Strategy for the prevention of bacterial complications with inhaled nitrogen oxide in newborns

Abstract

BACKGROUND: The nitrogen oxide molecule (NO) is a one of the most important factors in the anti-infectious resistance of the body’s immune system.

AIM: This study aims to improve the effectiveness of preventing bacterial complications by including nitric oxide inhalations as part of traditional intensive care.

MATERIALS AND METHODS: Ninety-seven full-term newborns without signs of bacterial complications were included in a controlled, randomized, blind clinical trial. The main group (n = 44) received inhaled nitrogen oxide (iNO). The control group (n = 53) did not receive iNO. On days 1, 5, and 20 the plasma concentrations of IL-1β, IL-6, IL-8, TNF-α, G-CSF, sFas, FGF, and NO were determined by capture ELISA; CD3⁺CD19^–, CD3^–CD19⁺, CD3⁺CD4⁺, CD3⁺CD8⁺, CD69⁺, CD71⁺, CD95⁺, CD3⁺HLA-DR⁺, CD14⁺, CD3^–CD56⁺, Annexin-V⁺/FITC; PI⁺/PE — immunophenotype analysis.

RESULTS: In the main group, sepsis developed in 4 patients and 13 controls (p₁ = 0.04; p₂ = 0.005). Fatalities occurred in 6 patients, and 10 controls (p₁ = 0.37; p₂ = 0.59) in the main group. The median duration of the IVL in the main group was 5 days, and 10 days for controls (p = 0.00007). Stays in ORIT were main — 11 days for patients in the main group, and 15 days for controls (p = 0.026). On day 3, when compared with controls, patients in the main group had significantly reduced (p < 0.05) of TNF-α, IL-8 and IL-6, CD3⁺CD69^+, CD3⁺CD95⁺, lymphocytes in apoptosis, increasing (p < 0.05) G-CSF, sFas, FGF, NO; CD14⁺, CD3 ⁺CD19^–.

CONCLUSIONS: iNO used as a part of intensive care decreases the frequency of sepsis development, the duration of mechanical ventilation, and hospitalization. iNO also tends to decrease the lethal outcome frequency, reduces cytokine aggression, inhibits lymphocyte apoptosis, activates the monocyte-macrophage immunity and proliferative processes. It is appropriate to continue research.

Keywords

inhaled nitrogen oxide / newborn / bacterial complications / apoptosis / cytokines / newborns

References

[1] Singer M, Deutschman CS, Seymour CW. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016.315(8):801–810. DOI: 10.1001/jama.2016.0287

[2] Singer M., Deutschman C.S., Seymour C.W. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3) // JAMA. 2016. Vol. 315, No. 8. P. 801–810. DOI: 10.1001/jama.2016.0287

[3] Gotts JE, Matthay MA. Sepsis: pathophysiology and clinical management. BMJ. 2016;353:i1585. DOI: 10.1136/bmj.i1585

[4] Gotts J.E., Matthay M.A. Sepsis: pathophysiology and clinical management // BMJ 2016. Vol. 353. P. i1585. DOI: 10.1136/bmj.i1585

[5] Fleischmann C, Scherag A, Adhikari NK. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations. Am J Respir Crit Care Med; 2016;193(3):259–272. DOI: 10.1164/rccm.201504-0781OC

[6] Fleischmann C., Scherag A., Adhikari N.K. Assessment of Global Incidence and Mortality of Hospital-treated Sepsis. Current Estimates and Limitations // Am J Respir Crit Care Med. 2016. Vol. 193, No. 3. P. 259–272. DOI: 10.1164/rccm.201504-0781OC

[7] Fleischmann C, Goldfarb DM, Schlattmann P, et al. The global burden of paediatric and neonatal sepsis: a systematic review. The Lancet Respiratory medicine. 2018;6(3):223–230. DOI: 10.1016/S2213-2600(18)30063-8

[8] Fleischmann C., Goldfarb D.M., Schlattmann P., et al. The global burden of paediatric and neonatal sepsis: a systematic review // The Lancet Respiratory medicine. 2018. Vol. 6, No. 3. P. 223–230. DOI: 10.1016/S2213-2600(18)30063-8

[9] Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997;336:597–604. DOI: 10.1056/NEJM199702273360901

[10] Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure // N Engl J Med. 1997. Vol. 336. P. 597–604. DOI: 10.1056/NEJM199702273360901

[11] Bankalari E. Lungs newborns. Problems and contradictions in neonatology. Moscow: Logosfera; 2015. P. 342–354.

[12] Банкалари Э. Легкие новорожденных. Под ред. Полина Р., пер. с англ.; под ред. Д.Ю. Овсянникова. М.: Логосфера, 2015. С. 342–354.

[13] Hajishengallis G, Chavakis T, Hajishengallis E, Lambris JD. Neutrophil homeostasis and inflammation: novel paradigms from studying periodontitis. J Leukoc Biol. 2015;98(4):539–548. DOI: 10.1189/jlb.3VMR1014-468R

[14] Hajishengallis G., Chavakis T., Hajishengallis E., Lambris J.D. Neutrophil homeostasis and inflammation: novel paradigms from studying periodontitis // J Leukoc Biol. 2015. Vol. 98, No. 4. P. 539–548. DOI: 10.1189/jlb.3VMR1014-468R

[15] Savchenko AA, Borisov AG, Zdzitovetsky DE, Gvozdev II. Cytokine regulation of respiratory burst in blood neutrophils for prediction of abdominal sepsis in patients with extended purulent peritonitis. Medical Immunology. 2016;18(5):475–482. (In Russ.) DOI:10.15789/1563-0625-2016-5-475-482

[16] Савченко А.А., Борисов А.Г., Здзитовецкий Д.Е., Гвоздев И.И. Цитокиновая регуляция респираторного всплеска в нейтрофилах крови для прогнозирования абдоминального сепсиса у больных с расширенным гнойным перитонитом // Медицинская иммунология. 2016. Т. 18, № 5. С. 475–482. DOI: 10.15789/1563-0625-2016-5-475-482

[17] Pukhtinskaya MG, Estrin VV. Effect of inhaled nitric oxide on apoptosis of lymphocytes in newborns in critical states. Critical Care. 2014;18(1):288. DOI: 10.1186/cc13478

[18] Puhtinskaya M.G., Estrin V.V. Effect of inhaled nitric oxide on apoptosis of lymphocytes in newbors in critical states // Critical Care. 2014. Vol. 18, No. 1. P. 288. DOI: 10.1186/cc13478

[19] Sosunov AA. Nitric oxide as an intercellular mediator. Soros Educational Journal. 2000;6(12):27–34. (In Russ.)

[20] Сосунов А.А. Оксид азота как межклеточный медиатор // Соросовский просветительский журнал. 2000. Т. 6, № 12. С. 27–34

[21] Shurygina IA, Shurygin MG, Ayushinov NI. Expression of apoptosis markers during development of adhesion process in abdominal cavity in experiment. Journal of the Russian Academy of Medical Sciences. 2014;69(5–6):29–33. (In Russ.)

[22] Шурыгина И.А., Шурыгин М.Г., Аюшинов Н.И. Экспрессия маркеров апоптоза при развитии процесса адгезии в брюшной полости в эксперименте // Журнал РАМН. 2014. Т. 69, № 5–6. С. 29–33.

[23] 38th International Symposium on Intensive Care and Emergency Medicine. Crit Care. 2018;22(1):P018. DOI: 10.1186/s13054-018-1973-5

[24] 38th International Symposium on Intensive Care and Emergency Medicine // Critical Care. 2018. Vol. 22 Suppl 1. P. P018. DOI: 10.1186/s13054-018-1973-5

[25] Youn YА. The role of cytokines in seizures: interleukin (IL)-1β, IL-1Ra, IL-8, and IL-10. Korean J Pediatr. 2013;56(7):271–274. DOI: 10.3345/kjp.2013.56.7.271

[26] Youn Y.А. The role of cytokines in seizures: interleukin (IL)-1β, IL-1Ra, IL-8, and IL-10 // Korean J Pediatr. 2013. Vol. 56, No. 7. P. 271–274. DOI: 10.3345/kjp.2013.56.7.271

[27] Solov’eva AG, Kuznetsova VL, Peretyagin SP, et al. The Role of Nitric Oxide in Free-radical Oxidation Processes. Bulletin of the Russian Military Medical Academy. 2016;53(1):228–233. (In Russ.)

[28] Соловьева А.Г., Кузнецова В.Л., Перетягин С.П., и др. Роль оксида азота в процессах свободнорадикального окисления // Вестник Российской военно-медицинской академии. 2016. № 1–53. С. 228–233.

[29] Novikov VE, Levchenkova OS, Pozhilova EV. Mitochondrial nitric oxide synthase and its role in the mechanisms of cell adaptation to hypoxia. Reviews of Clinical Pharmacology and Drug Therapy. 2016;14(2):38–46. (In Russ.) DOI: 10.17816/RCF14238-46

[30] Новиков В.Е., Левченкова О.С., Пожилова Е.В. Митохондриальная синтаза оксида азота и ее роль в механизмах адаптации клеток к гипоксии // Обзоры по клинической фармакологии и лекарственной терапии. 2016. Т. 14, № 2. С. 38–46. DOI: 10.17816/RCF14238-46

[31] Burov AA. Nitrogen oxide therapy in neonatology. Neonatology. 2014;(4):45–51. (In Russ.)

[32] Буров А.А. Терапия оксидом азота в неонатологии // Неонатология; 2014. №. 4. С. 45–51.

[33] Burov AA, Grebennikov VA, Krychko DS. Project clinical practice guideline for persistent pulmonaty hypertension of the newborn: diagnostics and therapy. Neonatology: News, Opinions, Training. 2014;1(3):145–161. (In Russ.)

[34] Буров А.А., Гребенников В.А., Крычко Д.С. Проект клинического протокола диагностики и терапии персистирующей легочной гипертензии у новорожденных // Неонатология: новости, мнения, обучение. 2014. Т. 1, № 3. С. 145–161.

[35] Bellamy TC, Wood J, Garthwaite J. On the activation of soluble guanylyl cyclase by nitric oxide. Proc Natl Acad Sci USA. 2002;99(1):507–510. DOI: 10.1073/pnas.012368499

[36] Bellamy T.C., Wood J., Garthwaite J. On the activation of soluble guanylyl cyclase by nitric oxide // Proc Natl Acad Sci USA. 2002. Vol. 99, No. 1. P. 507–510. DOI: 10.1073/pnas.012368499

[37] Field D. Neonatal Ventilation With Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants With Severe Respiratory Failure: The INNOVO Multicentre Randomised Controlled Trial (ISRCTN 17821339). Pediatrics; 2005;115(4):926–936. DOI: 10.1542/peds.2004-1209

[38] Field D. Neonatal Ventilation with Inhaled Nitric Oxide Versus Ventilatory Support Without Inhaled Nitric Oxide for Preterm Infants with Severe Respiratory Failure: The INNOVO Multicentre Randomised Controlled Trial (ISRCTN 17821339) // Pediatrics. 2005. Vol. 115, No. 4. P. 926–936. DOI: 10.1542/peds.2004-1209

[39] Finer NN, Barrington KJ. Nitric oxide for respiratory failure in infants born at or near term. Cochrane Database Syst Rev. 2001;(4):CD0000399. DOI: 10.1002/14651858.CD000399.

[40] Finer N.N., Barrington K.J. Nitric oxide for respiratory failure in infants born at or near term // Cochrane Database Syst Rev. 2001. No. 4. P. CD0000399. DOI: 10.1002/14651858.CD0000399

[41] Ballard RA, Truog WE, Cnaan А. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation. N Engl J Med. 2006;355(4):343–353. DOI: 10.1056/NEJMoa061088

[42] Ballard R.A., Truog W.E., Cnaan А. Inhaled nitric oxide in preterm infants undergoing mechanical ventilation // N Engl J Med. 2006. Vol. 355, No. 4. P. 343–353. DOI: 10.1056/NEJMoa061088

[43] De Nadai C, Sestili Р, Cantoni О, et al. Nitric oxide inhibits tumor necrosis factor-alpha-induced apoptosis by reducing the generation of ceramide. Proc Natl Acad Sci USA. 2000;97(10):5480–5485. DOI: 10.1073/pnas.070062397

[44] De Nadai C., Sestili Р., Cantoni О., et al. Nitric oxide inhibits tumor necrosis factor-alpha-induced apoptosis by reducing the generation of ceramide // Proc Natl Acad Sci USA. 2000. Vol. 97, No. 10. P. 5480–5485. DOI: 10.1073/pnas.070062397

[45] Reutov VP, Sorokina EG, Kositzin NS. Problems of nitric oxide and cyclic recurrence in biology and medicine. Uspehi sovremennoj biologii. 2005;125(1):41–65. (In Russ.)

[46] Реутов В.П., Сорокина Е.Г., Косицин Н.С. Проблемы оксида азота и цикличности в биологии и медицине // Успехи современной биологии. 2005. Т. 125, № 1. С. 41–65.

[47] Kinsella JP, Cutter GR, Walsh W. Early inhaled nitric oxide therapy in premature newborns with respiratory failure. N Engl J Med. 2006;355(4):354–364. DOI: 10.1056/NEJMoa060442

[48] Kinsella J.P., Cutter G.R., Walsh W. Early inhaled nitric oxide therapy in premature newborns with respiratory failure // N Engl J Med. 2006. Vol. 355, No. 4. P. 354–364. DOI: 10.1056/NEJMoa0624011

[49] Kinsella JP, Neish SR, Shaffer E. Low dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn. Lancet. 1992;340(8823):819–820. DOI: 10.1056/NEJMoa060442

[50] Kinsella J.P., Neish S.R., Shaffer E. Low dose inhalational nitric oxide in persistent pulmonary hypertension of the newborn // Lancet. 1992. Vol. 340, No. 8823. P. 819–820. DOI: 10.1056/NEJMoa060442

[51] Stabnitsky VA, Chuchalin AG. Inhalation nitric oxide: opportunities to improve oxygenation in acute respiratory distress syndrome. Pulmonology. 2015;25(2):180–186. (In Russ.) DOI: 10.18093/0869-0189-2015-25-2-180-186

[52] Штабницкий В.А., Чучалин А.Г. Ингаляционный оксид азота: возможности улучшения оксигенации при остром респираторном дистресс-синдроме // Пульмонология. 2015. Т. 25, № 2. С. 180–186. DOI: 10.18093/0869-0189-2015-25-2-180-186

[53] Puchtinskaya M.G., Estrin V.V. Prevention of bacterial complications by correction of blood T-lymphocytes apoptosis in newborns with respiratory pathology. Medical Herald of the South of Russia. 2013;(4):134–138.

[54] Пухтинская М.Г., Эстрин В.В. Профилактика бактериальных осложнений коррекцией апоптоза Т-лимфоцитов крови у новорожденных с респираторной патологией // Медицинский вестник Юга России. 2013. № 4. С. 134–138.

[55] Movchan YeA. Endothelium and thrombocyte disfunction at chronic renal diseases: new look at the old problem of disorders in homeostatic system in glomerulonephritis patients. Bulletin of Siberian Medicine. 2008;Suppl 2:88–96. (In Russ.).

[56] Мовчан Э.А. Дисфункция эндотелия и тромбоцитов при хронической болезни почек: новый взгляд на старую проблему нарушений в системе гемостаза у пациентов с гломерулонефритом // Бюллетень сибирской медицины. 2008. Приложение 2. С. 88–96.

[57] Alekseeva SN, Ivanova ON. Effect of pregnant women ‘s smoking on the anthropometric indicators of newborns. Siberian Medical Journal (Irkutsk). 2013;117(2):81–84. (In Russ.)

[58] Алексеева С.Н., Иванова О.Н. Влияние курения беременных на антропометрические показатели новорожденных // Сибирский медицинский журнал (Иркутск). 2013. Т. 117, № 2. С. 81–84.

[59] Alexandrovitch US, Vizisnov KV. Acute respiratory distress syndrome in pediatric practice. Messenger of Intensive Therapy. 2014;(3):23–29. (In Russ.)

[60] Александрович С.А., Визиснов К.В. Острый респираторный дистресс-синдром в детской практике // Вестник интенсивной терапии. 2014. № 3. С. 23–29.

[61] Boytsov EV, Bialashova MA, Ovsyannikov DU. Modern insights into interstitial lung diseases in children. Journal RAMS. 2015;70(2):227–236. (In Russ.) DOI: 10.15690/vramn.v70i2.1317

[62] Бойцов Е.В., Бялашова М.А., Овсянников Д.У. Современное понимание интерстициальных заболеваний легких у детей // Журнал РАМН. 2015. Т. 70, 2. С. 227–236. DOI: 10.15690/vramn.v70i2.1317

[63] Pukhtinskaya M.G., Estrin V.V., Gulova E.S. Clinical and diagnostic significance of apoptosis in the pathogenesis of neutropenia and bacterial complications in newborns with respiratory distress syndrome. Cytokines and inflammation. 2011;10(2):66–69. (In Russ.).

[64] Пухтинская М.Г., Эстрин В.В., Гулова Е.С. Клинико-диагностическое значение апоптоза в патогенезе нейтропении и бактериальных осложнений у новорожденных с респираторным дистресс-синдромом // Цитокины и воспаление. 2011. Т. 10, № 2. С. 66–69.

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Pukhtinskaya M.G., Estrin V.V.