The use of statins in postoperative adhesion prevention.

Postoperative adhesion formation is the most frequent complication of surgery, although often not recognized as such. With an incidence of 55% to 100% in all abdominal operations, adhesions are responsible for an increased risk of small bowel obstruction, chronic abdominal pain, and infertility.1,2 The economic burden of adhesion-related hospital readmissions and reoperations is enormous, considering the annual costs exceeding $1 billion in the United States alone.3,4 Recently, the results of the third Surgical and Clinical Adhesions Research study were published, indicating a readmission risk of approximately 30% due to adhesions after colorectal surgery.5 Various strategies, such as application of liquids and membranes, are used in an attempt to prevent adhesion formation. As of yet, no strategy is capable of complete prevention. Surgical trauma to the peritoneum is the main cause of postoperative adhesion formation. Peritoneal damage induces an inflammatory response that ultimately leads to up-regulation of the expression of tissue factor by macrophages and mesothelial cells. This causes activation of the extrinsic pathway of the coagulation cascade, eventually leading to the formation of a fibrinous exudate. Under normal circumstances, this fibrinogenesis is in balance with fibrinolysis. The process of fibrinolysis is driven by the enzyme plasmin, which is derived from its inactive substrate plasminogen by tissue-type plasminogen activator (tPA). On its turn, tPA is inhibited in its reaction by plasminogen activator inhibitor-1 (PAI-1), to maintain a balance. In the abdominal cavity, tPA is responsible for 95% of the plasminogen conversion.6 Intra-abdominal surgery disturbs the balance between tPA and PAI-1 resulting in a decreased fibrinolytic activity and an increase in fibrin exudate, eventually leading to an increase in adhesion formation.7 When the peritoneum is slightly damaged and mesothelial cells are mostly intact, there will be a dynamic balance between fibrinogenesis and fibrinolysis and adhesion-free healing may then take place; reepithelialization is complete 5 to 8 days after the initial trauma.8 When more severe trauma is caused during an operation, loss of mesothelial integrity will occur, exposing the underlying connective tissue and extracellular matrix. Normal fibrinolytic activity will be lost for at least 48 hours post-trauma,9 although individual differences are present in patients. The fibrinous adhesions will organize into fibrous adhesion due to ingrowth of fibroblasts and endothelial cells that is followed by capillary formation and incorporation of collagen, all stimulated by cytokines and growth factors (day 4 to day 10).9 Statins (3-hydroxy-methylglutaryl-coenzyme A reductase inhibitors) antagonize the enzyme HMG-CoA reductase, which catalyzes the rate-limiting step in hepatic cholesterol synthesis. This leads to reduction in the synthesis and secretion of lipoproteins by the liver, as well as up-regulation of LDL receptors on hepatocytes, increasing clearance of circulating apolipoprotein E- and B-containing lipoproteins.10 Clinically, the statins are currently used solely for their lipid-lowering effects in the treatment and prevention of atherosclerosis and cardiovascular disease. However, various experimental studies have shown statins to also have antioxidant, anti-inflammatory, and pro-fibrinolytic properties,11–14 all of which may play a role in the process of adhesion formation and its prevention. In this issue, Aarons et al report the results of an experimental in vivo study in which they investigated the effect of statins on postoperative adhesion formation and wound healing in rats, as well as the results of several in vitro experiments with human mesothelial cells in which they aimed to elucidate the mechanism of action. To determine the effect of lovastatin and atorvastatin on adhesion formation, rats were operated using a model in which, after laparotomy, 6 ischemic buttons were created on the parietal peritoneum, laterally to the laparotomy. The statins were administered intraperitoneally or orally, both in a 30-mg/kg concentration. At time of death, each animal received a percent adhesion score based on the number of buttons with attached adhesions. The experiment showed a significant reduction in adhesion formation after 7 days but only after local administration. Given orally, the statins did not reduce the number of formed adhesions. Neither did statins given 6 hours or more postoperatively. Furthermore, a model of colon-anastomotic healing was used to assess the impact of statins on wound healing. At time of death, anastomotic bursting pressure was measured. The burst pressures of colonic segments of the statin-treated group were found to be higher compared with controls, implying that statin administration does not impair anastomotic healing. In various in vitro experiments, it became clear that statins inhibit the Rho-protein pathway. The small GTP-ase Rho can regulate several aspects of cellular function (predominantly through its downstream effector Rho-kinase)15; by preventing the protein to become activated, statins increase tPA production and decrease PAI-1 production by the human mesothelial cells, and hence increase their fibrinolytic potential. The authors conclude that statins can reduce postoperative adhesion formation if administered topically and within 6 hours after the initial operation. Statins have not been used as adhesion-preventing drugs before, but these first results are very promising. An increase in the tPA/PAI-1 ratio up-regulates fibrinolysis and fewer adhesions are formed. However, several considerations remain pertinent, and additional information is needed before one should even contemplate clinical use of statins in adhesion prevention. The authors used a single dose of statins as high as 30 mg/kg, which proved to be effective. However a dose-response curve should have been included. High-dosed statin use is related to various complications: myotoxicity, ranging from mild to rhabdomyolysis and impaired liver and renal function, are rare, but well-recognized, side effects of statins.16 This has been emphasized by the withdrawal of cerivastatin in August 2001 after the drug was associated with approximately 100 rhabdomyolysis-related deaths.17 By conducting a dose-response experiment, important data may be retrieved regarding the efficacy of lower doses. We should be aware of the fact that the dose used in this experiment is a 25-fold higher than the doses used clinically. As for the therapeutic window, the authors found statins to have effect if administered within 6 hours after the initial operation, whereas administration after 24 hours had no effect. However, to further unravel the therapeutic window, more timepoints should be included in future experiments. Furthermore, statins only seem to have their adhesion-preventing effect if administered topically, whereas given orally no reduction in adhesion formation is observed. This could be explained by the fact that statins are, at least partially, metabolized by the liver. If given orally, the first-pass effect possibly causes the statins to reach the peritoneal cavity in a concentration too low to have any effect. In patient care, statins are given orally instead of topically and, importantly, in a significantly lower dose. What will be the systemic impact of a topical intraperitoneal dose as high as 30 mg/kg? It is very likely that statins are resorbed by the peritoneum, leading to unacceptably high systemic levels, followed by complications as mentioned earlier. As stated before, the way the authors addressed the problem of postoperative adhesion formation is new and refreshing. By interfering with the primary mechanism of adhesion formation rather than, for example, by means of a membrane preventing 2 layers of tissue to adhere to each other, a considerable step forward is made. However, we should be aware of the practical problems regarding the current use and dose-dependent side effects of statins.