ANESTH ANALG 1990;71:4114
411
Effect of Cardiopulmonary Bypass on Plasma Levels of Nifedipine Robert I. Katz, MD, Marc S. Kanchuger, MD,K. Franklin Patton, MD,and Thomas R. Eide, MD KATZ RI, KANCHUGER MS, PATTON KF, EIDE TR. Effect of cardiopulmonary bypass on plasma levels of nifedipine. Anesth Analg 1990;71:411-4.
Blood levels of many medications are acutely lowered by cardiopulmonary bypass (CPB). Because nifedipine is often used to provide protection from coronary ischemia, a determination of the effect of CPB on plasma nifedipine levels might help to determine the potential clinical benefit of nifedipine during and after bypass. Four samples of blood were drawn from each of eight patients undergoing cardiac surgery: one before, two during, and one after CPB. Although plasma levels of nifedipine declined during and after bypass ( P < 0.05, analysis of variance), the timecourse and slope of the decline indicate that this was an
Since its introduction into clinical practice, the calcium channel blocker nifedipine has proven to be an effective agent for treatment of chronic stable angina (l),for prevention of coronary ischemia (2), and for control of hypertension (3). Because of its beneficial effects in the patient with ischemic heart disease, nifedipine is a part of the therapeutic regimen of many patients scheduled for coronary artery bypass surgery. Although any surgical situation may involve changes in normal physiology, cardiac surgery is unique in requiring a period of total, artificial cardiopulmonary support. Some of the more obvious changes occurring during cardiopulmonary bypass (CPB) include a lowered metabolic rate due to hypothermia and a dilution of hematocrit and serum proteins by the pump prime solution. Blood levels of some medications, such as pancuronium (4) and propranolol (5), are acutely lowered by CPB. The
Received from the Departments of Anesthesiology, State University of New York at Stony Brook, Stony Brook, New York, and Northport Veterans Administration Hospital, Northport, New York. Accepted for publication June 25, 1990. Address correspondence to Dr. Katz, Department of Anesthesiology, State University of New York at Stony Brook, Stony Brook, NY 11794. 01990 by the International Anesthesia Research Society
effect of normal metabolism of the drug rather than an effect of physiologic changes occurring during CPB. A n important additional finding was that the majority of patients had subtherapeutic levels of nifedipine before bypass, suggesting that additional nifedipine given during and after surgery might be of benefit. The effect of the CPB circuit itself was also examined in vitro by mixing nifedipine into a pump prime solution that was then recirculated with 2 U of outdated blood while levels of nifedipine were measured for 3 h. Plasma levels did not change in either a CPB circuit exposed to light or kept in a darkened room.
Key Words: PHARMACOLOGY, CALCIUM BLOCKERS-nifedipine. ANESTHESIA, CARDIOVASCULAR-CardiOPUhOnZlry bypass.
serum levels of others, such as cefazolin (6), are not affected. Despite the known effects of nifedipine in treating and preventing myocardial ischemia, it has been shown that chronic administration of nifedipine does not reduce the incidence of ischemia during and after cardiac surgery (7). Acting on the supposition that subtherapeutic levels of nifedipine might be responsible for this lack of efficacy, we have examined the effect of total CPB on plasma levels of chronically administered nifedipine.
Methods and Materials The study was divided into two parts: first, plasma nifedipine levels were determined in patients undergoing CPB; second, plasma nifedipine levels were determined in an in vitro preparation consisting of a CPB circuit filled with blood to which nifedipine had been added. With the approval of the Committee on Research Involving Human Subjects, and after having obtained informed consent, 10 subjects were studied. All had been taking oral nifedipine for at least 1 wk before surgery at a daily dose ranging between 10 and 20 mg every 8 h. On the morning of surgery, approximately
412
KATZ ET AL.
ANESTH ANALG 1990;71:4113
1 h before arrival in the operating room, all patients received their last preoperative dose of nifedipine. p-Adrenergic antagonists, nitrates, and other cardiac medications were all continued through the morning of surgery. Preoperative sedation consisted of a combination of either intramuscular morphine-scopolamine or intramuscular morphine-lorazepam. All patients were given 30 mL of oral sodium citrate (Bicitra) to neutralize stomach acid. Monitored variables included pulmonary and radial arterial pressures, electrocardiogram, hemoglobin oxygen saturation, end-tidal Pco,, and rectal and central arterial temperatures. Anesthesia was induced with intravenous sufentanil (10 pgikg), followed by intravenous vecuronium (10 mg) for muscle relaxation. After tracheal intubation, mechanical ventilation was instituted with 100% oxygen. Five milliliters of blood was drawn from the radial artery catheter for determination of serum nifedipine concentration at the time the aortic cannula was placed (point A), which was approximately 30 min before the start of CPB (which was approximately 4 h after the last oral dose of nifedipine). Additional samples were drawn 30 min after institution of CPB (point a), approximately 30 min before the termination of bypass (point C, at which time the last proximal graft had been placed and the patient had been rewarmed), and 30 min after termination of bypass (point D). All samples were protected from light and placed on ice before freezing. Nifedipine levels were determined by National Medical Services (Willow Grove, Pa.) using highpressure liquid chromatography with electrochemical detection, a method with an accuracy of *lo% and the ability to detect a nifedipine concentration as low as 2 ngimL. Results reported as "none detected" were considered to be zero for purposes of analysis. Therapeutic levels of serum nifedipine were considered to be 25100 ngimL (8). Results were compared to previously established pharmacokinetic data for nifedipine in normal volunteers (9). The second part of our study examined the effect of the bypass circuit itself upon plasma nifedipine levels. A CPB circuit was set up in a standard fashion but with the venous line connected to the arterial line in order to complete the circuit. Two units of whole blood (outdated), 250 mL of 5% albumin, 50 g of mannitol, 10,000 U of heparin, and lactated Ringer's solution to a final volume of 2 L were added to the circuit. The pH was adjusted to 7.4 with NaHCO,. The final hematocrit was approximately 20%. Nifedipine (0.5 mg) was added to this solution. The temperature was maintained at 23°C. The mixture was pumped at a flow rate of 2 L/min using a roller
150 -
Hours 1
2
3
4
5
6
7
8
Points A B C D FiRure 1. Mean plasma nifedipine concentrations after 20-mg oral (-0-) and 10-mg oral doses (-A-), adapted from Raemsch and Sommer (by permission of American Heart Association, Inc., and K. D. Raemsch of Reference 9), plus mean plasma nifedipine concentrations at points A, B, C, and D ( + ) in the present study. *P < 0.05 from point A.
pump (Cobe) and pumped through a M2000 membrane oxygenator (Shiley, Irvine, Calif.), EC3840 arterial filter (Pall, Glen Cove, N.Y.), reservoir bag (Bently BMR 1900), and cardiotomy reservoir (Bard H 4700) using standard polyvinylchloride tubing. Fivemilliliter samples of blood were assayed for nifedipine after 1 min (time 0) to allow for mixing, and then every 30 min for 3 h. To examine the effect of light on nifedipine in the CPB circuit, this test was conducted both in the presence of normal operating room fluorescent light and in a dark room. The data were examined by analysis of variance for repeated measures, with the Fisher probable least significant difference test as a multiple comparison test to determine statistically significant differences between time points. P < 0.05 was considered to be statistically significant. Results are reported as mean
* SEM.
Results Results for part 1 are summarized in Figure 1. One patient had a difficult surgical dissection, and CPB did not start until 8 h after his morning dose of nifedipine. Plasma levels of nifedipine in this patient were 0 at all four data points. One patient had a nifedipine level at point A that was much higher than
CARDIOPULMONARY BYPASS AND PLASMA NIFEDIFINE
ANESTH ANALG 1990;71:411-4
Table 1. Nifedipine Plasma Levels in Isolated Cardiopulmonary Bypass Circuits (ng/mL) Time from baseline (min)
Plasma level in light (n = 1) Plasma level in dark ( n = 1)
0
30
60
90
120
150
180
12
12
16
14
16
14
16
10
13
12
15
14
12
12
those of any other patient. An examination of this patient’s records revealed that his nifedipine dose had been changed from 20 mg every 8 h to 20 mg every 6 h on arrival in the hospital 2 days before. Both of these patients were excluded from the statistical analysis. The mean CPB time of the remaining patients was 2.5 -+ 0.3 h. The mean concentration of the eight samples at point A was 18 f 4 ng/mL. The mean concentration for points B, C, and D was 12 f 3, 11 f 5, and 8 ? 3 ng/mL, respectively. Analysis revealed a statistically significant difference (P < 0.05) Results for part 2 are summarized in Table 1. There were no changes in serum nifedipine levels obtained from the CPB circuit over the 3 h of the study, either in fluorescent light or in a darkened room.
Discussion The results of our study demonstrate that plasma nifedipine levels in patients decline during CPB. There are many factors that might, in theory, lead to changes in blood levels of a medication on CPB. These include increased volume of distribution due to the addition of pump prime; dilution of red blood cells and plasma proteins by the pump prime; and decreased hepatic and renal metabolism and excretion secondary to hypothermia and altered tissue perfusion. However, if nifedipine levels were reduced by the CPB itself, one would expect the decrease to be precipitous; the plasma level would go down abruptly when CPB started, as hemodilution and changes in volume of distribution occur within seconds of starting CPB. In this study, the initial blood sample was drawn from our patients at approximately 4 h after their last dose of nifedipine, and the last sample was drawn an average of 3.5 h after that. Our degradation curve closely parallels the terminal portion of the previously established nifedipine degradation curve (Figure 1)(9) in normal patients. These results suggest that the decrease in plasma nifedipine levels during CPB is not due to the CPB itself but
413
rather to the normal metabolism and elimination of the drug. Part 2 of our study revealed that nifedipine does not bind to the materials of the CPB circuit, and that the presence of normal fluorescent lighting in an operating room does not affect levels of nifedipine in blood circulating through a CPB circuit, despite the well-described tendency of this agent to undergo photodegradation (10). Prior pharmacokinetic studies have determined that nifedipine has a serum half-life of approximately 3 h (9,ll). The duration of action with chronic administration is questionable. At least one study has shown accumulation with repeated dosages (lo), but Raemsch and Sommer could demonstrate no accumulation after 7 days of chronic administration (9), and our own previous work (12), as well as the current study, showed that a majority of patients chronically taking nifedipine have subtherapeutic levels at approximately 4 h after the last oral administration. When beginning treatment of a patient with nifedipine, it is uncommon to routinely measure plasma nifedipine levels to determine therapeutic effect. As presently prescribed, the dose of nifedipine is adjusted to relieve the individual patient’s symptoms. However, there seems to be a “window” in blood levels of nifedipine in most patients, a time lasting up to an hour or longer, when the serum level of nifedipine is zero or almost zero, before the every-8-h dosing of the drug. The clinical significance of this fact is presently unknown. Because very few patients appear to have a therapeutic level of nifedipine by the end of CPB, it cannot be said whether or not a therapeutic level during and after bypass will lead to better results. However, our previous work has demonstrated that sublingual nifedipine given after discontinuation of CPB can reduce coronary artery graft resistance (12) even in patients who are chronically taking the drug before surgery. This suggests that therapeutic plasma levels might offer continued benefit after bypass. Slogoff and Keats have demonstrated that the incidence of intraoperative ischemia in cardiac surgery patients taking nifedipine or diltiazem is greater than it is in patients taking either these medications plus a P-adrenergic blocker or a P-adrenergic blocker alone (7). Our study raises the possibility that this lack of benefit might be due, at least in part, to subtherapeutic blood levels of the calcium channel blocker during surgery. Knight et al. (13) found that the incidence of myocardial ischemia in the immediate postoperative period after coronary artery bypass grafting is essentially the same as that during the preoperative peri-
414
ANESTH ANALG 1990;71:411-4
od-40% and 42%, respectively-and this despite the fact of coronary revascularization. Similarly, Slogoff and Keats reported (14) that perioperative myocardial ischemia is a significant risk factor in the development of postoperative myocardial infarction. It seems clear that the prevention of myocardial ischemia in the perioperative period is a desirable goal. Our study demonstrates that whether or not nifedipine can provide this protection is questionable. Considering that many patients have extremely low blood levels of nifedipine within 4 h of administration (in our study, six of eight patients had levels considered to be subtherapeutic before bypass), it seems likely that there are many hours during and after surgery when the patient is deprived of any beneficial effects of his or her medication; even operations lasting for only an hour or so often necessitate a period when oral medications cannot be taken afterward. In Europe, intravenous, rectal, and ”slow-release” oral preparations of nifedipine are all available. The drug is reliably absorbed by rectum (9), and the slowrelease oral form provides detectable blood levels for over 24 h (15). In the United States, however, the slow-release form has only recently been available and the only alternative to the oral route is the sublingual administration of nifedipine. It may well be that the patient scheduled for cardiac surgery who has been chronically taking nifedipine would benefit by a switch to the slow-release form before surgery and the fasting, postoperative patient who has been chronically taking nifedipine might benefit by sublingual administration of this medication.
References 1. Parisi AF, Strauss WE, Mclntyre KM, et al. Considerations in evaluating new antianginal drugs. Circulation 1982;65(Suppl I):I3%42.
KATZ ET AL.
2. Antunin E, Muller J, Goldberg S, et al. Nifedipine therapy for coronary artery spasm: experience in 127 patients. N Engl J Med 1980;302:1269-73. 3. Aoki K, Kondo S, Mochizuk A, et al. Anti-hypertensive effect of cardiovascular calcium antagonists in hypertensive patients in the absence and presence of beta adrenergic blockade. Am Heart J 1987;96:21&26. 4. DHollander AA, Duvaldestin P, Henzel D, Nevelsteen M, Bomblet JP. Variations in pancuronium requirements, plasma concentration, and urinary excretion induced by cardiopulmonary bypass with hypothermia. Anesthesiology 1983;58:5059. 5. Plachetka JR, Salomon NW, Copeland JC. Plasma propranolol before, during and after cardiopulmonary bypass. Clin Pharmacol Ther 1981;30:745-51. 6. Akl BF, Richardson G. Serum cezazolin levels during cardiopulmonary bypass. Ann Thorac Surg 1980;29:109-12. 7. Slogoff S, Keats AS. Does chronic treatment with calcium entry blocking drugs reduce perioperative myocardial ischemia? Anesthesiology 1988;68:67&80.
8. Calcium channel antagonists. Drug facts and c o m p a r i s o n s the September quarterly index: facts and comparison division. Philadelphia: JB Lippincott, 1988:149:A.P. 9. Raemsch KD, Sommer J. Pharmacokinetics and metabolism of nifedipine. Hypertension 1983;5(Suppl II):1118-24. 10. Tucker FA, Minty PSB, MacGregor GA. Study of nifedipine photodecomposition in plasma and whole blood using capillary gas-liquid chromatography. J Chromatogr 1985;342:193-8.
11. Gutierrez LM, Lesko LJ, Whipps R, Carliner N, Fisher M. Pharmacokinetics and pharmacodynamics of nifedipine in patients at steady state. J Clin Pharmacol 1986;26:587-92. 12. Eide TR, Katz RI, Poppers PJ. The effect of sublingual nifedipine on coronary venous graft resistance immediately following cardiopulmonary bypass. Anesth Analg 1989;68:4624. 13. Knight AA, Hollenberg M, London MJ, et al. Perioperative myocardial ischemia: importance of the preoperative ischemic pattern. Anesthesiology 1988;68:681-8. 14. Slogoff S, Keats AS. Does perioperative myocardial ischemia lead to postoperative myocardial infarction? Anesthesiology 1985;62:107-14. 15. Lobo J, Jack DB, Kendall MJ. The intra- and inter-subject variability of nifedipine pharmacokinetics in young volunteers. Eur J Clin Pharmacol 1986;30:57-60.
411
Effect of Cardiopulmonary Bypass on Plasma Levels of Nifedipine Robert I. Katz, MD, Marc S. Kanchuger, MD,K. Franklin Patton, MD,and Thomas R. Eide, MD KATZ RI, KANCHUGER MS, PATTON KF, EIDE TR. Effect of cardiopulmonary bypass on plasma levels of nifedipine. Anesth Analg 1990;71:411-4.
Blood levels of many medications are acutely lowered by cardiopulmonary bypass (CPB). Because nifedipine is often used to provide protection from coronary ischemia, a determination of the effect of CPB on plasma nifedipine levels might help to determine the potential clinical benefit of nifedipine during and after bypass. Four samples of blood were drawn from each of eight patients undergoing cardiac surgery: one before, two during, and one after CPB. Although plasma levels of nifedipine declined during and after bypass ( P < 0.05, analysis of variance), the timecourse and slope of the decline indicate that this was an
Since its introduction into clinical practice, the calcium channel blocker nifedipine has proven to be an effective agent for treatment of chronic stable angina (l),for prevention of coronary ischemia (2), and for control of hypertension (3). Because of its beneficial effects in the patient with ischemic heart disease, nifedipine is a part of the therapeutic regimen of many patients scheduled for coronary artery bypass surgery. Although any surgical situation may involve changes in normal physiology, cardiac surgery is unique in requiring a period of total, artificial cardiopulmonary support. Some of the more obvious changes occurring during cardiopulmonary bypass (CPB) include a lowered metabolic rate due to hypothermia and a dilution of hematocrit and serum proteins by the pump prime solution. Blood levels of some medications, such as pancuronium (4) and propranolol (5), are acutely lowered by CPB. The
Received from the Departments of Anesthesiology, State University of New York at Stony Brook, Stony Brook, New York, and Northport Veterans Administration Hospital, Northport, New York. Accepted for publication June 25, 1990. Address correspondence to Dr. Katz, Department of Anesthesiology, State University of New York at Stony Brook, Stony Brook, NY 11794. 01990 by the International Anesthesia Research Society
effect of normal metabolism of the drug rather than an effect of physiologic changes occurring during CPB. A n important additional finding was that the majority of patients had subtherapeutic levels of nifedipine before bypass, suggesting that additional nifedipine given during and after surgery might be of benefit. The effect of the CPB circuit itself was also examined in vitro by mixing nifedipine into a pump prime solution that was then recirculated with 2 U of outdated blood while levels of nifedipine were measured for 3 h. Plasma levels did not change in either a CPB circuit exposed to light or kept in a darkened room.
Key Words: PHARMACOLOGY, CALCIUM BLOCKERS-nifedipine. ANESTHESIA, CARDIOVASCULAR-CardiOPUhOnZlry bypass.
serum levels of others, such as cefazolin (6), are not affected. Despite the known effects of nifedipine in treating and preventing myocardial ischemia, it has been shown that chronic administration of nifedipine does not reduce the incidence of ischemia during and after cardiac surgery (7). Acting on the supposition that subtherapeutic levels of nifedipine might be responsible for this lack of efficacy, we have examined the effect of total CPB on plasma levels of chronically administered nifedipine.
Methods and Materials The study was divided into two parts: first, plasma nifedipine levels were determined in patients undergoing CPB; second, plasma nifedipine levels were determined in an in vitro preparation consisting of a CPB circuit filled with blood to which nifedipine had been added. With the approval of the Committee on Research Involving Human Subjects, and after having obtained informed consent, 10 subjects were studied. All had been taking oral nifedipine for at least 1 wk before surgery at a daily dose ranging between 10 and 20 mg every 8 h. On the morning of surgery, approximately
412
KATZ ET AL.
ANESTH ANALG 1990;71:4113
1 h before arrival in the operating room, all patients received their last preoperative dose of nifedipine. p-Adrenergic antagonists, nitrates, and other cardiac medications were all continued through the morning of surgery. Preoperative sedation consisted of a combination of either intramuscular morphine-scopolamine or intramuscular morphine-lorazepam. All patients were given 30 mL of oral sodium citrate (Bicitra) to neutralize stomach acid. Monitored variables included pulmonary and radial arterial pressures, electrocardiogram, hemoglobin oxygen saturation, end-tidal Pco,, and rectal and central arterial temperatures. Anesthesia was induced with intravenous sufentanil (10 pgikg), followed by intravenous vecuronium (10 mg) for muscle relaxation. After tracheal intubation, mechanical ventilation was instituted with 100% oxygen. Five milliliters of blood was drawn from the radial artery catheter for determination of serum nifedipine concentration at the time the aortic cannula was placed (point A), which was approximately 30 min before the start of CPB (which was approximately 4 h after the last oral dose of nifedipine). Additional samples were drawn 30 min after institution of CPB (point a), approximately 30 min before the termination of bypass (point C, at which time the last proximal graft had been placed and the patient had been rewarmed), and 30 min after termination of bypass (point D). All samples were protected from light and placed on ice before freezing. Nifedipine levels were determined by National Medical Services (Willow Grove, Pa.) using highpressure liquid chromatography with electrochemical detection, a method with an accuracy of *lo% and the ability to detect a nifedipine concentration as low as 2 ngimL. Results reported as "none detected" were considered to be zero for purposes of analysis. Therapeutic levels of serum nifedipine were considered to be 25100 ngimL (8). Results were compared to previously established pharmacokinetic data for nifedipine in normal volunteers (9). The second part of our study examined the effect of the bypass circuit itself upon plasma nifedipine levels. A CPB circuit was set up in a standard fashion but with the venous line connected to the arterial line in order to complete the circuit. Two units of whole blood (outdated), 250 mL of 5% albumin, 50 g of mannitol, 10,000 U of heparin, and lactated Ringer's solution to a final volume of 2 L were added to the circuit. The pH was adjusted to 7.4 with NaHCO,. The final hematocrit was approximately 20%. Nifedipine (0.5 mg) was added to this solution. The temperature was maintained at 23°C. The mixture was pumped at a flow rate of 2 L/min using a roller
150 -
Hours 1
2
3
4
5
6
7
8
Points A B C D FiRure 1. Mean plasma nifedipine concentrations after 20-mg oral (-0-) and 10-mg oral doses (-A-), adapted from Raemsch and Sommer (by permission of American Heart Association, Inc., and K. D. Raemsch of Reference 9), plus mean plasma nifedipine concentrations at points A, B, C, and D ( + ) in the present study. *P < 0.05 from point A.
pump (Cobe) and pumped through a M2000 membrane oxygenator (Shiley, Irvine, Calif.), EC3840 arterial filter (Pall, Glen Cove, N.Y.), reservoir bag (Bently BMR 1900), and cardiotomy reservoir (Bard H 4700) using standard polyvinylchloride tubing. Fivemilliliter samples of blood were assayed for nifedipine after 1 min (time 0) to allow for mixing, and then every 30 min for 3 h. To examine the effect of light on nifedipine in the CPB circuit, this test was conducted both in the presence of normal operating room fluorescent light and in a dark room. The data were examined by analysis of variance for repeated measures, with the Fisher probable least significant difference test as a multiple comparison test to determine statistically significant differences between time points. P < 0.05 was considered to be statistically significant. Results are reported as mean
* SEM.
Results Results for part 1 are summarized in Figure 1. One patient had a difficult surgical dissection, and CPB did not start until 8 h after his morning dose of nifedipine. Plasma levels of nifedipine in this patient were 0 at all four data points. One patient had a nifedipine level at point A that was much higher than
CARDIOPULMONARY BYPASS AND PLASMA NIFEDIFINE
ANESTH ANALG 1990;71:411-4
Table 1. Nifedipine Plasma Levels in Isolated Cardiopulmonary Bypass Circuits (ng/mL) Time from baseline (min)
Plasma level in light (n = 1) Plasma level in dark ( n = 1)
0
30
60
90
120
150
180
12
12
16
14
16
14
16
10
13
12
15
14
12
12
those of any other patient. An examination of this patient’s records revealed that his nifedipine dose had been changed from 20 mg every 8 h to 20 mg every 6 h on arrival in the hospital 2 days before. Both of these patients were excluded from the statistical analysis. The mean CPB time of the remaining patients was 2.5 -+ 0.3 h. The mean concentration of the eight samples at point A was 18 f 4 ng/mL. The mean concentration for points B, C, and D was 12 f 3, 11 f 5, and 8 ? 3 ng/mL, respectively. Analysis revealed a statistically significant difference (P < 0.05) Results for part 2 are summarized in Table 1. There were no changes in serum nifedipine levels obtained from the CPB circuit over the 3 h of the study, either in fluorescent light or in a darkened room.
Discussion The results of our study demonstrate that plasma nifedipine levels in patients decline during CPB. There are many factors that might, in theory, lead to changes in blood levels of a medication on CPB. These include increased volume of distribution due to the addition of pump prime; dilution of red blood cells and plasma proteins by the pump prime; and decreased hepatic and renal metabolism and excretion secondary to hypothermia and altered tissue perfusion. However, if nifedipine levels were reduced by the CPB itself, one would expect the decrease to be precipitous; the plasma level would go down abruptly when CPB started, as hemodilution and changes in volume of distribution occur within seconds of starting CPB. In this study, the initial blood sample was drawn from our patients at approximately 4 h after their last dose of nifedipine, and the last sample was drawn an average of 3.5 h after that. Our degradation curve closely parallels the terminal portion of the previously established nifedipine degradation curve (Figure 1)(9) in normal patients. These results suggest that the decrease in plasma nifedipine levels during CPB is not due to the CPB itself but
413
rather to the normal metabolism and elimination of the drug. Part 2 of our study revealed that nifedipine does not bind to the materials of the CPB circuit, and that the presence of normal fluorescent lighting in an operating room does not affect levels of nifedipine in blood circulating through a CPB circuit, despite the well-described tendency of this agent to undergo photodegradation (10). Prior pharmacokinetic studies have determined that nifedipine has a serum half-life of approximately 3 h (9,ll). The duration of action with chronic administration is questionable. At least one study has shown accumulation with repeated dosages (lo), but Raemsch and Sommer could demonstrate no accumulation after 7 days of chronic administration (9), and our own previous work (12), as well as the current study, showed that a majority of patients chronically taking nifedipine have subtherapeutic levels at approximately 4 h after the last oral administration. When beginning treatment of a patient with nifedipine, it is uncommon to routinely measure plasma nifedipine levels to determine therapeutic effect. As presently prescribed, the dose of nifedipine is adjusted to relieve the individual patient’s symptoms. However, there seems to be a “window” in blood levels of nifedipine in most patients, a time lasting up to an hour or longer, when the serum level of nifedipine is zero or almost zero, before the every-8-h dosing of the drug. The clinical significance of this fact is presently unknown. Because very few patients appear to have a therapeutic level of nifedipine by the end of CPB, it cannot be said whether or not a therapeutic level during and after bypass will lead to better results. However, our previous work has demonstrated that sublingual nifedipine given after discontinuation of CPB can reduce coronary artery graft resistance (12) even in patients who are chronically taking the drug before surgery. This suggests that therapeutic plasma levels might offer continued benefit after bypass. Slogoff and Keats have demonstrated that the incidence of intraoperative ischemia in cardiac surgery patients taking nifedipine or diltiazem is greater than it is in patients taking either these medications plus a P-adrenergic blocker or a P-adrenergic blocker alone (7). Our study raises the possibility that this lack of benefit might be due, at least in part, to subtherapeutic blood levels of the calcium channel blocker during surgery. Knight et al. (13) found that the incidence of myocardial ischemia in the immediate postoperative period after coronary artery bypass grafting is essentially the same as that during the preoperative peri-
414
ANESTH ANALG 1990;71:411-4
od-40% and 42%, respectively-and this despite the fact of coronary revascularization. Similarly, Slogoff and Keats reported (14) that perioperative myocardial ischemia is a significant risk factor in the development of postoperative myocardial infarction. It seems clear that the prevention of myocardial ischemia in the perioperative period is a desirable goal. Our study demonstrates that whether or not nifedipine can provide this protection is questionable. Considering that many patients have extremely low blood levels of nifedipine within 4 h of administration (in our study, six of eight patients had levels considered to be subtherapeutic before bypass), it seems likely that there are many hours during and after surgery when the patient is deprived of any beneficial effects of his or her medication; even operations lasting for only an hour or so often necessitate a period when oral medications cannot be taken afterward. In Europe, intravenous, rectal, and ”slow-release” oral preparations of nifedipine are all available. The drug is reliably absorbed by rectum (9), and the slowrelease oral form provides detectable blood levels for over 24 h (15). In the United States, however, the slow-release form has only recently been available and the only alternative to the oral route is the sublingual administration of nifedipine. It may well be that the patient scheduled for cardiac surgery who has been chronically taking nifedipine would benefit by a switch to the slow-release form before surgery and the fasting, postoperative patient who has been chronically taking nifedipine might benefit by sublingual administration of this medication.
References 1. Parisi AF, Strauss WE, Mclntyre KM, et al. Considerations in evaluating new antianginal drugs. Circulation 1982;65(Suppl I):I3%42.
KATZ ET AL.
2. Antunin E, Muller J, Goldberg S, et al. Nifedipine therapy for coronary artery spasm: experience in 127 patients. N Engl J Med 1980;302:1269-73. 3. Aoki K, Kondo S, Mochizuk A, et al. Anti-hypertensive effect of cardiovascular calcium antagonists in hypertensive patients in the absence and presence of beta adrenergic blockade. Am Heart J 1987;96:21&26. 4. DHollander AA, Duvaldestin P, Henzel D, Nevelsteen M, Bomblet JP. Variations in pancuronium requirements, plasma concentration, and urinary excretion induced by cardiopulmonary bypass with hypothermia. Anesthesiology 1983;58:5059. 5. Plachetka JR, Salomon NW, Copeland JC. Plasma propranolol before, during and after cardiopulmonary bypass. Clin Pharmacol Ther 1981;30:745-51. 6. Akl BF, Richardson G. Serum cezazolin levels during cardiopulmonary bypass. Ann Thorac Surg 1980;29:109-12. 7. Slogoff S, Keats AS. Does chronic treatment with calcium entry blocking drugs reduce perioperative myocardial ischemia? Anesthesiology 1988;68:67&80.
8. Calcium channel antagonists. Drug facts and c o m p a r i s o n s the September quarterly index: facts and comparison division. Philadelphia: JB Lippincott, 1988:149:A.P. 9. Raemsch KD, Sommer J. Pharmacokinetics and metabolism of nifedipine. Hypertension 1983;5(Suppl II):1118-24. 10. Tucker FA, Minty PSB, MacGregor GA. Study of nifedipine photodecomposition in plasma and whole blood using capillary gas-liquid chromatography. J Chromatogr 1985;342:193-8.
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