Intratympanic steroid injection adjunct to myringotomy with ventilation tube insertion for otitis media with effusion in children with cleft palate – a matched pair randomized controlled trial

Abstract

Background:

To evaluate the efficacy of adjunctive intratympanic dexamethasone therapy in improving outcomes of myringotomy with ventilation tube insertion for bilateral otitis media with effusion in children with cleft palate.

Methods:

Children with cleft palate aged 2–12 years were recruited. Dexamethasone or placebo was administered intratympanically based on randomized allocation, with contralateral ear receiving the alternate treatment.

Results:

Twenty-three children with cleft palate (mean age: 33.04 ± 27.80 months) were enrolled. Baseline demographics were comparable between groups (p > 0.05). Both dexamethasone and placebo groups demonstrated significant hearing level improvements at 1-month follow-up (p < 0.001). Patients with otitis media with effusion duration ⩽ 3 months exhibited superior outcomes in the dexamethasone group (mean difference: −3.18 dB HL, 95% CI: −4.88 to −1.49, p = 0.002). Patients with cleft palate without other anomalies demonstrated a significant improvement in the dexamethasone group (mean difference: −3.24 dB HL, 95% CI: −5.04 to −1.43, p = 0.002). No significant differences in adverse events were observed between groups (p > 0.05).

Conclusions:

Early intratympanic dexamethasone injection adjunct to myringotomy with ventilation tube insertion is recommended for otitis media with effusion in children with cleft palate.

Keywords

Otitis media otitis media with effusion middle ear ventilation tympanostomy tube insertion steroids

Introduction

Otitis media with effusion (OME) was the most common ear disease found in children with cleft lip/palate. OME is characterized by fluid accumulation in the middle ear without signs or symptoms of an acute ear infection.¹

OME is highly prevalent in children with cleft lip/palate, with incidence rates ranging from 50% to 80% within the first 6 years of life. Up to 90% of these children experience hearing loss, often leading to developmental delays.^2
–6

According to the American Academy of Otolaryngology—Head and Neck Surgery, myringotomy with ventilation tube insertion is recommended for children with OME persisting for more than 3 months, or for at-risk children such as those with cleft lip/palate or other craniofacial anomalies.¹

Steroids are biologically active organic compounds with anti-inflammatory properties. They can reduce middle ear fluid, inhibit mucin production, and enhance Eustachian tube function.⁷ Systemic or topical intranasal steroids have been explored as alternatives to surgery for OME. However, meta-analyses have shown no significant benefit in resolving effusion or improving hearing loss.⁸

Intratympanic steroid administration has been proposed as a superior delivery method, offering high local concentrations in the middle ear with minimal systemic absorption.⁹ A study comparing intratympanic steroids to placebo in children over 12 and adults with OME found improvements in subjective symptoms and quality of life for the steroid group (p < 0.05).¹⁰

Another study investigating the use of intratympanic steroids as an adjunct to myringotomy and ventilation tube insertion in children reported lower rates of symptom recurrence and postoperative complications (p < 0.05).¹¹

To our knowledge, no randomized controlled trial has evaluated the efficacy of intratympanic steroids as an adjuvant therapy to myringotomy and ventilation tube insertion in children with cleft lip/palate.

This study aimed to investigate the efficacy of intratympanic steroids compared to placebo in improving hearing levels and assessing adverse events among cleft lip/palate children undergoing myringotomy with ventilation tube insertion.

Materials and methods

Study design and setting

A matched-pair randomized controlled trial was conducted from November 2019 to December 2020 at the Faculty of Medicine, Department of Otorhinolaryngology, Khon Kaen University, Thailand.

Participants

Patients aged 2–12 years with cleft lip/palate who underwent myringotomy with ventilation tube insertion for OME were invited to participate. OME was defined as: (1) otoscopic findings of a retracted tympanic membrane, air-bubble/air-fluid level in the middle ear, or reduced tympanic membrane mobility under pneumatic otoscopy and (2) type B tympanometry. Participants must have documented evidence of hearing loss that necessitated myringotomy with ventilation tube insertion prior to enrollment in this study.

We excluded the patients with mucociliary diseases such as cystic fibrosis, nasal and nasopharyngeal tumors, and allergy to steroids.

Randomization

A statistician generated a randomization list using block randomization with variable block sizes. Allocation assignments were sealed in sequentially numbered, opaque envelopes. Eligible patients were assigned to treatment groups by opening the next sequential envelope.

Blinding

This study was double-blinded. Attending physicians, surgeons, patients, and evaluators were masked to treatment allocation. A research assistant prepared identical-appearing syringes containing dexamethasone or normal saline (placebo).

Treatment regimen

Following myringotomy with ventilation tube insertion under general anesthesia, dexamethasone or placebo was administered intratympanically based on randomized allocation, with the contralateral ear receiving the alternate treatment.

Dexamethasone (4 mg/ml) and normal saline were prepared in identical 1 ml syringes attached to 25-gauge spinal needles. To maintain blinding, both solutions exhibited similar appearance and viscosity. Patients were positioned supine with their heads turned 30°–45° away from the surgeon during administration.

The middle ear was filled with the solution until it began to leak from the ventilation tube. Patients maintained a supine position with their head turned for at least 30 min to facilitate absorption of the solution into the middle ear mucosa.

Ofloxacin ear drops were administered twice daily to both ears to prevent infection and tube obstruction. Paracetamol was prescribed for pain management based on patient weight. In accordance with American Academy of Otolaryngology—Head and Neck Surgery guidelines, systemic antibiotics, antihistamines, and intranasal steroids were not used pre- or post-ventilation tube insertion.¹

Outcomes and follow-up

Physical examination findings, hearing levels, and complication data were collected 1 month postoperatively.

Hearing assessment methods varied by age. Auditory brainstem response was used for children aged 2–6 months, visual reinforcement audiometry for 6–24 months, play audiometry for 2–4 years, and pure tone audiometry for children over 4 years.

Statistical analysis

The sample size was calculated based on the expected difference in hearing level between ears was 2 ± 3 dB HL.¹¹ With a significance level of 0.5 and power of 90%, the total number of pairs required with a 5% loss to follow-up adjustment was determined to be 23.

Statistical analyses were performed using the SPSS version 20 (SPSS Inc., IL, US). Data were described as either means (for the continuous variables) or frequencies and percentages (for the categorical variables). Significant differences between groups were determined using the paired t-test for continuous variables. The McNemar test were used to determine whether there was a significant difference between the expected frequencies and the observed frequencies. For all tests, p < 0.05 was considered statistically significant.

Ethical considerations

This study was approved by the Khon Kaen University Ethics Committee in Human Research (HE621420) and registered in the Thai Clinical Trials Registry (TCTR20200526001). Written informed consent to participate in this study was provided by all patients enrolled. All authors abided by the Declaration of Helsinki.

Results

Twenty-three patients (9 males, 14 females) participated. Mean age was 33.04 ± 27.80 months, and mean OME duration was 8.04 months. Baseline hearing levels were comparable between ears (Figure 1 and Table 1).

Figure 1.

Participant flow diagram.

Table 1.

Demographic data.

Baseline variable	n = 23
Sex (male:female)	9:14
Age (mean)	33.04 (months)
Conditions
Cleft palate only	18 (78.3%)
Cleft palate with cerebral palsy	3 (13.0%)
Cleft palate with down syndrome	2 (8.70%)
Duration of middle ear effusion (mean)	8.04 (months)
Baseline hearing level
Dexamethasone (mean, dB HL)	47.35 ± 15.73
Placebo (mean, dB HL)	47.39 ± 14.46

Hearing levels significantly improved in both groups at 1-month follow-up. Dexamethasone-treated ears demonstrated a mean hearing level improvement of 17.90 dB HL (95% CI: 11.01–24.79, p < 0.001) from 46.48 to 28.90 dB HL. The placebo group showed a similar improvement of 18.00 dB HL (95% CI: 11.36–24.63, p < 0.001) from 48.26 to 31.00 dB HL. While a trend toward better outcomes was observed in the dexamethasone group (−2.10 dB HL, 95% CI: −4.39 to 0.19, p = 0.070), this difference did not reach statistical significance (Table 2).

Table 2.

The hearing level between intratympanic dexamethasone and placebo at 1 month.

Hearing level (dB HL)	Dexamethasone (n = 23)	Placebo (n = 23)	Mean difference (95% CI)	p-Value^a
Baseline	47.35 ± 15.73	47.39 ± 14.46	−0.04 (−2.33 to 2.24)	0.969
1 month	28.90 ± 13.32	31.00 ± 10.99	−2.10 (−4.39 to 0.19)	0.070

Paired t-test.

Patients with OME for ⩽ 3 months demonstrated a significant improvement in the dexamethasone-treated ear (mean difference: −3.18 dB HL, 95% CI: −4.88 to −1.49, p = 0.002). However, no significant difference was observed in patients with effusion duration > 3 months (p > 0.05; Table 3).

Table 3.

Efficacy of dexamethasone according to the duration of effusion.

Durations	Dexamethasone	Placebo	Mean difference (95% CI)	p-Value^a
3 months or less	(n = 12)	(n = 12)
Hearing level (dB HL)	29.09 ± 14.29	32.27 ± 13.11	−3.18 (−4.88 to −1.49)	0.002*
More than 3 months	(n = 11)	(n = 11)
Hearing level (dB HL)	28.67 ± 12.88	29.44 ± 8.22	−0.78 (−5.96 to 4.40)	0.738

Paired t-test.

Statistically significance.

Patients with cleft palate without other anomalies demonstrated a significant improvement in the dexamethasone-treated ear (mean difference: −3.24 dB HL, 95% CI: −5.04 to −1.43, p = 0.002). No significant difference was observed in the cleft palate with other anomalies group (Table 4).

Table 4.

Efficacy of dexamethasone according to the type of anomalies.

Type of anomalies	Dexamethasone	Placebo	Mean difference (95% CI)	p-Value^a
Cleft palate only	(n = 18)	(n = 18)
Hearing level (dB HL)	24.29 ± 4.44	27.53 ± 4.33	−3.24 (−5.04 to −1.43)	0.002*
Cleft palate with other anomalies	(n = 5)	(n = 5)
Hearing level (dB HL)	55.00 ± 18.03	50.67 ± 17.79	4.33 (−14.31 to 22.98)	0.423

Paired t-test.

Statistically significance.

At 1-month follow-up, ventilation tube clot occurred in one ear (4.35%) in the dexamethasone group and two ears (8.69%) in the placebo group (relative risk (RR): 0.50, 95% CI: 0.05–5.14, p = 0.999). Tube dislodgement was observed in one ear in each group (RR: 1.00, 95% CI: 0.06–15.04, p = 0.500). No otorrhea or bleeding was reported (Table 5).

Table 5.

Adverse events.

Adverse events	Dexamethasone (n = 23)	Placebo (n = 23)	Relative risk (95% CI)	p-Value^a
Clot in ventilation tube	1 (4.35%)	2 (8.6%)	0.50 (0.05–5.14)	>0.999
Tube dislodges	1 (4.35%)	1 (4.35%)	1 (0.06–15.04)	0.500
Otorrhea	0	0	—	—
Bleeding	0	0	—	—

McNemar test.

Discussion

Cleft lip/palate, a congenital craniofacial anomaly, is associated with a high incidence of OME. Potential etiologies for OME in this population include immature Eustachian tube development, abnormalities of Eustachian tube-associated musculature, and craniofacial bone anomalies.^12
–14 While in typically developing children, OME may arise from: (1) an inflammatory and immune response leading to cytokine production and protein-rich exudate formation, (2) chronic inflammation induced by bacterial or fungal biofilms, or (3) gastroesophageal reflux or allergic reactions.^15
–17

Steroids, with their anti-inflammatory properties, have been employed to alleviate OME symptoms, particularly in cases with chronic inflammatory components. Previous studies have demonstrated the efficacy of intratympanic steroids in children without craniofacial anomalies.¹¹

Managing OME is more complex in cleft lip/palate patients due to anatomical abnormalities compounded by chronic middle ear and Eustachian tube inflammation. Consequently, there was a need to evaluate the efficacy of intratympanic steroids specifically in this patient population.

Both dexamethasone and placebo groups experienced significant hearing level improvements following myringotomy with ventilation tube insertion (p < 0.05). While a trend toward better outcomes was observed in the dexamethasone group at 1-month follow-up, this difference of 2.10 dB HL (95% CI: −0.19 to 4.39, p = 0.070).

Patients with OME duration ⩽ 3 months demonstrated a significant improvement in the dexamethasone-treated ear at 1-month follow-up (mean difference: −3.18 dB HL, 95% CI: −4.88 to −1.49, p = 0.002). These findings suggest that early intervention may be beneficial for cleft lip/palate patients.

Children with cleft palate alone demonstrated better outcomes compared to those with cleft palate and additional anomalies. These findings align with a retrospective cohort study reporting longer recovery times and increased tympanostomy tube complications in patients with craniofacial syndromic features and cleft palate.¹⁸

Ventilation tube obstruction occurred in two patients (8.6%). This rate is comparable to the 7% incidence reported in a meta-analysis of 134 studies,¹⁹ One study found the composition of tube clots to resemble mucoid effusion rather than blood or cerumen.²⁰ Currently, there was no consensus on the best procedure to clear the clot.²¹

The limitations of this study include a relatively short follow-up period, which restricts the ability to gather comprehensive data on hearing improvements and the long-term safety of the intervention. Additionally, incorporating patient-reported outcomes, such as quality of life and symptom burden, would provide a more holistic evaluation of the intervention’s overall impact. Furthermore, as the study was conducted exclusively in children with cleft palate, the findings may not be generalizable to other populations.

While the study found significant improvements in hearing levels, the difference between the dexamethasone and placebo groups did not reach statistical significance in the overall cohort. This may be due to the small sample size. To enhance the conclusiveness of our findings, a larger randomized controlled trial with extended follow-up is recommended. While a 1-month follow-up demonstrated improvements, longer-term assessments, including weekly evaluations, could reveal more significant differences.

Intratympanic dexamethasone may be particularly beneficial for treating OME in cleft lip/palate patients, especially those with effusion durations of 3 months or less.

Conclusions

Early intratympanic dexamethasone injection adjunct to myringotomy with ventilation tube insertion is recommended for OME in children with cleft palate particularly in those with effusion lasting ⩽3 months and without other anomalies.

Footnotes

Acknowledgements

The authors would like to thank the staff and nurses at Srinagarind Hospital for their excellent care of the patients. The Khon Kaen Ear, Hearing, and Balance Research Group for their support.

ORCID iD

Patorn Piromchai

Ethical considerations

Ethical approval for this study was obtained from the Khon Kaen University Ethics Committee in Human Research (Approval Number/ID: HE621420).

Consent to participate

Written informed consent was obtained from all subjects before the study.

Author contributions

Patorn Piromchai: Conceptualization, formal analysis, funding acquisition, methodology, supervision, validation, writing – review & editing. Jutarat Anutragulchai: Investigation, methodology, formal analysis, writing – original draft. Kwanchanok Yimtae: Conceptualization, supervision, writing – review & editing. Somchai Srirompotong: Conceptualization, supervision, writing – review & editing. Panida Thanawirattananit: Conceptualization, investigation, supervision, writing – review & editing.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was granted by The Center of Cleft Lip-Cleft Palate and Craniofacial Deformities, Khon Kaen University under Tawanchai Royal Grant Project (Tawanchai Center; Grant Number: TWG6304).

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Data availability statement

Due to ethical reasons and patients’ confidentiality, the datasets for this study can be requested from the corresponding author with an appropriate reason.

Trial registration

Thai Clinical Trials Registry (TCTR20200526001).

References

Rosenfeld

Shin

Schwartz

, et al. Clinical practice guideline: otitis media with effusion (update). Otolaryngol Head Neck Surg 2016; 154: S1–S41.

Flynn

Moller

Jonsson

, et al. The high prevalence of otitis media with effusion in children with cleft lip and palate as compared to children without clefts. Int J Pediatr Otorhinolaryngol 2009; 73: 1441–1446.

Piromchai

Kasemsiri

Vatanasapt

, et al. Ear, nose, throat and craniofacial diseases community services initiative of Khon Kaen University. J Med Assoc Thai 2016; 99(Suppl 5): S81–S85.

Lokman

Loh

Said

, et al. Incidence and management of middle ear effusion in cleft palate patients. Med J Malaysia 1992; 47: 51–55.

Piromchai

Laohasiriwong

Saesiew

, et al. Ear, nose, throat, and craniofacial disease screening in primary school: Khon Kaen University 2017 initiative. J Med Assoc Thai 2018; 101: 77.

Machado

Santos

Leitao

, et al. Cleft palate and ventilation tubes: a prophylactic dilemma. J Laryngol Otol 2023; 137: 501–505.

Mandel

Casselbrant

ML.

Recent developments in the treatment of otitis media with effusion. Drugs 2006; 66: 1565–1576.

Berkman

Wallace

Steiner

, et al. Otitis media with effusion: comparative effectiveness of treatments. Rockville, MD: Agency for Healthcare Research and Quality (US), 2013.

Lustig

LR.

The history of intratympanic drug therapy in otology. Otolaryngol Clin North Am 2004; 37: 1001–1017.

10.

Yang

Zhao

, et al. Longitudinal results of intratympanic injection of budesonide for otitis media with effusion in children over 12 years and adults. Otol Neurotol 2014; 35: 629–634.

11.

Amer

El-Anwar

Elfeky

AE.

The efficacy of adjuvant intratympanic steroid treatment for otitis media with effusion in children. Int Arch Otorhinolaryngol 2016; 20: 244–247.

12.

Kuo

Lien

Chu

, et al. Otitis media with effusion in children with cleft lip and palate: a narrative review. Int J Pediatr Otorhinolaryngol 2013; 77: 1403–1409.

13.

Sharma

Nanda

Problems of middle ear and hearing in cleft children. Indian J Plast Surg 2009; 42: S144–S148.

14.

Kemaloglu

Kobayashi

Nakajima

Analysis of the craniofacial skeleton in cleft children with otitis media with effusion. Int J Pediatr Otorhinolaryngol 1999; 47: 57–69.

15.

Vanneste

Page

Otitis media with effusion in children: pathophysiology, diagnosis, and treatment. A review. J Otol 2019; 14: 33–39.

16.

Van Hoecke

De Paepe

Lambert

, et al. Haemophilus influenzae biofilm formation in chronic otitis media with effusion. Eur Arch Otorhinolaryngol 2016; 273: 3553–3560.

17.

Hermansson

Ryan

, et al. Panel 4: recent advances in otitis media in molecular biology, biochemistry, genetics, and animal models. Otolaryngol Head Neck Surg 2013; 148: E52–E63.

18.

Ungkanont

Tabthong

Komoltri

, et al. Association of cleft palate and craniofacial syndromic anomalies with the outcome of tympanostomy tube insertion and time to recovery from recurrent otitis media with effusion. Adv Oral Maxillofac Surg 2021; 2: 100036.

19.

Kay

Nelson

Rosenfeld

RM.

Meta-analysis of tympanostomy tube sequelae. Otolaryngol Head Neck Surg 2001; 124: 374–380.

20.

Westine

Giannoni

Antonelli

PJ.

Defining tympanostomy tube plugs. Laryngoscope 2002; 112: 951–954.

21.

Burke

Walvekar

Lin

, et al. Common agents used to unblock blood clots within tympanostomy tubes: an ex vivo study and review of literature. Int J Pediatr Otorhinolaryngol 2009; 73: 1725–1728.