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Aminophylline for Angina Pectoris Boon or Bust?
Theophylline Therapy A Continuing Dilemma pirom tr . Th r in li
}" this issue (see pages I, 44) Drs. Lam and Newhouse have written a timely review on theophylline . Use of this drug has increased at an extraordinary rate over the past two decades. While its popularity may be beginning to wane, several million North Americans still take the drug on a regular basis, and there are many vocal and influential advocates of theophylline within the medical community. Unfortunately, theophylline is a drug that is illsuited for widespread administration. The complex pharmacokinetics, the narrow therapeutic index, and the potential for life-threatening toxic reactions guarantee that instances of serious misadventure will occur when theophylline is prescribed for large numbers of patients. The precise magnitude of the risk of serious toxicity is not known, but numerous reports in the literature uniformly support the conclusion that incidents are not isolated . 1·3 A careful retrospective review of our experience at the Minneapolis (Minn) Veterans Administration Medical Center indicates that the recognized risk of a fatal or life-threatening complication of theophylline therapy is approximately 0.5 percent per year in a population largely composed of elderly patients with chronic obstructive pulmonary disease (COPD) and with complicated medical problems. Caution must be exercised in extrapolating this figure to the community at large, but, as a very conservative estimate, it is likely that several thousand patients experience a serious adverse reaction to theophylline each year in the United States alone, and the actual number might run into the tens of thousands. Drs. Lam and Newhouse point out that numerous alternatives to theophylline now exist, and in most clinical settings a well-designed regimen of inhaled drugs provides superior therapy with a high degree of safety. Logic dictates that methylxanthines should be relegated to the third or fourth line of therapy in treating both COPD and asthma, and it is appropriate to ask whether they are now obsolete. Unfortunately, the evidence does not permit a definitive answer. Drs. Lam and Newhouse review clinical studies indicating that adding theophylline to other treatment measures is of no clinical benefit in treating acute exacerbations ofCOPD or asthma. However, the drug may be helpful in those patients with stable COPD or chronic asthma who are already receiving inhalant therapy. The effects of theophylline in this setting are so modest as to be of questionable clinical relevance in many patients, but larger effects may be seen in selected individuals. Even small changes may be important in the severely disabled.
all pati nts, unn cessaril,
xposing man to th :o t and lif< -threatenin risk of a drug that carrie no b n fi t? r ·b uld th phyllin b denied to all p r n wh might d ri b - onlroll d trial of tr atm nt in th individual patient, a ·u ·t d hy uyatt and hi a · iat ·; rna b th id al ' a f addr th is probl m but the t chniqu it ' ·n probabl · nul gain "·d clini ·al pra ·ti · . The use of theophylline may decline in coming years, but it is unlikely to disappear. Prescribing habits tend to be deeply engrained, and most physicians are reluctant to forego any form of therapy that offers reasonable hope of benefiting a.severely incapacitated patient. Therefore, the first challenge for the clinical investigator is to define more sharply the indications for methylxanthine therapy. The second challenge is to supplant theophylline entirely through the continued development of better and safer forms of treatment. Dennis E. Niewoehner; M.D . , F.C .C.P. Minneapolis Pulmonary Section, Veterans Administration Medical Center. REFERENCES
1 Woodmck AA. Johnson MA . Geddes OM . Theophylline prescrihing. semm concentrations, and toxicity. LaJI(:e t 1983; 2:610-12 2 Mountain RD, NeffTA. Oral theophylline intoxication: a serious error of patient and physician unde rstandin!(. Arch Inte rn Med 1984; 144:724-27 3 Aitken ML, Martin TR. Life-threatening theophylline toxicity is not predictahle hy semm levels. Chest 1987; 91:10-4 4 Cuyatt CH, Sackett D, Taylor ow: Chong J, Roberts R, Pugsley SO. Determining optimal the rapy: randomized trials in individual patients. N Eng! J Med 1986; 314:889-92
Aminophylline for Angina Pectoris Boon or Bust? recent reports have suggested that theoSeveral phylline might have a beneficial effect in the treatment of angina pectoris. 14 This concept is not new: methylxanthines were first suggested more than 90 years ago for this condition.5 Loss of interest in See pages 1, 3, 5, 44 theophylline for the treatment of coronary disease was related , at least in part, to its side effects and reports of sudden death following its administration.6.7 Of CHEST I 98 I 1 I JULY. 1990
5
interest, the rationale for its use has changed antithetically: previously, this methylxanthine's coronary vasodilating properties were viewed as the basis for its efficacy, 8·9 whereas now its putative vasoconstrictive actions, 10 producing a more favorable distribution of myocardial Bow, are believed to explain its effects. Although early investigations, especially those performed in the anesthetized dog, demonstrated coronary vasodilatation following theophylline administration, 11-13 recent studies have disclosed other actions: theophylline is an antagonist of the potent vasodilator, adenosine, 13- 16 and would be expected to attenuate a maldistribution of myocardial Bow that might result from high concentrations of this nucleoside, such as that which occurs when dipyridamole, an inhibitor of adenosine deaminase, is administered. 17 A study in awake dogs also has disclosed coronary vasoconstriction following theophylline administration; however, that finding was observed only when the dosage of theophylline was sufficiently low to obviate tachycardia.10 Indeed, at higher concentrations vasodilatation was found. 10 In those studies in which theophylline has been tested as an anti-anginal drug, a dosage high enough to produce tachycardia was generally administered.1 .... Also, in individuals with coronary disease, a dosage of theophylline that had a comparable effect on exercise tolerance as sublingual isosorbide dinitrate produced no change in coronary artery diameter even though vasodilation was observed with the nitrate. 4 Other hemodynamic mechanisms might, therefore, be important. Theophylline also is a vasodilator and might improve myocardial subendocardial Bow by reducing left ventricular diastolic pressure. 18 Moreover, anginal relief and electrocardiographic improvement following theophylline administration might not necessarily denote a favorable effect on myocardial ischemia. When adenosine is administered to healthy subjects without coronary disease, chest pains with features of angina pectoris but without electrocardiographic changes may ensue; theophylline pretreatment prevents this occurrence. 19·20 Furthermore, we have found that when theophylline is administered to the dog, there is an immediate increase in serum potassium concentration; this effect is not prevented by autonomic blockade or calcium channel blockers, though a late-occurring decrease in the serum potassium level is prevented by such autonomic blockade. 21 Perhaps the favorable actions of theophylline on the electrocardiographic abnormalities associated with myocardial ischemia may be a reBection of transmembrane potential changes that might occur in response to these changes in potassium concentration. Experiments that we have performed in the dog raise additional concerns regarding the purported antianginal effects of theophylline. 22 When theophylline was administered intravenously to produce con6
centrations considered therapeutic in humans, myocardial lactate extraction decreased, a phenomenon that was related to absence of the enhanced inotropy generally expected with this methylxanthine. Furthermore, premedication and concomitant administration of verapamil with theophylline prevented the disturbance of myocardial lactate metabolism and was associated with an improvement in cardiac performance. These observations would dispute the notion that theophylline exerts a favorable action on myocardial energetics in the dosages used to treat angina pectoris. 22 Even if theophylline might have some physiologic effects that could ameliorate myocardial ischemia, its proarrhythmic actions would still be of concern. In experimental studies in the dog, theophylline has been found to produce tachycardia, shorten both atrial and ventricular refractory periods, enhance atrial fibrillation and promote ventricular fibrillation. 20•22 •23 Although verapamil antagonized the tachycardic effects of theophylline, neither this calcium channel blocker nor autonomic blockade inBuenced the actions of theophylline on myocardial refractory periods.21 Other studies in dogs24 and rats25 have demonstrated that theophylline lowers ventricular fibrillation threshold and produces ventricular tachyarrhythmias. We also have performed a cross-sectional study of 100 hospitalized individuals with pulmonary disease receiving theophylline. Patients having therapeutic serum concentrations of theophylline had 3.5 times the likelihood of having arrhythmias than comparable individuals having lower levels; moreover, serum theophylline concentration emerged as the strongest independent determinant of arrhythmia in this population.26 Thus, despite decades in which theophylline has been available for use in the treatment of angina pectoris, clinical experience has not demonstrated a clear role for this drug in this condition. Indeed, the gastrointestinal, central nervous system and cardiovascular side effects have limited its use even in chronic pulmonary conditions where its benefits are less equivocal. Moreover, the variability of its pharmacokinetics, 27-29 which can be markedly inBuenced by many factors-even a viral infection, renders it a particularly treacherous drug: a dosage that has produced therapeutic concentrations for a long period may inexplicably suddenly result in toxic levels. Of interest, in one of the recent reports in which theophylline was tested as an antianginal drug, one third of the subjects were excluded because of the drug's side effects. 4 Although the spate of recent reports of theophylline use in treating angina pectoris may yield new insights into the actions of this old drug, the body of established experimental evidence and clinical experience would suggest that it is entirely premature Editorials
to encourage its use in the treatment of coronary disease. HowardS. Friedman, M.D., F.C.C.P., and George Bittar; M.D., Brooklyn Section of Cardiology, Department of Medicine, the Brooklyn Hospital-Caledonian Hospifal, and the Department of Medicine, State University of New York Health Science Center at Brooklyn, Brooklyn, NY. Reprint requests: Dr.Friedman,121 DeKDlb Avenue, Brooklyn 10028
REFERENCES 1 Picano E , Pogliani M, Lattanzi F, Distante A, L'Abbate A. Exercise capacity after acute aminophylline administration in angina pectoris. Am J Cardiol1989; 63:14-16 2 Crea F, Glassi AR, Kaski JC, Pupita G, El'llunimi H, Davies GJ, et al. Effect of theophylline on exercise-induced myocardial ischemia. Lancet 1989; 1:683-86 3 Emdin M, Picano E, Lattanzi F, L'Abbate A. Improved exercise capacity with acute aminophylline administration in patients with syndrome X. JAm CoD Cardiol1989; 14:1450-55 4 Crea F, Pupita G, Galassi A, El-'llunimi H, Kaski JC , Davies GJ, et al. Comparative effects of theophylline and isosorbide dinitrate on exercise capacity in stable angina pectoris, and their mechanisms of action. Am J Cardiol1989; 64:1098-1102 5 Askanzy S. Klinisches uber Diuretin. Dt Arch Klin Med 1895; 56:209-22 6 Adams GM . Aminophylline deaths. JAMA 1943; 123:1115 7 Bresnick E, Woodare WK, Sageman CB. Fatal reactions to intravenous administration of aminophyUine. JAMA 1948; 136: 397-98 8 Smith FM, Rathe HW, Paul WD. Theophylline in the treatment of disease of the coronary arteries. Arch Intern Med 1935; 56: 1250-62 9 Gilbert NC, Fenn GK. The effect of the purine base diuretics on the coronary Bow. Arch Intern Med 1929; 44:118-27 10 Rutherford JD, Vatner SF, Braunwald E . Effects and mechanism of action of aminophylline on cardiac function and regional blood Row distribution in conscious dogs. Circulation 1981; 63: 378-87 11 Stoland 00, Ginsberg AM, Loy DL, Herbert PE. Studies on coronary circulation: IV:A. the duration of the coronary dilator action of theophylline ethylene-diamine. B. the effect ofinsulinfree pancreatic extract on the coronary circulation. J Pharmacal Exper Therap 1983; 51:387-97 12 Melville KI, Lu FC. Effect of epinephrine, aminophylline nitroglycerine and papaverine on coronary inftow and on heart contraction, as recorded concurrently. J Pharmacol Exper Therap 1950; 19:286-303 13 Oei HH, Hale TH, Gandhi SS, Pilla TJ, Wergria R. Effect of aminophylline on coronary circulation and cardiac metabolism. Arch Int Pharmacodyn 1977; 299:95-104 14 Giles Rw, Wilcken EL. Reactive hyperaemia in the dog heart: intel"relations between adenosine, ATP, and aminophylline and the effect of indomethacin. Cardiovasc Res 1977; 11:113-21 15 Radford MJ, McHale PA, Sadick N, Schwartz GC, Greenfield JC Jr. Effect ofaminophylline on coronary reactive and functional hyperaemic response in conscious dogs. Cardiovasc Res 1984; 18:377-83 16 Randall JR, Jones CE. Adenosine antagonist aminophylline attennates pacing-induced coronary functional hyperemia. Am J Physiol1985; 246:H1-H7 17 Afonso S. Inhibition of coronary vasodilating action of dipyridamole and adenosine by aminophylline in the dog. Circ Res 1979; 26:743-52
18 Howarth S, McMichael J, Sharpey-Schafer EP. The circulatory action of theophylline ethylenediamine. Clin Sci 1947; 6:12535 19 Sylven C, Beennann 8 , Jonzon B, Brandt R. Angina pectorislike pain provoked by intravenous adenosine in healthy volunteers. Br Med J 1986; 293:227-30 20 Sylven C. Angina pectoris: clinical characteristics, neurophysiological and molecular mechanisms. Pain 1989; 36:145-67 21 Bittar G, Friedman HS, Nguyen T, \brperian V, Dominguez A. Cardiac electrophysiological effects of theophylline: influence of autonomic and calcium channel blockade (Abstract). Clin Res 1989; 37:837A 22 Bittar G, Friedman HS, Dominguez A, Vorperian V. Theophylline produces myocardial ischemia at a therapeutic blood concentration, an effect blocked by verapamil (Abstract). Chest 1989; 252S 23 Bittar G, Friedman HS, Nguyen T, Dominguez A. Theophylline ethylenediamine (aminophylline) promotes atrial and ventricular fibriUation [Abstract]. Clin Res 1988; 36:204A 24 Horowitz LN, Spear JF, Moore EN, Rogers R. Effects of aminophylline on the threshold of initiating ventricular fibrillation during respiratory failure. Am J Cardiol1975; 35:376-79 25 Green M, Guideri G, Lehr D. Role of a- and b-adrenergic activation in ventricular fibrillation death of corticoid-pretreated rats. J Pharm Sci 1980; 69:441-44 26 Bittar G, Friedman HS. Arrhythmogenicity of theophylline in hospitalized patients: relation to serum concentration (Abstract). Chest 1989; 96:133S 27 Jacobs MH, Senior RM , Kessler G . Clinical experience with theophylline: relationships between dosage , serum concentration, and toxicity. JAMA 1979; 235:1983-86 28 Hendeles L, Bighley L, Richardson RH, Hepler CD, Carmichael J. Frequent toxicity from IV aminophylline infusions in critically ill patients. Drug Intelligence Clin Pharm 1977; 11:1217 29 Arbab OA, Wiggins J, Ayres JG , Stableforth DE. The use of parenteral aminophylline in patients taking slow release theophylline preparations: an observation of clinical practice. Br J Dis Chest 1985; 79:161-71
Weaning from Cardiopulmonary Bypass Theory and Practice The pathophysiologic mechanisms responsible for the often unexpected difficulties encountered when a patient is weaned from cardiopulmonary bypass (CPB) continue to challenge the cardiologist, anesthesiologist, and cardiac surgeon. To the former, pump failure in the immediate postoperative period hints at a possible inaccurate assessment of the extent of viable myocardium, left ventricular contractile reserve, or the hemodynamic significance of a valvular lesion. For the cardiac surgeon, the suggestion of an inadequate technical repair hovers over the operating theater. These usually inappropriate anxieties notwithstanding, temporary left ventricular dysfunction is frequently present during the first 24 hours after cardiac surgery.'-3 Moreover, because of improvements in surgical technique and intraoperative myocardial CHEST I 98 I 1 I JULY. 1990
7
}" this issue (see pages I, 44) Drs. Lam and Newhouse have written a timely review on theophylline . Use of this drug has increased at an extraordinary rate over the past two decades. While its popularity may be beginning to wane, several million North Americans still take the drug on a regular basis, and there are many vocal and influential advocates of theophylline within the medical community. Unfortunately, theophylline is a drug that is illsuited for widespread administration. The complex pharmacokinetics, the narrow therapeutic index, and the potential for life-threatening toxic reactions guarantee that instances of serious misadventure will occur when theophylline is prescribed for large numbers of patients. The precise magnitude of the risk of serious toxicity is not known, but numerous reports in the literature uniformly support the conclusion that incidents are not isolated . 1·3 A careful retrospective review of our experience at the Minneapolis (Minn) Veterans Administration Medical Center indicates that the recognized risk of a fatal or life-threatening complication of theophylline therapy is approximately 0.5 percent per year in a population largely composed of elderly patients with chronic obstructive pulmonary disease (COPD) and with complicated medical problems. Caution must be exercised in extrapolating this figure to the community at large, but, as a very conservative estimate, it is likely that several thousand patients experience a serious adverse reaction to theophylline each year in the United States alone, and the actual number might run into the tens of thousands. Drs. Lam and Newhouse point out that numerous alternatives to theophylline now exist, and in most clinical settings a well-designed regimen of inhaled drugs provides superior therapy with a high degree of safety. Logic dictates that methylxanthines should be relegated to the third or fourth line of therapy in treating both COPD and asthma, and it is appropriate to ask whether they are now obsolete. Unfortunately, the evidence does not permit a definitive answer. Drs. Lam and Newhouse review clinical studies indicating that adding theophylline to other treatment measures is of no clinical benefit in treating acute exacerbations ofCOPD or asthma. However, the drug may be helpful in those patients with stable COPD or chronic asthma who are already receiving inhalant therapy. The effects of theophylline in this setting are so modest as to be of questionable clinical relevance in many patients, but larger effects may be seen in selected individuals. Even small changes may be important in the severely disabled.
all pati nts, unn cessaril,
xposing man to th :o t and lif< -threatenin risk of a drug that carrie no b n fi t? r ·b uld th phyllin b denied to all p r n wh might d ri b - onlroll d trial of tr atm nt in th individual patient, a ·u ·t d hy uyatt and hi a · iat ·; rna b th id al ' a f addr th is probl m but the t chniqu it ' ·n probabl · nul gain "·d clini ·al pra ·ti · . The use of theophylline may decline in coming years, but it is unlikely to disappear. Prescribing habits tend to be deeply engrained, and most physicians are reluctant to forego any form of therapy that offers reasonable hope of benefiting a.severely incapacitated patient. Therefore, the first challenge for the clinical investigator is to define more sharply the indications for methylxanthine therapy. The second challenge is to supplant theophylline entirely through the continued development of better and safer forms of treatment. Dennis E. Niewoehner; M.D . , F.C .C.P. Minneapolis Pulmonary Section, Veterans Administration Medical Center. REFERENCES
1 Woodmck AA. Johnson MA . Geddes OM . Theophylline prescrihing. semm concentrations, and toxicity. LaJI(:e t 1983; 2:610-12 2 Mountain RD, NeffTA. Oral theophylline intoxication: a serious error of patient and physician unde rstandin!(. Arch Inte rn Med 1984; 144:724-27 3 Aitken ML, Martin TR. Life-threatening theophylline toxicity is not predictahle hy semm levels. Chest 1987; 91:10-4 4 Cuyatt CH, Sackett D, Taylor ow: Chong J, Roberts R, Pugsley SO. Determining optimal the rapy: randomized trials in individual patients. N Eng! J Med 1986; 314:889-92
Aminophylline for Angina Pectoris Boon or Bust? recent reports have suggested that theoSeveral phylline might have a beneficial effect in the treatment of angina pectoris. 14 This concept is not new: methylxanthines were first suggested more than 90 years ago for this condition.5 Loss of interest in See pages 1, 3, 5, 44 theophylline for the treatment of coronary disease was related , at least in part, to its side effects and reports of sudden death following its administration.6.7 Of CHEST I 98 I 1 I JULY. 1990
5
interest, the rationale for its use has changed antithetically: previously, this methylxanthine's coronary vasodilating properties were viewed as the basis for its efficacy, 8·9 whereas now its putative vasoconstrictive actions, 10 producing a more favorable distribution of myocardial Bow, are believed to explain its effects. Although early investigations, especially those performed in the anesthetized dog, demonstrated coronary vasodilatation following theophylline administration, 11-13 recent studies have disclosed other actions: theophylline is an antagonist of the potent vasodilator, adenosine, 13- 16 and would be expected to attenuate a maldistribution of myocardial Bow that might result from high concentrations of this nucleoside, such as that which occurs when dipyridamole, an inhibitor of adenosine deaminase, is administered. 17 A study in awake dogs also has disclosed coronary vasoconstriction following theophylline administration; however, that finding was observed only when the dosage of theophylline was sufficiently low to obviate tachycardia.10 Indeed, at higher concentrations vasodilatation was found. 10 In those studies in which theophylline has been tested as an anti-anginal drug, a dosage high enough to produce tachycardia was generally administered.1 .... Also, in individuals with coronary disease, a dosage of theophylline that had a comparable effect on exercise tolerance as sublingual isosorbide dinitrate produced no change in coronary artery diameter even though vasodilation was observed with the nitrate. 4 Other hemodynamic mechanisms might, therefore, be important. Theophylline also is a vasodilator and might improve myocardial subendocardial Bow by reducing left ventricular diastolic pressure. 18 Moreover, anginal relief and electrocardiographic improvement following theophylline administration might not necessarily denote a favorable effect on myocardial ischemia. When adenosine is administered to healthy subjects without coronary disease, chest pains with features of angina pectoris but without electrocardiographic changes may ensue; theophylline pretreatment prevents this occurrence. 19·20 Furthermore, we have found that when theophylline is administered to the dog, there is an immediate increase in serum potassium concentration; this effect is not prevented by autonomic blockade or calcium channel blockers, though a late-occurring decrease in the serum potassium level is prevented by such autonomic blockade. 21 Perhaps the favorable actions of theophylline on the electrocardiographic abnormalities associated with myocardial ischemia may be a reBection of transmembrane potential changes that might occur in response to these changes in potassium concentration. Experiments that we have performed in the dog raise additional concerns regarding the purported antianginal effects of theophylline. 22 When theophylline was administered intravenously to produce con6
centrations considered therapeutic in humans, myocardial lactate extraction decreased, a phenomenon that was related to absence of the enhanced inotropy generally expected with this methylxanthine. Furthermore, premedication and concomitant administration of verapamil with theophylline prevented the disturbance of myocardial lactate metabolism and was associated with an improvement in cardiac performance. These observations would dispute the notion that theophylline exerts a favorable action on myocardial energetics in the dosages used to treat angina pectoris. 22 Even if theophylline might have some physiologic effects that could ameliorate myocardial ischemia, its proarrhythmic actions would still be of concern. In experimental studies in the dog, theophylline has been found to produce tachycardia, shorten both atrial and ventricular refractory periods, enhance atrial fibrillation and promote ventricular fibrillation. 20•22 •23 Although verapamil antagonized the tachycardic effects of theophylline, neither this calcium channel blocker nor autonomic blockade inBuenced the actions of theophylline on myocardial refractory periods.21 Other studies in dogs24 and rats25 have demonstrated that theophylline lowers ventricular fibrillation threshold and produces ventricular tachyarrhythmias. We also have performed a cross-sectional study of 100 hospitalized individuals with pulmonary disease receiving theophylline. Patients having therapeutic serum concentrations of theophylline had 3.5 times the likelihood of having arrhythmias than comparable individuals having lower levels; moreover, serum theophylline concentration emerged as the strongest independent determinant of arrhythmia in this population.26 Thus, despite decades in which theophylline has been available for use in the treatment of angina pectoris, clinical experience has not demonstrated a clear role for this drug in this condition. Indeed, the gastrointestinal, central nervous system and cardiovascular side effects have limited its use even in chronic pulmonary conditions where its benefits are less equivocal. Moreover, the variability of its pharmacokinetics, 27-29 which can be markedly inBuenced by many factors-even a viral infection, renders it a particularly treacherous drug: a dosage that has produced therapeutic concentrations for a long period may inexplicably suddenly result in toxic levels. Of interest, in one of the recent reports in which theophylline was tested as an antianginal drug, one third of the subjects were excluded because of the drug's side effects. 4 Although the spate of recent reports of theophylline use in treating angina pectoris may yield new insights into the actions of this old drug, the body of established experimental evidence and clinical experience would suggest that it is entirely premature Editorials
to encourage its use in the treatment of coronary disease. HowardS. Friedman, M.D., F.C.C.P., and George Bittar; M.D., Brooklyn Section of Cardiology, Department of Medicine, the Brooklyn Hospital-Caledonian Hospifal, and the Department of Medicine, State University of New York Health Science Center at Brooklyn, Brooklyn, NY. Reprint requests: Dr.Friedman,121 DeKDlb Avenue, Brooklyn 10028
REFERENCES 1 Picano E , Pogliani M, Lattanzi F, Distante A, L'Abbate A. Exercise capacity after acute aminophylline administration in angina pectoris. Am J Cardiol1989; 63:14-16 2 Crea F, Glassi AR, Kaski JC, Pupita G, El'llunimi H, Davies GJ, et al. Effect of theophylline on exercise-induced myocardial ischemia. Lancet 1989; 1:683-86 3 Emdin M, Picano E, Lattanzi F, L'Abbate A. Improved exercise capacity with acute aminophylline administration in patients with syndrome X. JAm CoD Cardiol1989; 14:1450-55 4 Crea F, Pupita G, Galassi A, El-'llunimi H, Kaski JC , Davies GJ, et al. Comparative effects of theophylline and isosorbide dinitrate on exercise capacity in stable angina pectoris, and their mechanisms of action. Am J Cardiol1989; 64:1098-1102 5 Askanzy S. Klinisches uber Diuretin. Dt Arch Klin Med 1895; 56:209-22 6 Adams GM . Aminophylline deaths. JAMA 1943; 123:1115 7 Bresnick E, Woodare WK, Sageman CB. Fatal reactions to intravenous administration of aminophyUine. JAMA 1948; 136: 397-98 8 Smith FM, Rathe HW, Paul WD. Theophylline in the treatment of disease of the coronary arteries. Arch Intern Med 1935; 56: 1250-62 9 Gilbert NC, Fenn GK. The effect of the purine base diuretics on the coronary Bow. Arch Intern Med 1929; 44:118-27 10 Rutherford JD, Vatner SF, Braunwald E . Effects and mechanism of action of aminophylline on cardiac function and regional blood Row distribution in conscious dogs. Circulation 1981; 63: 378-87 11 Stoland 00, Ginsberg AM, Loy DL, Herbert PE. Studies on coronary circulation: IV:A. the duration of the coronary dilator action of theophylline ethylene-diamine. B. the effect ofinsulinfree pancreatic extract on the coronary circulation. J Pharmacal Exper Therap 1983; 51:387-97 12 Melville KI, Lu FC. Effect of epinephrine, aminophylline nitroglycerine and papaverine on coronary inftow and on heart contraction, as recorded concurrently. J Pharmacol Exper Therap 1950; 19:286-303 13 Oei HH, Hale TH, Gandhi SS, Pilla TJ, Wergria R. Effect of aminophylline on coronary circulation and cardiac metabolism. Arch Int Pharmacodyn 1977; 299:95-104 14 Giles Rw, Wilcken EL. Reactive hyperaemia in the dog heart: intel"relations between adenosine, ATP, and aminophylline and the effect of indomethacin. Cardiovasc Res 1977; 11:113-21 15 Radford MJ, McHale PA, Sadick N, Schwartz GC, Greenfield JC Jr. Effect ofaminophylline on coronary reactive and functional hyperaemic response in conscious dogs. Cardiovasc Res 1984; 18:377-83 16 Randall JR, Jones CE. Adenosine antagonist aminophylline attennates pacing-induced coronary functional hyperemia. Am J Physiol1985; 246:H1-H7 17 Afonso S. Inhibition of coronary vasodilating action of dipyridamole and adenosine by aminophylline in the dog. Circ Res 1979; 26:743-52
18 Howarth S, McMichael J, Sharpey-Schafer EP. The circulatory action of theophylline ethylenediamine. Clin Sci 1947; 6:12535 19 Sylven C, Beennann 8 , Jonzon B, Brandt R. Angina pectorislike pain provoked by intravenous adenosine in healthy volunteers. Br Med J 1986; 293:227-30 20 Sylven C. Angina pectoris: clinical characteristics, neurophysiological and molecular mechanisms. Pain 1989; 36:145-67 21 Bittar G, Friedman HS, Nguyen T, \brperian V, Dominguez A. Cardiac electrophysiological effects of theophylline: influence of autonomic and calcium channel blockade (Abstract). Clin Res 1989; 37:837A 22 Bittar G, Friedman HS, Dominguez A, Vorperian V. Theophylline produces myocardial ischemia at a therapeutic blood concentration, an effect blocked by verapamil (Abstract). Chest 1989; 252S 23 Bittar G, Friedman HS, Nguyen T, Dominguez A. Theophylline ethylenediamine (aminophylline) promotes atrial and ventricular fibriUation [Abstract]. Clin Res 1988; 36:204A 24 Horowitz LN, Spear JF, Moore EN, Rogers R. Effects of aminophylline on the threshold of initiating ventricular fibrillation during respiratory failure. Am J Cardiol1975; 35:376-79 25 Green M, Guideri G, Lehr D. Role of a- and b-adrenergic activation in ventricular fibrillation death of corticoid-pretreated rats. J Pharm Sci 1980; 69:441-44 26 Bittar G, Friedman HS. Arrhythmogenicity of theophylline in hospitalized patients: relation to serum concentration (Abstract). Chest 1989; 96:133S 27 Jacobs MH, Senior RM , Kessler G . Clinical experience with theophylline: relationships between dosage , serum concentration, and toxicity. JAMA 1979; 235:1983-86 28 Hendeles L, Bighley L, Richardson RH, Hepler CD, Carmichael J. Frequent toxicity from IV aminophylline infusions in critically ill patients. Drug Intelligence Clin Pharm 1977; 11:1217 29 Arbab OA, Wiggins J, Ayres JG , Stableforth DE. The use of parenteral aminophylline in patients taking slow release theophylline preparations: an observation of clinical practice. Br J Dis Chest 1985; 79:161-71
Weaning from Cardiopulmonary Bypass Theory and Practice The pathophysiologic mechanisms responsible for the often unexpected difficulties encountered when a patient is weaned from cardiopulmonary bypass (CPB) continue to challenge the cardiologist, anesthesiologist, and cardiac surgeon. To the former, pump failure in the immediate postoperative period hints at a possible inaccurate assessment of the extent of viable myocardium, left ventricular contractile reserve, or the hemodynamic significance of a valvular lesion. For the cardiac surgeon, the suggestion of an inadequate technical repair hovers over the operating theater. These usually inappropriate anxieties notwithstanding, temporary left ventricular dysfunction is frequently present during the first 24 hours after cardiac surgery.'-3 Moreover, because of improvements in surgical technique and intraoperative myocardial CHEST I 98 I 1 I JULY. 1990
7