- Email: [email protected]
Cardiac toxicity of intravenous terbutaline for the treatment of severe asthma in children: A prospective assessment
Cardiac toxicity of intravenous terbutaline for the treatment of severe asthma in children: A prospective assessment Vincent W. Chiang, MD, Jeffrey P. Burns, MD, Nader Rifai, PhD, Steven E. Lipshultz, MD, M. Jacob Adams, MD, and Debra L. Weiner, MD, PhD Objective: To examine the cardiac toxicity as measured by elevations in serum cardiac troponin T (cTnT) and to compare creatine kinase (CK) and creatine kinase MB (CK-MB) and findings on electrocardiography (ECG) as markers of cardiac toxicity with cTnT during the infusion of intravenous terbutaline for the treatment of severe asthma in children. Study design: Prospective cohort study of patients receiving intravenous terbutaline for severe asthma. Results: Only 3 (10%) of the 29 patients had elevations in cTnT. Each underwent mechanical ventilation for >72 hours, which was the earliest point at which cTnT elevations were identified. Eighteen (62%) patients had an elevation in CK, and 3 had an elevation in CK-MB fraction without an elevated cTnT. Twenty (69%) patients had ECG findings consistent with ischemia, and 19 of these patients had the ischemic findings on their preterbutaline ECG. Elevations in CK and CK-MB and ischemic changes on ECG did not correlate with elevations in cTnT. Both mechanical ventilation (P = .02) and prolonged administration (>72 hours) of intravenous terbutaline (P = .02) were significantly associated with elevations in cTnT. Conclusions: We found no clinically significant cardiac toxicity from the use of intravenous terbutaline for severe asthma as measured by serum cTnT elevations. (J Pediatr 2000;137:73-7)
The administration of inhaled β2adrenergic agonists and systemic corticosteroids has emerged as the first-line therapy for patients with acute severe asthma.1 For patients who do not re-
spond adequately to initial treatment, the continuous nebulization of inhaled short-acting β2-agonists is recommended as the most safe and efficacious means of escalating drug delivery.2-4 In
From the Division of Emergency Medicine and the Departments of Anesthesia and Laboratory Medicine, Children’s Hospital, Harvard Medical School, Boston, Massachussetts; and the Division of Pediatric Cardiology and the Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Presented in part at the 9th Pediatric Academic Societies Meeting, New Orleans, Louisiana, May 1-5, 1998. Submitted for publication July 29, 1999; revision received Dec 10, 1999; accepted Feb 10, 2000. Reprint requests: Vincent W. Chiang, MD, Division of Emergency Medicine, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9/21/106567 doi:10.1067/mpd.2000.106567
those patients who continue to deteriorate despite the administration of continuous inhaled β2-agonists and maximal doses of corticosteroids, intravenous β2agonists (such as isoproterenol and terbutaline) must occasionally be added. There have been reports of apparent myocardial toxicity in children treated with parenteral β-agonists.5 As a result, the most recent National Heart, Lung, and Blood Institute guidelines no longer recommend parenteral therapy with any intravenous β-agonist.1 cTnT CK CK-MB ECG NSST Tn
Cardiac troponin T Creatine kinase Creatine kinase MB Electrocardiography Nonspecific ST segment Cardiac troponin
Cardiac troponin appears to be a specific biochemical marker for identifying significant myocardial injury. Troponins are a complex of proteins that regulate the calcium-mediated action of actin and myosin in muscle. In serum specimens from both adults and children without cardiac disease, Tn concentrations were below the minimal concentration detectable by the assay.6,7 Furthermore, in both adult and pediatric patients with myocardial injury, there were not only elevations in Tn concentrations, but there was also a significant correlation between increasing Tn concentrations and an increase in mortality.7-9 Furthermore, cardiac troponin T and I have been found to be both more specific and more sensitive than creatine kinase 73
CHIANG ET AL
THE JOURNAL OF PEDIATRICS JULY 2000
Table I. Patient characteristics of enrolled and “missed” patients
N Mean age (y) Male/female Mean length of time of continuous inhaled albuterol before initiation of intravenous terbutaline infusion (h) Mean steroid dose (mg/kg/d) Mean maximal terbutaline dose (µg/kg/min) Mean length of time of terbutaline infusion (h) Mean CK (IU/L) Percent of patients with elevated CK (>150 IU/L)
Enrolled patients
Missed patients
P value
29 9.1 ± 6.5 12:17 3.7 ± 1.5
4 11.6 ± 3.9 2:2 4.0 ± 1.4
.47 .57 .69
Data Analysis 2.9 ± 1.0 2.4 ± 1.5
2.5 ± 1.0 1.3 ± .5
.53 .01
53.3 ± 49.2
5.5 ± 3.4
<.001
961 ± 2102 59 (17/29)
139 ± 47 0 (0/4)
.45 .04
MB for the serologic diagnosis of acute myocardial injury.8,9 The objectives of this study were to (1) examine the potential cardiac toxicity as measured by elevations in serum cTnT and (2) to compare CK, CK-MB, and findings on electrocardiography as markers of cardiac toxicity with serum cTnT during the infusion of intravenous terbutaline for the treatment of severe asthma in children.
METHODS We conducted a prospective observational cohort study of patients who received intravenous terbutaline for acute severe asthma at Children’s Hospital, Boston, between January and November 1997. Consecutive patients arriving at the emergency department or multidisciplinary intensive care unit (with more than 50,000 visits and 1600 admissions annually, respectively) requiring intravenous terbutaline were identified and enrolled by one of the study investigators (V.W.C.). The decision to initiate and discontinue terbutaline infusion was solely at the discretion of the treating attending physician. Initiation of intravenous terbutaline occurred only 74
rates were obtained hourly and as needed per unit protocol. Sera were separated immediately after collection and stored at –70°C until analysis was performed. cTnT levels were measured by noncompetitive immunoassay on the Elecsys 1010 analyzer (Roche Diagnostics, Indianapolis, Ind).
after patients failed to respond to continuous nebulized albuterol at 0.5 mg/kg/h. A protocol for the use of terbutaline at our institution required a loading dose of 10 µg/kg over a 10minute period followed by a maintenance infusion of 0.4 µg/kg/min. The dose was escalated in increments of 0.2 µg/kg/min, as recommended by the first expert panel report of the National Heart, Lung, and Blood Institute.10 The dose of the terbutaline infusion was titrated to either a therapeutic benefit or until significant side effects (tachycardia, tremulousness, anxiety) were noted by the treating physicians. Patients continued to receive continuous inhaled albuterol as tolerated. Patients with known cardiac disease were excluded from the study. The study protocol was approved by the Children’s Hospital Institutional Review Board. Informed consent was obtained from all study participants or their families. Baseline measurements of cTnT, CK, CK-MB, and ECG were obtained before the initiation of treatment and then daily while the patients received intravenous terbutaline. The patients’ age, sex, weight, heart rate, and medication list were also recorded. Heart
All analyses were performed with SPSS version 6.1 for the Macintosh. Continuous variables were compared with the use of the 2-tailed Student t test. Proportions were compared with the use of Pearson χ2, Fisher exact, or Spearman correlation tests, as appropriate. A paired t test was used to compare findings before the initiation of and during the terbutaline infusion. A P value of <.05 was considered significant. Blinded review (S.E.L., M.J.A.) of the electrocardiograms was performed with the examination of heart rate, axis, QT and QTc intervals, ST segment changes, T-wave changes, and Q-wave width. Normal ECG standards and evidence of myocardial infarction and ischemia were based on previously accepted and published criteria.11,12 Signs of acute myocardial infarction included: 1. Wide Q waves (>35 ms) in leads I, III, V1, and V6 2. ST segment elevation of >2 mm 3. Prolonged QTc interval (>440 ms) with accompanying Q-wave abnormalities Signs of myocardial ischemia included: 1. Abnormally inverted T waves 2. ST segment depression >2 mm 3. ST segment elevation between 1 and 2 mm 4. Nonspecific ST segment changes
RESULTS During the study period, 34 consecutive patients received intravenous terbutaline for acute severe asthma. Of these, 29 (85%) patients were enrolled. One patient was excluded from the
CHIANG ET AL
THE JOURNAL OF PEDIATRICS VOLUME 137, NUMBER 1 study as a result of underlying cardiac disease. This patient had been treated with doxorubicin for a malignancy and had abnormal left ventricular fractional shortening by echocardiography. This patient had elevated CK and cTnT levels before undergoing intravenous terbutaline therapy. For the remaining 4 patients, the study investigators were not notified in sufficient time to obtain consent for entry into the study. The only significant differences were that the nonenrolled patients received a lower maximum intravenous dose of terbutaline over a shorter interval than the enrolled patients and that none of the non-enrolled patients had elevations in CK (Table I). Only 3 (10%) of the 29 (95% CI 2,27) patients enrolled in the study had a detectable cTnT level (>.02 ng/mL, the lower limit of the assay) during terbutaline therapy. The peak cTnT levels were 0.125, 0.048, and 0.031 ng/mL, respectively. Two of these 3 patients had an elevated CK level (>150 IU/L) before the start of the terbutaline infusion. All 3 had further elevations of their CK levels, but their CK-MB fractions (<5% CK-MB) all remained within the normal range. These 3 patients required mechanical ventilation and intravenous terbutaline for >72 hours (the earliest interval from the onset of intravenous terbutaline therapy at which an elevation of cTnT was noted). These 3 patients also underwent mechanical ventilation for the longest period (mean 115 vs 37 hours, P = .005) and received a significantly longer terbutaline infusion (mean 126 vs 45 hours, P = .004) compared with the other patients. Both mechanical ventilation (P = .02) and prolonged administration (>72 hours) of intravenous terbutaline (P = .02) were significantly associated with elevations in cTnT. Of the 26 patients without elevations in cTnT, 13 (50%) patients had an elevated CK before the initiation of the terbutaline infusion. Eighteen patients had an increase of their CK, whereas 8
Table II. Correlation between cTnT and other clinical or laboratory findings
cTnT cTnT Spearman (<.02 ng/mL) (≥.02 ng/mL) correlation P value CK elevations (>150 IU/L) Yes No CK-MB elevations (>5%) Yes No Ischemic findings on ECG Yes No
14 12
3 0
.29
.13
3 23
0 3
–.11
.55
17 9
3 0
.22
.23
actually had a decrease of their CK during the terbutaline therapy. Only 3 patients also had an elevated CK-MB fraction (>5% CK-MB), and none of these 3 had an elevation in cTnT. All of the elevations in CK and CK-MB occurred during the first 24-hour period that the patients were receiving intravenous terbutaline. Elevations in CK and CK-MB were not correlated with elevations in cTnT (Table II). All 29 of the patients enrolled in the study had a baseline (before the initiation of intravenous terbutaline) electrocardiogram for review; 19 (66%) of these 29 baseline electrocardiograms revealed signs of possible ischemia. In addition, all patients had at least one electrocardiogram obtained during terbutaline therapy, allowing for paired analysis. Only 1 of the 10 patients with a normal baseline electrocardiogram had a subsequent electrocardiogram with signs of possible ischemia. This patient had an elevation in CK but had no elevation in CK-MB or cTnT. Of the total 60 electrocardiograms obtained, 48 (80%) had signs of possible ischemia as suggested by NSST changes. Only 4 patients had findings on ECG other than NSST changes suggestive of possible ischemia. None of these 4 patients had elevations in cTnT. None of the ECGs had any signs of myocardial infarction. Neither NSST changes nor other ischemic changes were significantly correlated with
cTnT elevations (Table II). Furthermore, paired analysis revealed no significant difference in ischemic findings on ECG before and during the terbutaline infusion (P = .33).
DISCUSSION The use of intravenous terbutaline for the treatment of patients with severe asthma remains controversial, partly because of concerns for potential cardiac toxicity. Previous investigators have cited both elevations in CK and ischemic changes on ECG as evidence of this potential cardiac toxic effect.5,13-15 These studies were all limited by having only elevations in CK or findings on ECG to measure cardiac toxicity. Our study used Tn to evaluate the cardiac safety profile of intravenous terbutaline in the setting of severe asthma. We did not find any clinically significant cardiac toxicity from the use of intravenous terbutaline. Only 3 (10%) of 29 patients had any potential cardiac toxicity as measured by elevations in cTnT. These 3 patients also required mechanical ventilation and the longest duration of parenteral terbutaline. The elevations in cTnT were not seen until after 72 hours of intravenous therapy. Furthermore, the elevations in cTnT were minimal, with elevations of 0.031, 0.048, and 0.125 ng/mL. Elevations of cTnT above 0.2 to 0.3 ng/mL 75
CHIANG ET AL
have been shown to be associated with high risk for myocardial ischemia or injury.16-19 It should be noted that low levels of cTnT elevations (>0.1 ng/mL) in selected pediatric populations may represent inflammatory or chronic changes as opposed to signs of acute ischemic injury.7,20 Further evidence that the cardiac toxic effect of terbutaline in these 3 patients was minimal is that although 2 of the 3 had elevations in CK before the start of the terbutaline infusion, none had elevations in their CK-MB fraction during therapy. Previous investigators have found that the measurement of cTnT is superior to that of CK or CKMB in identifying cardiac injury, because cTnT levels are not elevated in normal children but are elevated in children with cardiac disease.7,20-23 Also, none of these 3 patients had any new ischemic changes on ECG during therapy, and all had NSST changes on ECG before the start of the terbutaline infusion. This result suggests that other treatments (eg, continuous nebulized albuterol) may have been responsible for these findings. In fact, elevations in CK and CK-MB without underlying cardiac injury have been reported previously with the use of continuous inhaled albuterol.3,24 We believe that the CK findings in the patients without cTnT elevation also support the lack of cardiac toxicity of intravenous terbutaline. Elevations in CK have been reported previously with the use of terbutaline,25,26 and some have postulated that this elevation originates from injury to skeletal muscle associated with increased work of breathing.26 This possibility is supported by the fact that half of our patients had elevations in CK before the initiation of the terbutaline infusion. The cause of the elevations in CK-MB fraction in the absence of cTnT elevation in 3 patients is unclear but may simply represent the subsequent re-expression of the B subunit after skeletal muscle injury.27,28 No correlation was found between elevations in CK or CKMB with elevations in cTnT. 76
THE JOURNAL OF PEDIATRICS JULY 2000 Our ECG findings also fail to support significant cardiac injury from the use of intravenous terbutaline. Another striking finding was that more than half of our patients fulfilled at least one criterion for myocardial ischemia even before the initiation of terbutaline therapy. Yet, no correlation was found between ischemic changes on ECG with elevations in cTnT. Several limitations of our study must be acknowledged. First, we were unable to enroll every eligible patient during the study period. We believe that this is a minor limitation, because the non-enrolled patients were “less sick” than the enrolled patients. Also, our relatively small sample size may have prevented us from detecting a higher incidence of cTnT elevations, because our CI was rather large (2% to 27%). Finally, our ECG data were limited by the fact that we were able to review only 79% of the total patient treatment days (although every patient enrolled in the study had at least 2 electrocardiograms for paired analysis). It should also be noted that we did not attempt to study the efficacy of intravenous terbutaline for the treatment of patients with severe asthma. Several studies have found the improvement in respiratory status from the use of intravenous versus nebulized terbutaline to be comparable.29-31 Two of these studies concluded that inhaled bronchodilator therapy is preferable to the intravenous formulation, however, because of the “potential risks” of systemic side effects despite no difference in observed side effects.30,31 Furthermore, other investigators have found the dose-response curve for intravenous terbutaline to be quite variable between individuals, which makes an ideal dosing regimen difficult to identify.32 Despite these limitations, we believe that the cardiac toxicity of intravenous terbutaline for the treatment of patients with severe asthma is not clinically important and, if it does exist, it occurs only in the sickest of patients (ie, those who require prolonged me-
chanical ventilation). The long-term significance of the mild elevations in cTnT in these patients remains unclear and will require further evaluation. We recommend that clinicians who use intravenous terbutaline for the treatment of patients with severe asthma should continue monitoring patients for evidence of potential cardiac toxicity while recognizing the limitations of the ECG and CK levels in this setting. We thank Gary R Fleisher, MD, and Michael Shannon, MD, for their thoughtful review of the manuscript.
REFERENCES 1. National Asthma Education and Prevention Program. Expert panel report 2: guidelines for the diagnosis and management of asthma. Washington, DC: National Institutes of Health; 1997. 2. Kelly HW, McWilliams BC, Katz R, Murphy S. Safety of frequent high dose nebulized terbutaline in children with acute severe asthma. Ann Allergy 1990;64:229-33. 3. Katz RW, Kelly HW, Crowley MR, Grad R, McWilliams BC, Murphy SJ. Safety of continuous nebulized albuterol for bronchospasm in infants and children. Pediatrics 1993;92:666-9. 4. Beveridge RC, Grunfeld AF, Hodder RV, Verbeek PR. Guidelines for the emergency management of asthma in adults. CMAJ 1996;155:25-37. 5. Maguire JF, O’Rourke PP, Colan SD, Geha RS, Crone R. Cardiotoxicity during treatment of severe childhood asthma. Pediatrics 1991;88:1180-6. 6. Adams JE, Abendschein DR, Jaffe AS. Biochemical markers of myocardial injury. Is MB creatine kinase the choice for the 1990s? Circulation 1993; 88:750-63. 7. Lipshultz SE, Rifai N, Sallan SE, Lipsitz SR, Dalton V, Sacks DB, et al. Predictive value of cardiac troponin T in pediatric patients at risk for myocardial injury. Circulation 1997;96:2641-8. 8. Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, et al. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med 1996;335:1342-9. 9. Ohman EM, Armstrong PW, Christenson RH, Granger CB, Katus HA,
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Hamm CW, et al. Cardiac troponin T levels for risk stratification in acute myocardial ischemia. N Engl J Med 1996;335:1333-41. National Asthma Education and Prevention Program. Expert panel report: guidelines for the diagnosis and management of asthma. Washington, DC: National Institutes of Health; 1991. Towbin JA, Bricker JT, Garson A Jr. Electrocardiographic criteria for diagnosis of acute myocardial infarction in childhood. Am J Cardiol 1992;69: 1545-8. Rautaharju PM, Davignon A, Soumis F, Boiselle E, Choquette A. Evolution of QRS-T relationship from birth to adolescence in Frank-lead orthogonal electrocardiograms of 1492 normal children. Circulation 1979;60:196-204. Chazan R, Tadeusiak W, Jaworski A, Droszcz W. Creatine kinase (CK) and creatine kinase isoenzyme (CK-MB) activity in serum before and after intravenous salbutamol administration of patients with bronchial asthma. Int J Clin Pharmacol Ther Toxicol 1992;30: 371-3. Page R, Ray W, Friday G, Fireman P. Isoproterenol associated myocardial dysfunction during status asthmaticus. Ann Allergy 1987;57:402-4. Matson JR, Loughlin GM, Strunk RC. Myocardial ischemia complicating the use of isoproterenol in asthmatic children. J Pediatr 1978;92:776-8. Panteghini M, Cuccia C, Pagani F, Turla C. Comparison of the diagnostic performance of two rapid bedside biochemical assays in the early detection of acute myocardial infarction. Clin Cardiol 1998;21:394-4. Lindahl B, Venge P, Wallentin L for the FRISC Study Group. Relation between Troponin T and the risk of subsequent cardiac events in unstable
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coronary artery disease. Circulation 1996;93:1651-7. Stubbs P, Collinson P, Moseley D, Greenwood T, Noble M. Prognostic significance of admission troponin T concentrations in patients with myocardial infarction. Circulation 1996; 94:1291-7. Spies C, Haude V, Fitzner R, Schroder K, Overbeck M, Runkel N, et al. Serum cardiac troponin T as a prognostic marker in early sepsis. Chest 1998;113:1055-63. Herman EH, Lipshultz SE, Rifai N, Zhang J, Papoian T, Yu ZX, et al. Use of cardiac troponin T levels as an indicator of doxorubicin-induced cardiotoxicity. Cancer Res 1998;58:195-7. Herman EH, Zhang J, Lipshultz SE, Rifai N, Chadwick D, Takeda K, et al. Correlation between serum levels of cardiac troponin-T and the severity of chronic cardiomyopathy induced by doxorubicin. J Clin Oncol 1999;17: 2237-43. Taggart DP, Hadjinikolas L, Hooper J, Albert J, Kemp M, Hue D, et al. Effects of age and ischemic times on biochemical evidence of myocardial injury after pediatric cardiac operations. J Thorac Cardiovasc Surg 1997;113: 728-35. Hirsch R, Landt Y, Porter S, Canter CE, Jaffe AS, Ladenson JH, et al. Cardiac troponin I in pediatrics: normal values and potential use in the assessment of cardiac injury. J Pediatr 1997;130:872-7. Moler FW, Johnson CE, Van Laanen C, Palmisano JM, Nasr SZ, Akingbola O. Continuous versus intermittent nebulized terbutaline: plasma levels and effects. Am J Respir Crit Care Med 1995;151:602-6. Stephanopoulos DE, Monge R, Schell KH, Wyckoff P, Peterson BM. Contin-
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uous intravenous terbutaline for pediatric status asthmaticus. Crit Care Med 1998;26:1744-8. Sykes AP, Lawson N, Finnegan JA, Ayres JG. Creatine kinase activity in patients with brittle asthma treated with long term subcutaneous terbutaline. Thorax 1991;46:580-3. Cummins P, Young A, Auckland ML, Michie CA, Stone PC, Shepstone BJ. Comparison of serum cardiac specific troponin-I with creatine kinase, creatine kinase-MB isoenzyme, tropomyosin, myoglobin and C-reactive protein release in marathon runners: cardiac or skeletal muscle trauma? Eur J Clin Invest 1987;17:317-24. Siegel AJ, Lewandrowski KB, Strauss HW, Fischman AJ, Yasuda T. Normal post-race antimyosin myocardial scintigraphy in asymptomatic marathon runners with elevated serum creatine kinase MB isoenzyme and troponin T levels. Evidence against silent myocardial cell necrosis. Cardiology 1995;86: 451-6. Van Renterghem D, Lamont H, Elinck W, Pauwels R, Van der Straeten M. Intravenous versus nebulized terbutaline with acute severe asthma: a double blind randomized study. Ann Allergy 1987;59:313-6. Williams SJ, Winner SJ, Clark TJ. Comparison of inhaled and intravenous terbutaline in acute severe asthma. Thorax 1981;36:629-32. Pierce RJ, Payne CR, Williams SJ, Denison DM, Clark TJ. Comparison of intravenous and inhaled terbutaline in the treatment of asthma. Chest 1981;79:506-11. Fuglsang G, Pedersen S, Borgstrom L. Dose-response relationships of intravenously administered terbutaline in children with asthma. J Pediatr 1989; 114:315-20.
77
The administration of inhaled β2adrenergic agonists and systemic corticosteroids has emerged as the first-line therapy for patients with acute severe asthma.1 For patients who do not re-
spond adequately to initial treatment, the continuous nebulization of inhaled short-acting β2-agonists is recommended as the most safe and efficacious means of escalating drug delivery.2-4 In
From the Division of Emergency Medicine and the Departments of Anesthesia and Laboratory Medicine, Children’s Hospital, Harvard Medical School, Boston, Massachussetts; and the Division of Pediatric Cardiology and the Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York.
Presented in part at the 9th Pediatric Academic Societies Meeting, New Orleans, Louisiana, May 1-5, 1998. Submitted for publication July 29, 1999; revision received Dec 10, 1999; accepted Feb 10, 2000. Reprint requests: Vincent W. Chiang, MD, Division of Emergency Medicine, Children’s Hospital, 300 Longwood Ave, Boston, MA 02115. Copyright © 2000 by Mosby, Inc. 0022-3476/2000/$12.00 + 0 9/21/106567 doi:10.1067/mpd.2000.106567
those patients who continue to deteriorate despite the administration of continuous inhaled β2-agonists and maximal doses of corticosteroids, intravenous β2agonists (such as isoproterenol and terbutaline) must occasionally be added. There have been reports of apparent myocardial toxicity in children treated with parenteral β-agonists.5 As a result, the most recent National Heart, Lung, and Blood Institute guidelines no longer recommend parenteral therapy with any intravenous β-agonist.1 cTnT CK CK-MB ECG NSST Tn
Cardiac troponin T Creatine kinase Creatine kinase MB Electrocardiography Nonspecific ST segment Cardiac troponin
Cardiac troponin appears to be a specific biochemical marker for identifying significant myocardial injury. Troponins are a complex of proteins that regulate the calcium-mediated action of actin and myosin in muscle. In serum specimens from both adults and children without cardiac disease, Tn concentrations were below the minimal concentration detectable by the assay.6,7 Furthermore, in both adult and pediatric patients with myocardial injury, there were not only elevations in Tn concentrations, but there was also a significant correlation between increasing Tn concentrations and an increase in mortality.7-9 Furthermore, cardiac troponin T and I have been found to be both more specific and more sensitive than creatine kinase 73
CHIANG ET AL
THE JOURNAL OF PEDIATRICS JULY 2000
Table I. Patient characteristics of enrolled and “missed” patients
N Mean age (y) Male/female Mean length of time of continuous inhaled albuterol before initiation of intravenous terbutaline infusion (h) Mean steroid dose (mg/kg/d) Mean maximal terbutaline dose (µg/kg/min) Mean length of time of terbutaline infusion (h) Mean CK (IU/L) Percent of patients with elevated CK (>150 IU/L)
Enrolled patients
Missed patients
P value
29 9.1 ± 6.5 12:17 3.7 ± 1.5
4 11.6 ± 3.9 2:2 4.0 ± 1.4
.47 .57 .69
Data Analysis 2.9 ± 1.0 2.4 ± 1.5
2.5 ± 1.0 1.3 ± .5
.53 .01
53.3 ± 49.2
5.5 ± 3.4
<.001
961 ± 2102 59 (17/29)
139 ± 47 0 (0/4)
.45 .04
MB for the serologic diagnosis of acute myocardial injury.8,9 The objectives of this study were to (1) examine the potential cardiac toxicity as measured by elevations in serum cTnT and (2) to compare CK, CK-MB, and findings on electrocardiography as markers of cardiac toxicity with serum cTnT during the infusion of intravenous terbutaline for the treatment of severe asthma in children.
METHODS We conducted a prospective observational cohort study of patients who received intravenous terbutaline for acute severe asthma at Children’s Hospital, Boston, between January and November 1997. Consecutive patients arriving at the emergency department or multidisciplinary intensive care unit (with more than 50,000 visits and 1600 admissions annually, respectively) requiring intravenous terbutaline were identified and enrolled by one of the study investigators (V.W.C.). The decision to initiate and discontinue terbutaline infusion was solely at the discretion of the treating attending physician. Initiation of intravenous terbutaline occurred only 74
rates were obtained hourly and as needed per unit protocol. Sera were separated immediately after collection and stored at –70°C until analysis was performed. cTnT levels were measured by noncompetitive immunoassay on the Elecsys 1010 analyzer (Roche Diagnostics, Indianapolis, Ind).
after patients failed to respond to continuous nebulized albuterol at 0.5 mg/kg/h. A protocol for the use of terbutaline at our institution required a loading dose of 10 µg/kg over a 10minute period followed by a maintenance infusion of 0.4 µg/kg/min. The dose was escalated in increments of 0.2 µg/kg/min, as recommended by the first expert panel report of the National Heart, Lung, and Blood Institute.10 The dose of the terbutaline infusion was titrated to either a therapeutic benefit or until significant side effects (tachycardia, tremulousness, anxiety) were noted by the treating physicians. Patients continued to receive continuous inhaled albuterol as tolerated. Patients with known cardiac disease were excluded from the study. The study protocol was approved by the Children’s Hospital Institutional Review Board. Informed consent was obtained from all study participants or their families. Baseline measurements of cTnT, CK, CK-MB, and ECG were obtained before the initiation of treatment and then daily while the patients received intravenous terbutaline. The patients’ age, sex, weight, heart rate, and medication list were also recorded. Heart
All analyses were performed with SPSS version 6.1 for the Macintosh. Continuous variables were compared with the use of the 2-tailed Student t test. Proportions were compared with the use of Pearson χ2, Fisher exact, or Spearman correlation tests, as appropriate. A paired t test was used to compare findings before the initiation of and during the terbutaline infusion. A P value of <.05 was considered significant. Blinded review (S.E.L., M.J.A.) of the electrocardiograms was performed with the examination of heart rate, axis, QT and QTc intervals, ST segment changes, T-wave changes, and Q-wave width. Normal ECG standards and evidence of myocardial infarction and ischemia were based on previously accepted and published criteria.11,12 Signs of acute myocardial infarction included: 1. Wide Q waves (>35 ms) in leads I, III, V1, and V6 2. ST segment elevation of >2 mm 3. Prolonged QTc interval (>440 ms) with accompanying Q-wave abnormalities Signs of myocardial ischemia included: 1. Abnormally inverted T waves 2. ST segment depression >2 mm 3. ST segment elevation between 1 and 2 mm 4. Nonspecific ST segment changes
RESULTS During the study period, 34 consecutive patients received intravenous terbutaline for acute severe asthma. Of these, 29 (85%) patients were enrolled. One patient was excluded from the
CHIANG ET AL
THE JOURNAL OF PEDIATRICS VOLUME 137, NUMBER 1 study as a result of underlying cardiac disease. This patient had been treated with doxorubicin for a malignancy and had abnormal left ventricular fractional shortening by echocardiography. This patient had elevated CK and cTnT levels before undergoing intravenous terbutaline therapy. For the remaining 4 patients, the study investigators were not notified in sufficient time to obtain consent for entry into the study. The only significant differences were that the nonenrolled patients received a lower maximum intravenous dose of terbutaline over a shorter interval than the enrolled patients and that none of the non-enrolled patients had elevations in CK (Table I). Only 3 (10%) of the 29 (95% CI 2,27) patients enrolled in the study had a detectable cTnT level (>.02 ng/mL, the lower limit of the assay) during terbutaline therapy. The peak cTnT levels were 0.125, 0.048, and 0.031 ng/mL, respectively. Two of these 3 patients had an elevated CK level (>150 IU/L) before the start of the terbutaline infusion. All 3 had further elevations of their CK levels, but their CK-MB fractions (<5% CK-MB) all remained within the normal range. These 3 patients required mechanical ventilation and intravenous terbutaline for >72 hours (the earliest interval from the onset of intravenous terbutaline therapy at which an elevation of cTnT was noted). These 3 patients also underwent mechanical ventilation for the longest period (mean 115 vs 37 hours, P = .005) and received a significantly longer terbutaline infusion (mean 126 vs 45 hours, P = .004) compared with the other patients. Both mechanical ventilation (P = .02) and prolonged administration (>72 hours) of intravenous terbutaline (P = .02) were significantly associated with elevations in cTnT. Of the 26 patients without elevations in cTnT, 13 (50%) patients had an elevated CK before the initiation of the terbutaline infusion. Eighteen patients had an increase of their CK, whereas 8
Table II. Correlation between cTnT and other clinical or laboratory findings
cTnT cTnT Spearman (<.02 ng/mL) (≥.02 ng/mL) correlation P value CK elevations (>150 IU/L) Yes No CK-MB elevations (>5%) Yes No Ischemic findings on ECG Yes No
14 12
3 0
.29
.13
3 23
0 3
–.11
.55
17 9
3 0
.22
.23
actually had a decrease of their CK during the terbutaline therapy. Only 3 patients also had an elevated CK-MB fraction (>5% CK-MB), and none of these 3 had an elevation in cTnT. All of the elevations in CK and CK-MB occurred during the first 24-hour period that the patients were receiving intravenous terbutaline. Elevations in CK and CK-MB were not correlated with elevations in cTnT (Table II). All 29 of the patients enrolled in the study had a baseline (before the initiation of intravenous terbutaline) electrocardiogram for review; 19 (66%) of these 29 baseline electrocardiograms revealed signs of possible ischemia. In addition, all patients had at least one electrocardiogram obtained during terbutaline therapy, allowing for paired analysis. Only 1 of the 10 patients with a normal baseline electrocardiogram had a subsequent electrocardiogram with signs of possible ischemia. This patient had an elevation in CK but had no elevation in CK-MB or cTnT. Of the total 60 electrocardiograms obtained, 48 (80%) had signs of possible ischemia as suggested by NSST changes. Only 4 patients had findings on ECG other than NSST changes suggestive of possible ischemia. None of these 4 patients had elevations in cTnT. None of the ECGs had any signs of myocardial infarction. Neither NSST changes nor other ischemic changes were significantly correlated with
cTnT elevations (Table II). Furthermore, paired analysis revealed no significant difference in ischemic findings on ECG before and during the terbutaline infusion (P = .33).
DISCUSSION The use of intravenous terbutaline for the treatment of patients with severe asthma remains controversial, partly because of concerns for potential cardiac toxicity. Previous investigators have cited both elevations in CK and ischemic changes on ECG as evidence of this potential cardiac toxic effect.5,13-15 These studies were all limited by having only elevations in CK or findings on ECG to measure cardiac toxicity. Our study used Tn to evaluate the cardiac safety profile of intravenous terbutaline in the setting of severe asthma. We did not find any clinically significant cardiac toxicity from the use of intravenous terbutaline. Only 3 (10%) of 29 patients had any potential cardiac toxicity as measured by elevations in cTnT. These 3 patients also required mechanical ventilation and the longest duration of parenteral terbutaline. The elevations in cTnT were not seen until after 72 hours of intravenous therapy. Furthermore, the elevations in cTnT were minimal, with elevations of 0.031, 0.048, and 0.125 ng/mL. Elevations of cTnT above 0.2 to 0.3 ng/mL 75
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have been shown to be associated with high risk for myocardial ischemia or injury.16-19 It should be noted that low levels of cTnT elevations (>0.1 ng/mL) in selected pediatric populations may represent inflammatory or chronic changes as opposed to signs of acute ischemic injury.7,20 Further evidence that the cardiac toxic effect of terbutaline in these 3 patients was minimal is that although 2 of the 3 had elevations in CK before the start of the terbutaline infusion, none had elevations in their CK-MB fraction during therapy. Previous investigators have found that the measurement of cTnT is superior to that of CK or CKMB in identifying cardiac injury, because cTnT levels are not elevated in normal children but are elevated in children with cardiac disease.7,20-23 Also, none of these 3 patients had any new ischemic changes on ECG during therapy, and all had NSST changes on ECG before the start of the terbutaline infusion. This result suggests that other treatments (eg, continuous nebulized albuterol) may have been responsible for these findings. In fact, elevations in CK and CK-MB without underlying cardiac injury have been reported previously with the use of continuous inhaled albuterol.3,24 We believe that the CK findings in the patients without cTnT elevation also support the lack of cardiac toxicity of intravenous terbutaline. Elevations in CK have been reported previously with the use of terbutaline,25,26 and some have postulated that this elevation originates from injury to skeletal muscle associated with increased work of breathing.26 This possibility is supported by the fact that half of our patients had elevations in CK before the initiation of the terbutaline infusion. The cause of the elevations in CK-MB fraction in the absence of cTnT elevation in 3 patients is unclear but may simply represent the subsequent re-expression of the B subunit after skeletal muscle injury.27,28 No correlation was found between elevations in CK or CKMB with elevations in cTnT. 76
THE JOURNAL OF PEDIATRICS JULY 2000 Our ECG findings also fail to support significant cardiac injury from the use of intravenous terbutaline. Another striking finding was that more than half of our patients fulfilled at least one criterion for myocardial ischemia even before the initiation of terbutaline therapy. Yet, no correlation was found between ischemic changes on ECG with elevations in cTnT. Several limitations of our study must be acknowledged. First, we were unable to enroll every eligible patient during the study period. We believe that this is a minor limitation, because the non-enrolled patients were “less sick” than the enrolled patients. Also, our relatively small sample size may have prevented us from detecting a higher incidence of cTnT elevations, because our CI was rather large (2% to 27%). Finally, our ECG data were limited by the fact that we were able to review only 79% of the total patient treatment days (although every patient enrolled in the study had at least 2 electrocardiograms for paired analysis). It should also be noted that we did not attempt to study the efficacy of intravenous terbutaline for the treatment of patients with severe asthma. Several studies have found the improvement in respiratory status from the use of intravenous versus nebulized terbutaline to be comparable.29-31 Two of these studies concluded that inhaled bronchodilator therapy is preferable to the intravenous formulation, however, because of the “potential risks” of systemic side effects despite no difference in observed side effects.30,31 Furthermore, other investigators have found the dose-response curve for intravenous terbutaline to be quite variable between individuals, which makes an ideal dosing regimen difficult to identify.32 Despite these limitations, we believe that the cardiac toxicity of intravenous terbutaline for the treatment of patients with severe asthma is not clinically important and, if it does exist, it occurs only in the sickest of patients (ie, those who require prolonged me-
chanical ventilation). The long-term significance of the mild elevations in cTnT in these patients remains unclear and will require further evaluation. We recommend that clinicians who use intravenous terbutaline for the treatment of patients with severe asthma should continue monitoring patients for evidence of potential cardiac toxicity while recognizing the limitations of the ECG and CK levels in this setting. We thank Gary R Fleisher, MD, and Michael Shannon, MD, for their thoughtful review of the manuscript.
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