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Journal of Otolaryngology - Head & Neck... 2024Adenotonsillectomy is one of the most common surgical procedures worldwide. The current standard for securing the airway in patients undergoing adenotonsillectomy is... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Adenotonsillectomy is one of the most common surgical procedures worldwide. The current standard for securing the airway in patients undergoing adenotonsillectomy is endotracheal tube (ETT) intubation. Several studies have investigated the use of the laryngeal mask airway (LMA) in this procedure. We conducted a systematic review and meta-analysis to compare the safety and efficacy of the LMA versus ETT in adenotonsillectomy.
METHOD
Databases were searched from inception to 2022 for randomized controlled trials and comparative studies. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. The primary outcome is the rate of perioperative respiratory adverse events (PRAEs). Secondary outcomes included the rate of conversion to ETT, desaturations, nausea/vomiting, and surgical time. A subgroup analysis, risk of bias, publication bias, and Grading of Recommendations Assessment, Development, and Evaluation (GRADE) assessments were also performed.
RESULTS
Twelve studies were included in the analysis (4176 patients). The mean overall conversion to ETT was 8.36% [95% confidence interval (CI) = 8.17, 8.54], and for the pediatric group 8.27% (95% CI = 8.08, 8.47). The mean rate of conversion to ETT secondary to complications was 2.89% (95% CI = 2.76, 3.03) while the rest was from poor surgical access. Overall, there was no significant difference in PRAEs [odds ratio (OR) 1.16, 95% CI = 0.60, 2.22], desaturations (OR 0.79, 95% CI = 0.38, 1.64), or minor complications (OR 0.89, 95% CI = 0.50, 1.55). The use of LMA yielded significantly shorter operative time (mean difference -4.38 minutes, 95% CI = -8.28, -0.49) and emergence time (mean difference -4.15 minutes, 95% CI = -5.63, -2.67).
CONCLUSION
For adenotonsillectomy surgery, LMA is a safe alternative to ETT and requires less operative time. Careful patient selection and judgment of the surgeon and anesthesiologist are necessary, especially given the 8% conversion to ETT rate.
Topics: Humans; Tonsillectomy; Adenoidectomy; Laryngeal Masks; Intubation, Intratracheal; Postoperative Complications
PubMed: 38899617
DOI: 10.1177/19160216241263851 -
Clinical Otolaryngology : Official... Jun 2024Tonsillectomy and adenoidectomy are common surgical procedures that cause persistent pain, bleeding, and functional limitations. We aimed to investigate the efficacy of... (Review)
Review
OBJECTIVES
Tonsillectomy and adenoidectomy are common surgical procedures that cause persistent pain, bleeding, and functional limitations. We aimed to investigate the efficacy of celecoxib compared with a placebo for managing post-tonsillectomy or adenoidectomy pain and other adverse events.
DESIGN
Systematic review and meta-analysis.
METHODS
We conducted a systematic literature search in the PubMed, Cochrane, and Google Scholar databases from inception until July 2023. Dichotomous outcomes have been reported as risk ratios (RR) while continuous outcomes were reported using mean differences (MD). A funnel plot was drawn to investigate publication bias.
RESULTS
From 1394 records identified, 6 randomised double-blind trials comprising 591 participants undergoing tonsillectomy and/or adenoidectomy were eligible for inclusion. A high dose (400 mg) of celecoxib was effective in decreasing the pain score for 'worst pain' after the procedure (MD: -10.98, [95% CI: -11.53, -10.42], p < .01, I = 0%) while a low dose (200 mg) was not significantly effective (p = 0.31). For managing other outcomes such as vomiting (RR: 1.37 [95% CI: 0.69, 2.68], p = 0.37, I = 67%), diarrhoea (RR: 1.41, [95% CI: 0.75, 2.64], p = .29, I = 42%), dizziness/drowsiness (RR: 0.90, [95% CI: 0.71, 1.15], p = .48, I = 0%), functional recovery time (p = .74), and headache (p = .91), there was no significant difference between the group on celecoxib and the placebo group regardless of dosage. Finally, there was no significant difference (RR: 1.02, [95% CI: 0.91, 1.15], p = .69, I = 0%) in the effect of the intervention on minimum bleeding, moderate bleeding, and profuse bleeding.
CONCLUSION
This meta-analysis provides robust evidence pooled from high-quality trials and raises questions about the efficacy of celecoxib for tonsillectomy and/or adenoidectomy, challenging existing perceptions.
PubMed: 38877737
DOI: 10.1111/coa.14177 -
Gastroenterology Research Apr 2024Inflammatory bowel disease (IBD) is a group of chronic inflammatory gastrointestinal disorders that are caused by genetic susceptibility and environmental factors and...
BACKGROUND
Inflammatory bowel disease (IBD) is a group of chronic inflammatory gastrointestinal disorders that are caused by genetic susceptibility and environmental factors and affects a significant portion of the global population. The gut-associated lymphoid tissue (GALT) is known to play a crucial role in immune modulation and maintaining gut microbiota balance. Dysbiosis in the latter has a known link to IBD. Therefore, the increasing prevalence of adenoidectomy in children should be explored for its potential association with IBD. The objective of this paper was to assess the association between adenoid tissue removal and the risk of developing Crohn's disease (CD) and ulcerative colitis (UC).
METHODS
We conducted a pooled meta-analysis to evaluate the extended clinical outcomes in patients who underwent appendicectomy and tonsillectomy compared to those who did not. Our approach involved systematically searching the PubMed database for relevant observational studies written in English. We followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines to collect data from various time periods, and to address the diversity in study results; we employed a random-effects analysis that considered heterogeneity. For outcomes, odds ratios (ORs) were pooled using a random-effects model.
RESULTS
Seven studies, out of a total of 114,537, met our inclusion criteria. Our meta-analysis revealed a significant association between appendicectomy and CD (OR: 1.57; 95% confidence interval (CI): 1.01 - 2.43; heterogeneity I = 93%). Similarly, we found a significant association between tonsillectomy and CD (OR: 1.93; 95% CI: 0.96 - 3.89; I = 62%). However, no significant association was observed between appendicectomy and UC (OR: 0.60; 95% CI: 0.24 - 1.47; I = 96%), while a modest association was found between tonsillectomy and UC (OR: 1.24; 95% CI: 1.18 - 1.30; I = 0%).
CONCLUSIONS
In summary, we found that the trend of appendicectomy is linked to higher odds of CD, and tonsillectomy is more likely associated with increased odds for both CD and UC, with a risk of bias present.
PubMed: 38716286
DOI: 10.14740/gr1672 -
Journal of Personalized Medicine Mar 2024(1) Background: Supraglottic airway devices (SAD) have been used in children and adolescents undergoing adenotonsillectomies under general anesthesia. This systematic... (Review)
Review
(1) Background: Supraglottic airway devices (SAD) have been used in children and adolescents undergoing adenotonsillectomies under general anesthesia. This systematic review and meta-analysis investigate the safety and efficacy of using SADs when compared to an endotracheal tube (ETT). (2) Methods: After registering with PROSPERO, databases like PubMed, Scopus, OviD, CINAHL, and Cochrane Library were searched using relevant keywords from the year 2000. We used RoB-2 for risk-of-bias assessment, GRADE for assessing the quality of evidence, RevMan 5.2 for qualitative meta-analysis, and trial sequential analysis (TSA) to corroborate the significant findings of meta-analysis. (3) Results: Out of 200 studies, 5 randomized-controlled trials fulfilled inclusion criteria. The quality of evidence was moderate for laryngospasm, low for airway device failure, and very low for recovery time. The incidence of laryngospasm was comparable between SADs and ETT (RR: 0.80, 95% CI-0.36, 1.80, = 0.59). The incidence of airway device failure was significantly higher with SADs than ETT (RR: 11.29, 95% CI: 2.73, 46.66, = 0.0008). The postoperative recovery time was significantly less with SADs than with ETT use (MD: -4.33, 95% CI: -5.28, -3.39, < 0.0001), which was confirmed by the TSA. (4) Conclusions: The results of this review suggests that use of SADs can provide a lesser postoperative recovery time and comparable incidence of laryngospasm, with a higher incidence of failure of SAD when compared to ETT. Use of SAD for pediatric and adolescent adenotonsillectomies should be individualized based on patient characteristics, and on the expertise of the anesthesiologist and the surgeons involved.
PubMed: 38541053
DOI: 10.3390/jpm14030311 -
Sleep Medicine Apr 2024To study the role of adenotonsillectomy (ADT) for obstructive sleep apnea (OSA) in children with mucopolysaccharidosis (MPS). (Review)
Review
OBJECTIVE
To study the role of adenotonsillectomy (ADT) for obstructive sleep apnea (OSA) in children with mucopolysaccharidosis (MPS).
METHODS
A systematic review were performed following the PRISMA guideline. PubMed and Embase were searched for studies regarding adenotonsillectomy for OSA in children with MPS. The MINOR Score were applied for quality assessment of the included studies.
RESULTS
Nineteen studies were eligible for inclusion: fifteen were retrospective and four prospective. A total of 1406 subjects were included. The samples size varied from 2 to 336, the male to female ratio is 1.2 and mean age varied from 2.4 to 11 years. Overall, 56.2 % (IC 95%: 53.6-58.8) of the included subjects underwent ADT. MPS I and II are the two most operated types. Three studies, including 50 children, reported improvement in polysomnographic parameters after surgery. Two authors described the duration of follow-up: 8.4 and 9.8 years, respectively.
CONCLUSIONS
More than half of children with MPS underwent ADT for the treatment of OSA, although few evidence demonstrated improvement in term of polysomnographic parameters. The two types of MPS most involved are type I and II. Considering the disease progression and anesthetic risks, multidisciplinary management may help identify the subgroup of children with MPS who benefit from ADT for the treatment of OSA.
Topics: Child; Male; Humans; Female; Child, Preschool; Retrospective Studies; Prospective Studies; Polysomnography; Adenoidectomy; Tonsillectomy; Sleep Apnea, Obstructive; Mucopolysaccharidoses
PubMed: 38402648
DOI: 10.1016/j.sleep.2024.02.030 -
Children (Basel, Switzerland) Feb 2024This review investigates the relationship between pediatric obstructive sleep apnea, often associated with adenotonsillar hypertrophy, and cardiovascular health,... (Review)
Review
This review investigates the relationship between pediatric obstructive sleep apnea, often associated with adenotonsillar hypertrophy, and cardiovascular health, particularly pulmonary hypertension. We conducted a comprehensive literature search using electronic databases, including Medline Pub-Med, Scopus, and the Web of Science. The study analyzed a total of 230 articles and screened 48 articles, with 20 included in the final analysis, involving 2429 children. The PRISMA flowchart visually illustrates the selection process, and the ROBINS-E and -I tools help ensure the reliability and validity of the evidence produced by these studies. These studies explored various aspects, including the severity of obstructive sleep apnea, cardiac anomalies, cardiac stress markers, risk factors for pulmonary hypertension, and the impact of adenoidectomy and tonsillectomy on cardiac function. The research found that adenotonsillar hypertrophy and obstructive sleep apnea are significant risk factors for cardiovascular complications, especially pulmonary hypertension, in children. Adenoidectomy and tonsillectomy may provide effective treatments. Following adenoidectomy in relation to obstructive sleep apnea, there appears to be a reduction in mean pulmonary artery pressure during echocardiographic examination. However, the efficacy of these procedures can vary based on the severity of obstructive sleep apnea and individual cardiac conditions. The study also identified concerns regarding data bias. The authors emphasize the need for well-designed clinical studies, including both healthy patients with adenotonsillar hypertrophy and vulnerable children with genetic disorders, to ensure that clinical decisions are based on solid scientific evidence.
PubMed: 38397319
DOI: 10.3390/children11020208 -
The Laryngoscope Jul 2024To assess whether adenotonsillectomy improves levels of inflammatory and cardiometabolic markers in children with polysomnographically diagnosed obstructive sleep apnea... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
To assess whether adenotonsillectomy improves levels of inflammatory and cardiometabolic markers in children with polysomnographically diagnosed obstructive sleep apnea (OSA).
DATA SOURCES
Two authors independently searched PubMed, Embase, and Cochrane databases up to August 16, 2022, for studies relating to pre- and post-operative levels of serum markers in pediatric patients undergoing adenotonsillectomy.
REVIEW METHODS
Data were extracted from included articles into a structured proforma. Meta-analyses of the standardized mean difference (SMD) were conducted in random-effects models. We calculated the probability of benefit (POB) and number needed to treat (NNT) for outcomes that demonstrated a statistically significant effect after adenotonsillectomy. The primary outcomes were changes in serum markers including C-reactive protein (CRP), high-sensitivity CRP (hs-CRP), Insulin-like growth factor 1 (IGF-1), interleukin-10 (IL-10), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), Brain natriuretic peptide (BNP), insulin, glucose, total cholesterol, triglyceride, low-density lipoprotein (LDL), high-density lipoprotein (HDL).
RESULTS
We screened 1616 studies and included 26 studies with 1331 participants. Meta-analysis was performed on 20 of the included studies. Adenotonsillectomy was associated with a significant decrease in insulin levels (SMD = -0.322, 95% Confidence Interval (CI) = -0.583 to -0.061), CRP (SMD = -0.946, 95% CI = -1.578 to -0.314), and BNP (SMD = -1.416, 95% CI = -2.355 to -0.477) and significant increase in levels of IGF-1 (SMD = 0.691, 95% CI = 0.207 to 1.176). There were no significant changes in levels of triglyceride, total cholesterol, TNF-α, LDL, HDL, glucose, IL-10, and IL-6.
CONCLUSION
In children with polysomnographically diagnosed OSA, adenotonsillectomy was associated with improvements in serum biomarkers, comprising lower CRP, insulin, and BNP, and higher IGF-1. Laryngoscope, 134:3030-3037, 2024.
Topics: Humans; Sleep Apnea, Obstructive; Tonsillectomy; Adenoidectomy; Biomarkers; Child; C-Reactive Protein; Interleukin-10; Interleukin-6; Insulin-Like Growth Factor I; Tumor Necrosis Factor-alpha; Natriuretic Peptide, Brain; Child, Preschool
PubMed: 38380991
DOI: 10.1002/lary.31249 -
Cureus Jan 2024Grisel's syndrome is an uncommon cervical spine condition marked by non-traumatic rotational subluxation of the atlantoaxial joint. This systematic review aims to... (Review)
Review
Grisel's syndrome is an uncommon cervical spine condition marked by non-traumatic rotational subluxation of the atlantoaxial joint. This systematic review aims to collect potential evidence from relevant studies that reported symptoms, diagnostic methods, and management options among pediatric cases of Grisel's syndrome post otolaryngology procedures, which can aid and guide the diagnosis and management in clinical practice. We conducted both electronic and manual search strategies within the potential databases and included case reports, case series, and articles; however, review papers and correspondence papers were excluded. The post-otolaryngology procedures included adenoidectomy, tonsillectomy, tympanoplasty, cochlear implantation, double opposing Z plasty and pharyngeal flap, and adenotonsillectomy. In this systematic review, we identified and analyzed 20 studies encompassing a total of 24 pediatric patients with Grisel's syndrome following otolaryngology procedures. The patient demographics revealed a fairly even distribution between females (45.83%) and males (50.00%), with ages ranging from 2.5 to 12 years. The most common otolaryngology procedures associated with Grisel's syndrome were adenoidectomy (29.17%) and adenotonsillectomy (33.33%). Clinical symptoms included neck pain (75.00%), torticollis (50.00%), and limited neck mobility (20.83%), while diagnostic confirmation primarily relied on CT scans (50.00%). Treatment strategies varied, with conservative measures being the most frequent choice, followed by surgical interventions in four cases (16.67%). Complications were reported in 20.83% of cases. Due to the rarity of this condition, our findings are limited to case reports only, which may limit the generalizability of results. Grisel syndrome can be effectively managed through conservative treatment, including antibiotics and anti-inflammatory drugs if diagnosed timely. Early diagnosis and prompt management are essential to avoid neurological and fatal complications. This analysis would contribute to improving clinical knowledge and treatment strategies while providing additional insights into this rare condition.
PubMed: 38187032
DOI: 10.7759/cureus.51739 -
The Laryngoscope Jun 2024Adenotonsillectomy is one of the most common surgical procedures performed on children. Caregivers are often concerned about voice change after the procedure, and such... (Meta-Analysis)
Meta-Analysis Review
OBJECTIVE
Adenotonsillectomy is one of the most common surgical procedures performed on children. Caregivers are often concerned about voice change after the procedure, and such concerns remain unsettled. This meta-analysis analyzed voice change in children after adenotonsillectomy.
DATA SOURCES
The PubMed, Medline, EMBASE, and Cochrane databases.
REVIEW METHODS
The study protocol was registered on PROSPERO. Two authors independently searched for articles using keywords "adenoidectomy," "tonsillectomy, "voice," "nasalance,"and "speech." English articles specifying voice changes after adenotonsillectomy were pooled with standardized mean difference (SMD) using random-effects model. Evaluation methods were computerized acoustic voice analysis, aerodynamic analysis, nasometer, rhinomanometry, evaluations from a speech-language pathologist or otolaryngologist, and a caregiver assessment questionnaire.
RESULTS
Twenty-three studies with 2154 children were analyzed (mean age: 8.0 y; 58% boys; mean sample size: 94 children). Due to insufficient data for other outcome variables, this meta-analysis only summarized changes in the computerized acoustic voice analysis 1 month and 3 months after surgery. The computerized acoustic analysis revealed significant changes in jitter (SMD = -0.36; 95% confidence interval [CI]: -0.60 to -0.11), shimmer (SMD = -0.34; 95% CI: -0.57 to -0.11), and soft phonation index (SMD = -0.36; 95% CI: -0.57 to -0.15) at 1 month after surgery. Parameters including fundamental frequency, jitter, noise-to-harmonics ratio, and shimmer were not significantly changed at 3 months after surgery.
CONCLUSIONS
This meta-analysis observed small improvements in jitter, shimmer, and soft phonation index 1 month after surgery. No significant effects were observed in voice outcomes 3 months after surgery. Laryngoscope, 134:2538-2550, 2024.
Topics: Humans; Tonsillectomy; Adenoidectomy; Child; Voice Quality; Voice Disorders; Female; Male; Postoperative Complications
PubMed: 37909678
DOI: 10.1002/lary.31140 -
The Cochrane Database of Systematic... Oct 2023Otitis media with effusion (OME) is an accumulation of fluid in the middle ear cavity, common amongst young children. The fluid may cause hearing loss. When persistent,... (Review)
Review
BACKGROUND
Otitis media with effusion (OME) is an accumulation of fluid in the middle ear cavity, common amongst young children. The fluid may cause hearing loss. When persistent, it may lead to developmental delay, social difficulty and poor quality of life. Management of OME includes watchful waiting, autoinflation, medical and surgical treatment. Adenoidectomy has often been used as a potential treatment for this condition.
OBJECTIVES
To assess the benefits and harms of adenoidectomy, either alone or in combination with ventilation tubes (grommets), for OME in children.
SEARCH METHODS
The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 20 January 2023.
SELECTION CRITERIA
Randomised controlled trials and quasi-randomised trials in children aged 6 months to 12 years with unilateral or bilateral OME. We included studies that compared adenoidectomy (alone, or in combination with ventilation tubes) with either no treatment or non-surgical treatment.
DATA COLLECTION AND ANALYSIS
We used standard Cochrane methods. Primary outcomes (determined following a multi-stakeholder prioritisation exercise): 1) hearing, 2) otitis media-specific quality of life, 3) haemorrhage.
SECONDARY OUTCOMES
1) persistence of OME, 2) adverse effects, 3) receptive language skills, 4) speech development, 5) cognitive development, 6) psychosocial skills, 7) listening skills, 8) generic health-related quality of life, 9) parental stress, 10) vestibular function, 11) episodes of acute otitis media. We used GRADE to assess the certainty of evidence for each outcome. Although we included all measures of hearing assessment, the proportion of children who returned to normal hearing was our preferred method to assess hearing, due to challenges in interpreting the results of mean hearing thresholds.
MAIN RESULTS
We included 10 studies (1785 children). Many of the studies used concomitant interventions for all participants, including insertion of ventilation tubes or myringotomy. All included studies had at least some concerns regarding the risk of bias. We report results for our main outcome measures at the longest available follow-up. We did not identify any data on disease-specific quality of life for any of the comparisons. Further details of additional outcomes and time points are reported in the review. 1) Adenoidectomy (with or without myringotomy) versus no treatment/watchful waiting (three studies) After 12 months there was little difference in the proportion of children whose hearing had returned to normal, but the evidence was very uncertain (adenoidectomy 68%, no treatment 70%; risk ratio (RR) 0.97, 95% confidence interval (CI) 0.65 to 1.46; number needed to treat to benefit (NNTB) 50; 1 study, 42 participants). There is a risk of haemorrhage from adenoidectomy, but the absolute risk appears small (1/251 receiving adenoidectomy compared to 0/229, Peto odds ratio (OR) 6.77, 95% CI 0.13 to 342.54; 1 study, 480 participants; moderate certainty evidence). The risk of persistent OME may be slightly lower after two years in those receiving adenoidectomy (65% versus 73%), but again the difference was small (RR 0.90, 95% CI 0.81 to 1.00; NNTB 13; 3 studies, 354 participants; very low-certainty evidence). 2) Adenoidectomy (with or without myringotomy) versus non-surgical treatment No studies were identified for this comparison. 3) Adenoidectomy and bilateral ventilation tubes versus bilateral ventilation tubes (four studies) There was a slight increase in the proportion of ears with a return to normal hearing after six to nine months (57% adenoidectomy versus 42% without, RR 1.36, 95% CI 0.98 to 1.89; NNTB 7; 1 study, 127 participants (213 ears); very low-certainty evidence). Adenoidectomy may give an increased risk of haemorrhage, but the absolute risk appears small, and the evidence was uncertain (2/416 with adenoidectomy compared to 0/375 in the control group, Peto OR 6.68, 95% CI 0.42 to 107.18; 2 studies, 791 participants). The risk of persistent OME was similar for both groups (82% adenoidectomy and ventilation tubes compared to 85% ventilation tubes alone, RR 0.96, 95% CI 0.86 to 1.07; very low-certainty evidence). 4) Adenoidectomy and unilateral ventilation tube versus unilateral ventilation tube (two studies) Slightly more children returned to normal hearing after adenoidectomy, but the confidence intervals were wide (57% versus 46%, RR 1.24, 95% CI 0.79 to 1.96; NNTB 9; 1 study, 72 participants; very low-certainty evidence). Fewer children may have persistent OME after 12 months, but again the confidence intervals were wide (27.2% compared to 40.5%, RR 0.67, 95% CI 0.35 to 1.29; NNTB 8; 1 study, 74 participants). We did not identify any data on haemorrhage. 5) Adenoidectomy and ventilation tubes versus no treatment/watchful waiting (two studies) We did not identify data on the proportion of children who returned to normal hearing. However, after two years, the mean difference in hearing threshold for those allocated to adenoidectomy was -3.40 dB (95% CI -5.54 to -1.26; 1 study, 211 participants; very low-certainty evidence). There may be a small reduction in the proportion of children with persistent OME after two years, but the evidence was very uncertain (82% compared to 90%, RR 0.91, 95% CI 0.82 to 1.01; NNTB 13; 1 study, 232 participants). We noted that many children in the watchful waiting group had also received surgery by this time point. 6) Adenoidectomy and ventilation tubes versus non-surgical treatment No studies were identified for this comparison.
AUTHORS' CONCLUSIONS
When assessed with the GRADE approach, the evidence for adenoidectomy in children with OME is very uncertain. Adenoidectomy may reduce the persistence of OME, although evidence about the effect of this on hearing is unclear. For patients and carers, a return to normal hearing is likely to be important, but few studies measured this outcome. We did not identify any evidence on disease-specific quality of life. There were few data on adverse effects, in particular postoperative bleeding. The risk of haemorrhage appears to be small, but should be considered when choosing a treatment strategy for children with OME. Future studies should aim to determine which children are most likely to benefit from treatment, rather than offering interventions to all children.
Topics: Child; Humans; Child, Preschool; Otitis Media with Effusion; Adenoidectomy; Quality of Life; Otitis Media; Hemorrhage
PubMed: 37870083
DOI: 10.1002/14651858.CD015252.pub2