Acute non-variceal upper gastrointestinal bleeding: Changes and advances over the past years

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ACHAIKI IATRIKI | 2024; 43(1):39–47

Review

Christos Sotiropoulos, Christos Konstantakis, Odysseas Ampazis, Georgia Diamantopoulou, Georgios Theocharis, Konstantinos Thomopoulos

Division of Gastroenterology, Department of Internal Medicine, University Hospital of Patras, Patras, Greece

Received: 27 Aug 2023; Accepted: 13 Dec 2023

Corresponding author: Christos Sotiropoulos, Resident Gastroenterologist, 55, Kosti Palama Str., 26442, Patras, Greece, Tel.: +30 6944231906, E-mail: cr.sotiropoulos@hotmail.com

Key words: Acute non-variceal upper gastrointestinal bleeding, (ANVUGIB), peptic ulcer, proton pump inhibitors (PPIs), endoscopy, hemostasis

 

Abstract

Acute non-variceal upper gastrointestinal bleeding (ANVUGIB) is an emergent situation, with significant morbidity and mortality. The initial approach to the patient’s resuscitation includes intravenous fluids and red blood cell transfusions where needed, followed by proton pump inhibitors (PPIs) administration. Esophagogastroscopy should be performed within 24 hours from admission, while earlier endoscopy could be considered in patients at high risk, such as hemodynamically unstable patients. Endoscopic intervention is indicated for high risk non-variceal bleeding (active bleeding, non-bleeding visible vessel). The current article reviews up-to-date strategies for patient’s risk stratification, initial management, causes of ANVUGIB, timing of endoscopy, role of proton pump inhibitors and antithrombotic agents.

INTRODUCTION AND EPIDEMIOLOGY

Acute non-variceal upper gastrointestinal bleeding (ANVUGIB), despite advances in diagnosis and management, remains a life-threatening emergency with considerable morbidity and mortality [1]. The incidence of acute upper gastrointestinal bleeding is approximately 100 cases per 100,000 inhabitants and appears to be decreasing in recent years, due to the reduction in the incidence of peptic ulcer bleeding [2].

Although, peptic ulcer (figure 1a-b) remains the most common cause of acute upper gastrointestinal bleeding its incidence has decreased [2]. In general, the prevalence of Helicobacter pylori (H. pylori) infection has been declining and due to successful eradication regimens, thus, H. pylori related peptic ulcer disease is less frequent today [3]. In addition, prophylactic co-administration of proton pump inhibitors (PPIs) to users of aspirin and/or nonsteroidal anti-inflammatory drugs (NSAIDs) and/or use of selective COX-2 inhibitors, in some cases, have led to the reduction in the incidence of peptic ulcer related bleeding [4].

On the other hand, other causes are being increasingly encountered like esophagitis, neoplasms, angiodysplasias, Dieulafoy’s lesions etc. [5] (figure 1c-f). This increase is mainly due to the increased use of antithrombotic medication of the elderly population that causes acute bleeding from a pre-existing non-bleeding lesion [5]. Nowadays, there is evidence that bleeding episodes are less severe, but the patients are more frail and older with more comorbidities [6].

Figure 1. Causes of ANVUGIB. 1A, 1B: Peptic ulcer, 1C: Esophagitis, 1D: Dieulafoy’s lesion, 1E: Angiodysplasias, 1F: Neoplasm.
Source: Personal records.

In more than 80% of the cases, bleeding is self-limiting, while in less than 20% we have continued or recurrent bleeding (95% of recurrences occur in the first three days from the onset of bleeding) [7]. With advances in endoscopic treatment, less than 3% of patients will require emergency surgical hemostasis [7]. Shock on admission, low admission hemoglobin levels, active spurting bleeding on endoscopy, ulcers of the posterior-lower wall of the duodenum and large ulcers are associated with an increased probability of recurrence of bleeding in patients with ANVUGIB [8].

Despite advances in the diagnostic and therapeutic field, mortality has not been considerably reduced and remains static, at around 5%, in recent years [9]. Mortality is mainly attributed to the accompanying diseases that are common in these patients and not to the blood extravasation itself, which is being treated [10]. Less than 20% of deaths are directly associated with massive blood loss [10]. There is also evidence that weekend admission is associated with a significant increase in mortality in patients with ANVUGIB, emphasizing the importance of careful management of these patients, regarding not only endoscopy but also supportive care [11].

   Today, patients with ANVUGIB are older (average age 65-70 years) and the increased incidence of bleeding is mainly due to the increased use of antithrombotic agents and/or NSAIDs [5]. More than 75% of the patients have some co-morbidity, with cardiovascular disease being the predominant one, while over 50% of the patients receive some antithrombotic treatment or combinations and this percentage is constantly increasing [6].

It is important to emphasize that patients hospitalized with ANVUGIB have a substantial 30-day readmission rate following discharge and this is mainly not due to recurrent bleeding but due to other causes, mainly metastatic cancer or cardiovascular disease [12, 13].

Initial management – Principles of treating a patient with upper gastrointestinal bleeding

Clinical assessment of the severity of bleeding and blood loss, placement of wide bore intravenous access and resuscitation remain the cornerstone of management, regardless of the cause of bleeding [14]. After the stabilization of the patient, an endoscopy should be performed which provides diagnosis, treatment, and prognosis [14]. In patients with persisting hypotension, despite fluid resuscitation, intensive care is necessary [14].

Placing a nasogastric catheter (levin) in upper gastrointestinal bleeding for suction and lavage has no significant benefit and is not currently recommended [14]. Differential diagnosis of bleeding between upper and lower digestive tract is mandatory and should be done based on the clinical presentation [14]. Elevated blood urea with normal creatinine is a helpful factor, because it increases in upper gastrointestinal bleeding, as the protein components of the blood are absorbed in the small intestine and metabolized in the liver to create urea but are lost in colonic bleeding [14].  

Risk assessment

As the majority of patients will not develop rebleeding or complications, it is important to stratify patients with ANVUGIB into low or high risk for rebleeding, need for intervention and death, even on admission [15-17]. Various risk assessment scores have been developed and validated, both on admission and before endoscopy (including clinical and laboratory parameters) and later after endoscopy (incorporating also endoscopic findings), like Rockall score, AIMS65 and Glasgow-Blatchford score [15-17]. Pre-endoscopy risk scoring would also enable patients who are at very low risk to avoid admission to hospital (or be discharged earlier) [15-17].

In an international multicenter study these scores have been compared prospectively in 3012 patients [18]. Glasgow-Blatchford score was found more accurate in predicting, in general, need for any hospital-based intervention or death at 30-days in all countries, with a score 0 or 1 being the optimum threshold for identification of patients at low risk and suitable for outpatient management [18]. However, no score had significant predictive value for any separate outcome, including need for endoscopic treatment, rebleeding and mortality; therefore, their clinical utility to direct management of high-risk patients seems limited [18]. Moreover, less than 19% of patients have Glasgow-Blatchford score ≤1, so the majority of patients should be closely monitored in the first days [18].

Based on the available evidence European Society of Gastrointestinal Endoscopy (ESGE) recommends the Glasgow-Blatchford score using a cut-off of ≤1 to identify low-risk patients, who can be safely managed as outpatients [14].

Timing of endoscopy

   Early endoscopy (within 24h) has been found more beneficial compared to later endoscopy, in patients with acute gastrointestinal bleeding from previous studies over the past three decades, although it is questionable whether it improves mortality [19,20].

Urgent endoscopy (during the first 6h) has been tried in the past to improve clinical outcome of patients with upper gastrointestinal bleeding, however, no difference in rebleeding and mortality was observed and the effect on the length of hospital varies [21,22]. Urgent endoscopy has not been shown to be better than endoscopy performed within the first 24 hours of hospitalization [21,22].

In a recent nationwide Danish cohort study including 12.601 patients no association between timing of endoscopy and mortality in hemodynamically stable patients with an ASA score (American Society of Anesthesiologists) of 1 to 2 was found [23]. Even in hemodynamically stable patients with an ASA score of 3 to 5, endoscopy 12 to 36 hours after admission to the hospital was associated with lower in-hospital mortality, while in patients with hemodynamic instability, endoscopy 6 to 24 hours after admission to the hospital was associated with lower in-hospital mortality [23].

ESGE guidelines do not recommend urgent endoscopy (≤12 hours) due to lack of improvement in clinical outcome of the patients [14]. Although exact timing of endoscopy is still challenging, endoscopy should be performed after careful and adequate resuscitation and optimum management of underlying comorbidities, on a case-by-case basis, always taking all the necessary precautions and ensuring ideal conditions in terms of equipment and personnel [14].

Pre-endoscopy proton-pump inhibitors

In a previous meta-analysis including six randomized controlled trials (RCTs), PPI treatment initiated before endoscopy at the emergency department led to a reduction of participants with stigmata of recent hemorrhage and requirement for endoscopic therapy during index endoscopy, without affecting clinically important outcomes, namely mortality, rebleeding or need for surgery [24]. As more than two thirds of patients with bleeding suffer from hydrochloric acid secretion related diseases, PPIs from admission are suggested to all patients with ANVUGIB [24].

Endoscopic hemostatic methods

In patients with active bleeding or non-bleeding visible vessel, because of the high probability of rebleeding, endoscopic hemostasis with various methods is important as it reduces the recurrence of bleeding and therefore the need for blood transfusions, length of hospitalization and need for emergency surgical hemostasis [25].

Oozing bleeding, although is considered high-risk for rebleeding, may have been overestimated as, compared with Forrest Ia, Iia and Iib lesions, has a very low rebleeding rate following successful hemostasis [26].

   The management of lesions with adherent clot is controversial. Although not fully established, a strategy of careful clot detachment (to avoid bleeding) and adjunctive endoscopic hemostasis, when necessary, is recommended in patients with adherent clot [25]. Lesions with clean base or pigmented flat spots are of negligible risk of rebleeding and do not require endoscopic intervention and are amenable to early discharge [25].  

   A variety of endoscopic hemostatic methods has been developed and tested during the past years including thermal coagulation methods, mechanical modalities, like through-the-scope clips and bands and injection of various substances, mainly adrenaline solution [27] (figure 2). The best endoscopic hemostatic method depends on the type and location of the lesion, the severity of the bleeding, the endoscopist-nurse experience and the available equipment in each case [27].

Figure 2. Endoscopic hemostatic methods. 2A: Through-the-scope clip, 2B: Banding, 2C: Adrenaline injection, 2D: Argon plasma coagulation (APC).
Source: Personal records.

   Many studies and meta-analyses have shown that endoscopic injections of substances are equivalent to each other, mechanical methods of hemostasis are equivalent to thermal methods, mechanical and thermal methods are superior to endoscopic injections of substances and combination of endoscopic therapies is superior to monotherapy in arresting bleeding and preventing recurrence [28].

   Epinephrine injection can be used to temporarily reduce bleeding and aid visualization of the bleeding lesion before the use of another endoscopic modality [28]. Some lesions need specific endoscopic hemostatic methods like argon plasma coagulation for angiodysplasias and band ligation or even radiofrequency ablation for watermelon stomach [30, 31].

   During the last decade several new modalities have been introduced in endoscopic hemostasis, mainly hemostatic powders or gels (Hemospray, Purastat, etc..) and over-the-scope clips (or cap-mounted clips). More studies are required to establish their role in the endoscopic management of ANVUGIB [32-34]. Probably, local hemostatic agents may be used as the first line hemostatic method for diffuse bleeding from a tumor, while over the scope clips can be used as rescue therapy for patients with persistent or recurrent bleeding despite initial hemostasis, but further studies are required [35-37].

   Attempts have been made by using a through-the-scope Doppler probe before and after endoscopic hemostasis to better assess arterial submucosal blood flow [38]. Although it was found that this technique reduces rebleeding compared to the standard visual inspection, this modality has not gained wide popularity [38].

   Performing a second endoscopy in the absence of recurrence (second look endoscopy) is not recommended but should be done when the endoscopist is not satisfied with the applied endoscopic hemostasis [39].

Post-endoscopy medical therapy in patients with ANVUGIB

   As more than two thirds of patients with bleeding suffer from hydrochloric acid secretion related diseases, PPIs from admission are suggested to all patients with ANVUGIB. It has been suggested that high doses (initially intravenous bolus 80mg and then 8mg/hour for 72 h) achieve faster a higher gastric Ph which would lead to faster ulcer healing and inhibition of pepsin activation, which dissolves the clot (at Ph< 6) [40]. However, in comparative studies and meta-analyses this was not completely confirmed [40]. Nevertheless, in patients at high risk for rebleeding, high doses of PPIs are recommended, given continuously or intermittently [41,42]. Also in a previous study, double oral esomeprazole 40 mg twice daily for two weeks after a 3-day infusion reduced peptic ulcer rebleeding in high-risk patients compared with standard dose once daily [43].

   Somatostatin and tranexamic acid have no benefit in non-variceal upper gastrointestinal bleeding and should not be used for the treatment of ANVUGIB outside the context of a randomized trials [44,45].

Blood product transfusions

   A more restrictive transfusional approach is recommended for patients with ANVUGIB today [41,42]. A meta-analysis of five RCTs including 1,965 patients with gastrointestinal bleeding revealed significantly lower all-cause mortality and rebleeding rates in patients allocated to a restrictive versus a liberal transfusion strategy, with no difference in risk of ischemic events [46]. A target of maintaining hemoglobin level of 9 mg/dl in patients with coronary disease and 7-8 mg/dl in younger patients without accompanying diseases and especially in patients with liver cirrhosis/portal hypertension is recommended, in order to avoid heart function overload and portal pressure increase in cirrhotic patients [46].

Ongoing or recurrent bleeding

   On recurrence of bleeding, re-endoscopy (and endoscopic hemostasis if possible) should be attempted, as it may lead to permanent hemostasis and reduce the need for emergency surgical hemostasis with less morbidity [47]. Use of newer hemostatic modalities, like over the scope clips, may increase the rate of permanent hemostasis [48]. It should be emphasized that a correct assessment of the lesion and the bleeding vessel is crucial and unnecessary repeated endoscopic hemostasis must be avoided, while there should be close co-operation between the endoscopist and the surgeon [47].

   In cases of older patients and/or with severe co-morbidity, where surgery is accompanied by high morbidity and mortality, selective arterial embolization of the bleeding vessel has given good results. Immediate and permanent cessation of bleeding can be achieved in 85-90% of cases without significant complications [49].  On the other hand, there is no evidence for prophylactic angiographic embolization after initial endoscopic control of bleeding in patients with high-risk peptic ulcers [50].

Negative endoscopy in a patient with upper gastrointestinal bleeding

   If there is not a cause of bleeding in the gastroscopy, it is most likely that the cause is in the lower digestive tract and in these cases, in massive bleeding, we proceed to a CT-angiography and in less massive bleedings to an ileocolonoscopy and capsule enteroscopy after complete preparation of the intestine [51]. In some cases, a bleeding lesion in the range of upper GI endoscopy might be missed or not assessed correctly by the endoscopist, such as lesions in a difficult area (lesser curvature of the stomach, duodenal angle) or in areas covered by blood/clots or incorrect assessment in less obvious lesions due to hypovolemia or intermittent bleeding (e.g. angiodysplasia) [51]. In the event of rebleeding after a negative endoscopy, re-endoscopy of the upper GI tract for a better assessment should be reevaluated before proceeding with a lower GI endoscopy, especially in patients with increased blood urea on admission [52].

   Performing capsule enteroscopy within two days from the onset of bleeding results in a higher diagnostic yield, higher therapeutic intervention rate and shorter hospital stay [53]. Therefore, capsule enteroscopy application within the first 48 hours could improve the outcome of patients with overt obscure gastrointestinal bleeding [53].

Management of antithrombotic agents during acute bleeding.

   Today, more and more patients presenting with ANVUGIB are taking aspirin and/or other antithrombotic drugs [54]. Antithrombotics should be interrupted while in some cases where bleeding occurs immediately after placement of coronary stents, continuation of these drugs is vital and possibly in patients with non-severe self-limiting bleeding they should be continued with co-administration of high-dose PPIs and endoscopic hemostasis [55].  

   In cases of discontinuation of antithrombotic drugs, the question is (which is) the most appropriate time of reintroduction [56]. It has been shown that delayed re-initiation is associated with an increased incidence of fatal cardiovascular events, while rapid re-initiation is associated with an increased, but non-significant, risk of rebleeding [56]. Today, it is recommended to re-initiate aspirin on the 3rd-7th day, following successful endoscopic hemostasis, depending on the necessity of administration and the severity of the bleeding [54].  

   In patients taking vitamin K antagonists, who present with a bleeding event, fresh frozen plasma is preferred to vitamin K because of its immediate effect and the easiness to regain the previous level of anticoagulation once the bleeding stops [57]. However, fresh frozen plasma administration should not be routinely used, but could be considered for patients with a life-threatening gastrointestinal bleeding or a highly increased INR, substantially exceeding the therapeutic range [58]. Complete normalization of clotting times is not necessary to perform endoscopy. Endoscopy and endoscopic hemostasis, if needed, can be performed when prothrombin time drops to therapeutic levels [59].  

   Warfarin anticoagulants should be re-administered as soon as possible if there is a documented reason [60]. For as long as the patient does not receive oral anticoagulants and following cessation of bleeding, we administer heparin (intravenously or subcutaneously) which has a more direct and controlled anticoagulant effect and is easily reversible by stopping it [60].  

   Regarding the newer oral anticoagulant drugs, reversal agents can be administered in special cases, but due to the short half-life (12-18 hours), the limited evidence of benefit and the high cost, their administration is not recommended [61-62]. In severe cases of bleeding with dabigatran, hemodialysis may help, while it does not help in cases with apixaban and rivaroxaban which are more tightly bound to plasma proteins [61-62].

General preventive measures of patients with bleeding

   After bleeding has stopped, the underlying disease should be treated to reduce the risk of bleeding recurrence [63]. Patients with ulcers should be tested for Helicobacter pylori infection and, if present, eradication therapy is mandatory [63]. Eradication of Helicobacter pylori leads to 75% lower risk of ulcer rebleeding compared to those under only continued antisecretory therapy [63]. Although H. pylori detection tests exhibit lower sensitivity during acute bleeding, testing and eradication regimens may be started as soon as possible, because delays in H. pylori eradication therapy are associated with time-dependent increase in the risk of recurrent ulcer and complications [64].  

  Based on our experience, patients should avoid NSAIDs in any form and if indicated COX-2 selective prostaglandin inhibitors may be an alternative solution, which do not have significant gastric toxicity. Before starting treatment with aspirin and/or NSAIDs in patients with a positive history of ulcer, an endoscopy should be performed to exclude the presence of ulcers. When aspirin or NSAIDs are necessary, co-administration with PPIs is mandatory. Also in older people, PPIs should be co-administered (in the standard dose) with NSAIDs or aspirin, which seems to prevent peptic ulcer disease and complications.

CONCLUSIONS

   Upper gastrointestinal bleeding remains a common cause of hospital admissions worldwide. RCTs and meta-analyses confirm improved outcomes from a relatively restrictive approach to blood transfusion and a benefit from post-endoscopy high dose PPIs for high risk peptic ulcer bleeding. Endoscopic therapy has advanced dramatically today with recent additions, including hemostatic powder spray, over-the-scope clips and doppler probes, to join the established and widely used injection therapies, thermal probes, and clips. According to the above, a multidisciplinary collaboration is required to optimize outcomes of patients presenting with ANVUGIB.

Conflict of interest disclosure: None to declare.

Declaration of funding sources: None to declare.

Author Contributions: Christos Sotiropoulos, Christos Konstantakis, Odysseas Ampazis, Georgia Diamantopoulou, Georgios Theocharis: data collection & drafting of the article; Konstantinos Thomopoulos: drafting of the article & critical revision of the article for important intellectual content & final approval of the article. All authors read and approved the final manuscript.

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