Reading - Post-Op Adhesion

8/3/2019 Reading - Post-Op Adhesion

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ATENEO DE DAVAO UNIVERSITY

COLLEGE OF NURSING

IN PARTIAL FULFILLMENT OF THE REQUIREMENTS

IN RELATED LEARNING EXPERIENCE

READINGThe Use of Statins in Postoperative Adhesion Prevention

Submitted by:

KARL JOSE N. IBARRIENTOS

Student

Submitted to:

MS. MAGNOLIA MAY A. JADULANG RN,MN

Clinical Instructor

December 14, 2011


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The Use of Statins inPostoperative AdhesionPrevention

J B. C. van der Wal, MD and JJeekel, MD, PhDFrom the Department of General Surgery, ErasmusUniversity Medical Center, Rotterdam, The Netherlands.

Ann Surg. 2007 February; 245(2): 185186.

doi: 10.1097/01.sla.0000253071.06793.e6Copyright 2007 Lippincott Williams & Wilkins, Inc.

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 hospitalreadmissions 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 ofliquids 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 aninflammatory 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 betweenfibrinogenesis 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


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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. Thefibrinous 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,1114 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 onadhesion 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


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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 reducepostoperative 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 considerationsremain 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 thetherapeutic 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.


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Footnotes

Reprints: J. Jeekel, MD, PhD, Department of General

Surgery, Erasmus University Medical Center,

Molewaterplein 40-50, Room Ff 218, Rotterdam, The

Netherlands. E-mail:[email protected].

REFERENCES

1. Menzies D, Ellis H. Intestinal obstruction from

adhesions: how big is the problem?Ann R Coll Surg

Engl. 1990;72:6063. [PMC free article] [PubMed]

2. Ellis H. Internal overhealing: the problem of

intraperitoneal adhesions. World J Surg. 1980;4:303

306. [PubMed]

3. Ray NF, Denton WG, Thamer M, et al. Abdominal

adhesiolysis: in patient care and expenditures in the

United States in 1994. J Am Coll Surg. 1993;186:19.

4. Ray NF, Larsen JWJ, Stillman RJ, et al. Economic

impact of hospitalizations for lower abdominal

adhesiolysis in the United States in 1988. Surg

Gynecal Obstet. 1993;176:271276.

5. Parker MC, Wilson MS, Menzies D, et al. TheSCAR-3 study: 5-year adhesion-related readmission

risk following lower abdominal surgical

procedures. Colorectal Dis. 2005;7:551

558. [PubMed]

6. Holmdahl L, Falkenberg M, Ivarsson ML, et al.

Plasminogen activators and inhibitors in peritoneal

tissue.APMIS. 1997;105:2530. [PubMed]

7. Scott-Coombes D, Whawell S, Vipond MN, et al.

Human intraperitoneal fibrinolytic response to electivesurgery. Br J Surg. 1995;82:414417. [PubMed]

8. Raftery AT. Regeneration of parietal and visceral

peritoneum: a light microscopical study. Br J Surg.

1973;60:293299. [PubMed]

9. Raftery AT. Effect of peritoneal trauma on

peritoneal fibrinolytic activity and intraperitoneal

adhesion formation: an experimental study in the

rat. Eur Surg Res. 1981;13:397401. [PubMed]

10. Halcox JP, Deanfield JE. Beyond the laboratory:

clinical implications for statin

pleiotropy.Circulation.2004;109(suppl 1):II42II48. [PubMed]

11. Bruni F, Pasqui AL, Pastorelli M, et al. Effect of

atorvastatin on different fibrinolysis mechanisms in

hypercholesterolemic subjects. Int J Cardiol.

2004;95:269274. [PubMed]

12. Rosenson RS. Statins in atherosclerosis: lipid-

lowering agents with antioxidant

capabilities.Atherosclerosis. 2004;173:1

12. [PubMed]13. Schonbeck U, Libby P. Inflammation, immunity,

and HMG-CoA reductase inhibitors: statins as

antiinflammatory agents? Circulation.2004;109(suppl

1):II18II26. [PubMed]

14. Haslinger B, Goedde MF, Toet KH, et al.

Simvastatin increases fibrinolytic activity in human

peritoneal mesothelial cells independent of

cholesterol lowering. Kidney Int. 2002;62:1611

1619.[PubMed]

15. Budzyn K, Marley PD, Sobey CG. Targeting Rho

and Rho-kinase in the treatment of cardiovascular

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16. Tiwari A, Bansal V, Chugh A, et al. Statins and

myotoxicity: a therapeutic limitation. Expert Opin Drug

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17. Fuhrmans V. Bayer discloses higher death toll

from Baycol. Wall Street Journal. 2002;Sect. A10.

SOURCE:

http://www.ncbi.nlm.nih.gov/pmc/articles/PM

C1876976/

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