Acupuncture for Reduction of Inflammation
Condition: Thyroid or Parathyroid Surgery
MeSH terms: Thyroid Diseases; Inflammation
Study type: Interventional

Summary: 
      This study is being done because the investigators wish to study ways to improve recovery
      after surgery. Injury, including surgical injury, causes inflammation. Inflammation is the
      body's attempt to protect itself and to start the healing process. Some surgical
      complications are related to the body's natural inflammatory response. Although mainly a
      healing response, inflammation can also have side effects which delay recovery. The
      investigators wish to determine the effect of acupuncture on post-operative surgical pain. An
      increase in pain after surgery can cause distress for patients. Acupuncture is an alternative
      medicine methodology originating in China that treats patients by manipulating thin, solid
      needles that have been inserted into acupuncture points in the skin. Acupuncture has been
      used for the reduction of pain. The investigators would like to see if acupuncture during
      surgery can provide a lower level of pain, reduced pain medication requirement, and a lower
      incidence of nausea and vomiting.
    

Detailed description: 
      Acupuncture has traditionally been used in Asia and is increasingly popular in Western
      countries to treat a variety of conditions (1). In recent years, acupuncture is widely used
      to assist in improving pain and inflammatory diseases (2). However, the mechanisms associated
      with these treatments that influence the immune system are not yet understood.

      Cytokines like interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and interleukin-6
      (IL-6) are proposed to be proximal mediators in the early stages of inflammation. They
      modulate many of the early inflammatory response that is induced by tissue injury, infection,
      or an immune stimulus (3, 4). Although the response is a critical first line of defense
      against pathogens, when the inflammatory reaction is uncontrolled, it can cause more damage
      to the host than the initial stimulus. TNF-α is a pro-inflammatory cytokine that is very
      effective in local and systemic inflammations (5). In addition, TNF-α increases the
      production of other inflammatory cytokines such as IL-1β, IL-6, and interleukin-18 (IL-18)
      during the inflammatory process. Therefore, it initially brings infections under control,
      produces coagulation in the damaged tissue, and stimulates tissue improvement. An excessive
      increase of TNF-α level causes an extreme immune reaction and contributes to the development
      of atherosclerosis, shock, endotoxemia, and chronic inflammatory diseases such as rheumatoid
      arthritis, ankylosing spondylitis, and inflammatory bowel disease (5-7). Yim and colleagues
      reported a decrease in increased serum TNF-α, IL-6, and interferon gamma levels by arthritis
      as a result of electroacupuncture treatment (9). In a rat model for ulcerative colitis,
      acupuncture inhibited the expression of IL-1β and IL-6 (10). It has been reported that
      acupuncture significantly reduces complete Freund's adjuvant-induced hind paw edema and mouse
      air pouch inflammation (11, 12). Acupuncture could also improve immune dysfunction after
      surgical stress both in human and animals (13, 14).

      Some cytokines are pro-inflammatory, but others are anti-inflammatory (3). The
      anti-inflammatory interleukins comprise interleukine-4 (IL-4) and interleukine-10 (IL-10) and
      these are considered as mediating the down-regulation of immune-inflammatory conditions.
      Acupuncture for treatment of the ulcerative colitis rats is possibly related with the
      decrease of IL-1β, a pro-inflammatory cytokine, and the increase of IL-4, an
      anti-inflammatory cytokine (15).

      Therefore, it is reasonable to expect that the protective action of acupuncture is exerted by
      the modulation of pro- and anti-inflammatory cytokines. The restoration of balance between
      pro- and anti-inflammatory cytokines by acupuncture gives into the mechanisms underlying the
      immune-modulation effect of acupuncture.

      Inflammation is associated with pain hypersensitivity that is produced by the release of
      inflammatory mediators. The pro-inflammatory cytokines play an essential role in pain
      sensitization (16). The peripheral effects of these cytokines on sensitizing nociceptors have
      been well documented (16). Post-operative surgical pain can cause significant physiologic and
      psychologic distress for patients. An increase in pain duration and intensity after surgery
      can contribute to a variety of complications, including delayed ambulation, pulmonary and
      thromboembolic complications, increased length of hospital stay, and generalized distress and
      anxiety. Effective post-surgical pain relief requires a multidisciplinary effort and
      influences patients' satisfaction with care and successful outcomes (17). Acupuncture has
      been used for a long time for the reduction of pain. In light of these factors, the use of
      acupuncture that may allow a reduction in the dosage of conventional analgesics is highly
      valuable because it can lower the incidence of possible adverse effects. Several trials have
      demonstrated that patients receiving acupuncture prior to surgery have a lower level of pain,
      reduced opioid requirement, a lower incidence of post-operative nausea and vomiting, and
      lower sympatho-adrenal responses (18). The local release of β-endorphin could be responsible
      for the analgesic effect. β-endorphin may be interacting with cytokines to reduce pain and
      acupuncture may amplify the interaction between β-endorphin and cytokines.

      The investigators will ask patients undergoing thyroid and parathyroid surgery to determine
      how acupuncture restores a balance of pro- and anti-inflammatory cytokines to reduce pain and
      inflammation before, during, and after surgery. The effect of acupuncture on post-surgical
      pain will be evaluated.

      Protocol A prospective randomized, double-blinded (patient and data collector), study of 30
      patients undergoing thyroid or parathyroid surgery under general anesthesia, will be
      conducted to compare the effects of acupuncture on the levels of circulating cytokines
      between acupuncture group and control group. The control group is to receive the same
      anesthetic and surgical techniques without the acupuncture.

      The principal investigator will use the Large intestine 4 (LI-4), the Large intestine 11
      (LI-11), and the Stomach 36 (ST-36) acupuncture points (acupoints). LI-4 and LI-11 acupoints
      lie on the Large intestine meridian (pathway). The Large intestine meridian runs through the
      frontal neck region including the thyroid. LI-4 point is located in the middle of the 2nd
      metacarpal bone on the radial side and LI-11 point is located at the lateral end of the
      transverse cubital crease. Acupuncture on these two acupoints showed increased
      immune-modulatory effects including cytotoxicity of leukocytes (19, 20). ST-36 point is
      located on the outside of the anterior crest of the tibia and just below the knee. This point
      is the most commonly used to reduce general body pain (21). The acupuncture procedures will
      be performed by an anesthesiologist licensed to do so.

      After cleaning the skin with alcohol swabs, an acupuncture needle (30 Gauge, 0.30X30
      millimeter, Mac Spring Handle Needle, Korea) will be swiftly inserted approximately 5-10 mm
      deep bilaterally at both LI-4 and LI-11 acupoints of each arm and at ST-36 acupoint of each
      leg. Electroacupuncture (EA) will be delivered by a stimulator (Digital Electronic
      Acupunctoscope 4-C, Model AWQ-104L™ Hong Kong, Dist by Lhasa Medical, Weymouth, MA) via
      electrodes from the stimulator at 10 Hz frequency with the electrical current of continuous
      wave. This setting showed significant anti-hyperalgesic effects in a rat inflammation model
      (22, 23) and also inhibited the up-regulation of IL-1β and its messenger Ribonucleic acid
      (mRNA) compared to the sham control in a rat model of bone cancer pain (24). EA is a
      particularly therapeutic method in which a small electrical charge is applied to acupuncture
      needles inserted at the acupoints. EA has the advantage of combining the stimulation of both
      needles and electricity compared to manual acupuncture alone, and may potentiate the effect
      of the acupuncture treatment along the meridians. One end of electrode will be attached to
      the acupuncture needle handle at LI-4 acupoint, and another end will be attached to the
      acupuncture needle handle at LI-11acupoint bilaterally. For EA on ST-36, one end of electrode
      will be attached at the right side ST-36 acupoint and another end will be attached at the
      left side ST-36 acupoint. A symmetrical biphasic wave will be delivered to the electrodes so
      that the electrode will be alternately positive and negative and the bilateral LI-4, LI-11,
      and ST-36 acupoints will be stimulated alternately. Mild muscle twitching will be observed.

      The investigator will stimulate the acupoints as follows:

        1. EA will be performed for 30 min (a time that is similar to that used in clinical
           practice).

        2. EA will stop after 30 min of the treatment, but leave the needles on the acupoints.

        3. Subsequently, EA will be re-initiated for an additional 30 min.

      This advanced EA technique showed more increased nitric oxide production in the second
      interval of EA than that of the first interval, and reduced blood pressure at the end of the
      second interval in our preliminarily study (25). In addition, this technique increased
      transient receptor potential vanilloid type-1 receptor immunoreactivity in the acupoints
      compared to that of non-acupoints (26). The advanced EA treatment will be started just before
      the beginning of surgery.

      At the conclusion of the surgical procedure, the acupuncture needles will be removed. The
      subjects will be awakened and after meeting the criteria for extubation will be transferred
      to the Post Anesthesia Care Unit (PACU).

      Blood Samples A second intravenous line will be placed in the other arm after the induction
      of anesthesia and prior to surgical incision to collect blood samples. 15 ml of blood will be
      collected at three time points: (1) preinduction, (2) just after the advanced EA treatment
      (3) after arrival in PACU and prior to additional medication administration (approximately
      120 minutes post preinduction sample). These specimens will be placed into vacutainer tubes
      with no anti-coagulant. Blood will be drawn with a syringe attached directly to the
      angiocatheter which has been placed intravenously. To prevent hemolysis, blood will be
      transferred without a needle, to a vacutainer whose top has been removed. The vacutainer top
      will be replaced and specimens labeled with study name, subject's study ID number, sample
      number, and dated. Bloods from the first two time points will be kept refrigerated until the
      final sample is obtained postoperatively. Blood samples will be transported to the Institute
      for Complementary and Alternative Medicine/School of Health Related Professions
      Interprofessional Health Research Laboratory within the Department of Clinical Lab Sciences
      (G level, Bergen Building, 65 Bergen St., Newark). They will be centrifuged, serum removed,
      aliquoted, and stored at -80C until analysis.

      Laboratory Analysis Samples will be analyzed for levels of cortisol, C-reactive proteins, and
      cytokines interleukin (IL)-1α, IL-1β, IL-1ra, IL-2, IL-6, IL-8, IL-10, and TNF-α, by
      appropriate methods, including ELISA or multiplex fluorescent bead technology. All samples
      will be run in duplicate on with plates and reagents of the same lot. In addition we will
      test Adrenocorticotropic hormone (ACTH), glucose and insulin to evaluate the response of the
      stress. Any samples varying greater than 15% between duplicates will be repeated.
    

Intervention name(s): acupuncture; no acupuncture
Intervention type(s): Device; Device
Intervention description(s): One half of subjects will receive a standardized acupuncture regiment; placebo
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: acupuncture; inflammation; thyroid; parathyroid