Multistage Sclerotherapy for Extensive Lymphatic Malformations With Airway Involvement in Infant: A Protocol to Prevent Tracheotomy

Accepted Manuscript Multistage Sclerotherapy for Extensive Lymphatic Malformations with Airway Involvement in Infant: A Protocol to Prevent Tracheotomy An-Wei Chen, MD, Tao Wang, MD, Ying-Ying Huang, MD, Shao-Hua Liu, MD, PhD PII:

S0278-2391(17)30304-X

DOI:

10.1016/j.joms.2017.03.006

Reference:

YJOMS 57693

To appear in:

Journal of Oral and Maxillofacial Surgery

Received Date: 7 November 2016 Revised Date:

8 March 2017

Accepted Date: 9 March 2017

Please cite this article as: Chen A-W, Wang T, Huang Y-Y, Liu S-H, Multistage Sclerotherapy for Extensive Lymphatic Malformations with Airway Involvement in Infant: A Protocol to Prevent Tracheotomy, Journal of Oral and Maxillofacial Surgery (2017), doi: 10.1016/j.joms.2017.03.006. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Multistage Sclerotherapy for Extensive Lymphatic

Malformations with Airway Involvement in Infant： ：A Protocol to Prevent Tracheotomy An-Wei Chen, MD1, Tao Wang, MD2, Ying-Ying Huang, MD3, Shao-Hua Liu, MD,

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PhD4. 1, Attending Staff, Department of Oral & Maxillofacial Surgery, Qilu Hospital, and Institute of Stomatology, Shandong University, Jinan, China.

2, Attending Staff, Department of Oral & Maxillofacial Surgery, Qilu Hospital, and

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Institute of Stomatology, Shandong University, Jinan, China.

3, Resident, Department of Oral & Maxillofacial Surgery, Qilu Hospital, and Institute of Stomatology, Shandong University, Jinan, China.

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4, Professor and Department Head, Department of Oral & Maxillofacial Surgery, Qilu Hospital, and Institute of Stomatology, Shandong University, Jinan, China.

Corresponding author: Name: Shao-Hua Liu Address: Shandong University, 107#, Wenhua Xi Road, Jinan 250012, PR China.

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Telephone: +86 0531-8216775 Fax number: +86 0531-82169075

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Email: [email protected]

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Multistage Sclerotherapy for Extensive Lymphatic Malformations with Airway Involvement in Infants：A Protocol to Prevent

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Tracheotomy

Purpose: The management of extensive head and neck lymphatic malformations (LMs) in infants is challenging because of life threatening

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upper airway compression. The aim of this study was to present a

tracheotomy in these patients.

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management protocol and evaluate the clinical outcomes for preventing

Materials and Methods: Fifteen infants with extensive head and neck LMs and airway involvement were enrolled between August 2010 and

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September 2015 in Qilu Hospital Shandong University. According to various key factors associated with airway compression of patients in the perioperative period, different types of anesthesia, treatment times,

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sclerosant concentrations and sclerotherapy protocol were used.

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Multistage sclerotherapy was performed with bleomycin A5. All patients were followed up at 1, 3, 6, and 12 months. More extended follow-up was offered if the patients had a residual lesion requiring supplementary sclerotherapy. Reviews on the site and size of the lesion, times and duration of treatments, therapeutic response, airway complications and conduction of tracheotomy were performed. Results: Lesions of LMs in the head and neck were located on the floor

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of the mouth, tongue and neck. An overall average of five treatments was required; a lesion reduction of more than 50% of the volume was achieved in all patients. Regarding the efficacy, morphological resolution

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was achieved in 3 cases (20%, 3/15), and there was a significant response in 12 cases (80%, 12/15). Eight patients (53.3%, 8/15) with microcystic LMs demonstrated immediate swelling and had more serious upper

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airway symptoms than the preoperative status, and 2 patients (13.3%,

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2/15) had feeding difficulty. No upper airway obstruction occurred and no tracheotomy was performed in the patients in this study. Conclusions: Multistage sclerotherapy with bleomycin A5 is a safe and effective treatment for extensive head and neck LMs in infants with

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airway involvement. A routine perioperative protocol is essential for

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reducing airway complications.

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Introduction Lymphatic malformations (LMs), traditionally called cystic hygromas, are benign lesions that result from localized congenital malformations of

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the lymphatic system. LMs consist of multiple dilated locules or sacs, that are lined with a single layer of endothelium supported by connective tissue stroma; they are interspersed with lymphocyte follicle cells and

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occasionally germinal centers [1]. They can be found at any age;

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approximately 50% are present at birth, and 90% are diagnosed before 2 years of age [2]. More than 70% of LMs are found in the head and neck region, which may be related to the rich lymphatic system of this area[1]. Although LMs are benign lesions, the management of extensive head and

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neck LMs in infants is challenging because of life-threatening complications, such as airway compression[3, 4]. Sclerotherapy is an effective treatment strategy for LMs in head and neck[5]; however, severe

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airway complications were reported in the perioperative period, and a

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tracheotomy was sometimes needed [3, 6, 7]. Tracheotomy provides a stable and secure airway, but it bears major risks, such as accidental decannulation,

mucous

plugging,

false

tract

creation,

stomal

complications (i.e., cellulitis and granuloma formation) and trachea in nominate fistula formation[8]. In addition, social stigmatization and daily care needs for the infants with a tracheotomy puts a heavy burden on the patients and their families [9, 10]. Therefore, the attempt to reduce severe

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airway stress and avoid tracheotomy is very important. To the best of our knowledge, a detailed protocol to prevent tracheotomy has not been intensively discussed in the literature. The aim of this study

for preventing tracheotomy in these patients.

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Materials and Methods

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was to present a management protocol and evaluate the clinical outcomes

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Patients

A retrospective review of consecutive infants with LMs was performed. All patients were treated at our institution between August 2010 and September 2015. The study was approved by the research ethics

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committee of Qilu Hospital Shandong University, and informed consent was obtained from their parents or guardians. The diagnosis was made by clinical exam according to guidelines for the

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diagnosis and therapy of the vein and lymphatic disorders [11], and it was

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confirmed by magnetic resonance image (MRI) examination. The signal intensity in MRI was intermediate on T1-weighted images and hyper intense on T2-weighted images with no enhancement after contrast injection.

Injectable agents The drugs used for lesion injection were bleomycin A5 hydrochloride (Tianjin Taihe Pharmaceutical Co Ltd, Tianjin, China), 5 mg/mL

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dexamethasone sodium phosphate (Zhejiang Xianju Pharmaceutical Co Ltd, Zhejiang, China) , normal saline (Qingdao Huaren Pharmaceutical Co Ltd, Qingdao, China), and 2% lidocaine hydrochloride (100 mg/5 mL,

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Shanghai Zhaohui Pharmaceutical Co Ltd, Shanghai, China). Protocol

All patients were given immediate sclerotherapy once extensive head and

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neck LMs were diagnosed.

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To guard patients against upper respiratory tract obstruction, as a prophylactic, endotracheal intubation and tracheostomy were prepared in the perioperative period.

Sclerotherapy was performed under conscious-sedation and local

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infiltration anesthesia at the puncture site with 2% lidocaine hydrochloride or general anesthesia with a laryngeal mask airway according to the patients’ status of obstruction symptoms. An intravenous

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drip of 0.2 mg/kg dexamethasone was given intraoperatively to control

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post-sclerotherapy edema.

For macrocystic LMs, sclerotherapy was performed with ultrasound guidance. The first step was a percutaneous insertion of 0.7-mm diameter winged needles into the lesion. Following thorough drainage of the fluid in the cysts, 8 mg of bleomycin A5 powder was dissolved in 4 mL of normal saline with 1 mL of dexamethasone (5 mg). The bleomycin A5 solution was injected, and an intraluminal lavage was conducted with the

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same solution. The total amount of bleomycin A5 was less than 1 mg/kg in one session. For microcystic LMs, intralesional injection of bleomycin A5 was

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performed; 8 milligrams of bleomycin A5 powder was dissolved in 5 mL of normal saline with the addition of 1 mL of dexamethasone (5 mg) and 1mL of 2% lidocaine hydrochloride. The degree of edema after treatment

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of microcytic LMs is greater than that of macrocystic, because the

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treatment of microcytic LMs is the local infiltration of the sclerosant. The same volume of higher concentration of sclerosing agent leads to inflammatory edema higher than the lower concentration, so a lower concentration was chosen in the microcytic cases. The injection was

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performed as for infiltration injection with 0.5-mm diameter needles; after the injection, the lesion was compressed for 5 min to prevent bleeding and effusion of the sclerosant.

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Multistage sclerotherapy was performed to control the postsclerotherapy

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edema. For patients with macrocystic LMs, all macrocysts were injected under ultrasound guidance; also, complete drainage and sclerosing agent lavage were conducted in each cyst. For patients with a mixed type of LMs (macrocystic and microcystic), sclerotherapy was performed in macrocysts in the first stage, and microcystic LMs were treated after one month. For patients with microcystic LMs, we first treated the lesions away from the airway; the region near the respiratory tract was treated

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second, when post-sclerotherapy edema had disappeared. All patients were admitted to the intensive care unit after sclerotherapy. Intravenous dripping of dexamethasone was continued 12 hourly for 2-3

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days in decreasing dose according to the extent of post-sclerotherapy edema. If no postoperative complications occurred, patients were discharged home within 1 or 2 days. They were followed in the clinic at 1,

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3, 6, and 12 months. More extended follow-up was offered if the patients

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had a residual lesion requiring supplementary sclerotherapy. Our protocol above was summarized in Figure 1.

The treatment response was assessed based on clinical symptoms and MRI at the end of follow-up. The treatment efficacy was accessed

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according to the scoring system described by Achauer[12]. ‘Resolution’ meant clinical morphological disappearance of LMs. A ‘Significant response’ was recorded when a substantial reduction in the lesion size (>

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50% reduction or better) and/or no upper airway symptoms and no

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swallowing symptoms were observed. ‘No response’ was used to describe lesions with no appreciable reduction in the lesion size or functional benefit.

Results

All 15 patients (6 girls and 9 boys) had extensive head and neck LMs with multistage sclerotherapy in the study, as summarized in table 1. Patients were a mean of 3 months old (range, 9 days-7 months). Lesions

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were widely present on the floor of the mouth, tongue and neck. All patients underwent sclerotherapy for a mean (range) of 5 (2-13) treatments. The median duration of sclerotherapy was 10.7 months (range,

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2 - 36 months). The median duration of follow-up was 16.6 months (range, 6 - 29 months). A clinical size reduction of more than 50% volume was achieved in all patients. Regarding the efficacy,

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morphological resolution was achieved in 3 cases (20%, 3/15) and a

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significant response was observed in 12 cases (80%, 12/15). Significant response in case #6 was shown in Figure 2a- 2d.

Eight patients (53.3%, 8/15) patients with microcystic LMs demonstrated immediate swelling and had more serious upper airway symptoms than

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the preoperative status, and 2(13.3%， 2/15) patients had feeding difficulty. No upper airway obstruction occurred and no tracheostomy was

Discussion

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performed in the patients in this study.

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Infants with extensive head and neck LMs suffer significant upper airway problems [13-15]. Initial growth or enlargement of the lesions occurred in all cases, which is often associated with upper respiratory tract infections, and the breathing problems can become more serious as the lesions increase in size[3]. A delay in treatment would aggravate the breathing problems. Therefore, all patients were given immediate sclerotherapy once the diagnosis was established in this study.

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The choice of the anesthetic method for sclerotherapy is also crucial. It is difficult to use an oral trachea cannula in patients with extensive LM in the head and neck region, especially those with an oral floor and a widely

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involved body of tongue. In addition, upper airway mucosal edema after oral trachea cannulation often aggravates the dyspnea. Therefore, tracheotomy would be the only choice of a trachea cannulation for

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general anesthesia in such an event. In this study, owing to the adoption

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of local anesthesia, no tracheotomy was needed.

In previous reports, before sclerotherapy, tracheotomy (had been) was performed on some patients with LMs, however, the reasons (had been) were not particularly explained [3, 14]. There might be two reasons; one

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was therapeutic tracheotomy, and the other was necessary preparation for general anesthesia. In this study, two patients (#6 and #9) who were transferred from the neonatology department had dyspnea with obvious

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swelling of the tongue, mouth floor and neck. When the diagnosis of LMs

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was established, immediate puncture to drain the lymph liquid under local anesthesia was conducted. Then, the dyspnea was obviously alleviated, and tracheotomy was not performed. Leung and colleagues treated 13 children with low-flow vascular malformations of the head and neck using sclerotherapy, and one of the patient who had congenital extensive LMs underwent tracheotomy before sclerotherapy[14]. Emery et al performed tracheotomy in 10 of 37 patients who suffered head and neck

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LMs[3]. Shiels and colleagues treated 31 patients with head and neck LMs; 3 had serious infection with cellulitis and underwent tracheotomy [7]. The patients of our study did not have serious upper respiratory tract

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obstruction, and none of them required tracheotomy. With the development of the sclerotherapy, many types of sclerosing agents have been used to treat LMs, such as OK-432, bleomycin, ethanol

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and others [7, 16, 17]. Anhydrous ethanol has a stronger treatment effect

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than bleomycin, but it induces a serious inflammatory response and tissue edema, aggravating dyspnea. In one study, it was reported that tracheotomy was needed because of upper respiratory tract obstruction after anhydrous ethanol sclerotherapy[7]. Therefore, the use of

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sclerosants that could lead to a serious inflammatory response and tissue edema was prohibited. Bleomycin is a cytotoxic antitumor antibiotic that can be administered intralesionally by means of transcutaneous injection

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and is proved to be an exciting modulator of vascular anomalies [1]. For

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infants with respiratory symptoms caused by extensive LMs on the head and neck, bleomycin is an ideal choice; it is effective and the inflammatory edema response after injection is mild [17-19]. In the treatment of extensive head and neck LMs, the main goal is to reduce the occurrence of upper respiratory tract obstruction and avoid tracheotomy. In the cases in this study, the lesions had an obvious shrinkage, and the symptoms of the upper respiratory duct were

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obviously alleviated or disappeared. However, there were some limitations in this study. Because of the multistage treatment, more treatment repetitions and longer treatment

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duration were needed. In addition, the strength of our conclusions was limited by the small sample size. Further clinical controlled trials are needed.

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Conclusion

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Multistage sclerotherapy with bleomycin A5 is a safe and effective treatment for extensive head and neck LMs in infant with airway involvement. A routine perioperative protocol is essential for reducing airway complications.

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Patient consent/Ethical approval

All patients signed the informed consent and this work was approved by the ethical committee of Qilu Hospital Shandong University.

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None

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Conflict of interest

Funding statement: This study was supported by the National Natural Science Foundation of China (8167040721, 81641036) and the Key Research

&

Development

(2015GGH318012).

Project

of

Shandong

Province

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References 1.

Zhou Q, Zheng JW, Mai HM, Luo QF, Fan XD, Su LX, Wang YA, Qin ZP: Treatment guidelines

of lymphatic malformations of the head and neck. Oral Oncol 47:1105, 2011 2.

CM. B: Cystic hygroma. Lancet 335:511, 1990

3.

Emery PJ, Bailey CM, Evans JN: Cystic hygroma of the head and neck. A review of 37 cases. J

Laryngol Otol 98:613, 1984 Molino JA, Guillen G, Peiro JL, Garcia-Vaquero JA, Marhuenda C, Carreras E, Lloret J,

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4.

Martinez-Ibanez V: [Cervical cystic lymphangioma: still a challenge]. Cir Pediatr 23:147, 2010 5.

Zheng JW, Yang XJ, Wang YA, He Y, Ye WM, Zhang ZY: Intralesional injection of

Pingyangmycin for vascular malformations in oral and maxillofacial regions: An evaluation of 297 consecutive patients. Oral Oncology 45:872, 2009

Balakrishnan K, Menezes MD, Chen BS, Magit AE, Perkins JA: Primary surgery vs primary

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6.

sclerotherapy for head and neck lymphatic malformations. JAMA Otolaryngol Head Neck Surg 140:41, 2014 7.

Shiels WE, 2nd, Kang DR, Murakami JW, Hogan MJ, Wiet GJ: Percutaneous treatment of

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lymphatic malformations. Otolaryngol Head Neck Surg 141:219, 2009 8.

Konig AM: Pediatric tracheotomy. Hno 60:581, 2012

9.

Marom T, Joseph RA, Grindle CR, Shah UK: Tracheotomy after laryngotracheopasty: Risk

factors over 10 years. Journal of Pediatric Surgery 49:1206, 2014

10. Lewis CW, Carron JD, Perkins JA, Sie KC, Feudtner C: Tracheotomy in pediatric patients: a national perspective. Arch Otolaryngol Head Neck Surg 129:523, 2003

11. Agus GB, Allegra C, Antignani PL, Arpaia G, Bianchini G, Bonadeo P, Botta G, Castaldi A,

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Gasbarro V, Genovese G, Georgiev M, Mancini S, Stillo F: Guidelines for the diagnosis and therapy of the vein and lymphatic disorders. Int Angiol 24:107, 2005 12. Achauer BM, Chang CJ, Vander Kam VM: Management of hemangioma of infancy: review of 245 patients. Plast Reconstr Surg 99:1301, 1997

13. Rowley H, Perez-Atayde AR, Burrows PE, Rahbar R: Management of a giant lymphatic

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malformation of the tongue. Arch Otolaryngol Head Neck Surg 128:190, 2002 14. Leung M, Leung L, Fung D, Poon WL, Liu C, Chung K, Tang P, Tse S, Fan TW, Chao N, Liu K: Management of the low-flow head and neck vascular malformations in children: the sclerotherapy

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protocol. Eur J Pediatr Surg 24:97, 2014 15. de Serres LM, Sie KC, Richardson MA: Lymphatic malformations of the head and neck. A proposal for staging. Arch Otolaryngol Head Neck Surg 121:577, 1995 16. Chen WI, Huang ZQ, Chai Q, Zhang DM, Wang YY, Wang HJ, Wang L, Fan S: Percutaneous sclerotherapy of massive macrocystic lymphatic malformations of the face and neck using fibrin glue with OK-432 and bleomycin. International Journal of Oral and Maxillofacial Surgery 40:572, 2011 17. Bai Y, Jia J, Huang XX, Alsharif MJ, Zhao JH, Zhao YF: Sclerotherapy of Microcystic Lymphatic Malformations in Oral and Facial Regions. Journal of Oral and Maxillofacial Surgery 67:251, 2009 18. Acevedo JL, Shah RK, Brietzke SE: Nonsurgical therapies for lymphangiomas: a systematic review. Otolaryngol Head Neck Surg 138:418, 2008 19. Xu DP, Zhai QK, Cheng C, Gong H, Wang HW, Wang XK: Appraisal of Efficacy and Safety of Intralesional Injection of High Concentration of Bleomycin A5 for Treatment of Huge Macrocystic Lymphatic Malformations in Cervical Region. Journal of Craniofacial Surgery 25:1707, 2014

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Fig1. Sclerotherapy protocol to extensive head and neck Lymphatic Malformations (LMs) in infants with airway involvement

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Fig2a. Case 6 before sclerotherapy. Bilateral mouth floor and neck of the patient swollen significantly, and he is in the state of passive mouth opening. Fig2b. MRI shows the lesions before sclerotherapy of case 6. Macrocystic LMs are located at the bilateral mouth floor (black arrow); mixed LMs are located at the bilateral neck (white arrow).

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Fig2c. Final view of case 6. Left cheek is still slightly swollen.

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Fig2d. MRI shows the lymphatic malformation after sclerotherapy of case 6. Macrocystic LMs at the bilateral mouth floor are disappeared (red arrow); most of Mixed LMs at the bilateral neck are disappeared (white arrow).

Table 1: Details of the 15 patients and their treatments Age

No

Sex(

Lesion

Location

M/F)

Upper

airway

Type of LM

symptoms

No.of

Duration

Bleom

Treat-

of

-ycin

ment Sessio

M

Mouth floor

11d 1m

F

Mouth floor and neck

15d 3

1m

7m

M

M

6

7

5m

28d

5m 1d

breathing, snoring

microcystic

Noisy

Macrocystic

Right mouth floor and

Noisy

neck

snoring

Left mouth floor, and

Snoring

neck

2d 5

Macrocystic and

breathing,

snoring

8d 4

noisy

F

M

F

Tongue and mouth floor.

Noisy

Tongue, mouth floor, neck and face

Noisy

Tongue and mouth floor

snoring

breathing,

snoring

Trachetomy

Duration of follow-up

Outcome

A5

apy(M)

(mg)

11

16

5.45(2-6)

Swelling

No

12

Significant

4

7

6.75(5-8)

No

22

Significant

Swelling

8

12

3.75(2-6)

Swelling

No

27

Significant

Macrocystic

3

4

6.7(4-7)

No

No

10

Resolution

breathing,

Macrocystic

2

2

4.5(3-6)

No

No

12

Significant

breathing,

Macrocystic and

13

36

5.6(3-8)

Swelling

No

26

Significant

6

6

4.3(1-6)

Swelling

No

29

Significant

microcystic

snoring

Noisy

Macrocystic and

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2

Stridor,

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6m

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1

sclerother-

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-ns

Complications

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Patient

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breathing,

microcystic microcystic

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1m

F

19d

Right mouth floor, face and neck.

Snoring

Macrocystic and

5

6

9d

M

Mouth floor and neck

Snoring

Macrocystic

6

19

10

1m

M

Right neck

Snoring

Macrocystic

2

3

M

Right neck

Snoring

Macrocystic

2

F

Right face and neck

Snoring

Macrocystic and

5m

2

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25d

12

F

5m

M

Tongue, mouth floor. Neck

Stridor,

Mouth floor and neck

Noisy

breathing, snoring

snoring

M

Face and neck

Snoring

Macrocystic and

breathing,

Macrocystic and

No

No

20

Resolution

3(2-4)

No

No

13

Significant

4(4-4)

No

No

12

Resolution

15

3.25(14)

Swelling,

No

15

Significant

8

19

3.5(2-6)

Swelling,

No

19

Significant

4

10

4(3-6)

Swelling,

No

10

Significant

2

3

3(2-4)

No

No

6

Significant

microcystic

Macrocystic

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2m 3d

Significant

microcystic

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15

noisy

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14

1m 10d

11

4

microcystic

13

No

3.5(2-5)

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28d 1m

Swelling,

microcystic

9

11

4.2(2-6)

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8

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