Exercise and Cardiac Rehabilitation Cardiology 1992;81:172-177
Department of Medicine T, Ichilov Hospital, Tel-Aviv Sourasky Medical Center, and Cardiac Rehabilitation Institute, Sheba Medical Center. Tcl-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Keywords Blood pressure Exercise testing Heart rate Tropicamide
Influence of Ocular Tropicamide on Exercise Testing
Abstract This study was aimed to evaluate the effects of tropicamide 0.5% eye drops on cardiovascular parameters during exercise testing. The study group included 154 healthy subjects (mean age: 44.7 ± 8 years). The subjects were divided into three groups according to the size of the pupils at the onset of exer cise: A: pupils not dilated (n = 27). B: pupils partially dilated (n = 90) and C: pupils widely dilated (n = 37). They were com pared to 66 healthy controls (age 43.8 ± 8) who did not receive the drops. Rest and exercise parameters were affected in groups A and B. while the results of group C resembled those of the controls: (a) resting heart rate - 66.7, 66.6, 70.9 and 69.3. respectively (p = 0.03); (b) heart rate at 50 and 1 0 0 W - 104, 107, 110 and 111 (p = 0.01) and 131, 131, 137, 139, respectively (p = 0.01): and (c) peak systolic blood pres sure - 192, 186, 183, 175; respectively (p = 0.004). Reanalyz ing the data by scoring of visual impairment gave identical results. As a whole, the study group achieved higher work loads than the controls (126 vs. 119 W; p = 0.03). We conclude that the instillation of ocular tropicamide has definite effects on cardiovascular parameters, both at rest and during exer cise. Mainly, patients showed a lower heart rate at the initial levels of exercise. However, at symptom-limited level, tropi camide does not influence a patient’s ability to achieve the target heart rate, and stress testing results are not altered by the drug.
Received: May 17. 1992 Accepted: May 25. 1992
Amos Pines. MI) Department of Medicine T Ichilov Hospital 6 Weizman Street 64239 Tel-Aviv (Israel)
©1992 S. Karger AG. Basel 0008-6312/92/ 0813—0172S2.75/0
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/15/2019 10:46:38 AM
Amos Pines Enrique Z. Fisman Yaacov Drory Mordechai Averbuch Efraim Ben-Ari liana Gelernter Yoram Levo Jan J. Kellermann
Methods Patients Fundoscopic examination and exercise testing are included in the annual comprehensive checkup pro gram at the Sheba Medical Center. Fundoscopy usually precedes exercise testing. This prospective study included all healthy individuals examined over a period of 3 months. Participants were divided into two groups: ( I ) individuals who received 0.4 mg (4 drops) of 0.5% tropicamide ophthalmic solution (Mydramide. Fischer) 30-120 min prior to exercise testing (study group, n = 154. mean age 44.7 ± 8 years); and (2) individuals performing the exercise test without prior administration of the mydriatic agent (control group, n = 66, mean age 43.8 ± 8 years). The exami
nees were divided into four groups according to the time that had elapsed since the instillation of eye drops (=£30, 31-60, 61-90 and 91-120 min), and the subjec tive grade of vision impairment was established (not impaired, mild-to-modcrate impairment, severe im pairment). The size of the pupils was defined as widely dilated, moderately dilated or not dilated. Exercise Protocol The ergometric test was performed on a mechani cally braked Monark bicycle, following our protocol described elsewhere [II]. This near maximal exercise test (> 85% of predicted maximal heart rate according to age) is based on progressively increasing intermit tent work loads, each of 5 min duration. The initial work load was 50 W. Blood pressure was measured at rest and at the end of each work load. ECG was moni tored continuously, and heart rate was assessed from the ECG tracing. Statistics Student’s t test for independent observations or one-way ANOVA were used for the statistical analyses when appropriate.
Results The size of the pupils was negatively corre lated with the lime interv al between the onset of exercise testing and the instillation of eye drops (the wider the pupil, the lesser the time. r = -0.41, p < 0.001). Therefore, with regard to the remaining analyses, members of the study population were grouped according to their pupil size: group A (n = 27): pupils not dilated (95 ± 24 min after instillation), group B (n = 90): pupils partially dilated (70 ± 25 min) and group C (n = 37): pupils widely dilated (59 ± 28 min). At rest, the study group had a slower heart rate than the controls (66.7 ± 11 vs. 69.8 ± 9 beats/min, p = 0.05). The difference in the pulse rate was more evident when groups A or B were compared to group C or to the controls (table 1). A similar, though statistically insig nificant trend was observed for rest systolic blood pressure, which was lower in groups A
173
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The potential systemic toxicity of atropine ophthalmic solutions has been well docu mented [1-4]. The adverse manifestations, mainly seen in children under the age of 10, included mental disturbances, hyperpyrexia, skin flush, decreased gastrointestinal motility, tachycardia, arrhythmia and even death. Be cause of its side effects and long-lasting ac tion, atropine is no longer in use to dilate pupils prior to routine fundoscopic examina tion and has been substituted by the short-act ing parasympatholytic agent tropicamide [48], Maximal dilation following tropicamide eye drops occurs within 30 min and persists for 2-4 h. Systemic adverse reactions have been rarely described [4, 5, 9, 10], Tropicam ide has been widely used by primary care phy sicians. internists, cardiologists and ophthal mologists. Reviewing the literature, we could not find any documentation of hemodynamic changes associated with the local administra tion of tropicamide. In the framework of com prehensive checkup programs, exercise test ing is frequently performed shortly after tro picamide instillation. The influence of this drug on exercise is not established. This study examines the effects of ocular tropicamide on exercise testing in healthy individuals.
Table 1. Results of exercise testing in group A (undiluted pupils), group B (partially dilated pupils), group C (widely dilated pupils) and in the control group (means ± SD)
n Age, years Rest HR. beats/min SBP. mm Hg DBP. mm Hg Exercise HR. beats/min 50 W 100 W SBP. mm Hg 50 W 100 W SBP Peak exercise HR. beats/min SBP. mm Hg WL. W
Group A
Group B
Group C
27 45 ±8
90 46±8
37 42±6
Control 66 44 ±8
p (ANOVA)
NS
66.6+13 122.6+13 82.4 ±9
66.1 ±9 122.8 ±12 83.1 ±8
71.1 ±13 125.1 ±12 82.1 ±9
69.8 ±9 126.5 ±14 82.5 ±8
0.03 NS NS
103.8 ± 10 130.9 ± 13
107.1 ±12 131.4 ± 12
110.1 ± 14 136.9 ± 16
110.8 ± 14 139.6 ± 15
0.004 0.002
148.1 ±16 175.0 ± 21
147.6 ± 18 173.9 ±23
147.9 ± 10 174.7 ± 17
152.0 ± 19 173.2 ±21
NS NS
152.1 ± 13 192.4 ±23 127.7 + 30
149.8 ± 13 185.9 ±23 126.4 ±20
154.8 ± 14 182.9 ± 19 123.3 ± 16
154.4 ± 12 174.8 ±25 119.3 ± 19
NS 0.004 NS
HR = Heart rate: SBP = systolic blood pressure; DBP = diastolic blood pressure: WL = work load: NS = not significant.
174
the heart rate showed again the same pattern of a stepwise increase from groups A to C and the control group (table 1). There were no dif ferences in systolic or diastolic blood pres sures. Analysis of data according to patients' subjective grading of their visual impairment yielded results which were almost identical to the above distributions by pupil size (ta ble 2).
Discussion Despite the common belief that topically applied drugs, such as ophthalmic solutions, do not induce systemic reactions, physicians must be aware that such events occur fre quently. Indeed, our results show that 0.5%
Pincs/Fisman/Drory/Averbuch/ Rpn-Ari/Gelemler/I evo/Kellermann
Tropieamide and Exercise Testing
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/15/2019 10:46:38 AM
and B than in group C or the control group. There were no differences in diastolic blood pressure at rest among the four groups. As a whole, patients who received tropicamide achieved higher work loads than the controls (l 25.9 ± 21 vs. 119.3 ± 19W: p = 0.03). but when analyzed by pupil size, the intergroup differences were not statistically significant. A gradual decrease from groups A through C and the controls was observed for systolic blood pressure at peak exercise (ta ble 1). Since the objective of our exercise pro tocol is to achieve a specific age-dependent heart rate and as the participants’ mean age was similar for all groups, there were no sig nificant variations in the attained peak heart rate among the various groups. At the inter mediary work loads, namely at '50 and 100 W,
Table 2. Results of exercise testing analyzed according to the patients' subjective grading of vision impairment (means ± SD) Control Severe Mild-toNo impairment impairment moderate impairment n Rest HR. beats/min SBP. mm Hg DBP, mm Hg Exercise HR. beats/min 50 W I00W SBP. mm Hg 50 W 100W
43
79
18
P (ANOVA)
62
66.7 ± 10 119.7 ±12 80.3 ±8
66.6±I0 123.1 ±11 82.6±8
70.9 ± 13 128.3 ± 13 85.7±8
69.3 ±9 124.0 ± 14 82.9 ±8
0.03 NS NS
105.8 ± 11 130.7 ± 12
105.0± 11 132.9 ± 13
109.9 ± 16 135.7 ±18
110.8± 14 139.6 ± 15
0.01 0.01
148.0 ± 17 175.0 ± 21
147.4± 16 174.4 ±22
148.6 ± 12 172.2 ± 18
152.0 ± 19 173.2 ±21
NS NS
ocular tropicamidc can modulate several of the parameters of exercise testing. Individuals who received 0.4 mg tropicamide had a signif icantly lower heart rate at rest. This decrease in heart rate corresponds to the bradycardia which has been documented to follow small doses of atropine [12]. During exercise test ing. patients who received tropicamide achieved higher work loads. When hemody namic parameters were correlated with the pupil size, which reflects the time interval from instillation of the drug, a clear pattern of stepwise changes in heart rate, blood pressure and work load at peak exercise, as well as at 50 and 100 W seems to emerge. As expected, the pupils showed maximal mydriasis shortly af ter administration of the ophthalmic solution which waned over the following 90-120 min. Surprisingly, changes in parameters of exer cise tests were minimal in members of group C. although they displayed a maximal
drug effect on the pupil size. The hemody namic changes, in contrast to the local effect on the eye, were delayed and hence evident in groups A and B. These data indicate that the systemic effects of tropicamide occur only after the local mydriatic effect has waned. Analyzing all our above data according to a person's subjective grading of vision impair ment gave almost the same results, indicating that the cycloplegic and mydriatic effects of tropicamide concur. The main effect of atro pine on the heart is to alter the heart rate [ 1215], Although the predominant manifestation is tachycardia due to the vagolytic properties of atropine, with small to average doses of the drug, the initial effect may be a transient slow ing of the heart rate, probably induced by blockade of M 1 receptors on postganglionic parasympathetic neurones [ 12]. However, sig nificant alterations in cardiovascular parame ters were usually not found during dynamic
175
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The total number of patients is less than in table I due to missing data. Abbreviations as in table 1.
exercise following the administration of atro pine [ 13-15]. Similarly, the effects of atropine on isometric exercise (handgrip) were also found to be marginal [16]. Those studies ex amining the results of exercise tests during atropine treatment may be hampered by the small number of patients (less than 20) in volved in each. The effects of inhaled atropine or atropine derivatives or the effects of atro pine in combination with other drugs on exer cise parameters have been widely discussed [17, 18]. However, results do not necessarily reflect the isolated cardiotropic effects of atro pine. It could have been assumed that the effects of tropicamidc as an antimuscarinic agent are similar to those of atropine, namely lack of any significant influence on exercise-induced cardiovascular parameters. Nevertheless, we found definite effects possibly due to our large sample size or due to better stratification of study groups based on the local biological effects of the drug. Our findings are in keeping with the classical concept that at rest the heart rate is mainly controlled by the vagal tone [13. 19].
Although during dynamic exercise the sympathetic system takes over and plays a major role in the adaptation of the cardiac response to exercise [ 13. 19], the effect of tropicamide on the exertional heart rate was still evident. In conclusion, tropicamide should be added to other ophthalmic drugs (such as timolol), which were found to induce systemic hemodynamic changes at rest and during dy namic exercise. However, contrarily to timo lol which strongly reduces heart rate, the in fluence of tropicamide is only modest. Inter estingly, the systemic effects lagged after the local ones, and the maximal effects occurred only when the dilation of pupils had already waned, attesting to the brief mydriatic effect of tropicamide on the one hand and the good, but delayed systemic absorption of the drug following its instillation on the other hand. The patients of the study group showed a lower heart rate at the initial levels of exercise. However, it should be pointed out that at symptom-limited level tropicamide does not influence a patient’s ability to achieve the tar get heart rate, and stress testing results are not altered by the drug.
1 Davidson SI: Systemic effects of eye drops. Trans Ophthalmol Soc UK 1974:94:487-492. 2 Hoefnage! D: Toxic effects of atro pine and homatropine eyedrops in children. N Engl J Med 1961 ;264: 168-171. 3 Palmer EA: Drug toxicity in pediat ric ophthalmology. J Toxicol 1982; 1:181-210. 4 Bartlett JD: Administration of and adverse reactions to cycloplegic agents. Am J Optom Physiol Opt 1978:55:227-233.
176
5 Merrill DL, Goldberg B. Zavell S: Bis-tropicamide. a new parasympa tholytic. Curr Ther Res 1960:2:43— 50. ’ 6 Gettes BC: Tropicamide. a new cy cloplegic mydriatic. Arch Ophthal mol 1961;65:48-51. 7 Milder B: Tropicamide as a cyclo plegic agent. Arch Ophthalmol 1961:66:96-98.
Pines/Fisman/Drory/Averbuch/ Ben-Ari/Gelemter/Levo/Kellermann
8 Larkin KM. Charap A. Cheetham JK. Frank J: Ideal concentration of tropicamide with hvdroxyamphetamine I % for routine pupillary di lation. Ann Ophthalmol 1989:21: 340-344. 9 Mindel JS: Cholinergic pharmacolo gy: in Tasman W. Jaeger EA (eds): Duane's Foundations of Clinical Ophthalmology (revised edition). Philadelphia. Lippincott. 1990, pp 32-45. 10 Wahl JW: Systemic reactions to tro picamide. Arch Ophthalmol 1969; 82:320-321.
Tropicamide and Exercise Testing
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References
14 Chamberlain DA. Turner P. Sned don JM: Effects of atropine on heart-rate in healthy man. Lancet 1967;ii:12-15. 15 Abbott JA. Hirschfeld DS. Kunkel FW, Scheinman MM, Modin G: Graded exercise testing in patients with sinus node dysfunction. Am J Med 1977;62:330-388. 16 Sanders JS. Mark AL. Ferguson DW; Evidence for cholinergically mediated vasodilation at the begin ning of isometric exercise in hu mans. Circulation 1989:79:815— 824.
17 Tobin MJ. Hughes JA. Hutchison DCS: Effects of ipratropium bro mide and fenoterol aerosols on exer cise tolerance. Eur J Rcspir Dis 1984:65:441-446. 18 Wisenbcrg G. Zawadowski AG. Gebhardt VA. Prato FS. Goddard MD, Nichol PM. Rechnitzcr PA: Dopamine: Its potential for induc ing ischemic left ventricular dys function. J Am Coll Cardiol 1985:6: 84-92. 19 Bronk DW: The nervous mecha nism of cardiovascular control. Bal timore. Williams & Wilkins. 1935.
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11 Kcllcrmann JJ: Rehabilitation of patients with coronary heart disease. Prog Cardiovasc Dis 1975; 17:303— 328. 12 Brown JH: Atropine, scopolamine, and related antimuscarinic drugs; in Goodman Gilman A. Rail TW. Nies AS. Taylor P (eds): Goodman and Gilman's Pharmacological Basis of Therapeutics, ed 8. New York. Per gamon Press. 1991. pp 150-165. 13 Robinson BF. Epstein SE. Beiser GD. Braunwald E: Control of heart rate by the autonomic nervous sys tem. Circ Res 1966;19:400-411.
Department of Medicine T, Ichilov Hospital, Tel-Aviv Sourasky Medical Center, and Cardiac Rehabilitation Institute, Sheba Medical Center. Tcl-Hashomer, Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel
Keywords Blood pressure Exercise testing Heart rate Tropicamide
Influence of Ocular Tropicamide on Exercise Testing
Abstract This study was aimed to evaluate the effects of tropicamide 0.5% eye drops on cardiovascular parameters during exercise testing. The study group included 154 healthy subjects (mean age: 44.7 ± 8 years). The subjects were divided into three groups according to the size of the pupils at the onset of exer cise: A: pupils not dilated (n = 27). B: pupils partially dilated (n = 90) and C: pupils widely dilated (n = 37). They were com pared to 66 healthy controls (age 43.8 ± 8) who did not receive the drops. Rest and exercise parameters were affected in groups A and B. while the results of group C resembled those of the controls: (a) resting heart rate - 66.7, 66.6, 70.9 and 69.3. respectively (p = 0.03); (b) heart rate at 50 and 1 0 0 W - 104, 107, 110 and 111 (p = 0.01) and 131, 131, 137, 139, respectively (p = 0.01): and (c) peak systolic blood pres sure - 192, 186, 183, 175; respectively (p = 0.004). Reanalyz ing the data by scoring of visual impairment gave identical results. As a whole, the study group achieved higher work loads than the controls (126 vs. 119 W; p = 0.03). We conclude that the instillation of ocular tropicamide has definite effects on cardiovascular parameters, both at rest and during exer cise. Mainly, patients showed a lower heart rate at the initial levels of exercise. However, at symptom-limited level, tropi camide does not influence a patient’s ability to achieve the target heart rate, and stress testing results are not altered by the drug.
Received: May 17. 1992 Accepted: May 25. 1992
Amos Pines. MI) Department of Medicine T Ichilov Hospital 6 Weizman Street 64239 Tel-Aviv (Israel)
©1992 S. Karger AG. Basel 0008-6312/92/ 0813—0172S2.75/0
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/15/2019 10:46:38 AM
Amos Pines Enrique Z. Fisman Yaacov Drory Mordechai Averbuch Efraim Ben-Ari liana Gelernter Yoram Levo Jan J. Kellermann
Methods Patients Fundoscopic examination and exercise testing are included in the annual comprehensive checkup pro gram at the Sheba Medical Center. Fundoscopy usually precedes exercise testing. This prospective study included all healthy individuals examined over a period of 3 months. Participants were divided into two groups: ( I ) individuals who received 0.4 mg (4 drops) of 0.5% tropicamide ophthalmic solution (Mydramide. Fischer) 30-120 min prior to exercise testing (study group, n = 154. mean age 44.7 ± 8 years); and (2) individuals performing the exercise test without prior administration of the mydriatic agent (control group, n = 66, mean age 43.8 ± 8 years). The exami
nees were divided into four groups according to the time that had elapsed since the instillation of eye drops (=£30, 31-60, 61-90 and 91-120 min), and the subjec tive grade of vision impairment was established (not impaired, mild-to-modcrate impairment, severe im pairment). The size of the pupils was defined as widely dilated, moderately dilated or not dilated. Exercise Protocol The ergometric test was performed on a mechani cally braked Monark bicycle, following our protocol described elsewhere [II]. This near maximal exercise test (> 85% of predicted maximal heart rate according to age) is based on progressively increasing intermit tent work loads, each of 5 min duration. The initial work load was 50 W. Blood pressure was measured at rest and at the end of each work load. ECG was moni tored continuously, and heart rate was assessed from the ECG tracing. Statistics Student’s t test for independent observations or one-way ANOVA were used for the statistical analyses when appropriate.
Results The size of the pupils was negatively corre lated with the lime interv al between the onset of exercise testing and the instillation of eye drops (the wider the pupil, the lesser the time. r = -0.41, p < 0.001). Therefore, with regard to the remaining analyses, members of the study population were grouped according to their pupil size: group A (n = 27): pupils not dilated (95 ± 24 min after instillation), group B (n = 90): pupils partially dilated (70 ± 25 min) and group C (n = 37): pupils widely dilated (59 ± 28 min). At rest, the study group had a slower heart rate than the controls (66.7 ± 11 vs. 69.8 ± 9 beats/min, p = 0.05). The difference in the pulse rate was more evident when groups A or B were compared to group C or to the controls (table 1). A similar, though statistically insig nificant trend was observed for rest systolic blood pressure, which was lower in groups A
173
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/15/2019 10:46:38 AM
The potential systemic toxicity of atropine ophthalmic solutions has been well docu mented [1-4]. The adverse manifestations, mainly seen in children under the age of 10, included mental disturbances, hyperpyrexia, skin flush, decreased gastrointestinal motility, tachycardia, arrhythmia and even death. Be cause of its side effects and long-lasting ac tion, atropine is no longer in use to dilate pupils prior to routine fundoscopic examina tion and has been substituted by the short-act ing parasympatholytic agent tropicamide [48], Maximal dilation following tropicamide eye drops occurs within 30 min and persists for 2-4 h. Systemic adverse reactions have been rarely described [4, 5, 9, 10], Tropicam ide has been widely used by primary care phy sicians. internists, cardiologists and ophthal mologists. Reviewing the literature, we could not find any documentation of hemodynamic changes associated with the local administra tion of tropicamide. In the framework of com prehensive checkup programs, exercise test ing is frequently performed shortly after tro picamide instillation. The influence of this drug on exercise is not established. This study examines the effects of ocular tropicamide on exercise testing in healthy individuals.
Table 1. Results of exercise testing in group A (undiluted pupils), group B (partially dilated pupils), group C (widely dilated pupils) and in the control group (means ± SD)
n Age, years Rest HR. beats/min SBP. mm Hg DBP. mm Hg Exercise HR. beats/min 50 W 100 W SBP. mm Hg 50 W 100 W SBP Peak exercise HR. beats/min SBP. mm Hg WL. W
Group A
Group B
Group C
27 45 ±8
90 46±8
37 42±6
Control 66 44 ±8
p (ANOVA)
NS
66.6+13 122.6+13 82.4 ±9
66.1 ±9 122.8 ±12 83.1 ±8
71.1 ±13 125.1 ±12 82.1 ±9
69.8 ±9 126.5 ±14 82.5 ±8
0.03 NS NS
103.8 ± 10 130.9 ± 13
107.1 ±12 131.4 ± 12
110.1 ± 14 136.9 ± 16
110.8 ± 14 139.6 ± 15
0.004 0.002
148.1 ±16 175.0 ± 21
147.6 ± 18 173.9 ±23
147.9 ± 10 174.7 ± 17
152.0 ± 19 173.2 ±21
NS NS
152.1 ± 13 192.4 ±23 127.7 + 30
149.8 ± 13 185.9 ±23 126.4 ±20
154.8 ± 14 182.9 ± 19 123.3 ± 16
154.4 ± 12 174.8 ±25 119.3 ± 19
NS 0.004 NS
HR = Heart rate: SBP = systolic blood pressure; DBP = diastolic blood pressure: WL = work load: NS = not significant.
174
the heart rate showed again the same pattern of a stepwise increase from groups A to C and the control group (table 1). There were no dif ferences in systolic or diastolic blood pres sures. Analysis of data according to patients' subjective grading of their visual impairment yielded results which were almost identical to the above distributions by pupil size (ta ble 2).
Discussion Despite the common belief that topically applied drugs, such as ophthalmic solutions, do not induce systemic reactions, physicians must be aware that such events occur fre quently. Indeed, our results show that 0.5%
Pincs/Fisman/Drory/Averbuch/ Rpn-Ari/Gelemler/I evo/Kellermann
Tropieamide and Exercise Testing
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/15/2019 10:46:38 AM
and B than in group C or the control group. There were no differences in diastolic blood pressure at rest among the four groups. As a whole, patients who received tropicamide achieved higher work loads than the controls (l 25.9 ± 21 vs. 119.3 ± 19W: p = 0.03). but when analyzed by pupil size, the intergroup differences were not statistically significant. A gradual decrease from groups A through C and the controls was observed for systolic blood pressure at peak exercise (ta ble 1). Since the objective of our exercise pro tocol is to achieve a specific age-dependent heart rate and as the participants’ mean age was similar for all groups, there were no sig nificant variations in the attained peak heart rate among the various groups. At the inter mediary work loads, namely at '50 and 100 W,
Table 2. Results of exercise testing analyzed according to the patients' subjective grading of vision impairment (means ± SD) Control Severe Mild-toNo impairment impairment moderate impairment n Rest HR. beats/min SBP. mm Hg DBP, mm Hg Exercise HR. beats/min 50 W I00W SBP. mm Hg 50 W 100W
43
79
18
P (ANOVA)
62
66.7 ± 10 119.7 ±12 80.3 ±8
66.6±I0 123.1 ±11 82.6±8
70.9 ± 13 128.3 ± 13 85.7±8
69.3 ±9 124.0 ± 14 82.9 ±8
0.03 NS NS
105.8 ± 11 130.7 ± 12
105.0± 11 132.9 ± 13
109.9 ± 16 135.7 ±18
110.8± 14 139.6 ± 15
0.01 0.01
148.0 ± 17 175.0 ± 21
147.4± 16 174.4 ±22
148.6 ± 12 172.2 ± 18
152.0 ± 19 173.2 ±21
NS NS
ocular tropicamidc can modulate several of the parameters of exercise testing. Individuals who received 0.4 mg tropicamide had a signif icantly lower heart rate at rest. This decrease in heart rate corresponds to the bradycardia which has been documented to follow small doses of atropine [12]. During exercise test ing. patients who received tropicamide achieved higher work loads. When hemody namic parameters were correlated with the pupil size, which reflects the time interval from instillation of the drug, a clear pattern of stepwise changes in heart rate, blood pressure and work load at peak exercise, as well as at 50 and 100 W seems to emerge. As expected, the pupils showed maximal mydriasis shortly af ter administration of the ophthalmic solution which waned over the following 90-120 min. Surprisingly, changes in parameters of exer cise tests were minimal in members of group C. although they displayed a maximal
drug effect on the pupil size. The hemody namic changes, in contrast to the local effect on the eye, were delayed and hence evident in groups A and B. These data indicate that the systemic effects of tropicamide occur only after the local mydriatic effect has waned. Analyzing all our above data according to a person's subjective grading of vision impair ment gave almost the same results, indicating that the cycloplegic and mydriatic effects of tropicamide concur. The main effect of atro pine on the heart is to alter the heart rate [ 1215], Although the predominant manifestation is tachycardia due to the vagolytic properties of atropine, with small to average doses of the drug, the initial effect may be a transient slow ing of the heart rate, probably induced by blockade of M 1 receptors on postganglionic parasympathetic neurones [ 12]. However, sig nificant alterations in cardiovascular parame ters were usually not found during dynamic
175
Downloaded by: Karolinska Institutet, University Library 130.237.122.245 - 1/15/2019 10:46:38 AM
The total number of patients is less than in table I due to missing data. Abbreviations as in table 1.
exercise following the administration of atro pine [ 13-15]. Similarly, the effects of atropine on isometric exercise (handgrip) were also found to be marginal [16]. Those studies ex amining the results of exercise tests during atropine treatment may be hampered by the small number of patients (less than 20) in volved in each. The effects of inhaled atropine or atropine derivatives or the effects of atro pine in combination with other drugs on exer cise parameters have been widely discussed [17, 18]. However, results do not necessarily reflect the isolated cardiotropic effects of atro pine. It could have been assumed that the effects of tropicamidc as an antimuscarinic agent are similar to those of atropine, namely lack of any significant influence on exercise-induced cardiovascular parameters. Nevertheless, we found definite effects possibly due to our large sample size or due to better stratification of study groups based on the local biological effects of the drug. Our findings are in keeping with the classical concept that at rest the heart rate is mainly controlled by the vagal tone [13. 19].
Although during dynamic exercise the sympathetic system takes over and plays a major role in the adaptation of the cardiac response to exercise [ 13. 19], the effect of tropicamide on the exertional heart rate was still evident. In conclusion, tropicamide should be added to other ophthalmic drugs (such as timolol), which were found to induce systemic hemodynamic changes at rest and during dy namic exercise. However, contrarily to timo lol which strongly reduces heart rate, the in fluence of tropicamide is only modest. Inter estingly, the systemic effects lagged after the local ones, and the maximal effects occurred only when the dilation of pupils had already waned, attesting to the brief mydriatic effect of tropicamide on the one hand and the good, but delayed systemic absorption of the drug following its instillation on the other hand. The patients of the study group showed a lower heart rate at the initial levels of exercise. However, it should be pointed out that at symptom-limited level tropicamide does not influence a patient’s ability to achieve the tar get heart rate, and stress testing results are not altered by the drug.
1 Davidson SI: Systemic effects of eye drops. Trans Ophthalmol Soc UK 1974:94:487-492. 2 Hoefnage! D: Toxic effects of atro pine and homatropine eyedrops in children. N Engl J Med 1961 ;264: 168-171. 3 Palmer EA: Drug toxicity in pediat ric ophthalmology. J Toxicol 1982; 1:181-210. 4 Bartlett JD: Administration of and adverse reactions to cycloplegic agents. Am J Optom Physiol Opt 1978:55:227-233.
176
5 Merrill DL, Goldberg B. Zavell S: Bis-tropicamide. a new parasympa tholytic. Curr Ther Res 1960:2:43— 50. ’ 6 Gettes BC: Tropicamide. a new cy cloplegic mydriatic. Arch Ophthal mol 1961;65:48-51. 7 Milder B: Tropicamide as a cyclo plegic agent. Arch Ophthalmol 1961:66:96-98.
Pines/Fisman/Drory/Averbuch/ Ben-Ari/Gelemter/Levo/Kellermann
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