These articles have been accepted for publication in the British Journal of Dermatology and are currently being edited and typeset. Readers should note that articles published below have been fully refereed, but have not been through the copy-editing and proof correction process. Wiley-Blackwell and the British Association of Dermatologists cannot be held responsible for errors or consequences arising from the use of information contained in these articles; nor do the views and opinions expressed necessarily reflect those of Wiley-Blackwell or the British Association of Dermatologists This article is protected by copyright. All rights reserved. Accepted Date : 28-Jun-2014 Article type : Paediatric dermatology
Safety Profile of a Divided Dose of Propranolol on Heart Rate in Children with Infantile Hemangioma During 16 Weeks of Treatment Running title: The influence of propranolol on heart rate in IHs subjects. H. Song*1, H. Shi*#2, X. Zhang2, J. Wang2, Y. Yu2, W. Chen2 and H. Zhou1
1
2
Ningxia Medical University
Department of Dermatovenereology, Ningxia Medical University General Hospital, Yinchuan 750004, China
#
Corresponding Author:
Huijuan Shi Department of Dermatovenereology Ningxia Medical University General Hospital Yinchuan 750004, China. E-mail: [email protected] Ph: +86 139 9529 5912 Fax: 0086-0951-4082981 *
These authors contributed equally to this work.
Funding sources: None Declared
This article is protected by copyright. All rights reserved. Competing interests All the authors do not have any possible conflicts of interest. Bulleted statements (1) What's already known about this topic? Heart rates are thought to decrease during propranolol treatment for infantile hemangiomas (IH). (2) What does this study add? Our study describes the careful and close monitoring of heart rate during 16 weeks of propranolol treatment in IH subjects. We found that all heart rates were within the normal range and that a three times per day dosing regimen had no significant effects on heart rates in IH subjects. Our results reassure the safety of using propranolol at the dose of 2mg/kg/day on heart rates for up to 16 weeks of therapy.
Summary Background: Although propranolol has been accepted as a first-line drug for infantile hemangioma (IH), no study has systematically characterized changes in heart rates during long-term propranolol treatment. Objectives: To evaluate the influence of a divided dose of propranolol on heart rates in IH subjects. Methods: A prospective study was conducted from January 2009 to December 2013. All IH patients were administered propranolol at 0.67 mg per kilogram per day as a single dose on days 1 and 2, and gradually increased to the full dose (2mg/kg/d) on day 5, which was given in three divided doses. Heart rates were recorded before treatment and closely monitored during treatment. Heart rates in controls were monitored once a week. Results: All heart rates monitored during treatment were found to be within the normal range.
This article is protected by copyright. All rights reserved. Fluctuations in heart rates were observed after every dose from the first day to the first dose of the sixth day; however, from the second dose of the sixth day onwards, no significant differences (p>0.05) in heart rates were observed after every dose on successive days. During the second week of drug therapy, no significant differences in heart rates were observed at 1h after the first dose (p=1.00). Also, no significant differences (p=0.734) in heart rates were observed between patients at 1h after the first dose on Mondays versus controls from the first to sixteenth week of treatment. Conclusions: A three times per day dosing regimen of propranolol had no significant sustained effects on heart rates in IH subjects. [Key words] propranolol; heart rate; infantile hemangiomas
Introduction Propranolol, a non-selective beta-blocker, is increasingly recognized as an effective therapy in infantile hemangioma (IH) apart from its well established role in hypertension, supraventricular tachycardia, congestive heart failure and hyperthyroidism[1]. IH are the most common vascular tumors in infancy
[2]
having complete regression in 60% of 4-year-old
patients and 76% of 7-year-old patients[3]. Most IH are uncomplicated, but a few may have complications such as ulceration, threat to vision, airway obstruction, and congestive heart failure[4,5]. IH may also leave residual scarring or permanent distortion of facial landmarks[6,7]. The standard treatment course includes the use of oral/intralesional steroids, α-interferon, cytotoxins, embolization, pulsed dye laser and surgical resection[8]. These treatments are associated with complications and toxic side effects, including transient cosmetic disfigurement, scars that are difficult to repair and features of adrenal cortical dysfunction[8]. Propranolol has been accepted as a first-line drug by clinicians as a new therapy for infantile hemangioma since its first established use was in a case of severe infantile hemangioma by
This article is protected by copyright. All rights reserved. Leaute-labreze et al. in 2008[9]. Propranolol has potential side effects like bradycardia and hypotension, which mandate close monitoring of heart rate especially when it is used for a longer duration. In this context, we aimed to closely monitor heart rate of 31 IH children from January 2009 to December 2013, who were administered propranolol therapy. At the beginning, patients received propranolol at a dose of 0.67 mg/kg once daily, with the dose gradually increasing to the full dose (2mg/kg/d) by day 5, which was given in three divided doses.
Materials and Methods 1. Human Subjects All infantile hemangioma patients were recruited from the outpatient department of Ningxia Medical University General Hospital, with 38 cases enrolled but 31 cases proceeding towards the entire treatment course (Figure 1). A definite diagnosis of hemangioma was based upon standard guidelines proposed by Mulliken and Enjolras[10]. All parents of the study children were informed of the purpose of the study and signed a detailed informed consent describing the study design and possible adverse effects of propranolol treatment. The study was approved by the Medical Ethics Committee, which was affiliated with the Hospital of Ningxia Medical University. The inclusion criteria were as follows: children who were less than two years of age, with no organ and systemic diseases and who had not been previously treated with surgical therapy, laser, or other medications. Subjects were excluded if they had the following features: (1) sinus bradycardia, hypotension, cardiogenic shock, heart block (second to third degree atrioventricular block), severe or acute heart failure, (2) tracheobronchitis, pneumonia or bronchial asthma, (3) liver and kidney dysfunction (4) abnormal glucose tolerance or diabetes mellitus and (5) unwilling to attend follow-up visits. Healthy children (n=31) who were age and sex matched with IH cases were randomly
This article is protected by copyright. All rights reserved. chosen from the Tiansheng Community Clinic and considered the control group. All children in the control group were born in hospitals and underwent standard examinations, which included echocardiograms after birth. Subjects were only included if they had no organic diseases, including heart diseases, and if their parents took them regularly to the Community Clinic for regular physical examinations as per the study protocol.
2. Methods 2.1 Preparation for treatment: Basic vital signs (temperature, pulse, respirations and blood pressure) and weights were measured in subjects prior to treatment administration. Complete blood counts, liver and kidney function tests, blood glucose, electrocardiogram and echocardiogram were also obtained along with clinical evaluation of IH with photographs.
2.2 Therapeutic protocol: All patients were administered propranolol at a single dose of 0.67 mg per kilogram per day on days 1 and 2. On days 3 and 4, the drug dose was increased to 1.34 mg per kilogram per day and given in 2 divided doses. From day 5 onwards, the dose was increased to 2 mg/kg/day and given in three divided doses. This standard dose was continued until the end of the treatment. In the absence of side effects and a relatively stable heart rate, treatment was continued with the dose of 2
mg/kg/day. Heart rate was monitored
with a stethoscope at each visit in an outpatient clinic. During follow-ups, body weight was measured to adjust for medication doses. When a child suffered from a common cold or exhibited adverse reactions such as diarrhea, vomiting, shortness of breath and altered sleep pattern, the dose was reduced or temporarily discontinued based on the severity of the adverse effects. When the cold and adverse effects disappeared, the treatment regimen was restarted and the medication dose was optimized to 2 mg/kg/day.
This article is protected by copyright. All rights reserved. 2.3 Monitoring heart rates 2.3.1 Heart rates in healthy (control) children: Heart rate was clinically monitored in healthy children once a week when children were quiet. According to the Nelson Textbook of Pediatrics[11], the normal range for heart rate by age were as follows: 80-160 beats per minute in 1-11 month old infants, 80-130 beats per minute in 2 year old children, and 80-120 beats per minute in 4 year old children.
2.3.2 Heart rates in IH patients: Heart rate was recorded clinically prior to the initiation of treatment as well as with an electrocardiogram as an outpatient in the hospital. According to the pharmacokinetics of propranolol (peak plasma concentration reached by 1-1.5 hours and half-life of 2-3 hours), heart rate was monitored at one, two and four hours following consumption of propranolol in the first week of treatment. Patients were administered the first dose of propranolol at 7:00am, so heart rates were assessed at 8:00am, 9:00am and 11:00am. The second dose of propranolol was administered at 12:00pm (noon), so heart rates were monitored at 1:00pm, 2:00pm and 4:00pm. The third dose of propranolol was administered at 5:00pm, so heart rates were monitored at 6:00pm, 7:00pm and 9:00pm. During the second week of treatment, heart rate was monitored once a day after one hour following the first dose of propranolol treatment. Starting from the third week of treatment, heart rate was monitored once a week after one hour following administration of the first medication. 3. Statistical analysis: Data was analyzed using the SPSS 11.0 statistical software package. Treatment efficacy was expressed as values and percentages. Heart rate was expressed as mean ± standard deviation. Analysis of variance was used to compare repeated measurement data and a p value of < 0.05 was considered significant.
This article is protected by copyright. All rights reserved. Results 1. Patient characteristics Among 31 patients, 23 were female and 8 were male (female-to-male ratio of 3:1). The subjects’ mean age, weight and size of hemangioma at the onset of treatment was 6.4±4.7 months (ranged from 1 to 24 months), 7.62±1.58 kg (ranged from 5 to 11 kg) and 2.90±1.75 cm × 2.04±1.529 cm (ranged from 0.5cm×0.3cm to 8.0cm×6.0cm), respectively. No significant differences in age, sex and weight of children in case and control groups (p>0.05) were observed prior to treatment (Table 1). Multiple lesions were identified in 5 cases. The location of IH included the face and neck in 17 cases, trunk in 6 cases, limbs in 5 cases, buttocks in 2 cases and perineum in 1 case. All 31 children had a complete follow-up. In two infants, treatment was temporarily discontinued because of a common cold. 2. Changes in heart rate (1) Heart rates before treatment: Amongst the 31 IH cases, 16 children had sinus tachycardia. Thus, the average heart rate in the 31 cases was significantly higher compared with the control group (p=0.008) before treatment.
(2) Heart rates during treatment: (i) Heart rates of children on propranolol treatment were lower than prior to treatment except at 4h after drug treatment on the first day. However, all heart rates were within the normal range (Tables 2, 3 and 4). (ii) In the first week after drug therapy, fluctuations in heart rates were observed after every dose from the first day to the fifth day. A decrease in heart rate was most apparent at 1h after every dose, which then gradually increased and normalized but regardless, was found to be lower than heart rates prior to treatment. Heart rates fluctuations were also observed after the first dose on the sixth day, but fluctuations were much less pronounced than previously observed. Heart rates became more stable from the second dose on the sixth day onwards. After this point, no
This article is protected by copyright. All rights reserved. significant differences in heart rates were observed after each dose when compared with heart rates before treatment (Table 2). (iii) When patients were administered propranolol in three divided doses in a day, heart rates also did not significantly fluctuate and instead remained stable within the normal range. Moreover, comparisons of heart rates related to different doses of propranolol on the same day and on different days also revealed no significant differences (Table 2). (iv) During the second week after drug therapy, no significant differences (p>0.05) in heart rates were observed at 1h after the first dose (Table 3). (v) No significant differences (p=0.734) in heart rate were observed between patients versus controls at one hour after the first dose on every Monday from the first to sixteenth week of treatment (Table 4). A scatter diagram (Figure 2) showed that the heart rate of patients gradually decreased in the first week after treatment, but as time passed, the changes in heart rate were less apparent and not significantly different from controls. Table 4 and Figure 2 highlight that the heart rates of patients were relatively stable during the 16 week of propranolol treatment using divided doses.
Adverse reactions Mild adverse reactions were noted during the study, which included mild diarrhea in three children. In one patient diarrhea was observed in the second week after propranolol treatment. Propranolol treatment was temporally withdrawn in this patient, two days later the diarrhea subsided and the child was then continued on the previous dose of propranolol. Diarrhea was also observed in two other patients, one of which was observed in the seventeenth week, while in the other patient it was observed in the twenty-first week. In these two cases, the propranolol dose was reduced to two-thirds of the previous dose. Four days later, the diarrhea subsided and children were continued on standard propranolol doses. Adverse reactions such as dyspnea, cyanosis and changes in sleeping pattern were not
This article is protected by copyright. All rights reserved. observed in any of the 31 cases during the whole course of drug treatment.
Discussion Hemangiomas are the most common soft-tissue tumors in infants and usually occur on the face, head, neck and shoulder areas. Although many regress spontaneously, tumors in select patients require treatment. Since the first use of propranolol as an effective treatment for infantile hemangioma was reported by Leaute-labreze et al[9], there have been more clinical studies, which have established its beneficial effects
[12,13]
and thus, it is currently
recommended by many clinicians as a first-line drug for IH treatment[14-16]. In this study, we used propranolol to treat IH, and found that there were no serious adverse reactions. Love et al[17] found that with 40 years of extensive clinical use of beta-blockers, there have been no documented cases of death or serious cardiovascular morbidity as a direct result of propranolol in children under 6 years of age. Potential adverse reactions of propranolol include bradycardia and hypotension. Propranolol acts on β adrenergic receptors to antagonize sympathetic nerve excitability resulting in decreased heart rate and blood pressure. Leaute-labreze and colleagues had not reported any serious adverse effects as a result of propranolol treatment[9]. A retrospective study on propranolol use in 109 IH cases by Gan et al. also did not report any serious side effects
[18]
. However, studies by
Hermans et al. did observe hypotension in 3.4% of patients among 174 cases
[19]
. Other
occasionally reported side effects include hypoglycemia, diarrhea, shortness of breath and changes in sleep patterns
[20-23]
. Although glucose levels were not measured in our study,
parents were advised to pay close attention to the infants’ reactions after the propranolol treatment and to take them to the hospital immediately should they exhibit hypoglycemic symptoms (eg., limp, pale, cold to touch and unresponsive). However, these symptoms were not reported in our study.
This article is protected by copyright. All rights reserved. Siegfred et al. [24] have developed a treatment protocol to optimize propranolol safety. Briefly, the medication is to be given every 8 hours with an initial dose of 0.16 mg per kilogram of body weight. If vital signs and glucose levels remain normal, the dose is incrementally doubled to a maximum of 0.67 mg per kilogram per dose (maximum daily dose of 2.0 mg per kilogram)
[24]
. Studies by Tan et al. identified that when propranolol is
commenced at 0.25 mg per kg twice daily and then gradually increased to 1.5-2 mg/kg/d in divided doses that it is possible to reduce reported side effects[25]. In order to reduce potential adverse reactions of propranolol, our study adopted a therapeutic regimen as described in methods. Heart rate and blood pressure in infants on propranolol therapy should be closely monitored. The effect of propranolol on blood pressure in infants was found to be minimal in several studies [26-28], thus, only heart rates in infants require close monitoring. No significant effects of propranolol on heart rate were observed after 4 hours of medicine on the first day when compared to pretreatment heart rates. Heart rates monitored after one, two and four hours after propranolol treatment were significantly lower when compared to pretreatment heart rates. Regardless, all heart rates were considered within the normal range. No obvious fluctuations in heart rate were observed. Heart rates were changed at one, two and four hours after propranolol treatment, but a comparative analysis of heart rates at one, two and four hours after the first dose and second dose on the same day were not significantly different. Comparisons of heart rates at one, two and four hours after the first dose, second dose and third dose on the same day also revealed no significant differences. These observations suggest that with increasing drug dose of propranolol, the heart rates had not sustained reductions, but were relatively stable. Moreover, comparisons of heart rates related to different doses of propranolol on the same day and on different days also revealed no significant differences. These data show that the heart rate remained relatively stable even
This article is protected by copyright. All rights reserved. when children received propranolol at a dose of 2 mg/kg/day. Furthermore, there were no significant differences in heart rate at one hour after the first dose of propranolol every day in the second week of treatment, which persisted from the third week to the sixteenth week of treatment. This data suggests that propranolol had no significant effects on heart rate during 16 weeks. The scatter diagram (Figure 2) highlights the heart rates in patients during the 16-week treatment regimen when compared with that of controls. The heart rate of patients after treatment were lower but as time passed by, these changes in heart rate were less apparent and did not significantly differ from heart rates in controls. We also found that there was a slight downward trend in heart rate in both patients and controls over the course of the study, which is explained by the fact that when children grow older, their heart rates decrease physiologically
[11]
. A limitation of this study was that heart rates were monitored using a
stethoscope, which may lead to some variability. Heart rate monitoring by ECG or vital sign equipment is likely to provide more accurate results. The significant differences in heart rates of patients prior to treatment and controls in the present study were due to 16 IH patients exhibiting sinus tachycardia. The heart rates of IH patients with sinus tachycardia were significantly higher than those of the control group. In addition, the heart rates of IH children may be higher than controls which needs to be addressed in future studies. In conclusion, a 16-week regimen of propranolol treatment in children with IH at a dose of 2 mg/kg/d, which was administered in divided doses had no significant risks on bradycardia.
Authorship Both Hongbin Song and Huijuan Shi equally carried out the study and drafted the manuscript. Huijuan Shi also participated in the design of the study and revised the
This article is protected by copyright. All rights reserved. manuscript critically for important intellectual content. Xiaoming Zhang, Jianjun Wang and Yingyao Yu carried out the collection of cases and acquisition of data. Wenge Chen and Hui Zhou performed the analysis and interpretation of data and helped to draft the manuscript. All authors have read and approved the final manuscript.
References [1] Garin EH, Araya CE. Treatment of systemic hypertension in children and adolescents[J]. Curr Opin Pediatr 2009; 21(5):600-604. [2] Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics[J]. J Pediatr 2007; 150(3):291-294. [3] Margileth AM, Museles M. Cutaneous hemangiomas in children. Diagnosis and conservative management[J]. JAMA. 1965; 7(5):523–526. [4] Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment[J]. Pediatrics. 2006; 118(3):882-887. [5] Frieden IJ, Haggstrom AN, Drolet BA, et al. Infantile hemangiomas: current knowledge, future directions. Proceedings of a research workshop on infantile hemangiomas, April 7-9, 2005, Bethesda, Maryland, USA[J]. Pediatr Dermatol 2005; 22(5):383-406. [6] Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: clinical characteristics and response to therapy[J]. J Am Acad Dermatol.2001; 44(6):962– 972. [7] Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a “beard” distribution[J]. J Pediatr.1997; 131(4):643-6. [8] Itani MH, Fakih H. Response of facial haemangioma to oral propranolol. BMJ Case Rep 2009; 2009:1476.
This article is protected by copyright. All rights reserved. [9] Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy[J]. N Engl J Med 2008; 358(24):2649-2651. [10] Enjolras O, Mulliken JB. Vascular tumors and vascular malformations (new issues). Adv Dermatol 1997; 13:375-423. [11] Bernstein D. Evaluation of the Cardiovascular System. In: Nelson Textbook of Pediatrics (Richard E. Behrman, Robert M. Kliegman, Hal B. Jenson, eds), 16th edn. Beijing: Science Press, 2001; 1343-1350. [12] Jephson CG, Manunza F, Syed S, et al. Successful treatment of isolated subglottic haemangioma with propranolol alone[J]. Int J Pediatr Otorhinolaryngol 2009; 73(12): 1821-1823. [13] Buckmiller LM. Propranolol treatment for infantile hemangiomas[J]. Curr Opin Otolaryngol Head Neck Surg 2009; 17(6):458-459. [14] Wahlgren CF. Propranolol first choice in infantile hemangiomas. Large randomized trials are needed to determine the dosage and duration of treatment[J]. Lakartidningen 2013; 110(19-20):938-939. [15] Xiao Q, Li Q, Zhang B, Yu W. Propranolol therapy of infantile hemangiomas: efficacy, adverse effects, and recurrence[J]. Pediatr Surg Int 2013; 29(6):575-581. [16] Aletaha M, Salour H, Bagheri A, et al. Oral propranolol for treatment of pediatric capillary hemangiomas[J]. J Ophthalmic Vis Res 2012; 7(2):130-133. [17] Love JN, Sikka N. Are 1-2 tablets dangerous? Beta-blocker exposure in toddlers[J]. J Emerg Med 2004; 26(3):309-314. [18] Gan LQ, Ni SL, Tan Q, et al. A retrospective study of propranolol therapy in 109 infants with infantile hemangioma[J]. Pediatr Dermatol 2013; 30(2):270-272. [19] Hermans DJ, Bauland CG, Zweegers J, et al. Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions[J]. Br J
This article is protected by copyright. All rights reserved. Dermatol 2013; 168(4):837-843. [20] Holland KE, Frieden IJ, Frommelt PC, et al. Hypoglycemia in children taking propranolol for the treatment of infantile hemangioma[J]. Arch Dermatol 2010; 146(7):775-778. [21] Breur JM, de Graaf M, Breugem CC, et al. Hypoglycemia as a result of propranolol during treatment of infantile hemangioma: a case report[J]. Pediatr Dermatol 2011; 28(2):169-171. [22]
Abbott
J,
Parulekar
M,
Shahidullah
H,
et
al.
Diarrhea
associated
with propranolol treatment for hemangioma of infancy (HOI)[J]. Pediatr Dermatol 2010; 27(5):558. [23] De Graaf M, Breur JM, Raphaël MF, et al. Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants[J]. J Am Acad Dermatol 2011; 65(2):320-327. [24] Siegfried EC, Keenan WJ, AI-Jureidini S. More on propranolol for hemangiomas of infancy[J]. N Engl J Med 2008; 359(26):2846-2847. [25] Tan ST, Itinteang T, Leadbitter P. Low dose propranolol for infantile haemangioma[J]. J Plastic Reconstr Aesthetie Surg 2011; 64(3):292-299. [26] Kent AL, Kecskes Z, Shadbolt B, et al. Blood pressure in the first year of life in healthy infants born at term[J]. Pediatr Nephrol 2007; 22(10):1743–1749. [27] Ma X, Zhao T, Xiao Y. Preliminary experience on treatment of infantile hemangioma with low-dose propranolol in China[J]. Eur J Pediatr 2013; 172(5):653-659. [28] Torres-Pradilla M, Baselga E. Failure of intralesional propranolol in infantile hemangiomas[J]. Pediatr Dermatol 2014; 31(2):156-158.
This article is protected by copyright. All rights reserved. Figure 1. Study Flow Chart
Figure 2. Scatter diagram of heart rates in case group and control group before and during 16-week propranolol treatment.
Table 1 Baseline characteristics of children in case and control groups Weight(Kilogram Age(Months) Groups
Sex
s)
Other diseases
Mean±SD Mean±SD Female:Male Case
6.4±4.7
7.62±1.58
None
7.50±1.49
None
=23:8 Female:Male Control
6.6±4.8 =23:8
This article is protected by copyright. All rights reserved. Table 2: Heart rate (beats per minute) profile during the first week of propranolol treatment
Tim
Time after first
e
medication (at 7:00am)
Time after second
Time after third
medication (at
medication (at
12:00noon)
5:00pm)
Befo re 155± treat
1h
2h
4h
1h
First
144±
147±
153±1
day
17*
19*△
4△ ▲
143±
145±
152±1
17*
16*
6*△▲
142±
143±
149±1
139±
17*
16*
5*△▲
16*
2h
4h
1h
2h
4h
22 men t
Seco nd day Thir d
144±1 144±1 4*△ 5*△
day Four 141±
144±
147±1
140±
144±1 147±1
17*
17*△
7*△▲
15*
5*△
Fifth
142±
142±
147±2
138±
144±1 147±1
day
17*
18*
0*△
17*
8*△
139±
140±
141±1
139±
17*
16*
6*△▲
15*
th
6*△
day 138±
144±1 146±
16*
7*△
139±1 139±1
136±
139±1 138±
6*
15*
4*
8*△▲
16*△
Sixt h day
4*
12*
This article is protected by copyright. All rights reserved. Seve 135±
136±
138±1
135±
136±1 137±1
134±
136±1 135±
15*
13*
4*
13*
3*
14*
1*
nth 4*
11*
day Heart rates during treatment compared to pretreatment: *p
Safety Profile of a Divided Dose of Propranolol on Heart Rate in Children with Infantile Hemangioma During 16 Weeks of Treatment Running title: The influence of propranolol on heart rate in IHs subjects. H. Song*1, H. Shi*#2, X. Zhang2, J. Wang2, Y. Yu2, W. Chen2 and H. Zhou1
1
2
Ningxia Medical University
Department of Dermatovenereology, Ningxia Medical University General Hospital, Yinchuan 750004, China
#
Corresponding Author:
Huijuan Shi Department of Dermatovenereology Ningxia Medical University General Hospital Yinchuan 750004, China. E-mail: [email protected] Ph: +86 139 9529 5912 Fax: 0086-0951-4082981 *
These authors contributed equally to this work.
Funding sources: None Declared
This article is protected by copyright. All rights reserved. Competing interests All the authors do not have any possible conflicts of interest. Bulleted statements (1) What's already known about this topic? Heart rates are thought to decrease during propranolol treatment for infantile hemangiomas (IH). (2) What does this study add? Our study describes the careful and close monitoring of heart rate during 16 weeks of propranolol treatment in IH subjects. We found that all heart rates were within the normal range and that a three times per day dosing regimen had no significant effects on heart rates in IH subjects. Our results reassure the safety of using propranolol at the dose of 2mg/kg/day on heart rates for up to 16 weeks of therapy.
Summary Background: Although propranolol has been accepted as a first-line drug for infantile hemangioma (IH), no study has systematically characterized changes in heart rates during long-term propranolol treatment. Objectives: To evaluate the influence of a divided dose of propranolol on heart rates in IH subjects. Methods: A prospective study was conducted from January 2009 to December 2013. All IH patients were administered propranolol at 0.67 mg per kilogram per day as a single dose on days 1 and 2, and gradually increased to the full dose (2mg/kg/d) on day 5, which was given in three divided doses. Heart rates were recorded before treatment and closely monitored during treatment. Heart rates in controls were monitored once a week. Results: All heart rates monitored during treatment were found to be within the normal range.
This article is protected by copyright. All rights reserved. Fluctuations in heart rates were observed after every dose from the first day to the first dose of the sixth day; however, from the second dose of the sixth day onwards, no significant differences (p>0.05) in heart rates were observed after every dose on successive days. During the second week of drug therapy, no significant differences in heart rates were observed at 1h after the first dose (p=1.00). Also, no significant differences (p=0.734) in heart rates were observed between patients at 1h after the first dose on Mondays versus controls from the first to sixteenth week of treatment. Conclusions: A three times per day dosing regimen of propranolol had no significant sustained effects on heart rates in IH subjects. [Key words] propranolol; heart rate; infantile hemangiomas
Introduction Propranolol, a non-selective beta-blocker, is increasingly recognized as an effective therapy in infantile hemangioma (IH) apart from its well established role in hypertension, supraventricular tachycardia, congestive heart failure and hyperthyroidism[1]. IH are the most common vascular tumors in infancy
[2]
having complete regression in 60% of 4-year-old
patients and 76% of 7-year-old patients[3]. Most IH are uncomplicated, but a few may have complications such as ulceration, threat to vision, airway obstruction, and congestive heart failure[4,5]. IH may also leave residual scarring or permanent distortion of facial landmarks[6,7]. The standard treatment course includes the use of oral/intralesional steroids, α-interferon, cytotoxins, embolization, pulsed dye laser and surgical resection[8]. These treatments are associated with complications and toxic side effects, including transient cosmetic disfigurement, scars that are difficult to repair and features of adrenal cortical dysfunction[8]. Propranolol has been accepted as a first-line drug by clinicians as a new therapy for infantile hemangioma since its first established use was in a case of severe infantile hemangioma by
This article is protected by copyright. All rights reserved. Leaute-labreze et al. in 2008[9]. Propranolol has potential side effects like bradycardia and hypotension, which mandate close monitoring of heart rate especially when it is used for a longer duration. In this context, we aimed to closely monitor heart rate of 31 IH children from January 2009 to December 2013, who were administered propranolol therapy. At the beginning, patients received propranolol at a dose of 0.67 mg/kg once daily, with the dose gradually increasing to the full dose (2mg/kg/d) by day 5, which was given in three divided doses.
Materials and Methods 1. Human Subjects All infantile hemangioma patients were recruited from the outpatient department of Ningxia Medical University General Hospital, with 38 cases enrolled but 31 cases proceeding towards the entire treatment course (Figure 1). A definite diagnosis of hemangioma was based upon standard guidelines proposed by Mulliken and Enjolras[10]. All parents of the study children were informed of the purpose of the study and signed a detailed informed consent describing the study design and possible adverse effects of propranolol treatment. The study was approved by the Medical Ethics Committee, which was affiliated with the Hospital of Ningxia Medical University. The inclusion criteria were as follows: children who were less than two years of age, with no organ and systemic diseases and who had not been previously treated with surgical therapy, laser, or other medications. Subjects were excluded if they had the following features: (1) sinus bradycardia, hypotension, cardiogenic shock, heart block (second to third degree atrioventricular block), severe or acute heart failure, (2) tracheobronchitis, pneumonia or bronchial asthma, (3) liver and kidney dysfunction (4) abnormal glucose tolerance or diabetes mellitus and (5) unwilling to attend follow-up visits. Healthy children (n=31) who were age and sex matched with IH cases were randomly
This article is protected by copyright. All rights reserved. chosen from the Tiansheng Community Clinic and considered the control group. All children in the control group were born in hospitals and underwent standard examinations, which included echocardiograms after birth. Subjects were only included if they had no organic diseases, including heart diseases, and if their parents took them regularly to the Community Clinic for regular physical examinations as per the study protocol.
2. Methods 2.1 Preparation for treatment: Basic vital signs (temperature, pulse, respirations and blood pressure) and weights were measured in subjects prior to treatment administration. Complete blood counts, liver and kidney function tests, blood glucose, electrocardiogram and echocardiogram were also obtained along with clinical evaluation of IH with photographs.
2.2 Therapeutic protocol: All patients were administered propranolol at a single dose of 0.67 mg per kilogram per day on days 1 and 2. On days 3 and 4, the drug dose was increased to 1.34 mg per kilogram per day and given in 2 divided doses. From day 5 onwards, the dose was increased to 2 mg/kg/day and given in three divided doses. This standard dose was continued until the end of the treatment. In the absence of side effects and a relatively stable heart rate, treatment was continued with the dose of 2
mg/kg/day. Heart rate was monitored
with a stethoscope at each visit in an outpatient clinic. During follow-ups, body weight was measured to adjust for medication doses. When a child suffered from a common cold or exhibited adverse reactions such as diarrhea, vomiting, shortness of breath and altered sleep pattern, the dose was reduced or temporarily discontinued based on the severity of the adverse effects. When the cold and adverse effects disappeared, the treatment regimen was restarted and the medication dose was optimized to 2 mg/kg/day.
This article is protected by copyright. All rights reserved. 2.3 Monitoring heart rates 2.3.1 Heart rates in healthy (control) children: Heart rate was clinically monitored in healthy children once a week when children were quiet. According to the Nelson Textbook of Pediatrics[11], the normal range for heart rate by age were as follows: 80-160 beats per minute in 1-11 month old infants, 80-130 beats per minute in 2 year old children, and 80-120 beats per minute in 4 year old children.
2.3.2 Heart rates in IH patients: Heart rate was recorded clinically prior to the initiation of treatment as well as with an electrocardiogram as an outpatient in the hospital. According to the pharmacokinetics of propranolol (peak plasma concentration reached by 1-1.5 hours and half-life of 2-3 hours), heart rate was monitored at one, two and four hours following consumption of propranolol in the first week of treatment. Patients were administered the first dose of propranolol at 7:00am, so heart rates were assessed at 8:00am, 9:00am and 11:00am. The second dose of propranolol was administered at 12:00pm (noon), so heart rates were monitored at 1:00pm, 2:00pm and 4:00pm. The third dose of propranolol was administered at 5:00pm, so heart rates were monitored at 6:00pm, 7:00pm and 9:00pm. During the second week of treatment, heart rate was monitored once a day after one hour following the first dose of propranolol treatment. Starting from the third week of treatment, heart rate was monitored once a week after one hour following administration of the first medication. 3. Statistical analysis: Data was analyzed using the SPSS 11.0 statistical software package. Treatment efficacy was expressed as values and percentages. Heart rate was expressed as mean ± standard deviation. Analysis of variance was used to compare repeated measurement data and a p value of < 0.05 was considered significant.
This article is protected by copyright. All rights reserved. Results 1. Patient characteristics Among 31 patients, 23 were female and 8 were male (female-to-male ratio of 3:1). The subjects’ mean age, weight and size of hemangioma at the onset of treatment was 6.4±4.7 months (ranged from 1 to 24 months), 7.62±1.58 kg (ranged from 5 to 11 kg) and 2.90±1.75 cm × 2.04±1.529 cm (ranged from 0.5cm×0.3cm to 8.0cm×6.0cm), respectively. No significant differences in age, sex and weight of children in case and control groups (p>0.05) were observed prior to treatment (Table 1). Multiple lesions were identified in 5 cases. The location of IH included the face and neck in 17 cases, trunk in 6 cases, limbs in 5 cases, buttocks in 2 cases and perineum in 1 case. All 31 children had a complete follow-up. In two infants, treatment was temporarily discontinued because of a common cold. 2. Changes in heart rate (1) Heart rates before treatment: Amongst the 31 IH cases, 16 children had sinus tachycardia. Thus, the average heart rate in the 31 cases was significantly higher compared with the control group (p=0.008) before treatment.
(2) Heart rates during treatment: (i) Heart rates of children on propranolol treatment were lower than prior to treatment except at 4h after drug treatment on the first day. However, all heart rates were within the normal range (Tables 2, 3 and 4). (ii) In the first week after drug therapy, fluctuations in heart rates were observed after every dose from the first day to the fifth day. A decrease in heart rate was most apparent at 1h after every dose, which then gradually increased and normalized but regardless, was found to be lower than heart rates prior to treatment. Heart rates fluctuations were also observed after the first dose on the sixth day, but fluctuations were much less pronounced than previously observed. Heart rates became more stable from the second dose on the sixth day onwards. After this point, no
This article is protected by copyright. All rights reserved. significant differences in heart rates were observed after each dose when compared with heart rates before treatment (Table 2). (iii) When patients were administered propranolol in three divided doses in a day, heart rates also did not significantly fluctuate and instead remained stable within the normal range. Moreover, comparisons of heart rates related to different doses of propranolol on the same day and on different days also revealed no significant differences (Table 2). (iv) During the second week after drug therapy, no significant differences (p>0.05) in heart rates were observed at 1h after the first dose (Table 3). (v) No significant differences (p=0.734) in heart rate were observed between patients versus controls at one hour after the first dose on every Monday from the first to sixteenth week of treatment (Table 4). A scatter diagram (Figure 2) showed that the heart rate of patients gradually decreased in the first week after treatment, but as time passed, the changes in heart rate were less apparent and not significantly different from controls. Table 4 and Figure 2 highlight that the heart rates of patients were relatively stable during the 16 week of propranolol treatment using divided doses.
Adverse reactions Mild adverse reactions were noted during the study, which included mild diarrhea in three children. In one patient diarrhea was observed in the second week after propranolol treatment. Propranolol treatment was temporally withdrawn in this patient, two days later the diarrhea subsided and the child was then continued on the previous dose of propranolol. Diarrhea was also observed in two other patients, one of which was observed in the seventeenth week, while in the other patient it was observed in the twenty-first week. In these two cases, the propranolol dose was reduced to two-thirds of the previous dose. Four days later, the diarrhea subsided and children were continued on standard propranolol doses. Adverse reactions such as dyspnea, cyanosis and changes in sleeping pattern were not
This article is protected by copyright. All rights reserved. observed in any of the 31 cases during the whole course of drug treatment.
Discussion Hemangiomas are the most common soft-tissue tumors in infants and usually occur on the face, head, neck and shoulder areas. Although many regress spontaneously, tumors in select patients require treatment. Since the first use of propranolol as an effective treatment for infantile hemangioma was reported by Leaute-labreze et al[9], there have been more clinical studies, which have established its beneficial effects
[12,13]
and thus, it is currently
recommended by many clinicians as a first-line drug for IH treatment[14-16]. In this study, we used propranolol to treat IH, and found that there were no serious adverse reactions. Love et al[17] found that with 40 years of extensive clinical use of beta-blockers, there have been no documented cases of death or serious cardiovascular morbidity as a direct result of propranolol in children under 6 years of age. Potential adverse reactions of propranolol include bradycardia and hypotension. Propranolol acts on β adrenergic receptors to antagonize sympathetic nerve excitability resulting in decreased heart rate and blood pressure. Leaute-labreze and colleagues had not reported any serious adverse effects as a result of propranolol treatment[9]. A retrospective study on propranolol use in 109 IH cases by Gan et al. also did not report any serious side effects
[18]
. However, studies by
Hermans et al. did observe hypotension in 3.4% of patients among 174 cases
[19]
. Other
occasionally reported side effects include hypoglycemia, diarrhea, shortness of breath and changes in sleep patterns
[20-23]
. Although glucose levels were not measured in our study,
parents were advised to pay close attention to the infants’ reactions after the propranolol treatment and to take them to the hospital immediately should they exhibit hypoglycemic symptoms (eg., limp, pale, cold to touch and unresponsive). However, these symptoms were not reported in our study.
This article is protected by copyright. All rights reserved. Siegfred et al. [24] have developed a treatment protocol to optimize propranolol safety. Briefly, the medication is to be given every 8 hours with an initial dose of 0.16 mg per kilogram of body weight. If vital signs and glucose levels remain normal, the dose is incrementally doubled to a maximum of 0.67 mg per kilogram per dose (maximum daily dose of 2.0 mg per kilogram)
[24]
. Studies by Tan et al. identified that when propranolol is
commenced at 0.25 mg per kg twice daily and then gradually increased to 1.5-2 mg/kg/d in divided doses that it is possible to reduce reported side effects[25]. In order to reduce potential adverse reactions of propranolol, our study adopted a therapeutic regimen as described in methods. Heart rate and blood pressure in infants on propranolol therapy should be closely monitored. The effect of propranolol on blood pressure in infants was found to be minimal in several studies [26-28], thus, only heart rates in infants require close monitoring. No significant effects of propranolol on heart rate were observed after 4 hours of medicine on the first day when compared to pretreatment heart rates. Heart rates monitored after one, two and four hours after propranolol treatment were significantly lower when compared to pretreatment heart rates. Regardless, all heart rates were considered within the normal range. No obvious fluctuations in heart rate were observed. Heart rates were changed at one, two and four hours after propranolol treatment, but a comparative analysis of heart rates at one, two and four hours after the first dose and second dose on the same day were not significantly different. Comparisons of heart rates at one, two and four hours after the first dose, second dose and third dose on the same day also revealed no significant differences. These observations suggest that with increasing drug dose of propranolol, the heart rates had not sustained reductions, but were relatively stable. Moreover, comparisons of heart rates related to different doses of propranolol on the same day and on different days also revealed no significant differences. These data show that the heart rate remained relatively stable even
This article is protected by copyright. All rights reserved. when children received propranolol at a dose of 2 mg/kg/day. Furthermore, there were no significant differences in heart rate at one hour after the first dose of propranolol every day in the second week of treatment, which persisted from the third week to the sixteenth week of treatment. This data suggests that propranolol had no significant effects on heart rate during 16 weeks. The scatter diagram (Figure 2) highlights the heart rates in patients during the 16-week treatment regimen when compared with that of controls. The heart rate of patients after treatment were lower but as time passed by, these changes in heart rate were less apparent and did not significantly differ from heart rates in controls. We also found that there was a slight downward trend in heart rate in both patients and controls over the course of the study, which is explained by the fact that when children grow older, their heart rates decrease physiologically
[11]
. A limitation of this study was that heart rates were monitored using a
stethoscope, which may lead to some variability. Heart rate monitoring by ECG or vital sign equipment is likely to provide more accurate results. The significant differences in heart rates of patients prior to treatment and controls in the present study were due to 16 IH patients exhibiting sinus tachycardia. The heart rates of IH patients with sinus tachycardia were significantly higher than those of the control group. In addition, the heart rates of IH children may be higher than controls which needs to be addressed in future studies. In conclusion, a 16-week regimen of propranolol treatment in children with IH at a dose of 2 mg/kg/d, which was administered in divided doses had no significant risks on bradycardia.
Authorship Both Hongbin Song and Huijuan Shi equally carried out the study and drafted the manuscript. Huijuan Shi also participated in the design of the study and revised the
This article is protected by copyright. All rights reserved. manuscript critically for important intellectual content. Xiaoming Zhang, Jianjun Wang and Yingyao Yu carried out the collection of cases and acquisition of data. Wenge Chen and Hui Zhou performed the analysis and interpretation of data and helped to draft the manuscript. All authors have read and approved the final manuscript.
References [1] Garin EH, Araya CE. Treatment of systemic hypertension in children and adolescents[J]. Curr Opin Pediatr 2009; 21(5):600-604. [2] Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: demographic, prenatal, and perinatal characteristics[J]. J Pediatr 2007; 150(3):291-294. [3] Margileth AM, Museles M. Cutaneous hemangiomas in children. Diagnosis and conservative management[J]. JAMA. 1965; 7(5):523–526. [4] Haggstrom AN, Drolet BA, Baselga E, et al. Prospective study of infantile hemangiomas: clinical characteristics predicting complications and treatment[J]. Pediatrics. 2006; 118(3):882-887. [5] Frieden IJ, Haggstrom AN, Drolet BA, et al. Infantile hemangiomas: current knowledge, future directions. Proceedings of a research workshop on infantile hemangiomas, April 7-9, 2005, Bethesda, Maryland, USA[J]. Pediatr Dermatol 2005; 22(5):383-406. [6] Kim HJ, Colombo M, Frieden IJ. Ulcerated hemangiomas: clinical characteristics and response to therapy[J]. J Am Acad Dermatol.2001; 44(6):962– 972. [7] Orlow SJ, Isakoff MS, Blei F. Increased risk of symptomatic hemangiomas of the airway in association with cutaneous hemangiomas in a “beard” distribution[J]. J Pediatr.1997; 131(4):643-6. [8] Itani MH, Fakih H. Response of facial haemangioma to oral propranolol. BMJ Case Rep 2009; 2009:1476.
This article is protected by copyright. All rights reserved. [9] Leaute-Labreze C, Dumas de la Roque E, Hubiche T, et al. Propranolol for severe hemangiomas of infancy[J]. N Engl J Med 2008; 358(24):2649-2651. [10] Enjolras O, Mulliken JB. Vascular tumors and vascular malformations (new issues). Adv Dermatol 1997; 13:375-423. [11] Bernstein D. Evaluation of the Cardiovascular System. In: Nelson Textbook of Pediatrics (Richard E. Behrman, Robert M. Kliegman, Hal B. Jenson, eds), 16th edn. Beijing: Science Press, 2001; 1343-1350. [12] Jephson CG, Manunza F, Syed S, et al. Successful treatment of isolated subglottic haemangioma with propranolol alone[J]. Int J Pediatr Otorhinolaryngol 2009; 73(12): 1821-1823. [13] Buckmiller LM. Propranolol treatment for infantile hemangiomas[J]. Curr Opin Otolaryngol Head Neck Surg 2009; 17(6):458-459. [14] Wahlgren CF. Propranolol first choice in infantile hemangiomas. Large randomized trials are needed to determine the dosage and duration of treatment[J]. Lakartidningen 2013; 110(19-20):938-939. [15] Xiao Q, Li Q, Zhang B, Yu W. Propranolol therapy of infantile hemangiomas: efficacy, adverse effects, and recurrence[J]. Pediatr Surg Int 2013; 29(6):575-581. [16] Aletaha M, Salour H, Bagheri A, et al. Oral propranolol for treatment of pediatric capillary hemangiomas[J]. J Ophthalmic Vis Res 2012; 7(2):130-133. [17] Love JN, Sikka N. Are 1-2 tablets dangerous? Beta-blocker exposure in toddlers[J]. J Emerg Med 2004; 26(3):309-314. [18] Gan LQ, Ni SL, Tan Q, et al. A retrospective study of propranolol therapy in 109 infants with infantile hemangioma[J]. Pediatr Dermatol 2013; 30(2):270-272. [19] Hermans DJ, Bauland CG, Zweegers J, et al. Propranolol in a case series of 174 patients with complicated infantile haemangioma: indications, safety and future directions[J]. Br J
This article is protected by copyright. All rights reserved. Dermatol 2013; 168(4):837-843. [20] Holland KE, Frieden IJ, Frommelt PC, et al. Hypoglycemia in children taking propranolol for the treatment of infantile hemangioma[J]. Arch Dermatol 2010; 146(7):775-778. [21] Breur JM, de Graaf M, Breugem CC, et al. Hypoglycemia as a result of propranolol during treatment of infantile hemangioma: a case report[J]. Pediatr Dermatol 2011; 28(2):169-171. [22]
Abbott
J,
Parulekar
M,
Shahidullah
H,
et
al.
Diarrhea
associated
with propranolol treatment for hemangioma of infancy (HOI)[J]. Pediatr Dermatol 2010; 27(5):558. [23] De Graaf M, Breur JM, Raphaël MF, et al. Adverse effects of propranolol when used in the treatment of hemangiomas: A case series of 28 infants[J]. J Am Acad Dermatol 2011; 65(2):320-327. [24] Siegfried EC, Keenan WJ, AI-Jureidini S. More on propranolol for hemangiomas of infancy[J]. N Engl J Med 2008; 359(26):2846-2847. [25] Tan ST, Itinteang T, Leadbitter P. Low dose propranolol for infantile haemangioma[J]. J Plastic Reconstr Aesthetie Surg 2011; 64(3):292-299. [26] Kent AL, Kecskes Z, Shadbolt B, et al. Blood pressure in the first year of life in healthy infants born at term[J]. Pediatr Nephrol 2007; 22(10):1743–1749. [27] Ma X, Zhao T, Xiao Y. Preliminary experience on treatment of infantile hemangioma with low-dose propranolol in China[J]. Eur J Pediatr 2013; 172(5):653-659. [28] Torres-Pradilla M, Baselga E. Failure of intralesional propranolol in infantile hemangiomas[J]. Pediatr Dermatol 2014; 31(2):156-158.
This article is protected by copyright. All rights reserved. Figure 1. Study Flow Chart
Figure 2. Scatter diagram of heart rates in case group and control group before and during 16-week propranolol treatment.
Table 1 Baseline characteristics of children in case and control groups Weight(Kilogram Age(Months) Groups
Sex
s)
Other diseases
Mean±SD Mean±SD Female:Male Case
6.4±4.7
7.62±1.58
None
7.50±1.49
None
=23:8 Female:Male Control
6.6±4.8 =23:8
This article is protected by copyright. All rights reserved. Table 2: Heart rate (beats per minute) profile during the first week of propranolol treatment
Tim
Time after first
e
medication (at 7:00am)
Time after second
Time after third
medication (at
medication (at
12:00noon)
5:00pm)
Befo re 155± treat
1h
2h
4h
1h
First
144±
147±
153±1
day
17*
19*△
4△ ▲
143±
145±
152±1
17*
16*
6*△▲
142±
143±
149±1
139±
17*
16*
5*△▲
16*
2h
4h
1h
2h
4h
22 men t
Seco nd day Thir d
144±1 144±1 4*△ 5*△
day Four 141±
144±
147±1
140±
144±1 147±1
17*
17*△
7*△▲
15*
5*△
Fifth
142±
142±
147±2
138±
144±1 147±1
day
17*
18*
0*△
17*
8*△
139±
140±
141±1
139±
17*
16*
6*△▲
15*
th
6*△
day 138±
144±1 146±
16*
7*△
139±1 139±1
136±
139±1 138±
6*
15*
4*
8*△▲
16*△
Sixt h day
4*
12*
This article is protected by copyright. All rights reserved. Seve 135±
136±
138±1
135±
136±1 137±1
134±
136±1 135±
15*
13*
4*
13*
3*
14*
1*
nth 4*
11*
day Heart rates during treatment compared to pretreatment: *p
