Volume Number
121 4. Part
Brief Communications
1
surgery, and the hemopericardium was ultimately attributed to hemorrhagic pericarditis. Unfortunately, this patient had a prolonged hospital course requiring a protracted period of mechanical ventilation complicated by systemic infections, and she died approximately 6 weeks after her myocardial infarction of factors unrelated to cardiac tamponade. While other hemorrhagic complications of thrombolytic therapy have been widely reported,5 only four cases of tamponade attributed to thrombolytic-associated hemopericardium have been reported in the literature,6-8 and this is the first account of cardiac tamponade associated with tPA. The typical finding of pulsus paradoxus with equalization of pressures (Fig. 11, the angiographic results, the findings at the time of surgical exploration, and the rapid response to pericardiocentesis all indicate that the hypotensive episode was due to cardiac tamponade and not to cardiogenic shock. While the response to pericardiocentesis was rapid, it was also quite atypical. In their study of cardiac tamponade in medical patients, Guberman et a1.g demonstrated that the initially elevated pulmonary capillary wedge pressure typically remains elevated after pericardiocentesis, but the right atria1 and pericardial pressures drop quickly. In our patient, however, the right atria1 pressure remained elevated after pericardiocentesis, while the left ventricular end-diastolic pressure rose dramatically from 20 to 39 mm Hg (Figs. 1 and 2). This response is probably due to the inability of the left ventricle to accommodate the increased venous return. Pericardiocentesis during cardiac tamponade results in increased pulmonary and systemic venous return that is manifested by as much as a 60 % increase in both the left and right ventricular volumes.iO The less compliant, post-infarction left ventricle in this case was unable to accommodate the increased pulmonary venous return following pericardiocentesis. This then led to the observed rise in left ventricular end-diastolic pressure, Our experience with this case, and a review of the medical literature, leads us to make two important points. First, cardiac tamponade precipitated by hemorrhage into the pericardial space is an exceedingly rare complication with tPA therapy. Second, we recommend that additional care should be taken during the process of pericardiocentesis, since a mismatch between the increased venous return and the ability of the left ventricle to accommodate that return can lead to a rapid increase in the LVEDP. This rise in LVEDP could then manifest itself clinically as acute pulmonary edema and would further complicate the management of an already complex case. REFERENCES
1. Charlop S, Greenberg S, Greengart A, et al. Pericardial effusion early in acute myocardial infarction. Clin Cardiol 1989;12:252-4. 2. Galve E, Garcia-Del-Castillo H, Evangelista A, Batlle J, Permanyer-Miralda G, Soler-Soler J. Pericardial effusion in the course of myocardial infarction: Incidence, natural history and clinical relevance. Circulation 1986;73:294-9. 3. Pierard LA, Albert A, Henrard L, et al. Incidence and significance of pericardial effusion in acute myocardial infarction as
4. 5.
6.
7.
8.
9.
10.
1229
determined by two-dimensional echocardiography. J Am Co11 Cardiol 1986;8:517-20. The TIM1 Study Group. The Thrombolysis In Myocardial Infarction trial. N Engl J Med 1985;312:932-6. The TIM1 study group. The Thrombolysis In Myocardial Infarction (TIMI) trial-Phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Co11 Cardiol 1988;11:1-11. Walker WE, Fuentes F, Adams PR, et al. Hemopericardium and tamponade following intracoronary thrombolysis with streptokinase. Tex Heart Inst J 1985;12:203-6. Valeix B, Labrunie P, Jahjah F, et al. Hemopericardium after coronary recanalization by streptokinase during acute myocardial infarction. Arch Ma1 Coeur 1983;76:1081-4. Giles PJ, D’cruz IA, Killam HA. Tamponade due to hemopericardium after streptokinase therapy for pulmonary embolism. South Med J 1988;81:912-4. Guberman BA, Fowler NO, Engel PJ, Gueron M, Allen JM. Cardiac tamponade in medical patients. Circulation 1981; 64:633-40. Manyari DE, Kostuk WJ, Purves P. Effects of pericardiocentesis on right and left ventricular function and volumes in pericardial effusion. Am J Cardiol 1983;52:159-62.
Nitrate tolerance in angina pectoris: of transdermal nitroglycerin with a four-hour nitrate-free interval
Effect
Mark W.I. Webster, MB, ChB, D. Norman Sharpe, Renee Coxon, RN, and Jenny Hughes, MB. Auckland, New Zealand
MD,
Transdermal nitrate preparations produce a short-term improvement in symptoms and exercise capacity in patients with chronic stable angina, but usually fail to maintain this therapeutic benefit with continuous treatment.lm8 One strategy to avoid nitrate tolerance is to apply the nitrate patches intermittently. A nitrate-free interval of 8,10, or 12 hours appears sufficient to maintain the initial benefit, at least when assessed shortly after patch reapplication.6“0 We performed a placebo-controlled, double-blind, random-order, crossover study to determine whether a 4-hour nitrate-free interval was sufficient to allow the short-term benefit of transdermal nitroglycerin to be maintained. The protocol was approved by the institutional review committee and all participants gave informed consent. The study population consisted of 11 men and 1 woman, aged 36 to 71 years (mean 58) with chronic, stable, exercise-induced angina and a positive exercise test for myocardial ischemia. Patients were required to have a reproducible exercise end point (within 15%) and show at least a 15% From the Department of Medicine, Auckland Hospital. Supported in part by a grant from Ciba Geigy (New Zealand) Ltd. Reprint requests: D.N. Sharpe, MD, Dept. of Medicine, Auckland Hospital, Auckland 1, New Zealand. 4/4/27325
1230
Brief Communications
I 1. Time to onset of angina and total exercise time (mean * SD). Both exercise parameters were significantly increased with short-term (Acute) nitroglycerin patch application compared with baseline (p = 0.02, 0.01, respectively), but not compared with placebo (p = 0.14,0.17, respectively). This increase was attenuated 7 days later. Fig.
improvement in total exercise duration 60 minutes after application of 10 mg transdermal nitroglycerin. Nine patients were taking a P-blocker and eight were taking a calcium channel blocker; six were receiving both medications. Four had suffered a previous myocardial infarct. The mean duration of angina was 4 years (range 1 to 16 years). Exclusion criteria were a myocardial infarct within 3 months, unstable angina, significant hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >lOO mm Hg), valvular heart disease, heart failure, or electrocardiographic abnormalities precluding interpretation of ST segment changes. At the time of initial screening, long-acting nitrate preparations were discontinued; P-blockers and calcium-channel blockers were continued in unchanged dosage, taken at the same time each day. Exercise testing was with a Bosch bicycle ergometric system (ERG551, Bosch Corp., Medical Division, Broadview, Ill.) with an integrated programmer and a speed-independent constant loading system. An individualized protocol was devised for each patient to produce a total exercise duration of approximately 9 to 10 minutes, which we have previously shown to optimize test reproducibi1ity.l’ This was achieved by adjusting the initial load between 20 and 100 W, followed by a constant increment of 10 W every 2 minutes. The electrocardiograph
was monitored continually and the heart rate and blood pressure were recorded after each load increment, at the onset of angina and at the completion of exercise. Exercise end points were time to the onset of angina, total exercise duration (the time at which the patient would normally cease exertion), and heart rate-systolic blood pressure product at the onset of angina. After at least two preliminary assessments, the baseline exercise test was performed between 10 AM and noon. All subsequent tests were performed at the same time of day and the exercise conditions were carefully standardized.” In particular, patients were instructed to stop at the same level of angina1 discomfort on each occasion. The double-blind phase of the study consisted of two 7-day treatment periods in random order separated by a 3-day washout period. Treatment was with either transdermal nitroglycerin (Nitroderm TTS, Ciba-Geigy Corp., Summit, N.J.), 10 mg/24 hours, or matching placebo. Two 5 mg patches were applied to the anterior chest at 7 AM on the first treatment day and the acute exercise test was performed 4 hours later. Subsequently the patches were removed at 7 PM and were replaced by two new patches at 11 PM, providing a 4-hour nitrate-free interval. The long-term exercise test was performed at 11 AM on the seventh day of treatment, 12 hours after patch application. A diary record of angina frequency and sublingual nitroglycerin consumption was kept by all patients during the treatment periods. Exercise parameters were compared between treatment phases and with baseline measurements using a paired, two-tailed t test. A probability (p) value
121 4. Part
Brief Communications
1
surgery, and the hemopericardium was ultimately attributed to hemorrhagic pericarditis. Unfortunately, this patient had a prolonged hospital course requiring a protracted period of mechanical ventilation complicated by systemic infections, and she died approximately 6 weeks after her myocardial infarction of factors unrelated to cardiac tamponade. While other hemorrhagic complications of thrombolytic therapy have been widely reported,5 only four cases of tamponade attributed to thrombolytic-associated hemopericardium have been reported in the literature,6-8 and this is the first account of cardiac tamponade associated with tPA. The typical finding of pulsus paradoxus with equalization of pressures (Fig. 11, the angiographic results, the findings at the time of surgical exploration, and the rapid response to pericardiocentesis all indicate that the hypotensive episode was due to cardiac tamponade and not to cardiogenic shock. While the response to pericardiocentesis was rapid, it was also quite atypical. In their study of cardiac tamponade in medical patients, Guberman et a1.g demonstrated that the initially elevated pulmonary capillary wedge pressure typically remains elevated after pericardiocentesis, but the right atria1 and pericardial pressures drop quickly. In our patient, however, the right atria1 pressure remained elevated after pericardiocentesis, while the left ventricular end-diastolic pressure rose dramatically from 20 to 39 mm Hg (Figs. 1 and 2). This response is probably due to the inability of the left ventricle to accommodate the increased venous return. Pericardiocentesis during cardiac tamponade results in increased pulmonary and systemic venous return that is manifested by as much as a 60 % increase in both the left and right ventricular volumes.iO The less compliant, post-infarction left ventricle in this case was unable to accommodate the increased pulmonary venous return following pericardiocentesis. This then led to the observed rise in left ventricular end-diastolic pressure, Our experience with this case, and a review of the medical literature, leads us to make two important points. First, cardiac tamponade precipitated by hemorrhage into the pericardial space is an exceedingly rare complication with tPA therapy. Second, we recommend that additional care should be taken during the process of pericardiocentesis, since a mismatch between the increased venous return and the ability of the left ventricle to accommodate that return can lead to a rapid increase in the LVEDP. This rise in LVEDP could then manifest itself clinically as acute pulmonary edema and would further complicate the management of an already complex case. REFERENCES
1. Charlop S, Greenberg S, Greengart A, et al. Pericardial effusion early in acute myocardial infarction. Clin Cardiol 1989;12:252-4. 2. Galve E, Garcia-Del-Castillo H, Evangelista A, Batlle J, Permanyer-Miralda G, Soler-Soler J. Pericardial effusion in the course of myocardial infarction: Incidence, natural history and clinical relevance. Circulation 1986;73:294-9. 3. Pierard LA, Albert A, Henrard L, et al. Incidence and significance of pericardial effusion in acute myocardial infarction as
4. 5.
6.
7.
8.
9.
10.
1229
determined by two-dimensional echocardiography. J Am Co11 Cardiol 1986;8:517-20. The TIM1 Study Group. The Thrombolysis In Myocardial Infarction trial. N Engl J Med 1985;312:932-6. The TIM1 study group. The Thrombolysis In Myocardial Infarction (TIMI) trial-Phase I: hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. J Am Co11 Cardiol 1988;11:1-11. Walker WE, Fuentes F, Adams PR, et al. Hemopericardium and tamponade following intracoronary thrombolysis with streptokinase. Tex Heart Inst J 1985;12:203-6. Valeix B, Labrunie P, Jahjah F, et al. Hemopericardium after coronary recanalization by streptokinase during acute myocardial infarction. Arch Ma1 Coeur 1983;76:1081-4. Giles PJ, D’cruz IA, Killam HA. Tamponade due to hemopericardium after streptokinase therapy for pulmonary embolism. South Med J 1988;81:912-4. Guberman BA, Fowler NO, Engel PJ, Gueron M, Allen JM. Cardiac tamponade in medical patients. Circulation 1981; 64:633-40. Manyari DE, Kostuk WJ, Purves P. Effects of pericardiocentesis on right and left ventricular function and volumes in pericardial effusion. Am J Cardiol 1983;52:159-62.
Nitrate tolerance in angina pectoris: of transdermal nitroglycerin with a four-hour nitrate-free interval
Effect
Mark W.I. Webster, MB, ChB, D. Norman Sharpe, Renee Coxon, RN, and Jenny Hughes, MB. Auckland, New Zealand
MD,
Transdermal nitrate preparations produce a short-term improvement in symptoms and exercise capacity in patients with chronic stable angina, but usually fail to maintain this therapeutic benefit with continuous treatment.lm8 One strategy to avoid nitrate tolerance is to apply the nitrate patches intermittently. A nitrate-free interval of 8,10, or 12 hours appears sufficient to maintain the initial benefit, at least when assessed shortly after patch reapplication.6“0 We performed a placebo-controlled, double-blind, random-order, crossover study to determine whether a 4-hour nitrate-free interval was sufficient to allow the short-term benefit of transdermal nitroglycerin to be maintained. The protocol was approved by the institutional review committee and all participants gave informed consent. The study population consisted of 11 men and 1 woman, aged 36 to 71 years (mean 58) with chronic, stable, exercise-induced angina and a positive exercise test for myocardial ischemia. Patients were required to have a reproducible exercise end point (within 15%) and show at least a 15% From the Department of Medicine, Auckland Hospital. Supported in part by a grant from Ciba Geigy (New Zealand) Ltd. Reprint requests: D.N. Sharpe, MD, Dept. of Medicine, Auckland Hospital, Auckland 1, New Zealand. 4/4/27325
1230
Brief Communications
I 1. Time to onset of angina and total exercise time (mean * SD). Both exercise parameters were significantly increased with short-term (Acute) nitroglycerin patch application compared with baseline (p = 0.02, 0.01, respectively), but not compared with placebo (p = 0.14,0.17, respectively). This increase was attenuated 7 days later. Fig.
improvement in total exercise duration 60 minutes after application of 10 mg transdermal nitroglycerin. Nine patients were taking a P-blocker and eight were taking a calcium channel blocker; six were receiving both medications. Four had suffered a previous myocardial infarct. The mean duration of angina was 4 years (range 1 to 16 years). Exclusion criteria were a myocardial infarct within 3 months, unstable angina, significant hypertension (systolic blood pressure >180 mm Hg or diastolic blood pressure >lOO mm Hg), valvular heart disease, heart failure, or electrocardiographic abnormalities precluding interpretation of ST segment changes. At the time of initial screening, long-acting nitrate preparations were discontinued; P-blockers and calcium-channel blockers were continued in unchanged dosage, taken at the same time each day. Exercise testing was with a Bosch bicycle ergometric system (ERG551, Bosch Corp., Medical Division, Broadview, Ill.) with an integrated programmer and a speed-independent constant loading system. An individualized protocol was devised for each patient to produce a total exercise duration of approximately 9 to 10 minutes, which we have previously shown to optimize test reproducibi1ity.l’ This was achieved by adjusting the initial load between 20 and 100 W, followed by a constant increment of 10 W every 2 minutes. The electrocardiograph
was monitored continually and the heart rate and blood pressure were recorded after each load increment, at the onset of angina and at the completion of exercise. Exercise end points were time to the onset of angina, total exercise duration (the time at which the patient would normally cease exertion), and heart rate-systolic blood pressure product at the onset of angina. After at least two preliminary assessments, the baseline exercise test was performed between 10 AM and noon. All subsequent tests were performed at the same time of day and the exercise conditions were carefully standardized.” In particular, patients were instructed to stop at the same level of angina1 discomfort on each occasion. The double-blind phase of the study consisted of two 7-day treatment periods in random order separated by a 3-day washout period. Treatment was with either transdermal nitroglycerin (Nitroderm TTS, Ciba-Geigy Corp., Summit, N.J.), 10 mg/24 hours, or matching placebo. Two 5 mg patches were applied to the anterior chest at 7 AM on the first treatment day and the acute exercise test was performed 4 hours later. Subsequently the patches were removed at 7 PM and were replaced by two new patches at 11 PM, providing a 4-hour nitrate-free interval. The long-term exercise test was performed at 11 AM on the seventh day of treatment, 12 hours after patch application. A diary record of angina frequency and sublingual nitroglycerin consumption was kept by all patients during the treatment periods. Exercise parameters were compared between treatment phases and with baseline measurements using a paired, two-tailed t test. A probability (p) value
