Effects of Anesthetic Technique on Immune and Inflammatory Systems Following Radical Prostatectomy
Condition: Prostate Cancer
MeSH terms: Prostatic Neoplasms
Study type: Interventional
Phase: Phase 3

Summary: 
      Several recently published retrospective studies show that regional anaesthesia (RA) can
      reduce cancer-related mortality following surgical treatment of colorectal, breast and
      prostate cancers and malignant melanoma. If these results are true, then the choice of
      perioperative pain management is as beneficial, or even better, than the current oncological
      therapies. This theory needs to be investigated in a prospective, randomized and controlled
      trail. We shall perform a prospective, randomized study comparing the effects of Thoracic
      epidural analgesia (TEA) or patient controlled analgesia (PCA) on postoperative immunological
      and inflammatory markers in order to understand whether the protective effects, if any, of
      regional analgesia are due to changes in these markers or whether the underlying mechanisms
      is not mediated via this stress signalling pathway.
    

Detailed description: 
      Methods

      Thirty patients (ASA status 1-2) in the age group 50 - 75 years, undergoing elective radical
      retropubic prostatectomy would be included in this pilot study. The exact type of cancer, its
      staging, degree of spread to proximal or distant sites and the pathologic type of cancer
      would be recorded. Patients on chronic analgesic medication, endocrinologic and immunologic
      diseases, those with known allergy to LA and those where epidural catheter placement was
      contraindicated would be excluded. Patients would be allocated to one of three groups:
      General anesthesia combined with Epidural anesthesia during and after the operation (Group
      GE; n = 12), General anesthesia combined with Epidural during anesthesia and local anesthesia
      postoperatively (Group GL; n = 12), General anesthesia alone (Group GO; n = 10)

      Anesthesia and Surgery

      All patients would be premedicated with midazolam 0.1 mg/kg 15-30 min before planned surgery,
      which is a routine in our hospital. Paracetamol 1 g was given orally every 6 h starting with
      the first dose at the time of premedication. IV access would be attained in the preoperative
      holding area and further anxiolytic would be given as necessary intravenously.

      Epidural technique

      In patients in Group GE, an 18 G epidural needle would be inserted at the Th10-12 inter-space
      using the 'hanging-drop' or loss of resistance technique with the patient in the sitting
      position in the holding area. The epidural catheter would be inserted and subsequently tested
      for subarachnoid or intravascular placement using 3 ml of mepivacaine 2% with adrenaline,
      which is standard practice in our hospital. A bolus dose of 3-4 ml mepivacaine 2% with
      adrenaline would subsequently be injected and a loss of sensation to cold determined after 10
      min. If a sensory block to an upper level of Thoracic 8 dermatome and a minimal lower level
      of L2 is achieved, the patient would be considered to be ready for induction of anesthesia.
      If not, a further dose of 2-3 ml mepivacaine 2% with adrenaline would be injected epidurally.
      If this fails to achieve the desired block, it would be assumed that the catheter was
      incorrectly placed and the patient offered the choice of one more attempt at epidural
      catheter placement, or exclusion from the study.

      Patients in Group GO would not have an epidural catheter placed. Following transfer to the
      operating room and routine monitoring, anesthesia would be induced in all patients with
      fentanyl 2 mg/kg i.v. and propofol 1-2mg/kg until loss of eyelash reflex. Tracheal intubation
      would be performed after muscle relaxation with rocuronium 0.5 mg/kg and anesthesia
      maintained with 1-3% sevoflurane and 33% oxygen in air. Mechanical ventilation would be used
      in a low-flow system in order to maintain an end-tidal CO2 of between 4.5-5.5 kPa. In all
      patients, sevoflurane concentration would be adjusted in order to maintain adequate
      anesthetic depth, which would be measured using Auditory evoked potentials (AEP) and
      maintained between 15-25 (A-line). Tachycardia, despite adequate anesthetic depth, would be
      treated by giving fentanyl intermittently IV as an analgesic when required during the
      operation. At the end of surgery, muscle relaxation would be reversed using glycopyrrolate
      (0.2 mg) and neostigmine (2.5 mg). Radical retropubic prostatectomy would be performed in a
      standardized way using a lower-abdominal midline incision.

      Postoperative Management

      During the first 4 h postoperatively, patients in Group GO would receive morphine 1-2 mg IV
      intermittently for pain relief in the post-anesthesia care unit (PACU) in order that the
      numeric rating scale (NRS) (0 = no pain, 10 = worst imaginable pain) is < 3. Patients in
      Group GE would have an infusion of ropivacaine 0.2% 5-10 ml/h epidurally. In the event of
      pain, morphine (1-2 mg) would be administered intravenously as needed in both groups in order
      to provide good pain relief and NRS < 3.

      All patients would be observed in the PACU for 4 h before being transferred to the general
      urological ward. The epidural infusion/PCA pump would be continued as long as pain relief is
      needed using these techniques but for a minimum of 48 h. Subsequently, pain relief would be
      obtained using oral analgesics using a combination of paracetamol and NSAID drugs.

      Recording and Measurements

      The total amount of anesthetic and analgesic drugs required during the operation would be
      recorded. Anesthetic drug requirement would be determined by two methods: end-tidal
      concentration of sevoflurane recorded every 5 min and the weight of the vaporizer before and
      after each anesthetic. For all measurements, the time when the anesthetic gases were turned
      off was considered to be time zero (t = 0). In addition to the routine postoperative
      protocols, the following measurements were recorded:

      Pain intensity: At the site of the incision, 'deep' (visceral) pain and pain on coughing at
      1, 4, 12, 24 and 48 h was measured using the NRS.

      Rescue analgesic (morphine) consumption: during 0-4 h, 4-24 h and 24-48 h. Supplementary
      analgesic consumption: Additional analgesics administered in order to relieve pain would be
      recorded/day.

      Side effects: Nausea and/or vomiting (0-4 h, 4-24 h and 24-48 h), pruritus and all other
      complications were recorded.

      Surgical complications: the surgical incision would be inspected daily for evidence of
      infection and graded as either no evidence of infection (= 0), evidence of inflammation (=
      1), mild wound dehiscence or suspected infection (= 2) or pus formation with definite
      infection (= 3). After 48-72 h, the epidural catheter would be removed and the catheter tip
      sent for bacterial culture.

      Blood sampling:

      Patient serum or EDTA/Heparin plasma will be assessed for cytokine levels by a Luminex
      multiplex assay (Human Inflammation 12-Plex kit; GM.CSF, IFN-g, IL-1b, IL-2, IL-4, IL-5,
      IL-6, IL-8, IL-10, IL-12, TNF-a and VEGF from R&D system) and PGE2 levels will be measured by
      an ELISA kit from Cayman Chemicals Company. In addition, markers of systemic inflammatory
      response, including CRP, white blood cell count, differential count and total platelet count,
      will also be measured before and after surgery.

      Natural Killer (NK) cell activity in the blood would be measured using the FANKIA assay.
      Clusters of differentiation (CD) markers would be measured.

      Stress response would be measured using serum cortisol and prolactin levels.
    

Intervention name(s): Patient controlled analgesia (PCA); Thoracic Epidural Analgesia (TEA)
Intervention type(s): Drug; Drug
Intervention description(s): Morphine 1 mg/ml; Intra-operatively: Bupivacaine 0.5% with adrenaline Post-operatively: Ropivacaine 0.2% + sufentanil 1 ug
Other intervention name(s): Morphine = morphine; Bupivacaine = Marcain; Ropivacaine = Narop; Sufentanil = Sufenta
Intervention MeSH terms: Sufentanil; Morphine; Bupivacaine; Ropivacaine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Basic Science
Keywords: Analgesia: Thoracic epidural, patient controlled; Surgery: Radical retropubic prostatectomy; Immune system; Inflammation