Modest doses of nitroglycerin do not interfere with beef lung heparin anticoagulation in patients taking nitrates

Modest Doses of Nitroglycerin Anticoagulation

Do Not Interfere With Beef Lung Heparin in Patients Taking Nitrates

David L. Reich, MD, Bruce C. Hammerschlag, MD, Jacob H. Rand, MD, M. Herma Perucho-Powell, RN, and Daniel M. Thys, MD The results of a prior clinical report suggested that nitroglycerin may interfere with the anticoagulant effect of heparin. Therefore, 30 adult patients undergoing cardiac surgery were studied in a controlled, prospective fashion. Thirteen patients on chronic nitrate therapy received an intraoperative nitroglycerin infusion at 1 pg/ kg/min intravenously. Seventeen patients received no preoperative or intraoperative nitrates (control group). Heparin, 300 units/ kg, was administered to all patients in three consecutive doses: 40 units/ kg, 80 units/kg, and 180 units/kg. The activated coagulation time and activated partial thromboplastin time were measured prior to heparin, and 5 minutes after each heparin dose.

A

PUBLISHED report of an uncontrolled study concluded that nitroglycerin (NTG) interfered with the anticoagulant effect of heparin.’ Because no controlled clinical investigations have been performed to elucidate this potential drug interaction, a prospective, controlled study to investigate the influence of NTG on the anticoagulant effect of heparin was undertaken in patients on chronic nitrate therapy who were undergoing cardiac surgery. MATERIAL

AND METHODS

Thirty adult patients undergoing elective myocardial revascularization or single-valve replacement surgery were studied. Written informed consent was obtained from each patient, and the study protocol was approved by the Institutional Review Board. Patients were excluded from the study if they had received a heparin infusion within the previous week, or if they were receiving coumadin therapy. Heparin anticoagulation was assessed by using an automated activated coagulation time (ACT) device and an activated partial thromboplastin time (PTT). The Hemochron ACT Device (International Technidyne, Inc, Edison, NJ) required that 2 mL of blood be placed in prewarmed Celite tubes (International Technidyne, Inc, Edison, NJ) for each analysis2 The ACT analyses were performed in accordance with the manufacturer’s instructions. The PTT was obtained using centrifuged titrated plasma. The plasma was incubated for 3 to 5 minutes, and then tested in the automated Coag-A-Mate device (General Diagnostics, Organon Teknika Corp, Durham, NC). Anesthesia consisted of high-dose fentanyl (50 to 150 kg/kg), midazolam, pancuronium, and 100% oxygen. The patients were assigned to two groups based on current nitrate use. Patients on oral or intravenous preoperative nitrate therapy received an intravenous NTG (Nitroglycerin Injection USP, Solopak Laboratories, Franklin Park, IL) infusion at a rate of 1 ugikgimin. The infusion was begun immediately following placement of monitoring catheters prior to the induction of anesthesia, and continued until the onset of cardiopulmonary bypass. Those patients not on preoperative nitrate therapy received no NTG for the duration of the study. Following sternotomy, a Hemochron ACT and a PTT were obtained (TO). The full 300 unit/kg dose of beef lung heparin (Heparin Sodium Injection, USP, Organon, Inc, West Orange, NJ) was administered in three sequential doses via the right atria1 port of the pulmonary artery catheter (PAC). The first dose consisted of 40 units/kg. An ACT and PTT were drawn 5 minutes following this dose (Tl). An ACT and PIT were also drawn 5 minutes following

There were no differences in automated activated coagulation times or in activated partial thromboplastin times between the groups at any measurement period. The study is limited in that only patients on chronic nitrates were included in the treatment group and that only a modest dose of nitroglycerin was used. However, it is concluded that a modest dose of intravenous nitroglycerin does not interfere with the anticoagulant effect of boluses of beef lung heparin in patients undergoing cardiac surgery. Copyright o 1992 by W.B. Saunders Company KEY WORDS: heparin sodium, nitroglycerin,

cardiac surgery

the second dose, 80 units/kg, and the third dose, 180 units/kg, and were labeled T2 and 1’3, respectively. The second and third doses of heparin were given immediately following the withdrawal of coagulation testing specimens. The full heparin dose was thus given over a 10 to 12 minute period. All coagulation testing samples were drawn from the distal port of the PAC, after the catheter was cleared of heparinized flush solution by aspirating 10 mL of blood. PTT values could not be compared at T2 and T3 because all values were out of the test range, and these values do not correlate with heparin anticoagulation. The Mann-Whitney U Test was used to compare the ACT results between the groups at all test points. Fisher’s Exact Test and x2 analysis were used to compare contingency data. P values less than 0.05 were considered statistically significant. All analyses were two tailed. RESULTS

Thirteen patients were in the NTG group and 17 patients were in the control group. The NTG and control groups did not differ significantly in age, sex distribution, and weight. All patients in the NTG group were undergoing myocardial revascularization. Five of 17 patients in the control group were undergoing myocardial revascularization and the remainder were undergoing single-valve replacement. The number of patients receiving aspirin, and the preoperative IVY bleeding times, were significantly higher in the NTG group. Otherwise, coagulation parameters were not significantly different between the groups. These data are summarized in Table 1. Automated ACT values showed no significant differences between the groups at any study point (Table 2). After 40 units/kg of heparin (Tl), approximately half (9 of 17) of the patients in the control group had PIT values that were out of the testing range (more than 120 set). Using this threshold, a x2 analysis was used to compare this proportion to the 6 of 13 patients in the NTG group with similarly

From the Departments of Anesthesiology and Medicine, Mount Sinai Medical Center, New York, NY Address reprint requests to David L. Reich, MD, Department of Anesthesiology, Box 1010, Mount Sinai Medical Center, One Gustave L. Levy Place, New York, NY Copyright o I992 by W.B. Saunders Company 1053-0770/92/0606-0007$03.OOiO

Journal of Cardiothoracic and Vascular Anesthesia, Vol6, No 6 (December), 1992: pp 677-679

677

REICH ET AL

678

Table 3.

Table 1. Demographic Data

Parameter

Nitroglycew Group

Control Group

13

17

Number of Patients

12.0 2 0.3

Prothrombin time (SW)

12.1 + 0.4

Activated partial thromboplastin 34.8 r 9.5

32.7 + 2.4

Fibrinogen (mg/dL)

356 r 70

305 f 56

Platelet count (log/L)

269 r 47

239 t- 56

time (set)

7.7 2 3.1s

Ivy bleeding time (min)

6113”

3117

Persantine use

o/13

2117

*Higher than control group (P < 0.05).

elevated PTT values. No significant difference was detected (Table 3). At T2 and T3, all PTT values were out of the testing range and could not be analyzed. Following full heparinization (T3), 1 patient in the NTG group and 2 patients in the control group had ACT values less than 400 seconds (not significantly different). All of these patients achieved ACT values greater than 400 seconds following an additional intravenous bolus of 5,000 U of heparin. All patients completed the study protocol. There were no episodes of intraoperative myocardial ischemia and no significant coagulopathies following protamine neutralization. There were no episodes of significant hypotension attributable to the NTG infusions. DISCUSSION

The results of this study indicate that a clinically relevant dose of NTG had no inhibitory effect on the anticoagulant effect of beef lung heparin during cardiac surgery. Neither the ACT nor the PTT detected any statistically significant differences between patients who were receiving NTG infusions and those receiving no nitrate therapy. A previous report of 7 patients found that NTG infusions impaired the anticoagulant effect of porcine heparin following intravenous boluses of 5,000 U and continuous heparin infusions, and that this effect was not due to the propylene glycol vehicle in the NTG ampule.’ They also reported that discontinuation of the NTG resulted in a rebound effect, with PTT values higher than expected. However, their results were not analyzed statistically, and the study had no control group. Previous exposure to heparin and alterations in the level of antithrombin III may also have influenced the results of that study. For example, prolonged heparin therapy lowers levels of antithrombin III.4 Amin and Honow found no differences in antithrombin III concentration or activity in an in vitro study with various combinations of heparin and NTG, but it is conceivable that Table 2. Activated Coagulation Time During Heparinization HemochronACTValues (set) (Means ? SD) Nitroglycerin

During

Heparinization x2for PTT Values Following40 U/kg of Heparin Nitroglycerin

Control

PTT > 120 set (out of range)

6

9

PTT < 120sec

7

8

Total patients

13

17

5.9 +- 2.8

Aspirin use

Total HeparinDose

Activated Partial ThromboplastinTime

Control

Baseline

135 2 18

135?

40 U/kg

211 2 39

213 ? 36

18

120 U/kg

323 t 58

349 2 66

300 U/kg

523 r 105

574 ? 143

prolonged therapy with high doses of NTG may affect antithrombin III levels. The present results arc similar to those obtained by Lepor et al.6 The in vivo portion of that study consisted of 10 patients on heparin infusions whose PTT values did not change during or after a NTG infusion. The NTG doses used in that study (67 to 333 kg/min) were higher than those used in the current study. The pilot study performed by Becker et al7 raises the possibility that very high NTG doses might induce a qualitative defect in antithrombin III activity. They observed a positive correlation (r = 0.911) between NTG dose and antithrombin III antigen:activity ratio based on eight data points. The subgroup of two data points where the NTG dose was >350 bgimin (mean = 883 kgimin) were the only two points at which the antithrombin III antigen:activity ratio was elevated, and heparin requirements were increased. Thus, the conclusion of their paper is based on few data points, and should be considered tentative. The current study consisted of a larger sample, and multiple doses of beef lung heparin were used. Beef lung heparin is used at many cardiac surgical centers because it is less likely to result in hypotension following bolus administration,x and it is more easily neutralized by protamine9 than pork mucosal heparin. A clinically relevant dose of NTG was chosen. Higher doses were not used because significant hypotension occurred in a pilot study in which patients received 2-5 kg/kg/min of NTG. The current study did not investigate the potential effects of IV NTG on heparin anticoagulation in patients not receiving chronic nitrate therapy. It is theoretically possible that only acute nitrate therapy interferes with heparinization. Another potential source of bias in the study was the higher proportion of patients with ischemic heart disease in the NTG treatment group. Patients with ischemic heart disease might differ from those with valvular heart disease in their response to heparin anticoagulation. This could bc attributed to platelet function abnormalities,10 or to the higher incidence of aspirin and persantine usage in patients with ischemic heart disease. However, the one patient with an elevated Ivy bleeding time in the current study was in the NTG group, and did not exhibit an abnormal response to heparin. It is also unfortunate that a standardized laboratory test of heparin’s anticoagulant effect is not available at higher ranges of heparin dosing. It is possible that there is a subtle interaction between NTG and heparin that is not detected by ACT testing. However, ACT testing is accepted as the standard for intraoperative monitoring of heparinization. It

NITROGLYCERIN

679

AND HEPARIN INTERACTION

is unlikely that any clinically significant interaction between NTG and heparin would not be detected by ACT monitoring. Incomplete heparinization prior to cardiopulmonary bypass (CPB) may result in subclinical activation of the coagulation cascade and secondary fibrinolysis, or clotting of the pump oxygenator during CPB, although this remains a point of controversy. l1 Unexpected heparin resistance could also endanger patients during other procedures or conditions requiring anticoagulation. These include unstable angina, coronary angioplasty procedures, and hypercoagulable states. Thus, the potential inhibitory effect of NTG on heparin anticoagulation is an important issue to resolve.

The current study demonstrated that a 1 pg/kg/min dose of NTG (in patients on chronic nitrate therapy) did not interfere with beef lung heparin anticoagulation during cardiac surgery. The study design was limited, however, in that prior nitrate therapy and ischemic heart disease were more prevalent in the patients receiving NTG, and in the limited number of patients studied. The potential for NTG-induced heparin resistance at higher NTG doses merits further investigation. ACKNOWLEDGMENT The authors gratefully acknowledge the cooperation cardiothoracic operating room and laboratory staff.

of the

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erin-induced heparin resistance: A qualitative antithrombin III abnormality. Am Heart J 119:1254-1261,199O 8. Fiser WP, Read RC, Wright FE, Vecchio TJ: A randomized study of beef lung and pork mucosal heparin in cardiac surgery. Ann Thorac Surg 35:615-620,1983 9. Racanelli A, Fareed J, Walenga JM, Coyne E: Biochemical and pharmacologic studies on the protamine interactions with heparin, its fraction? and fragments. Semin Thromb Hemost 11:176-189, 1985 10. Elwood PC, Renaud S, Sharp DS, et al: Ischemic heart disease and platelet aggregation. The Caerphilly Collaborative Heart Disease Study. Circulation 83:38-44, 1991 11. Metz S, Keats AS: Low activated coagulation time during cardiopulmonary bypass does not increase postoperative bleeding. Ann Thorac Surg 49:440-444,199O