Abstract and Introduction

Abstract

Purpose of review: This review provides an update on the management of upper gastrointestinal bleeding with special attention to patient preparation, sedation, hemostatic techniques, and postprocedure care.
Recent findings: In a large multicenter clinical trial, nurse-administered propofol sedation had a complication rate of less than 0.2%. The optimal management for an ulcer with adherent clot was confirmed by a meta-analysis to be clot removal and endoscopic treatment of the underlying lesion. A number of prospective studies have demonstrated that capsule endoscopy is the most sensitive imaging modality for identifying lesions in the small bowel and that double-balloon enteroscopy is the least invasive modality available for the management of these lesions.
Summary: This update describes many recent advances in the diagnosis and management of upper gastrointestinal bleeding. However, clearly, much work needs to be done in this field. Since propofol is not available for use in all endoscopy units, is there a better alternative for deep sedation? Rebleeding occurs in 20% of patients after endoscopic therapy, and so can we provide better outcomes with newer technologies (endoscopic suturing devices)? Finally, what is the best management for Helicobacter pylori-negative, nonsteroidal antiinflammatory drug-negative ulcer patients?

Introduction

Acute upper gastrointestinal bleeding is one of the most common medical emergencies encountered, there being 250 000-300 000 hospitalizations annually.^[1] It is diagnosed clinically based on a clinical history of melena, hematemesis, or the presence of blood in a patient's nasogastric-tube lavage.^[2,3] In this review we will discuss guidelines for proper preparation, sedation, identification of bleeding source, hemostasis, and postprocedure care based on the latest data available in the literature.

Preparation

Proper resuscitation, determining the need for antibiotic prophylaxis, as well as assessing and correcting any potential coagulopathy, are crucial prior to any endoscopic intervention in patients with bleeding in the upper gastrointestinal tract.

Resuscitation

The importance of resuscitation in patients with upper gastrointestinal bleeding cannot be overemphasized. Baradarian et al.^[4] have shown that with adequate resuscitation, as defined by hemodynamic stability, there is a significant reduction in the incidence of postprocedure myocardial infarction (5/36 compared with 2/36; P < 0.04) and postprocedure mortality (4/36 compared with 1/36; P < 0.04) in patients with upper gastrointestinal bleeding. Since the method of resuscitation was not standardized, no recommendations can be made based on the results of the study.

Prophylaxis

Antibiotic prophylaxis is another key component in the preparation of this group of patients prior to endoscopic intervention. Studies have shown that patients with upper gastrointestinal bleeding, who undergo therapeutic procedures for hemostasis, are likely to develop transient bacteremia.^[5] The bacteremia is likely to remain harmless unless the patient has an underlying anatomical cardiac abnormality (valve disease, prosthetic valve, or history of endocarditis). Those patients with an underlying anatomical cardiac abnormality are considered at high risk since they are likely to seed these areas and develop endocarditis. Recommended antibiotic regimens are beyond the scope of this review but are nicely summarized in a review article by the American Heart Association.^[6]

Coagulopathy

Coagulation-factor and platelet-factor abnormalities should be assessed and corrected prior to endoscopy. In a retrospective review of postpolypectomy patients (n = 1657), coagulopathic patients were found to be at increased risk of postprocedure bleeding compared with their counterparts (odds ratio, 13.37; 95% confidence interval, 4.10-43.65).^[7] American Society for Gastrointestinal Endoscopy guidelines^[8] recommend the discontinuation of low-molecular-weight heparin 8 h before high-risk procedures, but no adjustments are required for low-risk procedures. For low-risk procedures, the antiplatelet regimen does not have to be altered, but for high-risk procedures, one can consider discontinuation of clopidogrel and ticlopidine 7-10 days before the procedure after weighing the risks and benefits on a case-by-case basis.^[8] According to these guidelines, aspirin, dipyridamole, and nonsteroidal antiinflammatory drug (NSAID) use does not seem to be associated with any such risk and would therefore not have to be discontinued before an endoscopic procedure. Applying this to our group of patients, who need urgent intervention, would seem to imply that patients on low-molecular-weight heparin and those on clopidogel or ticlopidine would need to receive appropriate transfusions with fresh frozen plasma or platelets, respectively, whereas those on aspirin, dipyridamole, or NSAIDs would not require any intervention.

Sedation

In most patients, an appropriate level of sedation can be reached through the use of a benzodiazepine combined with a narcotic.^[9] The benzodiazepine provides an amnesic effect while the narcotic provides an analgesic effect.^[10] Patients who receive monotherapy (benzodiazepine only) have more severe pain (28 compared with 9%; P < 0.001) and less procedure tolerance (18 compared with 5%; P < 0.01) than those who receive the combination.^[11] In older patients, and those with decreased pharyngeal sensation, less sedation may be needed.^[12] In younger patients and those who may have increased pharyngeal sensation, additional sedation may be needed. This can be done through the use of pharyngeal anesthesia in addition to the standard benzodiazepine/narcotic combination. A recently conducted meta-analysis demonstrated that more patients who feel minimal discomfort during an esophagogastroduodenoscopy had received pharyngeal anesthesia in addition to conventional sedation than those who had received conventional sedation alone (odds ratio, 1.88; 95% confidence interval, 1.13-3.12).^[13] In those patients chronically using narcotics, benzodiazepines, alcohol, or illicit drugs, 'deep sedation' may be needed.^[14] Deep sedation can be accomplished through general anesthesia or by adding another medication (droperidol, diphenhydramine, or propofol) to the benzodiazepine/narcotic combination described above,^[15,16] as follows. Droperidol is a neuroleptic agent, in the same class as haloperidol, with sedative effects that potentiate the actions of benzodiazepines and narcotics. Diphenhydramine is an antihistamine with a depressant effect on the central nervous system. In a double-blind randomized controlled trial, patients who were given an intravenous dose of diphenhydramine before receiving standard sedation required 10.1% less meperidine and 13.7% less midazolam. These patients also had statistically significant improvements in how they rated their pain and described their overall sedation.^[16] Propofol is an anesthetic agent approved for the induction and maintenance of general anesthesia.^[17] It is an ultra-short-acting hypnotic agent that provides amnesia, but only minimal levels of analgesia. Studies have shown that it interferes with cortical processes necessary for normal memory functions.^[18]

Of these three agents, propofol seems to be the agent of choice for safe deep sedation in most patients. In a national internet-based survey, routine use of propofol sedation for esophagogastroduodenoscopy was reported by 19-22% of practitioners. Community practitioners were more likely to use propofol than those at academic centers (P < 0.0002), and 43% of practitioners planned to incorporate it into their practice within the next year.^[19] This tendency seems to be supported by safety data. A review of the literature demonstrates that the incidence of hypoxia is 0.0-17.1%, with a mean value of 0.6% ( Table 1 ).^[20-28,29] In the largest of these studies, 36 743 patients underwent endoscopy with propofol administered by a gastrointestinal nurse at university hospitals in Indiana and Switzerland, and an ambulatory surgery center in Oregon. The overall event rate ranged from 0.09 to 0.19%.^[29] These values seem to be well within the range found in a comparable group of patients who underwent standard sedation, where the range of hypoxia was 0-17%, with a mean value of 6.5% ( Table 1 ).

Contraindications to the use of propofol include patients with an American Society of Anesthesia status of 3 or 4, patients with potentially difficult airway management, and patients at risk of aspiration, particularly those with upper gastrointestinal bleeding.^[30] Since patients with upper gastrointestinal bleeding have more than one contraindication to the use of propofol, they should undergo general anesthesia when they need deep sedation.

Identifying the Source of Bleeding

Although irrigation and suction are helpful in removing old blood and blood clots from the stomach, it is not unusual to have residual clots obscuring the endoscopic view and preventing proper identification of the source of bleeding. A number of interventions have been described to help remove these clots and improve endoscopic visibility. One such intervention is the use of intravenous erythromycin. In a prospective, randomized, double-blind trial, Frossard et al.^[31] demonstrated a clear stomach when intravenous erythromycin was administered in 42/51 (82%) of the patients compared to 18/54 (33%) in the placebo control group (P < 0.001). In another study, Coffin and coworkers^[32] showed that the use of intravenous erythromycin, by clearing the stomach and thereby improving the effectiveness of endoscopic hemostasis, significantly reduced the need for second-look endoscopy from 45.4% (10/22) in the placebo-treated group to 15.8% (3/19; P < 0.089) in the erythromycin-treated group. Another such intervention is the use of an endoscopic accessory device referred to as the irrigating hood.^[33] The irrigating hood is a device designed to be placed at the tip of the endoscope to allow forceful intragastric irrigation while maintaining an adequate intraluminal view of the bleeding site. Its use has been demonstrated to improve the endoscopic view and shorten procedure time.^[34]

Promoting Hemostasis

In this section, the optimal techniques currently available to promote hemostasis in patients with upper gastrointestinal bleeding are reviewed.

Promoting Hemostasis in Peptic Ulcer Disease

Patients with bleeding of the upper gastrointestinal tract caused by peptic ulcer disease can present in one of three ways: they can present with a clean-based ulcer, they can present with a visible vessel or an active arterial bleeder protruding from an ulcer, or they can present with an ulcer with an adherent clot.^[35]

Patients with clean-based ulcers need no intervention. In fact, in some studies, they can be treated as outpatients.^[35]

Patients with a nonbleeding visible vessel or an active arterial bleed will benefit from hemostatic intervention.^[36] This can be achieved through the use of injection therapy in conjunction with heat therapy or hemoclipping. A number of studies have demonstrated that these two types of combination therapy are superior to monotherapy. In a well designed, randomized, prospective clinical trial by Chung et al.,^[37] combination therapy (epinephrine injection followed by heat-probe therapy) significantly reduced the need for emergency surgery in patients bleeding from peptic ulcer disease compared to monotherapy (epinephrine injection alone) from 8/27 (29.6%) to 2/31 (6.5%). In another trial by Lo et al.,^[38] combination therapy (epinephrine injection followed by hemoclipping) reduced the rebleeding rate compared with monotherapy (epinephrine injection alone) from 21 to 3.8% (P = 0.008), with a reduction in the need for emergency surgery from 9 to 0% (P = 0.023). These findings have been further confirmed in a recent meta-analysis, involving 16 trials with 1673 patients, where the rebleeding rate decreased from 18.4 to 10.6% (odds ratio, 0.53; 95% confidence interval, 0.40-0.69).^[39] However, it is not clear whether hemoclips are better than heat therapy. In fact, in the meta-analysis, the decrease in rebleeding rate seemed to be similar whether the second intervention was heat therapy or hemoclipping, suggesting that the two interventions may be equivalent.^[39] Therefore, until more data are available, one has to assume that the two techniques are equivalent and that the best approach for any one situation should be guided by the location of the vessels and the expertise of the endoscopist.^[40]

Patients with ulcers who have an adherent clot should also be treated endoscopically. The best approach is to first remove the clot and then treat based on what lies beneath. This approach is supported by a number of well designed, randomized, placebo-controlled trials which have demonstrated that clot removal, followed by endoscopic therapy, can reduce the rate of recurrent bleeding from a range of 27.5-35.5% to a range of 0-8.7% when compared with the medically treated placebo control group ( Table 2 ).^[41-43]

This has been further supported by a meta-analysis of six studies, which included 240 patients from the USA, Hong Kong, South Korea, and Spain.^[44] In this study, patients in the endoscopic therapy group, who underwent clot removal followed by treatment of the underlying lesion with heat therapy and/or injection of sclerosants, had a statistically significant reduction in the rebleeding rate from 24.7 to 8.2% (P = 0.01) for a pooled relative risk of 0.35 (95% confidence interval, 0.14-0.83). Furthermore, patients in the endoscopic therapy group were less likely to undergo surgery with a pooled relative risk of 0.43 (95% confidence interval, 0.19-0.98).^[44] For best results, the recommended clot-removal technique and hemostasis is as follows:^[41,45] (1) injection at the base of the clot with a saline/epinephrine solution to promote hemostasis, (2) clot removal by suction or the guillotine technique, and (3) heat or hemoclip therapy applied to any underlying stigmata of bleeding until a footprint is formed.

Promoting Hemostasis in Gastric Varices

The first-line therapy for active bleeding from isolated gastric varices is endoscopic obliteration through banding and/or sclerotherapy.^[46,47] Although studies demonstrate good initial hemostasis in 82.9-90% of patients, long-term results have been suboptimal, with a high recurrent rate of bleeding.^[46] Second-line therapy relies on interventional radiology through transhepatic intravascular portosystemic shunting (TIPS).^[46,47] Unfortunately, it too is associated with a number of serious long-term side effects, including re-stenosis, rebleeding, and hepatic encephalopathy.

Over the past few years, endoscopic injection of tissue-adhesive agents has been shown to be very effective. Of these, the most successful has been N-butyl-cyanoacrylate (Histoacryl; B. Braun, Melsungen, Germany).^[48,49] Therefore, where available, these agents are rapidly becoming the first-line therapy for patients with gastric variceal bleeding. However, Histoacryl-injection therapy has been associated with pyrexia, bacteremia, embolization, and instrument malfunction (occlusion of the endoscope, sticking of the needle to a varix and obstruction of the injection catheter).^[50,51]

Approach in Patients With Unclear Source of Upper-gastrointestinal-Tract Bleeding

If a good view of the upper gastrointestinal tract is obtained during endoscopy, but no clear source of bleeding is identified in patients suspected of having an upper gastrointestinal source, the rest of the small bowel should be examined through an imaging study.^[52] This can be performed endoscopically (capsule endoscopy or push enteroscopy) or radiographically (small-bowel follow-through).^[52,53] Of these imaging tests, capsule endoscopy seems to be the method of choice. This has been confirmed in a number of prospective studies over the past few years ( Table 3 ) [54-62]. In a recent meta-analysis, capsule endoscopy had a significantly higher diagnostic yield than push enteroscopy (63 compared with 28%; P < 0.00001) and barium radiography (67 compared with 8%; P < 0.00001) in identifying the source of bleeding.^[63] The yield can be improved through the use of metoclopramide^[64] to accelerate bowel transit time and the use of a bowel preparation^[65] to both accelerate bowel transit time and improve visibility. Erythromycin did not seem to be as helpful.^[66]

When a small-bowel lesion is identified, double-balloon enteroscopy can be used to achieve hemostasis.^[67] Double-balloon enteroscopy is a new endoscopic technique that allows the endoscopist to reach any part of the small bowel to treat lesions.^[68]

Postprocedure Care

To improve outcome, proper postprocedure care and surveillance are needed. This aspect of patient management involves proper disposition, close observation, second-look endoscopy if needed, and proper pharmacologic therapy to potentiate the benefits of hemostasis.

Proper Disposition

Once hemostasis is established, high-risk patients need to be closely observed for signs of rebleeding. On the other hand, low-risk patients with a clean base or a flat spot can be safely discharged.

Over the years, a number of systems of multivariate analysis have been used to stratify patients into high and low categories for rebleeding risk. The most clinically useful of these seems to be the Rockall score.^[69] This score allocates points to each patient based on a number of parameters that are thought to be potential predictors of rebleeding risk. These include: age, shock, co-morbidities, etiology of the bleeding and endoscopic stigmata. A high point score (>8) indicates that the patient is at increased risk of rebleeding and requires close monitoring. A low point score (<7) indicates that the patient can be safely discharged with outpatient follow-up. The validity of the system was recently confirmed in a prospective cohort study.^[70] As expected, the rates of recurrent bleeding and mortality after endoscopic therapy increased with an increasing Rockall score. However, although the Rockall scoring system was useful in identifying high mortality rates (area under the receiver-operating-characteristic curve, 84.3%), it was inadequate in identifying risk for recurrent bleeding (area under the receiver-operating-characteristic curve, 63.4%).^[70] Nevertheless, it remains the most clinically useful way to stratify patients into high-risk and low-risk categories for the purpose of postprocedure care and management. Those deemed to be at high risk should be admitted to a critical-care unit for close monitoring, whereas those deemed to be at low risk can be considered for discharge.

Recently, a subgroup of patients with a nonbleeding visible vessel who may be at low risk for recurrent bleeding and death has been identified for potential early discharge from the hospital. This includes patients with an ulcer size of less than 15 mm, absence of hypovolemia, no associated severe disease, and appropriate family support.^[71] Although this approach was associated with a statistically significant decrease in cost of care per patient ($970 compared with $1595; P < 0.001), it is not standard of care and requires confirmation.

Proper Pharmacologic Therapy in Peptic Ulcer Disease

In patients with upper gastrointestinal bleeding caused by peptic ulcer disease, intravenous proton-pump-inhibitor therapy seems to be beneficial. Following successful endoscopic hemostasis, Lau et al.^[72] demonstrated that the use of intravenous omeprazole 40 mg every 12 h (Losec; Astra, Molndal, Sweden) reduced the rebleeding rate from 22.5% (27/120) to 6.7% (8/120).^[72] Increasing the frequency to every 6 h seems to provide even better protection. In a recent study by Lin et al.,^[73] this increase in frequency seemed to decrease the volume of blood transfusion needed, as well as the rebleeding rate when compared to the 12-h dose, or the use of intravenous cimetidine 400 mg every 12 h.

After 3 days of intravenous omeprazole treatment, the patient can be switched to daily 20 mg by mouth for 8 weeks.^[72] Therapy can be stopped after 8 weeks unless the patient has an associated Helicobacter pylori infection, is maintained on low-dose aspirin, or uses a nonselective NSAID. Patients with H. pylori infection are at higher risk of rebleeding and should receive a 14-day course of antibiotics in addition to proton-pump inhibitors.^[74,75] Patients taking low-dose aspirin or nonselective NSAIDs are at high risk from the development of recurrent ulcers and should receive proton-pump-inhibitor maintenance therapy.^[76,77] Patients who are H. pylori-negative, NSAID-negative, and have an idiopathic bleeding ulcer may not require any further therapy after the 8-week course of therapy is completed. However, recent studies indicate that this group of patients is at a statistically significant higher risk of complications at 12 months (13.4%) compared with H. pylori-positive ulcer patients who received eradication therapy (2.5%; P = 0.0002).^[78] Clearly, the best approach to this group of patients has yet to be determined.

Pharmacologic Therapy in Gastric Varices

In patients with upper gastrointestinal bleeding caused by gastric varices, the role of pharmacologic therapy is not clear since it has not been well studied.^[79] However, since gastric varices develop and bleed as a result of portal hypertension in a manner analogous to esophageal varices, until further data becomes available it is reasonable to assume that they would respond to the same type of pharmacologic therapy.^[80] Therefore, once hemostasis is achieved in patients bleeding from gastric varices, one should consider initiating intravenous octreotide therapy acutely until stable, followed by nonselective β-blocker therapy.^[81]

Future Directions

Although progress continues to be made in the management of patients with upper gastrointestinal bleeding, the results are still suboptimal.^[82] Two areas in the field that can benefit from improvement are our diagnostic capabilities and our therapeutic modalities.

Improved Diagnostic Capabilities

In spite of the improved capacity to identify mucosal bleeding sites in patients with upper gastrointestinal bleeding, initial hemostasis is not always successful for ulcers or varices, with failure rates up to 20%.^[82] Identifying feeding vessels and collaterals by endoscopic ultrasound may be a more fruitful approach for these recurrent bleeds.^[83,84] In a randomized controlled trial, sclerotherapy of collaterals, using endoscopic ultrasound guidance, seemed to decrease the recurrence of esophageal varices from 16.7 to 8.3% (P = 0.32).^[85] However, this approach awaits further confirmation before it can be recommended for routine use.

Another diagnostic problem, in patients with bleeding peptic ulcers, is the early identification of H. pylori infection. Histology seems to be the best method, yet obtaining a biopsy is not often done during an acute bleeding episode. One technology that may offer an answer is confocal laser endomicroscopy. This is a new technology that utilizes a powerful magnifying endoscope to look for H. pylori in vivo on a microscopic level.^[86] The practicality of this approach, however, has yet to be tested for routine use.

Improved Therapeutic Capabilities

Large bleeding vessels in the duodenal bulb, greater than 2 mm in size, cannot be reliably treated endoscopically. A number of stitching devices have been developed that may change this, including the Eagle Claw VII and the Cobra.^[87] As these devices become more flexible, they could expand the role of endoscopic intervention in this group of patients, obviating the need for salvage surgery which carries a mortality rate of approximately 25%.

Conclusion

Giant strides continue to be made in the management and care of patients bleeding from their upper gastrointestinal tract. Nevertheless, recurrent bleeding rates are still at times as high as 20%, with significant morbidity and mortality.^[82] Adopting new technologies (endoscopic ultrasound, confocal laser endomicroscopy and endoscopic suturing devices) may be helpful but will be insufficient in conquering this challenging problem. We must continue to keep our minds open to new possibilities and new approaches.

NSAID = nonsteroidal antiinflammatory drug

Wahid Wassef, MD, FACG, Division of Gastroenterology, University of Massachusetts Medical Center, University Campus, 55 Lake Avenue, North, Worcester, MA 01655, USA Tel: +1 508 856 3069; fax: +1 508 856 3981; e-mail: wassefw@ummhc.org