J Acupunct Meridian Stud 2016;9(5):234e241

Available online at www.sciencedirect.com

Journal of Acupuncture and Meridian Studies

journal homepage: www.jams-kpi.com

RESEARCH ARTICLE

Intraoperative Low-frequency
Electroacupuncture under General
Anesthesia Improves Postoperative Recovery
in a Randomized Trial
Dennis Grech 1, Zhifeng Li 2, Patrick Morcillo 2,
Evelyne Kalyoussef 3, David D. Kim 1,4, Alex Bekker 1, Luis Ulloa 2,*

1
Department of Anesthesiology, New Jersey Medical School, Rutgers University, Newark, NJ,
USA
2
Laboratory of Surgical Immunology, Department of Surgery, New Jersey Medical School,
Rutgers University, Newark, NJ, USA
3
Department of Otolaryngology, Head and Neck Surgery, New Jersey Medical School, Rutgers
University, Newark, NJ, USA
4
Departments of Pharmacology and Physiology, New Jersey Medical School, Rutgers
University, Newark, NJ, USA
Available online 4 April 2016

Received: Jan 13, 2016 Abstract

Revised: Mar 10, 2016 Neuronal stimulation improves physiological responses to infection and trauma, but the
Accepted: Mar 15, 2016 clinical potential of this strategy is unknown. We hypothesized that transdermal neural
stimulation through low-frequency electroacupuncture might control the immune re-
KEYWORDS sponses to surgical trauma and expedite the postoperative recovery. However, the effi-
cytokines; ciency of electroacupuncture is questioned due to the placebo effect. Here,
electroacupuncture; electroacupuncture was performed on anesthetized patients to avoid any placebo. This
inflammation; is a prospective double-blinded pilot trial to determine whether intraoperative electroa-
pain; cupuncture on anesthetized patients improves postoperative recovery. Patients with
physiological stress; electroacupuncture required 60% less postoperative analgesic, even they had pain scores
surgery similar to those in the control patients. Electroacupuncture prevented postoperative

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://
creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any me-
dium, provided the original work is properly cited.
* Corresponding author. Laboratory of Surgical Immunology, Department of Surgery, New Jersey Medical School, Rutgers University, 185
South Orange Avenue, Newark, NJ 07103, USA.
E-mail: Luis.Ulloa@Rutgers.edu (L. Ulloa).

pISSN 2005-2901 eISSN 2093-8152

http://dx.doi.org/10.1016/j.jams.2016.03.009
Copyright ª 2016, Medical Association of Pharmacopuncture Institute.
Intraoperative electroacupuncture 235

hyperglycemia and attenuated serum adrenocorticotropic hormone in the older and heav-
ier group of patients. From an immunological perspective, electroacupuncture did not
affect the protective immune responses to surgical trauma, including the induction of
interleukin-6 and interleukin-10. The most significant immunological effect of electroa-
cupuncture was enhancing transforming growth factor-b1 production during surgery in
the older and lighter group of patients. These results suggest that intraoperative electro-
acupuncture on anesthetized patients can reduce postoperative use of analgesics and
improve immune and stress responses to surgery.

1. Introduction many clinical studies on EA were not conclusive as the re-

sults were statistically similar to the placebo group [18,20].
The Centers for Disease Control and Prevention estimates We recently reported that EA regulated physiological re-
that there are over 51 million surgical procedures per- sponses to infection and trauma in anesthetized mice [9],
formed annually in the USA. Over 85% of surgical patients which are not susceptible to the placebo effect. Similar
report significant postoperative pain, with a higher inci- studies also indicated that ST36 stimulation induced anti-
dence in female patients [1]. Postoperative pain is treated nociceptive effects via adenosine A1 receptors [17]. The
with opioids that have multiple adverse side effects use of EA on anesthetized patients has been previously
including respiratory depression and decreased intestinal avoided assuming that general anesthesia may conceal the
motility [2]. These side effects increase the risk of surgical analgesic effects of EA. We hypothesized that low-
complications and delay postoperative recovery [3,4]. frequency EA may prevent physiological stress and
Furthermore, surgical trauma induces hyperglycemia, improve postoperative recovery. Low frequency EA acts on
physiological stress, and inflammation that can cause car- the arcuate nucleus of the hypothalamus, and converges in
diovascular, renal, and neurological complications the periaqueductal grey matter to induce endomorphin/
contributing to postoperative mortality [5e7]. Post- beta-endorphin/encephalin. The effects of endomorphin/
operative hyperglycemia is an insulin resistance process beta-endorphin/encephalin in low-frequency EA are medi-
that exacerbates inflammation, delays wound healing, and ated by the mu/delta opioid receptors [21]. Thus, low-
infections. Therefore, there is a clinical need of novel frequency EA can induce analgesic effects that depend on
strategies to reduce hyperglycemia and improve post- the activation of the opioidergic system. Here we per-
operative recovery. formed a prospective double-blinded randomized pilot
Neuromodulation represents efficient systems selected study to determine whether intraoperative EA (using acu-
by evolution to control physiological homeostasis [8e10]. points LI-4, LI-11, and ST-36) on anesthetized patients un-
Thus, neural stimulation can be a promising strategy to dergoing thyroid or parathyroid surgery could reduce the
attenuate surgical trauma. We reported that electrical use of analgesic, pain score, physiological stress, or im-
stimulation of the vagus nerve improves physiological re- mune cytokine responses. Given that our previous studies
sponses to infection and trauma [9,10]. These results were indicated that EA inhibited the production of inflammatory
confirmed by other investigators reporting that vagal cytokines [9], and surgical trauma induces inflammatory
stimulation improved physiological responses to experi- cytokines, we also analyzed whether intraoperative EA also
mental ischemia and reperfusion, hemorrhage, resuscita- regulated the immune cytokine responses.
tion, pancreatitis, colitis, endotoxemia, septic shock, and
severe sepsis [9e12]. In humans, surgical implantation of 2. Materials and methods
vagus nerve stimulators was first approved by the Food and
Drug Administration in 1997 for the treatment of refractory
epilepsy [13]. However, these studies have limited clinical 2.1. Clinical trial
implications because they were performed through a sur-
gical stimulation of the vagus nerve. Recently, we reported A prospective pilot study approved by the Institutional Re-
that transdermal neuronal stimulation with electro- view Board (Pro2012002417) of the New Jersey Medical
acupuncture (EA) also regulates physiological responses to School, Rutgers University, Newark, NJ, USA and registered at
infection and trauma [9]. Thus, transdermal neuronal clinicaltrials.gov (code NCT01937520). This was a prospective
stimulation with EA can represent a promising clinical double-blinded study with 20 patients undergoing thyroid and
approach to alleviate surgical trauma and improve post- parathyroid surgery randomized in two groups: EA (n Z 11)
operative recovery. group or sham (control, n Z 9) group. Participation was
EA is currently endorsed by the National Institutes of voluntary without economical compensation, and each
Health and the World Health Organization. Previous studies participant signed a written consent. Exclusion criteria
analyzed the potential of EA to alleviate postoperative pain include pre-existing diabetes, cardiovascular conditions, or
and nausea [14e16]. However, the results from these elevated levels of blood glucose, insulin, or tumor necrosis
studies were contradictory [16]. Many investigators ques- factor (TNF). Patient #11 was excluded because of pre-
tion these results because the patients were conscious and existing levels of TNF > 1 ug/mL prior to surgery. All pa-
therefore susceptible to placebo [14,15,17e19]. Indeed, tients underwent the induction of anesthesia with midazolam
236 D. Grech et al.

1e2.5 mg, propofol 1.0e2.0 mg/kg, fentanyl 1e3 mg/kg, and LI-11, and ST-36 acupoints would be stimulated alternately.
lidocaine 1 mg/kg. Then, anesthesia was maintained with Mild muscle twitching was observed. This setting showed
sevoflurane at a minimal alveolar concentration of 1.0e3.0 significant antihyperalgesic effects in a rat inflammation
mixed with 50% oxygen and 50% air. model [22,23] and also inhibited the upregulation of
interleukin (IL)-1b and its mRNA compared with the sham
2.1.1. Electroacupuncture (EA) control in a rat model of bone cancer pain [24].
Low-frequency EA consisted of two 30-minute treatments
stimulating simultaneously the He Gu (LI-4), Qu Chi (LI-11), 2.2. Clinical end-points
and Zu San Li (ST-36) acupoints simultaneously during the
maintenance phase of general anesthesia (Fig. 1A). LI-4 and
All analgesic treatments were converted to morphine
LI-11 acupoints lie on the large intestine meridian
equivalents of milligrams. Pain score (0e10) was deter-
(pathway). LI-4 point is located in the radial side of the
mined using a visual analog scale. The Quality of Recovery
hand at the middle of the second metacarpal bone; LI-11
scores, a nine-item validated tool (with a maximum best
point is located at the lateral end of the transverse cubi-
possible score of 18), was used to assess patient oriented
tal crease toward the elbow. ST-36 point is located on the
outcomes postoperatively.
outside of the anterior crest of the tibia and just below the
knee. EA was performed by a licensed anesthesiologist and
acupuncturist delivered by a stimulator (Digital Electronic 2.3. Serum analyses
Acupunctoscope 4-C, Model AWQ-104L Hong Kong, distrib-
uted by Lhasa Medical, Weymouth, MA, USA) at a 10-Hz All blood samples were collected during general anesthesia
frequency with continuous electrical current of wave from the radial arterial catheter. Blood samples were coag-
through 30-gauge EA needles. A symmetrical biphasic wave ulated for 120 minutes and centrifuge d at 800 g. Serum was
was delivered to the electrodes so that the electrode would aliquoted, and stored at 80 C. Hormones and immune cy-
be alternately positive and negative and the bilateral LI-4, tokines were analyzed using enzyme-linked immunosorbent

Figure 1 Electroacupuncture attenuated postoperative use of analgesia. (A) Control or two electroacupuncture (EA) treatments
of 30 minutes started w15 minutes after the induction of general anesthesia. Blood samples include: pre (before EA and surgery),
intra (after EA and during surgery), and post (during anesthesia but right after surgery). (BeE) Use of analgesics and pain score in
the control or EA group at the postanalgesia care unit (P) analyzing all the patients or female patients. (F) Use of analgesics at the
PACU in the age and body weight subgroups. (GeI) Use of analgesics, pain score, and Quality of Recovery (QoR) mean values of the
women with and without EA at the P and the 3 days after surgery. Graphs depict mean  standard error. * p < 0.1, ** p < 0.05.
eq Z equivalents.
Intraoperative electroacupuncture 237

assay as previously described [12], using human adrenocor-

Table 1 Demo graphics of the patients. Individual de-
ticotropic hormone (ACTH; CalBiotech, Spring Valley, CA,
mographics of the patients.
USA; catalogue number AC018T) and cortisol (CalBiotech;
catalogue number CO103S). Glucose was analyzed using the Patients Treat Sex Age (y) Weight (kg) Surgery
One Touch Ultra test (LifeScan Inc., Milpitas, CA, USA) [22]. 1 C F 33 80 T
TNF was analyzed using recombinant TNF (eBioscience 2 EA F 35 116 T
catalogue number 88-7346) as a standard curve and the 3 C F 51 104 T
capture (RRID:AB315249) and detection (Ab RRID:AB315255) 4 C F 45 67 T
antibodies (catalogue number 430201; Biolegend, San Diego, 5 C F 52 115 T
CA, USA). Human cytokines were analyzed using the Bio- 6 EA F 50 72.7 P
legend: IL2 (catalogue number 431801), IL6 (catalogue 7 EA F 61 63.6 P
number 430501), IL4 (catalogue number 430301), IL-10 8 C F 72 107 P
(catalogue numbers 571009, 501401, and 501501; Bio- 9 EA F 34 78 T
legend), and transforming growth factor-b1 (TGFb1) with 10 EA M 43 63.6 P
capture (21C11) and detection (19D8) antibodies (catalogue 11 EA F 43 56.8 P
numbers 580709, 525301, and 521705; Biolegend). Plates 12 EA M 44 99 T
were read at 450 nm with the VersaMax plate reader and 13 EA F 32 76.3 T
values were interpolated with the Open SoftMax Pro 3.5 14 C F 64 80 P
point-to-point regression software (Molecular Devices Corp, 15 EA F 55 e P
Sunnyvale, CA, USA). 16 EA F 48 61 T
17 C F 62 73 T
2.4. Statistical analyses 18 C F 52 74 P
19 EA F 47 90 T
We hypothesized that intraoperative EA may prevent hy- 20 C F 40 65 P
perglycemia, physiological stress, or inflammation. The C Z control; EA Z electroacupuncture; F Z female; M Z male;
principal outcome was analyzing serum levels of glucose, P Z parathyroid; T Z thyroid.
ACTH, cortisol, and immune (TNF, IL-2, IL-4, IL-6, IL-10, and
TGFb) cytokines. The second outcome was analyzing the
request of analgesics and the pain score. Sample size was
determined using standard deviation values and power Table 2 Distribution of the patients including sample size
analyses of our previous studies on EA in surgical-induced (n), average age, average body weight, number of patients
trauma and infection [9]. Statistical analyses were per- with thyroid (T) or parathyroid (P) surgery, and number of
formed using the Graphpad Prism 5.0 (La Jolla, CA, USA). female (F) patients.
Continuous variables were expressed as mean  standard n Age (y) Weight (kg) T P F
error. Normality and homogeneity of variance were
All 20 48.15  2.45 81.16  4.27 11 9 18
confirmed with Graphpad Prism 5.0 (GraphPad Software
Control 9 52.33  4.08 85.00  6.22 5 4 9
Inc, La Jolla, CA, USA) using the D’AgostinoePearson
EA 11 44.73  2.68 77.70  5.97 6 5 9
omnibus K2 test and the F-ratio of variances, respectively.
Results with non-normal distributions were analyzed with EA Z electroacupuncture.
the nonparametric ManneWhitney U test. Mean values with
normal distribution of two experimental groups were
analyzed using the parametric unpaired homoscedastic
Student t test; the Welch’s correction was used for samples patients with EA had a similar use of analgesics and pain
with different variances. Statistical analyses of more than score when the heterogeneous group (with both men and
two groups were performed with analysis of variance with women) of EA was compared with the control group (with
Bonferroni’s adjustment for multiple hypothesis testing. women only; Figs. 1B and C). Since sex affected the
Two-way analysis of variance was used to analyze the two threshold for analgesics and pain and both groups had the
factors of EA and time. Linear regressions were performed same number of women, we analyzed the effects of EA in
with Graphpad including the calculation of p values and women only. EA-treated women required 60% less analge-
squared correlation coefficients. sics than control women at the Postanalgesia Care Unit
(PACU), but both groups had similar pain scores (Figs. 1D
and E). We also compared the use of analgesics and pain
3. Results scores in the group of patients under or above the average
age (45 years) or body weight (75 kg). The request for an-
This prospective pilot study enrolled patients undergoing algesics and pain scores were similar in the subgroups of
thyroid and parathyroid surgery to analyze whether EA control patients with age (< 45 years vs. > 45 years) or
improves postoperative recovery. The demographics of the body weight (< 75 kg vs. > 75kg). However, EA significantly
patients (age, body weight, and surgical procedure) were reduced the request for analgesics in the younger (<
similar in the control and EA group (Tables 1 and 2). All 45 years) but not in the older patient group and induces a
patients were under general anesthesia during the EA and similar effect in the heavier and lighter patient groups
the blood collection, and thus they were blinded to the (Fig. 1F). After the hospital discharge, patients with or
treatment to avoid any placebo effect (Fig. 1A). The without EA had the same use of analgesics, pain scores, and
238 D. Grech et al.

quality of recovery during the 3 days after the surgery levels of both ACTH and cortisol in control patients by 10-
(Figs. 1GeI). and three-fold, respectively (Figs. 2A and C). Mean ACTH
The molecular mechanisms of EA were studied by serum levels were higher in the heavier (> 75kg) patient
analyzing the serum collected at three time points during group but similar between the two age subgroups (Fig. 2B).
anesthesia: preoperative before the surgery and EA; intra- Cortisol serum levels were statistically similar among all the
operative after the EA; postoperative during anesthesia but patient subgroups (Fig. 2D). EA reduced mean serum ACTH
right after surgery (Fig. 1A). Surgery increased the serum levels at the PACU by over 70% without affecting cortisol

Figure 2 Regulation of physiological stress and glycemia. (A,B) Blood from female patients with or without electroacupuncture
(EA) were collected before (Pre), during (Intra), and after (Post) surgery to analyze serum levels of adrenocorticotropic hormone
(ACTH). (C,D) Cortisol. (E,F) Glucose. (G) insulin. (B,D,F) Postoperative serum levels of ACTH, cortisol, and glucose in the age and
body weight subgroups. Graphs depict mean  standard error. * p < 0.1, ** p < 0.05, *** p < 0.005.
Intraoperative electroacupuncture 239

(Figs. 2A and C). EA reduced serum ACTH levels by over 80% request for analgesics in the EA group was a transient
in the older and heavier patient groups without affecting effect, and not due to a demographic difference in age,
the younger or lighter patient subgroups (Fig. 2B). One of sex, or body weight among the groups. In all, these results
the most significant effects of EA was preventing hyper- support the analgesic potential of EA, even when per-
glycemia. Surgery gradually increased hyperglycemia in the formed under general anesthesia.
control patients without affecting serum insulin levels The most significant effects of EA were preventing
(Figs. 2E and G), inducing a similar effect in all the patient postoperative stress and hyperglycemia. To our knowl-
subgroups. However, EA prevented hyperglycemia (Fig. 2E) edge, our study is the first evidence that EA in anes-
being more significant in the older and heavier patient thetized patients prevents postoperative hyperglycemia.
groups (Fig. 2F). Previous studies on EA and glycemia were performed in
EA also modulates the immune responses. TNF and IL-6 conscious patients susceptible to placebo. Most studies
are critical pyrogen and inflammatory cytokines produced were performed in diabetic patients with EA at the CV12
during the surgical trauma. IL-2 and IL-4 are critical cyto- acupoint to induce insulin production. However, post-
kines to induce cellular versus humoral immunity. Neither operative hyperglycemia is an insulin resistance process
surgery nor EA affected the serum levels of TNF, IL-2, or IL4 that exacerbates inflammation, delays wound healing,
(Figs. 3AeC). However, surgery increased serum IL-6 levels and infections. Given that EA reduced ACTH serum levels
by seven-fold postsurgery in the control and EA groups and that ACTH can induce insulin-resistant hyperglycemia
regardless of age and body weight (Figs. 3D and E). We also [23], EA may prevent hyperglycemia by inhibiting ACTH.
analyzed the critical anti-inflammatory cytokines IL-10 and In agreement with this hypothesis, EA attenuated both
TGFb1. Surgery increased serum IL-10 levels by two-fold ACTH and hyperglycemia with the same pattern in the
postsurgery in the control and EA groups regardless of age older and heavier patient groups. EA may inhibit ACTH
and body weight (Figs. 3F and G). The most significant production through a downstream neuronal network. LI4
immunological effect of EA was to increase serum TGFb1, a and LI11 acupoints lie on the large intestine meridian that
pivotal factor regulating the inflammation and wound attenuates sympathetic signals in the dorsal peri-
healing. Surgery increased serum TGFâ1 levels by four-fold aqueductal gray and the rostral ventrolateral medulla
postsurgery in the control patients (Fig. 3H). Serum TGFâ1 that innervates the paraventricular nucleus of hypothal-
levels were similar among the two control age subgroups amus. Meanwhile, ST36 activates the afferent sciatic
but 65% higher in the older than in the younger control nerve [17], which regulates the rostral ventrolateral nu-
group (Fig. 3I). EA induced three-fold higher serum TGFâ1 cleus via innervations from the paratrigeminal. Thus, LI4,
levels postsurgery (Fig. 3H). EA enhanced TGFâ1 serum LI11, and ST36 can converge at the paraventricular nu-
levels in the older and lighter patient groups but had no cleus of hypothalamus to inhibit corticotropin-releasing
significant effect in the younger and heavier patient groups hormone and thereby ACTH production from the pitui-
(Fig. 3I). tary gland. In turn, ACTH inhibition can then prevent
surgical-induced hyperglycemia. Our results concur with
previous studies indicating that EA affect neither intra-
4. Discussion operative ACTH nor cortisol levels during surgery [24]. Our
EA did not affect intraoperative serum levels of ACTH or
Previous studies of EA were performed on conscious pa- cortisol. However, EA inhibited postoperative ACTH levels
tients before or after anesthesia and therefore the pa- after the surgery. The specific regulation of ACTH without
tients were susceptible to a placebo effect [14e16,19]. To affecting cortisol has not been previously reported. By
our knowledge, our study describes the first clinical trial contrast, a recent study showed that EA can regulate both
of EA performed on anesthetized patients with all blood ACTH and cortisol in conscious patients [25]. This corre-
samples collected under general anesthesia. Low- lation likely involves the hypothalamicepituitaryeadrenal
frequency EA on anesthetized patients during surgery axis and the potential of ACTH to activate cortisol pro-
attenuated hyperglycemia, physiological stress, immune duction in the adrenal cortex. The inhibition of ACTH
responses, and postoperative request for analgesics. without affecting cortisol reveals the other factors regu-
Despite their similar demographics and pain scores, lating cortisol production.
women with EA required 60% less analgesics at the PACU. An important result was the potential of EA to induce
These results are important for four reasons: (1) all pa- TGFâ1 serum levels especially in the older and lighter
tients were under general anesthesia, and therefore patient groups. This pattern differs from the analgesic
blinded to the treatment to avoid any placebo effect. effects of EA in the younger patient groups, and the stress
Despite the general anesthesia, EA induced an anti- regulation of ACTH and hyperglycemia in the older and
nociceptive effect; (2) the lower amount of analgesics in heavier patient groups. Although these results are limited
the EA group did not cause a higher pain score. It is logical by the small sample size, the effects of age and body
to expect a lower pain score in the EA group, if both weight by EA are not well established. These different
groups would have received the same amount of analge- patterns may suggest different mechanisms induced by
sics; (3) female patients have a lower threshold for pain the stimulation of several acupoints to control TGFâ1,
and acupuncture than male patients. Thus, our results in pain, and physiological stress. Indeed, simultaneous
women are likely to be replicated in male patients; and stimulation of several acupoints at the same time has
(4) after the discharge, the groups had similar analgesic stronger effects than the stimulation of single acupoints
requirements and pain score, and quality of recovery [26]. For example, concurrent stimulation of LI11, CV12,
during the 3 days after the discharge. Thus, the lower and ST40 significantly attenuated atherosclerosis in
240 D. Grech et al.

Figure 3 Regulation of the Immune responses to surgical trauma. (A) Serum levels of tumor necrosis factor (TNF). (B) Interleukin
(IL)-2. (C) IL-4. (D) IL-6. (E) Glucose. (F,G) IL-10. (H,I) Transforming growth factor (TGF)b1 in control and electroacupuncture (EA)
groups at the indicated time points. (E,G,I) Postoperative serum levels of IL-6, IL-10, and TGFb1 in the postoperative (post)
samples. Graphs depict mean  standard error. * p < 0.1, ** p < 0.05.

hyperlipemic rats, but single acupoint stimulation did not We reported that ST36 inhibits inflammatory cytokines
[26]. Simultaneous stimulations trigger different mecha- TNF and IL-6 in septic mice [9]. Likewise, LI4 stimulation
nisms, which makes it harder to determine the discrete in rats prior to endotoxemia prevents TNF, IL-6, and IL-1,
mechanisms modulating a specific symptom. In addition to without affecting IL-10 or glucocorticoid levels [27]. Here,
the neuronal networks described above for LI11, LI4, and EA did not affect serum levels of TNF, IL-2, or IL-4 in
ST36, these stimulations can trigger other mechanisms to humans. One possible explanation is that the human and
control pain and the immune system. ST36 is the most rodent responses to EA may be different. Another possible
common acupoint used to control pain and inflammation explanation is that there was no major surgical induction
by inducing endorphins or via adenosine A1 receptor [17]. of TNF, IL-2, or IL-4. However, surgery significantly
Intraoperative electroacupuncture 241

induced the production of IL-6 and IL-10 but they were not [11] Huston JM, Ochani M, Rosas-Ballina M, Liao H, Ochani K,
affected by EA. These results suggest that EA does not Pavlov VA, et al. Splenectomy inactivates the cholinergic
cause immunosuppression preventing the immune re- antiinflammatory pathway during lethal endotoxemia and
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enhanced TGFb1 production. TGFâ1 is a critical factor
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Disclosure statement Electroacupuncture reduces duration of postoperative ileus
after laparoscopic surgery for colorectal cancer. Gastroen-
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ambulatory anesthesia. Curr Opin Anaesthesiol. 2013;26:
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