Percutaneous sclerotherapy in neonatal and infant head and neck lymphatic malformations: a single center experience

Journal of Pediatric Surgery (2011) 46, 2083–2095

www.elsevier.com/locate/jpedsurg

Percutaneous sclerotherapy in neonatal and infant head and neck lymphatic malformations: a single center experience Anne Marie Cahill a , Els Nijs a , Deddeh Ballah a,⁎, Deborah Rabinowitz g , Lynn Thompson b , Natalie Rintoul c , Holly Hedrick d , Ian Jacobs e , David Low f a

Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA b Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA c Department of Neonatology, Perelman School of Medicine at the University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA d Department of General Surgery, Perelman School of Medicine at the University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA e Department of Otorhinolaryngology, Perelman School of Medicine at the University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA f Department of Plastic Surgery, Perelman School of Medicine at the University of Pennsylvania, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA g Alfred I. duPont Hospital for Children, Wilmington, DE 19803, USA Received 3 March 2011; revised 22 June 2011; accepted 4 July 2011

Key words: Lymphatic malformation; Doxycycline; Sclerotherapy; Neonates; Infants

Abstract Purpose: To evaluate the clinical outcomes of percutaneous sclerotherapy for congenital head and neck lymphatic malformations in our institution. Materials and Methods: Over a 7-year period, 17 children (10 M, 7 F) mean age 5.8 months (5 days to 13 months) underwent 49 sclerotherapy procedures for congenital head and neck malformations. The imaging and clinical records were reviewed for each patient. Ten of 17 had macrocystic disease; 7 of 17 had microcystic disease. Imaging response was categorized by volume reductions of 0% to 25%, 25% to 50%, 50% to 75%, or 75% to 100%. A concentration of 10 mg/mL doxycycline was used routinely via catheter in 3 instillations with a dose range of 50 to 500 mg per session as per our standard protocol in 17 of 17 patients. In more recent patients, systemic doxycycline levels were obtained after instillations. Additional treatments included direct injection doxycycline (10/17), instillation of absolute ethanol (7/17) or sodium tetradecyl sulfate (4/17), or a combination of these methods. Results: Imaging improvement of ≥76% was noted in 11 of 17. Of these, 8 of 11 had macrocystic disease. Four of 17 had 51% to 75% resolution, of which 3/4 were mixed. Two of 17 children had 25% to 50% resolution with a mixed lesion. Seven of 49 peri-procedural complications: hemolytic anemia in 2 infants, hypoglycemic and metabolic acidosis in 3 neonates aged 7 to 10 days, transient hypotension during absolute alcohol instillation in 1 neonate, and self-limiting skin excoriation secondary to peri-catheter leakage of doxycycline in one neonate. Neonates prone to these systemic complications had doxycycline doses of greater than 250 mg and resulted in serum levels of N5 μg/mL but as high as 21 μg/mL.

⁎ Corresponding author. Tel.: +1 267 425 7122; fax: +1 267 425 7141. E-mail address: [email protected] (D. Ballah). 0022-3468/$ – see front matter © 2011 Elsevier Inc. All rights reserved. doi:10.1016/j.jpedsurg.2011.07.004

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A.M. Cahill et al. Delayed neural complications occurred in 7 of 49 procedures, Horner's syndromes in 4 of 49 procedures, transient left lip weakness in 1 of 49 procedures, right facial nerve palsy in 1 of 49 procedures, and transient left hemidiaphragm paralysis in 1/49 procedures. Conclusion: Our experience with catheter directed doxycycline sclerotherapy provides excellent results for large macrocystic head and neck lymphatic malformations. Microcystic and mixed lesions continue to provide a therapeutic challenge. © 2011 Elsevier Inc. All rights reserved.

1. Background Lymphatic malformations (LMs) are vascular anomalies that are thought to arise during fetal development from a primitive sac derived sequestration of lymphatic tissue [1]. These low-flow vascular malformations are characterized by permeative growth throughout all tissue layers [2] and account for 5% of all benign tumors in infants and children [3]. The most common region for lymphatic malformations is the head and neck [4,5]. Congenital lymphatic malformations are usually diagnosed within the first few years of life with 66% diagnosed at birth and 90% by 2 years of age [1]. These lesions can be categorized into three morphological types: microcystic, macrocystic, or mixed. The published literature varies somewhat in terms of size definition with macrocystic lesion being defined as greater than 1 to 2 cm [4,6,7] and microcystic lymphatic malformations being defined as cysts less than 1 to 2 cm in size [4,6,7]. Mixed lymphatic malformations have microcystic and macrocystic components to varying degrees [8]. Although benign lesions, lymphatic malformations can acutely increase in size owing to lesion infection or as a response to infection and hemorrhage [2,5,9,10] and compress adjacent structures, especially in the head and neck [1,11]. In the craniofacial region, these lesions may cause significant craniofacial bone deformities and disfigurement. Early treatment can avoid significant morbidity and aesthetic impairment [2]. Surgical resection has been historically considered the standard treatment. However, the published literature reports recurrences from 15% to 53% of patients with significant associated morbidity [3]. More recently, sclerotherapy using agents such as bleomycin, doxycycline, absolute ethanol, Ethibloc, OK-432, and sodium tetradecyl sulfate (STS) have been the preferred mode of treatment [1,3,8,12,13].

2. Methods and materials

(age at first treatment: 5 days-13 months), who underwent sclerotherapy for congenital head and neck lymphatic malformations during a 7-year period (2003-2009). Patients presented as follows: 10 patients (58.8%) were diagnosed in utero on prenatal ultrasound (US); 4 patients (23.5%) presented clinically with an infected, enlarging neck mass; 2 patients (11.8%) presented with respiratory symptoms— one with stridor and one with shortness of breath in the setting of an upper respiratory infection, and diagnosis was made on subsequent imaging—and 1 patient (5.9%) was diagnosed at birth with an asymptomatic neck mass. In this study, a macrocystic LM is defined as a lesion with greater than 50% of the cysts larger than 2 cm in diameter, mixed LM is defined as a lesion with less than 50% of the cysts larger than 2 cm in diameter, and microcystic disease is defined as a lesion with cysts all less than 2 cm. On preprocedure imaging, 10 children (58.8%) were diagnosed with macrocystic disease and 7 children (41.2%) were diagnosed with mixed disease. For pretreatment imaging, 14 (82.4%) of 17 patients had magnetic resonance imaging (MRI), 2 (11.8%) had US, and 1 (5.9%) had computed tomography (CT). The imaging and clinical records were reviewed for each patient. Imaging response was categorized by volume reductions of 0% to 25%, 26% to 50%, 51% to 75%, or 76% to 100%. Imaging follow-up was calculated as the time interval between the first pre-treatment imaging and last post-treatment imaging recorded. Clinical response was defined as 76% to 100% excellent, 51% to 75% moderate, 26% to 50% fair, and 0% to 25% poor, and assessment was based on the comparison between the pre-treatment and last post-treatment physical appearance. Our multidisciplinary protocol includes ultrasound follow-up imaging for patients with a good clinical response to sclerotherapy, obviating the need for repeat general anesthesia for MRI in infants and neonates. Since 2007, doxycycline levels were performed post instillation to evaluate the systemic absorption secondary to cyst wall inflammation.

2.1. Sclerotherapy technique After obtaining institutional review board approval, a retrospective study was performed. From January 2003 to October 2009, sclerotherapy of neonatal and infant head and neck lymphatic malformations was performed in 22 children at a single institution by an interventional radiologist with 10 years of experience. Seventeen out of 22 had follow-up imaging and were included in this study: 17 children, 10 males (58.8%) 7 females (41.2%), mean age 5.8 months

Infants and neonates with large head and neck lymphatic malformations abutting, compressing, or deviating the airway are all treated with catheter instillation and 3-day therapy as per Molitch et al [11]. During the course of the three sclerotherapy sessions, patients with lesions adjacent or compressing the airway remained intubated and monitored in an intensive care unit (ICU) setting. Those patients with

Percutaneous sclerotherapy in head and neck lymphatic malformations

Fig. 1

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Current institutional protocol for lymphatic malformation therapy.

lesions distant from the airway are treated without intubation for 3 consecutive days either as an outpatient or inpatient. Infants and neonates have glucose monitoring every 2 hours for the first 24 hours of the multi-day treatment and then every 4 hours until sclerotherapy is completed owing to the associated risk of hypoglycemia with elevated systemic doxycycline levels. Blood gases are obtained routinely every 6 hours for the first 24 hours and after as needed, to monitor for metabolic acidosis. A post-treatment MRI is performed on day 3 once 3-day catheter treatment is complete to evaluate peri-airway inflammation and deviation/compression before extubation. Patients routinely receive peri-extubation intravenous steroids. Patients also undergo a baseline hearing evaluation and car seat test before discharge. Infants younger than 6 months are discharged home on an apnea monitor. Older patients with cervicofacial LMs are treated as an outpatient unless airway compromise is suspected or likely post therapy. In our institution, macrocystic lymphatic malformation sclerotherapy is currently performed with catheter-directed therapy consistent of a 3-day instillation of doxycycline with a treatment interval of 24 hours at a concentration of 10 mg/

mL as per the protocol described by Molitch et al [11]. The volume instilled is generally equal in volume to the cyst volume. Vacuum drainage is then performed at 6 hours post instillation. The subsequent doxycycline instillation is performed at the bedside with US guidance. Microcystic lymphatic malformations are treated by direct injection with either doxycycline foam at a concentration of 10 mg/mL or sodium tetradecyl sulfate foam. Owing to the high incidence of spontaneous infection together with an increased risk upon accessing the lesion, prophylactic antibiotics have been recommended for sclerotherapy of lymphatic malformations [3,6,14]. We place children on prophylactic oral antibiotics once the catheters are removed until the catheter access sites have healed to reduce the risk of site infection (Fig. 1, algorithm for LM sclerotherapy).

3. Results Seventeen children underwent 49 technically successful sclerotherapy procedures. The average number of procedures per patient was 2.9 (range, 1–9 procedures).

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A.M. Cahill et al.

Percutaneous sclerotherapy in head and neck lymphatic malformations

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Fig. 2 Newborn male with large right neck mass (A), mixed on MRI (B), including airway involvement (C) and base of the tongue treated with a combination of direct doxycycline injection (D) and catheter instillation (E) in the macrocystic component of the neck and tongue lesion and STS foam in the microcystic component, demonstrating N75% reduction in the lesion size on 9-month follow-up MRI (F) and on clinical examination after tracheostomy removal (G).

Twenty-eight (57.1%) of 49 procedures were multipleday therapies, with intubation and patient admission to the ICU in 27 (96.4%) of 28 procedures and 1 (3.6%) of 28 performed in the hospital without intubation. Twenty (40.8%) of 49 procedures were multiple day therapies with general anesthesia. Fifteen (30.9%) of 49 procedures were single-day therapies under general anesthesia. Eight (16.3%) of 49 were multiple-day therapies under intravenous sedation. Six (12.2%) of 49 procedures were single-day therapy under intravenous sedation. During the course of therapy, 3 patients with diffuse mixed disease required tracheostomy access; 2 (66.7%) of 3 had lesions visualized in the airway (Fig. 2C), and 1 (33.3%) of 3 had acute airway compression. Fifteen (88.2%) of 17 procedures of the initial procedures were performed with catheter directed doxycycline injection. In addition, 3 (20%) of 15 of those procedures also included direct injection of doxycycline, 2 (13.3%) of 15 procedures were direct injection of absolute ethanol, and 1 (6.7%) of 15 procedures, catheter injection of a combination of sodium tetradecyl foam and absolute ethanol; 2 (11.8%) of 17procedures were performed with direct injection of doxycycline (1/17, 5.9%) or absolute ethanol (1/17, 5.9%) solely. There were 32 repeat procedures of which 17 (53.1%) of 32 procedures were solely with direct doxycycline injection; 8 (25%) of 32 procedures were solely catheter directed therapy, and 7 (21.9%) of 32 procedures were a combination of catheter-directed and direct injection. The average dose of doxycycline used per instillation was 210.6 mg (range 20-500 mg). The mean alcohol dose was

9.3 mL per instillation, and mean pure STS dose was 3.9 mL. Twenty-eight of 49 (57.1%) procedures required intubation in an ICU setting; 27 of 28, for multiday doxycycline therapy; and 1 of 28, for a 1-day therapy. Seven (25%) of those 28 procedures were in patients with prior intubation owing to airway deviation/compression. The mean intubation duration for these procedures was 8.0 days (2-28 days). In 26 (92.9 %) out of 28 intubated procedures, steroids were administered before extubation (Table 1). C-Arm CT imaging was performed in 14 (28.6%) of 49 procedures (Fig. 3). The median interval from pre-treatment imaging to posttreatment imaging was 17.9 months (1.1 months to 3.9 years). The median interval from last sclerotherapy to follow-up imaging was 3.0 months (3 days to 3.9 years). Eleven (64.7%) of 17 children had follow-up US imaging, 4 (23.5%) of 17children had follow-up MRI, and 2 (11.8%) of 17 children had follow-up CT imaging. Two infants in our patient group had incomplete follow-up (ie, not deemed completely treated at last procedure); one infant failed to return for subsequent therapies, and one infant had incomplete follow-up secondary to peri-procedural mortality that was deemed unrelated to sclerotherapy on postmortem examination (Table 2). There was a ≥76% imaging improvement noted in 11 (64.7%) of 17 children (Figs. 2-4), with 7 (41.2 %) of 17 children having N90% resolution. Eight (72.7%) out of 11 children with radiologic resolution ≥76%, and 6 (85.7%) of 7 children with N90% resolution had macrocystic disease. Resolution of 51% to 75% was seen in 4 (23.5%) of 17 children of which 3 (75.0%) of 4 were mixed, and 2 (11.8%) of 17

2088 Table 1

A.M. Cahill et al. Treatment regimen of predominantly macrocystic lymphatic malformations

Patient

Sex

Age

Predominant lesion type

Treatments

1

F

10 mo

Macrocystic

DE CDD DID DID DID DID DID DID DID CDD, DID CDD, CDD DID DID DID CDD, CDD DID DID CDD CDD, DID CDD, CDD CDD, CDD, CDD CDD DID

2

F

3 mo

Macrocystic

3

M

9d

Macrocystic

4 5

M F

10 mo 8d

Macrocystic Macrocystic

6

M

9 mo

Macrocystic

7

M

4 mo

Macrocystic

8

M

8d

Macrocystic

9 10

M F

5 mo 13 mo

Macrocystic Macrocystic

Interval from previous treatment (d)

Resolution

53 107 63 91 497 155 125 337

N90%

29

N90%

DID DID 24 92 99 252 DE 100 174 CES

31

DID

707 54

CES, DS CES

N90% N76% N76% 26%-50%

N76%

75

N76% N76%

60

N90%

Table demonstrates predominantly macrocystic-type lesions and sclerotherapy regimen. The macrocystic components were treated with catheter-directed therapy and the microcystic with direct injection. Microcystic components and macrocystic components responding to therapy and decreasing in size were treated with direct injection of sclerotherapy agents. Age corresponds to patient age at first sclerotherapy treatment. Time interval is from first day of previous treatment. CDD indicates catheter-directed doxycycline; DID, direct injection doxycycline; CES, catheter directed ethanol/STS foam combination; DS, direct injection STS foam; DE, direct ethanol injection.

children had 25% to 50% resolution with a mixed lesion. The clinical and radiologic response was consistent in all patients with 11 (64.7%) of 17 having excellent response, 4 (23.5%) of 17 having moderate response, and 2 (11.8%) of 17 with fair clinical response (Figs. 4-5). Doxycycline levels were obtained at post-instillation in more recent patients who received doxycycline as the sclerotherapy agent (Table 3). Serum levels ranged from 1.3 to N40 μg/mL at time interval of 1 hour to 38 hours post instillation. The normal intravenous doxycycline level is a range of 1.5 to 2.1 μg/mL. There were 7 (14.3%) of 49 peri-procedural complications: hemolytic anemia in 2 infants (4.1%), requiring blood transfusion, hypoglycemic and metabolic acidosis in 3 neonates aged 7-10 days (6.1 %), transient hypotension during absolute alcohol instillation in 1 neonate (2 %), and selflimiting skin excoriation secondary to peri-catheter leakage of doxycycline in one neonate (2%). Only one of the patients

with hemolytic anemia had concurrent ethanol therapy. None of the patients with simultaneous hypoglycemia and metabolic acidosis had concurrent ethanol sclerotherapy. Delayed neural complications occurred in 7 (14.3 %) of 49 procedures and included Horner's syndrome in 4 (8.2 %) of 49 procedures, right facial nerve palsy in 1 (2 %) of 49 procedures, transient left lip weakness in 1 (2 %) of 49 procedures, and transient left hemidiaphragm paralysis in 1 (2 %) of 49 procedures. One child with Horner's Syndrome required ptosis surgery for persistent eyelid weakness.

4. Discussion Different sclerosing agents have been used effectively including doxycycline, ethibloc, absolute alcohol, sodium tetradecyl sulfate, OK 432 and bleomycin [1,3,4,6,15-17].

Percutaneous sclerotherapy in head and neck lymphatic malformations

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Fig. 3 Patients with MRI images (A and C) before treatment and correlating intraprocedural with C-Arm CT (B and D) to evaluate the exact distribution of sclerosing agent and relationship with the airway.

Percutaneous sclerotherapy has proven to be an effective treatment using these agents with excellent response rates ranging between 20% and 64% of patients [6,11,15-22]. There is no standard protocol for doxycycline sclerotherapy of lymphatic malformations. There are many retrospective reports of various sclerotherapy agents and catheter and noncatheter techniques. Burrows et al reports treating microcysts (b30 mL of fluid) with US-guided direct injection of 10 mg/ mL of doxycycline drained after 4 hours [23]. In this series, the macrocysts were treated with additional doxycycline every day or every other day until the drainage ceased. Two studies by Shiels et al described the use of 20 mg/mL of doxycycline

by direct injection in microcysts and the use of dual chemoablation of 3% STS and 98% ethanol with catheters in macrocystic disease [3,6]. Cordes et al described a small series of pediatric macrocystic head and neck LMs treated with direct injection of doxycycline (10 mg/mL) [13]. The most closely aligned reported series to our is a study by Nehra et al reporting the treatment of a small series of infants and neonates with head and neck lymphatic malformations by direct injection of doxycycline (10 mg/ mL, max 200 mg). In this series, unlike our experience, only macrocysts were treated with sclerotherapy, the microcystic disease being treated with surgical resection. In addition

2090 Table 2

A.M. Cahill et al. Treatment regimen of mixed lymphatic malformations

Patient

Sex

Age

Lesion type

Treatment

1

M

5d

Mixed

CDD CDD CDD CDD, DID, CE, DIS CES, DID DID DID DID CDD CDD, DID CDD CDD, DID CDD CES CDD, DID CDD, DID CDD, DD CDD, DE CDD

2

M

1 mo

Mixed

3

F

13 mo

Mixed

4

M

7 mo

Mixed

5

F

6d

Mixed

6 7

F M

8 mo 10 mo

Mixed Mixed

Interval from previous treatment (d)

Resolution

8 6 23 40 57 212 91

N76%

896

26-50%

124

N76%

91

N76%

44 118

51%-75% N76% 51%-75%

Table demonstrates mixed-type lesions and sclerotherapy regimen. The macrocystic components were treated with catheter-directed therapy and the microcystic with direct injection. Microcystic components and macrocystic components responding to therapy and decreasing in size were treated with direct injection of sclerotherapy agents. Age corresponds to patient age at first sclerotherapy treatment. Time interval is from first day of previous treatment.

these procedures were not performed with image guidance unless the cysts could not be palpated, in which case intraoperative ultrasound was used to access the cysts [12]. Unlike our patient population, Nehra et al describes only three patients with large lesions adjacent to the airway requiring post procedure intubation. Our 3-day instillation protocol is based on the protocol from Molitch et al [11]. This method is used in patients with lesions with macrocystic components large enough to accommodate a catheter, regardless of symptomatology. Although 3-day ICU admission is costly, these patients have extensive, complex lesions with airway issues and require intubation for airway protection post-procedure regardless of single or multiday therapy, as swelling inevitably occurs. In addition, other studies also report that patients remain hospitalized for the duration of their sclerotherapy treatment [3,6,12,23]. Aggressive multi-day therapy for large head and neck LMs, with the intention of treating the majority of the macrocysts, may potentially reduce the number of subsequent therapies. Of note, 28/49 (57.1%) procedures in our experience required ICU admission—27 multiday therapies and 1 single day therapy; the remainder of our procedures were on an outpatient basis. In general macrocystic lesions are more responsive to any sclerotherapy agent than microcystic or mixed lesions with reported response rates between 88-100% reported using agents such as ethanol, doxycycline, OK432, and sodium tetradecyl sulfate [4,15,17,24]. When using doxycycline, the literature reports a response rate of 90% to 100% in macrocysts [12,17,23], 43% to 80% in mixed [12,17,23], and 43% to 100% in microcysts [3,6,17,23]. Our response

rates for macrocystic disease are consistent with other series in the literature. In our experience, the response rates of 75% and higher were in lesions that were predominantly macrocystic, and those less than 75% were mixed lesions. Considering the extensive nature of all of our lesions, we report a greater than 90% radiographic and clinical resolution in 41.2% of our patients, one of whom had mixed disease. Our results of greater than 50% resolution in 85.7% (6/7) mixed disease patients is consistent with other series [6]. Overall, complication rates are reported in a number of series to range from 22% to 46% and include fever, skin ulceration, pain, airway obstruction, and nerve damage [6,11,15-22]. Our neural complication rate of 14.3% is likely a factor of lesion location and secondary lesion swelling resulting in nerve compression, with three extensive neck lesions in the supraclavicular region, one extensive facial lesion and one lesion extending from the supraclavicular region to the mediastinum. Two of 7 patients with neural complications had ethanol as part of their treatment, both of whom had complete resolution of the complications. Only one of our neural complications required surgery owing to non-self-limiting resolution. Furthermore, electromyographic studies of rat femoral nerves showed normal conduction velocity in nerves with topical doxycycline exposure in contrast to complete loss of excitability in 80% and delayed conduction velocity in 20% of nerves with direct intraneural doxycycline injection [23,25]. Burrows et al reported in their large series of LMs only one case of Horner's syndrome; however, the patient population was older and lesion size and actual location with respect to neural elements was not detailed [23]. Thus, ethanol was not the cause of nerve

Percutaneous sclerotherapy in head and neck lymphatic malformations

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Fig. 4 Newborn male (A) with large macrocystic lymphatic malformation on MRI (B). Treated twice with catheter instillation of a combination of sodium tetradecyl sulfate, absolute ethanol, and doxycycline demonstrating N75% reduction in lesion size on 2-month followup MRI (C) and at 18-months of age clinical examination (D).

damage in our experience. Even though neural complications were attributable to compress and not ethanol use, we recommend the use of doxycycline and not ethanol in lesions adjacent to the facial nerve, sympathetic plexus, and phrenic nerve. Inflammation will invariable occur creating transient neurologic complications, but permanent neurologic injury is less likely with doxycycline. Doxycycline levels were obtained during the last three years of our 7-year experience. This data collection was prompted by a lack of knowledge on the systemic absorption of doxycycline during sclerotherapy in patients in whom

catheters are placed and those in which direct instillation without removal occur. Since our data collection was initiated, Burrows et al in 2008 reported random doxycycline levels in their series of older children with levels as high as 44 μg/mL (normal 1.5-2.1 μg/mL) within 2 hours of instillation further validating our data collection in neonates and infants [23]. We have demonstrated levels up to 20 times the upper limit of normal (1.5-2.1 μg/mL) even after 1 hour of instillation. The systemic levels of doxycycline recorded are significantly higher than the normal expected level for intravenous administration even at time intervals of 1 hour

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Fig. 5 Newborn male with large left neck mass (A), macrocystic on MRI (B) treated with a combination of catheter instillation and direct injection of doxycycline. The child displays N75% resolution of the lesion with no residual cysts and fatty tissue replacement on ultrasound at 22-month follow-up (C) and on clinical examination (D).

post instillation. It is not clear whether any other reported studies have analyzed glucose or acid base levels in their population during sclerotherapy even though it hypoglycemia is a known side effect of doxycycline [26,27] and acidosis and hemolytic anemia are known side effects of tetracycline [28-30]. Our peri- procedural complication rate of 14.3% is likely a factor of patient age and lesion size. All complications were experienced after patients received sclerotherapy with doxycycline. Given that these are rather large LMs which are of significant size when compared to neonates and infants, it is not surprising that these patients experienced systemic complications, such as hypoglycemia, metabolic acidosis, and hemolytic anemia. Doxycycline doses of greater then 250 mg resulted in serum levels of N5 μg/mL but as high as 21 μg/mL. Of note, all the systemic complications were easily recognizable and treatable. All neonates recovered without

sequelae. As a result, our current practice for treated neonatal lesions is to limit the dose of doxycycline at each instillation to a maximum of 150 mg at a concentration of 10 mg/mL. We are not recommending that all subjects undergo doxycycline serum level testing. We are raising awareness through our retrospective data of the potential risks and systemic complications associated with doses of doxycycline greater than 150 mg in infants and neonates. We have not seen these complications in older children in our clinical practice. Shiels et al reports excellent response rates for both macrocystic and microcystic head and neck lymphatic malformations by pre-treatment of macrocysts with STS foam before ethanol therapy and treatment of microcysts with doxycycline foam. Since STS is a detergent and it releases transmembrane lipoproteins from cell membranes, its use may result in greater penetration of the sclerotherapy agent into lymphatic malformation cells for increasing effectiveness [3].

Percutaneous sclerotherapy in head and neck lymphatic malformations Table 3

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Post-instillation doxycycline serum levels and systemic complications

Patient Weight (kg) Procedure Instillation Doxy dose (mg) Serum level (μg/mL) Hours post instillation Systemic complications 1

2

3 4

3.6

1

1

300

5.7

24

3.4

2

6.1 3

3 1

1 2 2 1 1 2

255 150 150 90 200 200

13.1 15.4 15.8 1.9 6.3 7.5

4 3 24 24 6 9

3 1 1

150 150 270

7.5 11.5 15

18 6 5

1 1 1 1 2 1 1 1 1 2 2 2 3 3 3 1 2 3 1 2 2 1 1 2 3 3 1 2 1 2 3 1 2 2 1 2 1 1 1 1 2

200 200 200 200 250 460 460 460 460 500 500 500 500 500 500 240 180 300 200 200 200 420 420 300 240 240 200 100 500 500 500 300 300 300 200 200 150 200 140 100 70

10.6 13.2 7.5 6.7 10.6 21.2 15 10.6 29.2 21.2 29.9 29.9 29.9 N40 21.2 N40 29.9 21.2 7.5 2.7 1.3 15 7.5 10.6 10.6 5.3 7.5 7.5 15 5.3 2.7 15 7.2 1.9 20.7 21.2 N40 6.8 3.6 4 N30

3 3.6

2 3

6 3.5 8.1

4 1 1

8

2

5

12.8

1

6

8.5

1

8.4

2

14.1

1

15.2

2

8

10.4

1

9

3.4

1

6 6.1 4 5.4

2 1 2 1

7

10 11

Normal therapeutic levels 1.5-2.1 μg/mL.

7.5 12 8 32 1 1 11 18 24 2.5 8 15 12 19 38 1 7 6 6 7 26 6 12 7 7 24 5.5 5.5 8 6 6.5 4.5 1.5 28.5 6.5 6.5 15 8.5 4 4 12

Hypoglycemia, metabolic acidosis Hemolytic anemia

Hypoglycemia, metabolic acidosis

Metabolic acidosis hypotension

Hemolytic anemia

2094 Ethanol alone by direct injection was last used in our practice in 2005. Since 2005, it has only been used in combination with STS foam for macrocysts as per Fig. 1 [3,6]. In our series in larger neonatal lesions (ie, N15 ml) in which the maximum dose of doxycycline was reached additional macrocystic lesions were treated with STS/ethanol combination to increase the overall deliverable dose of sclerotherapy agent in a single session. This is still our current practice today. Given that we used such high doses of doxycycline and experienced systemic complications, the potential risk of teeth staining is worth mentioning. Reversible teeth staining has been reported in adult teeth after a 30- to 45-day course of doxycycline 200 mg/d [31]. Volvovitz et al performed a prospective cohort study of 61 patients, 30 of whom were treated with doxycycline as children and 31 of whom were not and noted that the doxycycline therapy in children aged 2 to 8 years was not associated with tooth staining [32]. We recognize our study has limitations. There is no standard way to measure doxycycline serum levels for sclerotherapy, so our group, with input from the pharmacists concluded the best compromise may be to obtain serum levels 6 hours post each treatment and 24 hours after the last treatment. Practically, in infants and neonates, this has posed a problem in some cases with vascular access, consequently, many of these blood draws were taken during clinical rounds by experienced phlebotomists and not at the specified time. Nevertheless, our data is significant and highlights the fact that when doxycycline is instilled even for 1 hour, the systemic absorption is significant. In conclusion, our experience with catheter-directed doxycycline sclerotherapy provides excellent results for large macrocystic head and neck lymphatic malformations. Microcystic and mixed lesions continue to provide a therapeutic challenge. We have recognized in our series that neonatal doxycycline dosing is more critical and we recommend a total dose of 150 mg of doxycycline per instillation to reduce systemic side effects such as hypoglycemia, metabolic acidosis, and hemolytic anemia. The addition of an STS foam/ethanol combination in larger neonatal lesions, that is, N15 mL volume may be desirable to increase the deliverable dose of sclerotherapy agent per session. Our study is unique in that it focuses only on the treatment of large, complex head and neck LM in neonates and infants. Given that most LMs present before the age of 2 years, we feel that this study reveals valuable teaching points when treating this population. Doxycycline is generally a safe sclerotherapy agent. However, special considerations need to be made when treating neonates and infants.

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