Europace Advance Access originally published online on August 13, 2008
Europace 2008 10(10):1176-1181; doi:10.1093/europace/eun211
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Syncope
Consecutive administration of atropine and isoproterenol for the evaluation of asymptomatic sinus bradycardia
1 Cardiology Department, Thriasio General Hospital of Elefsina, G. Gennimatas Avenue, Elefsina, Athens, Greece; 2 General Hospital Melission A. Fleming, 14, 25th Martiou Street, Melissia, Athens, Greece; 3 General Hospital, Agia Olga, 3–5, Agias Olgas Street, Nea Ionia, Athens, Greece; 4 General State Chemical Laboratory, Department of Drugs and Narcotics, 16 Tsocha Street, Ampelokipi, Athens, Greece
Manuscript submitted 23 March 2008. Accepted after revision 25 July 2008.
* Corresponding author. Tel/fax: +30 21 0 7750373. E-mail address: rvav1962{at}yahoo.gr
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Abstract |
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Aims: Sinus node function is commonly evaluated by the atropine test. The isoproterenol test is less used. The aim of this study was to evaluate chronotropic reserve in patients with asymptomatic sinus bradycardia using the combined administration of atropine and isoproterenol.
Methods and results: A total of 100 patients were studied, 18–70 years old, with permanent, asymptomatic, sinus bradycardia and no detectable cardiac disease. The standard administration protocols for atropine and isoproterenol were used and successive heart rate recorded. Patients were stratified into three groups: Group A (control), showing normal response to atropine and isoproterenol; Group B, demonstrating abnormal response to atropine; Group C, with abnormal response to atropine and isoproterenol. No statistically significant difference was observed between Groups A and B (P = 0.11), whereas Group C differed statistically from both Groups A (P < 0.000001) and B (P = 0.000003) to a significant extent. By the end of the 3-year follow-up period, 47% of the Group C patients had undergone permanent pacemaker implantation (DDDR)—Kaplan–Maier survival curves predict only 35% survival without pacing—whereas none did so in Groups A and B.
Conclusions: In patients with deficient chronotropic response to atropine administration, isoproterenol tests could differentiate those with inadequate chronotropic reserves, possibly requiring preventive pacemaker implantations.
Key Words: Sick sinus syndrome, Atropine, Isoproterenol
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Introduction |
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The investigation of the sinus node function involves a large number of parameters and engages several invasive and non-invasive methods, with a view to improving diagnostic sensitivity and specificity. Of the existing pharmacological tests, the most commonly applied is the atropine test, whereas the isoproterenol test is less widely used.
In everyday life, psychosomatic stimulation acts progressively on the sinus node in two phases, through the parasympatholytic and/or the progressive sympathomimetic systems.1
–3 Atropine is a competitive antagonist of the muscarinic acetylcholine receptors (acetylcholine is the main neurotransmitter used by the parasympathetic nervous system). Isoproterenol is a sympathomimetic β adrenergic agonist medication. It is structurally similar to epinephrine (adrenaline), but acts for the most part on β receptors. Hence, the combination of atropine and isoproterenol would appear to be useful for a reliable evaluation of asymptomatic sinus bradycardia, mainly as far as the prognostic stratification of the results is concerned, and, in the case of a positive result, the choice of treatment could be permanent pacemaker implantation in relation to other valid indications.
The aim of this study was the pharmacological evaluation of chronotropic reserves in patients with asymptomatic sinus bradycardia by applying the atropine and isoproterenol tests in tandem.
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Material and methods |
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One hundred patients (58 men and 42 women, average age 52.4 years) who reported to the emergency department of Thriasio General Hospital, during a 5-year-period of collecting data, after first consulting with their personal physician and following the routine admission procedure in Greece, were enrolled in the study protocol. The subjects presented obvious asymptomatic sinus bradycardia [sinus rate (SR) < 60 b.p.m.], not associated with medication or sports, and were all free of symptoms, without any severe cardiac disorder (based on medical history received upon admission, clinical examination, ECG, and echocardiogram). None of them were on bradycardia medication.
In all patients, after a rest period of 30 min in a supine position, the following administration protocol was applied:
- Intravenous administration of 2 mg atropine and measurement of the maximum SR (normal response, SR
90 b.p.m.).
- Administration, immediately afterwards, of 0.24 mg% isoproterenol solution in increasing doses, starting from 2.4 µg/min (20 drops) up to a maximum of 7.2 µg/min (60 drops). Each stage lasted 2–3 min; the increasing rate of dosage was 1.2 µg/min (10 drops). Maximum SR was recorded with the use of a monitor (final response, SR 120 b.p.m.).
All patients gave informed consent to their participation in the study in accordance with the Helsinki Declaration as revised in 2000. The study protocol was approved by the Thriasio General Hospital Ethics Committee.
Statistical analysis
Patients were divided into groups based on their response to the two successive drug challenges. All stages of drug administration were analysed using two-way analysis of variance with one repeated factor. Individual comparisons were made using the Scheffe F method.4 The ability of SR values in the early stages of the drug test to predict the final rate response was analysed using logistic regression.5 Kaplan–Meier survival curves were plotted for the three groups of patients, showing survival rates without permanent pacing. The log rank test was used to compare these curves.
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Results |
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Although the baseline SRs in the population of the present study were identical or very similar (average 53.6 b.p.m. ± 5.7 b.p.m.), atropine administration defined two main groups: one with a normal response (
90 b.p.m., average 96.1 ± 7.6 b.p.m.) and the other with a lower SR (<90 b.p.m.) (average 77 ± 7.5). Combined administration of atropine and isoproterenol led to the stratification of three groups, as defined below (Table 1 and Figure 1).
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Group A (controls)
Twenty-three patients (average age 50.9 years) were included in this group with a mean baseline SR of 54.7 ± 6.6 b.p.m. All these patients had a normal response to both atropine (96.1 ± 7.6 b.p.m.) and isoproterenol (final mean SR 135.7 ± 7 b.p.m.), allowing them to serve as a control group. Group A differed significantly from the rest of the patients with abnormal response, in terms of SR both at rest (average 57 ± 5.3 b.p.m., P = 0.01) and after atropine administration (average 99 ± 7.5 b.p.m., P < 0.000001).
Group B
Group B comprised 47 patients (average age 52.1 years) with abnormal response to the atropine test (mean SR 81.2 ± 5.3 b.p.m.) and normal response to isoproterenol. Isoproterenol administration gave results very similar to those for Group A. In fact, there were no statistically significant differences between Groups A and B (atropine P = 0.19, peak isoproterenol rate P = 0.96, lines A–B P = 0.11, Figure 1), despite the fact that a different response to atropine is originally recorded, implying clear overlapping of the SR values.
It should be noted that the creation of Group B became necessary, bearing in mind the recording of final isoproterenol rates 120 b.p.m. in several patients, as discussed in the following paragraph (120 b.p.m. is considered the lowest normal response to sympathetic activation with isoproterenol).6
Group C
This group contained 30 patients (average age 54.0 years) with abnormal response both to atropine (<90 b.p.m.) and isoproterenol (<120 b.p.m.). The mean SR after atropine administration was 74.4 ± 6.1 b.p.m. There was no statistically significant difference in this value from that in Group B (P = 0.99), but it differed significantly from that in Group A (P = 0.000003) and those in the combination of Groups A and B (P = 0.000003). Nevertheless, this group of patients, as shown in Figure 1, lagged clearly in the SR response to both challenges compared with the other two groups. More specifically, patients in Group C were unable to respond adequately to the isoproterenol challenge. The final isoproterenol rate in Group C differed significantly (P < 0.0001) from Groups A and B (P < 0.000001). For the lines A, B, and C in Figure 1, statistical comparisons gave A–C, P < 0.000001 and B–C, P < 0.000001.
Groups B and C were easily distinguishable at the first stage of isoproterenol administration (2.4 µg/min) (Table 2A). Logistic regression analysis showed that at this stage the great majority of those with atropine responses of <90 b.p.m. could be classified into either Group B or Group C on the basis of their responses to isoproterenol. Recorded SRs of 94 b.p.m. stratified patients with abnormal atropine response into Group B, whereas SRs of 
85 b.p.m. indicated Group C (P < 0.000001). Intermediate values (86–93 b.p.m.) during the first stage of isoproterenol were insufficient for classification, and completion of the isoproterenol administration protocol was required.
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In Table 2B, the percentages of patients who had normal responses to isoproterenol (>120 b.p.m.) in relation to their atropine rates are presented. Patients with atropine rates of <70 b.p.m. formed a relatively homogeneous group, in which there was a small increase in heart rate after partial suppression of the parasympathetic stimuli, as well as an insufficient increase of the heart rate in response to sympathetic stimulation. The remaining patients (rate
71 b.p.m.), although sharing a deficient response to muscarinic blockade, exhibited a different response to sympathetic stimulation with isoproterenol. A significant percentage showed an increase in heart rates of 120 b.p.m. This supports the application of the isoproterenol test as an additional tool to the atropine test for the evaluation of sinus node bradycardia. In the majority of cases, it appears unnecessary to proceed to the administration of 60 drops/min in order to achieve a satisfactory diagnostic result. The first phase of isoproterenol administration (20 drops/min) had satisfactory discriminatory power, correctly predicting the final response in 82% of the patients.
Follow-up
The patients of this study were followed for 3 years. The follow-up consisted mainly of interviews over the phone. During this time, two patients from Group A and two patients from Group B died. In addition, six patients from Group A, seven patients from Group B, and four patients from Group C dropped out of the follow-up procedure.
By the end of the 3-year period of follow-up, 14 out of 30 patients originally enlisted in Group C (47%) had undergone permanent pacemaker implantation (DDDR). In Groups A and B, pacemaker implantation was not required in any patient. The permanent pacemaker implantation was decided by the patients’ personal physician due to the fact that the patients had already become symptomatic (dizziness, pro-syncope, and syncope). Two of the said patients were diagnosed with total atrioventricular block, and the rest presented sick sinus syndrome manifestations. Kaplan–Meier survival curves (cumulative proportion of pacing-free subjects) for the three groups during follow-up are shown in Figure 2. The survival curves for Group C predict only 35% survival without pacing. The probability of survival without pacemaker implantation was much lower in Group C than in the other groups (P < 0.0001).
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Table 3 sums up the results of the present study.
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Discussion |
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The means of creation and propagation of the sinus stimulus have been the subject of extensive study. According to latest data, the generation of the stimulus within the sinus node is multifocal, and concerns an area 10 times the area of the sinus node, extending both cranially and caudally. The atrial pacing complex has been the centre of discussion, involving both adrenergic and cholinergic receptors. More specifically, adrenergic receptors predominate in the cranial and cholinergic receptors in the caudal region. In this way, the function of the sinus node is stimulated by the sympathetic branch and inhibited by the parasympathetic branch of the autonomic nervous system.7
Dissociation of the sinus node from the neurovegetative effect can be achieved using sympatholytic and parasympatholytic drugs, and demonstrates the functional autonomy of the sinus node, expressed as an intrinsic heart rate that changes with age. According to current scientific opinion, under resting conditions the parasympathetic tone predominates, but reduces under conditions of bodily or mental stress in favour of the sympathetic. Recent data, however, suggest that there is a quantitative and qualitative difference in the cholinergic receptors among individuals.6,8
The principle of pharmacological testing is based on the activation and/or blocking of neurovegetative reactions.9–14
The most commonly applied pharmacological challenge is the atropine test. Cholinergic receptor blockade with atropine in healthy individuals increases heart rate. The more the cholinergic receptors blocked, the greater is the increase. The number of cholinergic receptors in each individual appears to determine the reaction to stress conditions. Extreme cholinergic deceleration of heart rate may have catastrophic consequences.15–17 Atropine is usually administered intravenously in a dosage of 0.025–0.04 mg/kg of body weight, or as 2–3 mg in total. Almost immediately there is a gradual increase in heart rate, which reaches its peak in 3 min. An increase of >15–20% in the heart rate of the individual, or an absolute value of the heart rate exceeding 90 b.p.m., is considered a normal response to atropine. Administration of smaller doses (<0.5 mg) may cause bradycardia, whereas larger doses (>3 mg) can cause ventricular tachycardia. There are no standardized values for normal response rates according to dosage, time elapsed from administration or age.
Isoproterenol has been used in intravenous administration in gradually increasing dosages (2.4–7.2 µg/min) until the appearance of ventricular extrasystoles. A normal increase in heart rate is that of >20–25% or 120 b.p.m.18 The latest data suggest that a small number of adrenergic receptors with low sensitivity to endogenous catecholamines, or low levels of catecholamines themselves, are responsible for the lack of an adequate response in terms of heart rate.
As stated, atropine administration to the patients of the present study led to the differentiation of two main groups: those with a normal response (heart rate 90 b.p.m.) and those without. The treatment of such asymptomatic patients is the intriguing question. Should they undergo an electrophysiological study with suspicion of sick sinus syndrome? Should they simply be followed up? Or should they undergo ‘preventive’ pacemaker implantation?19–24
It is well established that a normal sinus node response to atropine does not always imply sick sinus syndrome; nor does a ‘normal’ heart rate after atropine administration necessarily mean the sinus node is healthy.25 In the present study, the isoproterenol test was sequentially applied to further discriminate between normal cases and cases that need adequate follow-up, including possible ‘preventive’ pacemaker implantation in order to increase the life-expectancy of the patients (Figure 1).
More specifically, Group A (controls) with normal response to both atropine and isoproterenol presented a final, rather high mean SR (139.5 ± 5.4 b.p.m.). Responses to combined administration of atropine and isoproterenol reveal that under resting conditions the sinus node functions at low levels of the sympathetic tone, since atropine reduces the predominant parasympathetic tone (SR after atropine 96.1 ± 7.6 b.p.m. and generally 90 b.p.m.). Thus, the initial sinus bradycardia satisfies the corresponding haemodynamic needs at rest. In contrast, significant sympathetic activation is always available and is able to drastically increase the SR. This increase from baseline metabolic conditions can be achieved through isoproterenol administration. In the same way, when there are increased metabolic demands (e.g. psychosomatic stress), a similar response is achieved by endogenous catecholamines.
Group B consisted of patients with a reduced response to atropine, and normal response to isoproterenol administration, although slightly, but with statistically non-significant difference from Group A. This fact may suggest the possibility of mild, perhaps early stage organic damage to the sinus node–sympathetic combination. However, it is suggested that since the response to external agents is satisfactory, the same response may be expected to endogenous catecholamines as a result of psychosomatic stress in active daily life.
Group C was created on the basis of the isoproterenol response. It is interesting enough that although patients in this group presented only slightly lower and not statistically different heart rates from Group B, both at rest (49.6 ± 4.9 b.p.m.) and in response to atropine (74.4 ± 6.1 b.p.m.), they exhibited striking low responses to isoproterenol. These findings may lead to the conclusion that in this group there is an organic damage to the sinus node–sympathetic combination. It is worth mentioning that the average age in Group C was slightly higher than the other two groups. Nevertheless, this difference was proved statistically non-significant (P < 0.19).
Exercise testing could be equally applied for the evaluation of sinus bradycardia.26–30 As far as intrinsic heart rate is concerned,31 this test provides information on probable anatomic sinus node structure damage, regardless of whether there is coexistence or not of damage to the sympathetic system. The present study, on the other hand, has the advantage over exercise testing in that it determines the functional (directly) and the histological (indirectly) integrity of the sinus node. However, a more systematic approach to exercise testing should satisfy the following criteria: the exercise test should precede the atropine administration, and prepared protocols for exercise levels (endogenous catecholamine levels) should be available in agreement with those presented in Figure 1. In any case, the present study did not focus on comparison with other methods for the evaluation of sinus bradycardia that may or may not present high sensitivity or specificity, but aimed at the development of a new pharmacological challenge with diagnostic, prognostic and therapeutic contribution.
To conclude, the combined atropine–isoproterenol test could be used as a pharmacological method for the diagnostic, prognostic, and therapeutical approach to persons with asymptomatic sinus bradycardia. In view of the findings of the present study, a scheme of decision criteria for possible preventive permanent pacemaker implantation for individuals with asymptomatic sinus bradycardia, based on the combined atropine–isoproterenol tests could be proposed (Figure 3). Nevertheless, since there are no confounding factors on full analysis of the said patients groups, these data can be used as a pilot study and strongly support the organization of a randomized trial to address this question.
Conflict of interest: none declared.
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