Original Article Submitted: 29.12.2013 Accepted: 17.3.2014 Conflict of interest Priv.-Doz. Dr. Markus Zutt has received lecture fees from Candela Laser (Deutschland).
Kjell M. Kaune1,4*, Peter Lauerer2,5, Silke Kietz2,6, Christoph Eich3,7, Kai-Martin Thoms1, Michael P. Schön1, Markus Zutt1,4 * The first two authors contributed equally to the present article. (1) Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Germany (2) Department of Pediatric Hematology and Oncology, University Medical Center Göttingen, Germany (3) Department of Anesthesiology, Emergency and Intensive Care Medicine, University Medical Center Göttingen, Germany (4) Dermatology and Allergology, Klinikum Bremen-Mitte, Bremen, Germany (5) Department of Pediatric Cardiology and Intensive Care Medicine, University Medical Center Göttingen, Germany (6) Department of Pediatric Oncology and Hematology, University Medicine Greifswald, Germany (7) Department of Anesthesia, Pediatric Intensive Care, and Emergency Medicine, Auf der Bult Center for Children and Adolescents, Hannover, Germany
DOI: 10.1111/ddg.12354
Combination therapy of infantile hemangiomas with pulsed dye laser and Nd:YAG laser is effective and safe Summary Background: Infantile hemangiomas (IH) can cause severe complications such as obstruction, ulceration or heart failure. Therefore, in certain difficult-to-treat areas, or when there is no sign of involution, early and effective therapy is required. In rare instances, systemic treatments, like the beta-blocker propranolol and oral corticosteroids, can cause serious side effects. Effective and well-tolerated local treatment options are thus desirable as additive or alternative methods. Patients and Methods: In this retrospective interdisciplinary study, 38 children with 77 IH were treated with pulsed dye laser (PDL) (595 nm) and Nd:YAG laser (1,064 nm). The treatment success and side effects were evaluated according to objective and subjective parameters, including hemangioma thickness measured by ultrasound and the parents’ evaluation of treatment. Results: All 77 treated IH responded to the therapy, of which 52.8 % healed after the end of treatment and 47.2 % had only minimum residual components. The success of treatment was assessed by the parents in 92.6 % as very good or good. Transient blistering occurred as the main side effect in 45.9 %. Conclusions: Combination therapy with PDL and Nd:YAG laser represents an effective local method for IH with minimal side effects.
Introduction Infantile hemangiomas (IH) occur in 3–10 % of all infants (the ratio of girls to boys is 1.4–3 : 1); the relative risk is higher in premature and low-birth-weight babies [1–5]. Fetal hypo-
xia may be a triggering factor [6, 7]. IH are often invisible at birth, but become apparent during the first 4–6 weeks of life [5]. More than 60 % of IH form on the head or neck, about 25 % on the trunk, around 20 % on the extremities, and 5 % in the anogenital region [2]. Following a proliferation phase
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Original Article PDL/Nd:YAG laser therapy of infantile hemangiomas
during the first weeks and months after birth, most IH spontaneously begin to shrink within 3–6 months; the involution phase lasts 3–7 years [2, 5]. The annual regression rate is about 10 %; by the 5th year of life, 50 % of all IH regress, by the 7th year of life 70 %, and by the 9th year of life 90 % [8, 9]. Hence, following discussion with the parents, an expectant approach may be taken until spontaneous regression occurs (“active non-intervention”). About 25 % of patients experience complications requiring treatment [2]. Absolute treatment indications include impending obstructions (for example, ocular, perianal, or airway obstructions), ulcerations, as well as systemic complications (e.g., cardiac insufficiency or hypothyroidism). In patients with facial IH, rapid growth, pain, risk of scarring due to ulceration, and absence of regression are given relative indications for treatment [2, 10]. In past decades, systemic medications for difficult-to-treat IH included alpha interferon, vincristine, and especially corticosteroids; in recent years, the beta-blocker propranolol, an effective and safe treatment option, has also become available [7, 10–13]. Yet, in rare instances, systemic therapies may cause significant side effects, and thus well-tolerated local treatments are desirable. Cryotherapy with liquid nitrogen is a common treatment option, but due to lacking standardization, inadequate skin penetration, and the potential for ulceration, hyperpigmentation/loss of pigmentation, and scarring, this therapy is problematic [11, 14]. For the past two decades, various laser systems have been used to treat angiomas. Pulsed dye laser (PDL) has reportedly achieved excellent results when used on IH [15–20]. Given that many IH also spread subcutaneously, combination therapy with a laser system that allows for deeper penetration, such as an Nd:YAG laser (neodymium: yttrium-aluminum-garnet-laser) would seem to be a good option [21–24]. This interdisciplinary study evaluates combination treatment of infantile hemangiomas with PDL and Nd:YAG laser.
Patients and methods From 2009 until early 2011, 38 children with a total of 77 IH were treated at the University Medical Center Göttingen using PDL (Candela V-Beam pulsed dye laser, Candela Corporation, Boston, Mass., USA) and Nd:YAG laser (Gentle YAG TM, Candela Corporation, Boston, Mass., USA). All selected patients had a confident clinical diagnosis and an absolute or relative indication for treatment. The treatment indication was thoroughly assessed. Problematic sites on body orifices (eyes, ears, nose, mouth, genitalia) were the most frequent indications for laser therapy. In addition, a large number of IH were in the proliferation phase at the beginning of treatment; due to steady progression and no
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sign of involution, there was an indication for treatment. The endpoint of laser therapy was the induction of a proliferation stop. The parents of the patients were informed about possible risks and side effects of laser therapy as well as treatment alternatives. Upon agreeing to laser therapy, their written informed consent was obtained. Photo documentation was performed before beginning treatment and after each session. The laser therapy sessions were performed in a hospital setting. The patients were briefly given sevoflurane for anesthesia via a face mask. There was no need for invasive airway management or placement of an indwelling venous catheter. Treatment was first done with a Nd:YAG laser (wavelength: 1,064 nm) with an energy density of 90 J/cm2 and a pulse duration of 50 milliseconds. The spot size was 6 mm, and there was an integrated dynamic cooling device (dynamic cooling device®, DCD®); the parameters were 30–60–30. A single pass was used, without any overlapping pulses or double shots. Next, a pulsed dye laser was used (wavelength of 595 nm; energy density of 9 J/cm2; pulses of 3 milliseconds; spot size of 7 mm) with an integrated dynamic cooling device, DCD® (30–10). One to two passes of pulses with 10–20 % overlap were applied. Laser therapy lasted 3–5 minutes on average, followed by 24-hour surveillance. If there were no post-interventional complications (such as blistering), the energy density setting of the Nd:YAG laser was increased by around 5 J/cm 2 during subsequent sessions, and pulsed dye laser was increased by around 0.5 J/cm 2; no other settings were changed. The intervals between treatment sessions were 6–8 weeks, and treatment success was evaluated at 3–4 weeks post-therapy by physicians from two disciplines (dermatology and pediatrics) in a joint consultation. Any post-treatment blistering was treated with topical fusidic acid cream (Fucidine® cream). Adequate sun protection was advised for three months after the last laser treatment to prevent post-inflammatory pigmentation disorders. There was no need for postoperative analgesia. Before beginning treatment, the age of the patient at the time of onset of IH was documented (in weeks), as well his or her age at the time of initial treatment (in months), the duration of the mother's pregnancy (in weeks), the number of cutaneous hemangiomas, the site of the target hemangiomas (head/neck, thorax/abdomen, genital region, extremities), penetration depth before therapy (determined by ultrasound, in millimeters; the clinically thickest IH was measured if there were multiple lesions), and ultrasound assessment of vascularization (strong/moderate/minimal) was recorded. Color-coded duplex ultrasound was performed by the same examiner (M. Z.) using a Sonoace 8000 EX Prime (probe: L5–9 EC; Medison, Korea). Other parameters prior to therapy were elevation (yes/no), the presence of a subcutaneous component (yes/ no), color (livid/red/reddish), hemangioma surface area (mm × mm), prior treatment (yes/no – which), and whether there were
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1206
Original Article PDL/Nd:YAG laser therapy of infantile hemangiomas
any complications before laser therapy (bleeding, ulceration, necrosis). We recorded which laser systems (Nd:YAG, PDL, both) were used and the number of treatments. Patients with very thin IH, whose thickness could not be measured by ultrasound (patient numbers 24, 27, and 35), were given PDL therapy only; due to an inadequate response, patients 1 and 26 were switched from PDL monotherapy after the first cycle and were given combination therapy with PDL/Nd:YAG laser. Some patients with thicker IH (> 10 mm) began treatment with Nd:YAG laser monotherapy (patient numbers 12, 15, 17, 21, and 32), although three of these (patient numbers 12, 21, and 32) later additionally underwent PDL laser therapy. Following treatment, the size of the residual lesion (none/minimal), the degree of vascularization (strong/moderate/weak/none), and side effects (blistering, erosions, infection, scarring; number of occurrences) were evaluated. To present the data as clearly as possible, in patients with multiple lesions, a predominant value was taken, and in patients with more balanced findings, the value represents the IH with the largest diameter. In addition to the physician's evaluation, the results and satisfaction with the method were also assessed by the parents (graded 1–6). All values were rounded up or down to the nearest tenth.
Results The baseline parameters and results are summarized in Table 1 (see Online Supporting Information). A total of 77 IH were treated in 24 girls and 14 boys (ratio of girls to boys: 1.7 : 1). The IH manifested between 0 and 28 weeks of age (median [MD]: 1 week; average [MW]: 2.5 weeks); in 10/38 (26.3 %) of the infants, the IH was already present at birth, and in 34/38 (89.5 %) it developed by the 6th week of life. Treatment was begun between the 2nd month and the 60th (MD: 4.5 months; MW: 8.4 months). Nine out of 36 (25 %) of the infants were born prematurely (before the 37th week of pregnancy [GW]) (range 26–40 SSW; MD: 38 SSW; MW: 37.3 SSW). Three (3/36; 8.3 %) of the infants were born before the 32nd week of pregnancy. Eighteen of 38 (47.3 %) had multiple IH (range 1–8; MD: 1; MW: 2.0). Of the IH, 34/77 (44.2 %) were on the head or neck region, 26/77 (33.8 %) were on the thorax/abdomen, 7/77 (9.1 %) in the genital region, and 10/77 (13.0 %) on the extremities. The thicknesses of 21 IH were measured by ultrasound; the average thickness was 10.2 mm (MD: 9.5 mm). Vascularization, as assessed by color-coded duplex ultrasound, was strong in 25/36 (69.4 %); it was moderate in 10/36 (27.8 %); and in 1/36 (2.8 %), it was weak. In 32/38 (84.2 %) of patients, the IH were elevated, and in 27/38 (71.1 %) they had a subcutaneous component. In regard to clinical appearance, 3/38
(7.9 %) of the IH were livid, 29/38 (76.3 %) were red, and 6/38 (15.8 %) were reddish. The average size of the IH was 16.4 mm × 13.2 mm (sum: 1,129 mm × 912 mm; range 1 mm × 1 mm to 88 mm × 66 mm; MD: 15 mm × 10 mm); the average surface area was 296.8 mm2 (sum: 20,478.2 mm2; range 0.8–4,561.6 mm2; MD: 117.8 mm2). Twelve of the 38 (31.6 %) patients had undergone prior treatment: 9/12 (75 %) had undergone cryotherapy, two (16.7 %) had undergone unspecified laser treatment, and one each underwent (8.3 %) excision, propranolol or prednisone. The parents of 3/38 (7.9 %) of the infants reported complications related to the IH prior to therapy (3 × bleeding, 1 × ulceration, 1 × necrosis). On the whole, 88 laser sessions (range 1–6; MD: 2; MW: 2.3) were performed. Both lasers (PDL/ Nd:YAG) were used in 76/88 (86.4 %) of treatments, on 33/38 (86.8 %) of patients; in 12/88 (13.6 %) sessions, only one laser (6 × each PDL and Nd:YAG) was used. In the physician evaluation 6 weeks after treatment ended, 19/36 (52.8 %) of treated IH were no longer evident, and 17/36 (47.2 %) lesions had only minimal residual components; hence, all IH responded to treatment (Figure 1, 2). In the duplex ultrasound follow-up, 22/31 (71.0 %) patients had no vascularization, while 8/31 (25.8 %) had minimal vascularization, and 1/31 (3.2 %) had moderate vascularization. Side effects (i.e., blistering) occurred in 17/37 (45.9 %). The blisters appeared immediately after the intervention and generally healed, without scarring, a few days afterward, following treatment with a topical antiseptic. Erosions and scarring occurred one time each (2.7 %). Six weeks after treatment ended, the parents evaluated the success of treatment as follows: 18/27 (66.7 %) said “very good”, 7/27 (25.9 %) said “good”, and one each (3.7 %) said “satisfactory” or “adequate” (MW: 1.4). In terms of satisfaction with the method, the parents found in 15/27 (55.6 %) that it was “very good”, in 11/27 (40.7 %) it was “good”, and in only 1/27 (3.7 %) it was deemed “satisfactory.”
Discussion Previously, the treatment of IH has been complicated by serious side effects related to various systemic therapies such as oral corticosteroids, but with the beta-blocker propranolol, there is now a safe systemic treatment [7, 10–13]. Yet, in rare instances, propranolol can cause side effects such as hypoglycemia, hypotension, bradycardia, diarrhea, and hyperkalemia. Thus, well-tolerated local therapy may be a useful alternative in infantile hemangiomas [7, 12, 25, 26]. To the best of our knowledge, this is the largest study to date on successful combination therapy with PDL (595 nm) and Nd:YAG laser (1,064 nm) in IH. Various studies on PDL have shown response rates of 80–90 % [15–20]. Given that PDL is characterized by relatively selective absorption by hemoglobin,
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Figure 1 Patient no. 13 with a right-sided pre-auricular hemangioma: baseline (a), lightening after the first PDL/Nd:YAG laser combination therapy (b) and final findings with significantly decreased IH after three treatments (c).
it can achieve effective photothermolysis of vascular lesions [27]. Yet the maximum penetration depth of PDL is 0.75–1 mm [27, 28]. Considering that 40–50 % of IH extend into the subcutis, and in our sample too, almost all IH were much deeper than 0.75 mm (MW: 10.2 mm; 71.1 % with a subcutaneous component), the combination with a deeply penetrating laser, such as Nd:YAG laser (1,064 nm, penetration depth of 5–6 mm) is useful [5, 22, 27–29]. In addition, PDL can transform oxyhemoglobin into methemoglobin and lead
to thrombus formation [30]. The absorption of Nd:YAG laser by methemoglobin and thrombi is a further advantage of combining both laser systems. This can enable effective vessel destruction while sparing the surrounding tissue [27]. In our study, all 38 patients were successfully treated with combination therapy using PDL and Nd:YAG laser; 52.8 % of the IH healed completely and 47.2 % healed nearly completely. To the best of our knowledge, only two larger studies on this combination therapy for the treatment of IH have been
Figure 2 Patient no. 10 with IH located in the anogenital region: baseline (a), with significant improvement after one (b), and two (c) combination therapies with PDL/Nd:YAG laser.
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© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1206
ublished to date. Saafan and Salah treated 25 patients with p IH of the head and neck region, and reported that 72 % healed completely, 16 % healed with mild hyperpigmentation/ loss of pigmentation, or “structural skin changes,” and 12 % responded inadequately [29]. In a retrospective study by Alcántara-González and colleagues, all 22 patients benefited from PDL and Nd:YAG laser treatment, irrespective the stage of IH development [28]. In our sample, transitory blistering was a common event, although scarring occurred in only one patient. In the other published studies as well, combination therapy was shown to be associated with few side effects; only a small number of patients developed mild atrophy, ulcerations, or hyperpigmentation [28, 29]. Along with direct and transcutaneous methods, Nd:YAG laser therapy may be administered intralesionally [21, 23, 31, 32], although the latter procedure is only suitable for very deep IH, given the increased risk of complications [21, 31, 32]. Various cooling systems have been developed to protect the epidermis against thermal damage [19, 24, 33]. Application of ice or cold water may also be used to cool the blood vessels in the upper dermis, limiting the effects of the laser [24, 33]. Our PDL and Nd:YAG lasers are equipped with a dynamic cooling system, which applies cryogen spray (based on the chosen settings) for only 30 milliseconds; with the Nd:YAG laser, it was applied repetitively before and after the pulse, with a delay of 60 milliseconds. Nd:YAG lasers can cause severe pain and are therefore often used with general or local anesthesia [24, 28, 29]. Because many local anesthetics contain sympathomimetics and vasoconstrictors, they may diminish the effectiveness of laser treatment. Yet, administering classic general anesthesia with intubation, for such a brief treatment (three to ten minutes) hardly appears justified. Administration of regional anesthesia (e.g., caudal anesthesia for treating areas below the costal arch), is technically possible, but given the relatively low intraoperative pain level, the short time required for individual laser treatments, and the very minimal need for postoperative analgesia, it is usually not indicated. We therefore performed laser therapy after administering sevoflurane via a face mask, which provided adequate pain relief in all patients without causing any intraoperative or postoperative respiratory or cardiovascular complications [34]. Peripheral venous access was unnecessary. Face mask administration of sevoflurane anesthesia (on an empty stomach) is an established method which is used around the world for pediatric anesthesia, and is considered a very safe option. Sevoflurane has a broad therapeutic spectrum, and its adverse effects are predominantly dose-dependent (mainly respiratory and circulatory depression) [35]. Mastery of its use is one of the basics of pediatric anesthesia. Infantile hemangiomas are associated with premature delivery (ca. 20 % < 37th week of pregnancy; 6 % < 32nd week
of pregnancy) [3, 6, 7]. This finding was confirmed by our sample: 25 % of infants were born before the 37th week of pregnancy and 8.3 % before the 32nd. The very early clinical manifestation of IH was also apparent (26.3 % at birth, 89.5 % by the 6th week of life). According to the literature, only 1–2 % of infants have an IH at the time of birth, although development by the 6th week of life is well documented [7]. At 47.3 %, the percentage of children with multiple IH was somewhat higher than published data (about 30 %), although the average number (2.0 IH/patient), the girl/boy ratio (1.7 : 1), the percentage of lesions smaller than 3 cm (> 80 %), and the affected sites corresponded roughly to the figures reported by other studies [2, 3, 16, 31]. The 38 patients in our study required a total of 88 laser sessions (MW: 2.3). Follow-up with duplex ultrasound showed that in 96.8 %, at the time of stopping treatment, there was no, or only mild, vascularization. PDL monotherapy of IH generally required more than 5 sessions, and thus, combination treatment with Nd:YAG laser seems to considerably reduce the number of necessary treatments, while ensuring an adequate response [17, 20]. Along with the physician assessment of treatment success, our study also surveyed the parents. The good response to treatment was reflected by the parents’ evaluation: treatment success and the method used were rated as “very good” or “good” by 92.6 % and 96.3 % respectively. These results are even better than those from similar surveys done in PDL monotherapy studies [16, 18]. In summary, combined use of PDL (595 nm)/Nd:YAG laser therapy (1,064 nm), with short-term anesthesia has been shown to be an effective method for the treatment of infantile hemangiomas, and one which involves few side effects. Our results suggest that – depending on the treatment indication – treatment with PDL and Nd:YAG laser may be recommended as first-line therapy for superficial IH. For deeper lesions, systemic therapy (e.g., with propranolol) is advisable. Correspondence to Priv.-Doz. Dr. med. Markus Zutt Klinik für Dermatologie und Allergologie Klinikum Bremen-Mitte St.-Jürgen-Straße 1 28177 Bremen E-mail: [email protected]
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Kjell M. Kaune1,4*, Peter Lauerer2,5, Silke Kietz2,6, Christoph Eich3,7, Kai-Martin Thoms1, Michael P. Schön1, Markus Zutt1,4 * The first two authors contributed equally to the present article. (1) Department of Dermatology, Venereology and Allergology, University Medical Center Göttingen, Germany (2) Department of Pediatric Hematology and Oncology, University Medical Center Göttingen, Germany (3) Department of Anesthesiology, Emergency and Intensive Care Medicine, University Medical Center Göttingen, Germany (4) Dermatology and Allergology, Klinikum Bremen-Mitte, Bremen, Germany (5) Department of Pediatric Cardiology and Intensive Care Medicine, University Medical Center Göttingen, Germany (6) Department of Pediatric Oncology and Hematology, University Medicine Greifswald, Germany (7) Department of Anesthesia, Pediatric Intensive Care, and Emergency Medicine, Auf der Bult Center for Children and Adolescents, Hannover, Germany
DOI: 10.1111/ddg.12354
Combination therapy of infantile hemangiomas with pulsed dye laser and Nd:YAG laser is effective and safe Summary Background: Infantile hemangiomas (IH) can cause severe complications such as obstruction, ulceration or heart failure. Therefore, in certain difficult-to-treat areas, or when there is no sign of involution, early and effective therapy is required. In rare instances, systemic treatments, like the beta-blocker propranolol and oral corticosteroids, can cause serious side effects. Effective and well-tolerated local treatment options are thus desirable as additive or alternative methods. Patients and Methods: In this retrospective interdisciplinary study, 38 children with 77 IH were treated with pulsed dye laser (PDL) (595 nm) and Nd:YAG laser (1,064 nm). The treatment success and side effects were evaluated according to objective and subjective parameters, including hemangioma thickness measured by ultrasound and the parents’ evaluation of treatment. Results: All 77 treated IH responded to the therapy, of which 52.8 % healed after the end of treatment and 47.2 % had only minimum residual components. The success of treatment was assessed by the parents in 92.6 % as very good or good. Transient blistering occurred as the main side effect in 45.9 %. Conclusions: Combination therapy with PDL and Nd:YAG laser represents an effective local method for IH with minimal side effects.
Introduction Infantile hemangiomas (IH) occur in 3–10 % of all infants (the ratio of girls to boys is 1.4–3 : 1); the relative risk is higher in premature and low-birth-weight babies [1–5]. Fetal hypo-
xia may be a triggering factor [6, 7]. IH are often invisible at birth, but become apparent during the first 4–6 weeks of life [5]. More than 60 % of IH form on the head or neck, about 25 % on the trunk, around 20 % on the extremities, and 5 % in the anogenital region [2]. Following a proliferation phase
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1206
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Original Article PDL/Nd:YAG laser therapy of infantile hemangiomas
during the first weeks and months after birth, most IH spontaneously begin to shrink within 3–6 months; the involution phase lasts 3–7 years [2, 5]. The annual regression rate is about 10 %; by the 5th year of life, 50 % of all IH regress, by the 7th year of life 70 %, and by the 9th year of life 90 % [8, 9]. Hence, following discussion with the parents, an expectant approach may be taken until spontaneous regression occurs (“active non-intervention”). About 25 % of patients experience complications requiring treatment [2]. Absolute treatment indications include impending obstructions (for example, ocular, perianal, or airway obstructions), ulcerations, as well as systemic complications (e.g., cardiac insufficiency or hypothyroidism). In patients with facial IH, rapid growth, pain, risk of scarring due to ulceration, and absence of regression are given relative indications for treatment [2, 10]. In past decades, systemic medications for difficult-to-treat IH included alpha interferon, vincristine, and especially corticosteroids; in recent years, the beta-blocker propranolol, an effective and safe treatment option, has also become available [7, 10–13]. Yet, in rare instances, systemic therapies may cause significant side effects, and thus well-tolerated local treatments are desirable. Cryotherapy with liquid nitrogen is a common treatment option, but due to lacking standardization, inadequate skin penetration, and the potential for ulceration, hyperpigmentation/loss of pigmentation, and scarring, this therapy is problematic [11, 14]. For the past two decades, various laser systems have been used to treat angiomas. Pulsed dye laser (PDL) has reportedly achieved excellent results when used on IH [15–20]. Given that many IH also spread subcutaneously, combination therapy with a laser system that allows for deeper penetration, such as an Nd:YAG laser (neodymium: yttrium-aluminum-garnet-laser) would seem to be a good option [21–24]. This interdisciplinary study evaluates combination treatment of infantile hemangiomas with PDL and Nd:YAG laser.
Patients and methods From 2009 until early 2011, 38 children with a total of 77 IH were treated at the University Medical Center Göttingen using PDL (Candela V-Beam pulsed dye laser, Candela Corporation, Boston, Mass., USA) and Nd:YAG laser (Gentle YAG TM, Candela Corporation, Boston, Mass., USA). All selected patients had a confident clinical diagnosis and an absolute or relative indication for treatment. The treatment indication was thoroughly assessed. Problematic sites on body orifices (eyes, ears, nose, mouth, genitalia) were the most frequent indications for laser therapy. In addition, a large number of IH were in the proliferation phase at the beginning of treatment; due to steady progression and no
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sign of involution, there was an indication for treatment. The endpoint of laser therapy was the induction of a proliferation stop. The parents of the patients were informed about possible risks and side effects of laser therapy as well as treatment alternatives. Upon agreeing to laser therapy, their written informed consent was obtained. Photo documentation was performed before beginning treatment and after each session. The laser therapy sessions were performed in a hospital setting. The patients were briefly given sevoflurane for anesthesia via a face mask. There was no need for invasive airway management or placement of an indwelling venous catheter. Treatment was first done with a Nd:YAG laser (wavelength: 1,064 nm) with an energy density of 90 J/cm2 and a pulse duration of 50 milliseconds. The spot size was 6 mm, and there was an integrated dynamic cooling device (dynamic cooling device®, DCD®); the parameters were 30–60–30. A single pass was used, without any overlapping pulses or double shots. Next, a pulsed dye laser was used (wavelength of 595 nm; energy density of 9 J/cm2; pulses of 3 milliseconds; spot size of 7 mm) with an integrated dynamic cooling device, DCD® (30–10). One to two passes of pulses with 10–20 % overlap were applied. Laser therapy lasted 3–5 minutes on average, followed by 24-hour surveillance. If there were no post-interventional complications (such as blistering), the energy density setting of the Nd:YAG laser was increased by around 5 J/cm 2 during subsequent sessions, and pulsed dye laser was increased by around 0.5 J/cm 2; no other settings were changed. The intervals between treatment sessions were 6–8 weeks, and treatment success was evaluated at 3–4 weeks post-therapy by physicians from two disciplines (dermatology and pediatrics) in a joint consultation. Any post-treatment blistering was treated with topical fusidic acid cream (Fucidine® cream). Adequate sun protection was advised for three months after the last laser treatment to prevent post-inflammatory pigmentation disorders. There was no need for postoperative analgesia. Before beginning treatment, the age of the patient at the time of onset of IH was documented (in weeks), as well his or her age at the time of initial treatment (in months), the duration of the mother's pregnancy (in weeks), the number of cutaneous hemangiomas, the site of the target hemangiomas (head/neck, thorax/abdomen, genital region, extremities), penetration depth before therapy (determined by ultrasound, in millimeters; the clinically thickest IH was measured if there were multiple lesions), and ultrasound assessment of vascularization (strong/moderate/minimal) was recorded. Color-coded duplex ultrasound was performed by the same examiner (M. Z.) using a Sonoace 8000 EX Prime (probe: L5–9 EC; Medison, Korea). Other parameters prior to therapy were elevation (yes/no), the presence of a subcutaneous component (yes/ no), color (livid/red/reddish), hemangioma surface area (mm × mm), prior treatment (yes/no – which), and whether there were
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1206
Original Article PDL/Nd:YAG laser therapy of infantile hemangiomas
any complications before laser therapy (bleeding, ulceration, necrosis). We recorded which laser systems (Nd:YAG, PDL, both) were used and the number of treatments. Patients with very thin IH, whose thickness could not be measured by ultrasound (patient numbers 24, 27, and 35), were given PDL therapy only; due to an inadequate response, patients 1 and 26 were switched from PDL monotherapy after the first cycle and were given combination therapy with PDL/Nd:YAG laser. Some patients with thicker IH (> 10 mm) began treatment with Nd:YAG laser monotherapy (patient numbers 12, 15, 17, 21, and 32), although three of these (patient numbers 12, 21, and 32) later additionally underwent PDL laser therapy. Following treatment, the size of the residual lesion (none/minimal), the degree of vascularization (strong/moderate/weak/none), and side effects (blistering, erosions, infection, scarring; number of occurrences) were evaluated. To present the data as clearly as possible, in patients with multiple lesions, a predominant value was taken, and in patients with more balanced findings, the value represents the IH with the largest diameter. In addition to the physician's evaluation, the results and satisfaction with the method were also assessed by the parents (graded 1–6). All values were rounded up or down to the nearest tenth.
Results The baseline parameters and results are summarized in Table 1 (see Online Supporting Information). A total of 77 IH were treated in 24 girls and 14 boys (ratio of girls to boys: 1.7 : 1). The IH manifested between 0 and 28 weeks of age (median [MD]: 1 week; average [MW]: 2.5 weeks); in 10/38 (26.3 %) of the infants, the IH was already present at birth, and in 34/38 (89.5 %) it developed by the 6th week of life. Treatment was begun between the 2nd month and the 60th (MD: 4.5 months; MW: 8.4 months). Nine out of 36 (25 %) of the infants were born prematurely (before the 37th week of pregnancy [GW]) (range 26–40 SSW; MD: 38 SSW; MW: 37.3 SSW). Three (3/36; 8.3 %) of the infants were born before the 32nd week of pregnancy. Eighteen of 38 (47.3 %) had multiple IH (range 1–8; MD: 1; MW: 2.0). Of the IH, 34/77 (44.2 %) were on the head or neck region, 26/77 (33.8 %) were on the thorax/abdomen, 7/77 (9.1 %) in the genital region, and 10/77 (13.0 %) on the extremities. The thicknesses of 21 IH were measured by ultrasound; the average thickness was 10.2 mm (MD: 9.5 mm). Vascularization, as assessed by color-coded duplex ultrasound, was strong in 25/36 (69.4 %); it was moderate in 10/36 (27.8 %); and in 1/36 (2.8 %), it was weak. In 32/38 (84.2 %) of patients, the IH were elevated, and in 27/38 (71.1 %) they had a subcutaneous component. In regard to clinical appearance, 3/38
(7.9 %) of the IH were livid, 29/38 (76.3 %) were red, and 6/38 (15.8 %) were reddish. The average size of the IH was 16.4 mm × 13.2 mm (sum: 1,129 mm × 912 mm; range 1 mm × 1 mm to 88 mm × 66 mm; MD: 15 mm × 10 mm); the average surface area was 296.8 mm2 (sum: 20,478.2 mm2; range 0.8–4,561.6 mm2; MD: 117.8 mm2). Twelve of the 38 (31.6 %) patients had undergone prior treatment: 9/12 (75 %) had undergone cryotherapy, two (16.7 %) had undergone unspecified laser treatment, and one each underwent (8.3 %) excision, propranolol or prednisone. The parents of 3/38 (7.9 %) of the infants reported complications related to the IH prior to therapy (3 × bleeding, 1 × ulceration, 1 × necrosis). On the whole, 88 laser sessions (range 1–6; MD: 2; MW: 2.3) were performed. Both lasers (PDL/ Nd:YAG) were used in 76/88 (86.4 %) of treatments, on 33/38 (86.8 %) of patients; in 12/88 (13.6 %) sessions, only one laser (6 × each PDL and Nd:YAG) was used. In the physician evaluation 6 weeks after treatment ended, 19/36 (52.8 %) of treated IH were no longer evident, and 17/36 (47.2 %) lesions had only minimal residual components; hence, all IH responded to treatment (Figure 1, 2). In the duplex ultrasound follow-up, 22/31 (71.0 %) patients had no vascularization, while 8/31 (25.8 %) had minimal vascularization, and 1/31 (3.2 %) had moderate vascularization. Side effects (i.e., blistering) occurred in 17/37 (45.9 %). The blisters appeared immediately after the intervention and generally healed, without scarring, a few days afterward, following treatment with a topical antiseptic. Erosions and scarring occurred one time each (2.7 %). Six weeks after treatment ended, the parents evaluated the success of treatment as follows: 18/27 (66.7 %) said “very good”, 7/27 (25.9 %) said “good”, and one each (3.7 %) said “satisfactory” or “adequate” (MW: 1.4). In terms of satisfaction with the method, the parents found in 15/27 (55.6 %) that it was “very good”, in 11/27 (40.7 %) it was “good”, and in only 1/27 (3.7 %) it was deemed “satisfactory.”
Discussion Previously, the treatment of IH has been complicated by serious side effects related to various systemic therapies such as oral corticosteroids, but with the beta-blocker propranolol, there is now a safe systemic treatment [7, 10–13]. Yet, in rare instances, propranolol can cause side effects such as hypoglycemia, hypotension, bradycardia, diarrhea, and hyperkalemia. Thus, well-tolerated local therapy may be a useful alternative in infantile hemangiomas [7, 12, 25, 26]. To the best of our knowledge, this is the largest study to date on successful combination therapy with PDL (595 nm) and Nd:YAG laser (1,064 nm) in IH. Various studies on PDL have shown response rates of 80–90 % [15–20]. Given that PDL is characterized by relatively selective absorption by hemoglobin,
© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1206
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Figure 1 Patient no. 13 with a right-sided pre-auricular hemangioma: baseline (a), lightening after the first PDL/Nd:YAG laser combination therapy (b) and final findings with significantly decreased IH after three treatments (c).
it can achieve effective photothermolysis of vascular lesions [27]. Yet the maximum penetration depth of PDL is 0.75–1 mm [27, 28]. Considering that 40–50 % of IH extend into the subcutis, and in our sample too, almost all IH were much deeper than 0.75 mm (MW: 10.2 mm; 71.1 % with a subcutaneous component), the combination with a deeply penetrating laser, such as Nd:YAG laser (1,064 nm, penetration depth of 5–6 mm) is useful [5, 22, 27–29]. In addition, PDL can transform oxyhemoglobin into methemoglobin and lead
to thrombus formation [30]. The absorption of Nd:YAG laser by methemoglobin and thrombi is a further advantage of combining both laser systems. This can enable effective vessel destruction while sparing the surrounding tissue [27]. In our study, all 38 patients were successfully treated with combination therapy using PDL and Nd:YAG laser; 52.8 % of the IH healed completely and 47.2 % healed nearly completely. To the best of our knowledge, only two larger studies on this combination therapy for the treatment of IH have been
Figure 2 Patient no. 10 with IH located in the anogenital region: baseline (a), with significant improvement after one (b), and two (c) combination therapies with PDL/Nd:YAG laser.
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© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd. | JDDG | 1610-0379/2014/1206
ublished to date. Saafan and Salah treated 25 patients with p IH of the head and neck region, and reported that 72 % healed completely, 16 % healed with mild hyperpigmentation/ loss of pigmentation, or “structural skin changes,” and 12 % responded inadequately [29]. In a retrospective study by Alcántara-González and colleagues, all 22 patients benefited from PDL and Nd:YAG laser treatment, irrespective the stage of IH development [28]. In our sample, transitory blistering was a common event, although scarring occurred in only one patient. In the other published studies as well, combination therapy was shown to be associated with few side effects; only a small number of patients developed mild atrophy, ulcerations, or hyperpigmentation [28, 29]. Along with direct and transcutaneous methods, Nd:YAG laser therapy may be administered intralesionally [21, 23, 31, 32], although the latter procedure is only suitable for very deep IH, given the increased risk of complications [21, 31, 32]. Various cooling systems have been developed to protect the epidermis against thermal damage [19, 24, 33]. Application of ice or cold water may also be used to cool the blood vessels in the upper dermis, limiting the effects of the laser [24, 33]. Our PDL and Nd:YAG lasers are equipped with a dynamic cooling system, which applies cryogen spray (based on the chosen settings) for only 30 milliseconds; with the Nd:YAG laser, it was applied repetitively before and after the pulse, with a delay of 60 milliseconds. Nd:YAG lasers can cause severe pain and are therefore often used with general or local anesthesia [24, 28, 29]. Because many local anesthetics contain sympathomimetics and vasoconstrictors, they may diminish the effectiveness of laser treatment. Yet, administering classic general anesthesia with intubation, for such a brief treatment (three to ten minutes) hardly appears justified. Administration of regional anesthesia (e.g., caudal anesthesia for treating areas below the costal arch), is technically possible, but given the relatively low intraoperative pain level, the short time required for individual laser treatments, and the very minimal need for postoperative analgesia, it is usually not indicated. We therefore performed laser therapy after administering sevoflurane via a face mask, which provided adequate pain relief in all patients without causing any intraoperative or postoperative respiratory or cardiovascular complications [34]. Peripheral venous access was unnecessary. Face mask administration of sevoflurane anesthesia (on an empty stomach) is an established method which is used around the world for pediatric anesthesia, and is considered a very safe option. Sevoflurane has a broad therapeutic spectrum, and its adverse effects are predominantly dose-dependent (mainly respiratory and circulatory depression) [35]. Mastery of its use is one of the basics of pediatric anesthesia. Infantile hemangiomas are associated with premature delivery (ca. 20 % < 37th week of pregnancy; 6 % < 32nd week
of pregnancy) [3, 6, 7]. This finding was confirmed by our sample: 25 % of infants were born before the 37th week of pregnancy and 8.3 % before the 32nd. The very early clinical manifestation of IH was also apparent (26.3 % at birth, 89.5 % by the 6th week of life). According to the literature, only 1–2 % of infants have an IH at the time of birth, although development by the 6th week of life is well documented [7]. At 47.3 %, the percentage of children with multiple IH was somewhat higher than published data (about 30 %), although the average number (2.0 IH/patient), the girl/boy ratio (1.7 : 1), the percentage of lesions smaller than 3 cm (> 80 %), and the affected sites corresponded roughly to the figures reported by other studies [2, 3, 16, 31]. The 38 patients in our study required a total of 88 laser sessions (MW: 2.3). Follow-up with duplex ultrasound showed that in 96.8 %, at the time of stopping treatment, there was no, or only mild, vascularization. PDL monotherapy of IH generally required more than 5 sessions, and thus, combination treatment with Nd:YAG laser seems to considerably reduce the number of necessary treatments, while ensuring an adequate response [17, 20]. Along with the physician assessment of treatment success, our study also surveyed the parents. The good response to treatment was reflected by the parents’ evaluation: treatment success and the method used were rated as “very good” or “good” by 92.6 % and 96.3 % respectively. These results are even better than those from similar surveys done in PDL monotherapy studies [16, 18]. In summary, combined use of PDL (595 nm)/Nd:YAG laser therapy (1,064 nm), with short-term anesthesia has been shown to be an effective method for the treatment of infantile hemangiomas, and one which involves few side effects. Our results suggest that – depending on the treatment indication – treatment with PDL and Nd:YAG laser may be recommended as first-line therapy for superficial IH. For deeper lesions, systemic therapy (e.g., with propranolol) is advisable. Correspondence to Priv.-Doz. Dr. med. Markus Zutt Klinik für Dermatologie und Allergologie Klinikum Bremen-Mitte St.-Jürgen-Straße 1 28177 Bremen E-mail: [email protected]
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