Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis

Abstract

Background:

Sepsis is a life-threatening organ dysfunction caused by dysregulation of the host response to infection. Acupuncture is used for treatment of inflammatory diseases; however, its effectiveness and safety as a complementary therapy for sepsis has not been fully explored.

Methods:

Data were retrieved from eight databases. Randomized controlled trials (RCTs) that compared acupuncture plus conventional therapies versus conventional therapies alone were included. Pre-specified primary outcomes were mortality at 28 days and Acute Physiologic and Chronic Health Evaluation (APACHE) II scores.

Results:

A total of 17 studies with 1099 participants were included in this study. In terms of the primary outcomes, acupuncture plus routine therapy reduced mortality at 28 days (risk ratio (RR)): 0.69, 95% confidence interval (CI): 0.52 to 0.91, p < 0.001) and APACHE II scores (mean difference (MD): −2.84, 95% CI: −4.09 to −1.58, p < 0.001) at day 7 after treatment compared with routine therapy alone. In terms of secondary outcomes, acupuncture plus routine therapy reduced white blood cell counts and levels of procalcitonin (PCT), tumor necrosis factor (TNF)-α, interleukin (IL)-6 and lactic acid and intra-abdominal pressure (IAP), and improved CD3+, CD4+ and monocytes of human leukocyte antigen (HLA)-DR at day 7 after treatment compared with routine therapy alone. However, acupuncture plus routine therapy had no significant effects on levels of IL-10, C-reactive protein (CRP), CD8+ and CD4+/CD8+ ratios compared with routine therapy alone. Quality of evidence was low to very low for all parameters (GRADE).

Conclusion:

The available evidence showed that combination of acupuncture and routine therapy may have benefit for sepsis compared with use of routine therapy only. Due to the low degree of certainty regarding its effects, further research is required.

Trial registration number:

ICRD42019141491 (PROSPERO).

Keywords

acupuncture complementary therapy meta-analysis sepsis systematic review

Introduction

Sepsis is characterized by life-threatening organ dysfunction caused by dysregulation of host response to infection,¹ and represents a global health burden.² A recent study reported that 48.9 million people worldwide are affected by sepsis, and there were 11 million sepsis-related deaths in 2017.³ These numbers may be further exacerbated by the COVID-19 pandemic. Antimicrobial therapy, fluid administration and mechanical ventilation are conventional approaches for the treatment of sepsis.⁴ Although the mortality rate of in-hospital sepsis has decreased in recent years,⁵ it remains an economic burden as current treatment approaches are expensive.^6,7

Acupuncture is an important part of traditional Chinese medicine (TCM). Evidence has shown that acupuncture can be used for several inflammatory diseases, such as acute pancreatitis,⁸ ulcerative colitis⁹ and asthma.¹⁰ Furthermore, studies have shown that acupuncture may play an active role in the treatment of COVID-19 based on a bioinformatics/network topology strategy.¹¹ Animal experiments have shown that acupuncture can help reduce heart, lung, kidney, liver, gastrointestinal tract and immune system damage caused by sepsis.¹² The mechanism of action of acupuncture for sepsis is believed to involve modulation of inflammatory cytokines^13,14 and maintenance of immune balance.¹⁵ Electroacupuncture (EA) of the sciatic nerve controls systemic inflammation by inducing the vagus nerve to activate the aromatic l-amino acid decarboxylase, which mediates production of dopamine in the adrenal medulla. Furthermore, dopamine inhibits cytokine production through dopaminergic type 1 receptors.¹³ Several clinical trials have reported that acupuncture is effective in the management of sepsis;^16–19 however, according to published reports,^20,21 there is a lack of high-quality evidence for the efficacy and safety of acupuncture as a complementary therapy for sepsis. Therefore, we carried out a systematic review and meta-analysis of randomized controlled trials (RCTs) to assess the effectiveness of acupuncture in sepsis treatment.

Methods

This systematic review and meta-analysis was registered in PROSPERO (CRD42019141491), and its peer-reviewed protocol has been previously published.²²

Criteria for considering studies for this review

In this review, we explored RCTs that used acupuncture as a complementary therapy for sepsis. All participants of the included studies were diagnosed with sepsis.^1,4,23–29 To be included, the experimental group needed to include patients treated with acupuncture plus routine therapies, whereas the control group needed to include patients who had been treated with routine therapies only. Primary outcomes considered in this review included mortality at 28 days and Acute Physiologic and Chronic Health Evaluation (APACHE) II scores. Secondary outcomes included the following inflammatory and immune indices (measured in serum/plasma): tumor necrosis factor α (TNF-α) content, interleukin (IL)-6 content, IL-10 content, procalcitonin (PCT), lactic acid, level of T cell subsets (CD3+, CD4+, CD8+, CD4+/CD8+), monocytes of human leukocyte antigen (HLA)-DR, C-reactive protein (CRP) and white blood cell (WBC) count. Intra-abdominal pressure (IAP) and adverse events or reactions were also considered.

Search strategy and study selection

Studies included in the review were retrieved from three English language databases (PubMed, the Cochrane Central Register of Controlled Trials (CENTRAL) and Embase) and five Chinese language databases (China National Knowledge Infrastructure, Wan Fang Data, VIP database, Chinese Biomedical Database and TCM Literature Analysis and Retrieval Database) that were searched from their date of inception to 30 September 2020. The procedure used to carry out the search is shown in Supplemental Appendix File 1. In addition, we searched Google Scholar and the Chinese Clinical Trial Registry (ChiCTR) clinical trial registration platform, and manually searched the journals articles and conference proceedings in the library of Shandong University of TCM.

Two investigators (CZ and YZ) independently screened the studies by title and abstract, or full text where necessary. A third reviewer (XZ) made the final decision when disagreements occurred between the two.

Data extraction and quality assessment

Two investigators (LW and JX) independently retrieved data using a standardized data extraction form and a third investigator (HY) resolved differences of opinion. The name of the first author, year of publication, inclusion and exclusion criteria, number of patients and reviews, type of acupuncture and outcome measures were recorded. Two investigators (JX and LW) independently assessed the risk of bias using the Cochrane risk of bias tool for RCTs.³⁰

Statistical analysis

We calculated the risk ratio (RR) and 95% confidence interval (CI) for dichotomous data, and mean difference (MD) or standardized mean difference (SMD) with 95% CI for continuous data. Heterogeneity of studies was evaluated using the χ² test and I² statistics. Fixed-effects models were used for meta-analyses unless I² ⩾ 40%, in which case random-effects models were applied. Subgroup analyses were used to explore causes of heterogeneity. Sensitivity analyses of primary outcomes were used to confirm robustness of the findings. We planned to assess publication bias using funnel plots and Egger’s test if at least 10 trials were included. Quality and certainty of evidence were summarized using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach and presented as a “summary of findings” tables.³¹ Meta-analyses were conducted using Review Manager V.5.3 software (The Nordic Cochrane Centre, The Cochrane Collaboration, Copenhagen, 2014). Sensitivity analyses and Egger’s test were performed using Stata version 14.0 (StataCorp LLC, College Station, TX, USA).

Results

A total of 232 reports were retrieved through database searches. Out of the 232 reports, 194 duplicate publications or those unrelated to the search criteria were discarded and 16 reports were excluded as they did not match the inclusion criteria. A total of 22 reports from 17 studies that met the inclusion criteria were included in the systematic review or qualitative analysis^{16–19,32–49} (Figure 1).

Description of studies

All the included studies were conducted in China. Three reports were published in English^17,18,45 and 19 reports were published in Chinese.^{16,19,32–44,46–49} One study³⁴ comprised four reports, whereas two studies^32,45 each comprised two reports.

We analyzed a total of 1099 patients from the 17 RCTs. Out of these, 581 patients were treated with acupuncture plus routine therapies, whereas 558 patients were treated with routine therapies only. Detailed characteristics of the included studies are shown in Table 1.

Table 1.

Characteristics of the included studies.

Study (first author, year)	Sample size (A/C)	Mean age, years	Sex (male/female) A, C	Acupuncture		Outcomes
Study (first author, year)	Sample size (A/C)	Mean age, years	Sex (male/female) A, C	Traditional acupuncture point locations	Method and dose of acupuncture	Outcomes
Wu 2013³²	26/24	A: 73.50 ± 8.96 C: 69.88 ± 8.96	19/7, 16/8	ST36, ST25, ST37, ST39	EA 6 sessions in 3 days	⑥⑦⑬⑭
Cai 2014³⁵	16/14	A: 72.13 ± 9.35 C: 70.48 ± 9.23	10/6, 8/6	ST36, ST25, ST37, ST39	EA 10 sessions in 5 days	①②④
Hu 2014³⁴	29/29	A: 72.55 ± 12.84 C: 71.17 ± 12.25	20/9, 17/12	ST36, CV4	EA 14 sessions in 7 days	①②③④⑤⑨⑩⑪⑫⑬⑭⑮
Yu 2015³⁸	46/44	NR	NR	ST36, ST37, CV12, CV6, ST25, PC6	MA 5 sessions in 5 days	②⑮
Xiao 2015¹⁶	30/30	A: 69.96 ± 10.45 C: 65.42 ± 10.28	17/13, 16/14	ST36, GB34, PC6, CV4	MA 6 sessions in 6 days	①⑨⑩⑪⑫
Wu 2016³⁹	25/25	A: 63.6 ± 14.8 C: 67.3 ± 15.2	12/13, 13/12	ST36	EA 14 sessions in 7 days	①②④⑤⑦⑧⑩⑪⑭
Zeng 2016⁴⁰	32/28	A: 70 ± 5 C: 70 ± 7	20/12, 16/12	GV20, GV26, PC6	MA 14 sessions in 7 days	②③⑤⑨⑩⑪⑫
Jin 2016⁴²	23/20	A: 47.6 ± 8.5 C: 51.2 ± 7.9	17/6, 15/5	ST36, ST25, ST37, ST39	EA 14 sessions in 7 days	②⑥⑦⑧
Wang 2016⁴¹	32/28	A: 70.14 ± 5.28 C: 71.06 ± 6.64	20/12, 16/12	ST36, CV4	MA 14 sessions in 7 days	②⑤
Wei 2017⁴³	20/21	A: 71.9 ± 15.2 C: 68.3 ± 14.8	15/5, 13/8	GV13, CV12, GV10, ST25, ST36, GB34	MA 28 sessions in 28 days	①②④⑤⑮
Lin 2017⁴⁴	69/69	NR	NR	ST36, CV4	MA 14 sessions in 7 days	②⑤
Meng 2018⁴⁵	36/35	A: 61.7 ± 14.9 C: 59.8 ± 13.3	16/19, 19/17	ST36, ST37	EA 10 sessions in 5 days	①⑤⑥⑫⑮
Zeng 2018⁴⁶	37/35	A: 61.7 ± 10.0 C: 63.4 ± 10.3	20/17, 18/17	ST36, BL23, KI3, SP6	MA 14 sessions in 7 days	①②⑥⑦
Li 2019¹⁹	20/20	A: 67.1 ± 4.1 C: 65.9 ± 4.2	11/9, 13/7	Jia ji points (T6-T10 spinal levels)	MA 10 sessions in 10 days	②⑮
Wang L 2019⁴⁷	54/54	A: 74.41 ± 12.14 C: 75.32 ± 13.21	31/23, 30/24	ST36	MA 3 sessions in 3 days	②⑤⑭
Wang X 2019⁴⁸	20/20	A: 62.1 ± 15.59 C: 62.55 ± 15.73	8/12, 14/6	GV13, CV12, GV10, ST25, ST36, GB34	MA 7 sessions in 7 days	①②④⑤⑮
Sun 2019⁴⁹	36/32	A: 71.42 ± 8.55 C: 71.16 ± 7.91	22/14, 20/12	ST36, CV12, ST25, ST37, ST39	EA 14 sessions in 3 days	②④⑤⑮

EA: electroacupuncture; A: acupuncture; C: control; MA: manual acupuncture; NR: not reported.

① mortality at 28 days; ② APACHE II scores; ③ white blood cell (WBC) count; ④ C-reactive protein (CRP); ⑤ procalcitonin (PCT); ⑥ tumor necrosis factor α; ⑦ interleukin 6 (IL-6) content; ⑧ IL-10 content; ⑨ percentage of CD3+; ⑩ percentage of CD4+; ⑪ percentage of CD8+; ⑫ CD4+/CD8+; ⑬ monocytes of human leukocyte antigen (HLA)-DR; ⑭ lactic acid; ⑮ intra-abdominal pressure (IAP).

Risk of bias in included studies

Most studies included in this review were associated with low risk of bias in random sequence generation. However, risk of bias in allocation concealment was unclear and risk of performance/detection bias due to lack of blinding of participants/personnel and outcome assessors, respectively, was high. Twelve studies (71%) were at low risk of attrition bias, whereas 15 studies (88%) were at low risk of reporting bias. Detailed information is provided in Supplemental Appendix File 2.

Effects of interventions

Outcomes were measured at different time points. Mortality at 28 days and other outcomes on day 7 after treatment were selected and combined to give the main result in order to reduce heterogeneity secondary to variable time points. Moreover, subgroup analyses were used to evaluate results at all time points.

Mortality at 28 days

The experimental group showed lower mortality rates (fixed-effects RR: 0.69 (95% CI: 0.52 to 0.91)). Results showed no indication of statistical heterogeneity (I² = 0%, P = 0.72; Figure 2) and sensitivity analyses confirmed robustness of the results (Supplemental Appendix File 3A). The GRADE quality of this evidence was low (Table 2).

Table 2.

Summary of findings.

Outcome	Risk of bias	Inconsistency	Indirectness	Imprecision	Publication bias	Effect size (95% CI)	No. of participants (studies)	Quality of the evidence (GRADE)
Mortality at 28 days	Serious^a	Not serious	Not serious	Serious^b	Undetected	RR 0.69 (0.52, 0.91)	490 (9 studies)	Low
APACHE II	Serious^a	Serious^c	Not serious	Not serious	Strongly suspected^d	MD –3.34 (–4.07, –2.62)	720 (11 studies)	Very low
WBC count	Serious^a	Not serious	Not serious	Serious^b	Undetected	MD –2.87 (–4.35, –1.40)	118 (2 studies)	Low
CRP	Serious^a	Serious^c	Not serious	Serious^b	Undetected	MD –16.02 (–34.72, 2.67)	257 (5 studies)	Very low
PCT	Serious^a	Serious^c	Not serious	Not serious	Undetected	MD –1.49 (–2.32, –0.67)	586 (9 studies)	Low
TNF–α	Serious^a	Serious^c	Not serious	Serious^b	Undetected	MD –17.03 (–30.62, –3.43)	186 (3 studies)	Very low
IL–6	Serious^a	Serious^c	Not serious	Serious^b	Undetected	MD –16.28 (–23.74, –8.81)	165 (3 studies)	Very low
IL–10	Serious^a	Not serious	Not serious	Serious^b	Undetected	MD –3.16 (–9.85, 3.53)	93 (2 studies)	Low
CD3 +	Serious^a	Not serious	Not serious	Serious^b	Undetected	MD 6.51 (2.84, 10.18)	118 (2 studies)	Low
CD4 +	Serious^a	Serious^c	Not serious	Serious^b	Undetected	MD 6.74 (3.21, 10.27)	168 (3 studies)	Very low
CD8 +	Serious^a	Serious^c	Not serious	Serious^b	Undetected	MD 0.75 (–5.16, 6.66)	168 (3 studies)	Very low
CD4 +/CD8 +	Serious^a	Serious^c	Not serious	Serious^b	Undetected	MD 0.49 (–0.09, 1.07)	118 (2 studies)	Very low
HLA–DR	Serious^a	Not serious	Not serious	Serious^e	Undetected	MD 7.21 (1.75, 12.67)	58 (1 study)	Low
Lactic acid	Serious^a	Not Serious	Not serious	Serious^b	Undetected	MD –0.80 (–1.00, –0.60)	179 (3 studies)	Low
IAP	Serious^a	Serious^c	Not serious	Serious^b	Undetected	MD –1.65 (–2.34, –0.95)	381 (6 studies)	Very low

CI: confidence interval; GRADE: Grading of Recommendations Assessment, Development, and Evaluation; RR: risk ratio; APACHE II: Acute Physiologic and Chronic Health Evaluation II; MD: mean difference; WBC: white blood cell; CRP: C-reactive protein; PCT: procalcitonin; IL: interleukin; HLA-DR: monocytes of human leukocyte antigen DR; IAP: intra-abdominal pressure; TNF-α: tumor necrosis factor α.

High risk of bias owing to lack of blinding or/and allocation concealment (impossible by design).

The total sample size for this outcome may be less than the optimal information size.

I² was > 40%.

Egger’s test for publication bias showed p = 0.004.

Only one study was included.

APACHE II scores

A total of 11 studies reported APACHE II scores on day 7 after treatment (random-effects MD: −2.84 (95% CI: −4.09 to −1.58) with statistical heterogeneity (I² = 77%, p < 0.001; Figure 3). Sensitivity analyses showed that one study⁴⁹ contributed to statistical heterogeneity (Supplemental Appendix File 3B). Funnel plot and Egger’s test (p = 0.004) showed there was publication bias (Supplemental Appendix File 4). The GRADE quality of this evidence was very low (Table 2). Subgroup analysis showed that acupuncture plus routine therapies reduced the APACHE II scores more than the control group when treated with acupuncture for more than 3 days (Supplemental Appendix File 5, Figure S1).

WBC counts

Merged data showed that acupuncture plus routine therapies reduced WBC counts on day 7 after treatment compared with WBC counts in the control group (fixed-effects MD: −2.87 (95% CI: −4.35 to −1.40)). The data showed no statistical heterogeneity (I² = 0%, p = 0.39; Table 3). The GRADE quality of this evidence was low (Table 2). Subgroup analysis showed that acupuncture plus routine therapies did not reduce WBC counts compared with controls at day 3 after treatment (Supplemental Appendix File 5, Figure S2).

Table 3.

Results of secondary outcomes.

Secondary outcomes (at day 7 after treatment)	Studies	Participants	Result of heterogeneity		Statistical method	Result of meta-analysis
Secondary outcomes (at day 7 after treatment)	Studies	Participants	p value	I ²	Statistical method	Mean difference (95% CI)	p value
WBC count	2	118	0.39	0%	Fixed-effects models	−2.87 (−4.35, −1.40)	0.0001
CRP content	5	257	<0.001	91%	Random-effects models	−16.02 (−34.72, 2.67)	0.09
PCT content	9	586	<0.001	81%	Random-effects models	−1.49 (−2.32, −0.67)	0.0004
TNF-α content	3	186	0.001	85%	Random-effects models	−17.03 (−30.62, −3.43)	0.01
IL-6 content	3	165	0.1	57%	Random-effects models	−16.28 (−23.74, −8.81)	<0.0001
IL-10 content	2	93	0.46	0%	Fixed-effects models	−3.16 (−9.85, 3.53)	0.35
Percent of CD3+	2	118	0.79	0%	Fixed-effects models	6.51 (2.84, 10.18)	0.0005
Percent of CD4+	3	168	0.04	68%	Random-effects models	6.74 (3.21, 10.27)	0.0002
Percent of CD8+	3	168	<0.001	94%	Random-effects models	0.75 (−5.16, 6.66)	0.80
Ratio of CD4+ to CD8+	2	118	0.03	80%	Random-effects models	0.49 (−0.09, 1.07)	0.10
HLA-DR	1	58	NA	NA	Fixed-effects models	7.21 (1.75, 12.67)	0.01
Lactic acid content	3	179	0.27	24%	Fixed-effects models	−0.80 (−1.00, −0.60)	<0.00001
IAP	6	381	0.003	72%	Random-effects models	−1.65 (−2.34, −0.95)	<0.00001

CI: confidence interval; CRP: C-reactive protein; PCT: procalcitonin; TNF-α: tumor necrosis factor α; IL-6: interleukin 6; IL-10: interleukin 10; HLA-DR: monocytes of human leukocyte antigen DR; IAP: intra-abdominal pressure; WBC: white blood cell.

CRP content

Five studies reported CRP content at day 7 after treatment (random-effects MD: −16.02 (95% CI: −34.72 to 2.67)) and findings showed statistical heterogeneity (I² = 91%, p < 0.001; Table 3). The GRADE quality of this evidence was very low (Table 2). The finding was consistent with subgroup analysis results (Supplemental Appendix File 5, Figure S3).

PCT content

Analysis of merged data showed reduced PCT content for acupuncture plus routine therapies at day 7 after treatment compared with the control groups (random-effects MD: −1.49 (95% CI: −2.32 to −0.67)) and findings were statistically heterogeneous (I² = 81%, p < 0.001; Table 3). The GRADE quality of this evidence was low (Table 2). Subgroup analysis showed that acupuncture plus routine therapies reduced PCT content compared with the control when acupuncture treatment was administered for more than 3 days (Supplemental Appendix File 5, Figure S4).

TNF-α content

Analysis of merged data showed lower TNF-α content for acupuncture plus routine therapies at day 7 after treatment compared with the control group (random-effects MD: −17.03 (95% CI: −30.62 to −3.43)). Findings were statistically heterogeneous (I² = 85%, p = 0.001) for the merged data (Table 3). The GRADE quality of this evidence was very low (Table 2). Subgroup analysis showed that acupuncture plus routine therapies did not reduce TNF-α content count compared with the control group at day 3 after treatment (Supplemental Appendix File 5, Figure S5).

IL-6 content

Pooled analysis of three studies showed a random-effects MD of IL-6 content of −16.28 (95% CI: −23.74 to −8.81). Analysis showed statistical heterogeneity (I² = 57%, p = 0.1; Table 3). The GRADE quality of this evidence was very low (Table 2). Subgroup analysis showed lower IL-6 content for acupuncture plus routine therapies compared with the control group when acupuncture treatment was administered for more than 3 days (Supplemental Appendix File 5, Figure S6).

IL-10 content

Two studies reported IL-10 content at day 7 after treatment (fixed-effects MD: −3.16 (95% CI: −9.85 to 3.53)). Analysis showed no statistical heterogeneity for IL-10 content (I² = 0%, p = 0.46; Table 3). The GRADE quality of this evidence was low (Table 2). Subgroup analysis showed no significant differences in IL-10 content for acupuncture plus routine therapies compared with the control group, both at day 3 and day 7 after treatment (Supplemental Appendix File 5, Figure S7).

Percentage of CD3+

Analysis of merged data showed an increase in CD3+ levels after acupuncture plus routine therapies at day 7 after treatment compared with the levels of the control group (fixed-effects MD: 6.51 (95% CI: 2.84 to 10.18)). Notably, CD3+ data showed no statistical heterogeneity (I² = 0%, p = 0.79; Table 3). The GRADE quality of this evidence was low (Table 2). Similar findings were observed for subgroup analysis (Supplemental Appendix File 5, Figure S8).

Percentage of CD4+

Pooled analysis of three studies showed that the random-effects MD was 6.74 (95% CI: 3.21 to 10.27) with statistical heterogeneity (I² = 68%, p = 0.04; Table 3). The GRADE quality of this evidence was very low (Table 2). Subgroup analysis showed higher levels of CD4+ after acupuncture plus routine therapies compared with the control group when acupuncture treatment took more than 3 days (Supplemental Appendix File 5, Figure S9).

Percentage of CD8+

Three studies reported CD8+ levels as a percentage at day 7 after treatment (random-effects MD: 0.75 (95% CI: −5.16 to 6.66)) with statistical heterogeneity (I² = 94%, p < 0.001; Table 3). The GRADE quality of this evidence was very low (Table 2). Similar findings were reported at day 3 after treatment (Supplemental Appendix File 5, Figure S10).

Ratio of CD4+ to CD8+

Analysis of merged data showed an increase in the ratio of CD4+ to CD8+ at day 7 after acupuncture plus routine therapies compared with the ratio of the control group (random-effects MD: 0.49 (95% CI: −0.09 to 1.07)) with statistical heterogeneity (I² = 80%, p = 0.03; Table 3). The GRADE quality of this evidence was very low (Table 2). Subgroup analysis showed an increase in the ratio of CD4+ to CD8+ at day 3 or more after treatment by acupuncture plus routine therapies (Supplemental Appendix File 5, Figure S11).

HLA-DR content

One study reported acupuncture plus routine therapies increased HLA-DR content at day 7 after treatment (fixed-effects MD: 7.21 (95% CI: 1.75 to 12.67; Table 3). The GRADE quality of this evidence was low (Table 2). However, subgroup analysis at day 3 after treatment showed that acupuncture plus routine therapies had no significant effect on HLA-DR content compared with the control group (Supplemental Appendix File 5, Figure S12).

Lactic acid content

Acupuncture plus routine therapies reduced lactic acid levels at day 7 after treatment. Pooled analysis of three studies showed that the fixed-effects MD was −0.80 (95% CI: −1.00 to −0.60) and findings showed no statistical heterogeneity (I² = 24%, p = 0.27; Table 3). The GRADE quality of this evidence was low (Table 2). Similar results were reported at day 3 after treatment (Supplemental Appendix File 5, Figure S13).

IAP

Analysis of merged data showed low IAP levels at day 7 after acupuncture plus routine therapies compared with the control group (random-effects MD: −1.65 (95% CI: −2.34 to −0.95)) and data showed statistical heterogeneity (I² = 72%, p = 0.003; Table 3). The GRADE quality of this evidence was very low (Table 2). Subgroup analysis showed low levels of IAP at day 3 of treatment using acupuncture plus routine therapies (Supplemental Appendix File 5, Figure S14).

Adverse events or reactions

Only three studies^42,43,48 reported adverse events after acupuncture and routine therapy. The findings suggested that acupuncture was not associated with side effects.

Certainty of the evidence

Evidence from RCTs indicated with a low level of certainty show that acupuncture plus routine therapies reduced mortality at 28 days, WBC count, PCT content, lactic acid and increased the percentage of CD3+ and HLA-DR content. Very low-quality evidence suggested that acupuncture plus routine therapies were associated with reduced APACHE II scores, TNF-α content, IL-6 content and IAP and increased percentage of CD4+. Detailed information is shown in Table 2.

Discussion

Acupuncture confers anti-inflammatory effects and modulates immune balance, and therefore has been used to treat sepsis as a complementary therapy. Several animal experiments have explored the use of acupuncture; however, the therapeutic mechanism is not clear. To our knowledge, this study is the first registered systematic review and meta-analysis of RCTs focusing on acupuncture as a complementary therapy for sepsis.

In this systematic review and meta-analysis, we included 17 RCTs with a total of 1099 patients diagnosed with sepsis. The findings showed that acupuncture plus routine therapies reduce mortality at 28 days, and also reduced APACHE II scores, used to measure severity of illness in critically ill patients,⁵⁰ at day 7 after treatment compared with the control groups. These findings are consistent with reports from previous studies.^20,21 Sensitivity analyses showed statistical heterogeneity in a study by Sun et al.⁴⁹ This heterogeneity could be attributed to the missing data of 12 patients. Subgroup analyses showed that acupuncture plus routine therapies reduced APACHE II scores after a certain amount of stimulation.

Sepsis is often accompanied by systemic bacterial infections. In addition, WBC counts and levels of CRP, IL-6, IL-10, PCT and TNF-a are positively correlated with severity and of sepsis and impact its prognosis.^51–55 In this review, we evaluated the effect of acupuncture on WBC counts and CRP levels and found that acupuncture plus routine therapies reduced WBC count at day 7 after treatment, but not at day 3 after treatment. By contrast, the results showed that acupuncture plus routine therapies had no effect on CRP levels. Furthermore, acupuncture plus routine therapies reduced PCT and TNF-α levels at days 3 and 7 after treatment. We also evaluated the effect of acupuncture on IL-6 and IL-10 levels and found that acupuncture reduced IL-6 levels and had no effect on IL-10 levels at 7 days after treatment.

Sepsis elicits inflammation and immunosuppressive responses.⁵⁶ Immune suppression is characterized by apoptosis of T cells. This study evaluated the levels of CD3+, CD4+ and CD4+/CD8+ T-cell subsets and showed that acupuncture plus routine therapies improved the percentage of CD3+ and CD4+ at day 7 after treatment. By contrast, acupuncture plus routine therapies had no effect on the percentage of CD8+ and ratio of CD4+/CD8+, which is consistent with the report of a previous study.²⁰ HLA-DR is an independent predictor of the occurrence of nosocomial infection and sepsis-related mortality.^57,58 One study included in our review reported that acupuncture plus routine therapies improved HLA-DR levels at day 7 but had no effect at day 3 after treatment.

Sepsis-related mortality increases with rising initial lactate levels.^59,60 We found that acupuncture plus routine therapies reduced lactate acid levels at day 3 and day 7 after treatment. Patients with sepsis often present with gastrointestinal symptoms such as bloating and IAP is an indicator of the degree of abdominal distension. Included studies reported that acupuncture plus routine therapies reduced IAP at days 3, 6, 7 and 10 after treatment.

To our knowledge, two systematic reviews and meta-analyses have previously reported on use of acupuncture.^20,21 However, our study has several advantages over these previous systematic reviews. First, this study includes meta-analysis of 22 reports from 17 RCTs. Outcomes were pooled only once to avoid overestimating the effectiveness of acupuncture as an adjunct to routine therapies. Second, this study evaluated parameters related to the severity and/or prognosis of sepsis, including WBC counts and levels of CRP, IL-6, IL-10, CD3+, CD4+, CD4+/CD8+ and lactate acid and IAP. Third, we conducted a comprehensive subgroup analysis to evaluate outcomes following acupuncture plus routine therapies on patients with sepsis at different time points.

Needle type, traditional acupuncture point locations and duration and frequency of treatment are important factors affecting the efficacy/effectiveness of acupuncture. In this study, we conducted a subgroup analysis of the main results by acupuncture type (EA vs manual acupuncture; Supplemental Appendix File 5, Figures S15–S29), and the results were not significantly different to the main results shown above. In addition, we carried out subgroup analysis by frequency of acupuncture and found that this may be the factor that influences effectiveness (Supplemental Appendix File 5, Figure S33–S44). The results showed that two acupuncture sessions per day reduced mortality rates at 28 days as well as PCT and IAP on day 7 after treatment when compared to the control group, while such effects were not seen in the subgroup receiving only one acupuncture session per day. In our main results, we found that on day 7 day after treatment, 10/14 outcomes suggested that acupuncture plus routine therapies was more effective than routine therapies alone, while on day 3 after treatment, only 6/14 outcomes showed statistically significant differences. Taken together, these observations suggest that acupuncture as a complementary therapy for sepsis requires the accumulation of a certain amount of stimulation.

Needling location (e.g. traditional acupuncture point selection) is also believed to be an important factor affecting the efficacy/effectivness of acupuncture. In our review, ST36 was used in 15 of the 17 included studies. Acupuncture at ST36 has been found to regulate the immune system and to exert anti-inflammatory effects in clinical trials⁶¹ and animal experiments.^12,62 Therefore, ST36 may be an important needling location when using acupuncture as a complementary therapy for sepsis. Bases on the existing evidence, this study has generated preliminary evidence for the effectiveness of acupuncture as a complementary therapy for sepsis, when used as an adjunct to standard care, but delineation of the ideal treatment characteristics requires more original studies.

This study had some limitations. Most included studies had an unclear risk or high risk of bias in allocation concealment and blinding of participants. In addition, included studies were mostly small sample single-center RCTs. Therefore, the degree of certainty around our findings is low to very low. Furthermore, although acupuncture is generally considered to be a low-cost therapy, whether acupuncture lowers sepsis treatment cost is unknown based on current evidence. In addition to efficacy/effectiveness for sepsis treatment, cost-effectiveness is an important factor to consider in determining whether to use acupuncture clinically.

Conclusion

Based on the available studies, supplementing conventional treatment with acupuncture may be beneficial in sepsis. Effects may be attributable to (or reflected by) reductions in WBC counts, levels of PCT, TNF-α, IL-6 and lactate acid and IAP, as well as improvements in CD3+, CD4+ and HLA-DR following acupuncture. Consideration should be given to provide acupuncture twice a day, for more than 7 days, and to include needling at ST36. These findings imply that acupuncture could have a potential role as a complementary therapy for sepsis, although further research is required to increase the certainly around its effectiveness as an adjunct to routine therapy.

Supplemental Material

sj-docx-1-aim-10.1177_09645284221086288 – Supplemental material for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis

Supplemental material, sj-docx-1-aim-10.1177_09645284221086288 for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis by Jin Xian, Ling Wang, Changyun Zhang, Jian Wang, Yushuo Zhu, Huijuan Yu, Xin Zhang and Qiwen Tan in Acupuncture in Medicine

Supplemental Material

sj-pdf-2-aim-10.1177_09645284221086288 – Supplemental material for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis

Supplemental material, sj-pdf-2-aim-10.1177_09645284221086288 for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis by Jin Xian, Ling Wang, Changyun Zhang, Jian Wang, Yushuo Zhu, Huijuan Yu, Xin Zhang and Qiwen Tan in Acupuncture in Medicine

Supplemental Material

sj-pdf-3-aim-10.1177_09645284221086288 – Supplemental material for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis

Supplemental material, sj-pdf-3-aim-10.1177_09645284221086288 for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis by Jin Xian, Ling Wang, Changyun Zhang, Jian Wang, Yushuo Zhu, Huijuan Yu, Xin Zhang and Qiwen Tan in Acupuncture in Medicine

Supplemental Material

sj-pdf-4-aim-10.1177_09645284221086288 – Supplemental material for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis

Supplemental material, sj-pdf-4-aim-10.1177_09645284221086288 for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis by Jin Xian, Ling Wang, Changyun Zhang, Jian Wang, Yushuo Zhu, Huijuan Yu, Xin Zhang and Qiwen Tan in Acupuncture in Medicine

Supplemental Material

sj-pdf-5-aim-10.1177_09645284221086288 – Supplemental material for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis

Supplemental material, sj-pdf-5-aim-10.1177_09645284221086288 for Efficacy and safety of acupuncture as a complementary therapy for sepsis: a systematic review and meta-analysis by Jin Xian, Ling Wang, Changyun Zhang, Jian Wang, Yushuo Zhu, Huijuan Yu, Xin Zhang and Qiwen Tan in Acupuncture in Medicine

Footnotes

Acknowledgements

We would like to thank Freescience for English language editing.

Contributors

JX and LW designed the study, extracted the data, access the risk of bias, analyzed the data and drafted the manuscript. CZ, YZ and XZ identified the studies include the study. JW and YH revised the manuscript critically for important intellectual content, and QT made the decision to submit the report for publication. All authors read and approved the final version of the manuscript.

LW and JX contributed equally.

Declaration of conflicting interests

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

Funding

The authors disclosed receipt of the following financial support for the research, authorship and/or publication of this article: This study is supported by funding from TCM “Zhi Wei Bing” Scientific Research Innovation Team of Shandong University of Traditional Chinese Medicine.

Availability of data and materials

The data and material used for this meta-analysis are contained in the references.

ORCID iDs

Jin Xian

Qiwen Tan

Supplemental material

Supplemental material for this article is available online.

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Supplementary Material

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