Effects on Acute Phase Response and Cytokines

The acute-phase response and cytokines are important components of immunological function. Decreased production of cytokines reflecting a reduced inflammatory reaction after laparoscopy might be considered beneficial during the postoperative period.

C-reactive protein is the most widely studied acute-phase response protein following surgery. C-reactive protein levels usually rise 4 to 12 hours after surgery, peak at 24 to 72 hours and thereafter remain raised for about two weeks (12). Other acute-phase response proteins, such as fibrinogen and transferrin do not usually alter in a similar way in response to surgical trauma (15,16).

Postoperative C-reactive protein levels are significantly lower during the first two days after laparoscopic than after open surgery (17-19).

In a prospective randomized study of laparoscopic versus small-incision open cholecystectomy, Squirrell et al. (20) demonstrated significantly lower C-reactive protein levels following laparoscopic cholecystectomy. However, they found no differences in serum cortisol levels between the two groups and concluded that the neuro-endocrine component of the metabolic response, i.e., cortisol, was not influenced by the type of surgical access (20). These findings were contradicted by McMahon et al. (16), who found no differences in the levels of C-reactive protein or other acute-phase response proteins such as albumin and transferrin between laparoscopic and minilaparotomy cholecystectomy. Because open cholecystectomy in this study was performed through a much smaller incision than would normally be used for open surgical procedures, these results indicate that the trauma of abdominal access influences immunological function. Other studies of laparoscopic versus small-incision cholecystectomy also support this hypothesis (15).

The cytokines interleukin-1 (IL-1), tumor necrosis factor, and IL-6 are important molecules in acute-phase response (21,22). IL-1 and tumor necrosis factor receptors are believed to regulate cytokine activity and their serum levels indirectly reflect serum cytokine levels.

While no difference in soluble tumor necrosis factor receptor levels has been noted after laparoscopic and conventional surgery, serum IL-1 receptor levels are significantly lower after laparoscopy, indicating a lesser degree of inflammatory response to injury.

In summary, the outcomes of both animal and clinical studies clearly demonstrate lesser activation of cytokines IL-1, IL-6, and C-reactive protein following laparoscopic surgery compared with equivalent open procedures. However, differences in the activation of other cytokines such as tumor necrosis factor, IL-8, and changes in the levels of acute-phase response proteins like fibrinogen, albumin, and transferrin are less obvious.

While no difference in soluble tumor necrosis factor receptor levels has been noted after laparoscopic and conventional surgery, serum IL-1 receptor levels are significantly lower after laparoscopy, indicating a lesser degree of inflammatory response to injury (23).

IL-6 expression is believed to be directly proportional to the extent of surgical trauma (24) and a significant difference has been found in plasma levels after open and laparoscopic cholecystectomy (17-19,25). In a randomized controlled trial of laparoscopic versus conventional colorectal resection, Schwenk et al. (26) demonstrated a postoperative increase in IL-6 in both groups, with a more marked response after open surgery. Leung et al. (27) randomized patients to either laparoscopically assisted or open resection of rectosigmoid carcinoma and found no increase in tumor necrosis factor-a levels in either group. Serum levels of both IL-1p and IL-6 peaked two hours after operation, with a significantly smaller response after laparoscopic surgery. Others have found no consistency in IL-6 levels following different surgical approaches (28). Johnson et al. (29) demonstrated significantly higher serum IL-6 levels after laparoscopically assisted colectomy in dogs, compared with the conventional open approach, and Stage et al. (30) reported similar results in a prospective randomized clinical trial.

Hill et al. (31) failed to find any differences in the postoperative IL-6 level following laparoscopic and conventional inguinal hernia repair, which could be because the surgical insult caused by open hernia repair is not sufficient to generate increased levels of these markers. In a similar study, no difference in plasma cortisol, growth hormone, prolactin, and serum IL-6 levels was found following laparoscopic and open surgery for inguinal hernia, but a rise in C-reactive protein concentration and suppression of endotoxin-induced tumor necrosis factor-a production was recorded in both groups with greater changes after open hernia repair (32).

Kuntz et al. compared laparoscopically assisted and open colonic resection in a rat model and measured the serum levels of cortisone, neopterin, and IL-1p just before, during, and after operation, and on the first and seventh postoperative days. They detected significant differences between the study groups for all three variables on the first postoperative day. After a week the levels of cortisone and neopterin had returned to normal (33).

Comparing laparoscopically assisted surgery for Crohn's disease with open surgery, Kishi et al. (34) found C-reactive protein levels and leukocyte counts to be lower following laparoscopic surgery. Hildebrandt et al. also compared open and laparoscop-ically assisted resection for Crohn's disease and found increased levels of C-reactive protein, IL-6, IL-10 but without any demonstrable difference between the two groups. However, they reported significantly lower plasma granulocyte elastase levels after laparoscopic surgery compared with the open operation (35). It needs to be kept in mind that inflammatory bowel conditions such as Crohn's disease and ulcerative colitis can themselves cause alterations in cytokine levels and any changes following surgery whether laparoscopic or open need to be interpreted with a degree of caution (1).

In summary, the outcomes of both animal and clinical studies clearly demonstrate lesser activation of cytokines IL-1, IL-6, and C-reactive protein following laparoscopic surgery compared with equivalent open procedures. However, differences in the activation of other cytokines such as tumor necrosis factor, IL-8, and changes in the levels of acute-phase response proteins like fibrinogen, albumin, and transferrin are less obvious.

The majority of the clinical studies have shown an immunological advantage of laparoscopic over open cholecystectomy. The same cannot be said for laparoscopic colectomy and inguinal hernia repair, where results supporting advantages of the laparoscopic approach have been inconsistent.

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