Immune protective anesthesia during endoscopic colon surgery to improve long-term survival

Multimodal treatment of colon surgery has been improved dramatically in the
last decades due to a better selection of appropriate candidates, introduction
of minimal invasive surgery and optimized (neo)adjuvant treatment strategies.
Although these improvements led to a better short- and long-term survival,
still up to 40% of the patients with a stage II or III disease will develop
recurrence disease and/or distant metastases after curative intended colon
surgery. Further enhancements in survival might be achieved by a specific
anesthetic regime with respect to physical defense mechanism for
micro-metastases.

The majority of to date*s anesthetic literature is focused on the influence of
anesthesia on short-term outcome. However, influences of anesthesia on
long-term outcome should not be underestimated. During oncologic surgery,
immunological defense mechanisms are extremely important to eliminate
micro-metastases. Moreover, the risk for micro-metastases during oncologic
surgery is significant due to manipulation of a solid tumor causing the release
of tumor cells in the vascular and lymphatic system. Positive perioperative
circulating tumor cells are an independent risk factor for long-term outcome.
The primary defense against these micro-metastases includes natural killer (NK)
cells, cytotoxic T cells, mononuclear cells, and dendritic cells4. Other
cytokines involved in tumor progression and NK cell activation are IL 2, IL 6
and INF gamma. From several studies it has been suggested that frequently used
anesthetics and analgesics techniques might have a positive or negative
influence on immunological performance and consequently on long-term survival.

Epidural analgesia is one of the possible techniques that might contribute to a
preserved NK cell activity. It attenuates the neuroendocrine stress response
and reducing opioid requirements. Perioperative stress is responsible for the
release of pro- and anti-inflammatory cytokines, which suppress the cell
mediated immunity and NK cell activity in particular. The degree of surgical
trauma is proportional to the stress response and with the introduction of
endoscopic surgery significant decreased. Furthermore, epidural analgesia is
also known to reduce opioids requirements due to its analgesic properties. It
has been suggested that opioids have immunomodulatory effects resulting in both
cell-mediated and humeral decreased immunity. Opioids also stimulate
angiogenesis, an essential process in tumor development. Next to these negative
consequences, opioids have also some side effects like a decreased intestinal
motility and postoperative nausea and vomiting (PONV). Dexamethasone is a
glucocorticoid that is commonly used in anesthetic practice for prophylaxis
against PONV. The effect of relatively low dose glucocorticoids on the immune
response in cancer patients is not clear yet. In a randomized control trial,
dexamethasone was associated with a higher rate of distant recurrence in
patients undergoing colectomy for colon cancer. But opioids do have also some
positive effects, in particular in patients with inadequately controlled pain
which induce a significant stress response.

In an attempt to minimize perioperative stress and to tolerate intubation
without the need of supplement opioids, Dexmedetomidine (DEX) will be given by
continuous infusion. DEX is a potent α2-adrenerge agonist with sedative and
sympatholytic properties and hence its effect might be used as adjuvant in
anesthesia as stress response blocker, sedative and analgesic. From several
studies DEX is known to reduce levels of pro-inflammatory cytokines, cortisol,
perioperative opioid use and postoperative pain score.

Maintenance of anesthesia is divided in total intravenous anesthesia (TIVA) or
volatile anesthesia. From experimental research in rats, it has been suggested
that the use of older volatile anesthetics leads to an inverse relationship
with NK cell activity. Sevoflurane, a frequently used volatile anesthetic,
binds lymphocyte antigens which interfere with their activity. Propofol is the
most frequently used TIVA and is associated with a significantly decreased
production of prostaglandin E2. Moreover, propofol is not associated with a
suppressed NK cell cytotoxicity and is recently in a large retrospective study
associated with significant improved long-term outcome. Other intravenous
anesthetics like ketamine or thiopental are associated with tumor metastasis
and should therefore be avoided in cancer patients.

Although cancer surgery is one of the most commonly performed surgeries in
daily practice, there is not a specialized anesthetic regime for this specific
category of patients. Dosage and anesthetic techniques might be differing
substantial between anesthesiologists. Anesthesia in cancer patients should be
focused on long-term survival without compromising patient*s safety or comfort
in the perioperative phase. We hypothesis that an especially designed strategy
of anesthesia for cancer patients preserves immune response during endoscopic
colon surgery which will also improve long-term survival.

Main objective:
1. Is there a 24hr-postoperative difference in immunological response between
conventional and immune protective anesthesia?



Secondary objectives:
Is there a difference between patients with conventional and immune protective
anesthesia regarding:

1. Is there a 48hr-postoperative difference in immunological response between
conventional and immune protective anesthesia?
2. Postoperative complications according to the Clavien Dindo classification
3. Postoperative VAS (Visual Analogue Scale) score
4. Hospital stay
5. Anesthetic variables

Exploratory endpoint:
1. Cancer free survival of colon surgery (follow up to 5 years
postoperative)

Study design: multicenter randomized controlled trial (MRCT)
Duration: maximum of 4 years
Total number of patients: 300
Setting: laparoscopic colon surgery

Patients will be randomized in two groups:

1. Conventional anesthesia

2. Immune protective regime:

Escape medication
In the event of severe postoperative pain (Visual Analogue Scale (VAS) >= 4) and
in spite of the use of Paracetamol and a bolus of local anesthetics (dosage
according to the judgment of the anesthesiologist) trough a correct placed
epidural, escape medication with Dipidolor or Morphine will be given (scored
as: *treatment failure*). Dosage of Dipidolor or Morphine according to the
judgment of the anesthesiologist or to local protocols.

Immunological parameter concentrations will be measured by FACS and ELISA and
will be taken prior to surgery (T0), 24 hours (+/- 4 hours) after surgery (T1),
and 48 hours (+/- 4 hours) after surgery (T2).

Patients will be randomized in two groups:

1. Conventional anesthesia:
- Preopartive Paracetamol
- Intravenous analgesia with opioids and postoperative pain management with
Dipidolor or morphine according to local protocols.
- Anesthesia only with Sevoflurane; dosage according to the bispectral index
scale (BIS) with target values between 40 and 60.
- Ketamine, Clonidine and Dexamethason according to the judgment of the
anesthesiologist.
- No Dexmedetomidine, epidurale analgesia, continueous lidocaine or COX-2
inhibitor.


2. Immune protective regime:
- Single dose of preoperative Paracetamol and Midazolam (dosage according to
anesthesiologist)
- Analgesia perioperative: epidural (only with local anesthetic), Paracetamol,
Dexmedetomidine (between 0.2 and 1.0 ug/kg/hr without any bolus) starting
before epidural
- Analgesia postoperative: epidurale analgesia according to local protocols
(only with local anesthetic) and Paracetamol
- Anesthesia only with Propofol; dosage according to the bispectral index scale
(BIS) with target values between 40 and 60.
- Without peri- or postoperative use of opiates, Ketamine, Clonidine or
Dexamethason
- Hypotension should preferably be treated with phenylephrine

Since we aimed that this especially designed anesthesia strategy for cancer
patient*s preserves immune response during colon surgery, we expect a
beneficial effect in concentrations of NK cell activity and stress mediated
cytokines (lymphocytes and IL 6 concentrations). An intact immune response
might be related to a better tumor free survival.

Based on data from literature and our own experience in the UMCG, the
anesthetic department considers the use of the interventional anesthesia
strategy as safe and comfortable. All medications are frequently used and are
registered for use in the operating theatre (except for Dexmedetomidine).
Dexmedetomidine (α2-adrenerge agonist) is in the Netherlands registered for use
on the Intensive Care Unit (ICU) as a sedative agent. Dexmedetomidine may have
some effects on patient*s hemodynamic response (hypotension and/or
brady-arrhythmia). Under hemodynamic monitoring, Dexmedetomidine is considered
to be a safe drug with comparable mechanism of action as Clonidine, a
frequently used α2-adrenerge agonist.

Although epidural analgesia during endoscopic surgery is standard care in some
centers, patients diveded in the intervention group will always get epidural
analgesia. This technique is associated with some common (like decreased blood
pressure, loss of bladder control, itchy skin) and uncommon (severe headaches,
infection, epidural haematoma, nerve damage) effects/complications. The risk
for these effects/complications are not different from other patient categories
and epidural analgesia is performed on a daily routine. Unforeseen
complications or insufficient pain relief with the use of the interventional
anesthesia strategy will come clear during this study.

As hematological testing is performed on a frequent basis, burden and risks are
neglectable. Frequent vena punction carries limited risks and is usually well
tolerated. In addition, blood samples will be combined as much as possible.