Therapeutic hypothermia in treatment of different cerebral injuries

A.V. Butrov1, B.D. Torosyan1, D.V. Cheboksarov1,2, G.R. Makhmutova1,2

1 Peoples Friendship University of Russia (RUDN University), Moscow

2 Moscow City clinical hospital named author V.V. Vinogradov, Moscow

For correspondence: Andrey V. Butrov, DSci, Professor, department of anaestesiology and reanimatology with clinical rehabilitation course RUDN University, Moscow; e-mail: avbutrov@mail.ru

For citation: Butrov AV, Torosyan BD, Cheboksarov DV, Makhmutova GR. Therapeutic hypothermia in treatment of different cerebral injuries. Alexander Saltanov Intensive Care Herald. 2019;2:75-81.

DOI: 10.21320/1818-474X-2019-2-75-81


There is an increasing incidence of various cerebral eventsin Russia, as well as throughout the world. At the same time, despite of all the successes of modern medicine, the treatment outcomes of these patient groups haven’t improved. The main successes are based on faster patient delivery to hospitals and on the creation of specialized centers for this cohort of patients. At the same time, the effectiveness of pharmacological agents with neuroprotective activity is questionable. On the other hand, therapeutic hypothermia techniques have proven to be an effective method of neuroprotection in various cerebral events. These methods can be divided into local and general hypothermia. Each of these options has its own advantages and indications. Thus, the use of general hypothermia techniques maintains the target temperature of the whole body, these techniques are more controllable, but at the same time, the methods of local craniocerebral hypothermia allows to affect the target organ. The methods of hypothermia and thermostabilization have been proven to improve the treatment results of patients post-CPR and in children with neonatal hypoxia. The effectiveness of hypothermia in the remaining pathological conditions of the brain has not yet been investigated. Studies of the last 5 years have not revealed high efficacy of general hypothermia at TBI, so almost of all studies indicated that normothermia and hypothermia are equally effective. Studies are ongoing in patients with subarachnoid hemorrhage, subdural hematomas and ischemic stroke. Identifying groups of patients who are recommended for these methods for complex treatment can lead to progress in improving survival and neurological outcome.

Keywords: therapeutic hypothermia, craniocerebral hypothermia, traumatic brain injury, cerebral infarction, subarachnoid hemorrhage, cerebral hemorrhage

Received: 04.02.2019


References

  1. 01_Заболеваемость всего населения России в 2017 году [электронный документ]. Доступно по: https://www.rosminzdrav.ru/ministry/61/22/stranitsa-979/statisticheskie-i-informatsionnye-materialy/statisticheskiy-sbornik-2017-god. Ссылка активна на 20.01.2019. [Zabolevaemost’ vsego naseleniya Rossii v 2017 godu [Internet] Available from:https://www.rosminzdrav.ru/ministry/61/22/stranitsa-979/statisticheskie-i-informatsionnye-materialy/statisticheskiy-sbornik-2017-god (accessed 20.01.2019). (In Russ)]
  2. Simon D.J., Weimer R.M., McLaughlin T., et al. Caspase Cascade Regulating Developmental Axon Degeneration. Journal of Neuroscience, 2012 5; 32(49): 17540–17553. DOI: 10.1523/jneurosci.3012–12.2012
  3. Усенко Л.В., Царев А.В. Искусственная гипотермия в современной реаниматологии. Общая реаниматология. 2009; 5(1): 21–23. DOI: 10.15360/1813-9779-2009-1-21 [Usenko L.V., Carev A.V. Iskusstvennaya gipotermiya v sovremennoy reanimatologii. Obshaya reanimatologiya. 2009; 5(1): 21–23. DOI: 10.15360/1813-9779-2009-1-21. (In Russ)]
  4. MacLellan C.L., Davies L.M., Fingas M.S., Colbourne F. The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke; 2006; 37(5): 1266–1270. DOI: 10.1161/01.STR.0000217268.81963.78
  5. Lazzaro M.A., Prabhakaran S. Induced hypothermia in acute ischemic stroke. Expert Opin. Investig. Drugs, 2008; 17(8): 1161–1174. DOI: 10.1517/13543784.17.8.1161
  6. Keller E., Imhof H.G., Gasser S., et al. Endovascular cooling with heat exchange catheters: a new method to induce and maintain hypothermia. Intensive Care Med., 2003; 29(6): 939–943. DOI: 10.1007/s00134-003-1685-3
  7. Guluma K.Z., Hemmen T.M., Olsen S.E., Rapp K.S., Lyden P.D. A trial of therapeutic hypothermia via endovascular approach in awake patients with acute ischemic stroke: methodology. Acad. Emerg. Med., 2006; 13(8): 820–827.
  8. Van der Worp H.B., Macleod M.R., Kollmar R. Therapeutic hypothermia for acute ischemic stroke: ready to start large randomized trials. J. Cereb. Blood Flow Metab., 2010; 30(6): 1079–1093. DOI: 10.1038/jcbfm.2010.44
  9. Qiu W., Shen H., Zhang Y., Wang W., et al. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury. J. Clin. Neurosci. 2006; 13(10): 995–1000.
  10. Lazzaro M.A., Prabhakaran S. Induced hypothermia in acute ischemic stroke. Expert Opin. Investig. Drugs, 2008; 17(8): 1161–1174. DOI: 10.1517/13543784.17.8.1161
  11. Kallmünzer B., Krause C., Pauli E., et al. Standardized antipyretic treatment in stroke: a pilot study. Cerebrovasc. Dis. 2011; 31(4): 382–389. DOI: 10.1159/000321733
  12. Guluma K.Z., Oh H., Yu S.W., et al. Effect of endovascular hypothermia on acute ischemic edema: morphometric analysis of the ICTuS trial. Neurocrit. Care, 2008; 8(1): 42–47.
  13. Mayer S.A., Kowalski R.G., Presciutti M., et al. Clinical trial of a novel surface cooling system for fever control in neurocritical care patients. Crit. Care Med. 2004; 32: 2508–2515.
  14. Qiu W., Shen H., Zhang Y., et al. Noninvasive selective brain cooling by head and neck cooling is protective in severe traumatic brain injury. J. Clin. Neurosci. 2006; 13(10): 995–1000.
  15. Wang H., Olivero W., Lanzino G., et al. Rapid and selective cerebral hypothermia achieved using a cooling helmet. J. Neurosurg. 2004; 100(2): 272–277.
  16. Harms H., Prass K., Meisel C.,et al. Preventive antibacterial therapy in acute ischemic stroke: a randomized controlled trial. PLoS One. 2008; 3(5): e2158. DOI: 10.1371/journal.pone.0002158
  17. Chen J., Ji X., Ding Y., et al. A novel approach to reduce hemorrhagic transformation after interventional management of acute stroke: catheter-based selective hypothermia. Med. Hypotheses, 2009; 72(1): 62–63. DOI: 10.1016/j.mehy.2008.07.056
  18. Keller E., Mudra R., Gugl C., et al. Theoretical evaluations of therapeutic systemic and local cerebral hypothermia. J. Neurosci Methods. 2009; 178(2): 345–349. DOI: 10.1016/j.jneumeth.2008.12.030
  19. Бутров А.В., Шевелев О.А., Петрова М.В. и др. «АТГ-01 (аппарат терапевтической гипотермии — 01)» у больных в критических состояниях: учебное пособие. М.: Медиамед, 2014. [Butrov A.V., ShevelevO.A., PetrovaM.V., et al. “ATG-01 (apparat terapevticheskoy gipotermii — 01)” ubolnikh v kriticheskikh sostoyaniyakh: uchebnoyeposobiye. M.: Mediamed, 2014. (In Russ)]
  20. Polderman K.H. Mechanisms of action, physiological effects, and complications of hypothermia. Crit. Care Med. 2009; 37(7 Suppl.): S186–S202. DOI: 10.1097/CCM.0b013e3181aa5241
  21. Van der Worp H.B., Sena E.S., Donnan G.A., et al. Hypotermia in animal models of acute ishaemic stroke: a systematic review and meta-analysis. Brain. 2007; 130(Pt 12): 3063–3074.
  22. Faridar A., Bershad E.M., Emiru T., et al. Therapeutic hypothermia in stroke and traumatic brain injury. Front. Neurol. 2011; 27(2): 80. DOI: 10.3389/fneur.2011.00080
  23. Каленова И.Е., Шаринова И.А., Шевелев О.А., Бутров А.В. Опыт применения терапевтической гипотермии в лечении ишемического инсульта. Неврология, нейропсихиатрия, психосоматика. 2012; 2: 41–45. DOI: 10.14412/2074-2711-2012-380 [Kalenova I.E., Sharinova I.A., Shevelev O.A., Butrov A.V. Opit primeneniya terapevticheskoy gipotermii v lechenii ishemicheskogo insulta. Nevrologiya, neyropsikhiatriya, psikhosomatika. 2012; 2: 41–45. (In Russ)]
  24. Абудеев С.А., Попугаев К.А., Кругляков Н.М. и др. Влияние гипотермии на напряжение кислорода в паренхиме головного мозга при аневризматическом субарахноидальном кровоизлиянии. Анестезиология и реаниматология. 2016; 61(2): 155–158. DOI: 10.18821/0201-7563-2016-61-2-155-158 [Abudeev S.A., Popugev K.A., Kruglyakov N.M., et al. Vliyaniye gipotermii na napryajeniye kisloroda v parenkhime golovnogo mozga pri anevrizmaticheskom subarakhnoidalnom kroovoizliyanii. Anesteziologiya I reanimatologiya. 2016; 61(2): 155–158. (In Russ)]
  25. Prasad K., Krishnan P.R. Fever is associated with doubling of odds of short-term mortality in ischemic stroke: an updated meta-analysis. Acta Neurol. Scand., 2010; 122(6): 404–408. DOI: 10.1111/j.1600-0404.2010.01326.x
  26. Broessner G., Beer R., Lackner P., et al. Endovascularly based, long-term normothermia in ICU patients with cerebrovascular disease. Stroke. 2009; 40(12): e657–e665. DOI: 10.1161/STROKEAHA.109.557652
  27. Lazzaro M.A., Prabhakaran S. Induced hypothermia in acute ischemic stroke. Expert Opin. Investig. Drugs. 2008; 17(8): 1161–1174. DOI: 10.1517/13543784.17.8.1161
  28. Pastukhov A., Krisanova N., Maksymenko V., Borisova T. Personalized approach in brain protection by hypothermia: individual changes in non-pathological and ischemia-related glutamate transport in brain nerve terminals. EPMA J. 2016; 7: 26. DOI: 10.1186/s13167-016-0075-1
  29. Hua C., Ju W., Jin H., et al. Molecular chaperones and hypoxic-ischemic encephalopathy. Neural. Regen. Res. 2017; 12(1): 153–160. DOI: 10.4103/1673–5374.199008
  30. Giraud R., Siegenthaler N., Bendjelid K. Cardiac index during therapeutic hypothermia: which target value is optimal? Crit. Care. 2013; 17(2): 214. DOI: 10.1186/cc12523
  31. Bergman R., van Zanten A.R., et al. Haemodynamic consequences of mild therapeutic hypothermia after cardiac arrest. Eur. J. Anaesthesiol. 2010; 27(4): 383–387. DOI: 10.1097/EJA.0b013e3283333a7d
  32. Arabi Y.M., Casaer M.P., Chapman M., et al. The intensive care medicine research agenda in nutrition and metabolism. Intensive Care Med. 2017; 43(9): 1239–1256. DOI: 10.1007/s00134-017-4711-6
  33. Bergman R., van Zanten A.R., et al. Haemodynamic consequences of mild therapeutic hypothermia after cardiac arrest. Eur. J. Anaesthesiol. 2010; 27(4): 383–387. DOI: 10.1097/EJA.0b013e3283333a7d
  34. Leslie K., Bjorksten A.R., Ugoni A., Mitchell P. Mild core hypothermia and anesthetic requirement for loss of responsiveness during propofol anesthesia for craniotomy. Anesth. Analg., 2002; 94(5): 1298–1303.
  35. Martinello K., Hart A.R., Yap S., Mitra S., Robertson N.J. Management and investigation of neonatal encephalopathy: 2017 update. Arch. Dis. Child Fetal. Neonatal. Ed. 2017; 102(4): F346–F358. DOI: 10.1136/archdischild-2015-309639
  36. Perkins G.D., Olasveengen T.M., Maconochie I., et al. European Resuscitation Council Guidelines for Resuscitation: 2017 update. Resuscitation. 2018; 123: 43–50. DOI: 10.1016/j.resuscitation.2017.12.007
  37. Moler F.W., Silverstein F.S., Holubkov R., et al. THAPCA Trial Investigators. Therapeutic Hypothermia after In-Hospital Cardiac Arrest in Children. N. Engl. J. Med., 2017; 376(4): 318–329. DOI: 10.1056/NEJMoa1610493
  38. Crompton E.M., Lubomirova I., Cotlarciuc I., et al. Meta-Analysis of Therapeutic Hypothermia for Traumatic Brain Injury in Adult and Pediatric Patients. Crit. Care Med., 2017; 45(4): 575–583. DOI: 10.1097/CCM.0000000000002205
  39. Puccio A.M., Fischer M.R., Jankowitz B.T.,et al. Induced normothermia attenuates intracranial hypertension and reduces fever burden after severe traumatic brain injury. Neurocrit. Care, 2009; 11(1): 82–87. DOI: 10.1007/s12028-009-9213-0
  40. Sydenham E., Roberts I., Alderson P. Hypothermia for traumatic head injury. Cochrane Database Syst. Rev. 2017; 9: CD001048. DOI: 10.1002/14651858.CD001048
  41. Cooper D.J., Nichol A.D., Bailey M., et al. POLAR Trial Investigators and the ANZICS Clinical Trials Group. Effect of Early Sustained Prophylactic Hypothermia on Neurologic Outcomes Among Patients With Severe Traumatic Brain Injury: The POLAR Randomized Clinical Trial. JAMA. 2018; 320(21): 2211–2220. DOI: 10.1001/jama.2018.17075
  42. Shoji Y., Hiroyuki Y. Targeted temperature management in traumatic brain injury. J. Intensive Care, 2016; 4: 28. DOI: 10.1186/s40560-016-0137-4
  43. Broderick J., Connolly S., Feldmann E., et al., American Heart Association/American Stroke Association Stroke Council; American Heart Association/American Stroke Association. High Blood Pressure Research Council. Quality of Care and Outcomes in Research Interdisciplinary Working Group. Circulation. 2007; 116(16): e391–e413.
  44. Zazulia A.R., Diringer M.N., Derdeyn C.P., Powers W.J. Progression of mass effect after intracerebral hemorrhage. Stroke. 1999; 30(6): 1167–1173.
  45. Venkatasubramanian C., Mlynash M., Finley-Caulfield A., et al. Natural History of Perihematomal Edema After Intracerebral Hemorrhage Measured by Serial Magnetic Resonance Imaging. Stroke. 2011; 42(1): 73–80. DOI: 10.1161/strokeaha.110.590646
  46. MacLellan C.L., Davies L.M., Fingas M.S., Colbourne F. The influence of hypothermia on outcome after intracerebral hemorrhage in rats. Stroke. 2006; 37(5): 1266–1270.
  47. Gasser S., Khan N., Yonekawa Y., et al. Long-term hypothermia in patients with severe brain edema after poor-grade subarachnoid hemorrhage: feasibility and intensive care complications. J. Neurosurg. Anesthesiol. 2003; 15(3): 240–248.
  48. Kollmar R., Schellinger P.D., Steigleder T., et al. Ice-cold saline for the induction of mild hypothermia in patients with acute ischemic stroke: a pilot stud. Stroke. 2009; 40(5): 1907–1909. DOI: 10.1161/strokeaha.108.530410
  49. Georgiadis D., Schwarz S., Kollmar R., Schwab S. Endovascular cooling for moderate hypothermia in patients with acute stroke: first results of a novel approach. Stroke. 2009; 40(5): 1907–1909.
  50. Торосян Б.Д., Бутров А.В., Шевелев О.А. и др. Краниоцеребральная гипотермия — эффективное средство нейропротекции у пациентов с инфарктом мозга. Анестезиология и реаниматология, 2018; 3: 58–63. DOI: 10.17116/anaesthesiology201803158 [Torosyan B.D., Butrov A.V., Shevelev O.A., et al. Kraniocerebralnaya gipotermiya — effektivnoe sredstvo neyroprotekcii u pacientov s infarktom mozga. Anesteziologiya i reanimatologiya. 2018; 3: 58–63. (In Russ)]
  51. Winkel P., Bath P.M., Gluud C., et al. EuroHYP-1 trial investigators. Statistical analysis plan for the EuroHYP-1 trial: European multicentre, randomised, phase III clinical trial of the therapeutic hypothermia plus best medical treatment versus best medical treatment alone for acute ischaemic stroke. 2017; 18(1): 573. DOI: 10.1186/s13063-017-2302-z

Successful Completion of Pregnancy and Delivery in Patient in Coma

E.Yu. Upryamova1, A.L. Gridchik1, O.F. Serova2, M.V. Vatsik3, N.M. Smirnova3, E.M. Shifman4

1Moscow Regional Scientific Research Institute of Obstetrics and Gynecology, Moscow

2Moscow Regional Perinatal Center, Balashikha

3Domodedovo central hospital, Domodedovo

4M.F. Vladimirskiy Moscow Regional Research Clinical Institute, Moscow

For correspondence: Upryamova Ekaterina Yur’evna — MD, Senior Researcher of the Department of Anesthesiology and Intensive Care, Moscow Regional Scientific Research Institute of Obstetrics and Gynecology, Moscow; e-mail: kvyalkova@gmail.com

For citation: Upryamova EYu, Gridchik AL, Serova OF, Vatsik MV, Smirnova NM, Shifman EM. Successful Completion of Pregnancy and Delivery in Patient in Coma. Intensive Care Herald. 2016;4:62–66.


Severe neurological injury during pregnancy without intensive care for a woman is a potentially dangerous condition for both the mother and the fetus. High risk of secondary infection with the development of inflammatory complications, decompensation of vital functions of the mother due to the increased load on the organs and systems due to ongoing pregnancy have special requirements for the organization and carrying out of intensive care on the part of intensivist and obstetricians. In this clinical observation, we analyzed medical history, clinical and instrumental examination, especially prenatal care, intensive care and delivery of patient staying in persistent vegetative state being a result of severe traumatic brain injury.

The present clinical case is a unique event in Russian medical practice. Its uniqueness lies in the fact that the patient has spent in a coma in fact the entire pregnancy (4–5 weeks before a full-term period), that is more than 8 months. The obstetric department of Domodedovo central hospital performed cesarean section under general anesthesia when the term was around 36–37 weeks. In the 4th minute they extracted preterm alive weight 2180 g girl, 46 cm, with Apgar scores of 3–5 points. In May 2015, the specialists carried out in-depth examination of the child. According to the results of the survey, the child did not reveal any abnormalities in the development and health.

Thus, a consistent multidisciplinary approach, an individual program of intensive therapy, taking into account the type and extent of damage to the central nervous system, the parent status, gestational age and fetal condition allowed achieving significant results in the treatment and giving a chance to live for the child not yet born.

Keywords: pregnancy, delivery, traumatic brain injury, coma, persistent vegetative state, Glasgow score, Apgar score

Received: 23.09.2016


References

  1. Постановление Правительства Российской Федерации №294 от 15.04.2014 «Об утверждении государственной программы Российской Федерации “Развитие здравоохранения”». М., 2014. [Russian Federation Government Resolution № 294 of 15.04.2014. «On approval of the state program of the Russian Federation “Health Development”». Mоscow; 2014. (In Russ)]
  2. О материнской смертности в Российской Федерации в 2014 году: Информационное письмо. Минздрав РФ. 2014. [The maternal mortality rate in the Russian Federation 2014: Newsletter. The Ministry of Health of the Russian Federation. 2014. (In Russ)]
  3. Dillon W.P., Lee R.V., Tronolone M.J. et al. Life support and maternal death during pregnancy. JAMA. 1982; 248(9): 1089–1091. doi: 10.1001/jama.1982.03330090059030.
  4. Hnat M.D., Sibai B.M., Kovilam O. An initial Glasgow score of 4 and Apgar scores of 9 and 9: A case report of a pregnant comatose woman. Am. J. Obstet. Gynecol. 2003; 189(3): 877–87 doi: 10.1067/s0002-9378(03)00589-1.
  5. Яшлавский А. Рожденный в коме [электронный документ]. URL: http://www.mk.ru/editions/daily/article/2006/11/16/175182-rozhdennyiy-v-kome.html Ссылка активна на 14.09.2016. [Yashlavskii A. Born in coma [Internet]. URL: http://www.mk.ru/editions/daily/article/2006/11/16/175182-rozhdennyiy-v-kome.html. (accessed 14.09.2016). (In Russ)]
  6. Находившаяся в вегетативном состоянии немка родила здорового ребенка. [электронный документ]. URL: http://medportal.ru/mednovosti/news/2009/10/12/vegbirth/. Ссылка активна на 14.09.2016. [German in a vegetative state has given birth to a healthy baby [Internet]. URL: http://medportal.ru/mednovosti/news/2009/10/12/vegbirth/ (accessed 14.09.2016). (In Russ)]
  7. Bush M.C., Nagy S., Berkowitz R.L., Gaddipati S. Pregnancy in a persistent vegetative state: case report, comparison to brain death, and review of the literature. Obstet. Gynecol. Surv. 2003; 58(11): 738–748. doi: 10.1097/01.ogx.0000093268.20608.53.
  8. Feldman D.M., Borgida A.F., Rodis J.F., Campbell W.A. Irreversible maternal brain injury during pregnancy: a case report and review of the literature. Obstet. Gynecol. Surv. 2000; 55(11): 708–714. doi: 10.1097/00006254-200011000-00023.
  9. Slattery M., Morrison J.J. Preterm delivery. Lancet. 2002; 360(9344): 1489–1497. doi: 10.1016/s0140-6736(02)11476-0.

Basic Therapy of Traumatic Brain Injury Using Catecholamine Agonist

E.АLebedeva1, E.GMarkaryan2, S.ABelyaevskij2, G.ASasian2, A.S. Sogikyan3, S.ADoroshenko2, E.VYartsev2, M.ТKlochkova2, M.LSkoblo4

1 Rostov state medical University, Rostov-on-Don

2 City hospital ambulance, Rostov-on-Don

3 Road clinical hospital at the station Rostov-Glavny, Rostov-on-Don

4 City hospital № 6, Rostov-on-Don

For correspondence: Elena А. Lebedeva — MD, associate Professor of the Department of anesthesiology and intensive care of the “Rostov state medical University”; e-mail: okulus@yandex.ru

For citation: Lebedeva EА, Markaryan EG, Belyaevskij SA, et al. Basic Therapy of Traumatic Brain Injury Using Catecholamine Agonist. Alexander Saltanov Intensive Care Herald. 2018;1:79–82.

DOI: 10.21320/1818-474X-2018-1-79-82


In order to determine the safety of the use of amantadine in intensive treatment of victims with severe traumatic brain injury, a prospective controlled blind randomized study was conducted, in which 31 patient were included. The first group consisted of 19 persons who underwent intensive treatment. In group II (18 people), amantadine was included in the intensive care package. The use of amantadine in the complex intensive treatment of severe traumatic brain injury at the earliest possible time (3rd day after injury), provided the correction of hemodynamics and respiration does not change the structure and does not exacerbate the manifestations of polyorgan insufficiency.

Keywords: traumatic brain injury, amantadine

Received: 31.12.2017


References

  1. Селезнев С.А., Багненко С.Ф., Шапот Ю.Б. и др. Травматическая болезнь и ее осложнения. СПб.: Политехника, 2004. [Seleznev S.A., Bagnenko S.F., Shapot Yu.B., et al. Travmaticheskaya boleznʼ i ee oslozhneniya. Saint-Petersburg: Politekhnika, 2004. (In Russ)]
  2. Беляевский А.Д., Лебедева Е.А., Куртасов А.А., Немкова З.А. Процессы адаптации и патологического воздействия в развитии травматической болезни. Современные проблемы науки иобразования. 2012; 3: 82. [Belyaevsky A.D., Lebedeva E.A., Kurtasov A.A., Nemkova Z.A. Adaptation and pathological effects in the development of traumatically disease. Modern problems of science and education. 2012; 3: 82. (In Russ)]
  3. Dutton R.P., Stansbury L.G., Leone S., et al. Trauma mortality in mature trauma systems: are we doing better? An analysis of trauma mortality patterns, 1997–2008. J. Trauma. 2010; 69(3): 620–626. doi: 10.1097/TA.0b013e3181bbfe2a/.
  4. Osier N.D., Dixon C.E. Catecholaminergic based therapies for functional recovery after TBI. Brain Res. 2015 Dec 19. 2016;1640(Pt A):15–35 [Internet]. URL: https://www.clinicalkey.com/#!/content/journal/1-s2.0–S0006899315009658 (accessed 15.12.2017).
  5. Bope E.T., Kellerman R.D. Connʼs Current Therapy. Elsevier, 2016: 647–724.
  6. ЛебедеваЕ.А. Особенности течения оксидативного стресса и развития адаптационных реакций организма в остром периоде травматической болезни. Известия высших учебных заведений. Ростов. 2012; 2: 122–126. [Lebedeva E.A. Osobennosti techeniya oksidativnogo stressa i razvitiya adaptatsionnykh reaktsii organizma v ostrom periode travmaticheskoi bolezni. Izvestiya vysshikh uchebnykh zavedenii. Rostov. 2012; 2: 122–126. (In Russ)]
  7. Kim J.H., Lee H.W Hwang J., et al. Microglia-inhibiting activity of Parkinsonʼs disease drug amantadine. Neurobiol. Aging. 2012; 33(9): 2145–2159. doi: 10.1016/j.neurobiolaging.2011.08.011.
  8. БелкинA.A., Щеголев A.B., Кондратьев А.Н., и др. Использование амантадина сульфата (ПК-Мерц) в период выхода из комы: результаты многоцентрового исследования. Анестезиология и реанимация. 2008; 2: 70–72. [Belkin A.A., Shchegolev A.B., Kondratʼev A.N., et al. Ispolʼzovanie amantadina sulʼfata (PK-Merts) v period vykhoda iz komy: rezulʼtaty mnogotsentrovogo issledovaniya. Anesteziologiya i reanimatsiya. 2008; 2: 70–72. (In Russ)]
  9. БелкинА.А., Щеголев А.В., Бельский Д.В. и др. ПК-Мерц при вегетативном статусе и «малом сознании».
Рецепт. 2008; 5(61): 66–70. [Belkin A.A., Shchegolev A.V., Belʼskij D.V., et al. PK-Merts pri vegetativnom statuse i «malom soznanii».
Retsept. 2008; 5(61): 66–70. (In Russ)]
  10. Распоряжение Правительства РФ от 23.10.2017 № 2323-р «Об утверждении перечня жизненно необходимых и важнейших лекарственных препаратов на 2018 год, а также перечней лекарственных препаратов для медицинского применения и минимального ассортимента лекарственных препаратов, необходимых для оказания медицинской помощи» [электронный ресурс]. URL: http://www.consultant.ru/document/cons_doc_LAW_281261/ (дата обращения: 15.12.2017). [Rasporyazhenie Pravitel’stva RF ot 23.10.2017 №2323-r “Ob utverzhdenii perechnya zhiznenno neobkhodimykh i vazhnejshikh lekarstvennykh preparatov na 2018 god, a takzhe perechnej lekarstvennykh preparatov dlya meditsinskogo primeneniya i minimal’nogo assortimenta lekarstvennykh preparatov, neobkhodimykh dlya okazaniya meditsinskoj pomoshhi” [Internet]. URL: http://www.consultant.ru/document/cons_doc_LAW_281261/ (accessed: 15.12.2017). (In Russ)]
  11. Клиническая рекомендация «Лечение пострадавших с тяжелой черепно-мозговой травмой». М., 2014 [электронный ресурс]. URL:http://cr.rosminzdrav.ru/#!/schema/342 (дата обращения: 15.12.2017). [Klinicheskaya rekomendatsiya “Lechenie postradavshikh s tyazheloj cherepno-mozgovoj travmoj”. M., 2014 [Internet]. URL: http://cr.rosminzdrav.ru/#!/schema/342 (accessed: 15.12.2017). (In Russ)]
  12. Giacino J.T., Whyte J., Bagiella E., et al. Placebo-Controlled Trial of Amantadine for Severe Traumatic Brain Injury. N. Engl. J. Med. 2012; 366(9): 819–826. doi: 10.1056/NEJMoa1102609.
  13. Wang T., Huang X.J., Van K.C., et al. Amantadine improves cognitive outcome and increases neuronal survival after fluid percussion traumatic brain injury in rats. J.Neurotrauma. 2014; 31(4): 370–377. doi: 10.1089/neu.2013.2917.