Bohomolets 4th year Surgery Appendicitis


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By Dr. Tatyana Kravchenko from Surgery department#1

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Bohomolets 4th year Surgery Appendicitis

  1. 1. O.O.Bogomolets National Medical University Department of Faculty Surgery #1 “Approved” at the Methodist Faculty Surgery Department # 1 Council “__”_____2008, protocol #_____ Head of Faculty Surgery Department # 1 Professor _______ M.P.ZakharashStudy Guide for Practical Work for Teachers and Students Topic: “Appendicitis”. Course 4 Foreign Students’ Medical Faculty Duration of the lesson – 45 min. Worked out by Assistant T.Kravchenko Kyiv 2008
  2. 2. I. The theme actualityAbout 8% of people in Western countries have appendicitis at some time during theirlife, with a peak incidence between 10 and 30 years of age. Acute appendicitis is themost common general surgical emergency, and early surgical intervention improvesoutcomes. The diagnosis of appendicitis can be elusive, and a high index of suspicionis important in preventing serious complications from this disease.II. Student must know: - embryology and anatomy of appendix - historical perspective of appendicitis - pathophysiology of appendicitis - bacteriology of appendicitis - diagnosis of appendicitis - diagnostic algorithm - treatmentIII. Student must be able to: - to interpret correctly the present manifestations of disease and investigation results - to differentiate appendicitis - to diagnose and make the chart of treatment - to apply the instrumental methods of examination - to conduct examination of patient - to interpret data of examinationsIV. Education aims of the study - forming the deontology presentations, skills of conduct with the patients
  3. 3. - to develop deontology presentations, be able to carry out deontology approach to the patient - to develop the presentations of influence of ecological and socio-economic factors on the state of health - to develop sence of responsibility for a timeliness and loyalty of professional actions - to lay hands on ability to set psychological contact with a patient and his familyV. The contents of a themeEmbryology and anatomyThe appendix, ileum, and ascending colon are all derived from the midgut. Theappendix first appears at the 8th week of gestation as an outpouching of the cecumand gradually rotates to a more medial location as the gut rotates and the cecumbecomes fixed in the right lower quadrant.The appendiceal artery, a branch of the ileocolic artery, supplies the appendix.Histologic examination of the appendix indicates that goblet cells, which producemucus, are scattered throughout the mucosa. The submucosa contains lymphoidfollicles, leading to speculation that the appendix might have an important, as yetundefined, immune function early in development. The lymphatics drain into theanterior ileocolic lymph nodes. In adults, the appendix has no known function.The length of the appendix varies from 2 to 20 cm, and the average length is 9 cm inadults. The base of the appendix is located at the convergence of the taeniae along theinferior aspect of the cecum, and this anatomic relationship facilitates identification ofthe appendix at operation. The tip of the appendix may lie in a variety of locations.The most common location is retrocecal but within the peritoneal cavity. It is pelvic in
  4. 4. 30% and retroperitoneal in 7% of the population. The varying location of the tip of theappendix likely explains the myriad of symptoms that are attributable to the inflamedappendix.Historical PerspectiveIn 1886, Reginald Fitz of Boston correctly identified the appendix as the primarycause of right lower quadrant inflammation. He coined the term appendicitis andrecommended early surgical treatment of the disease. Richard Hall reported the firstsurvival of a patient after removal of a perforated appendix, which launched focusedattention on the surgical treatment of acute appendicitis. In 1889, Chester McBurneydescribed characteristic migratory pain as well as localization of the pain along anoblique line from the anterior superior iliac spine to the umbilicus. McBurneydescribed a right lower quadrant muscle-splitting incision for removal of the appendixin 1894. The mortality rate from appendicitis improved with the widespread use ofbroad-spectrum antibiotics in the 1940s. Recent advances have included improvedpreoperative diagnostic studies, interventional radiologic procedures to drainestablished periappendiceal abscesses, and the use of laparoscopy to confirm thediagnosis and exclude other causes of abdominal pain. Laparoscopic appendectomywas first reported by the gynecologist Kurt Semm in 1982 but has only gainedwidespread acceptance in recent years.PathophysiologyObstruction of the lumen is believed to be the major cause of acute appendicitis. Thismay be due to inspissated stool (fecalith or appendicolith), lymphoid hyperplasia,vegetable matter or seeds, parasites, or a neoplasm. The lumen of the appendix issmall in relation to its length, and this configuration may predispose to closed-loopobstruction. Obstruction of the appendiceal lumen contributes to bacterial overgrowth,and continued secretion of mucus leads to intraluminal distention and increased wall
  5. 5. pressure. Luminal distention produces the visceral pain sensation experienced by thepatient as periumbilical pain. Subsequent impairment of lymphatic and venousdrainage leads to mucosal ischemia. These findings in combination promote alocalized inflammatory process that may progress to gangrene and perforation.Inflammation of the adjacent peritoneum gives rise to localized pain in the right lowerquadrant. Although there is considerable variability, perforation typically occurs afterat least 48 hours from the onset of symptoms and is accompanied by an abscess cavitywalled-off by the small intestine and omentum. Rarely, free perforation of theappendix into the peritoneal cavity occurs that may be accompanied by peritonitis andseptic shock and can be complicated by the subsequent formation of multipleintraperitoneal abscesses.BacteriologyThe flora in the normal appendix is very similar to that in the colon, with a variety offacultative aerobic and anaerobic bacteria. The polymicrobial nature of perforatedappendicitis is well established. Escherichia coli, Streptococcus viridans, andBacteroides and Pseudomonas species are frequently isolated, and many otherorganisms may be cultured. Among patients with acute nonperforated appendicitis,cultures of peritoneal fluid are frequently negative and are of limited use. Amongpatients with perforated appendicitis, peritoneal fluid cultures are more likely to bepositive, revealing colonic bacteria with predictable sensitivities. Because it is rarethat the findings alter the selection or duration of antibiotic use, some authors havechallenged the traditional practice of obtaining cultures.Bacteria Commonly Isolated in Perforated Appendicitis1. AEROBICBacteroides fragilis 80%Bacteroides thetaiotaomicron 61%
  6. 6. Bilophila wadsworthia 55%Peptostreptococcus species 46%AEROBICEscherichia coli 77%Streptococcus viridans 43%Group D streptococcus 27%Pseudomonas aeruginosa 18%DiagnosisHistoryAppendicitis needs to be considered in the differential diagnosis of nearly everypatient with acute abdominal pain. Early diagnosis remains the most important clinicalgoal in patients with suspected appendicitis and can be made primarily on the basis ofthe history and physical exam in most cases. The typical presentation begins withperiumbilical pain (due to activation of visceral afferent neurons) followed byanorexia and nausea. The pain then localizes to the right lower quadrant as theinflammatory process progresses to involve the parietal peritoneum overlying theappendix. This classic pattern of migratory pain is the most reliable symptom of acuteappendicitis. A bout of vomiting may occur, in contrast to the repeated bouts ofvomiting that typically accompany viral gastroenteritis or small bowel obstruction.Fever ensues, followed by the development of leukocytosis. These clinical featuresmay vary. For example, not all patients become anorexic. Consequently, the feeling ofhunger in an adult patient with suspected appendicitis should not necessarily deter onefrom surgical intervention. Occasional patients have urinary symptoms or microscopichematuria, perhaps owing to inflammation of periappendiceal tissues adjacent to theureter or bladder, and this may be misleading. Although most patients withappendicitis develop an adynamic ileus and absent bowel movements on the day ofpresentation, occasional patients may have diarrhea. Others may present with small
  7. 7. bowel obstruction related to contiguous regional inflammation. Therefore,appendicitis needs to be considered as a possible cause of small bowel obstruction,especially among patients without prior abdominal surgery.Physical ExaminationPatients with acute appendicitis typically look ill and are lying still in bed. Low-gradefever is common (∼38°C). Examination of the abdomen usually reveals diminishedbowel sounds and focal tenderness with voluntary guarding. The exact location of thetenderness is directly over the appendix, which is most commonly at McBurneyspoint (located one third of the distance along a line drawn from the anterior superioriliac spine to the umbilicus). The normal appendix is mobile, so it may becomeinflamed at any point on a 360-degree circle around the base of the cecum. Thus, thesite of maximal pain and tenderness can vary. Peritoneal irritation can be elicited onphysical examination by the findings of voluntary and involuntary guarding,percussion, or rebound tenderness. Any movement, including coughing (Dunphyssign), may cause increased pain. Other findings may include pain in the right lowerquadrant during palpation of the left lower quadrant (Rovsings sign), pain on internalrotation of the hip (obturator sign, suggesting a pelvic appendix), and pain onextension of the right hip (iliopsoas sign, typical of a retrocecal appendix).Rectal and pelvic examinations are most likely to be negative. However, if theappendix is located within the pelvis, tenderness on abdominal examination may beminimal, whereas anterior tenderness may be elicited during rectal examination as thepelvic peritoneum is manipulated. Pelvic examination with cervical motion may alsoproduce tenderness in this setting.If the appendix perforates, abdominal pain becomes intense and more diffuse, andabdominal muscular spasm increases, producing rigidity. The heart rate rises, with anelevation of temperature above 39°C. The patient may appear ill and require a briefperiod of fluid resuscitation and antibiotics before the induction of anesthesia.
  8. 8. Occasionally, pain may improve somewhat after rupture of the appendix, although atrue pain-free interval is uncommon.Laboratory StudiesThe white blood cell count is elevated with more than 75% neutrophils in mostpatients. A completely normal leukocyte count and differential is found in about 10%of patients with acute appendicitis. A high white blood cell count (>20,000/mL)suggests complicated appendicitis with either gangrene or perforation. A urinalysiscan also be helpful in excluding pyelonephritis or nephrolithiasis. Minimal pyuria,frequently seen in elderly women, does not exclude appendicitis from the differentialdiagnosis because the ureter may be irritated adjacent to the inflamed appendix.Although microscopic hematuria is common in appendicitis, gross hematuria isuncommon and may indicate the presence of a kidney stone. Other blood tests aregenerally not helpful and are not indicated in the patient with suspected appendicitis.RadiographyAlthough they are commonly obtained, the indiscriminate use of plain abdominalradiographs in the evaluation of patients with acute abdominal pain is unwarranted. Inone study of 104 patients with acute onset of right lower quadrant pain, interpretationof plain x-rays changed the management of only 6 patients (6%), and in one casecontributed to an unnecessary laparotomy. A calcified appendicolith is visible on plainfilms in only 10% to 15% of patients with acute appendicitis; however, its presencestrongly supports the diagnosis in a patient with abdominal pain. Plain abdominalfilms may be useful for the detection of ureteral calculi, small bowel obstruction, orperforated ulcer, but such conditions are rarely confused with appendicitis. Failure ofthe appendix to fill during a barium enema has been associated with appendicitis, butthis finding lacks both sensitivity and specificity because up to 20% of normalappendices do not fill.
  9. 9. Among patients with abdominal pain, ultrasonography has a sensitivity of about 85%and a specificity of more than 90% for the diagnosis of acute appendicitis.Sonographic findings consistent with acute appendicitis include an appendix of 7 mmor more in anteroposterior diameter, a thick-walled, noncompressible luminalstructure seen in cross section referred to as a target lesion, or the presence of anappendicolith. In more advanced cases, periappendiceal fluid or a mass may be found.Ultrasonography has the advantages of being a noninvasive modality requiring nopatient preparation that also avoids exposure to ionizing radiation. For these reasons,it is commonly used in children and in pregnant patients with equivocal clinicalfindings suggestive of acute appendicitis. Disadvantages of ultrasonography includeoperator-dependent accuracy and difficulty interpreting the images by those other thanthe operator. Because performance of the study may require hands-on participation bythe radiologist, ultrasonography may not be readily available at night or on weekends.Pelvic ultrasound can be especially useful in excluding pelvic pathology, such as tubo-ovarian abscess or ovarian torsion, that may mimic acute appendicitis.Ultrasound of a normal appendix illustrating the thin wall in both coronal (left) andlongitudinal (right) planes. In appendicitis, there is distention and wall thickening andblood flow is increased, leading to the so-called ring-of-fire appearance.Computed tomography (CT) is commonly used in the evaluation of adult patients withsuspected acute appendicitis. Improved imaging techniques, including the use of 5-mm sections, have resulted in increased accuracy of CT scanning, which has asensitivity of about 90% and a specificity of 80% to 90% for the diagnosis of acuteappendicitis among patients with abdominal pain. Controversy remains as to theimportance of intravenous, oral gastrointestinal, and rectal contrast in improvingdiagnostic accuracy. In general, CT findings of appendicitis increase with the severityof the disease. Classic findings include a distended appendix greater than 7 mm indiameter and circumferential wall thickening, which may give the appearance of ahalo or target. As inflammation progresses, one may see periappendiceal fat stranding,
  10. 10. edema, peritoneal fluid, phlegmon, or a periappendiceal abscess. CT detectsappendicoliths in about 50% of patients with appendicitis and also in a smallpercentage of people without appendicitis. Among patients with abdominal pain, thepositive predictive value of the finding of an appendicolith on CT remains high atabout 75%.CT scan of the abdomen or pelvis in a patient with acute appendicitis may reveal anappendicolith, CT typically shows a distended appendix with diffuse wall-thickeningand periappendiceal fluid. The appendix may be described as having muralstratification, referring to the layers of enhancement and edema within the wall andthis may also be referred to as a target sign. cecum; terminal ileum.Should CT be used routinely in the diagnostic evaluation of patients with suspectedappendicitis? In our opinion, no. In the setting of typical right lower quadrant pain andtenderness with signs of inflammation in a young patient, a CT scan is unnecessary,wastes valuable time, and exposes the patient to the risks for allergic contrast reaction,nephropathy, aspiration pneumonitis, and ionizing radiation. The latter carriesincreased risk in children in whom the rate of radiation-induced cancer has beenestimated at 0.18% following an abdominal CT scan. Moreover, a negative study maybe misleading, particularly early in the inflammatory process. CT has proved mostvaluable among older patients in whom the differential diagnosis is lengthy, theclinical findings may be confusing, and appendectomy carries increased risk. Amongpatients with atypical symptoms, CT scan may reduce the negative appendectomy rate(i.e., the fraction of pathologically normal appendices that are removed). Selective useof CT scans seems most appropriate, and as always, the study needs to be obtainedonly in settings in which it has a significant potential to alter management.The morbidity of perforated appendicitis far exceeds that of a negative appendectomy.Thus, the strategy has been to set a low enough threshold for removal of the appendixso as to minimize the cases of missed appendicitis. With increased use of CT scans,the frequency of negative explorations has declined in recent years without an
  11. 11. accompanying rise in the number of perforations. A recent analysis of more than75,000 patients in 1999 to 2000 revealed a negative appendectomy rate of 6% in menand 13.4% in women.Diagnostic LaparoscopyAlthough most patients with appendicitis will be accurately diagnosed based onhistory, physical exam, laboratory studies, and if necessary, imaging techniques, thereare a small number in whom the diagnosis remains elusive. For these patients,diagnostic laparoscopy can provide both a direct examination of the appendix and asurvey of the abdominal cavity for other possible causes of pain. We use thistechnique primarily for women of childbearing age in whom preoperative pelvicultrasound or CT scan fails to provide a diagnosis. Concerns about the possibleadverse effects of a missed perforation and peritonitis on future fertility sometimesprompt earlier intervention in this patient population.Diagnostic AlgorithmPatients in whom the diagnosis of appendicitis is being considered should have asurgical evaluation. Early involvement of the surgical team in the diagnosticevaluation of these patients may improve diagnostic accuracy and help to avoidexpensive and unnecessary diagnostic studies. Experienced clinicians accuratelydiagnose appendicitis based on a combination of history, physical exam, andlaboratory studies about 80% of the time. We stratify patients based on their clinicalfindings starting with the extremes, which are easier to identify. Patients with a highprobability of uncomplicated appendicitis undergo surgery. Patients suspected ofhaving an appendiceal abscess undergo further imaging, typically ultrasonography forchildren or CT for adults. The next step in the evaluation of patients in whom thelikelihood of appendicitis is believed to be low is determined by the probability andseverity of alternate diagnoses under consideration. Many of these patients will bedischarged with a planned follow-up visit or phone call the next day. Most olderpatients with abdominal pain undergo CT before discharge because of the high
  12. 12. prevalence of surgical pathology in this patient population. The remaining patients arebelieved to have an intermediate probability of having appendicitis. Children andpregnant women in this category typically undergo abdominal ultrasonography.Women in their childbearing years may undergo pelvic ultrasonography or CT scandepending on the index of suspicion of pelvic pathology. Among patients that wouldotherwise be admitted to the hospital for observation, CT may reduce hospital costs byreducing length of stay. Following the completion of imaging studies, the patient is re-examined to determine whether pain and tenderness have localized to the right lowerquadrant. If the diagnosis remains uncertain at this point, patients either undergodiagnostic laparoscopy, especially in fertile women, are admitted for observation andre-examination, or are discharged with follow-up the next day.TreatmentMost patients with acute appendicitis are managed by prompt surgical removal of theappendix. A brief period of resuscitation is usually sufficient to ensure the safeinduction of general anesthesia. Preoperative antibiotics cover aerobic and anaerobiccolonic flora. For patients with nonperforated appendicitis, a single preoperative doseof antibiotics reduces postoperative wound infections and intra-abdominal abscessformation. Postoperative oral antibiotics do not further reduce the incidence ofinfectious complications in these patients. For patients with perforated or gangrenousappendicitis, we continue postoperative intravenous antibiotics until the patient isafebrile.Several prospective randomized studies have compared laparoscopic and openappendectomy, and the overall differences in outcomes remain small. The percentageof appendectomies performed laparoscopically continues to increase. Obese patientshad less pain and shorter hospital stays after laparoscopic versus open appendectomy.Patients with perforated appendicitis had lower rates of wound infections following
  13. 13. laparoscopic removal of the appendix. Patients treated laparoscopically had improvedquality-of-life scores 2 weeks after surgery and lower readmission rates. As comparedwith open appendectomy, the laparoscopic approach involves higher operating roomcosts, but these have been counterbalanced in some series by shorter lengths of stay.For patients in whom the diagnosis remains uncertain after the preoperativeevaluation, diagnostic laparoscopy is useful because it allows the surgeon to examinethe remainder of the abdomen, including the pelvis, for abnormalities. Our practice isto perform appendectomies laparoscopically in fertile women, obese patients, andcases of diagnostic uncertainty; otherwise, the approach is determined by patient orsurgeon preference.Open appendectomy is usually easily performed through a transverse right lowerquadrant incision (Davis-Rockey) or an oblique incision (McArthur-McBurney). Incases with a large phlegmon or diagnostic uncertainty, a subumbilical midline incisionmay be used. For uncomplicated cases we prefer a transverse, muscle-splittingincision lateral to the rectus abdominis muscle over McBurneys point. Localanesthetic, administered before the incision, reduces postoperative pain. After theperitoneum is entered, the inflamed appendix is identified by its firm consistency anddelivered into the field. Particular attention is paid to gentle handling of the inflamedtissues to minimize the risk for rupture during the procedure. In difficult cases,enlarging the incision and working down the trajectory of the taeniae on the cecumwill often facilitate localization and delivery of the appendix. The meso-appendix isdivided between clamps and ties. The base of the appendix is skeletonized at itsjunction with the cecum. A heavy absorbable tie is placed around the base of theappendix, and the specimen is clamped and divided. An absorbable purse-string sutureor Z stitch is placed into the cecal wall, and the appendiceal stump is inverted into afold in the wall of the cecum. Simple ligation and inversion probably have equivalentoutcomes. If the base of the appendix and adjacent cecum are extensively indurated,
  14. 14. an ileocecal resection is performed. The wound is closed primarily in most casesbecause the wound infection rate is less than 5%.Laparoscopic appendectomy offers the advantage of diagnostic laparoscopy combinedwith the potential for shorter recovery and incisions that are less conspicuous. If a CTscan was obtained preoperatively, it needs to be reviewed by the surgeon for usefulinformation regarding the position of the appendix relative to the cecum. Afterinjection of local anesthetic, we place a 10-mm port into the umbilicus, followed by a5-mm port in the suprapubic midline region and a 5-mm port midway between thefirst 2 ports and to the left of the rectus abdominis muscle. The 5-mm, 30-degreescope is moved to the central port with the surgeon and assistant both on the patientsleft. With the patient in Trendelenburgs position and rotated left-side down, we gentlysweep the terminal ileum medially and follow the taeniae of the cecum caudad tolocate the appendix, which is then elevated. The mesoappendix is divided using a 5-mm harmonic scalpel or Liga-Sure, or between clips, depending on the thickness ofthis tissue. We typically encircle the appendix with two heavy absorbable Endoloopscinched down at the base of the appendix and then place a third Endoloop about 1 cmdistally and divide the appendix. In cases in which the base is indurated and friable,we use a 30-mm endoscopic stapler to divide the appendix. For most cases, however,the considerable added cost of the stapler is unwarranted. Any spillage of fluid ispromptly aspirated, and similarly any identified appendicoliths are removed to preventpostoperative abscess formation. The appendix is placed into a specimen bag andremoved with the port through the umbilical wound. Fascia at the 10-mm trocar site isclosed, and all wounds are closed primarily.VI. Lesson topic control questions.Key points:- Acute appendicitis is the most common general surgical emergency, and early surgical intervention improves outcomes.
  15. 15. - The diagnosis of appendicitis can be elusive, and a high index of suspicion is important in preventing serious complications from this disease.- Appendicitis needs to be considered in the differential diagnosis of nearly every patient with acute abdominal pain.- Early diagnosis remains the most important clinical goal in patients with suspected appendicitis and can be made primarily on the basis of the history and physical exam in most cases.- In some cases diagnosis is not easy and includes, endoscopy, ultrasound, plain abdominal films or CT, laboratory tests and laparoscopy- Appendectomy remains the only curative treatment for appendicitisCases(1)A 15-year-old boy is admitted and physical findings consistent with appendicitis.Which finding is most likely to be positive? 1. Pelvic crepitus 2. Iliopsoas sign 3. Murphy sign 4. Flank echymosis 5. Periumbilical ecchymosisThe answer is 2.The iliopsoas sign in the lower abdomen and psoas region that is elicited when thigh isflexed against resistance. It suggests an inflammatory process, such as appendicitis.Crepitus suggests a rapidly spreading gas-forming infection. Murphy sign is elicitedby palpating the right upper quadrant during inspiration and suggests acutecholecystitis. Flank and periumbilical ecchymoses suggest retroperitonealhemorrhage.
  16. 16. (2)A 23-years-old male presents to the emergency room (ER) at night with abdominalpain beginning the prior afternoon. The pain is described as crampy with intermittentepisodes of sharp pain, and non radiating. It is located in the right lower quadrant(RLQ) with an intensity of 8/10 which has progressively worsened since it started. Healso has nausea and vomiting that began soon after onset of pain. He denies fever ,chills, or dysuria. Physical examination revealed RLQ tenderness, no palpable masses,a soft abdomen, with normal bowel sounds. He states no change in bowel habits. Labstudies reveal negative urine analysis (UA), WBC of 13,500, and Hgb gms/dl. Thepatient is taken to the operating room (OR) without obtaining a computed tomography(CT) scan of the abdomen and pelvis. Intra-operatively, the appendix appears normal.On further evaluation, the distal ileum appears inflamed with fat wrapping. Yournotice the cecum is not involved. What is your management at this time? 1. Perform appendectomy 2. Leave appendix and ileum as-is and close. Colsult GI 3. Perform appendectomy and distal ileum resection 4. Perform appendectomy and stricturoplasty of the terminal ileum 5. Run the small bowel to rule out Meckel’s diverticulumAnswer is 1.The patient presented with a classic history for appendicitis. Twenty percent of allexplorations for appendicitis turn out to be negative; therefore, other sources of painmust be sought. On exploration, the patient had classical sighns of Crohn’s disease,including fat wrapping, which is pathognomonic for Crohn’s disease. DifferentiatingCrohn’s from appendicitis is extremely difficult, especially without preoperative CTof abdomen/pelvis. The history of previous episodes of colicky abdominal pain withbouts of diarrhea may lead to a suspected diagnosis of Crohn’s. Management ofdisease intraoperatively is to perform appendectomy if no cecal involvement in order
  17. 17. to eliminate possibility of appendicitis versus Crohn’s in the future. If the cecum isinvolved you do not perform appendectomy because of risk of fistula formation.VII. Supporting materials required for teaching1. Participation in clinical duties on admission2. Working in libraryVII. Literature1. Townsend CM, Harris JW. Sabiston’s Textbook of Surgery, 16th ed. Philadelphia, PA: W.B. Saunders Co, 2001, vol.442. Schwartz SI, Schires GT, Spencer FC, Daly JM, Fischer JE, Galloway AC. Principles of Surgery, 7th ed. New York: McGraw-Hill, 1999, vol.273. Bruce E. Jarrell, R.Antthony Carabasi. Surgery, 3rd ed. Williams & Wilkins, 1998