Prevalence and Management of Complications of Percutaneous Ethanol Injection for Cystic Thyroid Nodules: A Systematic Review of Literature and Meta-analysis

Abstract

Background:

We assessed the prevalence of complications from percutaneous ethanol injection (PEI) for benign and cystic thyroid nodules (CTNs) and their management.

Methods:

We conducted a systematic review with meta-analysis of data from published observational studies on PEI of CTNs. We also included unpublished retrospectively collected data on complications after PEI from all consecutive patients with cytologically benign CTNs who underwent PEI at the Unit of Endocrinology and Metabolic Diseases, AOU University of Campania Luigi Vanvitelli (Naples, Italy) between June 1, 2021, and March 31, 2024. A random effects meta-analysis was performed on the prevalence rate data. Pooled prevalence data were presented with confidence intervals (CIs). The I ² statistic index was used to quantify the heterogeneity. The details of the complications and the management were qualitatively described.

Results:

The literature search yielded 1189 studies, of which 48 studies were included in the systematic review and meta-analysis, in addition to our institutional experience (3670 CTNs in total). The overall quality of each included study was judged as fair. The prevalence of “Overall” complications of PEI was 32% ([CI 25–40%], I ² 92.7%, 967 of 3195 thyroid nodules [TNs]). The prevalence of “Minor” complications of PEI was 32% ([CI 25–40%], I ² 92.7%, 952 of 3195 TNs). The prevalence of “Major” complications of PEI was 2% ([CI 1–2%], I ² 0%, 22 of 3670 TNs). Sensitivity analyses did not modify the results. The pooled prevalence rate of local pain was 21% (CI [16–27] I ² 90.3). Local pain was typically transient and mild, sometimes moderate, and requiring analgesics for few days. The pooled prevalence rate of dysphonia was 1% (CI [1–2], I ² 0). Dysphonia was transient and could last from several hours to 12 months after PEI.

Conclusions:

Complications of PEI for benign and CTNs are relatively common, but most are minor and usually transient, not requiring treatment. Dysphonia was a major complication, but it was uncommon and transient. PEI for CTNs could be considered a generally safe technique.

Introduction

Ultrasound (US)-guided minimally invasive treatments (MITs) (including ethanol ablation and thermal ablations) represent an alternative to surgery or even the first-line therapy for benign and locally symptomatic thyroid nodules (TNs).^1
–3 In this setting, percutaneous ethanol injection (PEI) is regarded as the best treatment for relapsing and symptomatic, benign cystic, or predominantly cystic thyroid nodules (CTNs).^1
–3 PEI is associated with high volume reduction rates that range from 80% to 100% and from 65% to 85.4% in purely CTNs and predominantly CTNs (PCTNs), respectively.^4,5 The high efficacy of PEI in reducing thyroid nodule volume persists over time.^4,5 Expert guideline and consensus panels have considered PEI to be a safe technique for TNs, as major complications have rarely been reported and side effects are deemed to be generally well manageable.^1
–3 However, although there is a large amount of data on the efficacy of PEI,^4,5 the safety data have not been extensively, rigorously reviewed. The technique of ethanol ablation has been used for decades, and there are few narrative reviews on the topic of complications.^6
–8 However, the actual prevalence of minor and major complications of PEI and the best management of the complications are not well defined.

Given the therapeutic importance of this issue for physicians performing thyroid ablation worldwide,⁹ the aim of this study was to assess the prevalence of complications of PEI in CTNs and PCTNs and their management through a systematic review and meta-analysis of the literature, including data from the authors’ institution.

Methods

Detailed methods of the systematic review

The primary outcome was the prevalence of complications of PEI under real-time US guidance for cytologically benign CTNs and PCTNs (meta-analysis). The secondary outcome was to assess the features and management of these complications (i.e., mechanisms of occurrence, severity, duration, therapy) (systematic review). We conducted a systematic review with meta-analysis of data from published observational studies on PEI of CTNs. We also included unpublished retrospectively collected data on complications after PEI from a cohort of CTNs who underwent PEI at the Unit of Endocrinology and Metabolic Diseases, AOU University of Campania “Luigi Vanvitelli (Naples, Italy). The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines¹⁰ were followed in reporting this systematic review and meta-analysis. The current systematic review and meta-analysis was not registered.

Search strategy

Two investigators (L.S. and P.F.) independently conducted a comprehensive literature search in the online databases of MEDLINE (PubMed), Scopus, and Web of Science using the following search terms and their combinations: ‘‘Ethanol’’ (or “Alcohol”), “Thyroid” (or “Thyroid nodule”). A commencement date limit was not used, and the last search was conducted on July 01, 2024. Only articles with English main text were considered for inclusion. The search strategy was refined to evaluate all references of the screened studies to identify additional relevant studies. The search was restricted to human studies.

Eligibility criteria and study selection

Records identified by our search strategy were screened using “the report of complications of PEI under real-time US guidance for cytologically benign CTNs and PCTNs” as the major criterion of inclusion. We excluded patient cohort cases where PEI was combined with other MITs. Articles examining the use of PEI for hot nodules, metastatic lymph nodes, locoregional recurrence of papillary thyroid cancer patients, parathyroid, or thyroglossal duct cysts were excluded. Only published research articles were considered for inclusion (i.e., experimental studies, observational studies, and case series). We excluded the following types of articles: (i) case reports, reviews, editorials, letters, commentaries, guidelines, and meeting abstracts; (ii) small studies with <10 patients; and (iii) research articles, including nodules treated with other chemical agents (i.e., polidocanol, saline, tetradecyl sulfate) or with missing ultrasound features (cystic or noncystic). Two researchers (L.S. and P.F.), applying the above criteria, independently reviewed titles and abstracts of the screened articles. Then, all authors independently reviewed the main text of the eligible articles to define their inclusion. Disagreements were resolved by consensus among all the reviewers.

Data extraction

For the included studies, the following data were coded and extracted independently and in duplicate by two investigators (L.S. and P.F.), in a piloted form: (i) author, publication year, country, study design; (ii) number of nodules (CTNs and PCTNs) undergoing PEI with sex and age of patients; (iii) nodule volume; (iv) number of sessions per nodule; (v) number of punctures per session of PEI; (vi) needle diameter; (vii) local anesthesia at the needle-puncture site and/or peri-thyroidal area; (viii) approach for needle entry during US guidance; (ix) anticoagulation and/or antiplatelet therapy discontinuation; (x) grade of ethanol and amount of injected ethanol for each session of PEI; (xi) ethanol reaspiration; and (xii) number and details of complications.

Measures

For the included studies, complications were subdivided into “Minor” (local pain; transient burning sense; neck hematoma; set of symptoms [one or more in a single patient], including dizziness/drunkenness and/or flushing and/or increased heartbeat and/or nausea and/or headache; fever; vasovagal reaction [VVR] with hypotension) and “Major” (dysphonia with or without dysphagia, arrhythmia, nodule infection, Horner’s syndrome, thyrotoxicosis or hypothyroidism, esophageal injury, tracheal injury, skin burning) complications, also according to the Society of Interventional Radiology guidelines.¹¹

Risk of bias assessment

The risk of bias of the included studies was assessed independently by two investigators (L.S. and N.D.M.) through the National Heart, Lung, and Blood Institute Quality Assessment Tool (https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools).¹²

Statistical analysis

Outcomes were assessed on a patient basis for each study. A proportion meta-analysis was performed with the DerSimonian and Laird method (random-effects model),¹³ where pooled data are weighted averages relative to the sample size of the single studies. Pooled data were presented with confidence intervals (CI) and displayed in a forest plot. I ² statistic index was used to quantify the between-study heterogeneity as follows: <25%, no heterogeneity; 25–50%, mild heterogeneity; 50–75%, moderate heterogeneity; and >75%, high heterogeneity. Trim and fill analysis and Egger’s linear regression test were used to evaluate for publication bias. Meta-regression and subgroup analyses were performed to explore the heterogeneity of results. The results of the meta-regression coefficient with the corresponding p value were reported. The sign of the regression coefficient indicated the “direction” of the relationship, while its value indicated the “degree” of the relationship. Analysis of variance test was carried out to evaluate the differences between the means of two or more data subgroups. A two-sided p value of <0.05 was regarded as significant for all analyses. Statistical analysis was performed using ProMeta 3.0 (Internovi, Cesena FC, Italy).

Detailed methods of the institutional retrospective study

This retrospective study was approved by the Institutional Review Board of University of Campania “Luigi Vanvitelli” (Naples, Italy) (Campania 2, 2024 0039/i). We included data from all consecutive patients who had cytologically benign CTNs and PCTNs and underwent PEI at the authors’ institution between June 1, 2021, and March 31, 2024. From our anonymous and electronic database, we extracted details on PEI complications with their management of PEI for CTNs and PCTNs. At our center, PEI was performed by the same experienced operator (L.S., with six years of clinical experience in performing PEI) who prospectively and accurately collected details. Moreover, all patients were in contact with the operator for at least six months after PEI. During this time, we did not have dropouts, and the reported data for each case were sufficiently comprehensive to answer to the study endpoints. PEI procedure consisted in one to two punctures for sessions, through a needle of 23 Gauge. During US guidance a lateral approach was used, and local anesthesia was not adopted. Anticoagulation therapy was discontinued 10 days before PEI, while antiplatelet therapy was not discontinued. Ninety-six percent ethanol was injected before or after cyst content evacuation in the amount of 20% of the initial nodule volume (≤10 mL), without early ethanol reaspiration. Data were reported descriptively.

Results

Institutional experience

Sixty-eight benign nodules (37 CTNs and 31 PCTNs, mean volume 16.3 ± 14.1 mL) from 68 patients (39 females and 29 males, mean age 50.0 ± 16.2 years) were treated with PEI (one session in 40 nodules and two sessions in 28 nodules during a mean follow-up of 12 months). We had 41 complications (60.3%, in 41 patients), subdivided into 40 minor complications (20 cases of transient burning sense, 11 cases of local pain, four cases of neck hematoma, three cases of set of symptoms, 2 cases of VVR with hypotension) and one major complication (one case of dysphonia). Local transient burning sense occurred during and/or after ethanol injection, resolving in few seconds or minutes. Local pain was mild, with need of nonsteroidal anti-inflammatory drugs for few days in two patients. Neck hematoma was managed with ice pack application, compression bandage, and glucocorticoids (prednisone 0.5 mg/kg daily) for a few days. VVR with hypotension spontaneously resolved in a few minutes. The set of symptoms, including one or more among dizziness/drunkenness and/or flushing and/or increased heartbeat and/or nausea and/or headache, appeared soon after ethanol injection and spontaneously solved in few minutes. Dysphonia (and dysphagia that lasted two weeks) occurred in one patient beginning few seconds after ethanol injection. Dysphonia was treated with 30 days of prednisone oral therapy, then 1 month of voice therapy, and the voice returned to normal after another 15 days.

Results of the literature search

The literature search initially yielded 1189 studies. All the studies were assessed, and the reasons for exclusion are shown in Figure 1 and Supplementary Table S1. Forty-eight observational retrospective studies,^{14

–61} plus our institutional experience, were eligible for the meta-analysis. Data were included from 3670 thyroid benign and cystic nodules subject to PEI from adult patients (≥18 years of age). Table 1 summarizes the general characteristics of the included studies. Seven studies were published between 1990 and 2000,^55

–61 10 studies between 2000 and 2010,^{45

–54} 17 between 2010 and 2020,^{28

–44} and 15 between 2020 to date (including our experience).^{14

–27} Twenty three studies were from Asia,^{14,16,19,24,28,32
–34,36

–44,46

–49,54,61} 21 studies were from Europe,^{15,18,20
–22,25
–27,31,35,45,50

–53,55

–60} 3 studies from America,^17,23,29 and 2 from Turkey.^21,30 Of 2757 TNs, of which we know how they were subdivided into CTNs and PCTNs, 53.4% were represented by CTNs. The volume of TNs greatly varied across the studies.

FIG. 1.

Flowchart of the study selection process. PEI, percutaneous ethanol injection; CTNs, cystic thyroid nodules; PCTNs, predominantly cystic thyroid nodules; MITs, minimally invasive treatments.

Table 1.

Summary of the General Characteristics of the Included Studies

First author	Year	Country	TNs, n	Age, years	Female, n	CTNs, n	PCTNs, n	Nodule volume (mL)	Sessions of PEI per nodule, n	Puncture per session of PEI, n	Needle size (gauge)	Local anesthesia (yes/no)	Approach during US guidance	Anticoagulation therapy discontinuation (yes/no)	Antiplatelet therapy discontinuation (yes/no)	Grade of ethanol (%)	Amount of injected ethanol for each session of PEI	Ethanol reaspiration (yes/no)
Scappaticcio L et al. (current study)	2024	Europe (Italy)	68	50.0 ± 16.2	39	37	31	16.3 ± 14.1	1.5 (mean)	1;2	23	No	Lateral	Yes	No	96	20% of the initial nodule volume (≤10 mL)	no
Nguyen VB et al.¹⁴	2023	Asia (Vietnam)	17	47.4 ± 15.5	13	7	10	5.2 ± 3.4	1	1	18	Yes	Trans-isthmic			99.5	50–70% of aspirated liquid volume	yes
Halenka M et al.¹⁵	2023	Europe (Czech Republic)	63	23.8 ± 4.9	54	63	0	<10–> 30	1.7 ± 0.7	1	18 or 20	No		Yes	No	96	1.5 mL (median)	no
Zhang Ya et al.¹⁶	2022	Asia (China)	30	45.9 ± 12.9	27	18	12	4.9 (mean)	2.5 (mean)	1		Yes				98	50–70% of aspirated liquid volume	no
Steinl et al.¹⁷	2022	America (USA)	31	49.5 ± 18.1	27			21.3 ± 15.4	1	1	16	Yes	Trans-isthmic			100	30% of the initial nodule volume (≤10 mL)	no
Maniam P et al.¹⁸	2022	Europe (UK)	56	50 (median)	44			19 (median)	1	1	19–21	Yes	Lateral or trans-isthmic			100	50% of aspirated liquid volume (≤20 mL)	no
Jeong SY et al.¹⁹	2022	Asia (Korea)	31			8	23	22 ± 24.8	1	1	18	No	Lateral			99	less than 50% of the aspirated liquid volume	yes
Reverter JL et al.²⁰	2021	Europe (Spain)	100	48 ± 12	58			12.7 (5.4–21.7)	1–5	1	20–23	No				99	30% of the aspirated liquid volume (≤2 mL)	no
Karatay E et al.²⁴	2021	Europe/Asia (Turkey)	46	49.5 ± 13.5	46	18	28	37.7 ± 50	1	1	25	Yes		Yes		99	5–10 mL	no
Hey SY et al.²⁵	2021	Europe (UK)	26	48 (41–55)	20			22.3 (9.3–37.8)	1	1	19–21	Yes				100	50% of the aspirated liquid volume (≤20 mL)	no
de Alcântara-Jones DM et al.²⁶	2021	America (Brasil)	20	50.1 ± 17.4		9	11		1	1		No				99.5	the aspirated liquid volume	no
Cho W et al.²⁷	2021	Asia (Korea)	61	43.1 (mean)	42	38	23	21.9 ± 15.2	1	1	17	Yes	Trans-isthmic			99.5	3.5 ± 1.2 mL	yes
Merchante Alfaro AA et al.²⁸	2021	Europe (Spain)	33	51.1 ± 12.5	27	16	17	11.6 (8.5–16.5)	1	1	21	Yes				96	15 − 25% of the initial nodule volume (≤4 mL)	no
Halenka M et al.²⁹	2020	Europe (Czech Republic)	200	49 (38–67)	157	49	151	8.5 (5.5–16)	1–9	1	18 or 20	No		Yes	No	96	2 (1–3) mL (≤10 mL)	no
Deandrea M et al.²⁷	2020	Europe (Italy)	358	53 ± 14	254			24 ± 27	2 ± 1	1	18–21	No				95	0.3–0.5 ethanol/mL of the aspirated liquid volume	no
Park HS et al.²⁸	2019	Asia (Korea)	221	47.5 ± 12.7–48.7 ± 12.4	168	94	127	18.0 ± 29.9–18.3 ± 17.6	1	1	16–18	Yes	Trans-isthmic			99	roughly 50% of the the aspirated liquid volume	yes/no
Iniguez-Ariza NM et al.²⁹	2019	America (USA)	20	50 (mean)	13	20	0	19.6 (median)	1;2	1	20–22	Yes/no					23% of the aspirated liquid volume	yes
Ozderya A et al.³⁰	2018	Europe/Asia (Turkey)	42	44.6 ± 13.9		12	30	1.7–68.1	1;2;3	1	27	No				96	20≤% of the initial nodule volume or ≤20% of the aspirated liquid volume	no
Negro R et al.³¹	2017	Europe (Italy)	101	42.3 ± 12.9	71			<10–> 30	1.2 ± 0.5–2.7 ± 0.5	1	20–22	Yes				100	1 ± 0.1–6 ± 4.1 mL	no
Gong X et al.	2017	Asia (China)	135	46.83 ± 11.31	85	70	65	15.23 ± 18.67	1	1	18 or 20	No					50% of the aspirated liquid volume	yes
Suh CH et al.³³	2015	Asia (Korea)	107	46.3 (mean)	78	0	107	20.8 ± 31.1	1	1	16 or 18	No	Trans-isthmic			99	50% of the aspirated liquid volume	yes
Baek JH et al.³⁴	2015	Asia (Korea)	24	50.8 ± 15.2	18			14.7 ± 13.7	1	1	16	Yes				99	50% of the aspirated liquid volume	yes
Reverter JL et al.³⁵	2015	Europe (Spain)	30	46 ± 10	25	19	11	18.2 ± 15.5	1;4;6	1	21	Yes				99	50% of the aspirated liquid volume (≤2 mL)	no
Sin In H et al.	2014	Asia (South Korea)	62	45.0 (mean)	46	11	53	7.2 (mean)	1	1	18 or 21 or 23	No				100	≤ 10 mL	no
Lv G et al.³⁷	2014	Asia (China)	71	42.5 (mean)	60	0	71	18.4 ± 10.8; 17.2 ± 10.7	1	1	18	Yes	Trans-isthmic			99	the aspirated liquid volume	yes/no
Kim DW et al.³⁸	2014	Asia (Korea)	25	44.0 (mean)	21	25	0	12.2 (mean)	1	1	18 or 21 or 23	No				100	1–10 mL	no
Basu N et al.³⁹	2014	Asia (India)	60	30.38 ± 8.68;28.66 ± 10.23	52	60	0	8.75 ± 5.66–7.97 ± 5.64	1	1	18 or 20 or 22	No				100	50–100% of the aspirated liquid volume	no
Sung JY et al.⁴⁰	2013	Asia (Korea)	25	45.0 ± 10.9	23	25	0	12.2 ± 11.0	1	1	16 or 18	Yes	Trans-isthmic			99	50% of the aspirated liquid volume	yes
Kim YJ et al.⁴¹	2012	Asia (Korea)	209	47.7 (mean)	161	127	90	15.7 ± 18.1	1–3	1	14–18	Yes	Trans-isthmic			99	50% of the aspirated liquid volume	yes
Jang SW et al.⁴²	2012	Asia (Korea)	94	40.4 (mean)	73			13.2 ± 15.2	1	1	16 or 18	No	Trans-isthmic			99	50% of the aspirated liquid volume	yes
Sung JY et al.⁴³	2011	Asia (Korea)	36	47.69 ± 13.00	26	36	0	13.83 ± 11.97	1.2 ± 0.4	1	16 or 18	Yes	Trans-isthmic			95–99	50% of the aspirated liquid volume	yes
Park NH et al.⁴⁴	2011	Asia (South Korea)	40	43 (mean)	29	14	26	7.2 (mean)	1	1	18 or 21 or 23	No				100	15–60% of the aspirated liquid volume	no
Raggiunti B et al.⁴⁵	2009	Europe (Italy)	110	42.1 ± 14.7	80			15.0 ± 18.8	5.3 ± 2.7	1	22	Yes				95	25% of the aspirated liquid volume	no
Jayesh SR et al.⁴⁶	2009	Asia (India)	15			0	15	10.4 (mean)	1; 2	1	21 or 22	No				95	50% of the aspirated liquid volume (4.8 mL mean)	no
Kanotra SP et al.⁴⁷	2008	Asia (India)	40	42.8 (5.2)	34	16	24	12.26 ± 3.6	1.5 (mean)	1	22	No				95	50% of the aspirated liquid volume	no
Lee SJ et al.⁴⁸	2005	Asia (South Korea)	432	42.5 ± 11.5	385	432	0	15.6 ± 12.6	2.3 ± 1.2	1	23	No				99.9	3.1 ± 2.2 mL	yes
Kim DW et al.⁴⁹	2005	Asia (South Korea)	60	44.7 (mean)	48	60		11.9 (mean)	1	1; 2	18 or 21 or 23	No				99.9	in the same or a lesser amount than the aspirated liquid volume (≤20 mL)	yes/no
Valcavi R et al.⁵⁰	2004	Europe (Italy)	135	18 to 85		86	49	19 ± 19	1;2;3	1	18–22	No	Trans-isthmic			95–100	50–70% of the aspirated liquid volume	no
Guglielmi R et al.⁵¹	2004	Europe (Italy)	58			0	58	13.7 ± 14	2.2 ± 1.3	1	22	Yes				95	25% of the aspirated liquid volume (≤10 mL)	no
Bennedbaek FN et al.⁵²	2003	Europe (Denmark)	33	48 (median)	29	26	7	8 (median)	1;2	1		No				99	36% of the aspirated liquid volume	no
Del Prete S et al.⁵³	2002	Europe (Italy)	98	44.8 ± 14.5	72	0	98	35.2 ± 20.1	1.8 ± 1.3	1	20–22	No				95	0.7–1.5 mL/mL of the initial nodule volume (≤15 mL)	no
Cho YS et al.⁵⁴	2000	Asia (South Korea)	22	40.7 (mean)	18	9	13	13.0 (mean)	1.2 (mean)	1	20–22	No				99.9	40–100% of the aspirated liquid volume	no
Zingrillo M et al.⁵⁵	1999	Europe (Italy)	43	44 ± 13	27	0	43	38.4 ± 32.5	1.5 ± 0.9	1	18	No				95	3–4 mL	no
Komorowski J et al.⁵⁶	1998	Europe (Poland)	23	44.5 ± 18.7	20			7.5 ± 3.2	1;5	1	6	No				96	1 mL/mL nodule volume	no
Zingrillo M et al.⁵⁷	1996	Europe (Italy)	20	44 ± 13	12	20	0	21 (mean)	1.7 ± 0.9	1	18	No				95	2–3 mL	no
Verde G et al.⁵⁸	1994	Europe (Italy)	32	41.8 ± 11.9	23	0	32	14.5 (median)	1	1	22	No				95	1–10 ml on the basis of the aspirated liquid volume	no
Monzani F et al.⁵⁹	1994	Europe (Italy)	20	24–72	15	20	0	12 (mean)	1–2	1	20–22	No				95	one third of the aspirated liquid volume	yes
Antonelli A et al.⁶⁰	1994	Europe (Italy)	26	44 ± 8	18	26	0		1–5	1	21	No				99.9	10–30% of the the aspirated liquid volume	no
Yasuda K et al.⁶¹	1992	Asian (Japan)	61	45.5 (mean)	54	1	60	13.2 (mean)	1	1	21	No				99.9	10% of the aspirated liquid volume	no

Blanks are missing data.

TN, thyroid nodule; CTNs, cystic thyroid nodules; PCTNs, predominantly cystic thyroid nodules; PEI, percutaneous ethanol injection; US, ultrasound.

In 23 studies (46.9%),^{14,17
–19,21

–25,28,32
–34,36

–40,42,44,49,58,61} the reported data, including those related to complications, referred to single-session PEI, whereas in the remaining studies, nodules could undergo more than one session of PEI. In all the included studies, except for the study by Kim DW⁴⁹ and our cohort where patients could undergo two punctures, the skin of patients was punctured one time to make both liquid aspiration and ethanol injection. The needle gauge sizes varied greatly depending on the study. In 30 studies (61.2%), local anesthesia at the needle-puncture site and/or peri-thyroidal area was not adopted.^{15,19,20,23,26,27,30,32,33,36,38,39,42,44,46,50,52

–61} The approach for needle entry during US guidance (trans-isthmic or lateral approach) was reported in only 14 studies (28.6%).^{14,17
–19,24,28,33,37,40

–43,50} Details on the anticoagulation and/or antiplatelet therapy discontinuation were reported in only four studies (8.2%) (including our experience).^15,21,26 The grades of ethanol for PEI varied from 95% to 100% across the studies. The amount of the injected ethanol for each session of PEI significantly varied across the studies. In 15 studies (30.6%),^{14,19,24,28,29,32
–34,37,40

–43,48,49,59} injected ethanol was reaspirated as the last step of the PEI procedure.

Study quality assessment

Supplementary Table S2 summarizes the quality assessment of the 48 included studies.

The overall quality of each included study was judged as fair. Specifically, the risk of bias for each study could be judged as low in 8 of 14 items. By contrast, all studies did not report any power or sample size justification. Participation rate of eligible persons was not mentioned in any of the included studies. In all studies, the risk of bias on blinding of outcome assessors and confounding variables were regarded as high.

Complications

Prevalence rates

In the pooled analysis, prevalence rate of “Overall” complications of PEI was 32% ([CI 25–40%], I ² 92.7%, 967 of 3195 TNs) (Supplementary Fig. S1). The pooled prevalence rate of “Minor” complications of PEI was 32% ([CI 25–40%], I ² 92.7%, 952 of 3195 TNs) (Supplementary Fig. S2). The pooled prevalence rate of “Major” complications of PEI was 2% ([CI 1–2%], I ² 0%, 22 of 3670 TNs) (Supplementary Fig. S3). Table 2 shows the pooled analyses. Table 3 summarizes the characteristics of the respective complications.

Table 2.

Results of the Meta-Analysis (Pooled Prevalences of Complications of PEI)

Outcome	Studies included, n	TNs, n	Complications, n	Pooled prevalence [CI]	Heterogeneity(%)	Publication bias(p value)
“Overall” Complications	40	3195	967	32 [25–40]	92.7	0.913
“Minor” Complications	40	3195	952	32 [25–40]	92.7	0.836
Local pain			663	21 [16–27]	90.32	0.135
Transient burning sense			187	2 [1–5]	89.28	0.000
Set of symptoms (Dizziness/drunkenness, and/or flushing, and/or increased heartbeat and/or nausea, and/or headache)			28	2 [1–3]	47.02	0.000
Neck hematoma			26	2 [1–3]	49.08	0.000
Fever			8	1 [1–2]	0.00	0.029
Vasovagal reaction with hypotension			4	1 [1–2]	0.00	0.067
“Major” Complications	49	3670	22	2 [1–2]	0.00	0.004
Dysphonia			18	1 [1–2]	0.00	0.004
Arrhythmia			2	1 [1–1]	0.00	0.053
Infection			1	1 [1–1]	0.00	0.511
Thyrotoxicosis			1	1 [1–1]	0.00	0.423

p value using Egger’s test.

Table 3.

Summary of the Main Characteristics of Complications

First author	Year	Country	Complication features and management of complications
Scappaticcio et al. (current study)	2024	Europe (Italy)	Local TBS occurred during and/or after ethanol injection, resolving in few seconds or minutes. Local pain was mild, with need of NSAIDs for few days only in 2 cases. Neck hematoma was managed with ice pack application, compression bandage, and SAIDs for few days. VVR with hypotension spontaneously solved in few minutes. Set of symptoms appeared soon after ethanol injection and spontaneously solved in few minutes. Dysphonia (and dysphagia that lasted two weeks) occurred in one patient few seconds after ethanol injection and was treated with 30 days of prednisone oral therapy, then one month of voice therapy, so that the voice returned to normal after another 15 days.
Nguyen VB et al.¹⁴	2023	Asia (Vietnam)
Halenka M et al.¹⁵	2023	Europe (Czech Republic)	Slight local pain subsiding within 48 hours
Zhang Ya et al.¹⁶	2022	Asia (China)	Local pain relieved within 1 week without the use of analgesics
Steinl GK et al.¹⁷	2022	America (USA)	Dysphonia and dysphagia to liquids that resolved within 24 hours
Maniam P et al.¹⁸	2022	Europe (UK)	Mild local pain controlled using simple analgesia; neck hematoma two days after PEI requiring aspiration of hemorrhagic cystic content; cyst infection 25 days post-PEI requiring incision and drainage of abscess
Jeong SY et al.¹⁹	2022	Asia (Korea)
Reverter JL et al.²⁰	2021	Europe (Spain)	Mild pain in 55% and moderate in 24% cases (transient with relief in some minutes); two patients presented neck hematoma, which was self-limited with external compression and local cold application with spontaneous partial reabsorption and totally with a subsequent PEI performed two weeks after
Karatay E et al.²⁴	2021	Europe/Asia (Turkey)	Temporary dysphonia was completely resolved at 3 months follow-up
Hey SY et al.²⁵	2021	Europe (UK)	Mild neck discomfort or pain which resolved with simple analgesics
de Alcântara-Jones DM et al.²⁶	2021	America (Brasil)	The patient with dysphonia reestablished her voice one week later
Cho W et al.²⁷	2021	Asia (Korea)	4 cases of intra-cystic hemorrhage (neck hematoma) recovered within a week; TBS within a few seconds after the injection of ethanol that subsided within 10 minutes; the heart rate increased to 150 beats/min without altered mental status and hospitalized for 1 day of observation
Merchante Alfaro AA et al.²⁸	2021	Europe (Spain)	Mild pain in 13 and moderate in 14 cases. Only in two cases pain persisted after PEI and needed NSAIDs. In all cases pain lasted <24 hours.
Halenka M et al.²⁹	2020	Europe (Czech Republic)	Mild pain that usually disappeared within several hours but no later than three days after the procedure; two patients with large complex cysts experienced dysphonia lasting for 7–14 days, subsiding spontaneouslywithout need for further specialized examination
Deanadrea M et al.²⁷	2020	Europe (Italy)	Transient pain in 48 patients
Park HS et al.²⁸	2019	Asia (Korea)	68 cases of pain during the procedure greater than lidocaine injection not needing medication; 6 cases of pain needing medication
Iniguez-Ariza NM et al.²⁹	2019	Florida (USA)	All these adverse effects were transient and resolved spontaneously
Ozderya A et al.³⁰	2018	Turkey (Istanbul)	Some of the patients complained of mild and transient pain at the injection site
Negro R et al.³¹	2017	Europe (Italy)	Transient sensation of pain with relief within minutes
Gong X et al.	2017	Asia (China)	In 35 cases mild or moderate localized pain with a duration of 1 to 5 days, and 2 of these cases required analgesics
Suh CH et al.³³	2015	Asia (Korea)	39 patients complained of grade 1 pain, but recovered completely within several minutes; however, EA was terminated early in one patient because of severe pain
Baek JH et al.³⁴	2015	Asia (Korea)	Dysphonia immediately After EA but the issue was completely resolved by the 2-month follow-up without treatment
Reverter JL et al.³⁵	2015	Europe (Spain)	Pain was mild in 43.5 % and moderate in 17.4 %. In all cases, this was a transient sensation of pain with relief within minutes
Sin In H et al.	2014	Asia (South Korea)	Mild pain or mild drunken sensation either during or several minutes after the procedure but the symptoms abated within 1 hour
Lv G et al.³⁷	2014	Asia (China)
Kim DW et al.³⁸	2014	Asia (Korea)	Mild pain during the initial EA (n = 2) and repeated EA (n = 5)
Basu N et al.³⁹	2014	Asia (India)	Most common side effect noted was TBS during PEI followed by transient dizziness
Sung JY et al.⁴⁰	2013	Asia (Korea)
Kim YJ et al.⁴¹	2012	Asia (Korea)	Mild pain during and immediately after the procedure that relieved within several minutes
Jang SW et al.⁴²	2012	Asia (Korea)	Patients complained of mild pain when removing the needle from the nodule. However, pain was usually relieved within several minutes
Sung JY et al.⁴³	2011	Asia (Korea)	Patients experienced only mild pain associated with needle puncture and removal
Park NH et al.⁴⁴	2011	Asia (South Korea)	Mild pain either during the procedure or several minutes later; however, no patient required oral analgesics for local pain
Raggiunti B et al.⁴⁵	2009	Europe (Italy)	In the first case of dysphonia, the patient swallowed during alcohol injection and dysphonia resolved spontaneously within 24 hours.In the second case, alcohol injection velocity combined with inadequate US monitoring of a leakage toward the posterior region and the lower thyroid lobe caused chemical irritation of the homolateral recurrent nerve and severe dysphonia. The patient was administered low-dose methylprednisolone therapy for 15 days. The recurrent nerve damage healed in 5 weeks resulting in normal outcome of laryngoscopic examination and full recovery of the normal voice
Jayesh SR et al.⁴⁶	2009	Asia (India)
Kanotra SP et al.⁴⁷	2008	Asia (India)	Local TBS at the injection site which lasted for a maximum of 1 hour
Lee SJ et al.⁴⁸	2005	Asia (South Korea)	Transient local pain over injection site. The temporary unilateral vocal cord paralyses were diagnosed by flexible laryngoscopy that fully recovered within 2 months. Hypotension normalized within 30 minutes
Kim DW et al.⁴⁹	2005	Asia (South Korea)	13 mild and 3 moderate cases of pain
Valcavi R et al.⁵⁰	2004	Europe (Italy)	Brief (less than 1-minute duration) burning sensation after needle extraction and no medication is needed. Mild pain may begin 6 to 8 hours after PEI and may persist for about 24 to 36 hours, which very rarely necessitated the administration of nonsteroidal analgesics (acetaminophen, 500 to 1,000 mg). We have never prescribed corticosteroids for patients undergoing PEI. Dysphonia occurred about 36 hours after PEI, and reduced ipsilateral vocal cord motility was observed, and spontaneous recovery ensued after 2 months.
Guglielmi R et al.⁵¹	2004	Europe (Italy)	Pain was mild in 75.8% of cases (44/58) and severe in 3.4% (2/58) of cases
Bennedbaek FN et al.⁵²	2003	Europe (Denmark)	Transient pain, with a duration of 10 minutes or less in six patients and 1 hour in one patient. Transient dysphonia lasting for 1 hour
Del Prete S et al.⁵³	2002	Europe (Italy)	The most common side effect was a transient local pain or burning sensation observed in 70 of 98 patients. 1 case of dysphonia lasting 12 months caused by transient paralysis of the left vocal cord
Cho YS et al.⁵⁴	2000	Asia (South Korea)	Local pain at the injection site which was transient and caused by leakage of a small amount of ethanol into the subcutaneous tissue
Zingrillo M et al.⁵⁵	1999	Europe (Italy)	Mild transient local pain, sometimes radiating to the ear or to the jaw and not requiring analgesics
Komorowski J et al.⁵⁶	1998	Europe (Poland)	11 cases of pain lasting to 24 hours and 3 lasting 1–5 days. Fever for up to 24 hours
Zingrillo M et al.⁵⁷	1996	Europe (Italy)	Mild transient pain, radiating to the ear or neck, that did not require analgesic drugs. 2-day fever
Verde G et al.⁵⁸	1994	Europe (Italy)	Three patients complained of mild transient cervical pain and no analgesics or antibiotics were administered
Monzani F et al.⁵⁹	1994	Europe (Italy)
Antonelli A et al.⁶⁰	1994	Europe (Italy)	Slight to moderate pain in 5 patients; severe pain that required a period of observation in 3 patients. In 1 patient about 30 minutes after ethanol injection: cervical pain, sweating, tachycardia that slowly disappeared within a few days (associated with suppressed thyrotropin and mild elevation of ft4 and ft3, which normalized after 1 week)
Yasuda K et al.⁶¹	1992	Asian (Japan)

Blanks are missing data.

TN, thyroid nodule; CI, confidence interval.

TBS, transient burning sense; NSAIDs, nonsteroidal anti-inflammatory drugs; SAIDs, steroidal anti-inflammatory drugs; VVR, vasovagal reaction; PEI, percutaneous ethanol injection; EA, ethanol ablation.

Local pain

The pooled prevalence rate of local pain was 21% (CI [16–27], I² 90.3, 663 cases of 3195 TNs). Pain was localized at the site of the ablated nodule, sometimes radiating to the ear or to the jaw.⁵⁵ Pain was associated with needle puncture and removal, and with ethanol retention and spread into the subcutaneous tissue.^28,54 Local pain was typically transient (minutes/few hours or few days after PEI) and mild, sometimes moderate and requiring analgesics (mainly nonsteroidal) for few days.⁵⁰ Only in one case EA was terminated early in one patient because of severe pain.³³

Transient burning sense

The pooled prevalence rate of transient burning sensation was 2% (CI [1–5], I² 89.3, 187 cases of 3195 TNs). Transient burning sense occurred at the injection site within a few seconds and resolving in few seconds or minutes (for a maximum of one hour).^39,47 Transient burning sensation did not require any medication.

Dizziness/drunkenness, and/or flushing, and/or increased heartbeat and/or nausea, and/or headache

The pooled prevalence rate of dizziness/drunkenness, and/or flushing, and/or increased heartbeat and/or nausea, and/or headache was 2% (CI [1–3], I² 47.0, 28 cases of 3195 TNs). One or more of these symptoms occurred during or several minutes after the procedure and spontaneously solved in few minutes or 1 hour.³⁶ These symptoms did not require any treatment.

Neck hematoma

The pooled prevalence rate of neck hematoma was 2% (CI [1–3], I² 49.1, 26 cases of 3195 TNs). Neck hematoma presented as a swelling of the neck at the injection site within a few seconds or minutes, or less often, some days after PEI.¹⁸ This was the consequence of an intra-cystic or extrathyroidal (i.e., intramuscular or subcutaneous) hemorrhage. Neck hematoma typically recovered within a week,²⁴ after treatment with ice pack application, compression bandage, and steroid analgesics for few days.

Fever

The pooled prevalence rate of fever was 1% (CI [1–2], I² 0, 8 cases of 3195 TNs). Fever usually disappeared within one to two days without treatment.^55,56

VVR with hypotension

The pooled prevalence of VVR with hypotension was 1% (CI [1–2], I ² 0, 4 cases of 3195 TNs). Hypotension generally resolved within 30 minutes without treatment.⁴⁸

Dysphonia

The pooled prevalence rate of dysphonia (with or without dysphagia) was 1% (CI [1–2], I ² 0, 18 cases of 3670 TNs). This was due to the chemical damage of the homolateral recurrent laryngeal nerve, after leakage of ethanol toward the posterior region and the lower thyroid lobe.⁴⁵ The small thickness of cyst wall, the high speed of alcohol injection, the patient swallowing during the alcohol injection, or some pores of the cystic lesion could promote dysphonia. Dysphonia usually appeared soon after the procedure (or rarely 36 hours after PEI).⁴⁹ The way of resolution of dysphonia could vary as follows: it spontaneously resolved within 24 hours or 7 days or it could require medical therapy and strict laryngoscopy follow-up. In two cases (one from our institute and one from the study by Raggiunti et al.⁴⁵) when the patient did not show spontaneous and gradual improvement, glucocorticoids and vocal therapy were adopted to accelerate the full recovery of the normal voice. Dysphonia was transient and could last from several hours to 12 months after PEI.⁵³

Arrhythmia

The pooled prevalence rate of arrhythmia was 1% (CI [1–1], I ² 0, 2 cases of 3670 TNs). It consisted of the following two cases of transient tachycardia: one requiring hospitalization for 1 day of observation;²⁴ the other case occurred during a new onset thyrotoxicosis event, lasting one week.⁶⁰

Infection

The pooled prevalence rate of cyst infection was 1% (CI [1–1], I ² 0, 1 case of 3670 TNs). This occurred 25 days post-PEI and required incision and drainage of the abscess.¹⁸

Thyrotoxicosis

The pooled prevalence rate of thyrotoxicosis was 1% (CI [1–1], I ² 0, 1 case of 3670 TNs). This occurred in one patient about 30 minutes after PEI and presented as sweating and tachycardia associated with TSH suppression and mild elevation of fT4 and fT3, which gradually normalized after one week without treatment.⁶⁰

Exploration of heterogeneity

A meta-regression was performed to evaluate the relationship between prevalence of complications of PEI and sample size, and the latter was divided into small (< 50 cases), medium (>50 cases and <100 cases), and large (>100 cases). As reported in Supplementary Table S3, the sample size did not significantly influence the prevalence of complications (“Overall,” “Major,” and “Minor” complications). Subgroup analysis was conducted to assess the impact of the country where PEI was performed (Asia vs. Europe) on prevalence of complications. Moreover, subgroup analysis served to explore if local anesthesia or alcohol respiration could impact on the prevalence of local pain. The prevalence of complications (“Overall”, “Major”, and “Minor” complications) did not statistically vary depending on the country. The prevalence of local pain did not vary depending on technical features (use of local anesthesia or ethanol respiration) (Supplementary Table S4 and Supplementary Table S5, respectively).

Discussion

A thorough understanding of the potential complications of MITs for benign TNs is needed in considering the safety of these procedures.⁹ Before and during the performance of MITs, operators should know how common the potential complications are and how to manage them. Patients should also accurately be informed about complications of PEI for CTNs.

As far as we know, this is the first comprehensive systematic review examining the complications of PEI for benign and CTNs and the management of these complications. We summarized complication details (prevalence and features of management) from a large cohort (more than 3000) of TNs. We observed more studies published from 2010 to date (more than 65% of the included studies) compared with prior years, highlighting the growing literature available on PEI in recent years. Almost all the included studies were from Asia and Europe.

The results of this meta-analysis indicated that the prevalence of “Overall” complications of PEI was relatively high since we found a complication in about one third of the ablated TNs. However, most of the complications of PEI for CTNs and PCTNs were represented by “Minor” complications. The pooled prevalence rates of “Overall” and “Minor” complications were equal, whereas “Major” complications occurred only in 2% of cases. Moreover, local pain covered about two thirds of both “Overall” and “Minor” complications since it was observed in 21% of cases. Pain was typically transient and mild, and analgesics were needed only in a minority of cases. Another relatively common side effect was represented by transient burning sense because it occurred in 187 cases (2% of pooled prevalence). Transient burning sense typically resolved in few seconds or minutes and did not require any treatment. One or more of the symptoms of dizziness/drunkenness, flushing, increased heartbeat, nausea, and headache accounted for 2% of complications, and none of these required any treatment. Neck hematoma also occurred in 2% of cases and typically resolved within a week, after treatment with ice pack application, compression bandage, and steroid analgesics. Among the “Minor complications,” fever and VVR with hypotension were even more rare (1% of prevalence), but still transient and managed without important treatment. We found a high level of heterogeneity for pain and transient burning sense, and this could potentially be due to several factors, including approach for needle entry, amount of ethanol injected, and experience of the operator, but we could not formally examine for this using the limited data available for review in the primary studies.

Among the “Major complications” dysphonia was the most common and relevant side effect. It occurred in 1% of cases (18 cases reported in literature to date); it was transient but potentially lasting until 12 months. In some cases, dysphonia required glucocorticoids and vocal therapy to accelerate the full recovery of the normal voice. Arrhythmia, cyst infection, and thyrotoxicosis were uncommon side effects (1% of prevalence), without permanent sequelae. For prevalences of “Major” complications we found absence of heterogeneity, but the analyses were limited by low event rates.

Through the sensitivity analyses, we finally confirmed that prevalence of complications of PEI (“Overall”, “Major”, and “Minor” complications) did not vary according to country (Asia vs. Europe) or the sample size of the included studies, findings that could imply that complications do not depend on location or the number of PEI procedures. Moreover, we also demonstrated that prevalence of local pain did not vary according to technical features (i.e., use of local anesthesia or ethanol reaspiration).

Our study does have some limitations. We were unable to determine whether the prevalence and/or type of management varied according to the sex, location of TNs (CTNs vs. PCTNs), position of TNs, amount and degree of ethanol injected, or needle size. We could not exclude that our results (mainly the prevalences of “Major” complications) were affected by publication bias. Furthermore, all of the studies included in this systematic review (including our own data) were subject to a retrospective design, with inherent methodologic limitations. The quality of included studies was thus relatively low. Because the current study was not registered in PROSPERO, this could be another limitation. Furthermore, we also could not analyze the prevalence rates of concurrent major and minor complications due to limitations of the available data in the published studies. Finally, because we excluded case reports, we did not consider anecdotal but serious complications of PEI for TNs (i.e., necrosis of the larynx and adjacent skin, Horner’s Syndrome, Graves’ disease without or with Graves’ ophthalmopathy, Plummer adenoma, acute suppurative thyroiditis).^8,62

–65

A major strength of this study is that this is the first comprehensive systematic review and meta-analysis on complications of PEI for cystic TNs and the management of these complications. Compared with previously published narrative reviews,^6
–8 our study may provide more accurate numeric estimates for complication rates and potentially be subject to less bias.

Conclusions

Based on the results of this study, complications of PEI for benign and CTNs are relatively common, but minor and usually transient, not needing relevant therapies. Dysphonia was a major complication, but it was uncommon and transient. Therefore, PEI for CTNs could be considered a safe technique. Our findings could be useful for the drafting of the dedicated form for written informed consent for PEI of CTNs.

Footnotes

Acknowledgments

The authors sincerely thank PNRR-ANTHEM (AdvaNced Technologies for HumancentrEd Medicine) project for oversight of the scientific activity of the researcher Lorenzo Scappaticcio. The authors also thank Dr. Vincenzo Morone, library information specialist at University of Naples Federico II (Naples, Italy), who assisted with the electronic search of literature. The authors greatly thank Doctor Alberto Gorgoni, journalist in Portugal, who patiently revised the vocabulary and grammar of our article.

Authors’ Contributions

L.C. designed the study, drafted it, approved the final version, and agreed for all aspects of the work. P.F. managed data analysis, critically reviewed it, approved the final version, and agreed for all aspects of the work. N.D.M. managed data analysis, critically reviewed it, approved the final version, and agreed for all aspects of the work. R.N. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. M.D. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. M.I.M. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. P.C. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. M.D.N. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. M.L. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. G.D. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. G.P. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. P.T. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. K.E. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work. G.B. interpreted results, critically reviewed the study, approved the final version, and agreed for all aspects of the work.

Author Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

Supplementary Material

Supplementary Fig. S1

Supplementary Fig. S2

Supplementary Fig. S3

Supplementary Table S1

Supplementary Table S2

Supplementary Table S3

Supplementary Table S4

Supplementary Table S5

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