Evaluation of the Effect of Ketamine on Hyperalgesia and IL-6 in Patients Underwent Laparoscopic Cholecystectomy With Remifentanil

Condition(s) targeted: Pain; Inflammatory Response

Intervention: Ketamine (Drug); Saline (Drug)

Phase: Phase 3

Status: Recruiting

Sponsored by: Federal University of São Paulo

Official(s) and/or principal investigator(s):
Plínio da Cunha Leal, Anesthesiologist, Principal Investigator, Affiliation: Federal University of São Paulo

Overall contact:
Plínio da Cunha Leal, Anesthesiologist, Phone: 55 (11) 6273-9646, Email: pliniocunhaleal@hotmail.com

The purpose of this study is to determine whether ketamine is effective in preventing hyperalgesia that use of remifentanil can cause.

Official title: Evaluation of the Effect of Ketamine on Hyperalgesia and IL-6 in Patients Underwent Laparoscopic Cholecystectomy With Remifentanil

Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Prevention

Primary outcome:

Pain

Inflammatory response

Detailed description: Relief of postoperative pain reduce complications and facilitate recovery. Notice a reduction in pulmonary complications, preservation of myocardial function, early mobilization, less incidence of thromboembolism, reduced time of ileus, attenuation of the stress response, improvement in metabolic response to trauma, decrease chronic pain syndromes and reduce length of stay in the hospital, early return to work and lower cost. Moreover, the pain should be treated for patient comfort.

The anesthetic techniques using opioids, regional analgesia and anti-inflammatory drugs promote better pain relief than those using only inhaled anesthetics.

Remifentanil is a potent opioid with ultra-short acting. Its metabolism is independent of the liver, with no accumulation of the drug and the onset and recovery occur quickly. Dose ranges from 6 a 60mcg/kg/h.

Opioids are associated with the phenomenon of hyperalgesia. Hyperalgesia is associated with activation of N-methyl-D-aspartate (NMDA) and an antagonist of these receptors could reduce the development of hyperalgesia.

Ketamine is an antagonist of NMDA receptors. The most important mechanism of action of ketamine is in glutamate receptors, thus becoming essential to their pharmacological action. Glutamate is the major excitatory neurotransmitter in the brain and existing spinal cord and participates in neuronal plasticity and hyperalgesia.

Ketamine inactivates the receptor through a non-competitive blockade by binding to the phencyclidine site intra channel NMDA receptor, partially covering the attachment point of magnesium, thereby altering the opening time channel.

Ketamine seems to reduce the consumption of anesthetics during the anesthesic surgical procedure, and promote post-operative analgesia.

Preemptive action is observed with ketamine in low doses (5μg/kg/min) intravenously, as well as by peridural.

The administration of ketamine in low doses in patients receiving nonsteroidal anti-inflammatory associated with opioid decreases hyperalgesia and allodynia.

NMDA receptor antagonists have the potential to impede or block hyperalgesia induced by tissue injury, inflammation, nerve injury and ischemia. The combination of NMDA antagonists with opioids is especially advantageous. Opioid acts by preventing the presynaptic release of neurotransmitters, while the NMDA antagonists act postsynaptically.

Interleukin-6 (IL-6), a molecule of approximately 21,000 daltons, is a cytokine detected early and its elevation is more correlated to the degree of tissue damage during surgery than the duration of surgery. It has been considered a predictor of intensity of trauma within 6 hours of hospital admission.

Interleukin-6 induces the hepatic synthesis of acute phase proteins of trauma, such as C-reactive protein (CRP). The CRP level reflects the impact of trauma and is associated with the extent of damaged tissue, but it takes 6 hours to be detected.

After surgical injury, IL-6 is detectable in 60 minutes, with peak blood between 4 and 6 hours and can persist for 10 days 16.

Sub-anesthetic doses of ketamine during induction of anesthesia reduced the serum levels of IL-6 in patients undergoing hysterectomy. In patients undergoing cardiac surgery, serum concentrations of IL-6 were suppressed by small doses of ketamine added to general anesthesia before the extracorporeal circulation and correlated with clinical signs during and after surgery.

The association of ketamine and remifentanil appears to be interesting to prevent hyperalgesia, with better analgesia and duration.

Minimum age: 18 Years. Maximum age: 78 Years. Gender(s): Both.

Criteria:

Inclusion Criteria:

- 40 patients > 18 years old

- both sexes

- ASA I or II

- undergoing laparoscopic cholecystectomy

Exclusion Criteria:

- patients with chronic pain

- myocardial ischemia

- psychiatric illness

- drug user

- those who received opioids in the previous week

Plínio da Cunha Leal, Anesthesiologist, Phone: 55 (11) 6273-9646, Email: pliniocunhaleal@hotmail.com

Federal University of São Paulo, São Paulo, Brazil; Recruiting
Plínio da Cunha Leal, Anesthesiologist, Email: pliniocunhaleal@hotmail.com
Rioko Kimiko Sakata, Email: riokoks.dcir@epm.br
Plínio da Cunha Leal, Anesthesiologist, Principal Investigator

Related publications:

Beilin B, Rusabrov Y, Shapira Y, Roytblat L, Greemberg L, Yardeni IZ, Bessler H. Low-dose ketamine affects immune responses in humans during the early postoperative period. Br J Anaesth. 2007 Oct;99(4):522-7. Epub 2007 Aug 6.

Starting date: September 2010
Last updated: September 27, 2011