In contrast to variceal hemorrhage, nonvariceal hemorrhage presents a favorable prognosis. The improved outcome can be attributed to a greater than 90% spontaneous cessation rate of bleeding and to the absence of a predisposition to multiorgan dysfunction that exists in decompensated cirrhosis. As outlined in Table 82-1, multiple studies pertaining to nonvariceal hemorrhage have identified clinical and endoscopic indicators that increase the risk for continued or recurrent bleeding, and therefore predict an adverse prognosis. The remaining mortality rate of 10% is largely due to rebleeding in patients with these factors. The important role of early therapeutic upper endoscopy in achieving hemostasis, reducing rebleeding, and improving short-term morbidity and mortality has been established10,11 and reiterated in a recent consensus statement addressing the management of nonvariceal bleeding.11a Furthermore, with regard to peptic ulcer disease, endoscopic characterization of high-risk ulcer lesions has led to the development of specific endoscopic therapies that have improved hemostatic efficacy and outcome compared with prior medical therapy.35
The evaluation and management of nonvariceal hemorrhage are outlined in Fig. 82-3. Following initial hemodynamic, pulmonary, and hematologic management, early upper endoscopic evaluation with therapeutic intent should be conducted. Emergent endoscopy should be pursued in the setting of hemodynamic instability that is refractory to fluid resuscitation. Acid-suppression therapy has demonstrated short-term efficacy only after endoscopic hemostasis has been achieved17,18 and therefore should be used as an adjunct to endoscopy. Since peptic ulcer disease accounts for the majority of nonvariceal bleeds and has been the focus of therapeutic developments, the different treatment modalities will be discussed in this context. The management of some nonulcer lesions, including stress-related mucosal damage (SRMD), will follow.
Peptic Ulcer Disease (PUD)
Progress in endoscopic diagnosis and therapy has been due largely to major improvements in endoscopic techniques and equipment. A number of hemostatic endoscopic methods have been developed,36 but the two used most commonly in the United States are contact thermal devices and injection therapy with epinephrine.
Thermal therapy is designed to produce coagulation and dehydration in the ulcer base surrounding the bleeding vessel, and this results in constriction and destruction of the submucosal feeding vessels supplying the surface artery. The two types of thermal therapy that have gained popularity are the bipolar probe and the heater probe. Bipolar probes heat contacted tissue by passing electricity via tissue water between positive and negative electrodes located at the tip of the probe. Once the contact tissue is fully desiccated, electrical conduction ceases, and deeper tissue coagulation is restricted. On the other hand, the heater probe uses a thermocouple at the end of the probe to generate heat, and this process does not depend on tissue water. Therefore, deeper tissue coagulation is achievable despite desiccation, although this increases the risk of perforation.
Injection therapy is aimed at causing vasoconstriction and necrosis of the bleeding vessel and surrounding tissue. Injection with epinephrine (1:10,000 dilution in saline) or absolute alcohol has been shown to be effective in achieving acute hemostasis.37 While epinephrine exerts a vasoconstrictive effect on the vessel, pure ethanol causes dehydration, contraction, and necrosis of the vessel and surrounding tissue. It should be noted that the rebleeding rate is high if epinephrine injection therapy is performed in isolation, and therefore, it should be combined with thermal coagulation therapy. The technique used in injection therapy involves the injection of the agent via an injector catheter in four quadrants within 2 to 3 mm of the active bleeding point in the ulcer base. While the volume of total epinephrine administered can range from 5 to 10 mL, the total volume of ethanol should not exceed 1 mL because extensive ulceration may occur.
Endoscopic Evaluation and Treatment in Pud
As outlined in Fig. 82-3, the endoscopic management of PUD is guided by the characteristics of the ulcer, which defines the lesion as exhibiting “major” or “minor” stigmata of ulcer hemorrhage. The major stigmata consist of (1) active bleeding, (2) a visible, nonbleeding vessel, and (3) an adherent clot, and these three lesions are associated with a high risk of rebleeding and therefore increased short-term mortality. The stigmata associated with a low risk of rebleeding include (1) a clean base and (2) a flat/pigmented spot, and these lesions have a favorable prognosis. Specific endoscopic treatment guidelines have been developed by the ASGE for each of these lesions14 based on multiple studies addressing the response of these lesions to thermal and injection therapy. These guidelines and subsequent studies have led to the following endoscopic treatment recommendations: (1) combination therapy with injection and thermal coagulation is superior to monotherapy either in active bleeding38,39 (Fig. 82-4) or for an adherent clot,40 (2) monotherapy with thermal coagulation is indicated for a nonbleeding visible vessel, and (3) no endoscopic therapy is required for low-risk lesions, which include a clean base and a flat/pigmented spot.
A. Bleeding gastric ulcer prior to therapy. B. Successful hemostasis following thermal and injection therapy.
In anticipation of initiating secondary prophylaxis for PUD, the visualization of a duodenal or gastric ulcer should prompt the endoscopist to obtain a gastric antral mucosal biopsy to test for Helicobacter pylori. The gastric biopsy may be difficult to perform during the acute phase of the bleeding, and the presence of blood or antiulcer medications may interfere with a biopsy urease test. In the absence of a gastric biopsy, a venous blood sample should be tested for H. pylori serology, or stool or breath testing should be performed. Furthermore, a negative gastric antral mucosal biopsy should be confirmed with a serologic test, especially if antiulcer therapy has been initiated prior to the biopsy.
While intravenous histamine receptor antagonists (H2RAs) are used commonly in the initial management of PUD bleeding, there is no evidence that this intervention improves short-term outcomes, such as rebleeding rates or transfusion requirements.41 The concept that more profound acid suppression with proton pump inhibitors (PPIs) will improve short-term outcomes has been investigated, and most studies have shown short-term efficacy of PPIs when administered after successful endoscopic hemostasis.42,43 Therefore, acid-suppressive therapy in the form of PPIs should be administered as an adjunct to endoscopic therapy and should not be used in lieu of an endoscopic evaluation. Studies comparing intravenous and oral PPI therapy are awaited; however, intravenous PPI therapy may ensure improved bioavailability in the setting of a bleeding gastrointestinal tract. The improved hemostatic efficacy of PPI over H2RA therapy may be due to the superior ability of PPI therapy to maintain a gastric pH above 6.0 and therefore protect an ulcer clot from fibrinolysis.44
Several studies have evaluated the efficacy of the splanchnic vasoconstrictors somatostatin and octreotide in the treatment of acute nonvariceal hemorrhage. A meta-analysis of these studies suggests that somatostatin and octreotide are associated with a reduced risk of continued bleeding and rebleeding in PUD.45 Therefore, in addition to acid-suppressive therapy, these agents also may be considered as pharmacologic adjuncts to endoscopic therapy.
In most cases of nonvariceal hemorrhage, endoscopic evaluation is able to visualize the bleeding lesion and deliver effective hemostatic therapy. However, in a minority of patients, the bleeding source is not visualized by endoscopy, thereby necessitating angiographic localization. Also, angiography offers the option of hemostatic therapy using arterial vasoconstrictors or embolization; however, this generally is reserved for patients who are poor surgical candidates or for the control of bleeding in an unstable patient awaiting surgery.
As mentioned previously, angiography can successfully localize brisk UGI bleeding (rate >0.5 mL/min) in 75% of cases,46 with most bleeding episodes (85%) originating from a branch of the left gastric artery. The right gastric and short gastric arteries account for the remainder of the sources.
UGI arterial bleeding can be controlled by the selective arterial infusion of vasoconstrictors such as vasopressin or embolization of particulate matter. Most studies indicate that selective intraarterial vasopressin is more effective than a peripheral intravenous infusion in achieving hemostasis.47 Since the vasoconstrictive action of vasopressin is more pronounced on terminal blood vessels such as arterioles, venules, and capillaries, this therapy is more effective in controlling bleeding from such vessels, as in diffuse hemorrhagic gastritis, rather than a duodenal ulcer bleed originating from a large gastroduodenal artery. In the setting of gastric bleeding, therapy appears to be equally effective when administered via the left gastric or celiac artery.48A usual therapeutic vasopressin dose is 0.2 unit/min, with a recommended maximum dose of 0.4 unit/min. If hemostasis is achieved, the infusion is continued in the ICU for 24 to 36 hours and then tapered over 24 hours. Rebleeding after cessation of the infusion is a concern48 and can be treated with repeat vasopressin treatment or embolization.
Embolization therapy uses various substances, most frequently a gelatin sponge (Gelfoam), to selectively embolize the bleeding vessel. Since this technique carries the risk of causing bowel wall ischemia and infarction due to nonspecific embolization, a target vessel must be accessible for selective catheterization of the bleeding site. Necrosis of the stomach, duodenum, gallbladder, liver, and spleen has been documented following nonspecific embolotherapy. Since the duodenum has a dual blood supply from the celiac artery and the superior mesenteric artery, spontaneous infarction of the duodenum is rare. The patient with advanced atherosclerotic vascular disease or with prior gastric surgery involving ligation of collateral vessels is at greater risk of infarction due to a compromised collateral circulation. In view of the higher morbidity associated with embolization therapy, it should be used only after unsuccessful intraarterial vasopressin therapy. Furthermore, embolization therapy should not be followed immediately by vasopressin therapy because this may compromise the collateral circulation, resulting in tissue infarction.
Surgical intervention for bleeding peptic ulcers should be considered in two situations. First, surgery is used to control life-threatening hemorrhage that is refractory to medical and endoscopic intervention. In fact, in patients who have a low operative risk and who have been stabilized effectively to allow surgery, angiographic therapy should not be attempted. Second, surgery should be considered in the patient in whom medical management has failed to heal or prevent recurrence of peptic ulceration, particularly if there have been previous complications attributable to PUD, such as bleeding. The patient who has recurrent hemorrhage owing to noncompliance with maintenance ulcer therapy should be considered for elective surgical therapy once bleeding has stopped. It should be emphasized that surgical morbidity and mortality are greatly reduced when the surgeon operates electively in the nonbleeding patient. Therefore, successful initial hemostasis using endoscopic and pharmacologic therapy is preferable prior to surgical intervention. In the setting of hemorrhage refractory to nonsurgical intervention, stabilization of cardiopulmonary status and optimization of hematologic parameters prepares the patient for emergent surgery and improves postoperative outcome.
The choice of surgical procedure depends on the location of the ulcer and on the stability of the patient. In the patient with an actively bleeding duodenal ulcer undergoing an emergent operation, the bleeding point of the ulcer will be oversewn and truncal vagotomy and pyloroplasty performed. Vagotomy and antrectomy may be considered if the patient has been stabilized adequately. In the setting of exsanguinating hemorrhage, gastric resection may be considered, but this procedure carries a high mortality of approximately 50%.49 Selective vagotomy with either pyloroplasty or antrectomy, an option in the elective situation, is not advisable in an unstable patient.
Gastric ulcer bleeding is treated with the same approach as a bleeding duodenal ulcer, except that resection is recommended if the situation permits. Partial gastrectomy carries a slightly lower mortality in the setting of gastric ulcer bleeding than when performed for a bleeding duodenal ulcer.50 Resection for an actively bleeding gastric carcinoma is recommended only when performed electively because it is a prolonged procedure that may be unsuitable for an unstable patient.
Following surgical intervention for bleeding peptic ulcers, mortality approaches 30%, with postoperative wound infection being the major complication.
Once successful hemostasis is achieved, secondary prophylaxis is initiated to prevent recurrent ulcer bleeding, especially following nonsurgical hemostatic therapy. If histologic or nonhistologic evaluation for H. pylori is positive, appropriate treatment should be initiated because this reduces the long-term (1-year) rate of rebleeding from gastric or duodenal ulcers.51 In addition, long-term acid suppressive therapy with oral H2RAs or PPIs is indicated, and nonsteroidal anti-inflammatory drugs (NSAIDs) should be avoided.
Mallory-Weiss tear generally is a self-limited cause of nonvariceal bleeding, rarely requiring more than supportive intervention. However, patients with portal hypertension are at increased risk of massive bleeding from Mallory-Weiss tears compared with those with normal portal pressures.52 In the rare instance of continued bleeding from a Mallory-Weiss tear in a patient without portal hypertension, endoscopic therapy with either thermal coagulation or injection therapy should be attempted prior to surgical oversewing of the lesion. In the presence of portal hypertension, thermal coagulation may worsen the bleeding; therefore, band ligation or sclerotherapy should be performed. Following hemostasis, acid-suppression therapy with H2RAs or PPIs may be given as adjunctive therapy to accelerate healing.
A Dieulafoy's lesion is a dilated aberrant submucosal vessel of unclear etiology that erodes the overlying epithelium in the absence of a primary ulcer. It is usually located along the high lesser curvature of the stomach near the gastroesophageal junction, although it has been found in all areas of the GI tract, including the esophagus and duodenum. Massive bleeding can occur when the eroding submucosal vessel is an artery. The endoscopic treatment of choice is a combination of epinephrine injection therapy and thermal coagulation.53 Also, endoscopic band ligation has been used successfully to achieve hemostasis in bleeding Dieulafoy's lesions.54 The risk of rebleeding after endoscopic therapy remains high (up to 40% in some reports) owing to the usually large size of the underlying artery. In the event of rebleeding, repeat endoscopic intervention may be attempted, following which surgical wedge resection of the lesion should be performed to achieve permanent hemostasis.
Stress-Related Mucosal Damage (SRMD)
SRMD, also referred to as stress ulcers or stress-related erosive syndrome (SRES), is the result of multiple-organ-system failure in the critically ill patient. The incidence of hemorrhage due to SRMD appears to be decreasing, probably as a result of significant advances in the intensive care management of the critically ill patient, including optimization of hemodynamic status and tissue oxygenation,55 and the early initiation of stress ulcer prophylaxis. However, in the event of SRMD-induced hemorrhage, the mortality rate is greater than 30% owing to the difficulty in controlling such bleeding and the poor prognosis of the underlying disease. With regard to etiology, gastric mucosal ischemia secondary to systemic (and splanchnic) hypoperfusion is considered to be the major inciting factor, with acid and pepsin assuming minor roles. Of note, acid and pepsin secretion are normal to low in most critically ill patients, and increased gastric acidity is observed only in patients exhibiting Cushing's ulcers related to central nervous system (CNS) trauma or infection.
Bleeding from SRMD may be overt and significant, resulting in hemorrhage and hemodynamic compromise, or occult and minimal, detectable only by Gastroccult testing of the gastric contents. Although occult bleeding due to SRMD may occur frequently in critically ill patients, it is of little clinical significance because few of these patients progress to overt bleeding. Multiple studies have attempted to assess the relative importance of the underlying disease processes and biochemical abnormalities in inducing SRMD.56,57 Two major risk factors identified are coagulopathy and mechanical ventilation for greater than 48 hours.56 Other suggested risk factors include sepsis, hypotensive shock, acidosis, peritonitis, extensive burns, hepatic failure, and renal failure, with multiple risk factors having an additive effect on the probability of SRMD.
Endoscopically, SRMD may appear as multiple shallow erosions or submucosal hemorrhage during the early stages. After the first several days of the ICU course, SRMD lesions are characterized by multiple, deeper, acute ulcerations, predominantly in the gastric lesser curvature or fundus, and these lesions can erode into the submucosa, causing massive hemorrhage. Bleeding usually manifests as oozing of blood from the margins of these lesions. However, submucosal penetration can cause hemorrhage from a major artery, with the typical endoscopic appearance of an ulcer with a visible vessel.
The mainstay of therapy for SRMD is supportive, with an attempt to reverse the underlying precipitating factors. Acid suppression in the form of intravenous H2RAs or PPIs may be used as adjunctive therapy to endoscopic or angiographic intervention. The role of endoscopic therapy in SRMD may be limited because the lesions usually are diffuse and not amenable to directed therapy. However, in the setting of a single dominant lesion or a few bleeding lesions, endoscopic therapy may achieve successful hemostasis in 90% of such cases.58 Therapeutic angiography is recommended for bleeding that is refractory to endoscopic therapy. Both intraarterial vasopressin therapy59 and embolotherapy60 are equally successful at controlling hemorrhage without major ischemic complications owing to the rich collateral blood supply of the gastric mucosa. Since the left gastric artery is the source in most cases of SRMD-induced bleeding, this vessel is a convenient target for embolization therapy.
Surgery usually should be avoided because a near-total gastrectomy is required in most instances, and mortality exceeds 50%. Gastrectomy should be undertaken only when massive hemorrhage persists despite nonsurgical therapy in a viable patient with treatable medical problems.
Since hemorrhage from SRMD presents a therapeutic challenge and carries a high mortality, much attention has been given to prophylactic therapy. Despite the existence of SRMD in the setting of low or normal acid secretion, prophylaxis has been directed toward acid suppression or neutralization. The superior efficacy of intravenous H2RAs compared with sucralfate in preventing SRMD has been demonstrated,61and therefore, H2RAs are preferred. Furthermore, prior concerns regarding the increased incidence of nosocomial pneumonia with acid-suppressive therapy has not been observed in subsequent studies. More recently, oral and intravenous PPIs have been added to the regimen of acid-suppressive therapy in the ICU and should assume increasing importance in the prophylaxis of SRMD.
In addition to pharmacologic therapy, adequate nutritional support and, in particular, enteral nutrition have been shown to decrease the incidence of SRMD.62,63 The prophylactic effect of enteral nutrition is not mediated by an increase in gastric pH and instead may involve an increase in gastric epithelial energy stores, which, in turn, maintain epithelial integrity and prevent necrosis and ulceration. Therefore, the initiation of adequate nutrition support in the critically ill patient, preferably via the enteral route, may play a prophylactic role against SRMD. In the absence of a functional gastrointestinal tract, total parenteral nutrition (TPN), which has demonstrated a protective effect against SRMD, can be considered, although the net effect may be harmful62 (see Chap. 11).