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Prostacyclin infusion during cardiopulmonary bypass in man
0049-3848/80/130267-04$02.00/O TKROMBOSISRESEARCH 19; 267-270, 1980 Printed in the USA. All rights reserved. Copyright (c) 1980 Pergamon Press Ltd
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COMMUNICATION
PROSTACYCLIN INFUSION DURING CARDIOPULMONARY BYPASS IN MAN
D K. RSdegran and C. Papaconstantinou Thoracic Surgical Clinic, Karolinska sjukhuset, 104 01 Stockholm 60, Sweden (Received 18.4.1980.Accepted by Editor U. Abildgaard) INTRODUCTION The thrtnabocytopenia and platelet dysfunction often observed during and after cardiopulmonary bypass (CPB) have been thought to contribute to bleeding co!nplications following open heart surgery. Pharmacologic protection of platelets by inhibition of their activation by certain stimuli might diminish blood loss in cardiac surgery provided that the hemostatic function of the platelets is not simultaneously inhibited or at least rapidly reversible following CPB. Prostacyclin seems to fulfill these criteria since it has been shown to protect platelet function and improve hemostasis during and after CPE in dogs (1). The present study (approved by the Ethics carmittee of the Karolinska Hospital) reports on some of our initial experiences with prostacyclin administration during CPB in cardiac surgery patients. The major objective of the study was to find a safe, effective and convenient method of administration of prostacyclin. Preservation of the platelet count during CPB was chosen as the main indicator of the effect of prostacyclin. MATERIALS AND METHODS The study comprises 29 adult patients undergoing cardiac surgery for aquired heart disease during the period June - November 1979. Anaesthesia was initiated and maintained with i.v. fentanyl and diazepam. Extracorporeal circulation was performed with a roller pump and Shdley 100 A bubble oxygenator primed with Ringer-acetate. Hypothermia to 25 C was induced in all patients. The gas to blood flow ratio in the oxygenator was kept at 1:l 1,4:1. Heparin was administered as a single bolus of 3 mg/kg b.w. before cannulation plus 50 mg added to the pump prime. Anticoagulation was checked iyJActivated Clotting Time (Hemchron (R), Int. Technidyne Corp., Metuchen, U.S.A.) Following bypass protamine chloride was given in a 1:l ratio . to ;Ajected heparin.
Key words: prostacyclin, cardiopulmonary bypass, man
267
PROSTACYCLINDURING CPB
268
Vo1.19, No.1/2
Blood samples for platelet count in blood and hematocrit were drawn into plastic syringes containingACD solution (I part to 9 parts of blood) from a wide bore cannula in the superior vena cava and during CPB from the venous line of the extracorporeal circuit. The platelets were counted with the aid of a Linson 431 A cell counter (Linson Instrument AB, Stockholm Sweden). The platelet counts were corrected for hemodilution with the aid of a factor derived from the hematocrit determinations. Prostacyclin (courtesy of UpJohn Ltd. Crawley, England) 1000 nanogram/ml #as dissolved in a glycine buffer (pH 10.5) no earlier than 48 hours before use, subjected to sterile filtration and kept refrigerated until use. Dosage and mode of administration is described below. Grou 1. Seven patients did not receive prostacyclin, but were otherwise trea& same way as patients to whom prostacyclin was admin'otered. Grou 2. Ten patientsreceived prostacyclin 2 - 20 ng -kg b.w.- I min-l by in *-Ts-. uslon into the right atrium from 15 minutes before and during the entire CPB period. Grou 3. Twelve patientsreceived prostacyclin 50 ng - kg b.w.-1 - min-1 into+ venous line of the extracorporeal circuit from start of bypass until 30 minutes on bypass only. Statistics. Data reported as mean 2 standard deviation. Significance testing by Student's t-test. ** = p < 0.01, *** = p < 0.001.. ??
RESULTS In patients receiving up to 20 ng. kg b.w.'l- min-1 of prostacyclin during CPB (group 2) the platelet count of blood, corrected for hemodilution, was not consistently better preserved than in control patients. There was no ticreasedbleeding tendency during or after CPB. One patient was reoperated for surgical bleedin . Otherwise all patients made an uneventful retovary._, 0 min Twelve patients 9group 3) received prostacyclin SO ng kg b.w. during the first 30 minutes of bypass only. The platelet count of blood was consistently better preserved in these patients than in the other patients (TABLE I ).The activated clotting time was after 10 minutes on $PB constantly above 1000 seconds in group 3 patients as compared with 544 - 117 seconds in control patients. There was noincreased bleeding tendency from cut surfaces or increased intraoperative blood loss in group 3 patients as compared with controls. Prostacyclin caused a pronounced fall in systemic vascular resistance (SVR calculated as mean arterial pressure in mn Hg divided by pump flow in l/min) resulting in lower arterial blood pressure and higher bypass flow than in control patients (TABLE II). One patient was reoperated for bleeding from a periosteal vessel. One patient died intraoperatively from myocardial infarction following initially successful coronary revascularization and weaning from CPB. All other patients recovered uneventfully. ??
TABLE I Platelet count, corrected for hemodilution, in % of pre-bypass value at 30, 60 and 90 minutes on CPB as well as 60 minutes after CPB. 30' Group 1 Group 3
67 ; 18 90 - 13**
60' + 19 ;; + 14**
90'
After CPB
59 + 17 + 10 93 + 11*** ;: + 11***
269
PROSTACYCLINDURING CPB
Vo1.19, No.1/2
TABLE II Data recorded at 30 minutes on bypass
P Ao' m
Hg
CPB flow, l/min
Group 1
Group 2
Group 3
54 + 19
43 + 16
26 + g**
2.5 c 0.7
2.6 2 0.4
3.1 r 0.6
SVR
24 + 15
17 +6
Hct, %
28 + 3
28 + 3
g + 3** 28 + 4
DISCUSSION Thrombocytopenia and loss of platelet function resultin from CPB have been thought to contribute to intra- and postoperative blee3.ing in cardiac surgery (2). Drugs with platelet anti-aggregatory properties such as dipyridamole have been tried with limited success to diminish platelet loss during CPB (3). Acetylshlicylic acid may even increase postoperative bleeding (4). In experimental studies,inhibition of platelet activation during CPB by infusion of prostaglandin El (5) has been shown, however, to result in significant protection of platelet number and function. Longmore et al. (1) using prostacyclin (prostaglandln 12) during CPB in dogs found pronounced beneficial effects on preservation of platelets as well as on hemostasis. Since little information was available concerning suitable dosage of prostacyflin d_ujing CP8 in man we started very cautiously.with only 2 nge kg b.w. min but since no complications occurred rapidly progre sed to administration 0; higher doses. However, even 20 ng kg b.w.‘l amin' f of prostacyclin did not result in a consistent protection of the platelet count during CPB. A still higher dose was therefore employed, but for the first 30 minutes of bypass only. By this mode of administration we were expecting to demonstrate a protective effect, if any, on the platelet count during the first 30 minutes of bypass and a fall in platelet count thereafter. To our surprise the platelet counts were consist ntly b tter preserved in patients receiving prostacyclin 50 ng . kg b.w.-fi min'P during as well as after prostacyclin infusion, even though bypass often continued for an hour longer. Although prostacyclin itself may be rapidly degraded in vivo (6), its effect on the platelets may be longer lasting. In spite of the inhibitory effect on platelets, no bleeding tendency was noted during or after prostacyclin infusion. In fact, slightly less postoperative drainage from the chest tubes was observed, although the number of patients is far to small to allow any definite conclusion. Prostacyclin has effects not only on platelets and hemostasis, but also on the circulatory system. We observed very low sy temic ascular resistance during infusion of prostacyclin 50 ng *kg b.w. -f . min' Y resulting in often very low perfusion pressures on CPB. This did not result in any evidence of nervous or other organ damage after bypass, however. Although we have as yet limited experience with the use of prostacyclin during CPB, the early results are encouraging enough to allow further studies not only in regard to hemostasis but also in regard to the function of various organs after CPB. ??
??
??
270
PROSTACYCLIN DURING CPB
Vo1.19,
No.112
REFERENCES 1. LONGMORE,D.B., BENNET, G., GUEIRRARA,D., SMITH, M., BUNTING, S., MONCADA, S., REED, P., READ, N.G., VANE, J.E. Prostacyclin:A solution to some problems of extracoroorealcirculation.Exwriments in arevhounds. LANCET 1; 1002-1005,1979. ' 2. BICK, R.L., SCHMALHORST,W.R. and ARBEGAST, N.R. Alterationsof hemostasis associatedwith cardiopulmonarybypass. ThrombosisRes. a, 285-302, 1976. 3. NUUTINEN,L.S. and MONONEN, P. Dipyridamoleand thrombocytecount in open heart surgery. J. Thor. Cardiouasc.Surg. 70, 707-711, 1975. 4. MICHELSON,E.L., MORGANROTH,J., TOROSIAN,M. and MACVAUGH III, H. Relationof preoperativeuse of aspirin to increasedmediastinalblood loss after coronary artery bypass graft surgery. J. Thor. Cardiovasc. Surg. 2, 694-697, 1978. 5. ADDONIZIO,V.P., STRAUSS, J.F., COLMAN, R.W. and EDMUNDS,L.H. Effects of prostaglandinEl on platelet loss during in vivo and in vitro extracorporealcirculationwith a bubble oxygenator.J. Thor. Cardiovasc.Surg. a, 119-126, 1979. 6. DUSTING,G.J., MONCADA, S. and VANE, J.R. Disappearanceof prostacyclin (PGIE) in the circulationof the dog. Br. J. Pharmacol.62(3), 414P-415P, 1978.
BRIEF
COMMUNICATION
PROSTACYCLIN INFUSION DURING CARDIOPULMONARY BYPASS IN MAN
D K. RSdegran and C. Papaconstantinou Thoracic Surgical Clinic, Karolinska sjukhuset, 104 01 Stockholm 60, Sweden (Received 18.4.1980.Accepted by Editor U. Abildgaard) INTRODUCTION The thrtnabocytopenia and platelet dysfunction often observed during and after cardiopulmonary bypass (CPB) have been thought to contribute to bleeding co!nplications following open heart surgery. Pharmacologic protection of platelets by inhibition of their activation by certain stimuli might diminish blood loss in cardiac surgery provided that the hemostatic function of the platelets is not simultaneously inhibited or at least rapidly reversible following CPB. Prostacyclin seems to fulfill these criteria since it has been shown to protect platelet function and improve hemostasis during and after CPE in dogs (1). The present study (approved by the Ethics carmittee of the Karolinska Hospital) reports on some of our initial experiences with prostacyclin administration during CPB in cardiac surgery patients. The major objective of the study was to find a safe, effective and convenient method of administration of prostacyclin. Preservation of the platelet count during CPB was chosen as the main indicator of the effect of prostacyclin. MATERIALS AND METHODS The study comprises 29 adult patients undergoing cardiac surgery for aquired heart disease during the period June - November 1979. Anaesthesia was initiated and maintained with i.v. fentanyl and diazepam. Extracorporeal circulation was performed with a roller pump and Shdley 100 A bubble oxygenator primed with Ringer-acetate. Hypothermia to 25 C was induced in all patients. The gas to blood flow ratio in the oxygenator was kept at 1:l 1,4:1. Heparin was administered as a single bolus of 3 mg/kg b.w. before cannulation plus 50 mg added to the pump prime. Anticoagulation was checked iyJActivated Clotting Time (Hemchron (R), Int. Technidyne Corp., Metuchen, U.S.A.) Following bypass protamine chloride was given in a 1:l ratio . to ;Ajected heparin.
Key words: prostacyclin, cardiopulmonary bypass, man
267
PROSTACYCLINDURING CPB
268
Vo1.19, No.1/2
Blood samples for platelet count in blood and hematocrit were drawn into plastic syringes containingACD solution (I part to 9 parts of blood) from a wide bore cannula in the superior vena cava and during CPB from the venous line of the extracorporeal circuit. The platelets were counted with the aid of a Linson 431 A cell counter (Linson Instrument AB, Stockholm Sweden). The platelet counts were corrected for hemodilution with the aid of a factor derived from the hematocrit determinations. Prostacyclin (courtesy of UpJohn Ltd. Crawley, England) 1000 nanogram/ml #as dissolved in a glycine buffer (pH 10.5) no earlier than 48 hours before use, subjected to sterile filtration and kept refrigerated until use. Dosage and mode of administration is described below. Grou 1. Seven patients did not receive prostacyclin, but were otherwise trea& same way as patients to whom prostacyclin was admin'otered. Grou 2. Ten patientsreceived prostacyclin 2 - 20 ng -kg b.w.- I min-l by in *-Ts-. uslon into the right atrium from 15 minutes before and during the entire CPB period. Grou 3. Twelve patientsreceived prostacyclin 50 ng - kg b.w.-1 - min-1 into+ venous line of the extracorporeal circuit from start of bypass until 30 minutes on bypass only. Statistics. Data reported as mean 2 standard deviation. Significance testing by Student's t-test. ** = p < 0.01, *** = p < 0.001.. ??
RESULTS In patients receiving up to 20 ng. kg b.w.'l- min-1 of prostacyclin during CPB (group 2) the platelet count of blood, corrected for hemodilution, was not consistently better preserved than in control patients. There was no ticreasedbleeding tendency during or after CPB. One patient was reoperated for surgical bleedin . Otherwise all patients made an uneventful retovary._, 0 min Twelve patients 9group 3) received prostacyclin SO ng kg b.w. during the first 30 minutes of bypass only. The platelet count of blood was consistently better preserved in these patients than in the other patients (TABLE I ).The activated clotting time was after 10 minutes on $PB constantly above 1000 seconds in group 3 patients as compared with 544 - 117 seconds in control patients. There was noincreased bleeding tendency from cut surfaces or increased intraoperative blood loss in group 3 patients as compared with controls. Prostacyclin caused a pronounced fall in systemic vascular resistance (SVR calculated as mean arterial pressure in mn Hg divided by pump flow in l/min) resulting in lower arterial blood pressure and higher bypass flow than in control patients (TABLE II). One patient was reoperated for bleeding from a periosteal vessel. One patient died intraoperatively from myocardial infarction following initially successful coronary revascularization and weaning from CPB. All other patients recovered uneventfully. ??
TABLE I Platelet count, corrected for hemodilution, in % of pre-bypass value at 30, 60 and 90 minutes on CPB as well as 60 minutes after CPB. 30' Group 1 Group 3
67 ; 18 90 - 13**
60' + 19 ;; + 14**
90'
After CPB
59 + 17 + 10 93 + 11*** ;: + 11***
269
PROSTACYCLINDURING CPB
Vo1.19, No.1/2
TABLE II Data recorded at 30 minutes on bypass
P Ao' m
Hg
CPB flow, l/min
Group 1
Group 2
Group 3
54 + 19
43 + 16
26 + g**
2.5 c 0.7
2.6 2 0.4
3.1 r 0.6
SVR
24 + 15
17 +6
Hct, %
28 + 3
28 + 3
g + 3** 28 + 4
DISCUSSION Thrombocytopenia and loss of platelet function resultin from CPB have been thought to contribute to intra- and postoperative blee3.ing in cardiac surgery (2). Drugs with platelet anti-aggregatory properties such as dipyridamole have been tried with limited success to diminish platelet loss during CPB (3). Acetylshlicylic acid may even increase postoperative bleeding (4). In experimental studies,inhibition of platelet activation during CPB by infusion of prostaglandin El (5) has been shown, however, to result in significant protection of platelet number and function. Longmore et al. (1) using prostacyclin (prostaglandln 12) during CPB in dogs found pronounced beneficial effects on preservation of platelets as well as on hemostasis. Since little information was available concerning suitable dosage of prostacyflin d_ujing CP8 in man we started very cautiously.with only 2 nge kg b.w. min but since no complications occurred rapidly progre sed to administration 0; higher doses. However, even 20 ng kg b.w.‘l amin' f of prostacyclin did not result in a consistent protection of the platelet count during CPB. A still higher dose was therefore employed, but for the first 30 minutes of bypass only. By this mode of administration we were expecting to demonstrate a protective effect, if any, on the platelet count during the first 30 minutes of bypass and a fall in platelet count thereafter. To our surprise the platelet counts were consist ntly b tter preserved in patients receiving prostacyclin 50 ng . kg b.w.-fi min'P during as well as after prostacyclin infusion, even though bypass often continued for an hour longer. Although prostacyclin itself may be rapidly degraded in vivo (6), its effect on the platelets may be longer lasting. In spite of the inhibitory effect on platelets, no bleeding tendency was noted during or after prostacyclin infusion. In fact, slightly less postoperative drainage from the chest tubes was observed, although the number of patients is far to small to allow any definite conclusion. Prostacyclin has effects not only on platelets and hemostasis, but also on the circulatory system. We observed very low sy temic ascular resistance during infusion of prostacyclin 50 ng *kg b.w. -f . min' Y resulting in often very low perfusion pressures on CPB. This did not result in any evidence of nervous or other organ damage after bypass, however. Although we have as yet limited experience with the use of prostacyclin during CPB, the early results are encouraging enough to allow further studies not only in regard to hemostasis but also in regard to the function of various organs after CPB. ??
??
??
270
PROSTACYCLIN DURING CPB
Vo1.19,
No.112
REFERENCES 1. LONGMORE,D.B., BENNET, G., GUEIRRARA,D., SMITH, M., BUNTING, S., MONCADA, S., REED, P., READ, N.G., VANE, J.E. Prostacyclin:A solution to some problems of extracoroorealcirculation.Exwriments in arevhounds. LANCET 1; 1002-1005,1979. ' 2. BICK, R.L., SCHMALHORST,W.R. and ARBEGAST, N.R. Alterationsof hemostasis associatedwith cardiopulmonarybypass. ThrombosisRes. a, 285-302, 1976. 3. NUUTINEN,L.S. and MONONEN, P. Dipyridamoleand thrombocytecount in open heart surgery. J. Thor. Cardiouasc.Surg. 70, 707-711, 1975. 4. MICHELSON,E.L., MORGANROTH,J., TOROSIAN,M. and MACVAUGH III, H. Relationof preoperativeuse of aspirin to increasedmediastinalblood loss after coronary artery bypass graft surgery. J. Thor. Cardiovasc. Surg. 2, 694-697, 1978. 5. ADDONIZIO,V.P., STRAUSS, J.F., COLMAN, R.W. and EDMUNDS,L.H. Effects of prostaglandinEl on platelet loss during in vivo and in vitro extracorporealcirculationwith a bubble oxygenator.J. Thor. Cardiovasc.Surg. a, 119-126, 1979. 6. DUSTING,G.J., MONCADA, S. and VANE, J.R. Disappearanceof prostacyclin (PGIE) in the circulationof the dog. Br. J. Pharmacol.62(3), 414P-415P, 1978.