesth. 2018;28(6): 493–506. doi: https://doi.org/10.1111/pan.13373

23. Hohmeister J, Kroll A, Wollgarten-Hadamek I, et al. Cerebral processing of pain in school-aged children with neonatal nociceptive input: an exploratory fMRI study. Pain. 2010;150(2):257–267. doi: https://doi.org/10.1016/j.pain.2010.04.004

24. Taddio A, Shah V, Gilbert-MacLeod C, Katz J. Conditioning and hyperalgesia in newborns exposed to repeated heel lances. JAMA. 2002;288(7):857–861. doi: https://doi.org/10.1001/jama.288.7.857

25. Bellù R, Romantsik O, Nava C, et al. Opioids for newborn infants receiving mechanical ventilation. Cochrane Database Syst Rev. 2021;3(3):CD013732. doi: https://doi.org/10.1002/14651858.CD013732.pub2

26. Bellù R, de Waal K, Zanini R. Opioids for neonates receiving mechanical ventilation: a systematic review and meta-analysis. Arch Dis Child Fetal Neonatal Ed. 2010;95(4):F241–F251. doi: https://doi.org/10.1136/adc.2008.150318

27. McPherson C, Miller SP, El-Dib M, et al. The influence of pain, agitation, and their management on the immature brain. Pediatr Res. 2020;88(2):168–175. doi: https://doi.org/10.1038/s41390-019-0744-6

28. Pillai Riddell RR, Racine NM, Gennis HG, et al. Non-pharmacological management of infant and young child procedural pain. Cochrane Database Syst Rev. 2015;2015(12):CD006275. doi: https://doi.org/10.1002/14651858.CD006275.pub3

29. Neonatology Branch of Chinese Medical Association; Editorial Board of Chinese Journal of Contemporary Pediatrics. Expert consensus on neonatal pain assessment and analgesia management (2020 edition). Zhongguo Dang Dai Er Ke Za Zhi. 2020;22(9): 923–930. doi: https://doi.org/10.7499/j.issn.1008-8830.2006181

30. Kassab M, Foster JP, Foureur M, Fowler C. Sweet-tasting solutions for needle-related procedural pain in infants one month to one year of age. Cochrane Database Syst Rev. 2012;12(12):CD008411. doi: https://doi.org/10.1002/14651858.CD008411.pub2

31. Shendurnikar N, Gandhi K. Analgesic effects of breastfeeding on heel lancing. Indian Pediatr. 2005;42(7):730–732.

32. Gomes Neto M, da Silva Lopes IA, Araujo ACCLM, et al. The effect of facilitated tucking position during painful procedure in pain management of preterm infants in neonatal intensive care unit: a systematic review and meta-analysis. Eur J Pediatr. 2020;179(5): 699–709. doi: https://doi.org/10.1007/s00431-020-03640-5

33. Cignacco E, Hamers JP, Stoffel L, et al. The efficacy of nonpharmacological interventions in the management of procedural pain in preterm and term neonates. A systematic literature review. Eur J Pain. 2007;11(2):139–152. doi: https://doi.org/10.1016/j.ejpain.2006.02.010

34. Ferber SG, Makhoul IR. Neurobehavioural assessment of skinto-skin effects on reaction to pain in preterm infants: a randomized, controlled within-subject trial. Acta Paediatr. 2008;97(2):171–176. doi: https://doi.org/10.1111/j.1651-2227.2007.00607.x

35. Ludington-Hoe SM, Hosseini R, Torowicz DL. Skin-to-skin contact (Kangaroo Care) analgesia for preterm infant heel stick. AACN Clin Issues. 2005;16(3):373–387. doi: https://doi.org/10.1097/00044067-200507000-00010

36. Nemergut ME, Yaster M, Colby CE. Sedation and analgesia to facilitate mechanical ventilation. Clin Perinatol. 2013;40(3): 539–558. doi: https://doi.org/10.1016/j.clp.2013.05.005

37. Weissman A, Aranovitch M, Blazer S, Zimmer EZ. Heel-lancing in newborns: behavioral and spectral analysis assessment of pain control methods. Pediatrics. 2009;124(5):e921–e926. doi: https://doi.org/10.1542/peds.2009-0598

38. Aldrink JH, Ma M, Wang W, et al. Safety of ketorolac in surgical neonates and infants 0 to 3 months old. J Pediatr Surg. 2011;46(6):1081–1085. doi: https://doi.org/10.1016/j.jpedsurg.2011.03.031

39. El-Mashad AE, El-Mahdy H, El Amrousy D, Elgendy M. Comparative study of the efficacy and safety of paracetamol, ibuprofen, and indomethacin in closure of patent ductus arteriosus in preterm neonates. Eur J Pediatr. 2017;176(2):233–240. doi: https://doi.org/10.1007/s00431-016-2830-7

40. Roofthooft DWE, Simons SHP, van Lingen RA, et al. Randomized Controlled Trial Comparing Different Single Doses of Intravenous Paracetamol for Placement of Peripherally Inserted Central Catheters in Preterm Infants. Neonatology. 2017;112(2):150–158. doi: https://doi.org/10.1159/000468975

41. Ohlsson A, Shah PS. Paracetamol (acetaminophen) for prevention or treatment of pain in newborns. Cochrane Database Syst Rev. 2020;1(1):CD011219. doi: https://doi.org/10.1002/14651858.CD011219.pub4

42. Rana D, Bellflower B, Sahni J, et al. Reduced narcotic and sedative utilization in a NICU after implementation of pain management guidelines. J Perinatol. 2017;37(9):1038–1042. doi: https://doi.org/10.1038/jp.2017.88

43. Truog R, Anand KJ. Management of pain in the postoperative neonate. Clin Perinatol. 1989;16(1):61–78.

44. Anderson BJ, Holford NH, Armishaw JC, Aicken R. Predicting concentrations in children presenting with acetaminophen overdose. J Pediatr. 1999;135(3):290–295. doi: https://doi.org/10.1016/s0022-3476(99)70122-8

45. Anderson BJ, van Lingen RA, Hansen TG, et al. Acetaminophen developmental pharmacokinetics in premature neonates and infants: a pooled population analysis. Anesthesiology. 2002;96(6):1336– 1345. doi: https://doi.org/10.1097/00000542-200206000-00012

46. Arana A, Morton NS, Hansen TG. Treatment with paracetamol in infants. Acta Anaesthesiol Scand. 2001;45(1):20–29. doi: https://doi.org/10.1034/j.1399-6576.2001.450104.x

47. van der Marel CD, Peters JW, Bouwmeester NJ, et al. Rectal acetaminophen does not reduce morphine consumption after major surgery in young infants. Br J Anaesth. 2007;98(3):372–379. doi: https://doi.org/10.1093/bja/ael371

48. Tinner EM, Hoesli I, Jost K, et al. Rectal paracetamol in newborn infants after assisted vaginal delivery may increase pain response. J Pediatr. 2013;162(1):62–66. doi: https://doi.org/10.1016/j.jpeds.2012.06.020

49. van den Anker JN, Tibboel D. Pain relief in neonates: when to use intravenous paracetamol. Arch Dis Child. 2011;96(6):573–574. doi: https://doi.org/10.1136/adc.2011.211060

50. Dani C, Lista G, Bianchi S, et al. Intravenous paracetamol in comparison with ibuprofen for the treatment of patent ductus arteriosus in preterm infants: a randomized controlled trial. Eur J Pediatr. 2021;180(3):807–816. doi: https://doi.org/10.1007/s00431-020-03780-8

51. Carbajal R, Eriksson M, Courtois E, et al. Sedation and analgesia practices in neonatal intensive care units (EUROPAIN): results from a prospective cohort study. Lancet Respir Med. 2015;3(10):796–812. doi: https://doi.org/10.1016/S2213-2600(15)00331-8

52. Donato J, Rao K, Lewis T. Pharmacology of Common Analgesic and Sedative Drugs Used in the Neonatal Intensive Care Unit. Clin Perinatol. 2019;46(4):673–692. doi: https://doi.org/10.1016/j.clp.2019.08.004

53. Olischar M, Palmer GM, Orsini F, et al. The addition of tramadol to the standard of i.v. acetaminophen and morphine infusion for postoperative analgesia in neonates offers no clinical benefit: a randomized placebo-controlled trial. Paediatr Anaesth. 2014;24(11):1149–1157. doi: https://doi.org/10.1111/pan.12477

54. Schmidt B, Adelmann C, Stützer H, et al. Comparison of sufentanil versus fentanyl in ventilated term neonates. Klin Padiatr. 2010;222(2):62–66. doi: https://doi.org/10.1055/s-0029-1225348

55. Anand KJ, Hall RW, Desai N, et al. Effects of morphine analgesia in ventilated preterm neonates: primary outcomes from the NEOPAIN randomised trial. Lancet. 2004;363(9422):1673–1682. doi: https://doi.org/10.1016/S0140-6736(04)16251-X

56. MacGregor R, Evans D, Sugden D, et al. Outcome at 5-6 years of prematurely born children who received morphine as neonates. Arch Dis Child Fetal Neonatal Ed. 1998;79(1):F40–F43. doi: https://doi.org/10.1136/fn.79.1.f40

57. Monk V, Moultrie F, Hartley C, et al. Oral morphine analgesia for preventing pain during invasive procedures in non-ventilated premature infants in hospital: the Poppi RCT. Southampton (UK): NIHR Journals Library; 2019.

58. Duong P, Tauzin M, Decobert F, et al. Continuous intravenous to oral morphine switch in very premature ventilated infants: A retrospective study on efficacy, efficiency, and tolerability. Paediatr Neonatal Pain. 2020;1(2):45–52. doi: https://doi.org/10.1002/pne2.12011

59. Saarenmaa E, Huttunen P, Leppäluoto J, et al. Advantages of fentanyl over morphine in analgesia for ventilated newborn infants after birth: A randomized trial. J Pediatr. 1999;134(2):144–150. doi: https://doi.org/10.1016/s0022-3476(99)70407-5

60. Franck LS, Vilardi J, Durand D, Powers R. Opioid withdrawal in neonates after continuous infusions of morphine or fentanyl during extracorporeal membrane oxygenation. Am J Crit Care. 1998;7(5):364–369.

61. Anand KJ, Willson DF, Berger J, et al. Tolerance and withdrawal from prolonged opioid use in critically ill children. Pediatrics. 2010;125(5): e1208–e1225. doi: https://doi.org/10.1542/peds.2009-0489

62. Ancora G, Lago P, Garetti E, et al. Efficacy and safety of continuous infusion of fentanyl for pain control in preterm newborns on mechanical ventilation. J Pediatr. 2013;163(3):645–651.e1. doi: https://doi.org/10.1016/j.jpeds.2013.02.039

63. Lago P, Benini F, Agosto C, Zacchello F. Randomised controlled trial of low dose fentanyl infusion in preterm infants with hyaline membrane disease. Arch Dis Child Fetal Neonatal Ed. 1998;79(3): F194–F197. doi: https://doi.org/10.1136/fn.79.3.f194

64. Orsini AJ, Leef KH, Costarino A, et al. Routine use of fentanyl infusions for pain and stress reduction in infants with respiratory distress syndrome. J Pediatr. 1996;129(1):140–145. doi: https://doi.org/10.1016/s0022-3476(96)70201-9

65. Puia-Dumitrescu M, Comstock BA, Li S, et al. Assessment of 2-Year Neurodevelopmental Outcomes in Extremely Preterm Infants Receiving Opioids and Benzodiazepines. JAMA Netw Open. 2021;4(7):e2115998. doi: https://doi.org/10.1001/jamanetworkopen.2021.15998

66. Jacobwitz M, Mulvihill C, Kaufman MC, et al. Ketamine for Management of Neonatal and Pediatric Refractory Status Epilepticus. Neurology. 2022;99(12):e1227–e1238. doi: https://doi.org/10.1212/WNL.0000000000200889

67. Samanta D. Ketamine in Refractory Neonatal Seizures. Pediatr Neurol. 2020;106:76. doi: https://doi.org/10.1016/j.pediatrneurol.2019.11.012

68. Hall RW, Shbarou RM. Drugs of choice for sedation and analgesia in the neonatal ICU. Clin Perinatol. 2009;36(2):15–26. doi: https://doi.org/10.1016/j.clp.2009.04.001

69. Mion G, Villevieille T. Ketamine pharmacology: an update (pharmacodynamics and molecular aspects, recent findings). CNS Neurosci Ther. 2013;19(6):370–380. doi: https://doi.org/10.1111/cns.12099

70. Poonai N, Canton K, Ali S, et al. Intranasal ketamine for procedural sedation and analgesia in children: A systematic review. PLoS One. 2017;12(3):e0173253. doi: https://doi.org/10.1371/journal.pone.0173253

71. Khoshrang H, Emir Alavi C, Rimaz S, et al. Efficacy of intranasal ketamine and midazolam for pediatric sedation: A double-blind, randomized clinical trial. Caspian J Intern Med. 2021;12(4): 539–543. doi: https://doi.org/10.22088/cjim.12.4.539

72. Green SM, Roback MG, Krauss B, et al. Predictors of emesis and recovery agitation with emergency department ketamine sedation: an individual-patient data meta-analysis of 8,282 children. Ann Emerg Med. 2009;54(2):171–180.e804. doi: https://doi.org/10.1016/j.annemergmed.2009.04.004

73. Buonsenso D, Barone G, Valentini P, et al. Utility of intranasal Ketamine and Midazolam to perform gastric aspirates in children: a double-blind, placebo controlled, randomized study. BMC Pediatr. 2014;14:67. doi: https://doi.org/10.1186/1471-2431-14-67

74. Stevens RA, Butler BD, Kokane SS, et al. Neonatal inhibition of Na+-K+-2Cl−-cotransporter prevents ketamine induced spatial learning and memory impairments. Neurotoxicol Teratol. 2017; 60:82–86. doi: https://doi.org/10.1016/j.ntt.2016.11.001

75. Huang H, Zhao C, Hu Q, et al. Neonatal Anesthesia by Ketamine in Neonatal Rats Inhibits the Proliferation and Differentiation of Hippocampal Neural Stem Cells and Decreases Neurocognitive Function in Adulthood via Inhibition of the Notch1 Signaling Pathway. Mol Neurobiol. 2021;58(12):6272–6289. doi: https://doi.org/10.1007/s12035-021-02550-3

76. Zhang Z, Bai H, Ma X, et al. Blockade of the NLRP3/caspase-1 axis attenuates ketamine-induced hippocampus pyroptosis and cognitive impairment in neonatal rats. J Neuroinflammation. 2021;18(1):239. doi: https://doi.org/10.1186/s12974-021-02295-9

77. de Tristan MA, Martin-Marchand L, Roué JM, et al. Association of Continuous Opioids and/or Midazolam During Early Mechanical Ventilation with Survival and Sensorimotor Outcomes at Age 2 Years in Premature Infants: Results from the French Prospective National EPIPAGE 2 Cohort. J Pediatr. 2021;232:38–47.e8. doi: https://doi.org/10.1016/j.jpeds.2020.12.069

78. Jacqz-Aigrain E, Daoud P, Burtin P, et al. Placebo-controlled trial of midazolam sedation in mechanically ventilated newborn babies. Lancet. 1994;344(8923):646–650. doi: https://doi.org/10.1016/s0140-6736(94)92085-0

79. Arya V, Ramji S. Midazolam sedation in mechanically ventilated newborns: a double blind randomized placebo controlled trial. Indian Pediatr. 2001;38(9):967–972.

80. Stevens MF, Werdehausen R, Gaza N, et al. Midazolam activates the intrinsic pathway of apoptosis independent of benzodiazepine and death receptor signaling. Reg Anesth Pain Med. 2011;36(4): 343–349. doi: https://doi.org/10.1097/AAP.0b013e318217a6c7

81. Duerden EG, Guo T, Dodbiba L, et al. Midazolam dose correlates with abnormal hippocampal growth and neurodevelopmental outcome in preterm infants. Ann Neurol. 2016;79(4):548–559. doi: https://doi.org/10.1002/ana.24601

82. Козлов И.А. Дексмедетомидин при анестезиолого-реаниматологическом обеспечении кардиохирургических вмешательств. Часть 1. Общие сведения об агонистах 2-адренорецепторов и их фармакодинамике // Кардиология и сердечно-сосудистая хирургия. — 2014. — Т. 7. — № 3. — С. 63–73.

83. Mahmoud M, Barbi E, Mason KP. Dexmedetomidine: What’s New for Pediatrics? A Narrative Review. J Clin Med. 2020;9(9):2724. doi: https://doi.org/10.3390/jcm9092724

84. O’Mara K, Gal P, Ransommd JL, et al. Successful use of dexmedetomidine for sedation in a 24-week gestational age neonate. Ann Pharmacother. 2009;43(10):1707–1713. doi: https://doi.org/10.1345/aph.1M245

85. Chrysostomou C, Schulman SR, Herrera Castellanos M, et al. A phase II/III, multicenter, safety, efficacy, and pharmacokinetic study of dexmedetomidine in preterm and term neonates. J Pediatr. 2014;164(2):276–282.e823. doi: https://doi.org/10.1016/j.jpeds.2013.10.002

86. Gertler R, Brown HC, Mitchell DH, Silvius EN. Dexmedetomidine: a novel sedative-analgesic agent. Proc (Bayl Univ Med Cent). 2001;14(1): 13–21. doi: https://doi.org/10.1080/08998280.2001.11927725

87. Sellas MN, Kyllonen KC, Lepak MR, Rodriguez RJ. Dexmedetomidine for the Management of Postoperative Pain and Sedation in Newborns. J Pediatr Pharmacol Ther. 2019;24(3):227–233. doi: https://doi.org/10.5863/1551-6776-24.3.227

88. Ren X, Ma H, Zuo Z. Dexmedetomidine Postconditioning Re duces Brain Injury after Brain Hypoxia-Ischemia in Neonatal Rats. J Neuroimmune Pharmacol. 2016;11(2):238–247. doi: https://doi.org/10.1007/s11481-016-9658-9

89. Ezzati M, Kawano G, Rocha-Ferreira E, et al. Dexmedetomidine Combined with Therapeutic Hypothermia Is Associated with Cardiovascular Instability and Neurotoxicity in a Piglet Model of Perinatal Asphyxia. Dev Neurosci. 2017;39(1-4):156–170. doi: https://doi.org/10.1159/000458438

90. Naveed M, Bondi DS, Shah PA. Dexmedetomidine Versus Fentanyl for Neonates With Hypoxic Ischemic Encephalopathy Undergoing Therapeutic Hypothermia. J Pediatr Pharmacol Ther. 2022;27(4): 352–357. doi: https://doi.org/10.5863/1551-6776-27.4.352

91. Cosnahan AS, Angert RM, Jano E, Wachtel EV. Dexmedetomidine versus intermittent morphine for sedation of neonates with ence phalopathy undergoing therapeutic hypothermia. J Perinatol. 2021;41(9): 2284–2291. doi: https://doi.org/10.1038/s41372-021-00998-8

92. O’Mara K, Gal P, Wimmer J, et al. Dexmedetomidine versus standard therapy with fentanyl for sedation in mechanically ventilated premature neonates. J Pediatr Pharmacol Ther. 2012;17(3): 252–262. doi: https://doi.org/10.5863/1551-6776-17.3.252

93. Morton SU, Labrecque M, Moline M, et al. Reducing Benzodiazepine Exposure by Instituting a Guideline for Dexmedetomidine Usage in the NICU. Pediatrics. 2021;148(5):e2020041566. doi: https://doi.org/10.1542/peds.2020-041566

94. Dersch-Mills DA, Banasch HL, Yusuf K, Howlett A. Dexmedetomidine Use in a Tertiary Care NICU: A Descriptive Study. Ann Pharmacother. 2019;53(5):464–470. doi: https://doi.org/10.1177/1060028018812089

95. Estkowski LM, Morris JL, Sinclair EA. Characterization of dexmedetomidine dosing and safety in neonates and infants. J Pediatr Pharmacol Ther. 2015;20(2):112–118. doi: https://doi.org/10.5863/1551-6776-20.2.112

96. Cortes-Ledesma C, Arruza L, Sainz-Villamayor A, MartínezOrgado J. Dexmedetomidine affects cerebral activity in preterm infants. Arch Dis Child Fetal Neonatal Ed. 2022;fetalneonatal-2021- 323411. doi: https://doi.org/10.1136/archdischild-2021-323411

97. van Dijkman SC, De Cock PAJG, Smets K, et al. Dose rationale and pharmacokinetics of dexmedetomidine in mechanically ventilated new-borns: impact of design optimisation. Eur J Clin Pharmacol. 2019;75(10):1393–1404. doi: https://doi.org/10.1007/s00228-019-02708-y

98. Chidambaran V, Costandi A, D’Mello A. Correction to: Propofol: A Review of its Role in Pediatric Anesthesia and Sedation. CNS Drugs. 2018;32(9):873. doi: https://doi.org/10.1007/s40263-018-0561-1

99. Fuentes R, Cortínez LI, Contreras V, et al. Propofol pharmacokinetic and pharmacodynamic profile and its elec troencephalographic interaction with remifentanil in children. Paediatr Anaesth. 2018;28(12):1078–1086. doi: https://doi.org/10.1111/pan.13486

100. Michelet R, Van Bocxlaer J, Allegaert K, Vermeulen A. The use of PBPK modeling across the pediatric age range using propofol as a case. J Pharmacokinet Pharmacodyn. 2018;45(6):765–785. doi: https://doi.org/10.1007/s10928-018-9607-8

101. Ulgey A, Güneş I, Bayram A, et al. Decreasing the need for mechanical ventilation after surgery for retinopathy of prematurity: sedoanalgesia vs. general anesthesia. Turk J Med Sci. 2015; 45(6):1292–1299. doi: https://doi.org/10.3906/sag-1401-24

102. Dekker J, Lopriore E, van Zanten HA, et al. Sedation during minimal invasive surfactant therapy: a randomised controlled trial. Arch Dis Child Fetal Neonatal Ed. 2019;104(4):F378–F383. doi: https://doi.org/10.1136/archdischild-2018-315015

103. Smits A, Thewissen L, Caicedo A, et al. Propofol Dose-Finding to Reach Optimal Effect for (Semi-)Elective Intubation in Neonates. J Pediatr. 2016;179:54–60.e9. doi: https://doi.org/10.1016/j.jpeds.2016.07.049

104. Slavik VC, Zed PJ. Combination ketamine and propofol for procedural sedation and analgesia. Pharmacotherapy. 2007;27(11): 1588–1598. doi: https://doi.org/10.1592/phco.27.11.1588

105. Jager MD, Aldag JC, Deshpande GG. A presedation fluid bolus does not decrease the incidence of propofol-induced hypotension in pediatric patients. Hosp Pediatr. 2015;5(2):85-91. doi: https://doi.org/10.1542/hpeds.2014-0075