Emprego de uma nova emulsão de perfluorocarbonos (OxygentMR) em circulação extracorpórea: estudo experimental em cães

Vicente, Walter V. A; Holman, William L; Spruell, Russell D; Ferguson, Edward R; Clymer, Janice J; Murrah, C. Patrie; Pacifico, Albert D

doi:10.1590/S0102-76381995000100005

Resumos

Testou-se uma nova emulsão de perfluorocarbonos (OxygentMR, Alliance Pharmaceutical, San Diego, CA 92121, EUA) em circulação extracorpórea (CEC) com hipotermia de 32ºC e hematócrito de 12%. Estudaram-se 42 cães, 12 dos quais não receberam a droga e serviram de controle (Grupo 1), enquanto os demais constituíram 3 grupos de 10 animais cada, tratados com doses de Oxygent de 1,5 ml/kg (Grupo 2), 3 ml/kg (Grupo 3) e 6 ml/kg (Grupo 4) as quais geraram fluorocritos de, respectivamente, 1 %, 2% e 3%. Foram analisadas variáveis do metabolismo do oxigênio (O2) em 6 diferentes fluxos de perfusão (Q), ordenados ao acaso. Reaqueceram-se os cães, interrompeu-se a CEC e acompanharam-se os animais por 1 hora. Diferenças intergrupos foram analisadas pelo teste das médias dos quadrados mínimos e pelo teste de Duncan, considerando-se significantes os valores de p< 0,05. Embora algo maiores no Grupo 4, a pressão parcial bem como o conteúdo arterial de oxigênio (CaO2) foram estatisticamente semelhantes ao grupo controle. A pressão parcial de O2 no sangue venoso misto (PvO2) do Grupo 4, em função do Q, mostrou-se significativamente maior (p < 0,03) que a do grupo controle, conquanto isto não tenha se repetido ao ser analisada em função da oferta tecidual de O2 . Também não houve diferença quanto ao consumo de O2 total e dissolvido, nem quanto aos gradientes sistêmico e miocárdico de lactato, porém a maior dose da emulsão (Grupo 4) expressa efeito dose-dependente benéfico, ainda que de natureza especulativa, do Oxygent sobre o metabolismo do oxigênio.

Perfluorocarbonos; Sangue; Circulação extracorpórea

A novel perfluorocarbon emulsion (OxygentTM - Alliance Pharmaceutical Corp., San Diego, CA 92121, USA) was tested during hypothermic (32ºC) cardio pulmonary bypass (CPB) under severe hemodilution (Hto = 12%). Forty-two mongrel dogs were allocated to 4 groups. Group 1 (n=12) was not given Oxygent and served as control whereas Groups 2, 3, and 4 (10 animals each) were given a bolus dose of the emulsion (1.5,3.0, and 6.0 ml/kg, respectively) at the onset of CPB. O2 metabolism variables were then studied at 6 randomized pump flow rates (Q) ranging from 0.25 to 3.0 l/min/m². After rewarming CPB was discontinued and the animals were followed-up for one hour and then killed by IV KGI injection. Differences between groups were evaluated by the least squares means and Duncan's tests and considered significant for p<0.05. Fluorocrit values remained stable on CPB Group 2 -1 %, Group 3 - 2%, and Group 4 - 3%). Although somewhat elevated, Group 4 arterial blood O2 partial pressure and content (CaO2) didn't reach statistical significance versus control. Group 4 mixed venous blood O2 partial pressure (PvO2) regressed against Q was significantly higher (p < 0.03) than control, but there was no statistical difference when this variable was regressed against O2 delivery rate. Groups were similar regarding total as well as dissolved O2 consumption and systemic and transmyocardial lactate gradients. A trend towards lower mortality rates was noticed in Groups 3 (20%) and 4 (10%) versus control (41.6%). Group 4 trend towards both reduced mortality and higher CaO2 as well as its significant PvO2 rise against Q suggest a beneficial, yet speculative, Oxygent dose dependent effect on O2 metabolism.

Perfluorocarbons; Oxygen metabolism; Extracorporeal circulation

ARTIGOS ORIGINAIS

Emprego de uma nova emulsão de perfluorocarbonos (Oxygent^MR) em circulação extracorpórea: estudo experimental em cães

Use of a new perfluorocarbon emulsion (Oxygent^TM) in a profoundly anemic canine model of hypothermic cardiopulmonary bypass

Walter V. A. Vicente^I; William L. Holman^II; Russell D. Spruell^II; Edward R. Ferguson^II; Janice J. Clymer^III; C. Patrie Murrah^II; Albert D. Pacifico^II

^IDa Disciplina de Cirurgia Torácica e Cardiovascular - Depto. de Cirurgia da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo

^IIDivision of Cardiothoracic Surgery. Univesity of Alabama at Birmingham and Birmingham V.A. Medical Center. Birmingham, AL, EUA

^IIIAlliance Pharmaceutical Corp. San Diego, CA, EUA

^{Endereço para correspondência} Endereço para correspondência: Walter V. A. Vicente Depto. de Cirurgia. H. C. Ribeirão Preto - Campus da USP Ribeirão Preto, SP, Brasil. CEP: 14049-900 Tel.: (016) 633.0836. Fax: (016) 633.1144

RESUMO

Testou-se uma nova emulsão de perfluorocarbonos (Oxygent^MR, Alliance Pharmaceutical, San Diego, CA 92121, EUA) em circulação extracorpórea (CEC) com hipotermia de 32ºC e hematócrito de 12%. Estudaram-se 42 cães, 12 dos quais não receberam a droga e serviram de controle (Grupo 1), enquanto os demais constituíram 3 grupos de 10 animais cada, tratados com doses de Oxygent de 1,5 ml/kg (Grupo 2), 3 ml/kg (Grupo 3) e 6 ml/kg (Grupo 4) as quais geraram fluorocritos de, respectivamente, 1 %, 2% e 3%. Foram analisadas variáveis do metabolismo do oxigênio (O₂) em 6 diferentes fluxos de perfusão (Q), ordenados ao acaso. Reaqueceram-se os cães, interrompeu-se a CEC e acompanharam-se os animais por 1 hora. Diferenças intergrupos foram analisadas pelo teste das médias dos quadrados mínimos e pelo teste de Duncan, considerando-se significantes os valores de p< 0,05. Embora algo maiores no Grupo 4, a pressão parcial bem como o conteúdo arterial de oxigênio (C_aO₂) foram estatisticamente semelhantes ao grupo controle. A pressão parcial de O₂ no sangue venoso misto (P_vO₂) do Grupo 4, em função do Q, mostrou-se significativamente maior (p < 0,03) que a do grupo controle, conquanto isto não tenha se repetido ao ser analisada em função da oferta tecidual de O₂ . Também não houve diferença quanto ao consumo de O₂ total e dissolvido, nem quanto aos gradientes sistêmico e miocárdico de lactato, porém a maior dose da emulsão (Grupo 4) expressa efeito dose-dependente benéfico, ainda que de natureza especulativa, do Oxygent sobre o metabolismo do oxigênio.

Descritores: Perfluorocarbonos, em circulação extracorpórea. Sangue, metabolismo. Circulação extracorpórea.

ABSTRACT

A novel perfluorocarbon emulsion (Oxygent^TM - Alliance Pharmaceutical Corp., San Diego, CA 92121, USA) was tested during hypothermic (32ºC) cardio pulmonary bypass (CPB) under severe hemodilution (Hto = 12%). Forty-two mongrel dogs were allocated to 4 groups. Group 1 (n=12) was not given Oxygent and served as control whereas Groups 2, 3, and 4 (10 animals each) were given a bolus dose of the emulsion (1.5,3.0, and 6.0 ml/kg, respectively) at the onset of CPB. O₂ metabolism variables were then studied at 6 randomized pump flow rates (Q) ranging from 0.25 to 3.0 l/min/m². After rewarming CPB was discontinued and the animals were followed-up for one hour and then killed by IV KGI injection. Differences between groups were evaluated by the least squares means and Duncan's tests and considered significant for p<0.05. Fluorocrit values remained stable on CPB Group 2 -1 %, Group 3 - 2%, and Group 4 - 3%). Although somewhat elevated, Group 4 arterial blood O₂ partial pressure and content (C_aO₂) didn't reach statistical significance versus control. Group 4 mixed venous blood O₂ partial pressure (PvO₂) regressed against Q was significantly higher (p < 0.03) than control, but there was no statistical difference when this variable was regressed against O₂ delivery rate. Groups were similar regarding total as well as dissolved O₂ consumption and systemic and transmyocardial lactate gradients. A trend towards lower mortality rates was noticed in Groups 3 (20%) and 4 (10%) versus control (41.6%). Group 4 trend towards both reduced mortality and higher C_aO₂ as well as its significant PvO₂ rise against Q suggest a beneficial, yet speculative, Oxygent dose dependent effect on O₂ metabolism.

Descriptors: Perfluorocarbons, in extracorporeal circulation. Oxygen metabolism. Extracorporeal circulation.

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Full text available only in PDF format.

AGRADECIMENTOS: Aos Srs. Ronnie Brown, Jefferson Dudleston e Fred Wallace, pela inestimável assistência técnica. À Sras. Laucéa Conrado S. Porciúncula e Marlene Lúcio, pela edição do texto. Ao CNPq, pela bolsa de estudos.

Trabalho realizado durante estágio de pós-doutorado nos EUA, financiado pelo Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).

Apresentado ao 22º Congresso Nacional de Cirurgia Cardíaca. Brasília, DF, 30 de março de a 1º de abril, 1995.

1 ALLIANCE PHARMACEUTICAL CORPORATION. Cardiovascular Pharmacology Division. Technical information. 1993.
2 BIRO, G. P. & BLAIS, P. Perfluorocarbon blood substitutes. Crit. Rev. Oncol. Hemat, 6: 311-374, 1987.
3 BRAZIER, J.; COOPER, N.; MALONEY Jr., J. V.; BUCKBERG, G. The adequacy of myocardial oxygen delivery in acute normovolemic anemia. Surgery, 75, 508-516, 1974.
4 CONFORTO, A. B. & FOCESI Jr., A. Soluções artificiais e de hemoglobina como substitutos de sangue: uma revisão. Medicina (Ribeirão Preto), 24: 41-52, 1991.
5 ENGELMAN, R. M.; ROUSOU, J. H.; DOBBS, W. A. Fluosol-DA: an artificial blood for total cardiopulmonary bypass. Ann. Thorac. Surg, 32: 528-535, 1981.
6 FAITHFULL, N. S. & CAIN, S. M. Critical levels of O₂ extraction following hemodilution with dextran and Fluosol-DA. J. Crit. Care, 3: 14-18, 1988.
7 FAITHFULL, N. S.; ERDMANN, W.; FENNEMA, M.; KOK, A. - Effects of haemodilution with fluorocarbons or dextran on oxygen tensions in the acutely ischaemic myocardium. Br. J. Anaesth, 58: 1031-1040,1986.
8 FEOLA, M.; SIMONI, J.; ANGELILLO, R.; LUHRUMA, Z.; KABAKELE, M.; MANZOMBI, M.; KALUILA, M. Clinical trial of a hemoglobin based blood substitute in patients with sickle cell anemia. Surg. Gynecol. Obstet, 174: 379-386, 1992.
9 FERGUSON, E. R.; CLYMER, J. J.; SPRUELL, R. D.; HOLMAN, W. L. - Perfluorocarbon oxygen transport: a comparative study of four oxygenator designs. Surg. Forum, 1994. (No prelo).
10 FOX, L. S.; BLACKSTONE, E. H.; KIRKLIN, J. W.; STEWART, R. W.; SAMUELSON, P. N. - Relationship of whole body oxygen consumption to perfusion flow rate during hypothermic cardioplegic cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg, 83: 239-248, 1982.
11 HEIMISCH, S. H.; MEISNER, H.; ERBEN, R.; BAUM, M.; MENDLER, N. The effect of hemodilution on regional myocardial function in the presence of coronary stenosis. Basic Res. Cardiol, 72: 344-364, 1977.
12 HOLMAN, W. L.; McGIFFIN, D. C; VICENTE, W. V. A.; SPRUELL, R. D.; PACIFICO, A. D. - Use of current generation perfluorocarbon emulsions in cardiac surgery. Biomat. Art. Cells Immob. Biotech. (No prelo).
13 HOLMAN, W. L; SPRUELL, R. D.; DIGERNESS, S. B.; DUDELSTON, J.; PACIFICO, A. D. - Oxyhemoglobin dissociation during hypothermic blood cardioplegia arrest. Circulation, 86 (Supl.2): 339-345, 1992.
14 HOLMAN, W. L.; SPRUELL, R. D.; FERGUSON, E. R.; CLYMER, J. J.; VICENTE, W. V. A.; MURRAH, P.; PACIFICO, A. D. - Tissue oxygenation with graded dissolved oxygen delivery during cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. (Encaminhado para publicação).
15 HOMER, L D.; WEATHERSBY, P. K.; KIESOW, L. A. - Oxygen gradients between red blood cells in the microcirculation. Microvasc. Res, 22: 308-323, 1981.
16 HONIG, C. R.; CONNETT, R. J.; GAYESKI, T. E. J. - Interaction of blood flow, diffusive transport and cell metabolism in isovolemic anemia. In: GOLDSTICK, T. K. (ed.) Oxygen transport to tissues - 13. New York, Plenum Press, 1992. p. 21-29.
17 KEIPERT, P. E.; FAITHFULL, S.; BRADLEY, J. D.; HAZARD, D. Y.; HOGAN, J.; LEVISETTI, M. S.; PETERS, R. M. - Oxygen delivery augmentation by low-dose perfluorochemical emulsion during profound normovolemic hemodilution. In: VAUPEL, P. (ed.) Oxygen transport to tissues-15, New York, Plenum Press. (No Prelo).
18 LONGMUIR, I. S. - The effect of hypothermia on the affinity of tissues for oxygen. Life Sciences, 7: 297-300, 1962.
19 LUGO, G.; ARIZPE, D.; DOMINGUEZ, G.; RAMIREZ, J.; TAMARIZ, O. - Relationship between oxygen consumption and oxygen delivery during anesthesia in high-risk surgical patients. Crit. Care Med, 21:64-69, 1993.
20 MEINERT, H.; FACKLER, R.; KNOBLICH, A.; MADER, J.; REUTER, P.; ROHLKE, W. - On the perfluorocarbon emulsions of second generation. Biomat. Art. Cells Immob. Biotech, 20: 805-818,1992.
21 RIESS, J. G. - Fluorocarbon-based in vivo oxygen transport and delivery systems. Vox Sang, 61: 225-239, 1991a.
22 RIESS, J. G. - Hemocompatible fluorocarbon emulsions. In: SHARMA, C. P. & SZYCHER, M. (eds.) Blood compatible materials and devices: perspectives towards the 21st century, Lancaster, Technomic Publishing Company, Inc., 1991b, cap. 14, p. 237-270.
23 RIESS, J. G.; DALFORS, G. K.; HANNA, G. K.; KRAFFT, M. P.; PELURA, T. J.; SCHUTT, E. G. - Development of highly fluid, concentrated and stable fluorocarbon emusions for diagnosis and therapy. Biomat Art. Cells. Immob. Biotech, 20: 839-842, 1992.
24 ROUSOU, J. A.; ENGELMAN, R. M.; ANISIMOWICZ, L.; DOBBS, W. A. - A comparison of blood and Fluosol-DA for cardiopulmonary bypass. J. Cardiovasc. Surg, 26: 447-453, 1985.
25 SAMSEL, R. W. & SCHUMACHER, P. T. - Determination of critical O₂ delivery from experimental data: sensitivity to error. J. Appl. Physiol, 64: 2074-2082, 1988.
26 SCHOLANDER, P. F. - Oxygen transport through hemoglobin solutions. Science, 131: 585-590,1960.
27 SIDI, A. & DAVIS, R. F. - Lactate extraction fails to accurately reflect regional lactate production in ischemic myocardium. J. Cardiothorac. Anesth, 3: 312-318, 1989.
28 SPAHN, D. R.; SMITH, R.; VERONEE, C. D.; MCRAE, R. L; WEI-CHIH, H.; MENIUS, A. J.; LOWE, J. E.; LEONE, B. J. - Acute isovolemic hemodiltion and blood transfusion. J. Thorac. Cardiovasc. Surg, 105: 694-704, 1993.
29 SPENCE, R. K.; CARSON, J.; CERNAIANU, A. C; DELROSSI, A. J. - Transfusion and surgery. Curr. Probl. Surg, 30: 1105-1180, 1993.
30 STONE, J. J.; PICCIONE Jr., W.; BERRIZBEITIA, L. D.; DANCE, G. R.; SCHOEN, F. J.; SHEMIN, R. J.; COHN, L. H. - Hemodynamic, metabolic, and morphological effects of cardiopulmonary bypass with a fluorocarbon priming solution. Ann. Thorac. Surg, 41: 419-424, 1986.
31 TUPPURAINEM, T.; SETTERGREN, G.; STENSVED, P. - The effect of arterial pH on whole body oxygen uptake during hypothermic cardiopulmonary bypass in man. J. Thorac. Cardiovasc. Surg, 98: 769-773, 1989.
32 ZAKHAROV, V. N. - Structural analysis of moving blood from the viewpoint of new principles of circulation mechanics. J. Cardiovasc. Surg, 35: 19-26, 1994.

Endereço para correspondência:

Walter V. A. Vicente

Depto. de Cirurgia. H. C. Ribeirão Preto - Campus da USP

Ribeirão Preto, SP, Brasil. CEP: 14049-900

Tel.: (016) 633.0836. Fax: (016) 633.1144

Datas de Publicação

Publicação nesta coleção
17 Fev 2011
Data do Fascículo
Mar 1995

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

[1] 1 ALLIANCE PHARMACEUTICAL CORPORATION. Cardiovascular Pharmacology Division. Technical information. 1993.

[2] 2 BIRO, G. P. & BLAIS, P. Perfluorocarbon blood substitutes. Crit. Rev. Oncol. Hemat, 6: 311-374, 1987.

[3] 3 BRAZIER, J.; COOPER, N.; MALONEY Jr., J. V.; BUCKBERG, G. The adequacy of myocardial oxygen delivery in acute normovolemic anemia. Surgery, 75, 508-516, 1974.

[4] 4 CONFORTO, A. B. & FOCESI Jr., A. Soluções artificiais e de hemoglobina como substitutos de sangue: uma revisão. Medicina (Ribeirão Preto), 24: 41-52, 1991.

[5] 5 ENGELMAN, R. M.; ROUSOU, J. H.; DOBBS, W. A. Fluosol-DA: an artificial blood for total cardiopulmonary bypass. Ann. Thorac. Surg, 32: 528-535, 1981.

[6] 6 FAITHFULL, N. S. & CAIN, S. M. Critical levels of O₂ extraction following hemodilution with dextran and Fluosol-DA. J. Crit. Care, 3: 14-18, 1988.

[7] 7 FAITHFULL, N. S.; ERDMANN, W.; FENNEMA, M.; KOK, A. - Effects of haemodilution with fluorocarbons or dextran on oxygen tensions in the acutely ischaemic myocardium. Br. J. Anaesth, 58: 1031-1040,1986.

[8] 8 FEOLA, M.; SIMONI, J.; ANGELILLO, R.; LUHRUMA, Z.; KABAKELE, M.; MANZOMBI, M.; KALUILA, M. Clinical trial of a hemoglobin based blood substitute in patients with sickle cell anemia. Surg. Gynecol. Obstet, 174: 379-386, 1992.

[9] 9 FERGUSON, E. R.; CLYMER, J. J.; SPRUELL, R. D.; HOLMAN, W. L. - Perfluorocarbon oxygen transport: a comparative study of four oxygenator designs. Surg. Forum, 1994. (No prelo).

[10] 10 FOX, L. S.; BLACKSTONE, E. H.; KIRKLIN, J. W.; STEWART, R. W.; SAMUELSON, P. N. - Relationship of whole body oxygen consumption to perfusion flow rate during hypothermic cardioplegic cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg, 83: 239-248, 1982.

[11] 11 HEIMISCH, S. H.; MEISNER, H.; ERBEN, R.; BAUM, M.; MENDLER, N. The effect of hemodilution on regional myocardial function in the presence of coronary stenosis. Basic Res. Cardiol, 72: 344-364, 1977.

[12] 12 HOLMAN, W. L.; McGIFFIN, D. C; VICENTE, W. V. A.; SPRUELL, R. D.; PACIFICO, A. D. - Use of current generation perfluorocarbon emulsions in cardiac surgery. Biomat. Art. Cells Immob. Biotech. (No prelo).

[13] 13 HOLMAN, W. L; SPRUELL, R. D.; DIGERNESS, S. B.; DUDELSTON, J.; PACIFICO, A. D. - Oxyhemoglobin dissociation during hypothermic blood cardioplegia arrest. Circulation, 86 (Supl.2): 339-345, 1992.

[14] 14 HOLMAN, W. L.; SPRUELL, R. D.; FERGUSON, E. R.; CLYMER, J. J.; VICENTE, W. V. A.; MURRAH, P.; PACIFICO, A. D. - Tissue oxygenation with graded dissolved oxygen delivery during cardiopulmonary bypass. J. Thorac. Cardiovasc. Surg. (Encaminhado para publicação).

[15] 15 HOMER, L D.; WEATHERSBY, P. K.; KIESOW, L. A. - Oxygen gradients between red blood cells in the microcirculation. Microvasc. Res, 22: 308-323, 1981.

[16] 16 HONIG, C. R.; CONNETT, R. J.; GAYESKI, T. E. J. - Interaction of blood flow, diffusive transport and cell metabolism in isovolemic anemia. In: GOLDSTICK, T. K. (ed.) Oxygen transport to tissues - 13. New York, Plenum Press, 1992. p. 21-29.

[17] 17 KEIPERT, P. E.; FAITHFULL, S.; BRADLEY, J. D.; HAZARD, D. Y.; HOGAN, J.; LEVISETTI, M. S.; PETERS, R. M. - Oxygen delivery augmentation by low-dose perfluorochemical emulsion during profound normovolemic hemodilution. In: VAUPEL, P. (ed.) Oxygen transport to tissues-15, New York, Plenum Press. (No Prelo).

[18] 18 LONGMUIR, I. S. - The effect of hypothermia on the affinity of tissues for oxygen. Life Sciences, 7: 297-300, 1962.

[19] 19 LUGO, G.; ARIZPE, D.; DOMINGUEZ, G.; RAMIREZ, J.; TAMARIZ, O. - Relationship between oxygen consumption and oxygen delivery during anesthesia in high-risk surgical patients. Crit. Care Med, 21:64-69, 1993.

[20] 20 MEINERT, H.; FACKLER, R.; KNOBLICH, A.; MADER, J.; REUTER, P.; ROHLKE, W. - On the perfluorocarbon emulsions of second generation. Biomat. Art. Cells Immob. Biotech, 20: 805-818,1992.

[21] 21 RIESS, J. G. - Fluorocarbon-based in vivo oxygen transport and delivery systems. Vox Sang, 61: 225-239, 1991a.

[22] 22 RIESS, J. G. - Hemocompatible fluorocarbon emulsions. In: SHARMA, C. P. & SZYCHER, M. (eds.) Blood compatible materials and devices: perspectives towards the 21st century, Lancaster, Technomic Publishing Company, Inc., 1991b, cap. 14, p. 237-270.

[23] 23 RIESS, J. G.; DALFORS, G. K.; HANNA, G. K.; KRAFFT, M. P.; PELURA, T. J.; SCHUTT, E. G. - Development of highly fluid, concentrated and stable fluorocarbon emusions for diagnosis and therapy. Biomat Art. Cells. Immob. Biotech, 20: 839-842, 1992.

[24] 24 ROUSOU, J. A.; ENGELMAN, R. M.; ANISIMOWICZ, L.; DOBBS, W. A. - A comparison of blood and Fluosol-DA for cardiopulmonary bypass. J. Cardiovasc. Surg, 26: 447-453, 1985.

[25] 25 SAMSEL, R. W. & SCHUMACHER, P. T. - Determination of critical O₂ delivery from experimental data: sensitivity to error. J. Appl. Physiol, 64: 2074-2082, 1988.

[26] 26 SCHOLANDER, P. F. - Oxygen transport through hemoglobin solutions. Science, 131: 585-590,1960.

[27] 27 SIDI, A. & DAVIS, R. F. - Lactate extraction fails to accurately reflect regional lactate production in ischemic myocardium. J. Cardiothorac. Anesth, 3: 312-318, 1989.

[28] 28 SPAHN, D. R.; SMITH, R.; VERONEE, C. D.; MCRAE, R. L; WEI-CHIH, H.; MENIUS, A. J.; LOWE, J. E.; LEONE, B. J. - Acute isovolemic hemodiltion and blood transfusion. J. Thorac. Cardiovasc. Surg, 105: 694-704, 1993.

[29] 29 SPENCE, R. K.; CARSON, J.; CERNAIANU, A. C; DELROSSI, A. J. - Transfusion and surgery. Curr. Probl. Surg, 30: 1105-1180, 1993.

[30] 30 STONE, J. J.; PICCIONE Jr., W.; BERRIZBEITIA, L. D.; DANCE, G. R.; SCHOEN, F. J.; SHEMIN, R. J.; COHN, L. H. - Hemodynamic, metabolic, and morphological effects of cardiopulmonary bypass with a fluorocarbon priming solution. Ann. Thorac. Surg, 41: 419-424, 1986.

[31] 31 TUPPURAINEM, T.; SETTERGREN, G.; STENSVED, P. - The effect of arterial pH on whole body oxygen uptake during hypothermic cardiopulmonary bypass in man. J. Thorac. Cardiovasc. Surg, 98: 769-773, 1989.

[32] 32 ZAKHAROV, V. N. - Structural analysis of moving blood from the viewpoint of new principles of circulation mechanics. J. Cardiovasc. Surg, 35: 19-26, 1994.