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— General SurGery — Board review Manual

Lower Gastrointestinal Bleeding

Volume9Part3 November2010

Part 3 Available Online

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Statement of editorial PurPoSe

The Hospital Physician General Surgery Board Review Manual is a study guide for residents and practicing physicians preparing for board examinations in general surgery. Each manual reviews a topic essential to current practice in the specialty of general surgery.

PuBliSHinG Staff

PRESIDENT, GRouP PuBLISHERBruce M. White

SENIoR EDIToR Robert Litchkofski

ExEcuTIvE vIcE PRESIDENTBarbara T. White

ExEcuTIvE DIREcToR of oPERaTIoNS

Jean M. Gaul

PRoDucTIoN DIREcToRJeff White

Copyright 2010, Turner White Communications, Inc., Strafford Avenue, Suite 220, Wayne, PA 19087-3391, www.turner-white.com. All rights reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted in any form or by any means, mechanical, electronic, photocopying, recording, or otherwise, without the prior written permission of Turner White Communications. The preparation and distribution of this publication are supported by sponsorship subject to written agreements that stipulate and ensure the editorial independence of Turner White Communications. Turner White Communications retains full control over the design and production of all published materials, including selection of topics and preparation of editorial content. The authors are solely respon-sible for substantive content. Statements expressed reflect the views of the authors and not necessarily the opinions or policies of Turner White Communications. Turner White Communications accepts no responsibility for statements made by authors and will not be liable for any errors of omission or inaccuracies. Information contained within this publication should not be used as a substitute for clinical judgment.

NoTE fRoM THE PuBLISHER:This publication has been developed without involvement of or review by the American Board of Surgery.

Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Evaluation.and.Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . 2

Surgical.Interventions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Postpolypectomy.Bleeding. . . . . . . . . . . . . . . . . . . . . . . . . 6

Obscure.Hemorrhage. . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Summary.Points. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9

Table.of.Contents

gEnERal.SuRgERy.BOaRD.REvIEw.Manual

lower.gastrointestinal.Bleeding

Series.Editor.and.Contributor:C ..neil.Ellis,.MDSystem Chair, Division of Colon and Rectal Surgery, West Penn Allegheny Health System, Pittsburgh, PA

Contributors:Jennifer.D ..Silinsky,.MDDepartment of Colon and Rectal Surgery, The Ochsner Clinic Foundation, New Orleans, LA

David.a ..Margolin,.MD,.FaCS,.FaSCRSDirector of Colon and Rectal Research, Department of Colon and Rectal Surgery, The Ochsner Clinic Foundation, New Orleans, LA

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GeneRal SuRGeRy BoaRd Review Manual

lower Gastrointestinal BleedingJennifer d. Silinsky, Md, david a. Margolin, Md, FaCS, FaSCRS, and C. neil ellis, Md

IntroductIon

Lower gastrointestinal bleeding (LGIB) is defined as any bleeding that originates distal to the ligament of Treitz. The incidence of LGIB in the United States is 20 to 27 cases per 100,000 persons per year. It occurs more commonly in men than women and with increas-ing frequency among the elderly. There is a 200-fold increase in risk of LGIB from the third decade to the ninth decade of life.1 Furthermore, patients increas-ingly are being treated with long-term anticoagulation/ antiplatelet therapy, which can increase a patient’s risk of developing LGIB by 22%.2

The patient’s description of the amount of hemor-rhage can be misleading, since it takes only a small amount of blood in the commode to discolor the water. Patients can have small amounts of blood mixed with mucous or stool, or they can experience large amounts of brisk bleeding. The history does not accurately pre-dict the outcome of the bleeding. Some patients will stop bleeding after their first episode, while others will continue bleeding, leading to significant blood loss. For most patients, however, the bleeding will resolve sponta-neously with only supportive care, and in the majority of cases, the actual site of bleeding will never be localized.

It is important to understand as a clinician that as many as 10% to 15% of patients with LGIB symptoms will have an upper gastrointestinal source of bleeding.3 The difficulty with management of LGIB is that bleed-ing can occur at any site throughout the gastrointestinal tract and may commonly be intermittent. If managed inappropriately, a patient may undergo surgery without localization of the bleeding source and after resection continue to bleed.4

EVALuAtIon And dIAGnoSIS

cASE pAtIEnt 1

A 57-year-old man with a history of hyperten-sion and hyperlipidemia presents for evalua-

tion following 3 episodes of passing bright red blood from his rectum. The last episode occurred about 20 minutes prior to presentation, with several “cups” of bright red blood being expelled. He occasionally takes an aspirin and has never had a colonoscopy or experi-enced similar symptoms. He has associated lighthead-edness and dizziness on standing. His blood pressure is 90/62 mm Hg and his pulse is 92 bpm in the supine po-sition. His blood pressure decreases to 72/48 mm Hg and his heart rate increases to 118 bpm upon sitting up. His hypertension is managed using an angiotensin- converting enzyme inhibitor. He denies any use of nonsteroidal anti-inflammatory medications (NSAIDs). The remainder of his history and physical examination is unremarkable.

• what should be the first steps in the management of this patient?

Initial Management

The ABCs of resuscitation (airway, breathing, circu-lation) should be the first steps in managing any patient who is actively hemorrhaging. Two large-bore intra-venous lines should be placed, and vital signs should be monitored frequently along with orthostatic blood pressures. Foley catheter placement is encouraged to ensure adequate urine output. Laboratory evaluation should include a hemoglobin and hematocrit, type and cross-matching of at least 2 units of packed red blood cells, and coagulation studies, as well as an electrolyte panel with liver enzymes in the event the patient has a history of hepatic dysfunction. Once adequate resus-citation and correction of any clotting abnormalities have been initiated, the patient can be further evalu-ated to determine the source of bleeding.

A nasogastric tube should be placed and gastric lavage performed since 11% to 17% of patients with LGIB symptoms can have an upper gastrointestinal source of bleeding.3 Bilious return should be achieved before the lavage is considered adequate. If no upper gastrointestinal source of bleeding is found, the na-sogastric tube can be removed. The anus and rectum should be examined closely with anoscopy and rigid

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proctoscopy. The mucosa should be evaluated for any evidence of bleeding internal hemorrhoids, ulcers, neo-plasms, or colitis. This is very important because if the rectum is normal and subsequent surgery is required, a rectal anastomosis would be a valid treatment option. If an anal or rectal source of bleeding is identified, it can generally be treated at the time of identification.

cASE 1 contInuEd

The patient’s vital signs improve after admin-istration of 2 L of intravenous normal saline.

Laboratory testing is significant for a hemoglobin of 7.5 g/dL and a platelet count of 250,000 cells/μL. The remainder of the laboratory values, including coagula-tion studies, are within normal limits. The patient is transfused with 2 units of packed red blood cells. There is no clinical evidence of ongoing hemorrhage.

• what diagnostic tests can be performed to localize the site of bleeding?

diagnostic testing for LGIB

It is first helpful to categorize patients based on the history and physical examination. Does the patient have LGIB that is (1) minor and self-limited, (2) major and self-limited, or (3) major and ongoing? If the bleeding is only minor and appears to be resolving, observation and subsequent colonoscopy may be all that is needed. Patients who experience massive amounts of ongoing hemorrhage with hemodynamic instability may require prompt surgical intervention. The area of controversy among clinicians occurs with patients who have major, self-limited bleeding, such as that observed in the case patient. Do these patients require diagnostic tests to lo-calize and attempt to control the bleeding? If so, when and what diagnostic tests are appropriate?

There are 3 diagnostic modalities for localizing the bleeding: radionuclide scanning, colonoscopy, and angiography. The radionuclide scan is the least invasive and the most sensitive diagnostic modality for ongo-ing bleeding. It can detect bleeding as slow as 0.1 to 0.5 mL/min, which makes it significantly more sensi-tive than angiography.5 Also, once the radionuclide is infused, repeat scanning can be performed in the event of intermittent bleeding. The disadvantage to radionu-clide scanning is that it lacks specificity for the precise location of the bleeding. Compared to angiography, it cannot reliably differentiate small bowel bleeding sources from large bowel sources.5 Also, radionuclide scanning can accurately localize only continuous bleed-

ing, not intermittent bleeding. The most commonly performed type of radionuclide testing is technetium-99m-(99mTc)-pertechnetate–labeled red blood cell scan. Current studies report accuracies ranging from 24% to 91%.5

Some authors suggest using nuclear imaging as a first-line diagnostic test as there are data to suggest that a positive 99mTc-pertechnetate–labeled red blood cell scan correlates with positive findings on angiography.6 If bleeding is identified within the first 2 minutes of scanning, there is a 60% chance of having a positive angiogram. The other value of labeled red blood cell scanning is that if no bleeding is detected, there is a 93% chance of a negative angiogram.6 There are also data to suggest that radionuclide scans can be used to predict which patients will require surgery. It has been reported that 24% of patients with evidence of bleed-ing on 99mTc-pertechnetate–tagged red blood cell scan will require subsequent surgery compared to only 7% of those without.6

Some clinicians feel that colonoscopy should be the first study used to evaluate patients with LGIB who are hemodynamically stable.7 If the patient’s clinical condi-tion allows, it is beneficial to have the patient undergo some sort of colon preparation prior to colonoscopy since this will allow for a more complete evaluation. The benefit to colonoscopy is that it can allow for exact localization of the bleeding and therapeutic interven-tion. Because landmarks are difficult to distinguish in the setting of active bleeding, tattooing of the site, if identified, will greatly assist the surgeon if surgery is required. In addition to localizing the bleeding, thera-peutic interventions can be utilized to stop the hemor-rhage. Heater probes, bipolar coagulation, injections of epinephrine, and endoscopic clips are some of the modalities that can be employed by most endoscopists.7 However, high-volume bleeding may prevent the en-doscopist from completing the colonoscopy. Massive LGIB can obscure the colonic lumen, with the blood absorbing the light, making visualization of the mucosa impossible.

Angiography also has the potential to be both diag-nostic and therapeutic for LGIB. Angiography can be beneficial in 3 types of patients: (1) the patient who has evidence of active bleeding within the first few minutes of radionuclide scanning; (2) the patient who is actively bleeding and requires emergent therapy because of hemodynamic instability; and (3) the patient with ob-scure, recurrent gastrointestinal bleeding that has not been localized with other less invasive testing. The rate



of hemorrhage needs to be at least 1 mL/min to be detected by angiography.8 Only 40% to 78% of patients who undergo angiography demonstrate a positive re-sult, so patient selection is important.9

If angiography demonstrates a source of bleeding, it can provide highly accurate localization, allowing for focused therapy. Intra-arterial vasopressin and arterial embolization are the 2 main modalities that can be employed to control LGIB. Vasopressin infusion will control hemorrhage in 91% of patients, but as many as 50% of hemorrhages may recur once the infusion is tapered.10–13 The benefit of embolization is immediate cessation of bleeding; however, if embolization of larger vessels is required, the risk of bowel ischemia may ex-ceed 20%.10–13

cASE 1 concLuSIon

The patient’s hemoglobin stabilizes after he re-ceives 2 units of packed red blood cells, and he

has no further bouts of hematochezia. He is able to un-dergo bowel preparation, and endoscopy is performed within 24 hours. Colonoscopy reveals diverticulosis of the sigmoid colon with no evidence of ongoing bleed-ing. He is discharged with iron supplements and an appointment for follow-up in 2 to 3 weeks.

cASE pAtIEnt �

A 75-year-old woman presents with hemato-chezia, which began 2 days ago. The amount

of blood has increased with each bowel movement, and she now feels weak and dizzy. She has a history of atrial fibrillation for which she takes warfarin. Her blood pressure is 100/75 mm Hg, and her heart rate is 110 bpm and irregular in the supine position. The remainder of her history and physical examination are unremarkable. On laboratory testing, her INR is 2.2.

• what steps should be taken in the initial manage-ment of this patient?

After the ABCs of resuscitation and the appropri-ate laboratory tests and upper gastrointestinal and anorectal examinations are performed, the clinician must evaluate the best way to reverse the anticoagulated state. In the case of a patient anticoagulated with war-farin, fresh frozen plasma, vitamin K, or recombinant factor VII may be necessary to reverse the effects. One must take into consideration the risk and benefits of reversing the anticoagulation as well as the reason anticoagulation is needed (eg, mechanical valve, endo-vascular stents, hypercoagulable states). Because there

are no current guidelines on when or by what route to reverse a patient’s anticoagulation, it must be handled on a case-by-case basis.

cASE � contInuEd

Upon further questioning, the patient reports that she has never had a colonoscopy or colon

imaging. Evaluation reveals some nonbleeding internal hemorrhoids on rigid proctoscopy and pink rectal mucosa with red blood in the vault. Nasogastric lavage is negative.

• what is the differential diagnosis for lGiB in this patient?

differential diagnosis for LGIB

There are multiple causes for LGIB and they include diverticulosis; angiodysplasia; ischemic, drug-related, and idiopathic colitis; inflammatory bowel disease, intestinal tumors; and anorectal and hemorrhoidal dis-ease. Diverticulosis is very common in Western society due to low levels of dietary fiber intake. This malady is one of the most common causes of LGIB in the United States. Diverticulosis becomes more common with each passing decade of life. By 60 years of age, patients have a 50% chance of having evidence of diverticulosis.14 Slow intestinal transit and the lack of bulk that dietary fiber provides causes increased intraluminal pressures, resulting in pulsion diverticulae at the sites where blood vessels penetrate the muscular layer of the colonic wall (vasa recta). Thinning of the media of the vasa recta predisposes them to intraluminal rupture. Also, a feca-lith may cause traumatic rupture of the vessel.

Because the majority of LGIB cases resolve without actual localization of the bleeding, we can only estimate the incidence of LGIB from diverticular disease, with current estimates ranging from 15% to 48%.15 Howev-er, most patients with this disease do not develop LGIB. Only 4%to 17% of patients with diverticular disease will demonstrate signs of hemorrhage.15 When patients do develop LGIB, bleeding will resolve spontaneously in about 80% to 90%.16 The mechanism of the bleed-ing and the risk associated with recurrent bleeding are unknown. It is thought that even though right-sided diverticula are less common than sigmoid diverticula, they are responsible for most cases of diverticular bleed-ing.16 However, it is very difficult to distinguish between bleeding from angiodysplasia and bleeding from diver-ticular disease.

Angiodysplasia is another common cause of LGIB.



Angiodysplastic lesions are thin-walled atriovenous mal-formations within the mucosa and submucosa that can be congenital or acquired. Increased intraluminal pressure, which is caused by the loss of the precapillary sphincter and thickening and ectasia of the postcapil-lary venule, is responsible for the development of acquired angiodysplasias. The frequency of angiodys-plasia increases with age, and these lesions are often as-sociated with aortic stenosis, chronic renal failure, and von Willebrand disease.17 Even though it is difficult to localize bleeding to a specific angiodysplastic lesion, an-giography is still the gold standard for diagnosing this malady. Angiodysplasias can also be seen on colonos-copy, where they appear as cherry red mucosal lesions, which may or may not have a central feeding vessel.

The multiple other etiologies of LGIB are not usu-ally associated with massive bleeding. Both Crohn’s disease and ulcerative colitis can cause hematochezia along with diarrhea. Ischemic colitis usually occurs in older patients with other cardiovascular comorbidities and is associated with abrupt onset of colicky pain with a mucoid, bloody diarrhea. Rarely do colonic malig-nancies bleed profusely. They usually cause an insidi-ous, slow bleed from an exophytic lesion.

cASE � concLuSIon

The patient receives 4 units of fresh frozen plasma over the next 12 hours. She undergoes

a 99mTc-pertechnetate–labeled red blood cell scan, which shows active bleeding within the first 2 minutes. She is then taken to the angiography suite where her bleeding is localized and embolized. She has no further bleeding and is restarted on her warfarin 3 days later. The cause of bleeding is not determined by the angi-ography, but the bleeding is controlled. It is routine to have patients follow up with an outpatient colonoscopy a few weeks later to attempt to evaluate the etiology of the bleeding.

SurGIcAL IntErVEntIonS

cASE pAtIEnt �

A 65-year-old man presents to the emergency department with several bouts of bright red

blood per rectum that began that morning. He had a similar bleeding episode several years ago that resolved on its own. He takes no anticoagulants or antiplatelet medications. His blood pressure is 80/40 mm Hg and

his heart rate is 132 bpm in a supine position. Two large-bore intravenous lines and a Foley catheter have been placed by the emergency physicians. His blood pressure increases to 90/56 mm Hg after 2 L of normal saline are administered. His hemoglobin is 6.5 g/dL. While you are examining him, he has another large bowel movement that consists of only blood. After he is transfused with 2 units of packed red blood cells, his blood pressure stabilizes. Radionuclide-tagged red blood cell scan and angiography do not localize the bleeding, and an attempted colonoscopy is aborted be-cause the large amount of blood makes visualization of the colon lumen impossible. Throughout the course of these attempted interventions, he receives 4 more units of packed red blood cells and his hemoglobin improves to 8.5 g/dL.

• what is the next step in this patient’s management?

The need for surgical intervention for LGIB is uncommon. Mortality with surgical intervention is sig-nificant and increases with the amount of blood trans-fused prior to the operation and with the number of patient comorbidities. Data suggest that there is a re-duced mortality in patients who have received less than 10 units of blood as compared with those requiring over 10 units (7% versus 27%).18 Therefore, it is necessary to be available to offer surgical intervention when a patient’s transfusion threshold reaches 6 to 7 units.

Once the decision to go to the operating room (OR) is made, both the OR team and the endoscopy team need to be notified. It is important to first try to localize the source of bleeding. This is oftentimes difficult if all preoperative imaging is negative. The patient’s stomach, duodenum, small bowel, ileocecal valve, and colon must be examined for tumors, ileitis, colitis, or a Meckel’s diverticulum. If there is no obvious source of bleeding, then endoscopy can become a very valuable tool. The endoscope can gain access to the bowel via a transgastric or transcolonic approach and can be used to transillumi-nate vascular anomalies or tumors. If any abnormalities are found, a segmental resection can be performed. If the source of bleeding still cannot be found and it ap-pears to be arising from the colon, then a total abdominal colectomy can be performed. In the hemodynamically stable patient, a primary anastomosis can be performed. However, if the patient is unstable or hypothermic, creat-ing an ileostomy is the safest decision.

Mortality associated with operative intervention for LGIB ranges from 10% to 35%, with increased transfu-sion requirements associated with increased mortality.19



Recurrent LGIB can occur in as many as 10% of patients if the bleeding site cannot be localized preoperatively. This risk is increased if the surgeon performs a segmen-tal resection of colon. Segmental resections carry similar mortality rates as total abdominal colectomies, but they have twice the bleeding recurrence rates.20 If the bleed-ing cannot be confidently localized, it is best to perform a total abdominal colectomy.

cASE � concLuSIon

Because of continuing LGIB with hemody-namic instability, the patient is taken to the

OR after resuscitation. Despite surgical exploration and intraoperative endoscopy, no source of bleeding is identified. Intraoperatively, the patient’s vital signs, body temperature, and hemoglobin remain stable, and he undergoes a total abdominal colectomy with an ileorectal anastomosis. The patient recovers from the surgery without recurrence of bleeding.

poStpoLYpEctoMY BLEEdInG

cASE pAtIEnt �

A 57-year-old man presents with mild hema-tochezia 4 days after undergoing a colonos-

copy with a polypectomy of a 1-cm sessile polyp in the ascending colon. He has a history of coronary artery disease, which required placement of a bare metal coronary stent. His routine medications of aspirin and clopidogrel were discontinued for 5 days prior to the colonoscopy. He restarted his aspirin and clopidogrel 3 days after the procedure. He is hemodynamically stable and the remainder of his history and physical examination are unremarkable. His hemoglobin in the emergency department is 12 g/dL.

• How often and at what point do postpolypectomy bleeds occur?

Postpolypectomy bleeding has been reported to occur in 0.2% to 6.1% of cases.21 It usually occurs within 7 days, but later presentation is not uncommon. Important factors in postpolypectomy bleeding are whether or not the patient is taking any type of antico-agulation or antiplatelet therapy and when the patient stopped taking it prior to the colonoscopy. There are no prospective randomized data to support when the medication should be stopped or restarted after a colo-noscopy. These decisions are made at the discretion of

the endoscopist. Some studies have shown that polyp size correlates with the risk of bleeding, with most show-ing that larger polyps tend to bleed more frequently.21 Also, the morphology of the polyp can be an important factor, as sessile polyps bleed more frequently than pedunculated ones.21 Most polyps that bleed are found in the right colon, followed by the sigmoid colon as the next most common location. The right colon is thought to be at greater risk because it has the thinnest wall and aggressive coagulation methods are not com-monly used. Advanced age, cardiovascular comorbidity, and renal disease were found to be the only variables statistically significant for predicting the need for blood transfusion.21 Of those patients requiring transfusion, most received packed red blood cells, followed by fresh frozen plasma and platelets. Patients who are admitted to the ICU are also more likely to receive a transfusion. On average as many as 50% of patients will require transfusion.21

cASE � concLuSIon

The patient has a negative clinical exam, which includes a rigid proctoscopy. He is admitted to

the floor for observation. His wife is concerned about his prognosis.

• what is the prognosis of a patient with a postpolyp-ectomy bleed?

Most patients have an excellent prognosis after post-polypectomy bleeding. The most frequently employed diagnostic and treatment modality is repeat colonos-copy. However, angiography and surgery may be re-quired in the rare patient who does not stop bleeding spontaneously or whose bleeding cannot be controlled endoscopically. Clips, injections with epinephrine, and cautery are some of the modalities that can be used endoscopically for control of the bleeding. However, commonly no stigmata of bleeding can be found and the patient continues to be managed conservatively.

oBScurE HEMorrHAGE

cASE pAtIEnt �

A 64-year-old woman is admitted due to LGIB with hemodynamic instability and requires

transfer to the ICU and transfusion of 2 units of red blood cells. Her history is significant for a prior epi-sode of LGIB 4 months ago, also with hemodynamic



instability, that required ICU admission and transfusion of 4 units of red blood cells. Mesenteric angiography dur-ing that admission failed to reveal a bleeding source. The patient subsequently underwent upper and lower endoscopy, but the etiology remained unidentified. Currently, she is asymptomatic. Her hemoglobin is 9.8 g/dL. The remainder of her history, physical exami-nation, and laboratory studies are unremarkable.

• what is the differential diagnosis for lGiB in this patient?

differential diagnosis

For patients with LGIB in whom the source of bleeding remains unidentified following routine inves-tigations, bleeding will recur in approximately 10%.22,23 For patients with clinically evident recurrent LGIB, the medical history and physical examination should be fo-cused on symptoms and signs of diseases likely to have been overlooked during the evaluation of the initial bleeding episode, especially those relating to the small bowel. 99mTc-pertechnetate radionuclide scanning and/or angiography can be repeated, with the same limitations and benefits as described earlier. Repeat upper and/or lower endoscopy is generally indicated early in the evaluation process. The incidence of bleed-ing lesions within the reach of a standard colonoscope in patients undergoing repeat evaluation of recurrent bleeding is about 20%.24

The lesions already described for the colon— vascular lesions, diverticular disease, and neoplasms—can cause obscure bleeding in the small bowel. The most common cause of obscure gastrointestinal bleed-ing is angiodysplasia of the small bowel.25 Small in-testinal angiodysplasia is associated with a variety of conditions, including renal failure, collagen vascular diseases, radiation injury, and von Willebrand disease. Neoplasms of the small intestine are also an important cause of obscure gastrointestinal bleeding. The most common benign tumor causing obscure bleeding is leiomyoma, while the most common malignant tumor is leiomyosarcoma. Benign tumors tend to bleed more often than malignant tumors.25

The differential diagnosis also includes Meckel’s diverticulae and small bowel ulcers related to use of NSAIDs. The presence of ulcers in the small bowel should be considered in any patient with obscure gastrointestinal bleeding. Evidence suggests that small bowel ulcer bleeding may be more prevalent than previously considered. For example, one study demon-

strated biochemical as well as endoscopic evidence of macroscopic injury to the small intestine in nearly 75% of healthy volunteers after 2 weeks’ ingestion of slow-release diclofenac.26 In a study of patients with obscure bleeding, 12% of patients were found to have small bowel ulcerations that were presumed to cause the bleeding.27 These patients were all taking NSAIDs and had multiple ileal and/or jejunal ulcerations, ranging in size from small to large and having a punched-out appearance with oozing hemorrhage or scar. Finally, Meckel’s diverticula are an important consideration in obscure bleeders and are the most common source of small bowel bleeding in patients younger than 25 years of age.25

• what tools are used to evaluate for small bowel bleeding?

Evaluation of Small Bowel Hemorrhage

Tools that are available to evaluate the small bowel for obscure bleeding include standard small bowel fol-low through, enteroclysis, various forms of CT scans, capsule endoscopy, and enteroscopy (either push, double-balloon, single-balloon, or intraoperative). In the past decade there has been an explosion of data published on these evaluation techniques. Radiograph-ic imaging studies in the small intestine fail to detect many mucosal lesions and are usually considered to be inadequate for evaluation of the small intestine.

Given the ease of use and wide availability of cap-sule endoscopy, it has acquired a central role in the evaluation of the small bowel in patients with obscure bleeding. Capsule endoscopy in patients with obscure bleeding has been examined in many small cohort and observational studies as well as in meta-analyses.28,29 The data indicate that the likelihood of identifying a potentially clinically important lesion by capsule en-doscopy is greater than by either enteroscopy or small-bowel barium radiography and that capsule endoscopy has a particular advantage in visualizing vascular and inflammatory lesions.7 However, there are several im-portant issues to consider. First, patient selection has a considerable influence on the success rate of capsule endoscopy. Evidence for ongoing bleeding, a low he-moglobin value, and ongoing transfusion requirements are associated with a higher likelihood of a significant lesion being identified on capsule endoscopy.30,31

Push enteroscopy has been reported to identify a source of bleeding in 24% to 75% of obscure bleed-ers, but most often identifies a source in about 30% of



patients.32,33 The major advantages of push enteroscopy are that it is readily available and relatively safe, and it allows both biopsy and therapeutic interventions to be performed. Data published within the past decade on the use of deep enteroscopy in patients with obscure gastrointestinal bleeding has focused largely on double-balloon enteroscopy. In one review, double-balloon enteroscopy led to identification of putative bleeding lesions in approximately two-thirds of patients.34 At pres-ent, there are not enough data with which to compare single-balloon enteroscopy or spiral enteroscopy with double-balloon enteroscopy in patients with obscure gastrointestinal bleeding. Intraoperative examination with an enteroscope or standard colonoscope per-mits visualization of most or all of the small intestine. Although this technique has been reported to detect abnormalities in 70% to 100% of patients with obscure bleeding,35,36 not all practitioners are this successful and recurrent bleeding is often problematic.23

In patients with recurrent LGIB that is not active and in whom diagnostic options have been exhausted, a potential approach is “provocative angiography,” in which bleeding is reactivated or augmented by the use of vasodilators, anticoagulants, and/or thrombolytics followed by visceral angiography. A bleeding source can be identified by this approach in 20% to 40% of patients37,38 and may allow therapy to be initiated. However, this procedure is invasive and needs to be carried out by highly skilled personnel; further study is needed to clarify its role in the management of this patient group.

cASE � contInuEd

The patient undergoes capsule endoscopy, which reveals multiple vascular ectatic lesions

in the ileum. She is scheduled for double-balloon enter-oscopy with fulguration of the angiodysplastic lesions. However, before the procedure can be performed, the patient returns to the emergency department with recurrent LGIB with hemodynamic instability. She remains hemodynamically labile despite transfusion of 4 units of red blood cells.

• what is the approach to treatment?

treatment

The general approach to the treatment of patients with recurrent bleeding is similar to that already de-scribed for the initial bleeding episode. The ABCs of resuscitation should be followed and any evidence of

hemodynamic instability aggressively treated. If a specif-ic small bowel lesion can be identified with subsequent investigation, a number of management options have been described. Angiodysplasia is the most common source of obscure small intestinal bleeding. The treat-ment of these lesions is difficult because they are rarely found in isolation. Patients with lesions that are readily identified or are actively bleeding are best treated en-doscopically by electrocoagulation, banding, injection therapy, or argon plasma coagulation.39–41 Perforation of the gastrointestinal tract, however, is a risk, particu-larly with electrocoagulation.

If surgical intervention is indicated because of ongo-ing active hemorrhage from angiodysplastic lesions, intraoperative enteroscopy may be used to identify and treat the lesions. A putative bleeding source is frequent-ly identified, but surgical resection of these lesions does not always prevent recurrent bleeding. Although some investigators have reported rebleeding rates as low as 20%,42 rebleeding in other studies has been sub-stantial.23 Surgical therapy is most effective in low-risk patients who have lesions that are clearly identified as the bleeding source.

The identification of ulcer disease means that the use of all NSAIDs should be discontinued. Bleeding from ulcers may be controlled by conventional endo-scopic means. The treatment of neoplastic lesions is specific to the type of tumor. Surgical resection is ap-propriate for patients found to have bleeding from a Meckel’s diverticulum.

cASE � concLuSIon

The patient undergoes intraoperative enter-oscopy with fulguration of multiple bleeding

vascular ectatic lesions in the ileum. Her postoperative course is uneventful and she is discharged home.

• what is the likelihood of recurrent bleeding in pa-tients with obscure bleeding?

prognosis

In a study of patients with obscure bleeding and positive findings on enteroscopy, 89% of the 95 patients who were followed had no further rebleeding after a mean follow-up period of 16 months.43 In another study, 45 patients with obscure bleeding were followed for an average of 30 months after enteroscopy; for patients who had abnormal initial findings at enteros-copy, 47% had recurrent bleeding or a need for iron/ transfusion therapy.44



SuMMArY poIntS

• LGIB is defined as bleeding distal to the ligament of Treitz, but 10% to 15% of LGIB symptoms are from an upper gastrointestinal source.

• ABCs are the first-line therapies for patients with LGIB.

• Knowledge of a patient’s medication list is important to help reverse any anticoagulation or antiplatelet therapy that may be in place.

• Diagnostic imaging may or may not be helpful in localizing the bleeding.

• Most bleeding will resolve with conservative manage-ment.

• Therapeutic interventions include colonoscopic in-tervention and angiographic vasopressin infusion or embolization.

• Surgery is warranted for unstable patients or those requiring more than 6 units of packed cells. Endos-copy should be available.

rEfErEncES

1. Chait M. Lower gastrointestinal bleeding in the elderly. Ann Long-Term Care 2007;15:40–6.

2. Landefeld CS, Goldman L. Major bleeding in outpatients treated with warfarin: incidence and prediction by fac-tors known at the start of outpatient therapy. Am J Med 1989;87:144–52.

3. Jensen DM, Machicado GA. Diagnosis and treatment of severe hematochezia. The role of urgent colonoscopy after purge. Gastroenterology 1988;95:1569–74.

4. Billingham RP. The conundrum of lower gastrointestinal bleeding. Surg Clin North Am 1997;77:241–57.

5. Sabiston DC, editor. Textbook of surgery: the biological basis of modern surgical practice. 14th ed. Philadelphia (PA): WB Saunders; 1991.

6. Ng D, Opelka FG, Beck DE, et al. Predictive value of technetium Tc 99m-labeled red blood cell scintigraphy for positive angiogram in massive lower gastrointestinal hemorrhage. Dis Colon Rectum 1997;40:471–7.

7. Kovacs TO, Jensen DM. Recent advances in the endo-scopic diagnosis and therapy of upper gastrointestinal, small intestinal, and colonic bleeding. Med Clin North Am 2002;86:1319–56.

8. Koval G, Brenner KG, Rosch J, et al. Aggressive angio-graphic diagnosis in acute LGI hemorrhage. Dig Dis Sci 1987;32:248–53.

9. Browder W, Cerise EJ, Litwin MS. Impact of emergency

angiography in massive lower gastrointestinal bleeding. Ann Surgery 1986;204:530–6.

10. Britt LG, Warren L, Moore OF 3rd. Selective management of lower gastrointestinal bleeding. Am Surgeon 1983;49: 121–5.

11. Gomes AS, Lois JF, McCoy RD. Angiographic treatment of gastrointestinal hemorrhage: comparison of vasopres-sin infusion and embolization. Am J Roentgenol 1986; 146:1031–7.

12. Ure J, Varnava AM, Longo WE. Diverticular bleeding. Semin Col Rect Surg 1994;5:32.

13. Bender JS, Wieneck RG, Bouwan DL. Morbidity and mortality following total abdominal colectomy for massive lower gastrointestinal bleeding. Am Surg 1991;57:536–40.

14. Sorbi D, Norton I, Conio M, et al. Postpolypectomy lower GI bleeding: descriptive analysis. Gastrointest Endosc 2000; 51:690–6.

15. Corman ML. Vascular diseases. In: Corman ML, editor. Colon and rectal surgery. 3rd ed. Philadelphia (PA): JB Lippincott; 1993:860–900.

16. Finne CO. The aggressive management of serious lower gastrointestinal bleeding. Probl Gen Surg 1992;9:597.

17. McGuire HW, Haynes BW. Massive hemorrhage from di-verticular disease of the colon: guidelines for therapy based on bleeding pattern in fifty cases. Ann Surg 1972;175:847.

18. Zuckerman DA, Bocchini TP, Birnbaum EH. Massive hemorrhage in the lower gastrointestinal tract in adults: di-agnostic imaging and intervention. AJR Am J Roentgenol 1993;161:703–11.

19. Gomes AS, Lois JF, McCoy RD. Angiographic treatment of gastrointestinal hemorrhage: comparison of vasopressin infusion and embolization. AJR Am J Roentgenol 1986; 146:1031–7.

20. Meyers MA, Alonso DR, Gray GF, Baer JW. Pathogenesis of bleeding colonic diverticulosis. Gastroenterology 1976; 71:577–83.

21. Gostout CJ. Angiodysplasia and aortic valve disease: let’s close the book on this association. Gastrointest Endosc 1995;42:398–402.

22. Jensen DM. Current diagnosis and treatment of severe ob-scure GI hemorrhage. Gastrointest Endosc 2003;58:256–66.

23. Leighton JA, Goldstein J, Hirota W, et al. Obscure gastroin-testinal bleeding. Gastrointest Endosc 2003;58:650–5.

24. Fry LC, Bellutti M, Neumann H, et al. Incidence of bleeding lesions within reach of conventional upper and lower endoscopes in patients undergoing double-balloon enteroscopy for obscure gastrointestinal bleeding. Aliment Pharmacol Ther 2009;29:342–9.

10 Hospital Physician Board Review Manual www.hpboardreview.com


25. Rockey DC. Occult and obscure gastrointestinal bleeding: causes and clinical management. Nat Rev Gastroenterol and Hepatol 2010;7:265–79.

26. Maiden L, Thjodleifsson B, Theodors A, et al. A quantita-tive analysis of NSAID-induced small bowel pathology by capsule enteroscopy. Gastroenterology 2005;128:1172–8.

27. Hayashi Y, Yamamoto H, Kita H, et al. Non-steroidal anti-inflammatory drug-induced small bowel injuries identi-fied by double-balloon endoscopy. World J Gastroenterol 2005;11:4861–4.

28. Triester SL, Leighton JA, Leontiadis GI, et al. A meta- analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with obscure gast-rointestinal bleeding. Am J Gastroenterol 2005;100:2407–18.

29. Marmo R, Rotondano G, Piscopo R, et al. Meta-analysis: capsule enteroscopy vs. conventional modalities in dia-gnosis of small bowel diseases. Aliment Pharmacol Ther 2005;22:595–604.

30. Pennazio M, Santucci R, Rondonotti E, et al. Outcome of patients with obscure gastrointestinal bleeding after capsule endoscopy: report of 100 consecutive cases. Gas-troenterology 2004;126:643–53.

31. May A, Wardak A, Nachbar L, et al. Influence of patient selection on the outcome of capsule endoscopy in patients with chronic gastrointestinal bleeding. J Clin Gastroenterol 2005;39:684–8.

32. Lin S, Rockey DC. Obscure gastrointestinal bleeding. Gas-troenterol Clin North Am 2005;34:679–98.

33. Zuckerman GR, Prakash C, Askin MP, Lewis BS. AGA tech-nical review on the evaluation and management of occult and obscure gastrointestinal bleeding. Gastroenterology 2000;118:201–21.

34. Raju GS, Gerson L, Das A, Lewis B. American Gastroen-terological Association (AGA) Institute technical review

on obscure gastrointestinal bleeding. Gastroenterology 2007;133:1697–717.

35. Eisen GM, Dominitz JA, Faigel DO, et al. Enteroscopy. Gastrointest Endosc 2001;3:871–3.

36. Kendrick ML, Buttar NS, Anderson MA, et al. Contribu-tion of intraoperative enteroscopy in the management of obscure gastrointestinal bleeding. J Gastrointest Surg 2001;5:162–7.

37. Malden ES, Hicks ME, Royal HD, et al. Recurrent gastroin-testinal bleeding: use of thrombolysis with anticoagulation in diagnosis. Radiology 1998;207:147–51.

38. Bloomfeld RS, Smith TP, Schneider AM, Rockey DC. Provocative angiography in patients with gastrointestinal hemorrhage of obscure origin. Am J Gastroenterol 2000; 95:2807–12.

39. Zuckerman GR, Prakash C. Acute lower intestinal blee-ding. Part II: etiology, therapy, and outcomes. Gastrointest Endosc 1999;49:228–38.

40. Gupta N, Longo WE, Vernava AM. Angiodysplasia of the lower gastrointestinal tract: an entity readily diagnosed by colonoscopy and primarily managed nonoperatively. Dis Colon Rectum 1995;38:979–82.

41. Bemvenuti GA, Julich MM. Ethanolamine injection for sclerotherapy of angiodysplasia of the colon. Endoscopy 1997;30:564–9.

42. Szold A, Katz LB, Lewis BS. Surgical approach to occult gastrointestinal bleeding. Am J Surg 1992;163:90–2.

43. Sun B, Rajan E, Cheng S, et al. Diagnostic yield and thera-peutic impact of double-balloon enteroscopy in a large cohort of patients with obscure gastrointestinal bleeding. Am J Gastroenterol 2006;101:2011–5.

44. Gerson LB, Batenic MA, Newsom SL, et al. Long-term out-comes after double-balloon enteroscopy for obscure gas-trointestinal bleeding. Clin Gastroenterol Hepatol 2009;7: 664–9.

272611-01

Copyright 2010 by Turner White Communications Inc., Wayne, PA. All rights reserved.

CODE: varies PUB/POST: NA PRODUCTION: Roseann Panariello LIVE: 7" x 10"

DESCRIPTION: Tygacil Brief – ISI Update TRIM: 8" x 11"

Delivery Support: 212.237.7000 FILE: 05A-001412-06B-varies-brief.indd SAP #: PFZ.PFZTYG.10068.B.011 BLEED: None

TYGACIL® (tigecycline) Brief SummarySee package insert for full Prescribing Information. For further product information and current package insert, please visit www.wyeth.com or call our medical communications department toll-free at 1-800-934-5556.INDICATIONS AND USAGETYGACIL is indicated for the treatment of adults with complicated skin and skin structure infections caused by Escherichia coli, Enterococcus faecalis (vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus agalactiae, Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Streptococcus pyogenes, Enterobacter cloacae, Klebsiella pneumoniae, and Bacteroides fragilis.TYGACIL is indicated for the treatment of adults with complicated intra-abdominal infections caused by Citrobacterfreundii, Enterobacter cloacae, Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae, Enterococcus faecalis(vancomycin-susceptible isolates), Staphylococcus aureus (methicillin-susceptible and -resistant isolates), Streptococcus anginosus grp. (includes S. anginosus, S. intermedius, and S. constellatus), Bacteroides fragilis, Bacteroides thetaiotaomicron, Bacteroides uniformis, Bacteroides vulgatus, Clostridium perfringens, and Peptostreptococcus micros.TYGACIL is indicated for the treatment of adults with community-acquired pneumonia infections caused by Streptococcus pneumoniae (penicillin-susceptible isolates), including cases with concurrent bacteremia, Haemophilus influenzae (beta-lactamase negative isolates), and Legionella pneumophila.CONTRAINDICATIONSTYGACIL is contraindicated for use in patients who have known hypersensitivity to tigecycline.WARNINGS AND PRECAUTIONSAnaphylaxis/Anaphylactoid ReactionsAnaphylaxis/anaphylactoid reactions have been reported with nearly all antibacterial agents, including TYGACIL, and may be life-threatening. TYGACIL is structurally similar to tetracycline-class antibiotics and should be administered with caution in patients with known hypersensitivity to tetracycline-class antibiotics.Hepatic EffectsIncreases in total bilirubin concentration, prothrombin time and transaminases have been seen in patients treated with tigecycline. Isolated cases of significant hepatic dysfunction and hepatic failure have been reported in patients being treated with tigecycline. Some of these patients were receiving multiple concomitant medications. Patients who develop abnormal liver function tests during tigecycline therapy should be monitored for evidence of worsening hepatic function and evaluated for risk/benefit of continuing tigecycline therapy. Adverse events may occur after the drug has been discontinued.Mortality Imbalance and Lower Cure Rates in Ventilator-Associated PneumoniaA study of patients with hospital acquired pneumonia failed to demonstrate the efficacy of TYGACIL. In this study, patients were randomized to receive TYGACIL (100 mg initially, then 50 mg every 12 hours) or a comparator. In addition, patients were allowed to receive specified adjunctive therapies. The sub-group of patients with ventilator-associated pneumonia who received TYGACIL had lower cure rates (47.9% versus 70.1% for the clinically evaluable population) and greater mortality (25/131 [19.1%] versus 14/122 [11.5%]) than the comparator.Use During Pregnancy TYGACIL may cause fetal harm when administered to a pregnant woman. If the patient becomes pregnant while taking tigecycline, the patient should be apprised of the potential hazard to the fetus. Results of animal studies indicate that tigecycline crosses the placenta and is found in fetal tissues. Decreased fetal weights in rats and rabbits (with associated delays in ossification) and fetal loss in rabbits have been observed with tigecycline [see USE INSPECIfIC POPULATIONS]. Tooth Development The use of TYGACIL during tooth development (last half of pregnancy, infancy, and childhood to the age of 8 years) may cause permanent discoloration of the teeth (yellow-gray-brown). Results of studies in rats with TYGACIL have shown bone discoloration. TYGACIL should not be used during tooth development unless other drugs are not likely to be effective or are contraindicated. Clostridium difficile-Associated DiarrheaClostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, including TYGACIL, and may range in severity from mild diarrhea to fatal colitis. Treatment with antibacterial agents alters the normal flora of the colon leading to overgrowth of C. difficile. C. difficile produces toxins A and B which contribute to the development of CDAD. Hypertoxin producing strains of C. difficile cause increased morbidity and mortality, as these infections can be refractory to antimicrobial therapy and may require colectomy. CDAD must be considered in all patients who present with diarrhea following antibiotic use. Careful medical history is necessary since CDAD has been reported to occur over two months after the administration of antibacterial agents. If CDAD is suspected or confirmed, ongoing antibiotic use not directed against C. difficile may need to be discontinued. Appropriate fluid and electrolyte management, protein supplementation, antibiotic treatment of C. difficile, and surgical evaluation should be instituted as clinically indicated. Patients With Intestinal PerforationCaution should be exercised when considering TYGACIL monotherapy in patients with complicated intra-abdominal infections (cIAI) secondary to clinically apparent intestinal perforation. In cIAI studies (n=1642), 6 patients treated with TYGACIL and 2 patients treated with imipenem/cilastatin presented with intestinal perforations and developed sepsis/septic shock. The 6 patients treated with TYGACIL had higher APACHE II scores (median = 13) versus the 2 patients treated with imipenem/cilastatin (APACHE II scores = 4 and 6). Due to differences in baseline APACHE II scores between treatment groups and small overall numbers, the relationship of this outcome to treatment cannot be established.Tetracycline-Class EffectsTYGACIL is structurally similar to tetracycline-class antibiotics and may have similar adverse effects. Such effects may include: photosensitivity, pseudotumor cerebri, and anti-anabolic action (which has led to increased BUN, azotemia, acidosis, and hyperphosphatemia). As with tetracyclines, pancreatitis has been reported with the use of TYGACIL. SuperinfectionAs with other antibacterial drugs, use of TYGACIL may result in overgrowth of non-susceptible organisms, including fungi. Patients should be carefully monitored during therapy. If superinfection occurs, appropriate measures should be taken. Development of Drug-Resistant BacteriaPrescribing TYGACIL in the absence of a proven or strongly suspected bacterial infection is unlikely to provide benefit to the patient and increases the risk of the development of drug-resistant bacteria.ADVERSE REACTIONSBecause clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. In clinical trials, 2514 patients were treated with TYGACIL. TYGACIL was discontinued due to adverse reactions in 7% of patients compared to 6% for all comparators. Table 1 shows the incidence of treatment-emergent adverse reactions through test of cure reported in 2% of patients in these trials.

Table 1. Incidence (%) of Adverse Reactions Through Test of Cure Reported in 2% of Patients Treated in Clinical Studies

Body System TYGACIL Comparatorsa

Adverse Reactions (N=2514) (N=2307)

Body as a WholeAbdominal pain 6 4Abscess 3 3Asthenia 3 2Headache 6 7Infection 8 5

Cardiovascular SystemPhlebitis 3 4

Digestive SystemDiarrhea 12 11Dyspepsia 2 2Nausea 26 13Vomiting 18 9

Hemic and Lymphatic SystemAnemia 4 5

Metabolic and NutritionalAlkaline Phosphatase Increased 4 3Amylase Increased 3 2Bilirubinemia 2 1BUN Increased 3 1Healing Abnormal 4 3Hypoproteinemia 5 3SGOT Increasedb 4 5SGPT Increasedb 5 5

Nervous SystemDizziness 3 3

Skin and AppendagesRash 3 4

a Vancomycin/Aztreonam, Imipenem/Cilastatin, Levofloxacin, Linezolid.b LFT abnormalities in TYGACIL-treated patients were reported more frequently in the post therapy period than those

in comparator-treated patients, which occurred more often on therapy.In all Phase 3 and 4 studies that included a comparator, death occurred in 3.9% (147/3788) of patients receiving TYGACIL and 2.9% (105/3646) of patients receiving comparator drugs. An increase in all-cause mortality has been observed across phase 3 and 4 clinical studies in TYGACIL treated patients versus comparator. The cause of this increase has not been established. This increase should be considered when selecting among treatment options. (See Table 2.)

Table 2. Patients with Adverse Events with Outcome of Death by Infection Type

TYGACIL Comparator Risk Difference*Infection Type n/N % n/N % % (95% CI)

Approved IndicationscSSSI 12/834 1.4 6/813 0.7 0.7 (-0.5, 1.9)cIAI 40/1382 2.9 27/1393 1.9 1.0 (-0.3, 2.2)CAP 12/424 2.8 11/422 2.6 0.2 (-2.3, 2.7) Combined 64/2640 2.4 44/2628 1.7 0.7 (-0.0, 1.6)Unapproved IndicationsHAP 65/467 13.9 56/467 12.0 1.9 (-2.6, 6.4) Non-VAPa 40/336 11.9 42/345 12.2 -0.3 (-5.4, 4.9) VAPa 25/131 19.1 14/122 11.5 7.6 (-2.0, 16.9)RP 11/128 8.6 2/43 4.7 3.9 (-9.1, 11.6)DFI 7/553 1.3 3/508 0.6 0.7 (-0.8, 2.2) Combined 84/1148 7.2 61/1018 6.0 1.2 (-1.0, 3.4)

CAP = Community-acquired pneumonia; cIAI = Complicated intra-abdominal infections; cSSSI = Complicated skin and skin structure infections; HAP = Hospital-acquired pneumonia; VAP = Ventilator-associated pneumonia; RP = Resistant pathogens; DFI = Diabetic foot infections.* The difference between the percentage of patients who died in TYGACIL and comparator treatment groups.a These are subgroups of the HAP population.Note: The studies include 300, 305, 900 (cSSSI), 301, 306, 315, 316, 400 (cIAI), 308 and 313 (CAP), 311 (HAP), 307 [Resistant gram-positive pathogen study in patients with MRSA or Vancomycin-Resistant Enterococcus (VRE)], and 319 (DFI with and without osteomyelitis).In comparative clinical studies, infection-related serious adverse events were more frequently reported for subjects treated with TYGACIL (7%) versus comparators (6%). Serious adverse events of sepsis/septic shock were more frequently reported for subjects treated with TYGACIL (2%) versus comparators (1%). Due to baseline differences between treatment groups in this subset of patients, the relationship of this outcome to treatment cannot be established [see WARNINGS AND PRECAUTIONS].The most common treatment-emergent adverse reactions were nausea and vomiting which generally occurred during the first 1 – 2 days of therapy. The majority of cases of nausea and vomiting associated with TYGACIL and comparators were either mild or moderate in severity. In patients treated with TYGACIL, nausea incidence was 26% (17% mild, 8% moderate, 1% severe) and vomiting incidence was 18% (11% mild, 6% moderate, 1% severe).In patients treated for complicated skin and skin structure infections (cSSSI), nausea incidence was 35% for TYGACIL and 9% for vancomycin/aztreonam; vomiting incidence was 20% for TYGACIL and 4% for vancomycin/aztreonam. In patients treated for complicated intra-abdominal infections (cIAI), nausea incidence was 25% for TYGACIL and 21% for imipenem/cilastatin; vomiting incidence was 20% for TYGACIL and 15% for imipenem/cilastatin. In patients treated for community-acquired bacterial pneumonia (CABP), nausea incidence was 24% for TYGACIL and 8% for levofloxacin; vomiting incidence was 16% for TYGACIL and 6% for levofloxacin.Discontinuation from tigecycline was most frequently associated with nausea (1%) and vomiting (1%). For comparators, discontinuation was most frequently associated with nausea (<1%).The following adverse reactions were reported infrequently (<2%) in patients receiving TYGACIL in clinical studies: Body as a Whole: injection site inflammation, injection site pain, injection site reaction, septic shock, allergic reaction, chills, injection site edema, injection site phlebitis Cardiovascular System: thrombophlebitis Digestive System: anorexia, jaundice, abnormal stools Metabolic/Nutritional System: increased creatinine, hypocalcemia, hypoglycemia, hyponatremia Special Senses: taste perversion Hemic and Lymphatic System: partial thromboplastin time (aPTT), prolonged prothrombin time (PT), eosinophilia, increased international normalized ratio (INR), thrombocytopenia Skin and Appendages: pruritus Urogenital System: vaginal moniliasis, vaginitis, leukorrheaPost-Marketing ExperienceThe following adverse reactions have been identified during postapproval use of TYGACIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish causal relationship to drug exposure. Anaphylaxis/anaphylactoid reactions, acute pancreatitis, hepatic cholestasis, and jaundice.DRUG INTERACTIONS WarfarinProthrombin time or other suitable anticoagulation test should be monitored if tigecycline is administered with warfarin [see CLINICAL PHARMACOLOGY (12.3) in full Prescribing Information]. Oral ContraceptivesConcurrent use of antibacterial drugs with oral contraceptives may render oral contraceptives less effective.USE IN SPECIfIC POPULATIONSPregnancyTeratogenic Effects—Pregnancy Category D [see WARNINGS AND PRECAUTIONS]Tigecycline was not teratogenic in the rat or rabbit. In preclinical safety studies, 14C-labeled tigecycline crossed the placenta and was found in fetal tissues, including fetal bony structures. The administration of tigecycline was associated with slight reductions in fetal weights and an increased incidence of minor skeletal anomalies (delays in bone ossification) at exposures of 5 times and 1 times the human daily dose based on AUC in rats and rabbits, respectively (28 mcg·hr/mL and 6 mcg·hr/mL at 12 and 4 mg/kg/day). An increased incidence of fetal loss was observed at maternotoxic doses in the rabbits with exposure equivalent to human dose. There are no adequate and well-controlled studies of tigecycline in pregnant women. TYGACIL should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.Nursing MothersResults from animal studies using 14C-labeled tigecycline indicate that tigecycline is excreted readily via the milk of lactating rats. Consistent with the limited oral bioavailability of tigecycline, there is little or no systemic exposure to tigecycline in nursing pups as a result of exposure via maternal milk. It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when TYGACIL is administered to a nursing woman [see WARNINGS AND PRECAUTIONS]. Pediatric UseSafety and effectiveness in pediatric patients below the age of 18 years have not been established. Because of effects on tooth development, use in patients under 8 years of age is not recommended [see WARNINGS AND PRECAUTIONS].Geriatric UseOf the total number of subjects who received TYGACIL in Phase 3 clinical studies (n=2514), 664 were 65 and over, while 288 were 75 and over. No unexpected overall differences in safety or effectiveness were observed between these subjects and younger subjects, but greater sensitivity to adverse events of some older individuals cannot be ruled out. No significant difference in tigecycline exposure was observed between healthy elderly subjects and younger subjects following a single 100 mg dose of tigecycline [see CLINICAL PHARMACOLOGY (12.3) in full Prescribing Information].Hepatic ImpairmentNo dosage adjustment is warranted in patients with mild to moderate hepatic impairment (Child Pugh A and Child Pugh B). In patients with severe hepatic impairment (Child Pugh C), the initial dose of tigecycline should be 100 mg followed by a reduced maintenance dose of 25 mg every 12 hours. Patients with severe hepatic impairment (Child Pugh C) should be treated with caution and monitored for treatment response [see CLINICAL PHARMACOLOGY (12.3)and DOSAGE AND ADMINISTRATION (2.2) in full Prescribing Information].OVERDOSAGENo specific information is available on the treatment of overdosage with tigecycline. Intravenous administration of TYGACIL at a single dose of 300 mg over 60 minutes in healthy volunteers resulted in an increased incidence of nausea and vomiting. In single-dose intravenous toxicity studies conducted with tigecycline in mice, the estimated median lethal dose (LD50) was 124 mg/kg in males and 98 mg/kg in females. In rats, the estimated LD50 was 106 mg/kg for both sexes. Tigecycline is not removed in significant quantities by hemodialysis.This Brief Summary is based on TYGACIL direction circular W10521C013 ET01, revised 09/09.

268774-01 © 2010 Pfizer Inc. All rights reserved. Printed in USA/August 2010

CODE: 268775-01 PUB/POST: Tygacil Single Page-A size PRODUCTION: R. Panariello LIVE: 7” x 10”

DESCRIPTION: Tygacil Single Page-A size Journal Ad TRIM: 7.75” x 10.5”

Delivery Support: 212.237.7000 FILE: 02A-001412-02B-268775-01.indd SAP #: PFZ.PFZTYG.10068.B.011 BLEED: 8.625” x 11.25”

TYGACIL is indicated for the treatment of adults with:Complicated skin and skin structure infections Escherichia coli, Enterococcus faecalis Staphylococcus aureus

Streptococcus agalactiae Streptococcus anginosus S. anginosus, S. intermedius S. constellatusStreptococcus pyogenes Enterobacter cloacae Klebsiella pneumoniae Bacteroides fragilisComplicated intra-abdominal infections Citrobacter freundii Enterobacter cloacae Escherichia coli Klebsiella oxytoca Klebsiella pneumoniae Enterococcusfaecalis Staphylococcus aureus Streptococcus anginosus S. anginosusS. intermedius S. constellatus Bacteroides fragilis Bacteroides thetaiotaomicron Bacteroides uniformis Bacteroides vulgatus Clostridium perfringensPeptostreptococcus microsCommunity-acquired bacterial pneumonia Streptococcus pneumoniaeHaemophilus infl uenzae Legionella pneumophila

Important Safety Information

An increase in all-cause mortality has been observed across phase 3 and 4 clinical studies in TYGACIL-treated patients versus comparator-treatedpatients. The cause of this increase has not been established. This increase in all-cause mortality should be considered when selecting amongtreatment options TYGACIL may cause fetal harm when administered to a pregnant woman The use of TYGACIL during tooth development may cause permanent discoloration of the teeth.

Clostridium diffi cile

Please see brief summary of Prescribing Information on adjacent page.References: 1.

Clin Infect Dis 2.Surg Infect 3. ®

*TYGACIL does not cover Pseudomonas aeruginosa.

Expanded broad-spectrumcoverage * is on your side

©

TYGACIL is in the 2009 IDSA/SIS guidelines forcIAI and the 2009 SIS guidelines for cSSSI.1,2

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