- Email: [email protected]
Variability of inotropic and chronotropic response during dobutamine stress echocardiography and possible implications for diagnostic accuracy
2. Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994;344:1383–1389. 3. Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, McKillop JH, Packard CJ. Prevention of coronary heart disease with pravastatin in men with hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl J Med 1995;333:1301–1307. 4. Sacks FM, Pfeffer MA, Moye LA, Rouleau JL, Rutherford JD, Cole TG, Brown L, Warnica JW, Arnold JM, Wun CC, Davis BR, Braunwald E. The effect of pravastatin on coronary events after myocardial infarction in patients with average cholesterol levels. Cholesterol and Recurrent Events Trial Investigators. N Engl J Med 1996;335:1001–1009. 5. Downs JR, Clearfield M, Weis S, Whitney E, Shapiro DR, Beere PA, Langendorfer A, Stein EA, Kruyer W, Gotto AM Jr. Primary prevention of acute coronary events with lovastatin in men and women with average cholesterol levels: results of AFCAPS/TexCAPS. Air Force/Texas Coronary Atherosclerosis Prevention Study. JAMA 1998;279:1615–1622. 6. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med 1998;339:1349 –1357. 7. Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20, 536 high-risk individuals: a randomised placebo-controlled trial. Lancet 2002;360:7–22. 8. Jones P, Kofenek S, Laurora I, Hunninghake D. Comparative dose efficacy study of atorvastatin versus simvastatin, pravastatin, lovastatin, and fluvastatin in patients with hypercholesterolemia (the CURVES Study). Am J Cardiol 1998; 81:582–587. 9. Rubin DB. Estimating causal effects from large data sets using propensity scores. Ann Intern Med 1997;127:757–763.
10. Joffe MM, Rosenbaum PR. Invited commentary: propensity scores. Am J
Epidemiol 1999;150:327–333. 11. Drake C, Fisher L. Prognostic models and the propensity score. Int J Epidemiol
1995;24:183–187. 12. D’Agostino RB Jr. Propensity score methods for bias reduction in the
comparison of a treatment to a non-randomized control group. Stat Med 1998; 17:2265–2281. 13. Newton KM, Wagner EH, Ramsey SD, McCulloch D, Evans R, Sandhu N, Davis C. The use of automated data to identify complications and comorbidities of diabetes: a validation study. J Clin Epidemiol 1999;52:199 –207. 14. Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 1991;325:373–381. 15. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Summary of the second report of the National Cholesterol Education Program (NCEP). JAMA 1993;269:3015–3023. 16. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary of the third report of the National Cholesterol Education Program (NCEP). JAMA 2001;285: 2486 –2497. 17. Majumdar SR, Gurwitz JH, Soumerai SB. Undertreatment of hyperlipidemia in the secondary prevention of coronary artery disease. J Gen Intern Med 1999;14:711–717. 18. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160:459 –467. 19. Feely J, McGettigan P, Kelly A. Growth in use of statins after trials is not targeted to most appropriate patients. Clin Pharmacol Ther 2000;67:438 –441. 20. Abookire SA, Karson AS, Fiskio J, Bates DW. Use and monitoring of “statin” lipid-lowering drugs compared with guidelines. Arch Intern Med 2001;161:53–58.
Variability of Inotropic and Chronotropic Response During Dobutamine Stress Echocardiography and Possible Implications for Diagnostic Accuracy Adrian Chenzbraun, MD, Marina Potekhin, MD, Michel Dreyfuss, MD, Tova Alper-Gendelman, RDMS, Frida Kott, RDMS, and Andre Keren, MD Chronotropic and inotropic response patterns were assessed during dobutamine stress echocardiography. Three heart rate response patterns were noted: nonresponders (48% of patients), slow responders (30% of patients), and fast responders (21% of patients). There was no relation between heart rate and contractile response. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:1451–1454)
D
obutamine stress echocardiography (DSE) has emerged during the last decade as a widely used technique for the diagnosis of ischemia, myocardial viability, and for coronary disease risk stratification.1– 8 What defines a diagnostic test in terms of a satisfactory inotropic or chronotropic response is less standardized. Reaching an age-predicted target heart rate is generally considered a prerequisite for a conclusive exercise test,9 and the use of atropine is recommended and widely used lately during DSE10 –12 to increase sensitivity. Most of the available large-scale From The Heiden Department of Cardiology, Bikur Cholim Hospital, Jerusalem, Israel. Dr. Chenzbraun’s address is: The Heiden Department of Cardiology, Bikur Cholim Hospital, 5 Strauss Street, PO Box 492, 91005 Jerusalem, Israel. E-mail: [email protected]. Manuscript received May 12, 2003; revised manuscript received and accepted August 26, 2003. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 December 15, 2003
studies do not specify whether negative tests in which the target heart rate was not reached were considered nondiagnostic or what was the degree of inotropic response.7,8,13 The possible variability of the inotropic response14 may also influence DSE sensitivity. The purpose of the present study was to assess the degree of variability and heterogeneity of the hemodynamic and chronotropic response during DSE in patients without echocardiographic evidence of ischemia. •••
Fifty-six consecutive DSE studies were prospectively analyzed for hemodynamic and chronotropic response during dobutamine infusion. There were 27 men and 29 women (aged 68 ⫾ 12 years, range 35 to 90); 15 patients (35%) were receiving -blocker therapy at the time of the study, 26 had arterial hypertension, and 15 were diabetic. Dobutamine was started at 5 g/kg/min and continued with 10 g/kg/min increments every 3 minutes, up to a maximal dosage of 50 g/kg/min. If ⱖ85% of the maximal age-predicted heart rate was not reached with dobutamine 50 g/kg/min, atropine sulfate 0.7 to 1 mg was given intravenously at the discretion of the supervising physician. The study was stopped when either the maximal dosage or the age-predicted heart rate was achieved, or earlier in case of patient discomfort, significant arrhythmia, systolic blood pressure 0002-9149/03/$–see front matter doi:10.1016/j.amjcard.2003.08.058
1451
min. Atropine was administered in 10 patients and it increased heart rate to target values in 4 of them. For the whole group, the increase in dobutamine to a maximal dose brought a significant increase in heart rate (114 ⫾ 22 vs 69 ⫾ 12 beats/min, p ⬍0.01), systolic blood pressure (150 ⫾ 27 vs 143 ⫾ 25 mm Hg, p ⫽ 0.04), cardiac output (9.3 ⫾ 3 vs 5 ⫾ L/min, p ⬍0.01), and fractional shortening (43 ⫾ 7% vs 36 ⫾ 5%, p ⬍0.01). However, these responses were far from homogenous in patient-level and subgroup analysis, with different timings and slopes for the flat and steep segments of the response curves. FIGURE 1. Representative heart rate (HR) response graphs: (A) fast responder; (B) Three response patterns were slow responder; (C) nonresponder. Note the sudden increase in heart rate of patient identified for heart rate among the B at the 50 g/kg/min stage after a flat response. bpm ⴝ beats per minute. patients who completed the study: nonresponders, 25 patients (48%); fast responders, 11 patients (21%); TABLE 1 Differences in Age, Basal Heart Rate, and -blocker Use According to and slow responders, 16 patients Heart Rate Response Pattern (30%; Figure 1). Advanced age, Nonresponders Responders Fast Responders Slow Responders higher heart rate at baseline, and no (n ⫽ 25) (n ⫽ 27) (n ⫽ 11) (n ⫽ 16) -blocker therapy were strongly asAge (yrs) 65 ⫾ 11 72 ⫾ 13* 76 ⫾ 9 65 ⫾ 14 sociated with responder status; fast Basal heart rate (beats/min) 65 ⫾ 10 74 ⫾ 11 76 ⫾ 9 75 ⫾ 12 response also appeared to be associ-blocker treatment 12 2* 1 1 ated with advanced age but without *p ⬍0.05 for comparison with the nonresponder group. reaching statistical significance (Table 1). Gender, hypertension, and diabetes were not related to response pattern. Slow responders varied decrease of ⬎20 mm Hg, or echocardiographic evi- largely in terms of percent heart rate increase at each dence of ischemia. Digital image acquisition was done stage; some patients exhibited a constant increase and in standard parasternal and apical views at baseline, others showed a sudden increase after a flat response low, and peak dobutamine doses. (Figures 1 and 2). Heart rate, blood pressure, left ventricular diameter The systolic blood pressure response was highly varifor fractional shortening calculation, and cardiac output able, with 16 patients (30%) actually ending with a lower using the left ventricular outflow tract diameter and the blood pressure at protocol completion. In those who had blood flow velocity–time integral at the same level were increased blood pressure, the mean increase was 20 ⫾ 14 recorded at baseline and at the end of each stage. mm Hg, but even in this group the pattern of blood The DSE protocol was considered complete if the pressure increase was not homogenous, with many patarget heart rate was achieved and/or at least the 40 tients showing no increase or even a transient decrease in g/kg/min stage was concluded. These types of reblood pressure at various stages (Figure 2). Age, gender, sponses were defined: patients who did not reach target hypertensive status, diabetes, and use of  blockers were heart rate upon completion of protocol, with or without atropine, were classified as heart rate nonresponders as not related to response pattern. Patients who had inopposed to heart rate responders in whom target heart creased systolic blood pressure during DSE tended to rate was reached with or without atropine. The later were have lower basal blood pressure levels (139 ⫾ 20 vs 151 further classified as quick responders if they reached ⫾ 23 mm Hg, p ⫽ 0.05) Most patients had increased cardiac output (54 of 55) their target heart rate at ⱕ30 g/kg/min or as slow or fractional shortening (46 of 52); however, the degree responders if they needed a higher dobutamine dosage of change in these 2 indexes at each of the protocol with or without atropine. Baseline clinical characteristics, -blocker use, and patterns of change in heart rate, stages showed a variable spread (Figure 3). The increase blood pressure, fractional shortening, and cardiac output in fractional shortening showed a weak inverse correlation with age and basal fractional shortening (r ⫽ ⫺0.3, were compared between these groups. p ⬍0.05) and no relation with gender, hypertension, The study had to be stopped because of side effects at dobutamine doses ⬍40 g/kg/min in 4 patients diabetes, or -blocker treatment. The increase in cardiac (7%). In the remaining 52 patients, the study was output was also weakly inversely correlated with age (r stopped at an average dobutamine dose of 40 g/kg/ ⫽ ⫺0.25, p ⫽ 0.05) and basal cardiac output (r ⫽ 1452 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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patients in whom increasing myocardial oxygen consumption for diagnostic purposes is not feasible by heart rate increase. Dobutamine was expected to circumvent this drawback mainly by increasing contractility, with or without a concomitant increase in heart rate or blood pressure.2,4,15 The diagnostic accuracy of DSE may depend on the inotropic and/or chronotropic response of patients undergoing the test. As such, assessment of the natural spectrum of responses to dobutamine infusion is FIGURE 2. Density plot of percent change in heart rate (A) and systolic blood presessential to define the limitations of sure (B) at each of the DSE protocol stages. Note the large variations, including actual drops at each stage. the method and improve its clinical use. Age-dependent differences in the hemodynamic response to dobutamine are expected16,17 and have been reported in clinical studies.18,19 Pellikka et al20 reported wide variations in heart rate and stroke volume response during dobutamine infusion in 47 patients without evidence of ischemia during DSE. Similar results were reported by Carstensen et al14 for fractional shortening and wall thickening in healthy subjects; in their study, a decrease in inotropic indexes was actually noted at high dobutamine doses in about 1/3 of the patients. FIGURE 3. Density plot of percent change in fractional shortening (A) and cardiac The present study included conoutput (B) at each of the DSE protocol stages. Note the large variations, including secutive patients referred for DSE. actual drops at each stage. The analysis was performed only in patients without permanent or new wall motion abnormalities to avoid the possible influence of left ventricular dysfunction or transient ischemia on the hemodynamic response to dobutamine infusion. Therefore, this patients group is well suited for defining the chronotropic and inotropic response to dobutamine in patients for whom DSE is considered the appropriate diagnostic modality. The wide stage-to-stage variability of the chronotropic response and its relation with other hemodynamic perFIGURE 4. Density plot of percentage increase in fractional shortformance indexes have not been systematically anaening in nonresponders (O), fast responders (X), and slow relyzed or accounted for. In this study we found 3 main sponders (ⴙ). patterns of heart rate response: no response in almost half of the patients, possibly related to -blocker ther⫺0.37, p ⬍0.05) and was not related to gender, diabetes, apy in only 50% of them; slow response in 1/3 of patients; and fast response in about 1/5 of patients. or -blocker therapy. Heart rate response showed a weak correlation (r ⫽ Advanced age was associated with both responder 0.26, p ⫽ 0.05) with systolic blood pressure response status and fast response pattern. Whether this reflects and a moderate association (r ⫽ 0.48, p ⬍0.01) with lower, and therefore faster to achieve, target heart rate cardiac output response. No correlation was found be- or an age-specific cathecolamine response status is not tween the increase in heart rate or systolic blood pressure clear, but similar results already have been reported.18 and the increase in fractional shortening; patients with Inotropic response, the mainstay of DSE technique, various degrees of fractional shortening increase were was also found to be nonhomogenous, with large evenly distributed between heart rate responders and patient variations regarding the timing and amount of change in contractility. Moreover, the inotropic and nonresponders (Figure 4). chronotropic responses were not related. Some pa••• Pharmacologic stress evolved as a test modality for tients showed an unsatisfactory increase in heart rate BRIEF REPORTS
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and at the same time an impressive increase in contractility. Whether atropine is still needed in these patients is not clear. The wide variability in chronotropic and inotropic response found during DSE and especially the lack of correlation between heart rate and contractility response underscore the need for proper diagnostic criteria, especially in heart rate nonresponder patients. Further studies are necessary to establish to what extent quantification of the inotropic response may ascertain the diagnostic value of DSE when heart rate increase is inadequate. 1. Bach DS, Armstrong WF. Dobutamine stress echocardiography. Am J Cardiol 1992;69:90H–96H. 2. Mazeika PK, Nadazdin A, Oakley CM. Dobutamine stress echocardiography for detection and assessment of coronary artery disease. J Am Coll Cardiol 1992;19:1203–1211. 3. Cohen JL, Ottenweller JE, George AK, Duvvuri S. Comparison of dobutamine and exercise echocardiography for detecting coronary artery disease. Am J Cardiol 1993;72:1226 –1231. 4. Marcovitz PA, Armstrong WF. Accuracy of dobutamine stress echocardiography in detecting coronary artery disease. Am J Cardiol 1992;69:1269 –1273. 5. Cigarroa CG, deFilippi CR, Brickner ME, Alvarez LG, Wait MA, Grayburn PA. Dobutamine stress echocardiography identifies hibernating myocardium and predicts recovery of left ventricular function after coronary revascularization. Circulation 1993;88:430 –436. 6. Smart SC, Sawada S, Ryan T, Segar D, Atherton L, Berkovitz K, Bourdillon PD, Feigenbaum H. Low-dose dobutamine echocardiography detects reversible dysfunction after thrombolytic therapy of acute myocardial infarction. Circulation 1993;88:405–415. 7. Das MK, Pellikka PA, Mahoney DW, Roger VL, Oh JK, McCully RB, Seward JB. Assessment of cardiac risk before nonvascular surgery: dobutamine stress echocardiography in 530 patients. J Am Coll Cardiol 2000;35:1647–1653. 8. Poldermans D, Fioretti PM, Boersma E, Bax JJ, Thomson IR, Roelandt JR, Simoons ML. Long-term prognostic value of dobutamine-atropine stress echo-
cardiography in 1737 patients with known or suspected coronary artery disease: a single-center experience. Circulation 1999;99:757–762. 9. Goldschlager N, Selzer A, Cohn K. Treadmill stress tests as indicators of presence and severity of coronary artery disease. Ann Intern Med 1976;85:277– 286. 10. Armstrong WF, Pellikka PA, Ryan T, Crouse L, Zoghbi WA. Stress echocardiography: recommendations for performance and interpretation of stress echocardiography. Stress Echocardiography Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 1998;11:97–104. 11. Elhendy A, van Domburg RT, Poldermans D, Bax JJ, Nierop PR, Geleijnse ML, Roelandt JR. Safety and feasibility of dobutamine-atropine stress echocardiography for the diagnosis of coronary artery disease in diabetic patients unable to perform an exercise stress test. Diabetes Care 1998;21:1797–1802. 12. Cornel JH, Balk AH, Boersma E, Maat AP, Elhendy A, Arnese M, Salustri A, Roelandt JR, Fioretti PM. Safety and feasibility of dobutamine-atropine stress echocardiography in patients with ischemic left ventricular dysfunction. J Am Soc Echocardiogr 1996;9:27–32. 13. Poldermans D, Arnese M, Fioretti PM, Salustri A, Boersma E, Thomson IR, Roelandt JR, van Urk H. Improved cardiac risk stratification in major vascular surgery with dobutamine-atropine stress echocardiography. J Am Coll Cardiol 1995;26:648 –653. 14. Carstensen S, Ali SM, Stensgaard-Hansen FV, Toft J, Haunso S, Kelbaek H, Saunamaki K. Dobutamine-atropine stress echocardiography in asymptomatic healthy individuals. The relativity of stress-induced hyperkinesia. Circulation 1995;92:3453–3463. 15. Sawada SG, Segar DS, Ryan T, Brown SE, Dohan AM, Williams R, Fineberg NS, Armstrong WF, Feigenbaum H. Echocardiographic detection of coronary artery disease during dobutamine infusion. Circulation 1991;83:1605–1614. 16. Docherty JR. Aging and the cardiovascular system. J Auton Pharmacol 1986;6:77–84. 17. van Brummelen P, Buhler FR, Kiowski W, Amann FW. Age-related decrease in cardiac and peripheral vascular responsiveness to isoprenaline: studies in normal subjects. Clin Sci 1981;60:571–577. 18. Poldermans D, Boersma E, Fioretti PM, van Urk H, Boomsma F, Man AJ. Cardiac chronotropic responsiveness to beta-adrenoceptor stimulation is not reduced in the elderly. J Am Coll Cardiol 1995;25:995–999. 19. Chenzbraun A, Khoury Z, Gottlieb S, Keren A. Impact of age on the safety and the hemodynamic response pattern during high dose dobutamine echocardiography. Echocardiography 1999;16:135–142. 20. Pellikka PA, Roger VL, McCully RB, Mahoney DW, Bailey KR, Seward JB, Tajik AJ. Normal stroke volume and cardiac output response during dobutamine stress echocardiography in subjects without left ventricular wall motion abnormalities. Am J Cardiol 1995;76:881–886.
Meta-Analysis of Randomized Clinical Trials on the Usefulness of Acetylcysteine for Prevention of Contrast Nephropathy* Daniel W. Isenbarger,
MD,
Steven M. Kent,
Multiple small studies of oral N-acetylcysteine for prevention of contrast nephropathy have been performed, demonstrating variable efficacy. We performed a meta-analysis of the randomized clinical trials to clarify the degree of benefit. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:1454 –1458)
From the Cardiovascular Service and General Internal Medicine Service, Walter Reed Army Medical Center, Washington, DC. Dr. Isenbarger’s address is: 7543 Spring Lake Drive, #D1, Bethesda, Maryland, 20817-6512. E-mail: [email protected]. Manuscript received May 19, 2003; revised manuscript received and accepted August 21, 2003. *The opinions, interpretations, conclusions, and recommendations expressed in this article are those of the authors and are not necessarily endorsed by the U.S. Army.
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©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 December 15, 2003
MD,
and Patrick G. O’Malley,
MD
ontrast nephropathy (CN) occurs in about 15% of unselected populations undergoing procedures inC volving intravascular radiocontrast administration. Higher rates are seen in those with diabetes and preexisting renal insufficiency.1 Dialysis is required in ⬍1% of patients, and has been associated with prolonged hospital stay and increased morbidity and mortality rates.1–3 Only saline hydration4 and low- or iso-osmolar contrast agents5 have demonstrated prevention of CN. N-acetylcysteine (NAC), an antioxidant, has recently been studied for prevention of CN.6 Given the common occurrence of CN, its potentially serious related outcomes, the low cost and simplicity of administering NAC, and the potential for significant benefits, we systematically assessed the randomized clinical trials of NAC for CN prevention to clarify the magnitude of treatment effects. •••
PubMed, Embase, BIOSIS, on-line clinical trial 0002-9149/03/$–see front matter doi:10.1016/j.amjcard.2003.08.059
10. Joffe MM, Rosenbaum PR. Invited commentary: propensity scores. Am J
Epidemiol 1999;150:327–333. 11. Drake C, Fisher L. Prognostic models and the propensity score. Int J Epidemiol
1995;24:183–187. 12. D’Agostino RB Jr. Propensity score methods for bias reduction in the
comparison of a treatment to a non-randomized control group. Stat Med 1998; 17:2265–2281. 13. Newton KM, Wagner EH, Ramsey SD, McCulloch D, Evans R, Sandhu N, Davis C. The use of automated data to identify complications and comorbidities of diabetes: a validation study. J Clin Epidemiol 1999;52:199 –207. 14. Stampfer MJ, Sacks FM, Salvini S, Willett WC, Hennekens CH. A prospective study of cholesterol, apolipoproteins, and the risk of myocardial infarction. N Engl J Med 1991;325:373–381. 15. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Summary of the second report of the National Cholesterol Education Program (NCEP). JAMA 1993;269:3015–3023. 16. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). Executive summary of the third report of the National Cholesterol Education Program (NCEP). JAMA 2001;285: 2486 –2497. 17. Majumdar SR, Gurwitz JH, Soumerai SB. Undertreatment of hyperlipidemia in the secondary prevention of coronary artery disease. J Gen Intern Med 1999;14:711–717. 18. Pearson TA, Laurora I, Chu H, Kafonek S. The Lipid Treatment Assessment Project (L-TAP): a multicenter survey to evaluate the percentages of dyslipidemic patients receiving lipid-lowering therapy and achieving low-density lipoprotein cholesterol goals. Arch Intern Med 2000;160:459 –467. 19. Feely J, McGettigan P, Kelly A. Growth in use of statins after trials is not targeted to most appropriate patients. Clin Pharmacol Ther 2000;67:438 –441. 20. Abookire SA, Karson AS, Fiskio J, Bates DW. Use and monitoring of “statin” lipid-lowering drugs compared with guidelines. Arch Intern Med 2001;161:53–58.
Variability of Inotropic and Chronotropic Response During Dobutamine Stress Echocardiography and Possible Implications for Diagnostic Accuracy Adrian Chenzbraun, MD, Marina Potekhin, MD, Michel Dreyfuss, MD, Tova Alper-Gendelman, RDMS, Frida Kott, RDMS, and Andre Keren, MD Chronotropic and inotropic response patterns were assessed during dobutamine stress echocardiography. Three heart rate response patterns were noted: nonresponders (48% of patients), slow responders (30% of patients), and fast responders (21% of patients). There was no relation between heart rate and contractile response. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:1451–1454)
D
obutamine stress echocardiography (DSE) has emerged during the last decade as a widely used technique for the diagnosis of ischemia, myocardial viability, and for coronary disease risk stratification.1– 8 What defines a diagnostic test in terms of a satisfactory inotropic or chronotropic response is less standardized. Reaching an age-predicted target heart rate is generally considered a prerequisite for a conclusive exercise test,9 and the use of atropine is recommended and widely used lately during DSE10 –12 to increase sensitivity. Most of the available large-scale From The Heiden Department of Cardiology, Bikur Cholim Hospital, Jerusalem, Israel. Dr. Chenzbraun’s address is: The Heiden Department of Cardiology, Bikur Cholim Hospital, 5 Strauss Street, PO Box 492, 91005 Jerusalem, Israel. E-mail: [email protected]. Manuscript received May 12, 2003; revised manuscript received and accepted August 26, 2003. ©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 December 15, 2003
studies do not specify whether negative tests in which the target heart rate was not reached were considered nondiagnostic or what was the degree of inotropic response.7,8,13 The possible variability of the inotropic response14 may also influence DSE sensitivity. The purpose of the present study was to assess the degree of variability and heterogeneity of the hemodynamic and chronotropic response during DSE in patients without echocardiographic evidence of ischemia. •••
Fifty-six consecutive DSE studies were prospectively analyzed for hemodynamic and chronotropic response during dobutamine infusion. There were 27 men and 29 women (aged 68 ⫾ 12 years, range 35 to 90); 15 patients (35%) were receiving -blocker therapy at the time of the study, 26 had arterial hypertension, and 15 were diabetic. Dobutamine was started at 5 g/kg/min and continued with 10 g/kg/min increments every 3 minutes, up to a maximal dosage of 50 g/kg/min. If ⱖ85% of the maximal age-predicted heart rate was not reached with dobutamine 50 g/kg/min, atropine sulfate 0.7 to 1 mg was given intravenously at the discretion of the supervising physician. The study was stopped when either the maximal dosage or the age-predicted heart rate was achieved, or earlier in case of patient discomfort, significant arrhythmia, systolic blood pressure 0002-9149/03/$–see front matter doi:10.1016/j.amjcard.2003.08.058
1451
min. Atropine was administered in 10 patients and it increased heart rate to target values in 4 of them. For the whole group, the increase in dobutamine to a maximal dose brought a significant increase in heart rate (114 ⫾ 22 vs 69 ⫾ 12 beats/min, p ⬍0.01), systolic blood pressure (150 ⫾ 27 vs 143 ⫾ 25 mm Hg, p ⫽ 0.04), cardiac output (9.3 ⫾ 3 vs 5 ⫾ L/min, p ⬍0.01), and fractional shortening (43 ⫾ 7% vs 36 ⫾ 5%, p ⬍0.01). However, these responses were far from homogenous in patient-level and subgroup analysis, with different timings and slopes for the flat and steep segments of the response curves. FIGURE 1. Representative heart rate (HR) response graphs: (A) fast responder; (B) Three response patterns were slow responder; (C) nonresponder. Note the sudden increase in heart rate of patient identified for heart rate among the B at the 50 g/kg/min stage after a flat response. bpm ⴝ beats per minute. patients who completed the study: nonresponders, 25 patients (48%); fast responders, 11 patients (21%); TABLE 1 Differences in Age, Basal Heart Rate, and -blocker Use According to and slow responders, 16 patients Heart Rate Response Pattern (30%; Figure 1). Advanced age, Nonresponders Responders Fast Responders Slow Responders higher heart rate at baseline, and no (n ⫽ 25) (n ⫽ 27) (n ⫽ 11) (n ⫽ 16) -blocker therapy were strongly asAge (yrs) 65 ⫾ 11 72 ⫾ 13* 76 ⫾ 9 65 ⫾ 14 sociated with responder status; fast Basal heart rate (beats/min) 65 ⫾ 10 74 ⫾ 11 76 ⫾ 9 75 ⫾ 12 response also appeared to be associ-blocker treatment 12 2* 1 1 ated with advanced age but without *p ⬍0.05 for comparison with the nonresponder group. reaching statistical significance (Table 1). Gender, hypertension, and diabetes were not related to response pattern. Slow responders varied decrease of ⬎20 mm Hg, or echocardiographic evi- largely in terms of percent heart rate increase at each dence of ischemia. Digital image acquisition was done stage; some patients exhibited a constant increase and in standard parasternal and apical views at baseline, others showed a sudden increase after a flat response low, and peak dobutamine doses. (Figures 1 and 2). Heart rate, blood pressure, left ventricular diameter The systolic blood pressure response was highly varifor fractional shortening calculation, and cardiac output able, with 16 patients (30%) actually ending with a lower using the left ventricular outflow tract diameter and the blood pressure at protocol completion. In those who had blood flow velocity–time integral at the same level were increased blood pressure, the mean increase was 20 ⫾ 14 recorded at baseline and at the end of each stage. mm Hg, but even in this group the pattern of blood The DSE protocol was considered complete if the pressure increase was not homogenous, with many patarget heart rate was achieved and/or at least the 40 tients showing no increase or even a transient decrease in g/kg/min stage was concluded. These types of reblood pressure at various stages (Figure 2). Age, gender, sponses were defined: patients who did not reach target hypertensive status, diabetes, and use of  blockers were heart rate upon completion of protocol, with or without atropine, were classified as heart rate nonresponders as not related to response pattern. Patients who had inopposed to heart rate responders in whom target heart creased systolic blood pressure during DSE tended to rate was reached with or without atropine. The later were have lower basal blood pressure levels (139 ⫾ 20 vs 151 further classified as quick responders if they reached ⫾ 23 mm Hg, p ⫽ 0.05) Most patients had increased cardiac output (54 of 55) their target heart rate at ⱕ30 g/kg/min or as slow or fractional shortening (46 of 52); however, the degree responders if they needed a higher dobutamine dosage of change in these 2 indexes at each of the protocol with or without atropine. Baseline clinical characteristics, -blocker use, and patterns of change in heart rate, stages showed a variable spread (Figure 3). The increase blood pressure, fractional shortening, and cardiac output in fractional shortening showed a weak inverse correlation with age and basal fractional shortening (r ⫽ ⫺0.3, were compared between these groups. p ⬍0.05) and no relation with gender, hypertension, The study had to be stopped because of side effects at dobutamine doses ⬍40 g/kg/min in 4 patients diabetes, or -blocker treatment. The increase in cardiac (7%). In the remaining 52 patients, the study was output was also weakly inversely correlated with age (r stopped at an average dobutamine dose of 40 g/kg/ ⫽ ⫺0.25, p ⫽ 0.05) and basal cardiac output (r ⫽ 1452 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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patients in whom increasing myocardial oxygen consumption for diagnostic purposes is not feasible by heart rate increase. Dobutamine was expected to circumvent this drawback mainly by increasing contractility, with or without a concomitant increase in heart rate or blood pressure.2,4,15 The diagnostic accuracy of DSE may depend on the inotropic and/or chronotropic response of patients undergoing the test. As such, assessment of the natural spectrum of responses to dobutamine infusion is FIGURE 2. Density plot of percent change in heart rate (A) and systolic blood presessential to define the limitations of sure (B) at each of the DSE protocol stages. Note the large variations, including actual drops at each stage. the method and improve its clinical use. Age-dependent differences in the hemodynamic response to dobutamine are expected16,17 and have been reported in clinical studies.18,19 Pellikka et al20 reported wide variations in heart rate and stroke volume response during dobutamine infusion in 47 patients without evidence of ischemia during DSE. Similar results were reported by Carstensen et al14 for fractional shortening and wall thickening in healthy subjects; in their study, a decrease in inotropic indexes was actually noted at high dobutamine doses in about 1/3 of the patients. FIGURE 3. Density plot of percent change in fractional shortening (A) and cardiac The present study included conoutput (B) at each of the DSE protocol stages. Note the large variations, including secutive patients referred for DSE. actual drops at each stage. The analysis was performed only in patients without permanent or new wall motion abnormalities to avoid the possible influence of left ventricular dysfunction or transient ischemia on the hemodynamic response to dobutamine infusion. Therefore, this patients group is well suited for defining the chronotropic and inotropic response to dobutamine in patients for whom DSE is considered the appropriate diagnostic modality. The wide stage-to-stage variability of the chronotropic response and its relation with other hemodynamic perFIGURE 4. Density plot of percentage increase in fractional shortformance indexes have not been systematically anaening in nonresponders (O), fast responders (X), and slow relyzed or accounted for. In this study we found 3 main sponders (ⴙ). patterns of heart rate response: no response in almost half of the patients, possibly related to -blocker ther⫺0.37, p ⬍0.05) and was not related to gender, diabetes, apy in only 50% of them; slow response in 1/3 of patients; and fast response in about 1/5 of patients. or -blocker therapy. Heart rate response showed a weak correlation (r ⫽ Advanced age was associated with both responder 0.26, p ⫽ 0.05) with systolic blood pressure response status and fast response pattern. Whether this reflects and a moderate association (r ⫽ 0.48, p ⬍0.01) with lower, and therefore faster to achieve, target heart rate cardiac output response. No correlation was found be- or an age-specific cathecolamine response status is not tween the increase in heart rate or systolic blood pressure clear, but similar results already have been reported.18 and the increase in fractional shortening; patients with Inotropic response, the mainstay of DSE technique, various degrees of fractional shortening increase were was also found to be nonhomogenous, with large evenly distributed between heart rate responders and patient variations regarding the timing and amount of change in contractility. Moreover, the inotropic and nonresponders (Figure 4). chronotropic responses were not related. Some pa••• Pharmacologic stress evolved as a test modality for tients showed an unsatisfactory increase in heart rate BRIEF REPORTS
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and at the same time an impressive increase in contractility. Whether atropine is still needed in these patients is not clear. The wide variability in chronotropic and inotropic response found during DSE and especially the lack of correlation between heart rate and contractility response underscore the need for proper diagnostic criteria, especially in heart rate nonresponder patients. Further studies are necessary to establish to what extent quantification of the inotropic response may ascertain the diagnostic value of DSE when heart rate increase is inadequate. 1. Bach DS, Armstrong WF. Dobutamine stress echocardiography. Am J Cardiol 1992;69:90H–96H. 2. Mazeika PK, Nadazdin A, Oakley CM. Dobutamine stress echocardiography for detection and assessment of coronary artery disease. J Am Coll Cardiol 1992;19:1203–1211. 3. Cohen JL, Ottenweller JE, George AK, Duvvuri S. Comparison of dobutamine and exercise echocardiography for detecting coronary artery disease. Am J Cardiol 1993;72:1226 –1231. 4. Marcovitz PA, Armstrong WF. Accuracy of dobutamine stress echocardiography in detecting coronary artery disease. Am J Cardiol 1992;69:1269 –1273. 5. Cigarroa CG, deFilippi CR, Brickner ME, Alvarez LG, Wait MA, Grayburn PA. Dobutamine stress echocardiography identifies hibernating myocardium and predicts recovery of left ventricular function after coronary revascularization. Circulation 1993;88:430 –436. 6. Smart SC, Sawada S, Ryan T, Segar D, Atherton L, Berkovitz K, Bourdillon PD, Feigenbaum H. Low-dose dobutamine echocardiography detects reversible dysfunction after thrombolytic therapy of acute myocardial infarction. Circulation 1993;88:405–415. 7. Das MK, Pellikka PA, Mahoney DW, Roger VL, Oh JK, McCully RB, Seward JB. Assessment of cardiac risk before nonvascular surgery: dobutamine stress echocardiography in 530 patients. J Am Coll Cardiol 2000;35:1647–1653. 8. Poldermans D, Fioretti PM, Boersma E, Bax JJ, Thomson IR, Roelandt JR, Simoons ML. Long-term prognostic value of dobutamine-atropine stress echo-
cardiography in 1737 patients with known or suspected coronary artery disease: a single-center experience. Circulation 1999;99:757–762. 9. Goldschlager N, Selzer A, Cohn K. Treadmill stress tests as indicators of presence and severity of coronary artery disease. Ann Intern Med 1976;85:277– 286. 10. Armstrong WF, Pellikka PA, Ryan T, Crouse L, Zoghbi WA. Stress echocardiography: recommendations for performance and interpretation of stress echocardiography. Stress Echocardiography Task Force of the Nomenclature and Standards Committee of the American Society of Echocardiography. J Am Soc Echocardiogr 1998;11:97–104. 11. Elhendy A, van Domburg RT, Poldermans D, Bax JJ, Nierop PR, Geleijnse ML, Roelandt JR. Safety and feasibility of dobutamine-atropine stress echocardiography for the diagnosis of coronary artery disease in diabetic patients unable to perform an exercise stress test. Diabetes Care 1998;21:1797–1802. 12. Cornel JH, Balk AH, Boersma E, Maat AP, Elhendy A, Arnese M, Salustri A, Roelandt JR, Fioretti PM. Safety and feasibility of dobutamine-atropine stress echocardiography in patients with ischemic left ventricular dysfunction. J Am Soc Echocardiogr 1996;9:27–32. 13. Poldermans D, Arnese M, Fioretti PM, Salustri A, Boersma E, Thomson IR, Roelandt JR, van Urk H. Improved cardiac risk stratification in major vascular surgery with dobutamine-atropine stress echocardiography. J Am Coll Cardiol 1995;26:648 –653. 14. Carstensen S, Ali SM, Stensgaard-Hansen FV, Toft J, Haunso S, Kelbaek H, Saunamaki K. Dobutamine-atropine stress echocardiography in asymptomatic healthy individuals. The relativity of stress-induced hyperkinesia. Circulation 1995;92:3453–3463. 15. Sawada SG, Segar DS, Ryan T, Brown SE, Dohan AM, Williams R, Fineberg NS, Armstrong WF, Feigenbaum H. Echocardiographic detection of coronary artery disease during dobutamine infusion. Circulation 1991;83:1605–1614. 16. Docherty JR. Aging and the cardiovascular system. J Auton Pharmacol 1986;6:77–84. 17. van Brummelen P, Buhler FR, Kiowski W, Amann FW. Age-related decrease in cardiac and peripheral vascular responsiveness to isoprenaline: studies in normal subjects. Clin Sci 1981;60:571–577. 18. Poldermans D, Boersma E, Fioretti PM, van Urk H, Boomsma F, Man AJ. Cardiac chronotropic responsiveness to beta-adrenoceptor stimulation is not reduced in the elderly. J Am Coll Cardiol 1995;25:995–999. 19. Chenzbraun A, Khoury Z, Gottlieb S, Keren A. Impact of age on the safety and the hemodynamic response pattern during high dose dobutamine echocardiography. Echocardiography 1999;16:135–142. 20. Pellikka PA, Roger VL, McCully RB, Mahoney DW, Bailey KR, Seward JB, Tajik AJ. Normal stroke volume and cardiac output response during dobutamine stress echocardiography in subjects without left ventricular wall motion abnormalities. Am J Cardiol 1995;76:881–886.
Meta-Analysis of Randomized Clinical Trials on the Usefulness of Acetylcysteine for Prevention of Contrast Nephropathy* Daniel W. Isenbarger,
MD,
Steven M. Kent,
Multiple small studies of oral N-acetylcysteine for prevention of contrast nephropathy have been performed, demonstrating variable efficacy. We performed a meta-analysis of the randomized clinical trials to clarify the degree of benefit. 䊚2003 by Excerpta Medica, Inc. (Am J Cardiol 2003;92:1454 –1458)
From the Cardiovascular Service and General Internal Medicine Service, Walter Reed Army Medical Center, Washington, DC. Dr. Isenbarger’s address is: 7543 Spring Lake Drive, #D1, Bethesda, Maryland, 20817-6512. E-mail: [email protected]. Manuscript received May 19, 2003; revised manuscript received and accepted August 21, 2003. *The opinions, interpretations, conclusions, and recommendations expressed in this article are those of the authors and are not necessarily endorsed by the U.S. Army.
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©2003 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 92 December 15, 2003
MD,
and Patrick G. O’Malley,
MD
ontrast nephropathy (CN) occurs in about 15% of unselected populations undergoing procedures inC volving intravascular radiocontrast administration. Higher rates are seen in those with diabetes and preexisting renal insufficiency.1 Dialysis is required in ⬍1% of patients, and has been associated with prolonged hospital stay and increased morbidity and mortality rates.1–3 Only saline hydration4 and low- or iso-osmolar contrast agents5 have demonstrated prevention of CN. N-acetylcysteine (NAC), an antioxidant, has recently been studied for prevention of CN.6 Given the common occurrence of CN, its potentially serious related outcomes, the low cost and simplicity of administering NAC, and the potential for significant benefits, we systematically assessed the randomized clinical trials of NAC for CN prevention to clarify the magnitude of treatment effects. •••
PubMed, Embase, BIOSIS, on-line clinical trial 0002-9149/03/$–see front matter doi:10.1016/j.amjcard.2003.08.059