Acute non-variceal upper gastrointestinal bleeding

Introduction

A major audit of upper gastrointestinal (UGI) bleeding in the UK carried out over 20 years ago reported an incidence of 103 patients per 100 000 adults per year. There is a twofold increase in likelihood of requiring hospitalisation among those residents from more deprived socioeconomic areas. Overall mortality from an episode of UGI bleeding was 14% in the UK study and a marked increase in mortality (33%) was observed if bleeding occurred following hospitalisation with another complaint. A more recent audit of patients admitted to UK hospitals during 2007 demonstrated a marked reduction in the proportion of patients requiring surgery, as well as a reduction in overall mortality (10% vs 14%), and a reduction in mortality rate for inpatients (26% vs 33%). This study also identified an increase in the proportion of patients admitted with variceal bleeding. Mortality rate in patients admitted with peptic ulcer bleeding decreased from 8.8% to 5.8%.

The typical patient with severe peptic ulcer bleeding is now elderly, often with medical comorbidities and taking antiplatelet therapy and/or on anticoagulants. Such patients are at greater risk of death despite skilled intervention and are less able to withstand surgery should this be necessary. Although the need for surgical intervention is now much reduced with the widespread availability of skilled endoscopic haemostasis, mortality following surgery remains high. As a result, alternatives to surgical intervention are increasingly being employed and will be discussed in this chapter.

Aetiology

In the earlier study reported in 1995 by Rockall, only 4% of patients had UGI bleeding due to varices, with the majority (35%) being attributed to peptic ulcer disease (PUD). Of some concern was the 25% of patients in this study where no cause for bleeding was identified, particularly as this group had a mortality of 20%. Similar figures were reported in the later study where, in patients with a diagnosis made, approximately 25% were due to duodenal ulcer and 25% to peptic ulceration in the stomach, oesophagus or a combination of sites. The other causes were due to a number of other conditions, including oesophagitis, gastritis and duodenitis, malignancy or Mallory–Weiss syndrome. In this later audit, the proportion of patients with variceal bleeding had increased to 11%, whereas the overall proportion with peptic ulcer remained unchanged.

Initial assessment and triage

Patients with acute UGI bleeding present with haematemesis, melaena or a combination of the two. Haematemesis is indicative of significant bleeding from a site proximal to the ligament of Treitz. Melaena usually indicates a bleeding site in the UGI tract, although bleeding from the small bowel or even the right colon may present in a similar way, depending on speed of passage. Presentation with haematemesis is associated with an increased risk of mortality compared with melaena. Coffee-ground vomiting is no longer considered a serious stigma of UGI bleeding. Patients with UGI blood loss may occasionally present with frank rectal bleeding (haematochezia), but this is indicative of major blood loss and, not surprisingly, is associated with an increased need for transfusion, surgery and mortality. A good example of this would be a patient who has previously undergone aortic aneurysm surgery who subsequently develops an aortoduodenal fistula related to the aortic graft.

Scoring systems

Risk stratification in patients with UGI haemorrhage is important as it assists decision-making in the need for emergency intervention and feasibility of safe outpatient management. Published guidelines suggest routine use of validated stratification tools in these patients. Multiple scoring tools have been previously reported, with the Rockall score and the Glasgow Blatchford score (GBS) being most extensively validated. Using data from the first National UK Audit, Rockall et al. derived a scoring system based on five significant risk factors for mortality. The Rockall system consists of an initial score from clinical parameters and a complete composite score after endoscopic assessment. Patients with an initial score of 0 (i.e. age < 60, no tachycardia, no hypotension and no comorbidity) had a very low mortality. The composite Rockall system, incorporating endoscopic information including cause of bleeding and stigmata of haemorrhage, has been validated in prospective studies, but is more accurate in predicting mortality than the risk of re-bleeding. ^,

The GBS aimed to allow early assessment of the need for intervention rather than risk of death ( Table 13.1 ). Based entirely on clinical risk markers before endoscopy, the GBS performed significantly better than the Rockall score at predicting the need for intervention and has now been validated in prospective studies from the UK and Hong Kong . In a prospective multicentre international validation study of 3012 patients, GBS was better in predicting the need for endoscopic treatment (AUROC = 0.75) when compared with the Rockall score and several other scores. A GBS of 7 or more is the optimal threshold (sensitivity of 80% and specificity of 57%). The small proportion of patients with a GBS of 0 or 1 have minimal chance of requiring intervention as well as risk of re-bleeding and death, thus outpatient management of these patients is considered safe and cost-effective. Given the superiority of GBS over Rockall score at predicting the need for intervention, GBS is now the stratification system of choice in many centres.

Table 13.1

Glasgow Blatchford score for predicting risk of re-bleeding or death in non-variceal upper gastrointestinal haemorrhage

Modified from Blatchford O, Murray WR, Blatchford M. A risk score to predict need for treatment for upper-gastrointestinal haemorrhage. Lancet 2000;356(9238):1318–21.

Admission risk marker	Score component value
Blood urea (mmol/L)
≥ 6.5 < 8.0	2
≥ 8.0 < 10.0	3
≥ 10.0 < 25.0	4
≥ 25	6
Haemoglobin (g/L) for men
≥ 120 < 130	1
≥ 100 < 120	3
< 100	6
Haemoglobin (g/L) for women
≥ 100 < 120	1
< 100	6
Systolic blood pressure (mmHg)
100–109	1
90–99	2
< 90	3
Other markers
Pulse ≥ 100 (per min)	1
Presentation with melaena	1
Presentation with syncope	2
Hepatic disease	2
Cardiac failure	2

Despite recommendations from guidelines, published nationwide registries consistently report a low adherence to the use of risk stratification tools in real-life practice. In the 2007 UK audit, only 19% (1250/6750) of patients had either Rockall score or GBS recorded in the medical notes. Risk stratification systems should be adopted into clinical management protocol for all patients presenting with UGI haemorrhage, as routine use of such a system would assist in detecting patients at high risk of re-bleeding or death, as well as increase cost-effectiveness by reducing unnecessary admission of low-risk patients.

The most recently published comprehensive guidelines on the management of UGI bleeding include data from published meta-analyses as well as expert opinion. ^, ^,

Initial management

While it may be appropriate to consider discharge for young patients with no haemodynamic compromise and a GBS of 0, particularly where there has been no witnessed frank haematemesis, most patients with a history of UGI bleeding will be admitted for observation and endoscopy. This will entail insertion of a large-bore intravenous cannula, administration of pre-warmed fluid to expand the intravascular volume and immediate blood samples taken for crossmatch, biochemistry, full blood count, coagulation screen and arterial blood gases. There is also some evidence that admission to a dedicated UGI bleeding unit is associated with a reduction in mortality. Such a unit requires a 24-hour on-call service for immediate endoscopy if required and early (within 24 hours) consultant-led endoscopy for all patients. Indications for urgent (out-of-hours) endoscopy vary, but the main factor determining the degree of urgency is the necessity for endostasis. Therefore, patients with evidence of ongoing haemorrhage, declared either by fresh haematemesis or haemodynamic instability despite initial fluid resuscitation, require emergency endoscopy. Most stable patients will undergo UGI endoscopy within 24 hours (usually on the morning after admission). In such patients, the purpose of endoscopy is twofold: first, patients with minor bleeds undergo full diagnostic assessment and if considered at low risk of re-bleeding can be discharged home; second, to identify the group of patients who have significant lesions and who require endoscopic therapy to reduce the risk of re-bleeding.

Massive haemorrhage

In those patients who have evidence of haemodynamic compromise, initial resuscitation should follow the appropriate guidelines and the local major haemorrhage protocol should be activated. Early intensive haemodynamic resuscitation is recommended for such patients. In an observational study of patients suffering from UGI haemorrhage with haemodynamic instability, intensive haemodynamic resuscitation was associated with a lower risk of myocardial infarction and mortality than the control ‘observation’ group. The type of intravenous fluid used for resuscitation remains contentious. A Cochrane review of 55 trials found no evidence to favour the use of colloid rather than crystalloid solutions during resuscitation in critically ill patients. As colloid solutions are more expensive, initial resuscitation with appropriate crystalloids is recommended.

Use of blood and blood products

Red cell replacement is likely to be required when 30% or more of the blood volume is lost. This can be difficult to assess, particularly in young patients, and clinical assessment of blood loss, coupled with the response to initial volume replacement, must guide the decision on the necessity of transfusion. While blood transfusion may achieve intravascular volume replenishment and enhance tissue oxygen delivery, a liberal transfusion strategy could be associated with worse clinical outcomes. In a randomised trial, 921 patients with acute UGI haemorrhage were randomised to restrictive transfusion strategy (target haemoglobin: 7–9 g/dL) and liberal transfusion strategy (target haemoglobin: 9–11 g/dL) groups. The restrictive RBC transfusion group had a significantly improved 6-week survival (95% vs 91%; hazard ratio [HR] 0.55, 95% confidence interval [CI] 0.33–0.92) and reduced re-bleeding (10% vs 16%; HR 0.68, 95% CI 0.47–0.98). Of note, patients with massive exsanguinating haemorrhage as well as significant medical comorbidities were excluded from the trial. A cluster randomised controlled trial (RCT) was subsequently conducted in the UK. Six university hospitals were randomised to either a restrictive or a liberal transfusion strategy (transfusion threshold of 8 g/dL vs 10 g/dL). The RCT enrolled 936 patients. Fewer patients in the restrictive transfusion group received red cell transfusion (33% vs 46%). Mean red cell transfused was 0.7 U compared with 1.2 U. No difference in clinical outcomes was observed between groups. However, in patients with significant cardiopulmonary disease, a higher target haemoglobin level should be considered in order to increase oxygen-carrying capacity.

Administration of platelets should aim to maintain a platelet count of more than 50 × 10 ⁹ /L, while coagulation factors are likely to be required when more than one blood volume has been lost. These are most commonly given in the form of fresh frozen plasma (FFP). The use of platelets, FFP and other agents, such as recombinant factor VIIa, should be guided by local protocols and early involvement of a haematologist.

Management of patients on antiplatelet agents and anticoagulants

Antiplatelet agents and anticoagulants are in common practice, and UGI haemorrhage is a serious complication for patients taking these drugs. Patients taking vitamin K antagonists (VKA) should be admitted with the drug withheld. In patients suffering from major bleeding with haemodynamic compromise, urgent reversal of VKA should be undertaken. This could be achieved by administration of prothrombin complex concentrates (PCC) or FFP. PCC contain clotting factors prepared from pooled and concentrated human plasma. The major advantages of PCC are faster onset of action and a smaller transfusion volume, thus a lower risk of fluid overload. PCC was associated with a quicker correction of international normalised ratio in a recent small-scale non-randomised study.

In recent years, use of non-VKA oral anticoagulants (NOACs) is increasingly popular in patients with non-valvular atrial fibrillation and venous thromboembolism. The risk of UGI haemorrhage is at least similar to that of VKA. These agents have a short and predictable anticoagulation effect, but rapid reversal in the setting of life-threatening haemorrhage is difficult. Vitamin K and FFP have not been found useful. The only reversal agent of dabigatran, idarucizumab, has been recently approved by the FDA. Administration of PCC or use of haemofiltration should be considered when urgent reversal of NOACs is necessary.

In patients with UGI haemorrhage who are taking antiplatelet agents, further management would depend on the severity of the bleeding, indication and the type of antiplatelet agents used. In general, patients on low-dose aspirin for secondary cardiovascular prophylaxis should have the drug resumed as soon as satisfactory haemostasis is confirmed after endoscopy. In a randomised study, patients who received continuous aspirin had a significantly lower all-cause short-term mortality compared with placebo, with the difference being attributable to cardiovascular, cerebrovascular or GI complications. Patients who are taking dual antiplatelet agents should at least continue with low-dose aspirin to avoid cardiovascular events. Patients on other antiplatelet agents such as clopidogrel, prasugrel or ticagrelor should consider switching back to low-dose aspirin or an early cardiology consultation if high-risk endoscopic stigmata was identified during endoscopy.

Early pharmacological treatment

UGI endoscopy is the mainstay of investigation and management of UGI bleeding, but there may also be a role for early treatment with acid suppression therapy. In vitro studies have shown that, at pH < 6, platelet aggregation and plasma coagulation are markedly reduced, a situation exacerbated by the presence of pepsin. It is therefore reasonable to expect acid suppression therapy to promote clot formation and stabilisation. A Cochrane review summarised six RCTs comparing proton pump inhibitors (PPIs) to either placebo or an histamine-2 receptor antagonist initiated prior to endoscopy. No significant impact of PPI therapy was demonstrated on mortality, surgery or re-bleeding rates. There was, however, a reduction in the proportion of patients with stigmata of recent haemorrhage at the time of endoscopy, and a reduction in the requirement for endoscopic therapy at the index endoscopy. A post-hoc cost-effective analysis was reported using data from a large randomised study in Asia. The study concluded that the strategy of pre-emptive use of PPI infusion was cost-saving because of reduced endoscopic therapy and hospitalisation, offsetting the cost of PPI therapy. It therefore seems reasonable to propose pre-endoscopic PPI therapy in patients admitted with UGI bleeding, but this should not delay or act as a substitute for early endoscopic intervention. There is no evidence to support the use of other agents such as somatostatin, octreotide or vasopressin in the pre-endoscopy setting, except where variceal bleeding is suspected.

Pre-endoscopy treatment with a PPI is recommended as it reduces the number of actively bleeding ulcers and increases the number of clean-based ulcers seen at the time of endoscopy. Early use of PPI reduces the need for endoscopic intervention and hospitalisation.

The use of pre-endoscopy prokinetic agents has also been advocated to improve endoscopic visualisation by reducing blood clots within the gastrointestinal tract lumen. Earlier meta-analysis showed that prokinetic agents reduced the need for repeat endoscopy. In another recent meta-analysis, pre-endoscopy erythromycin infusion significantly improved gastric mucosal visualisation, decreased the need for second-look endoscopy, red cell transfusion and duration of hospital stay.

Tranexamic acid, an antifibrinolytic agent, may also aid in haemorrhage control by reducing clot breakdown and its use in acute trauma has been proven in a recent large randomised study. In a recently conducted Cochrane review, the use of tranexamic acid in UGI haemorrhage appeared to be associated with a reduction in overall mortality. Unfortunately most of the included trials in the review were performed before the routine use of PPI and there was also a high dropout rate in some of the trials. In a large-scale placebo-controlled multicentre trial that enrolled 12 009 patients, the use of high-dose tranexamic acid infusion (intravenous tranexamic acid 1 g loading followed by 3 g infusion over 24 hours) did not reduce death from acute UGI bleeding (4% in the tranexamic acid and placebo group, respectively). The rate of venous thrombotic events (deep vein thrombosis and pulmonary embolism) was increased by twofold in those who received tranexamic acid (0.8% vs 0.4%). The use of tranexamic acid is not routinely recommended.

Endoscopy

UGI endoscopy is required for any patient with significant UGI bleeding. Patients with haemodynamic instability or evidence of continuing haemorrhage require emergency endoscopy, whereas the majority of patients will undergo endoscopy within 24 hours of admission. A systematic review of the literature supports a policy of early endoscopy, as this allows the safe discharge of patients with low-risk haemorrhage and improves outcome for patients with high-risk lesions. A recent randomised controlled trial that included 516 high-risk patients compared endoscopy within 6 hours of consultation to endoscopy the next morning. These patients belonged to a high-risk group (i.e. with an admission GBS of 12 or more) but were haemodynamically stable at randomisation. The primary outcome was 30-day mortality from all causes, which was 8.9% in the endoscopy within 6-hours group and 6.6% in the endoscopy within 24-hours group. (HR 1.35; 95% CI 0.72–2.54; P = 0.34). There was a higher rate of ulcers with active bleeding or visible vessels found at endoscopy within 6-hours group (66.4% vs 47.8%) and therefore a higher rate of endoscopic treatment. Most stable patients can safely receive endoscopy the next morning, although they should be monitored carefully for signs of further bleeding.

Early endoscopy is recommended for all patients with UGI haemorrhage.

In patients who are haemodynamically stable, urgent endoscopy within 6 hours does not improve mortality when compared with endoscopy within 24 hours (although patients require close haemodynamic monitoring).

Endoscopic technique

Endoscopy for UGI bleeding requires the support of a dedicated endoscopic unit with trained staff, availability of additional endoscopes and equipment, ready access to anaesthesia and operating theatre, and, increasingly, access to interventional radiology services. These procedures should be performed or supervised by experienced senior members of staff.

For the majority of stable patients, procedures can be safely carried out using standard diagnostic endoscopes. In the unstable patient or where continuing haemorrhage is suspected, the twin-channel or large (3.7 mm) single-channel endoscope is preferable and allows better aspiration of gastric contents as well as more flexibility with regard to the use of heater probes and other instruments. In unstable or obtunded patients, anaesthetic support is mandatory as an endotracheal tube should be passed before endoscopy to guard against aspiration. The use of a tilting trolley allows repositioning of the patient, which can facilitate visualisation of the proximal stomach when obscured by blood and clot. Initially, placing the patient in a head-up position may suffice, and if necessary rolling the patient into a right lateral and head-up position may be needed for complete visualisation of the gastric fundus. In general, lavage is more successful in achieving visualisation than endoscopic aspiration, as endoscope working channels rapidly block with clot. Lavage can be achieved using repeated flushes of saline down the endoscope working channel or with the use of the powered endoscopic lavage catheters such as that provided with the heater probe. With experience, it should rarely be necessary to proceed to surgery or angiography because of inability to visualise the bleeding site due to blood and clot in the stomach or duodenum.

Bleeding gastric ulcers are most likely within the antrum or at the incisura (77%), or less commonly higher on the lesser curve (15%), with ulcers at other sites within the stomach being uncommon. Ulcers at the incisura and proximal lesser curvature can be readily overlooked unless the endoscope is retroflexed within the stomach. The most common site for a bleeding duodenal ulcer is the posterior wall, sometimes with involvement of the inferior and superior walls of the first part of the duodenum. Anterior duodenal wall ulcers can ooze, but usually these ulcers perforate. Ulcers elsewhere in the duodenum are seen in less than 10% of patients. The presence of active bleeding at the time of endoscopy and the size of the ulcer, rather than its anatomical site, are the main endoscopic determinants of the risk of therapeutic failure.

Management of bleeding due to causes other than peptic ulceration

Gastritis/duodenitis

Bleeding due to gastritis or duodenitis may be associated with non-steroidal anti-inflammatory drug (NSAID) therapy or ingestion of alcohol. It may also be due to Helicobacter pylori and can be severe enough to cause superficial erosions. Such bleeding, however, is almost always self-limiting in the absence of bleeding disorders, and therapeutic intervention is not required at the time of endoscopy. Treatment with appropriate acid suppression therapy and early discharge is usually appropriate in the absence of other comorbid illness.

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