Dipyridamole preserved platelets and reduced blood loss after cardiopulmonary bypass

J

THORAC CARDIOVASC SURG

1988;96:332-41

Dipyridamole preserved platelets and reduced blood loss after cardiopulmonary bypass Cardiopulmonary bypass activates and depletes platelets, which may contribute to postoperativebleeding. In addition, activated platelets may be deposited in the coronary vasculature after ischemia and cardioplegia, which may delay recovery of cardiac function and metabolism and may contribute to early bypass graft occlusion. The antiplatelet agent dipyridamole reduces platelet activation and depletion and may decrease postoperative bleeding and transfusion requirements. A prospective randomized trial was conducted in 58 patients undergoingelective coronary bypass operations to compare the effects of oral (19 patients) and intravenous(21 patients) dipyridamoleto the results obtained in a control group (18 patients) who received no dipyridamole. Preoperative oral administration of dipyridamole resulted in lower plasma drug concentrations in the early postoperative period than perioperative intravenous administration (p = 0.0001 by analysis of variance). Postoperative arterial platelet counts were highest in the patients receiving intravenous dipyridamole, intermediate in those receiving oral dipyridamole, and lowest in the control group (p = 0.03 by analysis of variance). Postoperative blood loss and blood product transfusions were significantly reduced with both oral and intravenousdipyridamole (p = 0.04 by analysis of variance), Dipyridamolepreservedplatelets and reduced postoperativebleeding. Intravenous dipyridamoleresulted in higher platelet counts than oral dipyridamole and may be required to reduce postoperative bleeding in high-risk patients.

Kevin H. Teoh, MD, George T. Christakis, MD, Richard D. Weisel, MD, Pui-Yuen Wong, PhD, A. Vickie Mee, RT, Joan Ivanov, RN, M. Mindy Madonik, BSc, David S. Levitt, MD, Paul A. Reilly, PhD, Jack M. Rosenfeld, PhD, and Michael F. X. Glynn, MD, PhD, Toronto, Ontario, Canada

CardiOPUlmonary bypass activates and injures platelets, which may contribute to postoperative bleeding.!" Activated platelets may deposit on damaged or perturbed vascular endothelium and they may aggregate, fragment and release emboli into the microcirculation." Platiet deposition in the heart may promote electrical

From the Divisions of Cardiovascular Surgery and Hematology and the Departments of Clinical Biochemistry and Pharmacology, the Toronto General Hospital and the University of Toronto, Toronto, Ontario, Canada. Supported by the Heart and Stroke Foundation of Ontario (Grant T760) and the Canadian Heart Foundation. Presented in part at the Thirty-fifth Annual Scientific Session of the American College of Cardiology, Atlanta, Ga., March 1986. Received for publication July 2, 1987. Accepted for publication Dec. 16, 1987. Address for reprints: Richard D. Weisel, MD, Cardiovascular Surgery, Toronto General Hospital, 200 Elizabeth St., Eaton North 13-224, Toronto, Ontario M5G 2C4, Canada.

332

Table I. Clinical information Dipyridamole

No. of patients Age (yr) Male sex (%) NYHA (l/ll/ll/IV) CPB time (min) XCL time (min)

Control

Oral

Intravenous

18 61.6 ± 8.4 14 (77.8) 1/5/9/3

19 56.9 ± 6.3 14 (73.7) 1/8/9/1

21 57.1 ± 8.7 18 (85.7) 1/8/8/4

118 ± 30

104 ± 25

107 ± 35

66 ± 21

57 ± 14

62 ± 21

There were no differences between treatment groups. Values are reported as mean ± standard deviation. NYHA. New York Heart Association functional class: CPS. cardiopulmonary bypass: XCL, aortic cross-clamp,

instability or induce coronary spasm and platelet aggregation in vein grafts may foster early graft occlusion.>' Platelet deposition in the systemic circulation and in the bypass circuit may contribute to the thrombocytopenia

Volume 96 Number 2

Perioperative dipyridamole

August 1988

, ,

I I I I I

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10900 1400 10900 1400 0900

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+

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J

I

I 3 nAYS I POSTOP I

Fig. 1. Dosage regimens for oral and intravenous dipyridamole are depicted. ASA, acetylsalicylic acid; po, oral; OR. operating room; lCU, postoperative intensive care unit; hr, hours postoperative; NC, nasogastric tube; CPB,

cardiopulmonary bypass; XCI, aortic cross-clamp.

seen postoperativley.v? Platelet activation and depletion may be so severe as to contribute to postoperative bleeding. Hemostasis may be further compromised by the functional impairment of the remaining platelets.'? Platelet-inhibiting agents may preserve platelet counts during cardiopulmonary bypass by preventing platelet aggregation on foreign surfaces and at sites of endothelial injury. Antiplatelet agents such as aspirin (in high doses) that inhibit platelet adhesion and other hemostatic functions may increase postoperative bleeding. However, antiplatelet agents that preserve platelet adhesion, such as dipyridamole, may reduce postoperative bleeding and decrease the incidence of early coronary bypass graft occlusion. Dipyridamole, a pyridopyrimidine compound, limits platelet activation, aggregation, and granular release. The agent inhibits platelet phosphodiesterase activity, increases platelet cyclic adenosine monophosphate concentrations, and decreases calcium mobilization.I I, 12 Dipyridamole preserves platelet adhesion and therefore does not inhibit platelet hemostatic functions." Chesebroand colleagues? have demonstrated that preoperative oral dipyridamole (400 mg/day) and postoperative dipyridamole (225 rug/day) and aspirin (975 mg/day) improved early bypass graft patency. Unfortunately blood concentrationsof the drug were not measured and its effects on platelet counts were not reported. Preoperative oral administration may result in inadequate blood concentrations during cardiopulmonary bypass." An intravenous infusion may provide more uniform periop-

erative blood concentrations. However, the discontinuous and abrupt variations in blood levels associated with oral administration may provide better perioperative platelet protection. Therefore we instituted a prospective randomized trial in 58 patients undergoing elective coronary bypass procedures to compare the effects of oral and intravenous dipyridamole to the results obtained in a control group who received no dipyridamole. We evaluated perioperative plasma drug levels; thrombocyte, leukocyte, and erythrocyte counts; two platelet products (thromboxane B2 and platelet factor 4); and postoperative blood lossand transfusion requirements. Patients and methods

Fifty-eight patients scheduled for elective coronary bypass grafting agreed to participate in the triaL Each patient signed a consent form approved by the institutional human experimentation committee. Patients were eligible for the study if they had stable angina pectoris and double- or triple-vessel coronary arterydisease. Patients were excluded from the study if they were receiving aspirin or other antiplatelet agents during theweek before theoperation or if they had a history of hypersensitivity to dipyridamole or aspirin. Patients were randomized to receive intravenous dipyridamole* (21 patients), oral dipyridamole (19 patients), or no dipyridamole (18 patients, control). The dipyridamole dosage regimens are depicted in Fig. 1. Oral dipyridamole was given according to the protocol described by Chesebro and col*Dipyridamole and support were provided by Boehringer Ingelheim (Canada) Ltd., Burlington, Ontario.

334

The Journal of Thoracic and Cardiovascular Surgery

Teoh et al.

2.5 .....J

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4 hr I 09:00 14:00 I 09:00 14:00 09:00 CPS POST POST POST I 1 DAY , 2 DAYS ·3 DAYS XCl CPS XCl I POSTOP ~ POSTOP ,POSTOP

Fig. 2. Plasma dipyridamole concentrations (mean ± standard error) are illustrated. Intravenous administration resulted in more stable drug levels perioperatively (see Fig. I for abbreviations).

leagues.' Dipyridamole (100 mg) was instituted 36 hours before the operation and was given orally 4 times a day. On the morning of the operation the last preoperative oral dose was given with the antianginal medication. No dipyridamole was given intraoperatively. At 4 and II hours after cross-clamp release (corresponding to I and 7 hours postoperatively in the Chesebro report") a 100 mg tablet was crushed. suspended in water, and injected into the nasogastric tube after the stomach had been emptied. The nasogastric tube was flushed and clamped for 2 hours to permit gastric absorption. Aspirin (acetylsalicylic acid, 325 mg) was given with the II-hour postoperative dose of dipyridamole in the oral group. The patients randomized to receive intravenous dipyridamole had an infusion begun at a rate of 0.24 mg/kg/hr (400 mg/day in a 70 kg patient) 22 hours preoperatively, which was continued at that rate intraoperatively and postoperatively until 9:00 AM on the first postoperative day. The intravenous dose was based on previous work at our institution that demonstrated the safety and the effectiveness of this dose on perioperative platelet preservation." Beginning on the first postoperative day, dipyridamole (75 mg) and aspirin (325 mg) was given orally three times daily in both groups. The control group received neither dipyridamole nor aspirin. Perioperative patient management, The anesthetic management and conduct of cardiopulmonary bypass has been previously reported. IS Anesthesia was induced with fentanyl citrate (75 Ilg/kg) and pancuronium bromide (100 Ilg/kg). Ventilation was maintained with 100% oxygen, and isoflurane was added when necessary. Left atrial, radial arterial, and central venous pressure catheters were inserted intraoperative-

Iy. Heparin was administered at an initial dose of 300 units/kg, and the activated clotting time* was maintained greater than 400 seconds. Cardiopulmonary bypass was instituted with a two-staged right atrial and an ascending aortic cannula. A roller pump maintained nonpulsatile flows between 2.0 and 2.4 L/min/m 2• Phenylephrine or nitroprusside was used to maintain the mean arterial pressure between 60 and 85 mm Hg during cardiopulmonary bypass. Since platelet counts may be affected by the type of oxygenator employed,' patients were stratified to receive either a bubblet (25 patients) or a membranet (33 patients) oxygenator to provide an equal number of each oxygenator in each treatment group. Multidose cold crystalloid cardioplegia was employed for myocardial protection. Systemic hypothermia (25 0 C) was maintained during aortic occlusion. After discontinuation of cardiopulmonary bypass, heparin was reversed with protamine sulfate (I mg/kg); half the dose was given as a bolus and half by slow intravenous infusion. Postoperative management was directed by the surgeon and the intensive care unit physician who followed established guidelines for volume replacement and transfusions.t"" The left atrial pressure was maintained between 8 and 10 mm Hg by infusions of albumin or plasma since this pressure was found to be optimal for patients after elective coronary bypass *Hemochron, International Technidyne Corp., Edison. N.J. tShiley SIOOA, Shiley Inc., Irvine. Calif. :j:Bentley CM50. Bentley Laboratories. Inc.. Division of Baxter Healthcare Corporation. Irvine. Calif.

Volume 96 Number 2

Perioperative dipyridamole

August 1988

335

.6. IV • Oral • Control * p < 0.05 Different than Control t p<0.05 Different than IV - - - Lower Limit of Normal Range

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08:00 4 hr 09:00 14:00 09:00 14:00 09:00 1 DAY PRE CPS POST POST POST 1 DAY 2 DAYS 3 DAYS PREOP OP XCL CPS XCL POSTOP POSTOP POSTOP

Fig. 3. Arterial platelet counts (mean ± standard error) are illustrated. Dipyridamole preserved circulating platelets. Platelet counts were sigificantly higher with intravenous than oral dipyridamole on postoperative days 2 and 3 (see Fig. I for abbreviations).

grafting." Packed red cells were transfused if the hemoglobin level fell below 100 gmjL since lower levels were found to produce ischemic myocardial metabolism. I? Cryoprecipitate and platelets were infused in two patients in the control group, which controlled postoperative bleeding resulting from a coagulopathy. No patient had excessive bleeding and none required reoperation for bleeding. Postoperative blood loss and the number of units of blood products transfused were recorded prospectively. Potential complications of dipyridamole administration were investigated in each patient. Measurements. Blood was collected by venipuncture preoperatively and from the radial arterial catheter during and after the operation. Blood for platelet, leukocyte, and erythrocyte counts was collected in tubes containing ethylenediaminetetraacetic acid and analyzed by a Coulter counter. * Specimens for thromboxane B2, 6-keto-prostaglandin F 'a (6-keto-PGF ,a), platelet factor 4, and dipyridamole were collected in 10 ml glass tubes containing 0.033 mg of ethylenediaminetetraacetic acid, 1.6 mg of theophylline, 0.25 mg of 2-chloroadenosine, and 3.6 mg of indomethacin. The samples were spun in a refrigerated centrifuge at 1000 rpm for 10 minutes. The plasma (free of the buffy coat) was pipetted and stored at -20 0 C until analyzed. Thromboxane B1.t 6-keto-PGF ,a,t and platelet factor 4:1: were measured by radioimmunoassay employing the iodine 125 technique." Because postoperative platelet counts varied between groups, the thromboxane B2 and platelet factor 4 concentrations were divided by the 'Coulter counter, Model S-Plus, Coulter Electronics Inc., Hialeah, Fla. tNew England Nuclear, Boston, Mass. :j:Abbott Laboratories, Diagnostics Division, North Chicago, Ill.

platelet counts measured at each time period to provide an additional index of platelet activation, The ratios of thromboxane B1 per platelet and platelet factor 4 per platelet have been reported to provide better indices of platelet activation than the plasma concentrations," although this index is arbitrary, The cross reactivity, sensitivity, and specificity of these assays are provided in the appendix, Dipyridamole concentrations were determined by high-performance liquid chromatography'?" and plasma salicylate levels were assayed spectrophotometri-

cally."

Timing of measurements. Plasma dipyridamole concentrations were measured serially preoperatively, intraoperatively, and postoperatively. Measurements were made at times of expected peak and trough concentrations after oral administration preoperatively and postoperatively, Plasma salicylate levels were obtained postoperatively at 9:00 AM on days I, 2, and 3, Platelet, leukocyte, and erythrocyte counts were measured at 9:00 AM on the day before the operation, intraoperatively after anesthetic induction, after institution of cardiopulmonary bypass, after aortic cross-clamp release, after discontinuation of bypass and protamine administration, at 4 hours after cross-clamp release on the day of the operation and at 9:00 AM and 2:00 PM on postoperative days I, 2, and 3. Thromboxane B1 and 6-keto-PGF 'a concentrations were measured at the same time as the hematologic measurements. Platelet factor 4 was measured intraoperatively after anesthetic induction, during cardiopulmonary bypass, after discontinuation of bypass and protamine administration, and at 9:00 AM on postoperative day I. Statistical analysis. Statistical analysis was performed

*Dipyridamole assayswereperformed by Dr. J. Rosenfeld at McMaster University Medical Centre, Hamilton, Ontario.

The Journal of

3 3 6 Teoh et al.

Thoracic and Cardiovascular Surgery

Table II. Leukocyte and erythrocyte counts Leukocytes Time

24 hr preop. Induction On CPB XCL off After CPB Postop Day 0, 4 hr Day 1,9:00 AM Day 1, 2:00 PM Day 2, 9:00 AM Day 2, 2:00 PM Day 3, 9:00 AM

Control

oao: cells/L)

Oral

Erythrocytes (XIOi: cellsil.) Intravenous

6.0 6.6 2.7 7.7 9.5

± ± ± ± ±

0.6 3.1 1.14.9 4.4

7.7 ± 6.7 ± 3.3 ± 7.3 ± 10.6 ±

2.1 2.1 1.23.8 4.5

7.2 7.5 3.7 7.8 12.2

9.6 8.1 9.0 8.7 9.5 7.2

± ± ± ± ± ±

3.61.9 1.9 3.0 3.1 1.9

12.0 ± 6.8 ± 7.9 ± 7.9 ± 8.5 ± 6.8 ±

3.4-t 2.3 2.4 2.9 2.2 2.2

14.0 ± 9.6 ± 8.4 ± 8.4 ± 7.2 ± 7.3 ±

± ± ± ± ±

Control

Oral

Intravenous

2.4 2.6 1.63.4 4.6t

4.7 3.9 2.1 2.5 2.8

± ± ± ± ±

0.5 0.40.40.40.5-

4.8 4.1 2.3 2.4 3.1

± 0.5 ± 0.4± 0.4± 0.4±0.7-

4.9 4.1 2.1 2.4 2.7

± ± ± ± ±

0.8 0.50.40.70.4-

4.6-t 4.42.5 2.7 2.1 1.6

3.7 3.7 3.7 3.4 3.4 3.6

± ± ± ± ± ±

0.90.40.40.20.20.5-

3.7 3.4 3.8 3.7 3.6 3.7

± ± ± ± ± ±

3.9 3.7 3.7 3.8 3.7 3.8

± ± ± ± ± ±

0.60.40.4O.S-t 0.50.4-

0.40.80.90.40.50.6-

Leukocyte and erythrocyte counts were different between treatment groups by analysis of variance. Differences between groups were specified by Duncan's multiple ,range test (tdifferent from control). Leukocyte and erythrocyte counts were different with time by analysis of variance and the differences were specified by Duncan s test (·different from preoperative value). Values are reported as mean ± standard deviation. CPB, Cardiopulmonary bypass: XCL, aortic cross-clamp,

with the SAS statistical programs, * Clinical variables were compared using analysis of variance (ANDVA) and Duncan's multiple range test or x 2 analysis. Serial measurements were compared with repeated measures analysis of variance using the general linear model procedure," and Duncan's multiple range t tests were employed to specify differences when the F ratio of the AND VA was significant (p < 0.05). The main effects tested were the group (control, oral, or intravenous dipyridamole) and the timing of measurements. The mean and standard deviation are presented in the tables and text and the mean and standard error are presented in the figures. Statistical significance was assumed for a probability value less than 0.05.

Results The perioperative characteristics of the three groups are presented in Table I. The preoperative profile and the intraoperative course were similar among the three groups. The plasma dipyridamole levels are presented in Fig. 2. Both oral and intravenous dipyridamole administration resulted in similar plasma levels preoperatively. Plasma levels fell during cardiopulmonary bypass (timing, p = 0.012 by ANOVA) and were lower in the oral than the intravenous dipyridamole group (group, p = 0.0001 by ANOVA). Dipyridamole concentrations rose after the termination of cardiopulmonary bypass in the intravenous dipyridamole group and preoperative concentrations were achieved 4 hours postoperatively. In the oral dipyridamole group drug levels remained significantly below preoperative values until 2:00 PM on the first postoperative day. The plasma levels on the third postoperative day were nearly twice the preoperative -SAS Institute Inc., Box 8000, Cary, N.C.

levels in both groups (p < 0.05 by Duncan's test). Plasma levels were higher postoperatively despite lower daily dosages of dipyridamole (400 mg preoperatively versus 225 mg postoperatively). In the oral dipyridamole group salicylate levelson the first postoperative day were undetectable in 16 patients and the levels were low in three patients (0.07 ± 0.2 mmoljL), despite aspirin administration 11 hours postoperatively. Salicylate levels increased significantly on the second and third postoperative days and were similar in the two groups (day 2: oral 0.09 ± 0.05 mmol/L, intravenous 0.07 ± 0.04 mmol/L; day 3: oral 0.12 ± 0.08 mmoljL, intravenous 0.15 ± 0.09 mmoljL). The arterial platelet counts are illustrated in Fig. 3. Platelet counts were not significantly different among the three groups preoperatively. Platelet counts fell intraoperatively and postoperatively in all groups (timing, p = 0.0001 by ANOVA). Platelet counts fell after anesthesia induction in all groups but the fall was statistically significant in the control group and not in the two groups receiving preoperative dipyridamole. In addition, arterial platelet counts were statistically lower in the control group (p < 0.05 by Duncan's test). The institution of cardiopulmonary bypass reduced arterial platelet counts in all groups. The fall was associated with the hemodilution of cardiopulmonary bypass and was not statistically different among groups. Platelet counts were significantly different among groups intraoperatively and postoperatively (group, p = 0.03 by ANOVA). Early postoperative (postoperative days 0 to 3) platelet counts were significantly lower in the control group than in the oral or intravenous dipyridamole groups (p < 0.05 by Duncan's test). In the control

Volume 96 Number 2 August 1988

Table

m.

Perioperative dipyridamole

337

Thromboxane B} and 6-keto PGFl a concentrations Thromboxane B] !Ilg/L) Control

Time Preop. On CPB XCL off After CPB Postop. Day 0, 4 hr Day I, 9:00

1.21 1.04 1.40 1.26

AM

± ± ± ±

0.61 0.72 0.86 1.05

0.84 ± 0.47 1.24 ± 0.40

Oral 1.04 1.43 1.57 1.52

± ± ± ±

0.56 1.01 0.91 1.19

1.11 ± 0.65 1.18 ± 0.34

6-KetcrPGFl a !Ilg/L) Intravenous 1.08 1.01 1.47 1.14

± ± ± ±

0.65 0.60 0.89 0.52

1.15 ± 0.62 0.99 ± 0.45

Control

Oral

± ± ± ±

0.0 ± 0.0 0.29 ± 0.24* 0.20 ± 0.25* 0.06 ± 0.15

0.03 0.28 0.21 0.04

0.0 ± 0.04 0.0 ± 0.0

0.02 ± 0.04 0.01 ± 0.05

0.02 0.21 0.18 0.05

0.06 0.22* 0.18* 0.09

0.02 ± 0.05 0.0 ± 0.0

Intravenous ± ± ± ±

0.05 0.19* 0.21 * 0.10

Thromboxane B, levels were not different with time despite hemodilution on cardiopulmonary bypass (CPB). The 6-keto PGF l a values were different with time by analysis of variance and differences were specified by Duncan's test ('different from preoperative value). Values are reported as mean ± standard deviation. XCL, Aortic cross-clamp.

group, only 28% (five of 18 patients) had any postoperative platelet counts within the normal range (150 to 350 X 109 platelets per liter at our institution) compared to 50% (nine of 19 patients) in the oral dipyridamole group and 71% (15 of 21 patients) in the intravenous dipyridamole group (p = 0.02 by X2) . The intravenous dipyridamole group had significantly higher platelet counts on postoperative days 2 and 3 than either the oral dipyridamole group or the control group, which had the lowest counts (p < 0.05 by Duncan's test). Leukocyte counts fell with the institution of cardiopulmonary bypass in all groups and rose postoperatively (timing, p = 0.00 by ANOVA, Table 11). The counts were significantly different among groups (group p = 0.008 by ANOVA). The intravenous dipyridamole group had the highest and the control group the lowest leukocyte counts postoperatively. Erythrocyte counts were similar among groups preoperatively, intraoperatively, and early postoperatively (Table 11). Erythrocyte counts were different between groups on postoperative days 2 and 3 (group, p = 0.04 by ANOVA). The intravenous dipyridamole group had higher erythrocyte counts than the control group on postoperative day 2 (p < 0.05 by Duncan's test). Thromboxane B2 levels tended to be elevated during cardiopulmonary bypass and early postoperatively but the increase was not statistically significant (Table III). There were no significant differences between the groups. Since the platelets counts were different in the three groups, thromboxane B2 concentrations were corrected for platelet counts. The control group had significantly higher thromboxane B2 concentrations per platelet postoperatively (group, p = 0.04 by ANOVA, P < 0.05 by Duncan's test). The 6-keto-PGF la levels were significantly elevated during cardiopulmonary bypass (timing, p = 0.0001 by ANOVA, Table III). The levels tended to be higher in the dipyridamole

groups but the differences among groups were not statistically significant (group, p = 0.8 by ANOVA). Preoperative platelet factor 4 levels were lowest in the control group (group, p = 0.05 by ANOVA, P < 0.05 by Duncan's test, Table IV). Platelet factor 4 concentrations rose during bypass only in the control group (p < 0.05 by Duncan's test). There were no significant differences between groups when platelet factor 4 concentrations were corrected for platelet counts. Postoperative blood loss and the number of units of packed red cells transfused are presented in Fig. 4. Blood loss was greatest in the control group and was reduced 42% with oral and 46% with intravenous dipyridamole (group, p = 0.048 by ANOVA, P < 0.05 by Duncan's test). Blood loss was not different between those who received oral or intravenous dipyridamole. Packed red cell transfusions were significantly reduced by both oral and intravenous dipyridamole (group, p = 0.04 by ANOVA, p < 0.05 by Duncan's test), which were not significantly different. Both postoperative bleeding and amount of red cells transfused correlated significantly (p < 0.05) with the postoperative platelet counts. Stored plasma transfusions were greatest in the control group (3.3 ± 1.7 units per patient) and tended to be lower in both the intravenous (2.4 ± 1.9) and the oral (2.2 ± 1.4) dipyridamole groups (but the differences were not significant, group, p = 0.11 by ANOVA). Adverse reactions to dipyridamole were infrequent. Nausea was common postoperatively and the incidence was similar in the three groups (control, seven patients; oral dipyridamole, five patients; intravenous dipyridamole, six patients). In one patient nausea improved when oral dipyridamole was stopped. Phlebitis developed in three patients with the preoperative intravenous dipyridamole infusion. Urticarial skin reactions developed in two patients receiving dipyridamole.

338

The Journal of Thoracic and Cardiovascular

Teoh et al.

Surgery

* p < 0.05 Different than Control

Table IV. Platelet factor 4 concentrations Platelet factor 4

en

~

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(Jlg/L)

1.5

Time

en en

o

Preop.

.....J

"8

o CO

.~ c

*

1.0

On CPB After CPB Postop. day 1, 9:00 AM

Control 196 440 193 251

± 150 ± 181t ± 118 ± 390

Oral 590 509 301 263

± 491*

± 360 ± 227

± 240

Intravenous 445 555 315 335

± 505* ± 354 ± 192

± 353

Preoperative platelet factor 4 concentrations were different between treatment groups by analysis of variance. Differences between groups were specified with Duncan's test (* different from control). Platelet factor 4 levels were different with time only in the control group (tdifferent from preoperative value). Values are reponed as mean ± standard deviation. CPR Cardiopulmonary bypass.

4

:::J

Control

Oral

IV

Dipyridamole Fig. 4. Both oral and intravenous dipyridamole reduced total blood loss and packed red cell transfusions (mean ± standard error).

Discussion

Preoperative dipyridamole administration preserved platelet counts and reduced postoperative blood loss and transfusion requirements after elective coronary revascularization. Intravenous dipyridamole maintained plasma concentrations perioperatively and produced higher postoperative platelet and erythrocyte counts than oral dipyridamole. Dipyridamole administration. The oral dipyridamole regimen described by Chesebro and associates' achieved adequate plasma levels preoperatively and again 48 hours postoperatively. However, cardiopulmonary bypass decreased plasma levelsto less than one half of the preoperative levels. Administration of dipyridamole via the nasogastric tube at 4 and 11 hours postoperatively did not raise the plasma concentrations, probably because of inadequate gastrointestinal absorption. Delayed gastric absorption may also explain the inadequate plasma salicylate concentrations after aspirin was administered via the nasogastric tube. Intravenous administration of dipyridamole provided adequate plasma concentrations in the perioperative period. The higher plasma concentrations were associated with high-

er postoperative platelet and erythrocyte counts than oral dipyridamole administration. Both methods of dipyridamole administration reduced blood loss in lowrisk patients undergoing elective revascularization. However, postoperative blood loss was dependent on postoperative platelet counts, and intravenous dipyridamole may be required to reduce postoperative bleeding in high-risk patients. Preoperative intravenous administration was complicated by phlebitis in 14% of patients. To maintain stable perioperative plasma levels, we recommend oral dipyridamole administration for 36 hours preoperatively and intravenous administration (via a central venous catheter to avoid phlebitis) intraoperatively and early postoperatively. Oral administration can then be reinstituted 24 hours postoperatively when gastrointestinal function has returned. Platelets. Cardiac operations and cardiopulmonary bypass provide a potent stimulus for platelet activation. Exposure of blood to the synthetic surfaces of the bypass circuit, to blood-gas interfaces, or to injured endothelial surfaces may induce platelet activation. 1·3. 22 We6 have recently demonstrated that activated platelets are deposited in the heart after cardioplegic arrest. Myocardial platelet deposition was associated with the cardiac release of thromboxanes, potent coronary vasoconstrictors that may contribute to myocardial ischemic injury after coronary bypass.v " We 6 also demonstrated that intravenous dipyridamole reduced myocardial platelet deposition and thromboxane release. Endothelial injury at sites of coronary anastomoses may induce platelet adhesion and aggregation, which could produce coronary thrombosis or bypass graft occlusion." Platelet aggregation and depletion may produce postoperative thrombocytopenia, which together with the poor func-

Volume 96 Number 2 August 1988

tion of the remaining platelets may increase postoperative bleeding. Dipyridamole preserved postoperative platelet counts by reducing platelet activation, aggregation, and depletion. Dipyridamole limited platelet activation by inhibiting platelet phosphodiesterase activity and increasing piatelet cyclic adenosine monophosphate concentrations.'? 12,25,26 Dipyridamole reduced platelet depletion and reduced postoperative bleeding perhaps, because platelet adhesion was preserved" and permitted platelet hemostasis. Leukocytes. Cardiopulmonary bypass activates leukocytes and induces leukocyte margination and aggregation, especially within the pulmonary microvasculature, perhaps because of complement activation.":" Activated leukocytes release liposomal enzymes and generate thromboxanes, leukotrienes, and oxygen free radicals that may induce tissue injury. Pulmonary dysfunction has been associated with the pulmonary sequestration of activated leukocytes." We 6 recently found that leukocytes were deposited in the myocardium after coronary bypass operation and that dipyridamole reduced cardiac leukocyte deposition. In this study dipyridamole preserved leukocyte counts perhaps by reducing leukocyte activation, margination, and aggregation. Dipyridamole has not been described to have direct effects on leukocytes. However, dipyridamole may have reduced leukocyte activation indirectly by reducing platelet activation and preventing the platelet release of chemotactic factors.>" Erythrocytes. Erythrocyte counts were similar between groups for the first 48 hours postoperatively because hemoglobin concentrations were maintained greater than 100 gm/L by transfusions. Erythrocyte counts fell in the control group on the second postoperative day, which perhaps reflected the loss of erythrocytes damaged during cardiopulmonary bypass or those transfused postoperatively. Dipyridamole reduced postoperative bleeding and transfusions and increased postoperative erythrocyte counts. Intravenous dipyridamole administration was more effective than oral administration. Prostanoids. Arterial thromboxane concentrations were not reduced with dipyridamole. Ex vivo activation of thromboxanes during sample preparation may have increased the variability of the thromboxane B2 measurements. However, similar thromboxane concentrations were found despite higher platelet counts in the dipyridamole groups. Arterial concentrations of platelet factor 4 were increased during cardiopulmonary bypass, which sug-

Perioperative dipyridamole

339

gested intraoperative platelet activation.' We found no differences between groups because of the large variations in our measurements, an insufficient number of patients, or because dipyridamole had no effect on thromboxane or platelet factor 4 concentrations. Arterial 6-keto-PGF l a concentrations were also elevated during cardiopulmonary bypass. The increase has been attributed to cannulation and manipulation of the heart and great vessels,as well as endothelial stimulation by hemodilution, nonpulsatile perfusion, hypothermia, and platelet deposition.":" The 6-keto-PGF l a concentrations were higher in the dipyridamole-treated patients perhaps because dipyridamole facilitated endothelial prostacyclin production. Dipyridamole has been shown to increase prostacyclin production by the endothelium of the aorta" and the coronary arteries." Greater endothelial prostacyclin production may have contributed to platelet preservation in the dipyridamole-treated groups because prostacyclin is a potent antiaggregatory agent, 38 Postoperative bleeding. Postoperative blood loss and transfusion requirements were reduced with dipyridamole. Hicks and associates" also reported that preoperative dipyridamole reduced postoperative bleeding in patients undergoing elective coronary bypass procedures, and their blood loss was similar to ours (750 ± 236 ml). Dipyridamole may have reduced postoperative blood loss by preserving platelet hemostatic functions and preventing platelet depletion. As a consequence, red cell transfusions were reduced by 44% (1.5 units of packed red cells). Dipyridamole increased the availability of a scarce resource and may reduce postoperative morbidity by reducing the risk of transfusion reactions and hepatitis. Intravenous dipyridamole did not reduce blood loss or transfusion requirements more than oral dipyridamole in these low-risk patients undergoing elective coronary bypass operations. However, intravenous dipyridamole produced higher postoperative platelet and erythrocyte counts. High-risk patients including those requiring reoperation may require intravenous dipyridamole to reduce postoperative bleeding. In summary, preoperative dipyridamole preserved thrombocytes, leukocytes, and erythrocytes and reduced postoperative blood loss and transfusions. Intravenous administration provided more stable plasma levels and higher postoperative platelet and erythrocytes counts than did oral administration. We wish to acknowledge the assistance of Julie Rose, BSc, withthe hematologic measurements, Sharon Kamo, BSc, with the radioimmunoassay measurements, and Eslyn Kesper with

340

Teoh et al.

preparation of the manuscript. We also wish to thank the perfusionists of the Division of Cardiovascular Surgery at the Toronto General Hospital for their invaluable assistance. REFERENCES I. Harker LA, Malpass TW, Bronson HE, Hessel EA II, Slichter SJ. Mechanism of abnormal bleeding in patients undergoing cardiopulmonary bypass: acquired transient platelet dysfunction associated with selective a-granule release. Blood 1980;56:824-34. 2. Addonizio YP Jr, Smith 18, Strauss JF III, Colman RW, Edmunds LH. Thromboxane synthesis and platelet secretion during cardiopulmonary bypass with a bubble oxygenator. J THORAC CARDIOVASC SURG 1980;79:91-6. 3. Edmunds LH, Ellison N, Colman RW, et al. Platelet function during cardiac operation: comparison of membrane and bubble oxygenators. J THORAC CARDIOVASC SURG 1982;83:805-12. 4. Dutton RC, Edmunds LH Jr, Hutchinson JC, Roe BB. Platelet aggregate emboli produced in patients during cardiopulmonary bypass with membrane and bubble oxygenators and blood filters. J THORAC CARDIOVASC SURG 1974;67:258-65. 5. Feinberg H, Rosenbaum DS, Levitsky S, Silverman NA, Kohler J, LeBreton G. Platelet deposition after surgically induced myocardial ischemia: an etiologic factor for reperfusion injury. J THORAC CARDIOVASC SURG 1982; 84:815-22. 6. Teoh KH, Christakis GT, Weisel RD, et al. Prevention of myocardial platelet deposition and thromboxane release with dipyridamole. Circulation 1986;74(Pt 2):11I145-52. 7. Chesebro JH, Clements JP, Fuster Y, et al. A plateletinhibitor drug trial in coronary artery bypass operations: benefit of perioperative dipyridamole and aspirin therapy on early postoperative vein graft patency. N Engl J Med 1982;307:73-8. 8. Hope AF, Heyns Adu P, Lotter MG, et al. Kinetics and sites of sequestration of indium III-labeled human platelets during cardiopulmonary bypass. J THORAC CAR. D10VASC SURG 1981;81:880-6. 9. Peterson KA, Dewanjee MK, Kaye MP. Fate of indium III-labeled platelets during cardiopulmonary bypass performed with membrane and bubble oxygenators. J THORAC CARDIOVASC SURG 1982;84:39-43. 10. Beurling-Harbury C, Galvan G: Acquired decrease in platelet secretory ADP associated with increased postoperative bleeding in post-cardiopulmonary bypass patients and in patients with severe valvular heart disease. Blood 1978;52: 13-23. II. Best LC, McGuire MB, Jones PBB, et al. Mode of action of dipyridamole on human platelets. Thromb Res 1979; 16:367-77. 12. Mills DCB, Smith JB. The influence on platelet aggregation of drugs that affect the accumulation of adenosine 3:5-cyclic monophosphate in platelets. Biochem J 1971; 121: 185-96.

The Journal of Thoracic and Cardiovascular Surgery

13. Emmons PR, Harrison MJG, Honour AJ, Mitchell JRA. Effect of dipyridamole on human platelet behaviour. Lancet 1965;2:603-6. 14. Mahony C, Wolfram KM, Cocchetto DM, Bjornsson TD. Dipyridamole kinetics. Clin Pharmacol Ther 1982; 31:330-8. 15. Fremes SE, Weisel RD, Mickle DAG, et al. Myocardial metabolism and ventricular function following cold potassium cardioplegia. J THORAC CARDIOVASC SURG 1985; 89:531-46. 16. Weisel RD, Burns RJ, Baird RJ, et al. Optimal postoperative volume loading. J THORAC CARDIOVASC SURG 1983;85:552-63. 17. Weisel RD, Charlesworth DC, Mickleborough LL, et al. Limitations of blood conservation. J THORAC CARDIOVASC SURG 1984;88:26-38. 18. Davi G, Migneco G, Yigneri S, Tripi S, Scialabba A, Strano A. Platelet thromboxane production in liver cirrhosis. Prostaglandins Leukotrienes Med 1985; /9:99-1 04. 19. Rosenfeld J, Devereaux D, Buchanan MR, Turpie AGG. High performance liquid chromatographic determinations of dipyridamole. J Chromatogr 1982;231 :216-21. 20. Routh JI, Paul WD, Arredondo E, Dryer RL. Semimicro method for the determination of salicylate levels in blood. Clin Chern 1956;2:432-8. 21. Freund RJ, Littel RC. SAS for linear models. In: A guide to ANOYA and GLM procedures. Cary, North Carolina: SAS Institute, 1981. 22. Davies GC, Sobel M, Salzman EW: Elevated plasma fibrinopeptide A and thromboxane A 2 levels during cardiopulmonary bypass. Circulation 1980;61:808-14. 23. Teoh KH, Fremes SE, Weisel RD, et al. Cardiac release of prostacyclin and thromboxane A 2 during coronary bypass surgery. J THORAC CARDIOVASC SURG 1987; 93:120-6. 24. Dewanjee MK, Tago M, Jasa M, Fuster Y, Kaye MP. Quantification of platelet retention in aortocoronary femoral vein bypass graft in dogs treated with dipyridamole and aspirin. Circulation 1984;69:350-6. 25. Nuutinen LS, Pihlajaniemi R, Saarela E, Karkola P, Hollmen A. The effect of dipyridamole on the thrombocyte count and bleeding tendency in open-heart surgery. J THORAC CARDIOVASC SURG 1977;74:295-8. 26. Nuutinen LS, Mononen P. Dipyridamole and thrombocyte count in open-heart surgery. J THORAC CARDIOVASC SURG 1975;70:707-11. 27. Yigdahl RL, Mongin J, Marquis NR. Platelet aggregation: platelet phosphodiesterase and its inhibition by vasodilators. Biochem Biphys Res Comm 1971;42: I08894. 28. Kirklin JK, Westaby S, Blackstone EH, Kirklin JW, Chenoweth DE, Pacifico AD. Complement and the damaging effects of cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1983;86:845-57. 29. Hammerschmidt DE, Stroncek DF, Bowers TK, et al. Complement activation and neutropenia occurring during

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August 1988

cardiopulmonary bypass. J THORAC CARDlOVASC SURG 1981 ;81 :370-7. 30. Bolanowski PJP, Bauer J, Machiedo G, Neville WE. Prostaglandin influence on pulmonary intravascular leukocytic aggregation during cardiopulmonary bypass. J THORAC CARDlOVASC SURG 1977;73:221. 31. Fountain SW, Martin BA, Musclow CE, Cooper JD. Pulmonary leukostasis and its relationship to pulmonary dysfunction in sheep and rabbits. Circ Res 1980;46: 17580. 32. McDonald JWD, Ali M, Morgan E, Townsend ER, Cooper JD. Thromboxane synthesis by sourcesother than platelets in association with complement-induced pulmonary leukostasis and pulmonary hypertension in sheep. Circ Res 1983;52: 1-6. 33. Kobinia GS, LaRaia PJ, Peterson MB, et al. Cardiac prostacyclin kinetics during cardiopulmonary bypass. J THORAC CARDlOVASC SURG 1984;88:967-71. 34. Ylikorkala 0, Saarela E, Viinikka L. Increased prostaglandin and thromboxane production in man during cardiopulmonary bypass. J THORAC CARDIOVASC SURG 1981 ;82:245-7.

34 1

35. Watkins WO, Peterson WB, Kong DL, et al. Thromboxane and prostacyclin changes during cardiopulmonary bypass with and without pulsatile flows. J THORAC CARDIOVASC SURG 1982;84:250-6. 36. Santos MT, Martinez-Sales V, Valtes J, et al. Prostacyelin production by rat aorta "in vitro" is increased by the combined action of dipyridamoleand pentoxifylline. Prostaglandins 1985;29:113-22. 37. Blais KE, Black HU, Forster W, Ponicke K. Dipyridamole: a potent stimulator of prostacyclin (PGI 2) biosynthesis. Br J Pharmacol 1980;68:71-3. 38. Moncada S, Flower RJ, Vane JR. Prostaglandins, prostacyelinand thromboxane A2. In: Goodman LS, Gilman A, eds. The pharmacological basis of therapeutics. 6th ed. New York: Macmillan, 1980:668-81. 39. Hicks G, Jensen LA, Norsen LH, Quinn JR, Stewart SS, DeWeese JA. Platelet inhibitors and hydroxyethyl starch: safe and cost-effective interventions in coronary artery surgery. Ann Thorae Surg 1985;39:422-5.

Appendix. Thromboxane B1• 6-keto-PGF1w and platelet factor 4 125/

radioimmunoassay specifications

Thromboxane B2

6-keto-PGFl a

PGD, PGE, PGF, PGEI 6-keto-PG FI Other PG and FA

3.9% 0.23% 0.07% 0.06% 0.06% <0.02%

Interassay Intraassay

11.8% 6.2%

Platelet factor 4

Cross-reactivity 2.6% PGF, PGE I 1.9% 1.4% TXB, 1.1% PGE, <1.0% Other PG and FA

{3-Thromboglobulin

0.0%

Heparin EDTA

0.0% 0.0% 0.0% 0.0%

Citrate Dipyridamole

Coefficient of variation

7.4% 9.2%

5.4% 7.7%

Sensitivity

0.05 Ilg/L PG. Prostaglandin; FA, fatty acid; EDT A, ethylenediaminetetraacetic acid.

2.5 IlgfL