Современные методы ограничения системного воспалительного ответа при коррекции врожденных пороков сердца у детей в условиях искусственного кровообращения

Основные положения. В статье описаны патофизиологические аспекты искусственного кровообращения и механизмы развития системного воспалительного ответа при кардиохирургических операциях у детей. Представлены наиболее актуальные методы борьбы с системным воспалительным ответом, среди которых как способы в составе искусственного кровообращения, так и фармакологические методики.

Рост числа детей с врожденными пороками сердца требует разработки более совершенных технологий оперативного лечения. Однако хирургические методы коррекции по-прежнему в большинстве случаев требуют применения искусственного кровообращения. Несмотря на значительный прогресс в совершенствовании техники проведения искусственного кровообращения, остается нерешенным и актуальным вопрос системного воспалительного ответа (СВО), сопровождающего операции такого рода. В обзоре подробно представлены причины и механизмы развития данного осложнения. Охарактеризованы наиболее популярные методы ограничения СВО: стандартная и модифицированная ультрафильтрация, лейкоцитарные фильтры, фармакологическое воздействие (применение системных глюкокортикоидов, апротинина и антиоксидантов). Кроме того, оценена роль кардиоплегии и гипотермии в процессе ограничения системного воспаления. В кардиохирургических центрах по всему миру используют различные технические и фармакологические подходы, опираясь на результаты релевантных исследований, при этом до сих пор не разработаны четкие клинические рекомендации, направленные на снижение СВО во время искусственного кровообращения у детей. Указанное осложнение остается значимой проблемой у детей реанимационного профиля, определяя тяжесть состояния, удлиняя срок госпитализации и уменьшая выживаемость данной категории больных.

1. Boehne M., Sasse M., Karch A. Systemic inflammatory response syndrome after pediatric congenital heart surgery: Incidence, risk factors, and clinical outcome. Journal of cardiac surgery. 2017;32(2):116-125. doi:10.1111/jocs.12879

2. Guvener M., Korun O., Demirturk O.S. Risk factors for systemic inflammatory response after congenital cardiac surgery. Journal of cardiac surgery. 2015;30(1):92-96. doi:10.1111/jocs.12465

3. Wang Y., Lin X., Yue H., Kissoon N., Sun B. Evaluation of systemic inflammatory response syndrome-negative sepsis from a Chinese regional pediatric network. Collaborative Study Group for Pediatric Sepsis in Huai'an BMC Pediatr. 2019; 8; 19 (1): 11. doi:10.1186/s12887-018-1364-8 .

4. Toomasian C.J., Aiello S.R., Drumright B.L., Major T.C., Bartlett R.H., Toomasian J.M. The effect of air exposure on leucocyte and cytokine activation in an in-vitro model of cardiotomy suction. Perfusion 33: 538-545, 2018. doi:10.1177/0267659118766157

5. Cerejeira J., Firmino H., Vaz-serra A., Mukaetova-ladinska E.B. The neuroinflammatory hypothesis of delirium. Acta Neuropathologica. 2010; 119: 737-54. doi:10.1007/s00401-010-0674-1

6. Гребенчиков О.А., Лихванцев В.В., Плотников Е.Ю., Зорова Л.Д., Зоров Д.Б. Молекулярные механизмы развития и адресная терапия синдрома ишемии-реперфузии. Анестезиология и реаниматология. 2014; 3:59-67.

7. Harris N.R. Opposing effects of l-NAME on capillary filtration rate in the presence or absence of neutrophils. American Journal of Physiology-Gastrointestinal and Liver Physiology. American Physiological Society; 1997; 273(6):G1320-G1325. http://dx.doi.org/10.1152/ajpgi.1997.273.6.g1320

8. N. Rems L., Viano M., Kasimova M.A., Miklavcic D., Tarek M. The contribution of lipid peroxidation to membrane permeability in electropermeabilization: A molecular dynamics study. Bioelectrochemistry. 2019; 125: 46-57. doi:10.1016/j.bioelechem.2018.07.018

9. Oyewole A.O., Birch-Machin M.A. Mitochondria-targeted antioxidants. FASEB J. 2015;29(12):4766-4771. doi:10.1096/fj.15-275404

10. Neuhof C., Neuhof H. Calpain system and its involvement in myocardial ischemia and reperfusion injury. World Journal Cardiology. 2014; 6(7):638- 249 52. doi:10.1096/fj.15-275404

11. McDonald C.I., Fraser J.F., Coombes J.S., Fung Y.L. Oxidative stress during extracorporeal circulation. European Journal of Cardio-Thoracic Surgery. Oxford University Press (OUP); 2014; 46(6):937-43. doi:10.1093/ejcts/ezt637

12. Millar J.E., Fanning J.P., McDonald C.I., McAuley D.F., Fraser J.F. The inflammatory response to extracorporeal membrane oxygenation (ECMO): a review of the pathophysiology. Critical Care. 2016; 20(1): 387. doi:10.1186/s13054-016-1570-4

13. WangY.C.,Wu H.Y., Luo C.Y., LinT.W. Cardiopulmonary Bypass Time Predicts Early Postoperative Enterobacteriaceae Bloodstream Infection. Annals of Cardiothoracic Surgery. 2019;107(5):1333-1341. doi:10.1016/j.athoracsur.2018.11.020

14. Cochran A.J., Spilg W.G.S., Mackie R.M., Thomas C.E. Postoperative Depression of Tumour-directed Cell-mediated Immunity in Patients with Malignant Disease. BMJ. 1972; 4(5832): 67-70. doi:10.1136/bmj.4.5832.67

15. Tan H., Bi J., Wang Y., Zhang J. Zuo Z. Transfusion of Old RBCs Induces Neuroinflammation and Cognitive Impairment. Critical Care Medicine. 2015; 43(8): 276-86. doi:10.1097/CCM.0000000000001023.

16. Delaney M., Stark P.C., Suh M., Triulzi D.J., Hess J.R., Steiner M.E., Stowell C.P., Sloan S.R. The Impact of Blood Component Ratios on Clinical Outcomes and Survival. Anesthesia and Analgesia. 2017; 124(6): 1777-1782. doi:10.1213/ANE.0000000000001926.

17. Karkouti K. Transfusion and risk of acute kidney injury in cardiac surgery. British Journal of Anaesthesia. 2012; 109: 29-38. doi:10.1093/bja/aes422

18. Luo L., Wang D., Chen M., Li M. Effects of reinfusion of the remaining blood filtered by leukocyte depletion filter on postoperative cellar immune function after cardiopulmonary bypass Zhonghua Wei Zhong Bing Ji Jiu Yi Xue. 2019;31(8):989-993. doi: 10.3760/cma.j.issn.2095-4352.2019.08.015.

19. Ho K.M., Tan J.A. Benefits and Risks of Maintaining Normothermia during Cardiopulmonary Bypass in Adult Cardiac Surgery: A Systematic Review. Cardiovascular Therapeutics. 2009; 29(4): 260-79. doi:10.1111/j.1755-5922.2009.00114.x

20. Laffey J.G., Boylan J.F., Cheng D.C. The systemic inflammatory response to cardiac surgery: implications for the anesthesiologist. Anesthesiology. 2002;97:215-252. doi:10.1097/00000542-200207000-00030

21. Kirklin J.K., Westaby S., Blackstone E.H., Kirklin J.W., Chenoweth D.E., Pacifico A.D. Complement and the damaging effects of cardiopulmonary bypass. The Journal of Thoracic and Cardiovascular Surgery. 1983; 86(6): 845-857. doi:10.1016/s0022-5223(19)39061-0

22. Craddock P.R., Fehr J., Brigham K.L., Kronenberg R.S., Jacob H.S. Complement and Leukocyte-Mediated Pulmonary Dysfunction in Hemodialysis. New England Journal of Medicine. 1977; 296(14): 769-774. doi:10.1056/nejm197704072961401

23. Muraki R., HiraokaA., Nagata K., Nakajima K., Oshita T., Arimichi M., Chikazawa G., Yoshitaka H., Sakaguchi T. Novel method for estimating the total blood volume: the importance of adjustment using the ideal body weight and age for the accurate prediction of haemodilution during cardiopulmonary bypass. Interactive Cardiovascular and Thoracic Surgery. 2018; 27(6): 802-807. doi:10.1093/icvts/ivy173

24. Romson J.L., Hook B.G., Kunkel S.L., Abrams G.D., Schork M.A., Lucchesi B.R. Reduction of the extent of ischemic myocardial injury by neutrophil depletion in the dog. Circulation. 1983; 67(5): 1016-1023. doi:10.1161/01.cir.67.5.1016

25. Galasso G., Schiekofer S., D'Anna C., Gioia G.D., Piccolo R., Niglio T. No-Reflow Phenomenon. Angiology. 2013; 65(3): 180-189. doi:10.1177/0003319712474336

26. Aoki M., Jonas R.A., Nomura F., Kawata H., Hickey P.R. Anti-CD18 Attenuates Deleterious Effects of Cardiopulmonary Bypass and Hypothermic Circulatory Arrest in Piglets. Journal of Cardiac Surgery. 1995; 10(s4): 407-417. doi:10.1111/j.1540-8191.1995.tb00670.x

27. Seghaye M.-C., Duchateau J., Grabitz R.G., Nitsch G., Marcus C., Messmer B.J., Gotz von Bernuth. Complement, leukocytes, and leukocyte elastase in full-term neonates undergoing cardiac operation. The Journal of Thoracic and Cardiovascular Surgery. 1994; 108(1): 29-36. doi:10.1016/s0022-5223(94)70214-4

28. Durandy Y. Minimizing systemic inflammation during cardiopulmonary bypass in the pediatric population. Journal of Artificial Organs. 2014; 38(1): 11-18. doi:10.1111/aor.12195

29. Cavaillon J.-M., Adib-Conquy M. Compensatory anti-inflammatory response syndrome. Thrombosis and Haemostasis. 2009; 101(01): 36-47. doi:10.1160/th08-07-0421

30. Yu X., Chen M., Liu X., Chen Y., Hao Z., Zhang H., Wang W. Risk factors of nosocomial infection after cardiac surgery in children with congenital heart disease. BMC Infect Dis. 2020; 20(1): 64. doi:10.1186/s12879-020-4769-6

31. Ricci Z, Benegni S, Garisto C, Favia I, Haiberger R, Chiara LD. Endotoxin Activity in Neonates Undergoing Cardiac Surgery: Cohort Study.World Journal Pediatric Congenitial Heart Surgery. 2018; 9(1): 60-67. doi:10.1177/2150135117738005

32. Crossman D.C., Carr D.P., Tuddenham E.G., Pearson J.D., McVey J.H. The regulation of tissue factor mRNA in human endothelial cells in response to endotoxin or phorbol ester. J Biol Chem. 1990;265(17):9782-9787.

33. Taggart D.P., Sundaram S., McCartney C., Bowman A., McIntyre H., Courtney J.M., Wheatley D. J. Endotoxemia, complement, and white blood cell activation in cardiac surgery: A randomized trial of laxatives and pulsatile perfusion. The Annals of Thoracic Surgery. 1994; 57(2): 376-382. doi:10.1016/0003-4975(94)91000-6

34. Fiddian-Green R.G. Gut mucosal ischemia during cardiac surgery. Seminars in Thoracic and Cardiovascular Surgery. 1990; 2(4): 389-399.

35. Yuan S.M. Acute kidney injury after pediatric cardiac surgery. Pediatrics and Neonatology. 2019; 60(1): 3-11. doi:10.1016/j.pedneo.2018.03.007

36. Boehne M., Sasse M., Karch A., Dziuba F., Horke A., Kaussen T., Mikolajczyk R., Beerbaum P., Jack T. Systemic inflammatory response syndrome after pediatric congenital heart surgery: Incidence, risk factors, and clinical outcome. Journal of Cardiac Surgery. 2017;32(2):116-125. doi: 10.1111/jocs.12879.

37. Bellinger D.C., Wypij D., Rivkin M.J., DeMaso D.R., Robertson R.L., Dunbar-Masterson C., et al. Adolescents With d-Transposition of the Great Arteries Corrected With the Arterial Switch Procedure. Circulation. 2011; 124(12): 1361-9. doi:10.1161/circulationaha.111.026963

38. Magilligan D.J.Jr., Oyama C. Ultrafiltration during cardiopulmonary bypass: laboratory evaluation and initial clinical experience. Ann Thorac Surg. 1984;37(1):33-9. doi: 10.1016/s0003-4975(10)60706-0.

39. Chen F., You Y., Ding P., Wu K., Mo X. Effects of Balanced Ultrafiltration During Extracorporeal Circulation for Children with Congenital Heart Disease on Postoperative Serum Inflammatory Response. Fetal and pediatric pathology. 2019; 1-8. doi:10.1080/15513815.2019.1661050

40. Bierer J., Stanzel R., Henderson M., Sett S., Horne D. Ultrafiltration in Pediatric Cardiac Surgery Review. World Journal for Pediatric and Congenital Heart Surgery. 2019; 10(6): 778-788. doi:10.1177/2150135119870176

41. Gholampour Dehaki M., Niknam S., Azarfarin R., Bakhshandeh H., Mahdavi M. Zero-Balance Ultrafiltration of Priming Blood Attenuates Procalcitonin and Improves the Respiratory Function in Infants After Cardiopulmonary Bypass: A Randomized Controlled Trial. Journal of Artificial Organs. 2019; 43(2): 167-172. doi:10.1111/aor.13325

42. Lang S.M., Syed M.A., Dziura J., Rocco E., Kirshbom P., Bhandari V., Giuliano J.S. Jr. The Effect of Modified Ultrafiltration on Angiopoietins in Pediatric Cardiothoracic Operations. The Annals of Thoracic Surgery. 2014; 98(5): 1699-704. doi:10.1016/j.athoracsur.2014.06.053

43. Elayashy M., Madkour M.A., Mahmoud A.A.A., Hosny H., Hussein A., Nabih A., Lofty A., Hamza H.M., Hassan P., Wagih M., Mohamed A.K. Effect of ultrafiltration on extravascular lung water assessed by lung ultrasound in children undergoing cardiac surgery: a randomized prospective study. BMC Anesthesiology. 2019; 19(1): 93. doi: 10.1186/s12871-019-0771-1.

44. McNair E.D., McKay W.P., Mondal P.K., Bryce R.D. Transfusion Use and Hemoglobin Levels by Blood Conservation Method Post Cardiopulmonary Bypass. The Annals of Thoracic Surgery. 2020; S0003-4975(20)30541-5. doi:10.1016/j.athoracsur.2020.03.029

45. Hiramatsu T., Zund G., Schermerhorn M.L., Shinoka T., Miura T., Mayer J.E. Jr. Age differences in effects of hypothermic ischemia on endothelial and ventricular function. The Annals of Thoracic Surgery. 1995; 60(6 Suppl): S501-S504. doi:10.1016/0003-4975(95)00814-4

46. Cavigelli-Brunner A., Hug M.I., Dave H., Baenziger O., Buerki C., Bettex D., Cannizzaro V., Balmer C. Prevention of Low Cardiac Output Syndrome After Pediatric Cardiac Surgery: A Double-Blind Randomized Clinical Pilot Study Comparing Dobutamine and Milrinone. Pediatric Critical Care Medicine. 2018; 19(7): 619-625. doi:10.1097/PCC.0000000000001533

47. Kotani Y., Tweddell J., Gruber P., Pizarro C., Austin E.H. 3rd, Woods R.K., Gruenwald C., Caldarone C.A. Current cardioplegia practice inpediatric cardiac surgery: aNorthAmerican multiinstitutional survey. The Annals of Thoracic Surgery. 2013;96(3):923-9. doi: 10.1016/j.athoracsur.2013.05.052.

48. Kilic D., Gunaydin S., Kisa U., Sari T., Deveci O., Zorlutuna Y. Clinical efficacy of leukofiltration on cardiopulmonary bypass related inflammatory response: Fact or Foe?. Inflamm Res. 2009;58(6):292-297. doi:10.1007/s00011-008-7244-1

49. Alexiou C., Tang A.A., Sheppard S.V., Smith D.C., Gibbs R., Livesey S.A., Monro J.L., Haw M.P. The effect of leucodepletion on leucocyte activation, pulmonary inflammation and respiratory index in surgery for coronary revascularisation: a prospective randomised study. European Journal of Cardio-Thoracic Surgery. 2004;26: 294-300. doi:10.1016/j.ejcts.2004.04.017

50. Bigelow W.G., Lindsay W.K., Harrison R.C., Gordon R.A., Greenwood W.F. Oxygen transport and utilization in dogs at low body temperatures. American Journal of Physiology-Legacy Content. 1950; 161(3): 590-590. doi:10.1152/ajplegacy.1950.161.3.590-s

51. Lewis F.J., Varco R.L., Taufic M. Repair of atrial septal defects in man under direct vision with the aid of hypothermia. Surgery. 1954;36(3):538-556.

52. Sealy W.C., Brown I.W. Jr., Young W.G., Smith W.W., Lesage A.M. Hypothermia and extracorporeal circulation for open heart surgery: its simplification with a heat exchanger for rapid cooling and rewarming. Ann Surg. 1959;150(4):627-639. doi:10.1097/00000658-195910000-00008

53. Croughwell N., Smith L.R., Quill T., Newman M., Greeley W, Kern F., Joe Lu., Reves J.G. The effect of temperature on cerebral metabolism and blood flow in adults during cardiopulmonary bypass. The Journal of Thoracic and Cardiovascular Surgery. 1992; 103(3): 549-554. doi:10.1016/s0022-5223(19)34997-9

54. Doenst T., Schlensak C., Beyersdorf F. Cardioplegia in pediatric cardiac surgery: do we believe in magic? The Annals of Thoracic Surgery. 2003; 75(5): 1668-1677. doi:10.1016/s0003-4975(02)04829-4

55. Kaplan M., Karaagac A., Can T., Yilmaz S., Yesilkaya M.I., Olsun A., Aydogan H. Open Heart Surgery at Patient's Own Temperature Without Active Cooling. Heart Surgery Forum. 2018; 8; 21(3): E132-E138. doi:10.1532/hsf.1985

56. Schmitt K.R., Fedarava K., Justus G., Redlin M., Bottcher W., Delmo Walter E.M. Hypothermia During Cardiopulmonary Bypass Increases Need for Inotropic Support but Does Not Impact Inflammation in Children Undergoing Surgical Ventricular Septal Defect Closure. Journal of Artificial Organs. 2016; 40(5): 470-479. doi:10.1111/aor.12587

57. Le Deist F., Menasche P., Kucharski C., Bel A., Piwnica A., Bloch G. Hypothermia During Cardiopulmonary Bypass Delays but Does Not Prevent Neutrophil- Endothelial Cell Adhesion. Circulation. 1995 Nov;92(9):354-8. doi:10.1161/01.cir.92.9.354

58. Stocker C.F., Shekerdemian L.S., Horton S.B., Lee K.J., Eyres R., D'Udekem Y., Brizard C.P. The influence of bypass temperature on the systemic inflammatory response and organ injury after pediatric open surgery: a randomized trial. Journal of thoracic and cardiovascularar surgery. 2011; 142(1): 174-80. doi:10.1016/j.jtcvs

59. Xiong Y., Sun Y., Ji B., Liu J., Wang G., Zheng Z. Systematic Review and Meta-Analysis of benefits and risks between normothermia and hypothermia during cardiopulmonary bypass in pediatric cardiac surgery. Paediatric Anaesthesia. 2015; 25(2): 135-42. doi:10.1111/pan.12560

60. Newburger J.W., Jonas R.A., Wernovsky G., Wypij D., Hickey P.R., Kuban K.C., Farrell D.M., Holmes G.L., Helmers S.L., Constantinou J., Carrazana E., Barlow J.K., Walsh A.Z., Lucius K.C., Share J.C., Wessel D.L., Hanley F.L., Mayer J.E., Costaneda A.R., Ware J.H., et al. A Comparison of the Perioperative Neurologic Effects of Hypothermic Circulatory Arrest versus Low-Flow Cardiopulmonary Bypass in Infant Heart Surgery. New England Journal of Medicine. 1993; 329(15): 1057-1064. doi: 10.1056/NEJM199310073291501.

61. Merkle F., Boettcher W., Schulz F., Kopitz M., Koster A., Hennig E., Hetzer R. Reduction of microemboli count in the priming fluid of cardiopulmonary bypass circuits. J Extra Corpor Technol. 2003;35(2):133-138.

62. Myers G.J., Wegner J. Endothelial Glycocalyx and Cardiopulmonary Bypass. Journal of Extra-Corporeal Technology. 2017; 49(3): 174-181.

63. Pereira S.N., Zumba I.B., Batista M.S., Pieve Dd., Santos Ed., Stuermer R., Oliveira G.P., Senger R. Comparison of two technics of cardiopulmonary bypass (conventional and mini CPB) in the trans-and postoperative periods of cardiac surgery. Regionalization of Brazilian pediatric cardiovascular surgery. 2015; 30(4): 433-442. doi: 10.5935/1678-9741.20150046.

64. Holmannova D., Kolackova M., Mandak J., Kunes P., Holubcova Z., Holubec T., Krejsek J. Effects of conventional CPB and mini-CPB on neutrophils CD162, CD166 and CD195 expression. Perfusion. 2017; 32(2): 141-150. doi: 10.1177/0267659116669586

65. Nguyen B., Luong L., Naase H., Vives M., Jakaj G., Finch J., Boyle J., Mulholland J.W., Kwak J.H., Pyo S., de Luca A., Athanasiou T., Angelini G., Anderson J., Haskard D.O., Evans P.C. Sulforaphane pretreatment prevents systemic inflammation and renal injury in response to cardiopulmonary bypass. Journal of thoracic and cardiovascularar surgery. 2014; 148(2):690-697.e3. doi: 10.1016/j.jtcvs.2013.12.048.

66. Ferreira C.A., Vicente W.V., Evora P.R., Rodrigues A.J., Klamt J. G., Carlotti A.P., Carmona F., Manso P.H. Assessment of aprotinin in the reduction of inflammatory systemic response in children undergoing surgery with cardiopulmonary bypass. Rev Bras Cir Cardiovasc. 2010; 25(1): 85-98. doi: 10.1590/s0102-76382010000100018.

67. Kawamura T., Inada K., Nara N., Wakusawa R., Endo S. Influence of methylprednisolone on cytokine balance during cardiac surgery. Critical Care Medicine. 1999; 27(3): 545-548. doi:10.1097/00003246-199903000-00033

68. Whitlock R.P., Devereaux P.J., Teoh K.H., Lamy A., Vincent J., Pogue J., Paparella D., Sessler D.I., Karthikeyan G., Villar G.C., Zuo Y., Avezum A., Quantz M., Tagarakis G.I., Phah P.J., Abbasi S.H., Zheng H., Pettit S., Chrolavicius S., Yusuf S., SIRS Investigators. Methylprednisolone in patients undergoing cardiopulmonary bypass (SIRS): a randomised, double-blind, placebo-controlled trial. Lancet. 2015; 386(10000): 1243-1253. doi:10.1016/S0140-6736(15)00273-1

69. Keski-Nisula J., Pesonen E., Olkkola K.T., Ahlroth T., Puntila J., Andersson S. et al. High-Dose Methylprednisolone Has No Benefit Over Moderate Dose for the Correction of Tetralogy of Fallot. The Annals of Thoracic Surgery. 2016; 102(3): 870-876. doi:10.1016/j.athoracsur.2016.02.089

70. Dreher M., Glatz A.C., Kennedy A., Rosenthal T., Gaynor J.W. A Single-Center Analysis of Methylprednisolone Use during Pediatric Cardiopulmonary Bypass. Journal of Extra-Corporeal Technology.. 2015;47(3):155-159.

71. Lr Y.-C., Ridefelt P., Wiklund L, Bjerneroth G. Propofol induces a lowering of free cytosolic calcium in myocardial cells. Acta Anaesthesiologica Scandinavica. 1997; 41(5): 6338. doi:10.1111/j.1399-6576.1997.tb04756.x

72. Peng X., Li C., Yu W., Liu S., Cong Y., Fan G., Qi S. Propofol Attenuates Hypoxia-Induced Inflammation in BV2 Microglia by Inhibiting Oxidative Stress and NF-xB/Hif-1а Signaling. BioMed research international. 2020; 2020: 8978704. doi: 10.1155/2020/8978704.

73. Fudulu D., Angelini G. Oxidative Stress after Surgery on the Immature Heart. Oxidative Medicine and Cellular Longevity. 2016; 2016: 1-10. doi:10.1155/2016/1971452