Acupuncture in the treatment of post-stroke hiccup: A systematic Review and meta-analysis

ABSTRACT

Aim: Central hiccups following a stroke are a frequent complication, exerting adverse effects on both the stroke condition and the patient’s daily life. Existing treatments exhibit limited efficacy and pronounced side effects. Acupuncture has been explored as a supplementary intervention in clinical practice. This study aims to investigate the clinical effectiveness of acupuncture for post-stroke hiccups.

Methods: To identify published clinical randomized controlled trials addressing post-stroke hiccups treatment, comprehensive searches were conducted across PubMed, the Cochrane Library, EMBASE, Web of Science, Chinese Biological Medical (CBM), Wanfang Database, and China Science and Technology Journal (VIP). In addition, we scrutinized ClinicalTrials.gov and the Chinese Clinical Trial Registry. Employing Cochrane Handbook 5.1.0 and Review Manager 5.4 software, three authors independently reviewed literature, extracted data, and evaluated study quality. Data analysis was performed using Stata 16.0 and Review Manager 5.4.

Results: A total of 18 trials were encompassed in the analysis. In comparison to standard treatment, acupuncture exhibited a significant enhancement in treatment effectiveness (RR: 1.27, 95% CI: 1.21–1.33; P < 0.00001). Notably, Hiccup Symptom Score displayed a considerable decrease (WMD: −1.28, 95% CI: −1.64 to −0.93; P < 0.00001), concurrent with a noteworthy improvement in the quality of life (WMD: 8.470, 95% CI: 7.323–9.617; P < 0.00001). Additionally, the incidence of adverse reactions decreased (RR: 0.45, 95% CI: 0.16–1.25; P = 0.13), and there was a significant reduction in SAS (WMD: −7.23, 95% CI: −8.47 - −5.99; P < 0.00001).

Conclusions: Our investigation suggests that acupuncture could prove effective in post-stroke hiccup treatment. Nonetheless, due to concerns about the quality and size of the included studies, conducting higher-quality randomized controlled trials to validate their efficacy is imperative.

KEYWORDS:

• Traditional acupuncture
• stroke
• hiccup
• meta-analysis
• systematic review

1. Introduction

Hiccup presents a common yet complex challenge subsequent to a stroke. In a study conducted by Park et al., 51 patients diagnosed with Wallenberg Syndrome resulting from brainstem infarction were examined, revealing that 7 patients (13.7%) encountered hiccup episodes [1]. Epidemiological investigations underscore cerebrovascular disease as a foremost cause of mortality, with stroke accounting for at least one in five deaths and about a third of all cerebrovascular disease-related fatalities [2]. The emergence of diverse complications following a stroke frequently contributes to elevated rates of mortality and disability [3]. The onset of hiccups can lead to instances of choking, fostering Aspiration pneumonia, or inadequate intake of nutrition, significantly impacting the patients’ quality of life. This phenomenon affects both the acute-stage treatment and subsequent rehabilitation [4,5]. The underlying pathogenesis of hiccups lies in the stimulation of the hiccup reflex center [6]. While the precise anatomical locus of this center remains elusive, the Hiccup Reflex arc has been elucidated. This arc encompasses the afferent, central, and efferent nerves; stimulation of any segment thereof triggers hiccups [7]. Common medical practice leans towards initiating treatment with drugs like Baclofen or Gabapentin, followed by the use of dopamine blockers such as Metoclopramide, Chlorpromazine, and Haloperidol [8]. However, such drug interventions often result in evident adverse reactions, frequently causing dizziness or excessive sedation, counterproductive to the rehabilitation of stroke patients [9]. Consequently, attention has turned to complementary and alternative treatments. Acupuncture is embraced across many nations as an effective approach to address post-stroke hiccups. Acupuncture can enhance cerebral blood circulation, aid in restoring brain tissue excitability, heighten the sensitivity of diverse afferent nerve impulses, thereby enhancing neural function. Concurrently, acupuncture can gradually ameliorate blood supply to the hypothalamus, while also bidirectionally regulating gastrointestinal peristalsis, thereby mitigating hiccups [10]. The utility of acupuncture in post-stroke hiccup management remains a topic of debate, possibly attributed to varying efficacy criteria and the scarcity of high-quality randomized controlled trials. Consequently, a comprehensive and unbiased assessment of acupuncture’s efficacy in addressing post-stroke hiccups is imperative.

This study exclusively concentrates on prevalent acupuncture modalities, encompassing traditional acupuncture, body acupuncture, and hand acupuncture. In accordance with the stipulated inclusion and exclusion criteria, relevant randomized controlled trials were meticulously screened within the database. The aim was to evaluate the efficacy and safety of acupuncture in managing post-stroke hiccups, thereby furnishing an evidence-based foundation for clinical application.

2. Methods

PRISMA (Preferred Reporting Item for Systematic Review and Meta-Analysis) statement guidelines align with the approach adopted in this systematic review and meta-analysis [11]. We have registered this systematic review on PROSPERO: CRD42022337482.

2.1. Search strategy

We executed searches across PubMed, the Cochrane Library, EMBASE, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biological Medical (CBM), Wanfang Database, China Science and Technology Journal (VIP), as well as other databases for retrieval purposes. The search encompassed data creation until 1 February 2022. Moreover, the Chinese Clinical Trial Registry and Clinicaltrials databases were explored from their inception to 1 February 2022. We also meticulously investigated the references cited within the included studies. Chinese search terms comprised acupuncture, electroacupuncture, cerebrovascular accidents, cerebrovascular apoplexy, CVA, stroke, hiccup, and spasm of the diaphragm. The English search strategies may have been slightly adjusted to conform to individual database requirements. To manage references, we employed NoteExpress 3.5.0 software.

2.2. Eligibility criteria

2.2.1. Inclusion criteria

1. Patients diagnosed with post-stroke hiccup. Diagnosis relied on patients’ symptoms, including characteristic sound recognition [5].

2. The treatment group underwent standard forms of acupuncture or a combination with other treatments, irrespective of acupoint selection, treatment frequency, or duration. The control group utilized Metoclopramide. Both groups could receive equivalent fundamental treatment.

3. Studies were confined to randomized controlled trials (RCTs), and eligible articles were restricted to either Chinese or English language.

2.2.2. Exclusion criteria

1. Excluded were reviews, theoretical discussions, case reports, animal experiments, crossover trials, and non-RCTs.

2. Other acupuncture forms, such as ear acupuncture and acupoint injection, were excluded.

3. Studies with incomplete data or duplicate publications were excluded.

2.3. Outcome measurements

2.3.1. The primary outcome was the efficiency rate

Cured: Cessation after one treatment course, with no further episodes. Effective: Occasional brief episodes after one treatment course. Ineffective: Continuation of sporadic episodes. Total effective rate = (cured + effective)/total cases × 100% [12].

2.3.2. Hiccup symptom score

Scoring: 0 points for no hiccup per day, 3 points for < 5 times/hour without affecting eating, 6 points for 6–10 times/hour or < 5 times/hour affecting eating, 9 points for > 10 times/hour or < 10 times/min preventing eating or accompanying gastroesophageal reflux [13].

2.3.3. Life quality score

Assessed by the quality of life score [14]: Total score of 60, with < 20 indicating very poor; 21–30 indicating poor; 31–40 indicating fair; 41–50 indicating good; 51–60 indicating very good.

1. Adverse reaction

2. SAS (Self-Rating Anxiety Scale)

Used to assess psychological status in post-stroke complications [15]. Standard cutoff: 50, categorized as mild (50–59), moderate (60–69), and severe (>70).

2.4. Study selection and data extraction

All papers were managed using NoteExpress 3.5.0 software. Three authors (Jiaqi Wang, Bangqi Wu, and Yibing Li) independently screened and extracted data. Discrepancies were resolved by cross-checking the extracted data. Pertinent information, including first author, study type, country, publication year, age, sample size, treatment and control interventions, treatment duration, and outcomes, were recorded using Excel. Disagreements were resolved through consultation with the fourth author (Xuhui Wang).

2.5. Bias risk assessment

Three authors (Jiaqi Wang, Bangqi Wu, and Yibing Li) independently evaluated study quality using Cochrane Handbook 5.1.0 software. Bias risk was assessed for random sequence generation, allocation concealment, participant and researcher blinding, outcome assessor blinding, incomplete outcome data, and selective outcome reporting. Bias risk was categorized as ‘low,’ ‘high,’ or ‘unclear.’ Issues were addressed through discussions or consultation with the fourth author (Xuhui Wang).

2.6. Data analysis

Dichotomous outcomes were assessed using combined risk ratios (RR) with a 95% confidence interval (CI), while continuous outcomes were represented by the mean difference (MD) and 95% CI. Statistical heterogeneity was evaluated via forest plots and the I2 statistic. Sensitivity analysis was conducted to identify sources of heterogeneity [16]. Funnel plots and Egger’s tests were utilized to assess publication bias. Statistical analyses were performed using RevMan 5.2 and Stata 16.0.2.

3. Results

3.1. Study selection

Following the devised search strategy, a total of 1125 papers were retrieved from database inception until 1 February 2022. After removing duplicate entries, 547 records remained. Upon reviewing titles and abstracts, 427 records were subsequently excluded.

Out of the remaining 120 articles, 102 were excluded from analysis due to the following reasons upon full-text review: 94 studies utilized differing medications as control groups, three studies featured multiple control groups, four studies had inadequate data, and one study contained inaccurate data. Ultimately, 18 studies were included in this meta-analysis [12–15,17–30]. (Figure 1)

Figure 1. PRISMA flow diagram.

3.2. Study characteristics

All studies reported no significant differences in general information between intervention groups. Sixteen studies reported the effective rate [12–15,17–21,23,24,26–30], 12 studies presented the Hiccup Symptom Score [14,15,18–24,26,30,31], one study indicated improvements in the Life Quality Score [18], one study referred to the enhancement of SAS [24], and two studies noted adverse events [14,24]. Tables 1 and 2 outline the features of the included studies.

Table 1. Characteristics of included studies(1).

Study	Intervention		Number of patients (T/C)	Intervention period	Relevant outcomes	Study type
	T	C
Chen Shuang 2017	A+BT	M	90(45/45)	Lasted for 7 days	①②	RCT
Chi Xiangfeng 2019	A	M	54(27/27)	Lasted for 7 days	①②③	RCT
Cui Meijuan 2021	A	M	90(45/45)	Lasted for 7 days	①②③	RCT
Guo Hongyan 2020	A	M	46(23/23)	Lasted for 5 days	①	RCT
Guo Zhengang 2018	A	M	68(34/34)	Lasted for 7 days	①②	RCT
Liu Chaoyang 2009	A	M	62(31/31)	Unknown	①	RCT
Liu Limei 2012	A+EA	M	60(30/30)	Lasted for 3 days	①	RCT
Liu Yonggang 2021	A	M	90(45/45)	Lasted for 5 days	①	RCT
Su Changming 2007	A	M	80(40/40)	Lasted for 5 days	①	RCT
Wang Jinhua 2019	A	M	100(50/50)	Lasted for 7 days	②	RCT
Wang Liang 2020	A	M+BT	60(30/30)	Lasted for 7 days	①②	RCT
Wang Zhenguo 2019	A+AS	M	60(30/30)	Lasted for 7 days	①②④	RCT
Yang Jie 2015	A	M	98(49/49)	Lasted for 7 days	①②	RCT
Yang Lanlan 2019	A	M	92(46/46)	Lasted for 7 days	①②	RCT
Yang Qingtang 2017	A	M	96(48/48)	Lasted for 7 days	①②④⑤	RCT
Zhang Honglei 2020	A+EA	M	98(49/49)	Lasted for 7 days	①	RCT
Zhang Jun 2021	A	M	76(38/38)	Lasted for 4 weeks	①②	RCT
Zheng Desong 2016	A	M	96(48/48)	Lasted for 7 days	②	RCT

Abbreviation: T: treatment group; C: control group

A: acupuncture M: Metoclopramide EA: ear acupuncture

BT: Breath training AS: acupoint sticking

①the Effective Rate ②Hiccup Symptom Score ③Life Quality Score

④Adverse Reaction ⑤SAS(Self-Rating Anxiety Scale)

RCT: randomized controlled trial

Table 2. Characteristics of included studies(2).

Study	Year	Country	Study period	Age (years) (mean ± SD)
				T	C
Chen Shuang	2017	China	2015.1–2016.12	64	63
Chi Xiangfeng	2019	China	2015. 10–2017.12	58.48±9.09	57.96±8.53
Cui Meijuan	2021	China	2018 .3–2020.3	55.59±3.67	55.55±3.64
Guo Hongyan	2020	China	2018.1–2019.6	64.5	64.5
Guo Zhengang	2018	China	2014.6–2017.6	56.3±5.36	56.2±5.35
Liu Chaoyang	2009	China	2005 .5–2008.3	62	64
Liu Limei	2012	China	2008.8–2011.2	61.5	58.5
Liu Yonggang	2021	China	2020.1–2020.12	71.0±8.1	71.2±8.4
Su Changming	2007	China	2002.5–2006.10	56.6±15.2	57.9±13.6
Wang Jinhua	2019	China	2015.3–2016.4	62.35±4.2	59.6±5.5
Wang Liang	2020	China	2017.4–2020.4	61.43±5.69	61.85±6.12
Wang Zhenguo	2019	China	2017.7–2018 .6	58.00±10.23	58.20±11.18
Yang Jie	2015	China	2012.12–2013.12	61.32±5.59	62.07±5.63
Yang Lanlan	2019	China	2016 .3–2017.10	60.25±3.25	60.35±3.14
Yang Qingtang	2017	China	2014.6—2016 .6	65.50±7.39	64.25±8.89
Zhang Honglei	2020	China	2016.2–2018.8	60.98±12.79	61.34±13.15
Zhang Jun	2021	China	2010.3–2021.3	60.5±0.3	60.4±0.4
Zheng Desong	2016	China	2014.7–2015.3	62±5	63±4

NOTE: Abbreviation: SD: standard deviation; T: treatment group; C: control group.

3.3. Bias risk assessment

All 18 studies were randomized controlled trials. In accordance with the Cochrane tool, every study referencing randomization did so, excluding one study [19]. Seven studies did not specify the mechanism of randomization [12,13,15,18,27–29]. The random number table approach or computer-generated random number method was employed in 10 studies to generate random sequences [14,17,20–26,30]. Allocation concealment was not discussed in any study. Regarding outcome completeness, bias risk in all trials was rated as low. Other biases were marked as uncertain due to insufficient data. Overall, the included studies exhibited low-quality standards. Figure 2 and Figure 3 provide a summary of the quality assessment of eligible studies.

Figure 2. Diagram of the bias risk.

Note: Green: Low risk of bias; Yellow: Unclear risk of bias; Red: High risk of bias

Figure 3. Summarized bias risk.

3.4. Results of meta-analysis

3.4.1. Effective rate

Sixteen studies compared the effective rate at treatment completion [12–15,17–21,23–26,26–30], with 16 trials involving 1206 participants. As no significant heterogeneity was detected between the studies (I² = 9%, P = 0.35, P > 0.1), the fixed-effects model was applied for analysis. The results demonstrated a significantly higher effective rate in the treatment groups compared to the control groups (RR: 1.27, 95% CI: 1.21–1.33; P < 0.00001), with a notable group difference indicated by P < 0.00001. (Figure 4).

Figure 4. Outcome of meta-analysis.

3.4.2. Hiccup symptom score

Twelve studies reported hiccup symptom scores in the acupuncture and control groups [14,15,18–26,30]. The heterogeneity test revealed strong heterogeneity I² = 97%, P < 0.00001, prompting the selection of the random-effects model for meta-analysis (Figure 4, WMD: −1.28, 95% CI: −1.64, −0.93; P < 0.00001). The intervention group exhibited significantly lower hiccup symptom scores compared to the control group (P < 0.00001).

Given the pronounced heterogeneity (I² = 97%), meta-regression analysis was further conducted, including age and treatment duration. The meta-regression indicated no significant association between treatment effect and treatment duration(Coef. = 0.006, Std. Err. = 0.028, P = 0.823 (95% CI − 0.048, 0.060). Similarly, age showed no significant association with treatment effect (Coef. = 0.099, Std. Err. = 0.284, P = 0.727 (95% CI − 0.458, 0.657).

3.4.3. Life quality score

One study reported improvement in quality of life following treatment [18]. The fixed-effect model demonstrated a significant difference in quality of life improvement between the acupuncture and conventional drug groups (WMD: 8.470, 95% CI: 7.323 ~ 9.617; P < 0.00001).

3.4.4. Adverse events rate

Two studies reported adverse events [14,24]. In the first study [14], one case of skin rash occurred in the acupuncture group, while the control group featured two instances of sleepiness, one of dizziness, and three of nausea. The second study [24] included one case of hematoma, one of bleeding, and two of pain in the acupuncture group, with the control group having five cases of nausea, tiredness, and sleepiness. The fixed-effects model indicated a lower incidence of adverse events in the acupuncture group compared to the control group (RR: 0.45, 95% CI: 0.16 ~ 1.25; P = 0.13), although the difference was not statistically significant (P = 0.19).

3.4.5. SAS (Self-Rating Anxiety Scale)

Only one study reported SAS scores for the therapeutic and control groups after the entire treatment [24]. The results from the fixed-effects model demonstrated a significant difference between groups (P < 0.00001), indicating that SAS scores in the acupuncture group were lower than those in the control group (WMD: −7.23, 95% CI: −8.47~−5.99; P < 0.00001).

3.5. Bias test

3.5.1. Bias test of effective rate

A funnel plot analysis of the 16 studies indicated potential publication bias (Egger test, P < 0.05), which necessitated bias correction using the trim and fill method (Figure 5). After six iterations, 22 articles were hypothesized, eliminating publication bias. The combined effect of these 22 articles yielded RR = 3.278 (3.144–3.419). A comparison of results before and after the trim and fill method showed minimal changes, indicating relatively stable results. (Figure 6)

Figure 5. Bias test of the effective rate and hiccup symptom score.

Figure 6. Trim and fill method of the effective rate.

3.5.2. Bias test of hiccup symptom score

The bias test demonstrated P = 0.605 (P > 0.05), suggesting the absence of publication bias in this study. (Figure 5)

3.6. Sensitivity analysis

3.6.1. Sensitivity analysis of the effective rate

Sensitivity analysis of the 16 studies indicated no strong influence of any individual study on the results, suggesting robustness in the study findings. (Figure 7)

Figure 7. Sensitivity analysis.

3.6.2. Sensitivity analysis of hiccup symptom score

The sensitivity analysis of the 12 studies is as follows (Figure 7). It was found that no literature will have a strong impact on the results, suggesting that the results of this study are relatively robust.

3.7. The GRADE approach

The web version of GRADE pro was utilized to evaluate the evidence quality of outcome indicators. Due to a lack of blinding implementation, allocation concealment, and high heterogeneity among studies, potential publication bias may exist. With regard to outcome indicators, except for the hiccup symptom score, the evidence level ranged from moderate to low.

4. Discussion

Accumulating clinical studies have consistently demonstrated the efficacy of acupuncture in addressing hiccups following strokes. A prior meta-analysis indicated that acupuncture might be a promising approach in managing post-stroke hiccups when compared to simple drug therapy. However, the limited number of randomized controlled trials and the single outcome indicators in this study have compromised the overall quality of evidence [32]. Therefore, we embarked on a more comprehensive exploration of acupuncture’s effectiveness in post-stroke hiccup treatment. The outcomes of the meta-analysis showcase that the acupuncture group exhibited a higher effective rate compared to the control group, with a statistically significant difference. Moreover, the acupuncture group demonstrated a relatively higher level of safety, contributing positively to the emotional well-being and quality of life of critically ill rehabilitation patients.

Post-stroke hiccups arise from a complex interplay of various factors. Modern medical observations and research have indicated the close interrelation between post-stroke hiccups and other mechanisms, such as gastric disorders [33,34], upper gastrointestinal bleeding [31], abnormal neurotransmitters function [35], and electrolyte imbalances [36,37]. Ding proposed that acupuncture applied to the stomach area could inhibit the Vagus nerve through a reflex arc, leading to the reduction of 5-HT receptor release in the phrenic nerve. This inhibition helps mitigate the diaphragm spasms causing hiccups [38]. The acupuncture technique of ‘regulating the mind and stomach’ influences the visceral autonomic nerve center within the thalamus by modulating the mind. This, in turn, impacts the hiccup reflex arc and alleviates diaphragm spasms, effectively relieving hiccups [39].

For the current meta-analysis, studies meeting the inclusion criteria between 1995 and 2021 were incorporated to evaluate acupuncture’s efficacy in post-stroke hiccup treatment. In total, 18 studies with 1395 patients were included. As per the findings, acupuncture potentially surpasses the efficacy of Metoclopramide in managing post-stroke hiccups and appears to have a more favorable impact on hiccup symptoms. Acupuncture interventions also seem to ameliorate patient anxiety, elevate their quality of life, and exhibit low adverse event rates. Nevertheless, the limited number of included studies and the relatively low quality of evidence suggest that these outcomes might be influenced by the severity of the ailment. Consequently, further research is imperative to delve into whether acupuncture can substantially enhance patients’ quality of life and emotional well-being.

5. Limitations

The meta-analysis findings indicate a favorable impact of acupuncture on post-stroke hiccups. However, it’s essential to acknowledge certain limitations. Firstly, the majority of the included randomized controlled trials are based on small sample sizes, and the overall number of studies contributing to the results remains limited. This could potentially affect the robustness and generalizability of the findings. Secondly, within the included studies, there is a lack of uniformity in the criteria used to assess treatment efficacy, and the scope of outcome indicators is not comprehensive. This variability might have implications for accurately evaluating the true effect of acupuncture. To establish whether acupuncture yields a sustained and consistent effect on post-stroke hiccups, further research endeavors are warranted. These investigations should strive for larger sample sizes, standardized curative effect criteria, and comprehensive outcome indicators to enhance the accuracy and reliability of the assessments.

6. Conclusions

In conclusion, acupuncture appears to hold promise as an effective intervention for addressing post-stroke hiccups. Its potential lies in its ability to mitigate hiccup symptoms, enhance quality of life, and alleviate anxiety. However, it’s crucial to acknowledge that the outcomes might be influenced by the limited quality and potential publication bias of the combined studies. Urgently needed are large-scale, multi-center, high-quality randomized controlled trials to enhance the clinical applicability and further promote the utilization of acupuncture in post-stroke hiccup treatment. To achieve the most optimal clinical solution, future research should delve into the interplay between acupuncture and conventional drug therapies, seeking a comprehensive understanding of their relationship.

Disclosure statement

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

Additional information

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.