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Inhibition of the hypotensive effect of plasma protein solutions by C1esterase inhibitor
J
THORAC CARDIOVASC SURG
79:738-740, 1980
Inhibition of the hypotensive effect of plasma protein solutions by Ciesterase inhibitor The hypotensive effect of stable plasma protein solution (SPPS) is a well-known phenomenon. causing serious problems in surgical patients and patients supported by cardiopulmonary bypass. Kinins are believed to be responsible. A study was made to prevent this hypotension by adding Csesterase inhibitor to the SPPS and comparing this with 5% human albumin. The results show a significant difference between the effects of SPPS and SPPS plus Ciesterase inhibitor infusion on bypass. Five percent human albumin did not cause hypotension. Possible sequelae are discussed.
Peter van der Starre, M.D.,* Donald Sinclair, M.D.,** Johan Damen, M.D.,*** and Henk Brummelhuis, M.D.,**** Utrecht, The Netherlands
Since changing from a blood-saline prime to a plasma-saline prime for cardiopulmonary bypass, we have been troubled by marked hypotension at the start of bypass, necessitating the virtually routine use of a vasopressor to maintain an acceptable blood pressure. Several reports have noted hypotension associated with the rapid infusion of commercially prepared heattreated stable plasma protein solution (SPPS) for volume replacement in surgical patients'<" and in a prospective survey of its use in cardiopulmonary bypass,"- 4, 6 The present study was undertaken to identify the cause of the hypotension and to find a way of preventing it.
From the University of Utrecht, Utrecht, The Netherlands. Received for publication July 3, 1979. Accepted for publication Oct. 2, 1979. Address for reprints: Dr. D. Sinclair, Department ofCardio-Thoracic Surgery, University Children's Hospital, Nieuwegracht 137, 3512 LK Utrecht, The Netherlands. *Former Resident, Institute of Anaesthesiology, University Hospital, University of Utrecht. Present address: De Klokkenberg, Breda, The Netherlands. **Chief Anaesthesiologist, Department of Cardio-Thoracic Surgery, University Hospital and University Children's Hospital, University of Utrecht, The Netherlands. ***Staff member, Institute of Anaesthesiology, University Hospital, and Consultant Anaesthesiologist, Department of Cardio-Thoracic Surgery, University Hospital and University Children's Hospital, University of Utrecht, The Netherlands. ****Head Production and Production Development Plasma Components, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands.
738
Methods Thirty patients presenting for coronary artery bypass grafting were prospectively divided into three groups. The three groups were subjected the same type of premedication, anesthesia, and cannulation and the same method of bypass. All three groups were well matched for age and number of grafts received (Table I). The prime used in all cases consisted of 1,000 ml of SPPS and 1,250 ml of 0.9% sodium chloride. Phenylephrine was used if necessary at the start of bypass in 0.5 to 1 mg increments to maintain an acceptable arterial pressure in all patients. All patients were cooled to 28° C. A minimum of 45 minutes after the start of bypass and administration of phenylephrine, with conditions stable for at least 5 minutes at full flow (2.4 Llm 2 body surface area), and with nasopharyngeal temperature at 28° C, a challenge solution (22° C) was rapidly added to the circulating volume by way of the oxygenator reservoir. In Group A this challenge solution was 250 ml of SPPS. In Group B it was the same, but with 10 ml of Cjesterase inhibitor concentrate added. In Group C 250 ml of 5% human albumin was given. Changes is arterial pressures were noted and compared. These results were analyzed by means of Student's t test.
Results In Group A (SPPS alone) the blood pressure fell rapidly in all cases. Pressure started dropping 45 seconds after administration, reached its lowest point at
0022-5223/80/050738+03$00.30/0
© 1980 The C. V. Mosby Co.
Volume 79 Number5 May, 1980
C1 esterase inhibitor
739
Hageman Factor (XII) ... - - -C 1 Esterase inhibitor Prekallikrein -
Kallikrein
I
- -C1Esterase inhibitor
Kininogen - - - - Kinin Fig. 1. Pathway for kinin formation.
around 2.5 minutes, and returned to the previous value by 5 to 6 minutes. The mean decrease was 42% with a standard deviation of 7.7%. In Group B (SPPS pretreated with Cjesterase inhibitor) the pattern of blood pressure change was the same as in Group A, the mean fall being 6% with a standard deviation of 2.2%. The changes in both groups were highly significant, as was the difference between Groups A and B. In Group C no significant changes were observed. A mean increase of 2% in arterial pressure with a standard deviation of 0.64% is not statistically significant (p > 0.05).
Discussion The first reports on the hypotensive effects of heattreated SPPS during volume replacement in surgical patients and during cardiopulmonary bypass'r': 6, 7 suggested that a vasoactive substance might be present in the solution. Lyophilized plasma," although prepared by another method, had the same effect. The hypotension was thought to be due to vasodilatation caused by a bradykinin-type substance. Izaka and associates" showed that such a substance is present in SPPS and has a molecular weight of 1,000 to 10,000. It is thought to be produced during the heat treatment of the plasma. Alving and associates" suggested that the prekallikrein-activator activity was due to Hageman-factor fragments, with a molecular weight of 35,000. The pathway of kinin production is shown in Fig. 1. The effects of kinins are bronchospasm, vasodilatation, and increased capillary permeability. 10 Kallikreins may have the same effects as kinins but usually with slower onset. 11 In this study we used a Cjesterase inhibitor to determine whether vasodilatation was caused by kinins or not. This component inhibits the production of kinins. These kinins are normally produced and metabolized very rapidly, their half-life being 20 to 30 seconds."
Table I. Data on the three groups of patients involved in this study _ _ _ _ _---II_G_rO_U_p_A_
No. of patients Mean age (yr) Mean weight (kg) No. of coronary bypasses Infusion fluid used
250 mI SPPS
Arterial pressure change ± S.D. Significance
-42% ±7.7% p < 0.001
12 56 73 2.8
Group B
Group C
12 53 75 3.1
6 56 75 3.2
250 ml SPPS plus Cjesterase inhibitor -6% ±2.2% p < 0.05
250ml human albumin +2% <0.6% p > 0.05
Kinases are present in large quantity in plasma, red blood cells, and the pulmonary circulation. We accordingly postulate that the kinins are normally formed and rapidly broken down again from precursors once the SPPS mixes with blood. Human albumin preparations have no kinins or any of their precursors." Pang and associates" have recently shown that a significant rise of circulating bradykinins occurs during cardiopulmonary bypass and hypothermia. In our study, the blood pressure fall was in fact minimized with the administration of Cjesterase inhibited SPPS. This confirms the idea that the vasodilatation was due to kinins produced from the infused plasma. Although we have had no cases of bronchospasm when using SPPS, this is another theoretical problem when SPPS is used for cardiopulmonary bypass or for volume replacement in any patient. Five percent human albumin produced no significant blood pressure change. The slight rise in pressure could be attributed to the slight increase in volume of the system as a whole. Human albumin would appear to be a preferable preparation for use, cost factors aside. This
The Journal of
740
van der Starre et al,
conclusion would apply not only within the limited framework of this investigation, namely cardiopulmonary bypass, but also during volume replacement in hypovolemic situations in general. The routine use of Cjesterase inhibitor with SPPS is not possible because of limited supply and high cost. SPPS should therefore be abandoned in favor of human albumin preparations in all situations, or else one should be prepared to manage all clinically unacceptable hypotension with a vasoconstrictor. A change in the preparation of the plasma solution might eliminate the hypotension-inducing agents.
2 3
4
5
REFERENCES Harrison GA, Robinson M, Stacey RV: Hypotensive effects of stable plasma protein solution (SPPS). A preliminary communication. Med J Aust 2:1040-1041, 1971 Harrison GA, Torda TA, Schiff P: Hypotensive effects of stable plasma protein solution (SPPS). A preliminary communication. Med J Aust 2: 1308-1309, 1971 Bland JHL, Laver MB, Lowenstein E: Hypotension due to 5 percent plasma protein fractions. N Engl J Med 286: 109, 1972 Bland JHL, Laver MB, Lowenstein E: Vasodilator effect of commercial 5% plasma protein fraction solutions. JAMA 224:1721-1724, 1973 Alving BM, Hojima Y, Pisano JJ, Mason BL, Buckingham RE, Mozen MM, Finlayson JS: Hypotension associated with prekallikrein activator (Hageman factor fragments) in plasma protein fraction. N Engl J Med 299:6670, 1978
Thoracic and Cardiovascular Surgery
6 Torda TA, Harrison GA, McCulloch CH, Wright JS, Stacey R, Robertson M: Circulatory effects of stable plasma protein solution (SPPS). Med J Aust 1:798-800, 1973 7 Isbister JP, Biggs JC: Reaction to rapid infusion of stable plasma protein solution during large volume plasma exchange. Anaesth Intensive Care 4: 105-107, 1976 8 Kaye SE: The hypotensive effect of fresh lyophilized plasma. Anaesth Intensive Care 4:196-198, 1976 9 Izaka K, Tsutsui E, Mirna Y, Hasegawa: A bradykininlike substance in heat-treated human plasma protein solution. Transfusion 14:242-248, 1974 10 Haddy FJ, Emerson TE, Scott JB, Daugherty RM: The effect of the kinins on the cardiovascular system, Handbuch der Experimentelle Pharrnakologie: Bradykinin, Kallidin and Kallikrein, Vol 25, EG Erdos, ed., Berlin, 1970, Springer-Verlag, pp 362-384 II Brecher GA, Brobmann GF: Effect of kallikrein on the cardiovascular system, Handbuch der Experimentelle Pharmakologie: Bradykinin, Kallidin and Kallikrein, Vol 25, EG Erdos, ed., Berlin, 1970, Springer Verlag, pp 351-361 12 Ulevitch RJ, Cochrane CG: The chemistry and biology of the proteins of the Hageman factor activated pathways, Comprehensive Immunology: Biological Amplification Systems in Immunology, Vol 2, RA Good, SB Day, eds., New York, 1977, Plenum Medical Book Co. 13 Pang LM, Stalcup A, Upset JS, Hayes CJ, Bowman FO, Mellins RB: Increased circulating bradykinin during hypothermia and cardiopulmonary bypass in children. Circulation 60: 1503-1507, 1979
Copyright information The appearance of a code at the bottom of the first page of an original article in this journal indicates the copyright owner's consent that copies of the article may be made for personal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., 21 Congress Street, Salem, Mass. 01970,617-7443350, for copying beyond that permitted by Sections 107 or 108 of the U. S. Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale.
THORAC CARDIOVASC SURG
79:738-740, 1980
Inhibition of the hypotensive effect of plasma protein solutions by Ciesterase inhibitor The hypotensive effect of stable plasma protein solution (SPPS) is a well-known phenomenon. causing serious problems in surgical patients and patients supported by cardiopulmonary bypass. Kinins are believed to be responsible. A study was made to prevent this hypotension by adding Csesterase inhibitor to the SPPS and comparing this with 5% human albumin. The results show a significant difference between the effects of SPPS and SPPS plus Ciesterase inhibitor infusion on bypass. Five percent human albumin did not cause hypotension. Possible sequelae are discussed.
Peter van der Starre, M.D.,* Donald Sinclair, M.D.,** Johan Damen, M.D.,*** and Henk Brummelhuis, M.D.,**** Utrecht, The Netherlands
Since changing from a blood-saline prime to a plasma-saline prime for cardiopulmonary bypass, we have been troubled by marked hypotension at the start of bypass, necessitating the virtually routine use of a vasopressor to maintain an acceptable blood pressure. Several reports have noted hypotension associated with the rapid infusion of commercially prepared heattreated stable plasma protein solution (SPPS) for volume replacement in surgical patients'<" and in a prospective survey of its use in cardiopulmonary bypass,"- 4, 6 The present study was undertaken to identify the cause of the hypotension and to find a way of preventing it.
From the University of Utrecht, Utrecht, The Netherlands. Received for publication July 3, 1979. Accepted for publication Oct. 2, 1979. Address for reprints: Dr. D. Sinclair, Department ofCardio-Thoracic Surgery, University Children's Hospital, Nieuwegracht 137, 3512 LK Utrecht, The Netherlands. *Former Resident, Institute of Anaesthesiology, University Hospital, University of Utrecht. Present address: De Klokkenberg, Breda, The Netherlands. **Chief Anaesthesiologist, Department of Cardio-Thoracic Surgery, University Hospital and University Children's Hospital, University of Utrecht, The Netherlands. ***Staff member, Institute of Anaesthesiology, University Hospital, and Consultant Anaesthesiologist, Department of Cardio-Thoracic Surgery, University Hospital and University Children's Hospital, University of Utrecht, The Netherlands. ****Head Production and Production Development Plasma Components, Central Laboratory of The Netherlands Red Cross Blood Transfusion Service, Amsterdam, The Netherlands.
738
Methods Thirty patients presenting for coronary artery bypass grafting were prospectively divided into three groups. The three groups were subjected the same type of premedication, anesthesia, and cannulation and the same method of bypass. All three groups were well matched for age and number of grafts received (Table I). The prime used in all cases consisted of 1,000 ml of SPPS and 1,250 ml of 0.9% sodium chloride. Phenylephrine was used if necessary at the start of bypass in 0.5 to 1 mg increments to maintain an acceptable arterial pressure in all patients. All patients were cooled to 28° C. A minimum of 45 minutes after the start of bypass and administration of phenylephrine, with conditions stable for at least 5 minutes at full flow (2.4 Llm 2 body surface area), and with nasopharyngeal temperature at 28° C, a challenge solution (22° C) was rapidly added to the circulating volume by way of the oxygenator reservoir. In Group A this challenge solution was 250 ml of SPPS. In Group B it was the same, but with 10 ml of Cjesterase inhibitor concentrate added. In Group C 250 ml of 5% human albumin was given. Changes is arterial pressures were noted and compared. These results were analyzed by means of Student's t test.
Results In Group A (SPPS alone) the blood pressure fell rapidly in all cases. Pressure started dropping 45 seconds after administration, reached its lowest point at
0022-5223/80/050738+03$00.30/0
© 1980 The C. V. Mosby Co.
Volume 79 Number5 May, 1980
C1 esterase inhibitor
739
Hageman Factor (XII) ... - - -C 1 Esterase inhibitor Prekallikrein -
Kallikrein
I
- -C1Esterase inhibitor
Kininogen - - - - Kinin Fig. 1. Pathway for kinin formation.
around 2.5 minutes, and returned to the previous value by 5 to 6 minutes. The mean decrease was 42% with a standard deviation of 7.7%. In Group B (SPPS pretreated with Cjesterase inhibitor) the pattern of blood pressure change was the same as in Group A, the mean fall being 6% with a standard deviation of 2.2%. The changes in both groups were highly significant, as was the difference between Groups A and B. In Group C no significant changes were observed. A mean increase of 2% in arterial pressure with a standard deviation of 0.64% is not statistically significant (p > 0.05).
Discussion The first reports on the hypotensive effects of heattreated SPPS during volume replacement in surgical patients and during cardiopulmonary bypass'r': 6, 7 suggested that a vasoactive substance might be present in the solution. Lyophilized plasma," although prepared by another method, had the same effect. The hypotension was thought to be due to vasodilatation caused by a bradykinin-type substance. Izaka and associates" showed that such a substance is present in SPPS and has a molecular weight of 1,000 to 10,000. It is thought to be produced during the heat treatment of the plasma. Alving and associates" suggested that the prekallikrein-activator activity was due to Hageman-factor fragments, with a molecular weight of 35,000. The pathway of kinin production is shown in Fig. 1. The effects of kinins are bronchospasm, vasodilatation, and increased capillary permeability. 10 Kallikreins may have the same effects as kinins but usually with slower onset. 11 In this study we used a Cjesterase inhibitor to determine whether vasodilatation was caused by kinins or not. This component inhibits the production of kinins. These kinins are normally produced and metabolized very rapidly, their half-life being 20 to 30 seconds."
Table I. Data on the three groups of patients involved in this study _ _ _ _ _---II_G_rO_U_p_A_
No. of patients Mean age (yr) Mean weight (kg) No. of coronary bypasses Infusion fluid used
250 mI SPPS
Arterial pressure change ± S.D. Significance
-42% ±7.7% p < 0.001
12 56 73 2.8
Group B
Group C
12 53 75 3.1
6 56 75 3.2
250 ml SPPS plus Cjesterase inhibitor -6% ±2.2% p < 0.05
250ml human albumin +2% <0.6% p > 0.05
Kinases are present in large quantity in plasma, red blood cells, and the pulmonary circulation. We accordingly postulate that the kinins are normally formed and rapidly broken down again from precursors once the SPPS mixes with blood. Human albumin preparations have no kinins or any of their precursors." Pang and associates" have recently shown that a significant rise of circulating bradykinins occurs during cardiopulmonary bypass and hypothermia. In our study, the blood pressure fall was in fact minimized with the administration of Cjesterase inhibited SPPS. This confirms the idea that the vasodilatation was due to kinins produced from the infused plasma. Although we have had no cases of bronchospasm when using SPPS, this is another theoretical problem when SPPS is used for cardiopulmonary bypass or for volume replacement in any patient. Five percent human albumin produced no significant blood pressure change. The slight rise in pressure could be attributed to the slight increase in volume of the system as a whole. Human albumin would appear to be a preferable preparation for use, cost factors aside. This
The Journal of
740
van der Starre et al,
conclusion would apply not only within the limited framework of this investigation, namely cardiopulmonary bypass, but also during volume replacement in hypovolemic situations in general. The routine use of Cjesterase inhibitor with SPPS is not possible because of limited supply and high cost. SPPS should therefore be abandoned in favor of human albumin preparations in all situations, or else one should be prepared to manage all clinically unacceptable hypotension with a vasoconstrictor. A change in the preparation of the plasma solution might eliminate the hypotension-inducing agents.
2 3
4
5
REFERENCES Harrison GA, Robinson M, Stacey RV: Hypotensive effects of stable plasma protein solution (SPPS). A preliminary communication. Med J Aust 2:1040-1041, 1971 Harrison GA, Torda TA, Schiff P: Hypotensive effects of stable plasma protein solution (SPPS). A preliminary communication. Med J Aust 2: 1308-1309, 1971 Bland JHL, Laver MB, Lowenstein E: Hypotension due to 5 percent plasma protein fractions. N Engl J Med 286: 109, 1972 Bland JHL, Laver MB, Lowenstein E: Vasodilator effect of commercial 5% plasma protein fraction solutions. JAMA 224:1721-1724, 1973 Alving BM, Hojima Y, Pisano JJ, Mason BL, Buckingham RE, Mozen MM, Finlayson JS: Hypotension associated with prekallikrein activator (Hageman factor fragments) in plasma protein fraction. N Engl J Med 299:6670, 1978
Thoracic and Cardiovascular Surgery
6 Torda TA, Harrison GA, McCulloch CH, Wright JS, Stacey R, Robertson M: Circulatory effects of stable plasma protein solution (SPPS). Med J Aust 1:798-800, 1973 7 Isbister JP, Biggs JC: Reaction to rapid infusion of stable plasma protein solution during large volume plasma exchange. Anaesth Intensive Care 4: 105-107, 1976 8 Kaye SE: The hypotensive effect of fresh lyophilized plasma. Anaesth Intensive Care 4:196-198, 1976 9 Izaka K, Tsutsui E, Mirna Y, Hasegawa: A bradykininlike substance in heat-treated human plasma protein solution. Transfusion 14:242-248, 1974 10 Haddy FJ, Emerson TE, Scott JB, Daugherty RM: The effect of the kinins on the cardiovascular system, Handbuch der Experimentelle Pharrnakologie: Bradykinin, Kallidin and Kallikrein, Vol 25, EG Erdos, ed., Berlin, 1970, Springer-Verlag, pp 362-384 II Brecher GA, Brobmann GF: Effect of kallikrein on the cardiovascular system, Handbuch der Experimentelle Pharmakologie: Bradykinin, Kallidin and Kallikrein, Vol 25, EG Erdos, ed., Berlin, 1970, Springer Verlag, pp 351-361 12 Ulevitch RJ, Cochrane CG: The chemistry and biology of the proteins of the Hageman factor activated pathways, Comprehensive Immunology: Biological Amplification Systems in Immunology, Vol 2, RA Good, SB Day, eds., New York, 1977, Plenum Medical Book Co. 13 Pang LM, Stalcup A, Upset JS, Hayes CJ, Bowman FO, Mellins RB: Increased circulating bradykinin during hypothermia and cardiopulmonary bypass in children. Circulation 60: 1503-1507, 1979
Copyright information The appearance of a code at the bottom of the first page of an original article in this journal indicates the copyright owner's consent that copies of the article may be made for personal or internal use, or for the personal or internal use of specific clients. This consent is given on the condition, however, that the copier pay the stated per copy fee through the Copyright Clearance Center, Inc., 21 Congress Street, Salem, Mass. 01970,617-7443350, for copying beyond that permitted by Sections 107 or 108 of the U. S. Copyright Law. This consent does not extend to other kinds of copying, such as copying for general distribution, for advertising or promotional purposes, for creating new collective works, or for resale.