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Adhesions are fibrous bands that form between tissues and organs, often as a result of injury during surgery.

They may be thought of as internal scar tissue that connect tissues not normally connected.


1 Pathophysiology 2 Regions affected

o o o o o

2.1 Adhesive capsulitis 2.2 Abdominal adhesions 2.3 Pericardial adhesions 2.4 Peridural adhesions 2.5 Peritendinous adhesions

3 Association with surgery 4 Types 5 References 6 External links 7 See also

[edit]Pathophysiology Adhesions form as a natural part of the bodys healing process after surgery in the same way that a scar forms. The term "adhesion" is applied when the scar extends from within one tissue across to another, usually across a virtual space such as the peritoneal cavity. As part of the process, the body deposits fibrin onto injured tissues. The fibrin acts like a glue to seal the injury and builds the fledgling adhesion, said at this point to be "fibrinous." In body cavities such as the peritoneal,pericardial and synovial cavities, a family of fibrinolytic enzymes may act to limit the extent of the initial fibrinous adhesion, and may even dissolve it. In many cases however the production or activity of these enzymes are compromised because of injury, and the fibrinous adhesion persists. If this is allowed to happen, tissue repair cells such asmacrophages, fibroblasts and blood vessel cells, penetrate into the fibrinous adhesion, and lay down collagen and other matrix substances to form a permanent fibrous adhesion. In 2002, Giuseppe Martucciello's research group showed a possible role could be played by microscopic foreign bodies (FB) accidentally contaminating the operative field during [2] surgery. These data suggested that two different stimuli are necessary for adhesion formation: a direct lesion of the mesothelial layers and a solid substrate (FB). While some adhesions do not cause problems, others can prevent muscle and other tissues and organs from moving freely, sometimes causing organs to become twisted or pulled from their normal positions. [edit]Regions




In the case of adhesive capsulitis of the shoulder (also known as frozen shoulder), adhesions grow between the shoulder joint surfaces, restricting motion. [edit]Abdominal


Abdominal adhesions (or intra-abdominal adhesions) are most commonly caused by abdominal surgical procedures but may also be caused by pelvic inflammatory disease orendometriosis. The adhesions start to form within hours after surgery and may cause internal organs to attach to the surgical site or to other organs in the abdominal cavity. Adhesion-related twisting and pulling of internal organs can result in complications such as infertility and chronic pelvic pain. Surgery inside the uterine cavity (e.g., suction D&C,myomectomy, endometrial ablation) can result in Asherman's Syndrome (also known as intrauterine adhesions), a cause of infertility. Small bowel obstruction (SBO) is another significant consequence of post-surgical adhesions. A SBO may be caused when an adhesion pulls or kinks the small intestine and prevents the flow of content through the digestive tract. It can occur 20 years or more after the initial surgical procedure, if a previously benign adhesion allows the small bowel to spontaneously twist around itself and obstruct. SBO is an emergent, possibly fatal condition without immediate medical attention. According to statistics provided by the National Hospital Discharge Survey approximately 2,000 people die every year in the USA from [3] obstruction due to adhesions. Depending on the severity of the obstruction, a partial obstruction may relieve itself with conservative medical intervention. However, many obstructive events require surgery to lyse the offending adhesion(s) or resect the affected small intestine. [edit]Pericardial


Adhesions forming after cardiac surgery between the heart and the sternum place the heart at risk of catastrophic injury during re-entry for a subsequent procedure. [edit]Peridural


Adhesions and scarring as epidural fibrosis may occur after spinal surgery that restricts the free movement of nerve roots, causing tethering and leading to pain. [edit]Peritendinous


Adhesions and scarring occurring around tendons after hand surgery restrict the gliding of tendons in their sheaths and compromise digital mobility. [edit]Association

with surgery

A study in Digestive Surgery showed that more than 90% of patients develop adhesions following open abdominal surgery and 55%100% of women develop adhesions following pelvic [4] surgery. Adhesions from prior abdominal or pelvic surgery can obscure visibility and access at subsequent abdominal or pelvic surgery. In a very large study (29,790 participants) published in British medical journal The Lancet, 35% of patients who underwent open abdominal or pelvic surgery were readmitted to the hospital an average of two times after their surgery due to adhesion-related or [5] adhesion-suspected complications. Over 22% of all readmissions occurred in the first year after the [5] initial surgery. Adhesion-related complexity at reoperation adds significant risk to subsequent surgical [6] procedures.

Before the availability of adhesion barriers, adhesions were documented to be an almost unavoidable consequence of abdominal and pelvic surgery, and occurred in as much as 93% of all patients [7] undergoing abdominal surgery. [edit]Types Types of adhesions: 1. Fibrinous adhesions. These are causes of early postoperative obstruction which settles down within 35 days. The majority of fibrinous adhesions will disappear in due course of time. 2. Fibrous adhesions. If the infection is continuous or if foreign fibrinous material is converted into fibrous material.
[clarification needed]

is present, the

Adhesions Overview
An adhesion is a band of scar tissue that binds two parts of tissue or organs together. Adhesions may appear as thin sheets of tissue similar to plastic wrap or as thick fibrous bands. The tissue develops when the body's repair mechanisms respond to any tissue disturbance, such as surgery, infection, trauma, or radiation. Although adhesions can occur anywhere, the most common locations are within the abdomen, the pelvis, and the heart. Abdominal adhesions: Abdominal adhesions are a common complication of surgery, occurring in up to 90% of people who undergo abdominal or pelvic surgery. Abdominal adhesions also occur in a small number of people who have never had surgery. Most adhesions are painless and do not cause complications. However, adhesions cause the majority of small bowel obstructions in adults, and are believed to contribute to the development of chronic pelvic pain. Adhesions typically begin to form within the first few days after surgery, but they may not produce symptoms for months or even years. As scar tissue begins to restrict motion of the small intestines, passing food through the digestive system becomes progressively more difficult. The bowel may become blocked. In extreme cases, adhesions may form fibrous bands around an entire segment of the intestine. This constricts blood flow and leads to tissue death. Pelvic adhesions: Pelvic adhesions may involve any organ within the pelvis, such as the uterus, ovaries, Fallopian tubes, or bladder, and usually occur after surgery, such as after Csection or hysterectomy. Pelvic inflammatory disease (PID) results from an infection (usually a sexually transmitted disease) that frequently leads to adhesions in and around the Fallopian tubes. A woman's eggs pass through her Fallopian tubes into her uterus for reproduction. Fallopian adhesions can lead toinfertility and increased incidence of ectopic pregnancy in which a fetus develops outside the uterus. Heart adhesions: Scar tissue may form within the membranes that surround the heart (pericardial sac), thus restricting heart function. Infections, such as rheumatic fever, may lead to adhesions forming on heart valves and leading to decreased heart efficiency.

Adhesions Causes

Adhesions develop as the body attempts to repair itself. This normal response can occur after surgery, infection, trauma, or radiation. Repair cells within the body cannot tell the difference between one organ and another. If an organ undergoes repair and comes into contact with another part of itself, or another organ, scar tissue may form to connect the two surfaces.

Adhesions Symptoms
Doctors associate signs and symptoms of adhesions with the problems an adhesion causes rather than from an adhesion directly. As a result, people experience many complaints based on where an adhesion forms and what it may disrupt. Typically, adhesions show no symptoms and go undiagnosed. Most commonly, adhesions cause pain by pulling nerves, either within an organ tied down by an adhesion or within the adhesion itself. Adhesions above the liver may cause pain with deep breathing. Intestinal adhesions may cause pain due to obstruction during exercise or when stretching. Adhesions involving the vagina or uterus may cause pain during intercourse. Pericardial adhesions may cause chest pain. It is important to note that not all pain is caused by adhesions and not all adhesions cause pain. Small bowel obstruction (intestinal blockage) due to adhesions is a surgical emergency. o These adhesions trigger waves of cramp-like pain in the stomach. This pain, which can last seconds to minutes, often worsens when the person eats, which increases activity of the intestines. o Once the pain starts, the affected individual may vomit. This often relieves the pain. o The stomach may become tender and progressively bloated. o The person may hear high-pitched "tinkling" bowel sounds over the stomach, accompanied by increased gas and loose stools. o Fever is usually minimal or occurs later in the process. o Such intestinal blockage can correct itself. However, a person must see your doctor if the blockage progresses and conditions may develop: The bowel stretches further Pain becomes constant and severe Bowel sounds disappear Gas (flatulence) and bowel movements stop The belly expands and swells Fever may increase Further progression can tear the intestinal wall (perforation) and contaminate the abdominal cavity with bowel contents.

When to Seek Medical Care

See a doctor any time a person experiencesabdominal pain that doesn't resolve quickly, pelvic pain, chest pain, or unexplained fever. If the person has undergone surgery or has a history of medical illness, discuss any changes in recovery or condition with a doctor. If the person's abdominal pain is associated with high fever, continuous vomiting, swelling of the abdomen, chest pain, back pain, fainting or lightheadedness, gastrointestinal bleeding, go to the emergency department.

Adhesions Overview An adhesion is a band of scar tissue that binds 2 parts of your tissue together. They should remain separate. Adhesions may appear as thin sheets of tissue similar to plastic wrap or as thick fibrous bands. The tissue develops when the body's repair mechanisms respond to any tissue disturbance, such as surgery, infection, trauma, or radiation. Although adhesions can occur anywhere, the most common locations are within the stomach, the pelvis, and the heart.
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Abdominal adhesions: Abdominal adhesions are a common complication of surgery, occurring in up to 93% of people who undergo abdominal or pelvic surgery. Abdominal adhesions also occur in 10.4% of people who have never had surgery. Most adhesions are painless and do not cause complications. However, adhesions cause 60%-70% of small bowel obstructions in adults and are believed to contribute to the development ofchronic pelvic pain. Adhesions typically begin to form within the first few days after surgery, but they may not produce symptoms for months or even years. As scar tissue begins to restrict motion of the small intestines, passing food through thedigestive system becomes progressively more difficult. The bowel may become blocked. In extreme cases, adhesions may form fibrous bands around a segment of an intestine. This constricts blood flow and leads to tissue death.

Pelvic adhesions: Pelvic adhesions may involve any organ within the pelvis, such as the uterus, ovaries, fallopian tubes, or bladder, and usually occur after surgery. Pelvic inflammatory disease (PID) results from an infection (usually a sexually transmitted disease) that frequently leads to adhesions within the fallopian tubes. A woman's eggs pass through her fallopian tubes into her uterus for reproduction. Fallopian adhesions can lead to infertility and increased incidence of ectopic pregnancy in which a fetus develops outside the uterus. Heart adhesions: Scar tissue may form within the membranes that surround the heart (pericardial sac), thus restricting heart function. Infections, such as rheumatic fever, may lead to adhesions forming on heart valves and leading to decreased heart efficiency. Adhesions Causes Adhesions develop as the body attempts to repair itself. This normal response can occur after surgery, infection, trauma, or radiation. Repair cells within the body cannot tell the difference between one organ and another. If an organ undergoes repair and comes into contact with another part of itself, or another organ, scar tissue may form to connect the 2 surfaces. Adhesions Symptoms

Doctors associate signs and symptoms of adhesions with the problems an adhesion causes rather than from an adhesion directly. As a result, people experience many complaints based on where an adhesion forms and what it may disrupt. Typically, adhesions show no symptoms and go undiagnosed. Most commonly, adhesions cause pain by pulling nerves, either within an organ tied down by an adhesion or within the adhesion itself. o Adhesions above the liver may cause pain with deep breathing. Intestinal adhesions may cause pain due to obstruction during exercise or when stretching. Adhesions involving the vagina or uterus may cause pain during intercourse. Pericardial adhesions may cause chest pain. It is important to note that not all pain is caused by adhesions and not all adhesions cause pain. Small bowel obstruction (intestinal blockage) due to adhesions is a surgical emergency. These adhesions trigger waves of cramplike pain in your stomach. This pain, which can last seconds to minutes, often worsens if you eat food, which increases activity of the intestines. Once the pain starts, you may vomit. This often relieves the pain. Your stomach may become tender and progressively bloated. You may hear high-pitched tinkling bowel sounds over your stomach, accompanied by increased gas and loose stools. Fever is usually minimal. Such intestinal blockage can correct itself. However, you must see your doctor. If the blockage progresses, these conditions may develop: Your bowel stretches further. Pain becomes constant and severe. Bowel sounds disappear. Gas and bowel movements stop. Your belly will grow. Fever may increase. Further progression can tear your intestinal wall and contaminate your abdominal cavity with bowel contents. When to Seek Medical Care

o o o

o o o o o o o o o

See a doctor any time you experience abdominal pain, pelvic pain, chest pain, or unexplained fever. If you have undergone surgery or have a history of medical illness, discuss any changes in your recovery or condition with your doctor. Go to the nearest emergency department if chest pain, abdominal pain, pelvic pain, or unexplained fever occurs. Exams and Tests Doctors typically diagnose adhesions during a surgical procedure such as laparoscopy (putting a camera through a small hole into the stomach to visualize the organs). If they find adhesions, doctors usually can release them during the same surgery. Studies such as blood tests, x-rays, and CT scans may be useful to determine the extent of an adhesionrelated problem. However, a diagnosis of adhesions usually is made only during surgery. A physician, for example, can diagnose small bowel obstruction but cannot determine if adhesions are the cause without surgery. Adhesions Treatment - Self-Care at Home Adhesions must be diagnosed and treated by a physician. Medical Treatment Treatment varies depending on the location, extent of adhesion formation, and problems the adhesion is causing. Adhesions frequently improve without surgery. Therefore, unless a surgical emergency becomes evident, a doctor may treat symptoms rather than perform surgery. Surgery Two common surgical techniques used to treat abdominal adhesions are laparoscopy and laparotomy. With laparoscopy, a doctor places a camera into your body through a small hole in the skin to confirm that adhesions exist. The adhesions then are cut and released (adhesiolysis). In laparotomy, a doctor makes a larger incision to directly see adhesions and treat them. The technique varies depending on specific circumstances. Next Steps - Follow-up If you have undergone surgery or have a history of medical illness, always discuss changes in your recovery or condition with your doctor. Prevention Several surgical products have been developed to prevent adhesions from forming during surgery. However, the effectiveness of these products is debatable. Outlook Adhesions requiring surgery commonly come back because surgery itself causes adhesions. Synonyms and Keywords

adhesion, pelvic adhesion, heart adhesion, pericardial adhesion, intrauterine adhesion, sticky guts, tissue disturbance, surgery, infection, trauma, radiation, scar tissue, small-bowel obstruction, pelvic pain, chronic pelvic pain, intestinal adhesion, general adhesion, general adhesions, adhesion after surgery, adhesions after surgery, abdominal adhesion, adhesion causes, adhesion symp

Pathophysiol ogy and prevention of postoperativ e peritoneal adhesions

Willy Arung, Michel Meurisse and Olivier Detry.
Willy Arung, Department of General Surgery, Cliniques Universitaires de Lubumbashi, University of Lubumbashi, Lubumbashi 1825, Katanga Province, Congo Michel Meurisse, Olivier Detry, Department of Abdominal Surgery and Transplantation, CHU de Lige, University of Liege, Lige B4000, Belgium Author contributions: Arung W performed the review and wrote the manuscript; Meurisse M and Detry O supervised the review and corrected the manuscript. Correspondence to: Olivier Detry, Professor, Department of Abdominal Surgery and Transplantation, CHU de Lige, University of Liege, Lige B4000, Belgium. oli.detry@chu. Telephone: +32-4-

3667645 Fax: +32-43664069 Received May 4, 2011; Revised August 26, 2011; Accepted September 3, 2011; Top Abstract INTRODUCTION CONCLUSION References

Peritoneal adhesions represent an important clinical challenge in gastrointestinal surgery. Peritoneal adhesions are a consequence of peritoneal irritation by infection or surgical trauma, and may be considered as the pathological part of healing following any peritoneal injury, particularly due to abdominal surgery. The balance between fibrin deposition and degradation is critical in determining normal peritoneal healing or adhesion formation. Postoperative peritoneal adhesions are a major cause of morbidity resulting in multiple complications, many of which may manifest several years after the initial surgical procedure. In addition to acute small bowel obstruction, peritoneal adhesions may cause pelvic or abdominal pain, and infertility. In this paper, the authors reviewed the epidemiology, pathogenesis and various prevention strategies of adhesion formation, using Medline and PubMed search. Several preventive agents against postoperative peritoneal adhesions have been investigated. Their role aims in activating fibrinolysis, hampering coagulation, diminishing the inflammatory response, inhibiting collagen synthesis or creating a barrier between adjacent wound surfaces. Their results are encouraging but most of them are contradictory and achieved mostly in animal model. Until additional findings from future clinical researches, only a meticulous surgery can be recommended to reduce unnecessary morbidity and mortality rates from these untoward effects of surgery. In the current state of knowledge, pre-clinical or clinical studies are still necessary to evaluate the effectiveness of the several proposed prevention strategies of postoperative peritoneal adhesions. Keywords: Abdominal surgery, Laparoscopy, Complication, Occlusion,
Abdominal pain


Peritoneal adhesions represent an important clinical challenge in gastrointestinal surgery. Peritoneal adhesions are a consequence of

peritoneal irritation by infection or surgical trauma. They are a major cause of morbidity, resulting in multiple complications, many of which may manifest several years after the initial surgical procedure[1,2]. Development of peritoneal adhesions has been studied extensively, but to date, there has been no definitive strategy to prevent their formation, as controversies concerning the effectiveness of available preventive agents still exist. In addition, most of the available clinical literature concern gynecological patients; for patients undergoing general and/or abdominal surgery, no recommendations or guidelines exist[3]. The aim of this review is to present the epidemiology, pathogenesis and various prevention strategies of adhesion formation. We performed a literature search for this review in Medline and PubMed, using the key words: adhesions, intraperitoneal adhesions, intra-abdominal adhesions, adhesion reduction, adhesion prevention, adhesion formation, adhesion pathophysiology. We also reviewed the reference lists in all articles retrieved in the search, as well as those of major texts regarding peritoneal adhesion formation. Both clinical and experimental studies upon adhesion formation were retained. There was no restriction regarding publication language.

Definition, epidemiology and consequences of peritoneal adhesions

Peritoneal adhesions are pathological bonds usually between omentum, loops of bowel and the abdominal wall. These bonds may be a thin film of connective tissue, a thick fibrous bridge containing blood vessels and nerve tissue, or a direct contact between two organ surfaces[4]. According to their etiology, peritoneal adhesions may be classified as congenital or acquired, which can be postinflammatory or postoperative (the most frequent)[5]. Among postoperative adhesion formation, three processes may be distinguished:adhesion formation (adhesions formed at operative sites); de novo adhesion formation (adhesions formed at non-operative sites); and adhesion reformation (adhesions formed after the lysis of previous adhesions)[6] . Diamond et al[7] have distinguished type 1 and type 2 formation of postoperative peritoneal adhesions. Type 1 or de novo adhesion formation concerns adhesions formed at sites that did not have previous adhesions, including type 1A (no previous operative

procedure at the site of adhesions) and type 1B (previous operative procedures at the site of adhesions). Type 2 involves adhesion reformation, with two separate subtypes: type 2A (no operative procedure at the site of adhesions besides adhesiolysis) and type 2B (other operative procedures at the site of adhesions besides adhesiolysis)[7]. Peritoneal adhesions are mostly induced by surgical procedures in the peritoneal cavity, and their prevalence after major abdominal procedures has been evaluated at 63%-97%[8,9]. Overall, approximately one-third of patients who underwent open abdominal or pelvic surgery were readmitted an average of two times over the subsequent 10 years for conditions directly or possibly related to adhesions, or for further surgery that could potentially be complicated by adhesions; > 20% of all such readmissions occurred during the first year after initial surgery, and 4.5% of readmissions were for adhesive small bowel obstruction (ASBO)[1,10-13]. Colorectal surgery has proved to be the most important type of surgery that may cause intra-abdominal adhesions[14]. This surgery has the highest total number of inpatient episodes, inpatient days, operating time, theater time, and costs due to peritoneal adhesion-related intestinal obstruction[14]. Among open gynecological procedures, ovarian surgery had the highest rate of readmissions directly related to adhesions (7.5/100 initial operations)[13]. Small bowel obstructions (SBO) is the most common complication of peritoneal adhesions[1,2,8,9]. At Westminster Hospital (London, United Kingdom), intestinal obstruction accounted for 0.9% of all admissions, 3.3% of major laparotomies, and 28.8% of cases of large or SBO over 24 years[5]. A 1992 British survey has reported an annual total of 12 000-14 400 cases of adhesive intestinal obstruction. Barmparas et al[15] have studied the incidence and risk factors for ASBO following laparotomy. The overall incidence of ASBO was 4.6% and the risk of ASBO was highly influenced by the type of procedure, with ileal pouch-anal anastomosis being associated with the highest incidence of SBO[15]. In 1988 in the United States, admissions for adhesiolysis accounted for nearly 950 000 d of inpatient care[5]. All these studies have demonstrated that ASBO is a significant health issue both in the developed and developing

world. However, ASBO risk factors, such as the type of past surgical procedure, the site of adhesions, as well as the timing and recurrence rate of adhesive obstruction, remain unpredictable or poorly understood[5]. In addition to ASBO, peritoneal adhesions may cause pelvic or abdominal pain, and infertility[1,2,16]. Peritoneal adhesions may also prolong the time needed to gain access to the abdominal cavity at subsequent surgery[17,18], and may increase the risk of bowel injury during subsequent surgery[19]. Controversy remains on the role of peritoneal adhesions on abdominal pain. Adhesions have been implicated as a significant cause of chronic pelvic pain, and their surgical lysis has been proposed as the therapeutic modality of choice[20,21]. However, chronic pelvic pain is one of most common gynecological complaints and yet remains an enigma. A comparison of chronic pelvic pain patients and asymptomatic infertility patients has not revealed a significant difference in the density or the location of adhesions[22]. Thus, it is possible that a common mechanism for pelvic pain exists and that adhesions are only associated features. Bradykinin, histamine and other autocoids are able to stimulate pain receptors. For Rapkin et al[22], these findings question the role of pelvic adhesions as a cause of chronic pelvic pain. According to other authors, although adhesions are thought to cause pain indirectly by restricting organ motion, thus stretching and pulling smooth muscle of adjacent viscera or the abdominal wall, adhesions themselves are capable of generating pain stimuli. Sulaiman et al[23] have studied the distribution, location, size and type of nerve fibers present in human peritoneal adhesions, associated or not with chronic pelvic pain. They have found that nerve fibers, identified histologically, ultrastructurally, and immunohistochemically, were present in all examined peritoneal adhesions. Furthermore, fibers expressing the sensory neuronal markers calcitonin gene-related protein and substance P were present in all adhesions irrespective of reports of chronic abdominopelvic pain. That study has suggested that these structures may be capable of conducting pain after appropriate stimulation, and peritoneal adhesions are implicated as a cause of chronic abdominopelvic pain. In addition, many patients are relieved of their symptoms after

adhesiolysis[23]. As consequence, peritoneal adhesions have a significant economic impact. Their direct costs in Sweden can be estimated to be $13 million annually[24]. It has been estimated that in the United States, there are 117 hospitalizations for adhesion-related problems per 100 000 people, and the total cost for hospital and surgical expenditure is about $1.3 billion[25]. In some European countries, the direct medical costs for adhesion-related problems are more than the surgical expenditure for gastric cancer and almost as much as for rectal cancer[3,26,27]. Indeed, postoperative adhesions have a profound economic impact, including the surgical procedure itself, hospitalization, recuperation and lost productivity[25]. During 1988, excluding patient and indirect costs, hospitalization in the United States, accounting for 948 727 d of inpatient care, was responsible for an estimated $1179.9 million in expenditure, of which $925 million was associated with hospital costs and $254.9 million with surgeons fees[25]. The study of Ray et al[28] has demonstrated substantial costs associated with surgical procedures and hospitalization for adhesiolysis. During 1996, the total annual cost of adhesions management exceeded $2 billion, excluding recuperation and lost productivity[28]. Hospitalization for adhesiolysis alone cost > $700 million. Furthermore, > 300 000 patients are estimated to undergo surgery to treat adhesion-induced SBO in the United States annually[25]. Thus, developing effective strategies for adhesion prevention may help to reduce adhesions management costs and unnecessary morbidity and mortality rates.

Postoperative peritoneal adhesion pathophysiology

The first peritoneal adhesions were described at post-mortem examination of a patient with peritoneal tuberculosis in 1836. To explain this finding, it was suggested in 1849 that coagulated lymphatic vessels may turn into fibrinous adhesions[29,30]. Until now, the exact pathophysiology of peritoneal adhesions has remained elusive. Despite many clinical and experimental studies, peritoneal adhesions pathophysiology remains controversial. Aside from the normal peritoneal regeneration, the process of

postoperative peritoneal adhesion formation may be considered as the pathological part of healing following any peritoneal injury, particularly due to abdominal surgery[5,31]. The balance between fibrin deposition and degradation is crucial in determining normal peritoneal healing or adhesion formation. If fibrin is completely degraded, normal peritoneal healing may occur. In contrast, incompletely degraded fibrin may serve as a scaffold for fibroblasts and capillary in growth to form peritoneal adhesions. Peritoneal injury, due to surgery, infection or irritation, initiates inflammation with fibrinous exudate and fibrin formation[32]. Fibrin results from coagulation cascade activation that is activated in the peritoneal cavity, resulting in the formation of thrombin that triggers conversion of fibrinogen into fibrin. However, owing to activation of the fibrinolytic system, any intra-abdominal fibrin deposits must be lysed. After abdominal surgery, however, the equilibrium between coagulation and fibrinolysis is disturbed, in favor of the coagulation system. Thus, fibrin forms deposits are a matrix for ingrowth of fibrocollagenous tissue. Indeed, fibroblasts invade the fibrin matrix and the extracellular matrix (ECM) is produced and deposited. This ECM can still be completely degraded by the proenzymes of matrix metalloprotease (MMP), leading to normal healing. However, if this process is inhibited by tissue inhibitors of MMPs, peritoneal adhesions may be formed[33]. Generally, if fibrinolysis does not occur within 5-7 d of the peritoneal injury, the temporary fibrin matrix persists and gradually becomes organized with collagen-secreting fibroblasts. This process leads to peritoneal adhesion formation[34,35] and growth of new blood vessels mediated by angiogenic factors[13]. Activation of the fibrinolytic system results in the conversion of plasminogen into plasmin that is highly effective in the degradation of fibrin into fibrin degradation products. Tissue-type plasminogen activator (tPA) and urokinase-type plasminogen (uPA) are both plasminogen activators. They are expressed in endothelial cells, mesothelial cells and macrophages. tPA, a serine protease, is the main plasminogen activator and has a high affinity for fibrin. It binds to a specific receptor, which exposes a strong plasminogen-binding site on the surface of the fibrin

molecule. Therefore, in the presence of fibrin, the activation rate of plasminogen is strikingly enhanced, whereas in the absence of fibrin, tPA is a poor activator of plasminogen[36,37]. This results in higher plasminogen activation at the sites where it is required, whereas systemic activation is prevented. In the peritoneal cavity, tPA is responsible for 95% of plasminogen-activating activity[38]. uPA is equally effective in the degradation of fibrin[39], but its much lower affinity for fibrin results in a significantly lower plasminogen-activating activity. Besides activation of plasminogen, uPA may play an important role in tissue remodeling[40]. Plasminogen activation is hampered by plasminogen-activating inhibitor (PAI)-1 and 2 throughformation of inactive complexes. The most potent inhibitor of tPA and uPA is the glycoprotein PAI-1. PAI-2 is less effective in counteracting plasminogen activators. It probably plays a role in peritoneal tissue repair[41]. Both PA-1 and PAI-2 are produced by endothelial cells, mesothelial cells, monocytes, macrophages and fibroblasts. Other plasminogen activator inhibitors have been identified: PAI-3 and protease nexin 1. Several protease inhibitors, such as 2macroglobulin, 1-antitrypsin and 2-antiplasmin, inhibit plasmin directly. However, their roles in peritoneal fibrinolysis are not well defined[42]. The balance between plasminogen activators and plasminogen inhibitors is crucial in determining normal healing or adhesion formation (Figure1). Therefore, PAI-1 is considered to be an important factor in the development of adhesions and high PAI concentrations are found in adhesions and peritoneal tissue of patients with extensive adhesions[43,44].
Figure 1

Balance between plasminogen activators and plasminogen inhibitors. TIMP: Tissue inhib

metalloproteinases; MMP: Matrix metalloprotease; ECM: Extracellular matrix; tPA: Tissue

plasminogen activator; uPA: Urokinase-type plasminogen; PAI: Plasminogen-activating i

Several preventive agents against postoperative peritoneal adhesions have been investigated. Their roles are in activating fibrinolysis, hampering

coagulation, diminishing the inflammatory response, inhibiting collagen synthesis, or creating a barrier between adjacent wound surfaces. These prevention strategies can be grouped into four categories: general principles, surgical techniques, mechanical barriers, and chemical agents[3]. General principles and surgical techniques: Some basic principles should be respected during all abdominal surgical procedures. These principles are close to the Halstedian principles (W.S. Halsted 18521922), the first surgeon who recognized the importance of these measures[45]. Peritoneal damage should be avoided by careful tissue handling, meticulous hemostasis, continuous irrigation and avoiding unnecessary drying, ineffective use of foreign bodies, and suturing or clamping of tissue. The use of fine and biocompatible suture materials, atraumatic instruments and starch-free gloves is also recommended. Starched gloves are a significant risk factor for postoperative adhesions. Several experimental studies have shown that the use of starch-powdered gloves during laparotomy is associated with an increased risk of extensive postoperative peritoneal adhesions[46]. Foreign bodies most frequently found in postoperative adhesions are: surface powders from surgical gloves; lint from packs, drapes, or gowns; wood fibers from disposable paper items; and suture materials. However, recent data have suggested that, in the absence of an additional peritoneal injury, foreign bodies are an infrequent cause of adhesion induction[9,47]. Ordonez et al[48] have evaluated the effect of training on postoperative adhesion formation in a rabbit model. The training effect was evaluated by duration of surgery and amount of bleeding. This study has shown that there is a significant effect of experience on duration of surgery. With experience, duration of surgery progressively decreases, and postoperative adhesions also decrease in extent, tenacity, type and total score. According to these findings, surgical training and the respect of some basic principles (Halstedian principles) are important for adhesion prevention. Some intraoperative techniques, such as avoiding unnecessary peritoneal dissection or avoiding closure of the peritoneum, should be applied. Many experimental studies have shown that non-closure of the peritoneum is

associated with decreased peritoneal adhesion formation[49-51]. However, some studies have reported no difference[52,53] or even decreased peritoneal adhesion[54] with peritoneal closure. However, grafting or suturing peritoneal defects may increase peritoneal ischemia, devascularization, and necrosis, predisposing the site to decreased fibrinolytic activity and increased adhesion formation[55]. Furthermore, surgical trauma should be reduced as much as possible. The surgical approach (open vslaparoscopic) could play an important role in the development of adhesions. In most abdominal procedures, the laparoscopic approach is associated with a significantly lower incidence of postoperative peritoneal adhesions or adhesion-related re-admissions. Brokelman et al[56] have shown in a prospective trial that there is no difference in tPA antigen, tPA-activity, uPA antigen, or PAI-1 antigen concentrations in peritoneal biopsies taken at the beginning compared to the end of the laparoscopic procedure, irrespective of the intra-abdominal pressure or light activity. In contrast, some studies have reported no difference between both surgical approaches. A role for CO2 pneumoperitoneum in adhesion formation after laparoscopic surgery has been reported[48,57]. During laparoscopic surgery, CO2 pneumoperitoneum by itself has a real impact on abdominal adhesions. It has been demonstrated that adhesion formation increases with the duration of CO2 pneumoperitoneum and insufflation pressure[48,57]. Indeed, prolonged laparoscopic surgery requires long duration and large volume gas insufflations, which raise concerns about the adverse effects of prolonged gas insufflations[58]. The standard CO2 used in current laparoscopic practice is cold dry CO2, which is not physiological to the normal conditions of the peritoneal cavity[57]. Many studies have shown that short-duration laparoscopy, < 3 h, with cold dry CO2 insufflation can cause peritoneal alterations and result in numerous detrimental outcomes, including postoperative peritoneal adhesion formation[48,58]. The benefits of heated humidified CO2 insufflation (37 C and 95% relative humidity, physiological conditions) have been reported to include less hypothermia, less postoperative pains, shortened recovery room stay, better convalescence, less tumor spread and growth[48,58], and

less adhesion formation[35]. Furthermore, Molinas et al[59] have demonstrated that CO2 pneumoperitoneum increases postoperative peritoneal adhesions in a time- and pressure-dependent relationship, and that this increase is reduced by the addition of 2%-4% oxygen, suggesting peritoneal hypoxia as the driving mechanism. It supposes that when fibrinolytic activity decreases, the process of adhesion formation does not depend anymore on the surgical approach, but evolves on its own account. Mechanical barriers: Liquid or solid mechanical barriers may prevent postoperative peritoneal adhesion formation by keeping peritoneal surfaces separate during the 5-7 d required for peritoneal re-epithelialization. They prevent contact between the damaged serosal surfaces for the first few critical days. An ideal barrier should be biodegradable, safe, noninflammatory, non-immunogenic, persist during the critical remesothelialization phase, stay in place without sutures or staples, remain active in the presence of blood, and be rapidly and easily applied[60,61]. Also, it should not interfere with healing, promote infection, or cause adhesions. Barriers are currently considered the most useful adjuncts that may reduce postoperative peritoneal adhesion formation. Various solid or fluid barrier agents have been tested experimentally and in clinical trials. Liquids such as crystalloids, dextran, hyaluronic acid, cross-linked hyaluronic acid and icodextrin have been used to prevent adhesion. They separate injured surfaces by hydroflatation but their effectiveness is controversial. Crystalloids, such as saline and Ringers lactate, are used in large amounts but they are rapidly absorbed. The most commonly used hypertonic solution was 32% dextran 70, but it was abandoned because of serious complications[61]. Other liquid barriers that have the advantage of a longer residence time in the abdominal cavity, such as hyaluronic acid (Sepracoat, Genzyme Corporation, Cambridge, MA, United States), cross-linked hyaluronic acid (Intergel Hyalobarrier gel; Baxter, Pisa, Italy), and icodextrin (Adept, Baxter Healthcare Corporation, Deerfield, IL, United States) have shown promising results in experimental and clinical studies[61]. Brown et al[62] have demonstrated that Adept is a safe and effective adhesion reduction agent in laparoscopy. There are non-absorbable and bio-absorbable films, gels or solid

membranes. The most commonly used mechanical barriers are oxidized regenerated cellulose (Interceed; Johnson & Johnson Medical, Arlington, TX, United States), expanded polytetrafluoroethylene (Preclude Peritoneal Membrane; W.L. Gore and Associates Inc., Flagstaff, AZ, United States), hyaluronic acid-carboxymethylcellulose (Seprafilm; Genzyme Biosurgery, Cambridge, MA, United States) and polyethylenglycol (SprayGel; Confluent Surgical Inc., Waltham, MA, United States). Preclude is non-degradable and requires a second operation for removal. The most extensively studied bioabsorbable films are Seprafilm and Interceed. Seprafilm is absorbed within 7 d and excreted from the body within 28 d[63,64]. Prospective randomized controlled trials have shown the efficacy of Seprafilm in reducing the incidence and extent of postoperative adhesions[65-68]. However, Seprafilm may cause a significant impairment of anastomoses, and should not be applied to anastomosis cases[69]. Other experimental studies have demonstrated that covering lesions of the parietal peritoneum with microsurgically applied autologous peritoneal transplants can completely prevent severe peritoneal adhesion formation. However, the advantage of a synthetic barrier is that the material does not need to be obtained surgically and can be cut to size outside of the abdomen and then applied without sutures[70]. Chemical agents: Chemical agents generally prevent the organization of the persisting fibrin, by fibroblastic proliferation inhibition. Many agents are used to inhibit this proliferation such as, non-steroidal antiinflammatory drugs (NSAIDs), corticosteroids, calcium channel blockers, histamine antagonists, antibiotics, fibrinolytic agents, anticoagulants, antioxidants, hormones, vitamins, colchicines and selective immunosuppressors[60]. NSAIDs reduce peritoneal adhesions in some animal models by prostaglandin and thromboxane synthesis inhibition[9]. They decrease vascular permeability, plasmin inhibitors, platelet aggregation, and coagulation and also enhance macrophage function[9]. Rodgers et al[71] have shown that postoperative administration of anti-inflammatory drugs to the site of injury reduced the formation of postoperative adhesions in two animal models. A rat model has been used to investigate the efficacy

of nimesulide, a selective cyclooxygenase-2 inhibitor, in the prevention of adhesion formation. This study has shown that preoperative intramuscular or postoperative intraperitoneal administration of nimesulide to the site of injury reduced the formation of postoperative adhesion in this rat model[72]. Generally, some anti-inflammatory drugs may be effective in preventing adhesions, but there is no clinical significant evidence from any published study to recommend their use in humans for this purpose, and several side effects still have to be ascertained[73]. Corticosteroid therapy reduces vascular permeability and liberation of cytokines and chemotactic factors and has reduced peritoneal adhesion formation in some animal models[70]. However, corticosteroids have side effects, such as immunosuppression and delayed wound healing[60,74]. Kirdak et al[75] have investigated the effectiveness of different doses of methylprednisolone in preventing experimentally induced peritoneal adhesions in rats. They have found that there was no difference in the effectiveness of different methylprednisolone doses, administered topically, in preventing peritoneal adhesion formation, and furthermore, steroids did not prevent peritoneal adhesion development[75]. In animal models, these hormones may prevent adhesion formation, but some studies have not confirmed this effectiveness in humans[74]. Progesterone has been reported to have an anti-inflammatory as well as immunosuppressive effect, and may prevent adhesion formation[73]. However, Confino et al[76] have shown that there was no significant difference overall in the incidence of adhesion formation between progesterone-treated and control rabbits. They have revealed a beneficial effect of progesterone in the reduction of only minor adhesion formation formed after minor peritoneal damage[76]. Furthermore, it has been shown that neither estrogen nor gonadotropin-releasing hormone prevented adhesion formation, but there were fewer adhesions formed in estrogentreated than untreated animals[77]. The use of anticoagulants to prevent the formation of peritoneal adhesions has been enthusiastically reported in the literature[78]. Many molecules have been used, such as heparin or dicumarol, which prevents adhesion by increasing the fibrinolysis due to serine esterase activity[79]. Heparin is the

most widely investigated anticoagulant used for prevention of adhesions. However, its efficacy in reducing adhesion formation whether administered alone or in combination with interceed barrier has not been demonstrated in clinical trials[78]. Fibrinolytic agents such as recombinant tPA, when applied locally, have reduced adhesions in animal models[73]. However, these fibrinolytic agents may cause hemorrhagic complications[73]. Three different drugs, tPA (Actilyse; Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany), fondaparinux (Arixtra; GlaxoSmithKline, France), and activated drotrecogin alfa (Xigris; Elli Lilly and Co., DSM Pharmaceuticals, Inc. Greenville, NC, United States), which affect the coagulation process at various stages, have been studied for their effectiveness in preventing intraperitoneal adhesion formation in rats[80]. All three agents were effective in preventing adhesions when compared to the control group. Nevertheless, activated drotrecogin alfa seemed the most effective except when considering clinical applicability, in which case fondaparinux seemed to offer the greatest advantage[80]. However, further studies have suggested that all these approaches may have only limited success, impeded lack of safety, efficacy and many adverse effects without eliminating the problem of postoperative peritoneal adhesion formation[81,82]. Some antibiotics are commonly used for prophylaxis against postoperative infections and adhesion formation. Less peritoneal infection may lead to less peritoneal adhesion formation. Linezolid (Zyvox; Pfizer, New York, NY, United States) has been found to reduce intraperitoneal adhesion formation in a rat uterine horn model[83]. However, other studies have shown that intra-abdominal application itself causes adhesion formation[73]. Sortini et al[84] have shown that antibiotics led to greater adhesion formation by Zhlke score as compared to saline, whereas no difference was observed between antiseptics and saline. Indeed, antibiotics in intraperitoneal irrigation solutions have been demonstrated to increase peritoneal adhesion formation in rat models, and thus, are not recommended as a single agent for adhesion prevention[79]. Vitamin E is the most studied vitamin in adhesion prevention. In

vitro studies have demonstrated that vitamin E has antioxidant, antiinflammatory, anticoagulant and antifibroblastic effects, and decreases collagen production. It has been found to be effective for reducing adhesion formation by some authors[85]. Corrales et al[86] have shown that vitamin E, administered intraperitoneally, is as effective as carboxymethylcellulose membrane in preventing postoperative adhesions. By contrast, the same effect has not been achieved after intramuscular administration[87]. A significant difference has been found between intraperitoneal and intramuscular vitamin E administration[87]. Thus, intraperitoneal administration of vitamin E might be recommended to prevent adhesion formation. However, according to our literature review, there have been no human studies that have recommended the use of vitamin E for postoperative adhesion prevention. One study has been carried out to elucidate the effects of different concentrations of methylene blue on the process of peritoneal adhesion formation and to define its minimum dose that can effectively prevent the formation of such adhesions in a rat model[88]. It could be concluded that 1% methylene blue had the best anti-adhesion potential[88]. If methylene blue prevents peritoneal adhesions, it can cause significant impairment of anastomotic bursting pressure during the early phase of the wound healing process by its transient inhibitory effect on the nitric oxide pathway[89]. Adhesions are a result of the inflammatory response to tissue injury in the peritoneal space. Although the mechanism is unclear, local anesthetics are reported to have some anti-inflammatory effects, as shown in some animal studies[90]. These anti-inflammatory effects are related to the inhibition of neutrophils. It has also been shown that local anesthetics activate the fibrinolytic system, reduce factor VIII, plasminogen and 2-antiplasmin concentration, and inhibit platelet aggregation[91,92]. Thus, besides the accelerative effect of a mixture of 2.5% lidocaine and 2.5% prilocaine in the wound healing process, some studies have demonstrated that intraperitoneal lidocaine and prilocaine inhibit the formation of postoperative peritoneal adhesions without compromising wound healing in a bacterial peritonitis rat model[93]. Hepatocyte growth factor (HGF) can inhibit collagen deposition and has

fibrinolytic capacity[94,95]. Liu et al[96] have demonstrated that local application of recombinant adenovirus carrying the HGF gene reduced adhesion formation in a rat model. Other studies have investigated the use of gene therapy to manage postoperative adhesions. Smad7, a protein that occupies a strategic position in fibrinogenesis, inhibits transforming growth factor- and has the potential to attenuate postoperative adhesion. Guo et al[97] have investigated in an experimental model the therapeutic potential of exogenous Smad7 to prevent fibrinogenesis in postoperative intra-abdominal adhesion. In this rat model, ultrasound-microbubblemediated Smad7 transfection significantly decreased the incidence and severity of peritoneal adhesions, but the use of targeted gene therapy as a preventive agent against ASBO still needs extensive evaluation before any clinical trial.

Postoperative peritoneal adhesions are a major health problem with a significant economic impact. Fibrinolysis seems to be a key factor in determining the pathogenesis of adhesion formation and in its prevention. Several studies on this problem have been conducted. Their results are encouraging, but most of them are contradictory and have been conducted in animal models. Until additional findings from future clinical studies, only meticulous surgery can be recommended to reduce unnecessary morbidity and mortality rates from these untoward effects of surgery. In the current state of knowledge, preclinical or clinical studies are still necessary to evaluate the effectiveness of the several proposed prevention strategies for postoperative peritoneal adhesions.

Adhesive small bowel obstruction: epidemiology, biology and prevention

Jo-Anne P. Attard and Anthony R. MacLean
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Intraabdominal adhesions develop after abdominal surgery as part of the normal healing processes that occur after damage to the peritoneum. Over the last 2 decades, much research has gone into understanding the biochemical and cellular processes that lead to adhesion formation. The early balance between fibrin deposition and degradation seems to be the critical factor in adhesion formation. Although adhesions do have some beneficial effects, they also cause significant morbidity, including adhesive small bowel obstruction, infertility and increased difficulty with reoperative surgery. Several strategies have been employed over the years to prevent adhesion formation while not interfering with wound healing. This article summarizes much of our current understanding of adhesion formation and strategies that have been employed to prevent them.
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Les adhrences intra-abdominales font leur apparition aprs une chirurgie l'abdomen dans le cours des mcanismes de gurison normaux suivant un dommage au pritoine. Au cours des deux dernires dcennies, on a effectu beaucoup de recherches afin de comprendre les phnomnes biochimiques et cellulaires l'origine de la formation d'adhrences. L'quilibre prcoce entre le dpt de fibrine et sa dgradation semble jouer un rle critique dans la formation d'adhrences. Mme si les adhrences ont certains effets bnfiques, elles causent aussi une morbidit importante, y compris l'occlusion de l'intestin grle, l'infcondit et les difficults accrues dans le cas d'interventions chirurgicales ultrieures. On a suivi au fil des ans plusieurs stratgies pour prvenir la formation d'adhrences sans nuire la gurison de la plaie. Cet article rsume une grande partie des connaissances actuelles au sujet de la formation d'adhrences, ainsi que les stratgies que l'on a suivies pour les prvenir. Postoperative adhesions form after trauma to the peritoneal cavity and are a result of the biochemical and cellular response that occurs in an attempt to repair the peritoneum. Although there are beneficial effects to adhesions, they are the leading cause of small intestinal obstruction after abdominal surgery and can be the source of significant morbidity, in some cases leading to mortality. This review aims to provide general surgeons with a broad overview of what is currently known about adhesions, the cellular and molecular events that are involved in their formation, the latest re-search developments in this area and the current available methods of prevention.

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Peritoneal adhesions can be defined as abnormal fibrous bands between organs or tissues or both in the abdominal cavity that are normally separated.13 Adhesions may be acquired or congenital; however, most are acquired as a result of peritoneal injury, the most common cause of which is abdomino-pelvic surgery.4 Less commonly, adhesions may form as the result of inflammatory conditions, intraperitoneal infection or abdominal trauma.4 It is estimated that 93% to 100% of patients who undergo transperitoneal surgery will develop postoperative adhesions.5 The extent of adhesion formation varies from one patient to another and is most dependent on the type and magnitude of surgery performed, as well as whether any postoperative complications develop.6 Another surgical factor that has been shown to contribute to adhesion formation is intraperitoneal foreign bodies, including mesh, glove powder, suture material and spilled gallstones.7 Fortunately, most patients with adhesions do not experience any overt clinical symptoms. For others, adhesions may lead to any one of a host of problems and can be the cause of significant morbidity and mortality.8
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Adhesions and small bowel obstruction (SBO)

Intraabdominal adhesions are the most common cause of SBO in industrialized countries, accounting for approximately 65% to 75% of cases.5 There is a wide range of values reported in the literature for the risk of developing adhesive SBO after transperitoneal surgery, depending on the series of patients, how they were evaluated and the types of surgical procedures performed. In general, procedures in the lower abdomen, pelvis or both and those resulting in damage to a large peritoneal surface area tend to put patients at higher risk for subsequent adhesive obstruction.4 It is estimated that the risk of SBO is 1% to 10% after appendectomy,9,10 6.4% after open cholecystectomy,9 10% to 25% after intestinal surgery11,12 and 17% to 25% after restorative proctocolectomy (IPAA).1316 The relation between postoperative adhesions and intestinal obstruction is not a new concept. In 1872, Thomas Bryant described a fatal case of intestinal obstruction caused by intra-abdominal adhesions that developed after removal of an ovarian tumour.17 Since Bryant's report, a significant amount of time and money has been invested into research on intraabdominal adhesions, with a primary focus on the development of methods to prevent their formation. Despite substantial work in this area, little progress has been made; to this day, no clinical standard exists for any preventive measure, either surgical or pharmacological, to control the formation of postoperative adhesions.4
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Other complications of adhesions

SBO is probably the most severe consequence of intraabdominal adhesions, but it is not the only one, and the adverse effects of adhesions are not limited to the gut.4 For example, in

the gynecological literature, it has been found that adhesions are a leading cause of secondary infertility in women (responsible for 15%20% of cases)18 and, although controversial, there is evidence to suggest that they may be a cause of longer-term abdominal and pelvic pain.19 For patients with chronic renal failure, adhesions may make peritoneal dialysis impossible, and their presence may preclude the use of intraperitoneal chemotherapy in those patients who are candidates.4,6 For general surgeons, the presence of adhesions often makes reoperative surgery difficult and may increase the complication rate of the intended surgical procedure.20 In the current era of advanced laparoscopic surgery, adhesions have taken on an even greater significance, frequently making laparoscopic approaches more difficult and, in some cases, entirely impossible.4 Even with open reoperative surgery, extensive adhesiolysis is often necessary to ensure adequate exposure, not uncommonly resulting in prolonged operating times, increased blood loss and other complications.4,20,21 Inadvertent enterotomy is probably the best recognized complication of adhesiolysis, with an incidence of approximately 20% in reoperative surgery.20 These cases result in a poorer outcome for the patient, with prolonged hospitalization and a higher incidence of intensive care unit admissions.20
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Socioeconomic burden of adhesive SBO

The consequences of postoperative adhesion formation have become a significant burden socioeconomically, and the treatment of adhesion-related disease uses a significant portion of health care resources and dollars.8 From a large-scale epidemiological study in Scotland, for example, 5.7% of hospital readmissions over a 10-year period were found to be directly related to adhesions, and 3.8% of these admissions required operative management.8 In 1994, the estimated financial impact for direct patient care owing to adhesion-related disorders in the United States was US$1.3 billion.22 In Sweden, it is estimated that the health care burden owing to adhesive disease reaches $13 million annually.23 As the cost of health care continues to escalate and the number of patients requiring surgical care increases with the aging population, the financial burden of adhesions will continue to expand. Given the far-reaching consequences of postoperative adhesions, it is important that they not be viewed as an inevitable consequence of surgery for which little can be done.24 This knowledge should provide the impetus for further research in this area, to improve our understanding of the pathophysiology of adhesions and to enable the development of methods to alter the biological events that are necessary for their formation.
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Understanding the pathophysiology of adhesion formation

Holmdahl and Ivarsson25 have suggested that the inability to discover effective ways to reduce or abolish adhesion formation over the years has been due to a lack of insight into the basic tenets of peritoneal tissue repair. Only in the last 15 to 20 years have researchers started to unravel the complexities of this process, which involves several different cell

types, cytokines, coagulation factors and proteases, all acting together to restore tissue integrity.25 Although our understanding is far from complete, studies of adhesion formation thus far have determined what is believed to be the central pathophysiological mechanism leading to ad-hesion development.24,26 This is discussed below. If effective preventative and treatment strategies are to be developed, a more comprehensive understanding of this process at both the cellular and the molecular level, as well as the identification of inflammatory mediators involved, is essential. The key to preventing post-operative adhesions will most likely be based on selective inhibition of one or more of the critical factors required for their formation. Peritoneal wound healing differs from skin in both the mode of epithelialization and the consequences of fibrin deposition. To understand how the peritoneum responds to injury, some basic knowledge about its structure is required. The peritoneum consists of a single outer layer of mesothelial cells that are loosely anchored to a basement membrane and that detach readily with even the slightest trauma.21,25,27 The submesothelial layer consists of components of the extracellular matrix, along with capillaries and lymphatics.21,23,25 Fluid resorption and diffusion occurs freely across these layers.21 The fluid in the peritoneal cavity contains several different cell types, including leukocytes and macrophages.25 These cells, along with the mesothelium, secrete various cellular mediators that have roles in peritoneal healing, enabling modulation of the inflammatory response over a large surface area.21 The process of postoperative adhesion formation constitutes a complex interaction of biochemical events involved in inflammation, tissue repair, angiogenesis and innervation.28 Peritoneal injury occurs at the site of the actual procedure and in areas remote from the operative field, as a result of tissue and organ retraction during the course of surgery.1 Surgical trauma to the peritoneum can occur by various mechanisms: cutting, abrasion, ischemia, desiccation and coagulation.4 The latter 2 types of injury are unique in that they are directly toxic to the mesothelial cells that line the peritoneal cavity and to the underlying connective tissue.4 Ischemic injury is typically the result of tissue and organ retraction. Regardless of the mechanism, however, the response of the peritoneum to surgical trauma is the same25 (Fig. 1). Immediately after injury, there is bleeding and an increase in vascular permeability with fluid leakage from injured surfaces.21,25,28 Simultaneously, a posttraumatic inflammatory response occurs, with infiltration of inflammatory cells, release of pro-inflammatory cytokines and activation of the complement and coagulation cascades.25,27

FIG. 1. Biological events involved in peritoneal tissue repair and adhesion formation. The fluid exudate released from injured peritoneal surfaces is rich in plasma proteins especially fibrinogen.4,27 Activation of the coagulation cascade results in the formation of thrombin, which is necessary for the conversion of fibrinogen to fibrin.27 Fibrin functions to restore injured tissues and, once generated, is deposited along peritoneal surfaces. Fibrin is a tacky substance and causes adjacent organs or injured serosal surfaces to coalesce.24 Under normal circumstances, the formation of a fibrin matrix during wound healing is only temporary, and degradation of these filmy fibrinous adhesions by locally released proteases of the fibrinolytic system occurs within 72 hours of injury.2 Thus the process of fibrinolysis is not confined to the degradation of intravascular thrombi; it also has a key role in tissue remodelling and repair.25 Fibrinolysis allows mesothelial cells to proliferate and the peritoneal defect to be restored within 4 to 5 days, preventing the permanent attachment of adjacent surfaces.2,29 Adequate blood supply is critical for fibrinolysis, and since peritoneal injury results in ischemia, it also interferes with fibrinolysis.6 If fibrinolysis does not occur within 5 to 7 days of peritoneal injury, or if local fibrinolytic activity is reduced, the fibrin matrix persists.25 If this occurs, the temporary fibrin matrix gradually becomes more organized as collagen-secreting fibroblasts and other reparative cells infiltrate the matrix.4,24 The organization of fibrin bands over time and their transformation into mature fibrous adhesions is what enables them to persist.2 These mature adhesions are not simply composed of connective tissue; studies have demonstrated that, over time, they become highly organized cellular structures that contain arter-ioles, venules, capillaries and nerve fibres in addition to collagen.30 As described above, the fibrinolytic system has a key role in peritoneal wound healing, and disruption of this system results in adhesion formation. In addition to activators of fibrinolysis, there are also inhibitors that exist to maintain balance in the system (that is, to prevent excessive fibrin deposition and degradation). There are 2 major activators in the fibrinolytic system: tissue plasminogen activator (tPA) and urokinase-like plasminogen activator (uPA), both of which are capable of activating plasminogen to plasmin.2 Plasmin is a broad-range protease capable of degrading various molecules in the extracellular matrix (ECM), including fibrin.21,25 Of the 2 plasminogen activators, tPA is the most important in peritoneal wound healing because it has a specific affinity for fibrin that uPA lacks; it is responsible for 95% of the plasmin generated in the response to peritoneal injury.31 There is also a group of glycoproteins that act as inhibitors of fibrinolysis and are collectively referred to as plasminogen activator inhibitors (PAI). Two groups of PAIs exist: PAI-1 and PAI-2. However, PAI-1 is recognized as the dominant inhibitor of fibrinolysis in plasma.27,31,32 PAI-1 specifically prevents the formation of plasmin by directly binding to and inhibiting the activities of tPA and uPA, thereby preventing the degradation of fibrin.21 If fibrinolysis is a normal part of peritoneal healing, one may ask, what allows fibrin to become organized and fibrous adhesions to persist? In 1983, Moore and colleagues33 demonstrated that the peritoneum has powerful coagulation and fibrinolytic

capacity. As discussed above, under normal conditions (i.e., in an undisturbed abdominal cavity), fibrinolytic capacity exceeds coagulation.33Additional studies have shown that, in conditions where there is peritoneal injury, relative ischemia or both (such as when a patient has peritonitis or is undergoing surgery), peritoneal fibrinolytic capacity is depressed,31 and the relation between fibrinolysis and coagulation is reversed. Further, the reduction in peritoneal fibrinolysis after an operation seems to be inversely correlated to the degree of adhesion formation.34 Given these findings, it is believed that the decline in peritoneal fibrinolytic capacity after surgery is the common central pathway leading to adhesion formation.26,31 Both animal and human studies have shown that 2 major changes mediate the decline in fibrinolysis: a decrease in local tPA activity31 and an increase in PAI-1 locally and systemically.35 The reason for decreased activity of tPA appears to be 2-fold: a reduction in the absolute amount of tPA released by the injured peritoneum and the result of quenching any remaining tPA activity by PAI-1.25,32 The importance of tPA and PAI-1 in adhesion formation is further supported by studies in which it was discovered that patients with the most severe adhesions overexpress PAI-1 and have depressed tPA activity.31,32 Further, after surgery, tPA knockout mice seem to be more susceptible to adhesion formation, compared with uPA-deficient or wild-type mice.2 Although the specific molecular and biochemical events mediating the change in fibrinolytic activity have yet to be fully elucidated, it appears that cytokines, growth factors and angiogenesis factors, all of which are released by activated macrophages and other inflammatory cells in response to peritoneal injury, may have important roles in regulating this change. Elucidating the role of inflammatory mediators in adhesion formation has become the main current focus of research in this area. It is known that specific cytokines and growth factors are responsible for upregulating the expression of genes whose products may help to initiate adhesion formation, likely by coordinating the events responsible for the decline in fibrinolysis.21,25 Examples include genes for the neurokinin-1 (NK-1) receptor, transforming growth factor beta (TGF-), substance P (SP), intracellular adhesion molecule (ICAM-1) and vascular cell adhesion molecule (VCAM-1). An increase in the levels of mRNA transcribed from each of these genes has been found in the peritoneal tissue of rats early after surgical trauma.28 TGF- is the most thoroughly studied cytokine in adhesion formation.25 TGF- is a potent cytokine and growth factor that initiates, modulates and terminates tissue repair, and both TGF- and its receptor are elevated in peritoneal tissue and fluid after transperitoneal surgery.36 In vitro studies suggest that TGF- contributes to a decrease in peritoneal fibrinolytic capacity and may have a role in preventing the early dissolution of fibrinous adhesions.37 In vivo evidence for a role of TGF- in promoting adhesion formation comes from studies using an animal model of surgically induced adhesions, in which animals were given either intraperitoneal recombinant TGF- or placebo at the time of laparotomy. The animals that received TGF- had significantly more adhesions than the control group when reexamined several days later.38 Similarly, in a separate study, animals treated with a TGF-

neutralizing antibody had reduced adhesion formation after surgery, compared with controls.39 The exact mechanism through which TGF- mediates this response is not known; however, early studies suggest that it may involve the local regulation of PAI-1.40 Several proinflammatory interleukins have been studied for their potential role in adhesion formation. Although the role of many of these interleukins has yet to be defined, the role of interleukin-1 (IL-1) in the pathophysiology of adhesion formation is becoming clear. Studies have suggested that, in addition to promoting inflammation and primary coagulation, IL-1 also contributes to the overall decrease in local fibrinolytic capacity that is necessary for adhesions to form. The increased level of IL-1 that has been measured in peritoneal fluid postoperatively supports a local action for this substance in the peritoneal cavity.41 In vivo, IL-1 has been found to stimulate the release of PAI-1 in human mesothelial cells,42suggesting that it may play a part in inhibiting local fibrin degradation. Further support for its role in promoting adhesion formation and initiating tissue repair comes from a study in which rats treated with an antiIL-1 preparation developed significantly less surgically induced adhesions than did the controls.43 Recently, substance P (SP) has received attention with respect to its role in adhesion formation. SP is a neuropeptide that belongs to the tachykinin family of peptides, to which the NK receptors also belong. SP can be found in a variety of locations, including peritoneal fluid, and it has many biological effects most of which involve mediation of the inflammatory reaction.28 Through high-affinity binding to the NK-1 receptor, SP has been shown to affect the expression of intracellular adhesion molecules (such as ICAM-1 and VCAM-1) and TGF- in several cell types, all of which have also been shown to have a role in adhesion formation.28 Further support for a role of SP in adhesion formation comes from studies demonstrating the presence of SP-containing sensory neurons in peritoneal adhesions19,28 and animal studies with neural endopeptidase knockout mice.44 Neural endopeptidase is a cell surface enzyme that degrades SP, and mice lacking this enzyme develop intraabdominal adhesions more readily than their wild-type counterparts. Given these findings, it is likely that SP plays a central role in coordinating the pathogenesis of adhesion formation, and further investigations are warranted. With respect to a role for the NK-1 receptor (NK-1R) in adhesion formation, initial experiments by Reed and colleagues28 demonstrated that there is a significant increase in mRNA levels for both NK-1R and SP in peritoneal adhesion tissue by day 3 after surgery. Additional experiments showed that administration of a NK-1R antagonist (NK-1RA) to rats after surgery significantly reduced adhesion formation by 45%, compared with controls.45 NK-1RA blocks the binding of SP to NK-1, further supporting a role for both SP and NK-1 in adhesion formation. Evidence that SP and NK-1 specifically affect fibrinolysis comes from the same study, in which peritoneal samples were collected from nonoperated controls and from both experimental groups of animals (those who received the NK-1RA or placebo) 24 hours postsurgery. These investigators found that NK-1RA administration led to a significant increase in the expression of mRNA for tPA in both peritoneal fluid and tissue, compared with the operated and nonoperated controls. With the use of zymography,

investigators found that the fibrinolytic activity was also increased in the corresponding tissue samples.45
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Preventative strategies
The goal of adhesion prevention is to abolish or reduce the incidence, severity, extent and consequences of adhesions while retaining normal healing and preventing infection.4 Over the years, several strategies to prevent postoperative adhesion formation have been proposed, based on what has been learned about the underlying pathophysiology. Unfortunately, although numerous different strategies have been evaluated, few have been successful, and some have even been deleterious. To this day, there are no means of completely preventing postoperative adhesion formation. The only method available to treat adhesions that have already formed is surgical adhesiolysis. Lysis of adhesions is typically only performed in patients who develop complications from adhesions, such as SBO, pain or infertility, since most of the adhesions that are surgically removed will simply reform.5,24 Strict adherence to meticulous surgical technique has been advocated for many years by surgeons and surgical texts as a means to reduce adhesion formation after transperitoneal surgery.4 Although such efforts rarely prevent adhesions in most patients, the principle of good surgical technique to decrease peritoneal injury should not be discounted, because such practices can also influence the risk of developing com-plications associated with surgical procedures.6 The measures that have been described and advocated for decreasing adhesion formation include minimizing peritoneal foreign body exposure (e.g., using suture material only as necessary, eliminating glove powder by washing gloved hands before surgery), careful tissue handling, using cautery and retractors sparingly, ensuring meticulous hemostasis while avoiding dessication and ischemia, administering prophylaxis against infection and avoiding the use of overheated irrigation fluids.4,6 Given that strict adherence to careful surgery does not eliminate or prevent adhesion formation, there are some surgical adjuvants that have been developed and evaluated for the purpose of decreasing postsurgical adhesion formation. An in-depth, comprehensive discussion of each agent is beyond the scope of this review; therefore, a general overview of these agents will be provided. There are 6 main mechanisms that interfere with adhesion formation: those that decrease peritoneal damage, those that decrease the initial inflammatory response, those that prevent fibrin formation, those that increase fibrinolysis, those that prevent collagen deposition and those that act as barriers to adhesion formation (Table 1).

Table 1 The agents that act most directly to reduce adhesions do so by decreasing the deposition of fibrin, which is absolutely necessary for adhesion formation to occur. These agents include nonsteroidal antiinflammatory drugs (NSAIDs), which interfere with prostaglandin synthesis and decrease the initial inflammatory response, and anticoagulants such as heparin. The results from studies using NSAIDs have been conflicting in terms of their effectiveness in reducing adhesions,52,67 and their use is controversial due to the risk of bleeding. Immunomodulators, such as corticosteroids, have also been tested for their ability to prevent adhesions,51 but their effectiveness has been found to be equivocal68 or even deleterious in some studies.69 Once fibrin is formed, another method of adhesion prevention is to eliminate fibrin, usually by enzymatic degradation.6 Examples of agents that degrade fibrin are streptokinase and the synthetic tissue plasminogen activators. Unfortunately, although successful in reducing adhesion formation in animal models, the use of recombinant tissue plasminogen activator (rtPA) is limited not only by the significant cost and intra-peritoneal administration that is required, but also by the risk of hemorrhage that exists.58,70 There are other miscellaneous agents that have been tried with limited success. One agent that deserves to be mentioned is halofuginone, an inhibitor of type I collagen synthesis. Halofuginone acts to prevent the formation of permanent fibrous adhesions by decreasing collagen deposition in the fibrin matrix. Although effective in reducing adhesion formation in animal models, it has yet to be evaluated in humans.59,71 Concerns have been raised about the safety of halofuginone, specifically, the effects it may have on the biosynthesis of other critical matrix proteins and, therefore, the potential for impairing normal wound healing.6,59 The most promising group of agents to be evaluated for their effectiveness in decreasing surgically induced adhesions are known as barriers. Barriers exist in the form of a membrane or gel, and they act to separate damaged or injured peritoneal surfaces that may be at risk for adhesions. These agents exert their effects locally, at the specific site where they have been applied, and have no effect on remote areas in the peritoneal cavity. An ideal barrier does not yet exist; however, in creating one, the following characteristics should be kept in mind: antiadhesive, biocompatible, resorbable, adherent to the traumatized surface, effective on an oozing surface, applicable through the laparoscope and inexpensive.72

The first barrier to demonstrate efficacy in humans is composed of modified oxidized regenerated cellulose and is known as Interceed (Johnson & Johnson, New Brunswick, NJ).62 Although studies have found it to be successful in reducing adhesion formation in gynecological procedures, its use in general surgical procedures is not known. Further, it has been suggested that the efficacy of Interceed is significantly reduced in the presence of blood. In fact, it has been observed that adhesion formation can actually increase if the Interceed barrier is placed in areas where blood accumulation cannot be prevented (e.g., the pelvis), making it less acceptable to use.62 The Preclude Peritoneal Membrane (W.L. Gore & Associates, The Netherlands) is another barrier that has been evaluated and found to be successful in decreasing postoperative adhesions. It consists of expanded polytetrafluoroethylene (PTFE), which is also used to make Gore-Tex. Animal studies evaluating PTFE as an antiadhesion barrier have found it to be effective in preventing pelvic adhesions only if sufficient in size to cover the entire peritoneal defect, with at least a 1-cm overlap onto normal peritoneum.73 Unfortunately, PTFE is not bioabsorbable and requires suturing to keep it in place, making it undesirable for use as a barrier to prevent adhesions, especially in cases where future reoperative surgery is likely.65 In addition, the cost of PTFE and the large size required for it to be effective, makes routine use of it after abdomino-pelvic surgery difficult to justify. The most extensively studied barrier, and the most efficacious to date, is a hyaluronanbased agent that is available both as a viscous solution and as a membrane. Hyaluronan is a naturally occurring polysaccharide that is present in virtually all tissues and bodily fluids of vertebrate animals and plays several roles in cellular biology.64 Studies have suggested that hyaluronan-based agents have the potential to act by different mechanisms to decrease adhesion formation. For example, sodium hyaluronate seems to improve peritoneal healing by facilitating cell detachment and migration and by increasing the proliferation rate of mesothelial cells, thereby helping to restore denuded areas of the mesothelial lining.74 Other studies have suggested that hyaluronan might also increase the fibrinolytic response of mesothelial cells, although this has not yet been demonstrated in vivo.74 The bioresorbable membrane that consists of hyaluronan and carbo-xymethylcellulose is most commonly known as Seprafilm (Genzyme Corporation, Cambridge, Mass.). This membrane was introduced in 1996 for use as a barrier to decrease postsurgical adhesions. The same components of Seprafilm also exist as a solution known as Sepracoat (Genzyme Corporation, Cambridge, Mass.). This viscous, gel-like solution was developed for use as a coating during surgery to protect tissues against operative trauma; it was hoped that Sepracoat would act postoperatively as a medium to keep the intestines separated until the mesothelial lining was restored.27 Unfortunately, Sepracoat is short-lived in the peritoneal cavity and has only moderate efficacy against the formation of de novo adhesions, limiting its widespread use.75 Conversely, Seprafilm has been evaluated in human studies, all of which demonstrated a significant reduction in the formation of adhesions with use of this membrane.3,64,76Unlike its counterpart Sepracoat, which is applied during surgery, Seprafilm sheets are placed at potential sites of adhesion formation at the end of the

procedure, just before closure. The Seprafilm membrane hydrates to form a gel-like barrier within the next 24 to 48 hours. It slowly resorbs within 7 days of placement and is fully excreted by 28 days. The hyaluronan in Seprafilm is degraded in the same manner as the endogenous form.27 Both animal and human studies have found a significant decrease in adhesion formation with the use of Seprafilm. Becker and colleagues64 evaluated the use of Seprafilm after colectomy and IPAA with diverting loop ileostomy in patients with ulcerative colitis or familial adenomatous polyposis. They found that the use of Seprafilm halved the incidence of adhesions and significantly reduced the extent and severity of adhesions to the anterior abdominal wall when patients were reexplored laparoscopically at the time of ileostomy closure 8 to 12 weeks later. Fifty-one percent of patients in the treatment group and 6% of the control group were free of such adhesions at second look laparoscopy. In a large multicentre trial, Beck and colleagues76 evaluated the use of Seprafilm in patients undergoing various types of abdomino-pelvic procedures. Just before closure of the abdomen, each of the 1791 participating patients was randomized to receive Seprafilm or no treatment. The main objective of this study was to prospectively evaluate the long-term effectiveness of Seprafilm for the reduction of adhesion-related postoperative bowel obstruction after abdomino-pelvic surgery; the results are pending. A secondary objective was to evaluate the safety of Seprafilm by looking at the incidence of postoperative abscess formation and pulmonary embolism. Although there were no significant differences found between the treatment and control groups, a subgroup analysis demonstrated that when Seprafilm was wrapped around a fresh anastomosis, there was a significant increase in the number of anastomotic leakrelated events (e.g., peritonitis, fistula or abscess formation or both, anastomotic leak and sepsis). Given these findings, they concluded that, although the use of Seprafilm in the peritoneal cavity seems to be safe, it should not be used in areas that are in close proximity to fresh intestinal anastomoses. The other human studies that evaluated the effectiveness of Sepra-film for the reduction in postoperative adhesion formation are limited in that they failed to evaluate the clinically relevant outcomes. That is, it remains to be seen whether there is a reduction in long-term morbidity, particularly in the incidence of SBO, as a result of using Seprafilm. The trial by Beck and colleagues76 was designed specifically to address this question; the results, however, are still pending. More recently, 2 novel absor-bable antiadhesion barriers have been assessed in animal models; a nanostructured barrier made by electrospinning copolymers of polylactidecoglycolide (PLGA) and mixing it with cefoxitin65 and a polylactic acid film (SurgiWrap).66 The efficacy of these barriers in reducing adhesion formation was evaluated in a rat model of surgically induced adhesions. Both studies showed significantly decreased rates of adhesion formation in the treated animals. Further studies are needed to evaluate these novel compounds in terms of their safety profile and their efficacy in the reduction of peritoneal adhesions in humans.

A final strategy to decrease adhesion formation is to cause less operative trauma to the peritoneum. Laparoscopic surgery has the theoretical advantage of inducing fewer adhesions than open surgery, because there is typically less peritoneal damage incurred with the former technique. The purported advantages of laparoscopic surgery are supported by studies that have recently emerged, comparing rates of adhesion formation after laparoscopic surgery to conventional open surgery. Fifteen studies published from 1987 to 2001 were identified and recently reviewed by Gutt and colleagues.46Unfortunately, they were unable to carry out a metaanalysis, due to the significant diversity of the studies in terms of their designs, the end points evaluated and the adhesion scoring systems that were used. Most of the studies were experimental and used animal models to look at rates of adhesion formation. Only 3 of the studies identified by the reviewers were clinical. The reviewers found that all of the clinical studies and most of the experimental studies showed a reduction in the formation of adhesions after laparoscopic surgery, compared with open surgery. These findings are promising, especially given the recent advances that have been made in laparoscopic techniques and the increasing number of procedures that can now be performed this way. Further investigations (particularly human trials) are warranted before such conclusions can be made unequivocally. The existing studies are not without limitations, the most significant of which was the incomplete assessment of adhesion formation.
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The formation of peritoneal adhesions continues to plague patients, surgeons and society. Although research in this area is ongoing, there is currently no method that is 100% effective in adhesion prevention, nor is there any way to permanently remove them once they have formed. As our understanding of the specific mechanisms involved in peritoneal repair evolves, it seems likely that specific targets for adhesion prevention will be identified and evaluated. The bioresorbable membrane Sepra-film is currently the most effective adjuvant to decrease adhesion formation, and this barrier may be considered for use in patients in whom the formation of adhesions postoperatively is particularly undesirable. The long-term outcomes with this agent remain unknown. Newer products are being developed that seem promising, but their efficacy has yet to be proven in clinical trials. Until then, surgeons should continue to be meticulous in their operative technique and should seek to minimize injury to the peritoneal surface.

Abdominal Adhesions: Prevention and Treatment

by Subhuti Dharmananda, Ph.D., Director, Institute for Traditional Medicine, Portland, Oregon

Adhesions are strands or of scar tissue (fibrin bands; see illustration, below) that form in response to abdominal surgery and extend beyond the specific site of incision, sometimes forming separately from the incision site within the peritoneum. Scar tissue that mends the incision is normal, but the adhesions form additionally under some circumstances that are not fully understood. There are specific features of a surgical procedure that help induce the formation of adhesions. For example, drying of the tissues during surgery increases adhesion formation, a situation remedied by paying attention to the arid conditions and correcting them during then procedures. Intentional drying of the tissues, by applying gauze, is an otherwise desirable procedure to aid the surgeon's view of the area, but because of increased adhesions, it must be minimized. Tissues that become dry should be quickly moistened and air (carbon dioxide) that is passed over the surgery site to maintain cleanliness also must contain adequate moisture to prevent rapid drying of the exposed fluids. Laparotomy (open abdominal surgery) is more likely to produce adhesions than surgery performed via laparoscopy in which a small scope with attached microsurgical instruments is inserted through a slit in the abdomen (1-3).

Left: a representation of a normal peritoneum, the transparent membrane that wraps the pelvic and abdominal organs. Right: after surgical trauma, fibrous bands of collagen grow as part of the normal healing process and form adhesions. Adhesions connect tissues or structures that are normally separate. Adhesions in the abdomen or pelvic area can lead to infertility, pelvic pain, small bowel obstruction, or the need for repeat surgery (1).

The incidence of adhesions following abdominal surgery is cumulative with multiple surgeries and female gynecological surgeries give a particularly high rate of

adhesions. In one study, autopsy investigations indicated a 90% incidence of adhesions in patients with multiple surgeries, 70% incidence of adhesions in patients with a gynecologic surgery, a 50% incidence of adhesions with appendectomy, and a greater than 20% incidence of adhesions in patients with no surgical history. Adhesions may occur as the result of tissue damage to the abdomen besides surgery, including traumatic injury, inflammatory disease, intraperitoneal chemotherapy, and radiation therapy (1). The most frequent problem with adhesions is a constriction of the small intestine, producing constipation (sometimes complete bowel blockage, requiring emergency treatments). Abdominal pain is another common symptom, caused when the bands of scar tissue bind up the internal organs so that movements pull on them. Linkage of menstruation to changes in bowel function (e.g., inducing diarrhea) may occur as the result of scar tissue attaching the uterus to the intestine. Adhesions may also impair fertility in women by causing blockage of the fallopian tubes. It has been estimated that:

At least one-third of women who suffer from pelvic pain have adhesions as a cause of or contributor to the pain. Adhesions involving the ovaries or fallopian tubes are responsible for 15-20 percent of female infertility cases. Small bowel obstruction is often a surgical emergency and is particularly common after gynecological surgery.

To prevent adhesion formation, surgeons may now apply a fine fabric barrier to surround the organs, thus isolating them from the scar tissue strands (the barrier dissolves after the surgery). Although adhesions can be removed by surgical intervention (adhesiolysis) using a laparoscopic technique (4), recent studies suggested that such surgery produces limited benefits that are often short-term. Many patients are treated with multiple adhesiolysis procedures in an attempt to improve the symptoms of adhesions. Each year, 400,000 adhesiolysis procedures are performed in the U.S., costing the health care system about $2 billion in hospitalization and surgeon expenses. Most times, adhesions cause few, if any, notable effects. But, for those who do suffer from their adverse effects, the question arises as to whether the adhesions can be reduced or eliminated by methods other than further surgery.

CHINESE HERB MEDICINE FOR ADHESIONS The problem of developing abdominal adhesions is noted in the Chinese medical literature. Dr. Fu Kezhi, at the Harbin office of ITM, carried out a literature search, yielding several studies summarized here.

Chinese medicine has been applied both to prevention of adhesions and to their treatment when they cause bowel blockage. The preventive measure involves relatively immediate post-surgical intervention. The basis of the preventive therapy is to treat the abdominal stasis that occurs following surgery. Normally, after an abdominal surgery, the bowels are virtually paralyzed for many hours, up to two days in older patients and complicated surgeries. Doctors and nurses check for the return of bowel sounds (indicating movements) after the surgery, to make sure recovery is proceeding. Since obstructive constipation is one of the primary responses to developing adhesions, concern about bowel stasis is a clear concern. In China, an herbal formula used for treating constipation is administered about 6 hours after surgery, to assure the action of the bowels in a relatively short time with continued bowel responsiveness, indicating lack of adhesion formation. The formulas are usually a derivative of the ancient prescription Da Chengqi Tang (Major Rhubarb Combination). The traditional formula has four ingredients: rhubarb and mirabilitum as purgatives and chih-shih and magnolia as qi regulating herbs. The modifications of the formula usually involve adding additional qi regulating herbs (notably saussurea) and blood vitalizing herbs (especially persica, red peony, and salvia) to promote the circulation of qi and blood in the abdomen and prevent formation of adhesions, which are seen as the result of prolonged stasis. An example is the administration of a formula calledTao Zhi Zhi Po Fang, comprised of rhubarb, magnolia, chih-ko (in place of chih-shih), saussurea, persica, carthamus, leech, and salvia, provided 6 hours after abdominal surgery (5). Compared to a control group not treated with these herbs, bowel sounds and bowel functions resumed many hours earlier and the incidence of adhesions (determined by typical symptoms of adhesions appearing within the next three years) was significantly lowered. In another report (6), a modified Major Rhubarb Combination was administered after surgery while during surgery a protective barrier fluid was used to isolate the organs and prevent adhesions. The authors noted: Treatment by integrating traditional Chinese medicine and western medicine has been adopted in many surgical departments, especially the application of Modified Major Rhubarb Combination. The formula has the properties of inducing purgation, promoting qi circulation, resolving blood stagnation, and assuring that the hollow viscera remain unimpeded; specifically, stomach-qi can move

downward freely to eliminate fullness and distention, the qi in the abdomen can circulate freely, and the bowels remain open; it can stimulate early peristalsis of the bowels after surgery. When using the Modified Major Rhubarb Combination soon after surgery for adhesive bowel obstruction, it can markedly shorten the time period of intestine paralysis. Because the herbal treatment within hours after surgery is impractical for Western patients (and the use of purgatives would be objected to by the medical profession on grounds of it possibly causing damage), the question about treating existing adhesions arises. In Chinese investigations of this matter, the patients are usually those who have come to the hospital with a severe disorder, usually bowel blockage, for which surgery would be utilized. Patients may first be treated with herbs to see if this is successful in relieving the blockage, while surgery can be used as a back-up. The non-surgical treatment of adhesion-induced medical crisis is similar to that used for the preventive measure after surgery, at least in cases involving bowel blockage. For example, in one evaluation (7), patients were treated with a derivative of Major Rhubarb Combination made with: rhubarb (15 g), magnolia (10 g), chih-shih (10 g), mirabilitum (20 g), persica (10g), red peony (15 g), and stir-fried raphanus (45 g). Raphanus (radish seed) is used to aid the downward flow of qi, normalize digestion, and alleviate abdominal pain. The herbs were administered in 1-2 batches a day, orally or through a stomach tube. Of 250 patients treated this way, 88% were able to avoid surgery. As with the method for preventing adhesions in the first place, there is some doubt that this approach would be used in the West, as there is concern about using strong purgative treatments when bowel blockage exists. In China, the patients are carefully monitored while pursuing this treatment as an inpatient and are referred to surgery if the problem is not promptly resolved. Another report of this type of treatment approach involved use of two slightly different decoctions, depending on the differential diagnosis (8); these were:

Modified Major Rhubarb Combination: rhubarb (10-30 g), mirabilitum (6-15 g), magnolia (20 g), chih-shih (10 g), persica (10 g), red peony (10 g), and stir-fried raphanus seed (30g) Adhesion Lysis Decoction: cassia leaf (10g), mirabilitum (6-10 g), magnolia (10 g), lindera (10 g), persica (10 g), red peony (10 g), and stir-fried raphanus seed (10 g).

These formulations could be modified: for severe pain, add 10 grams each of corydalis, frankincense, and myrrh; for a case with vomiting, add 10 grams pinellia and 30 grams raw hematite. As in the previous study, these formulas prevented the need for surgery in about 86% of cases. Presumably, these therapies could be applied to Western patients suffering from constipation that has not developed into full obstruction requiring hospitalization; the formulas are not inherently different from traditional herb prescriptions now administered for acute constipation. For example, Major Rhubarb Combination is routinely sold as a dried extract granule by several Chinese herb suppliers worldwide. A limitation of the purgative herb therapy is that while it relieves the immediate crisis, the problem can return, because the adhesions are not gone. An attempt to resolve this dilemma was designed on the basis of using Chinese herb therapy to treat the obstructive crisis and then using laparoscopic surgery to remove the adhesions to prevent further occurrences. By so doing, one can usually avoid emergency surgery as a result of intestinal obstruction; instead, the surgery can proceed at a time when the intestinal functions have normalized and a less invasive surgical technique (laparoscopic surgery) can be utilized. In one study using this two-stage method (9), patients received one of three basic herb therapies for the intestinal obstruction:

Modified Major Rhubarb Combination: rhubarb, mirabilitum, chihshih, magnolia, persica, red peony, and stir-fried raphanus seed; Euphorbia Obstruction-relieving Decoction: euphorbia (gansui), rhubarb, magnolia, saussurea, persica, achyranthes, and red peony; or Entero-adhesion Lysis Decoction: cassia leaf, mirabilitum, magnolia, saussurea, lindera, persica, red peony, and stir-fried raphanus

In these formulations, rhubarb, euphorbia, and cassia leaf all serve the same function of inducing peristalsis. The purgative herb is the central ingredient in treatment, while the others are supportive; in one study (10), euphorbia was used as a single herb to treat intestinal obstruction due to adhesions in order to prevent the need for surgery. The desire of most patients would be to alleviate the problem of adhesions before a crisis of bowel obstruction occurs, and to treat other manifestations of adhesions, such as abdominal pain and reduced fertility. The Chinese literature appears silent on this issue, but there are some possibilities to be considered.

CAN ADHESIONS BE MODIFIED OR REMOVED WITHOUT SURGERY? Doctors and researchers are aware that scar tissue is difficult to remove or alter. One method of degrading undesirable scar tissue that has shown promise is to apply hyaluronidase, a mucolytic enzyme. Hyaluronidase breaks down hyaluronic acid, an ingredient of connective tissue. It is injected into the scar and may work best if the scar if physically degraded by surgical means and then treated by the enzyme to prevent reformation of the original scar mass. A new application of hyaluronidase is to provide it during surgery: protective barriers infused with hyaluronidase are being tried in an effort to further reduce the formation of the adhesions.
Hyaluronidase is a body component that is normally present but may be produced in large quantities in response to some stimuli. It primarily acts on hyaluron, the structural component of the extracellular matrix, comprised of hyaluronic acid (pictured left; these units repeat in long chains), one of several glucosaminoglycans (GAGs) that comprise connective tissues. Hyaluronidase is an important component in natural repair processes of tissues, where hyaluron is broken down and reformed.

Hyaluronidase can be viewed as a softening and flow-promoting enzyme. Hyaluronidase is excreted by bacteria as a means of helping breakdown and penetrate cellular barriers so that infection can proceed. Tumor cells may take advantage of hyaluronidase, secreting it as a means of penetrating into the surrounding tissues and aiding metastasis. The enzyme is used pharmaceutically in administering certain drug therapies to help the drugs penetrate cells more easily. The fact that existing scars may be degraded somewhat by the enzyme action suggests the possibility that herbal therapies could contribute to alleviating adhesion symptoms by stimulating the body's production of hyaluronidase (or other enzymes of similar function) to perform this task. Even if scar tissue is not removed, if it can be softened (made more elastic), there may be relief from its physical manifestations such as bowel blockage, pain, and some cases of infertility. Herbs that are reputed to aid healing of injuries, soften abdominal masses, and alleviate abdominal pain of various origins may act, in part, by breaking down undesirable collagens to alleviate the symptoms. Antifibrotic and mass reducing herbs are used to treat abdominal disorders such as uterine fibroids and liver fibrosis, and are also used to treat skin masses in scleroderma; it is possible that they function by increasing the degradation of fibrous tissue via hyaluronidase. Key herbs for reducing fibrosis and masses are listed in Table 1 (11). TABLE 1. Key Herbs for Reducing Fibrosis and Masses.

Herb Common Name (Pinyin) Achyranthes (niuxi/chuanniuxi) Arca shell (walengzi)

TCM Functions

Uses and Potential Applications

vitalize blood circulation, disperse blood stasis mass in the swelling abdomen, abdominal pain vitalize blood circulation, disperse blood stasis and phlegm mass in masses, control pain abdomen blood stasis mass in the abdomen, traumatic injury, abdominal pain due to stagnated blood

Carthamus (honghua)

vitalize blood, disperse stagnant blood

Cnidium (chuanxiong) Frankincense (ruxiang) Myrrh (moyao) Persica (taoren) Red peony (chishao) Salvia (danshen)

vitalize blood, promote qi circulation, control pain

abdominal pain, fibrosis

vitalize blood, control pain

traumatic injury, abdominal pain

vitalize blood, remove stagnant blood, control pain

blood stasis mass in the abdomen, abdominal pain blood stasis mass in the abdomen, traumatic injury abdominal pain, accumulation in abdomen inhibit fibrin deposition, promote fibrinolysis

vitalize blood

vitalize blood, disperse stagnant blood, control pain

vitalize blood

Sparganium (sanleng)

vitalize blood, promote qi circulation, disperse mass, control pain vitalizes blood, disperses stagnant blood

blood stasis mass in the abdomen, abdominal pain

Succinum (hupo) Tang-kuei (danggui)

abdominal pain due to obstruction abdominal pain, promotes fibrinolysis

vitalizes blood

Turtle shell (biejia) Zedoaria (ezhu)

disperse stagnant blood, soften blood stasis mass in the abdomen hardness, disperse accumulations vitalize blood, promote qi circulation, control pain blood stasis mass in the abdomen, abdominal pain

SAMPLE FORMULATIONS AND TREATMENT STRATEGY The herbs from the table above are ingredients in traditional and modern formulas used in resolving problems that are relevant to fibrous masses and adhesions. For example, a traditional formula for treating pain due to old trauma, which may reflect existence of adhesions, is Sanleng Heshang Tang (12). It is comprised of 12 herbs for regulating circulation of qi and blood and alleviating pain; the formula includes sparganium, zedoaria, myrrh, frankincense, and tang-kuei. A formula for "movable or immovable mass in the abdomen," Huoluo Xiaoling Dan, is made with just four herbs: salvia, myrrh, frankincense, and tang-kuei. A modern formula developed for treating uterine fibroids, Gong Zheng Tang, includes sparganium, zedoaria, achyranthes, tangkuei, and persica (13). A modern treatment for endometrial cysts isNei Yi Wan (14), which includes succinum and turtle shell. Herbs used to relieve skin hardening in scleroderma include tang-kuei, red peony, and salvia (15). These same herbs were commonly applied to treatment of liver fibrosis secondary to hepatitis (see: Treatment and prevention of liver fibrosis).

A treatment for existing adhesions would follow the pattern of treating any other abdominal mass or fibrotic condition, namely a high dose therapy administered for a period of 3-6 months. During this treatment, an effort to stretch the scar fibers, possibly stimulating the local response to softening the fibers, might be pursued via exercises and massage therapy. Care must be taken not to induce any damage during such efforts.