Blog

Variceal Bleeding Thumbnail
Nicholas McManus

Nicholas McManus

Acute Variceal Bleeding: An evidence based approach

Print 🖨 PDF 📄

Background

Variceal bleeding is a major complication of portal hypertension, causing approximately 70% of all upper GI bleeds in cirrhosis and is the leading cause of death in these patients.1,2 

Portal hypertension is defined as a hepatic venous pressure gradient (HVPG) of  >  5 mmHg. Actual variceal hemorrhage is unlikely to occur when the HVPG is less than 12 mmHg and a HVPG above 20 mmHg predicts failure to control bleeding and increased mortality.33 A 2008 study of 117 cirrhotics showed that over 80% of Child C patients have a hepatic venous pressure gradient (HVPG) of  > 20 mmHg.32

While placebo-controlled trials suggest 40%-50% of variceal bleeds will stop spontaneously, early mortality following an episode of acute variceal bleeding remains high, up to 24%.2,3 Re-bleeding after an event appears to directly correlate with risk of early death.2,3 Sepsis and multi-organ failure, especially if requiring renal replacement therapy, confer a dismal prognosis with over 90% mortality.4

In patients presenting to the Emergency Department with an acute variceal bleed, the decisions you make regarding initial treatment can tip the scale of mortality in either direction, and having an evidence based understanding of treatment modalities is absolutely essential.

Airway

A patient with active variceal hemorrhage is at high risk of aspiration. Early endotracheal intubation should strongly be considered prior to endoscopy, especially if concomitant hepatic encephalopathy is present.

Blood Transfusions

Optimal blood volume replacement remains somewhat controversial. Historical teachings suggest that if large amounts of blood are lost, then large amounts of blood are needed. However, in variceal bleeding, large volume resuscitation could literally be a death sentence. Stay with me…

Hypovolemia causes splanchnic vasoconstriction, which is exactly what we try to achieve with medications like Octreotide. Transfusion may counteract this splanchnic vasoconstrictive response leading to an increase in splanchnic blood flow and an increase in portal venous pressure. Thus, leading to worsening bleeding, subsequent rebleeding and death.

While blood products should be initiated promptly in cirrhotic patients with variceal bleeding, this should be done with caution. The American College of Gastroenterology (ACOG) recommends that transfusions should be aimed at maintaining hemoglobin concentrations at 7-8 g/L, except in patients with rapid ongoing bleeding or ischemic heart or cerebral disease, in which case this threshold should be raised.2,5,6 This recommendation is based on experimental studies that show that restitution of all lost blood leads to an increase in portal pressure to levels higher than they were at baseline and an elevated HVPG > 20 mmHg (measured within 24 hours of presentation) has been shown to be predictive of treatment failure.7,8.9

So, what does the evidence show?

Kravetz, 19867

    • 16 rats with portal hypertension.
    • Measured arterial and portal pressures before and after removing blood and again after transfusing the same volume of blood lost.
    • After blood transfusion, arterial pressure returned to baseline values while portal pressure increased by 20.4% +/- 3.2% (p < 0.01).
    • This increase in portal pressure was not observed in the 5 normal rats that were subjected to the same blood volume changes.

Study Conclusion: During hypovolemia, there is a marked reduction in portal pressure because of a reduction in portal venous inflow. Blood volume restitution returns the portal venous inflow to control values, but increases the portal pressure beyond control values due to an increase in portal-collateral resistance.

Castañeda, 200110

    • 38 cirrhotic rats
    • Assessed mortality based on restrictive transfusion (50% of estimated blood lost) vs aggressive transfusion (100% of estimated blood lost). 

Study Conclusion: transfusion policy aimed at completely replacing blood loss worsens the magnitude of bleeding and mortality from portal hypertensive-related bleeding in cirrhotic rats. On the contrary, moderate blood transfusion allowed hemodynamic stabilization and increased survival.

Villanueva, 201311

  • Single center randomized controlled trial.
  • 921 human patients with severe acute upper gastrointestinal bleeding. 
  • Randomization was stratified according to the presence or absence of liver cirrhosis.
  • Patients assigned to restrictive strategy (transfusion when the hemoglobin level fell below 7 g per deciliter) or to a liberal strategy (transfusion when the hemoglobin fell below 9 g per deciliter).

Bottom Line: Blood transfusion should be initiated as soon as possible with the goal of maintaining systolic blood pressure around 100 mmHg. Avoidance of significant hypovolemia and prolonged hypotension is particularly important in order to prevent renal failure and infection which are associated with increased risk of re-bleeding and death.2 Nevertheless, blood volume replacement and transfusion should be cautious and conservative since over-transfusion has been associated with rebound increases in portal pressure resulting in increased re-bleeding and death.

Fluids

I think we can extrapolate from the studies above, that too much volume leads to too much pressure within the portal system and leaky systems under pressure bleed faster. Therefore, ACOG recommends that vigorous resuscitation with saline solution should be avoided because it can worsen or precipitate a recurrent variceal hemorrhage and accumulation of ascites and fluid at other extravascular sites.2 

Vasoactive Medications

The American College of Gastroenterology recommends a combination of pharmacological therapy and endoscopic therapy as the most rational approach in the treatment of acute variceal hemorrhage. The use of pharmacological agents with few side effects allows prolonging therapy to 5 days, the period during which the risk of re-bleeding is the highest.5 Up to 25% of deaths from variceal hemorrhage occurs shortly after bleeding onset.2 Treatment with vasoactive drugs alone controls bleeding in up to 83% of patients.12 When a variceal bleeding is suspected, vasoactive drugs should be started as soon as possible, even before diagnostic confirmation. A number of trials have shown that early administration of these drugs reduces the rate of active bleeding during endoscopy, thus facilitating endoscopic procedures.2

Bañares, 200213

    • Meta-analysis of 8 trials comparing to endoscopic therapy alone to endoscopy plus pharmacological therapy (octreotide, somatostatin, vapreotide).
    • Assessed initial hemostasis, 5-day hemostasis, 5-day mortality, and adverse events.
    • All primary outcomes favored the combined therapy
    • Significant when drugs other than Octreotide were used and when high-risk cirrhotic patients were excluded
    • Showed improved initial control of bleeding (NNT=8) and 5-day hemostasis (NNT=5) without differences in severe adverse events
    • No significant change in mortality.

D’Amico, 200312

    • Meta-analysis of 15 trials comparing emergency sclerotherapy alone to sclerotheraphy + pharmacological treatment with either vasopressin ± nitroglycerin, terlipressin, somatostatin, or octreotide.
    • Outcome measures included failure to control bleeding, re-bleeding, blood transfusions, adverse events, and mortality.
    • Sclerotherapy alone was not superior to terlipressin, somatostatin, or octreotide for any outcome and to vasopressin for re-bleeding, blood transfusions, death, and adverse events
    • Risk differences (sclerotherapy alone):
      • Failure to control bleeding: -0.03 (CI -0.06 to 0.01)
      • Mortality: -0.035 (CI -0.07 to 0.008)
      • Adverse events: -0.08 (CI 0.02 to 0.14)

Study Conclusion: Available evidence does not support emergency sclerotherapy as the first-line treatment of variceal bleeding in cirrhosis when compared with vasoactive drugs, which control bleeding in 83% of patients.

Wells, 201226

    • Meta-analysis of 30 randomized controlled trials including 3111 patients
    • Evaluated vasopressin, somatostatin and their analogues, administered to patients with acute variceal bleeds
    • Results:
      • 7-day mortality: decreased with RR 0.74 (moderate quality of evidence
      • Hemostasis: improved with RR 1.21 (very low quality of evidence)
      • Transfusion requirements: 0.70 less units
      • Hospital duration: 0.71 less days spent in the hospital

Study Conclusion: Studies comparing different vasoactive agents did not show a difference in efficacy, although the quality of evidence was very low.

Comparison summary of different vasoactive agents...

Octreotide Sidebar…

The actual effects of octreotide on portal pressure only lasts about five minutes, even when used as an infusion.21 The only randomized controlled trial with octreotide as solo therapy was done all the way back in 1996 and failed to show benefit over placebo in the prevention of re-bleeding or decreasing mortality.20 A 2008 Cochrane review suggests negligible benefit of Octreotide as monotherapy.22 However, when added to endoscopy, octreotide has been shown to prevent early re-bleeding, but still has no effect on mortality.23 A large placebo-controlled trial is needed to assess mortality benefit. The treatment dose for variceal bleeds is with a 50 mcg IV bolus, followed by 50 mcg/hr drip.

Bottom Line: Vasoactive drugs are effective and safe and should be used as first line treatment of AVB as soon as variceal bleeding is suspected and should not be held pending confirmation of diagnosis and should be continued for 3-5 days. Available data does not provide firm conclusions regarding the superiority of one drug over the others. Terlipressin is the only drug shown to decrease mortality when used without endoscopy. All other medications must be used with early endoscopy for any benefit in mortality. While Terlipressin is the preferred drug in many countries, Octreotide is the agent available in the United States.

Fresh Frozen Plasma

ACOG gives loose recommendations of transfusion of FFP, stating that it can be considered in patients with significant coagulopathies. However, the INR does not predict the risk of bleeding in cirrhosis.24 While the INR may be elevated due to decreased synthesis of vitamin K-dependent clotting factors, cirrhotics live in a state of hemostatic rebalance and if anything, tend to be more hypercoagulable. 

image from Stravitz, 2012

Based on studies utilizing Thromboelastography (TEG) to compare coagulopathy profiles of cirrhotic patients to healthy individuals, patients with compensated cirrhosis often have normal TEG parameters.30 

Let's quickly discuss TEG in Variceal bleeds...

Specific parameters of TEG (r-time, k-time, and α-angle) indicated increased hypocoagulability in those who experienced early re-bleeding compared to those who did not. In contrast, none of the standard laboratory tests of hemostasis (INR, aPTT, or platelet count) differed between those who re-bled and those who did not.30

So, an we use TEG to determine need for FFP in acute variceal bleeds?

Rout, 201925

    • Randomized controlled trial of 60 cirrhotic patients with severe coagulopathy and acute variceal bleeding.
    • Randomized to either TEG-guided blood product transfusion or conventional transfusion
    • Primary outcome was the difference in the amount of FFP and platelet units transfused between the groups.
    • Secondary outcomes were re-bleeding at 5 days and 42 days, as well as 6-week mortality.
    • There were no differences in baseline characteristic and endoscopic findings between the 2 groups.

 

Study Conclusion: TEG-guided strategy was associated with reduced blood product transfusion to correct coagulopathy without compromising hemostasis in cirrhotic patients.

Does INR predict risk of bleeding? The short answer is...no

Hshieh, 201524

    • Retrospective review of 74 patients with cirrhosis admitted with variceal bleeding.
    • Control cohort included cirrhotics with history of non-bleeding esophageal varices admitted with ascites or encephalopathy.
    • All variceal bleeders were treated with octreotide, antibiotics, and band ligation.
    • Mean INR at presentation was lower in those with bleeding varices compared to non-bleeders (1.61 vs 1.74, P= 0.03).

Study Conclusion: FFP transfusion did not appear to change the INR level in patients with acute variceal bleeds. INR reflects liver dysfunction, not bleeding risk and correction of INR with FFP has little effect on hemostasis.

Further, FFP transfusion is not benign. Allergic and anaphylactic reactions, transfusion-associated lung injury, and volume overload are all very potential complications. 

Bottom Line: Don’t give FFP just to chase the INR. The evidence just isn’t there and you are more likely to increase portal pressure and increase re-bleeding risk from the unnecessary volume. And re-bleeding is directly correlated with mortality. A more reasonable approach would be to utilize thromboelastography to determine specific coagulation factor deficiencies. In fact, the first use of TEG was in patients with liver disease to guide pro-hemostatic factor repletion during liver transplantation and has been shown to be superior to INR and platelet count for estimating the risk of re-bleeding from esophageal varices.30,31

Platelets

Thrombocytopenia in cirrhosis is mainly due to either platelet sequestration (portal-hypertension–induced splenomegaly) and reduced production (eg, decreased thrombopoietin produced by liver, chronic hepatitis C, chemotherapy).27 In vitro studies showed that patients with cirrhosis generate as much thrombin as healthy individuals provided that their platelet count is at least 100 × 109/L.28 However, as platelet levels decrease, so does the amount of thrombin that is generated. In fact, if the platelet counts fall below 56 x 109/L, thrombin generation is only 10% of what it is at platelet levels over 100. This suggests that cirrhotic patients with platelet counts below this level may benefit from transfusion.

The theoretical goal in transfusing platelets in patients with cirrhosis (or anyone for that matter) is to improve platelet counts, which should reduce the risk of bleeding. 

So…..does it?

Tripodi, 201229

    • Looked at 36 cirrhotic patients with thrombocytopenia undergoing variceal ligations
    • Transfused one standard adult platelet dose
    • Evaluated effects of transfusion on thrombin generation and thromboelastometry 1 hour after transfusion
    • Results:
      • Average platelet count increased slightly (from 39 to 52)
      • No significant change in thrombin generation
      • Minor improvement in thromboelastometry, but no patients achieved normal values

Bottom Line: From available literature, it is not clear that platelet transfusion will reliably improve platelet count and hemostatic function. Patients with cirrhosis and platelet counts between 50,000 and 100,000 have fairly normal thrombin production and transfusion of platelets is unlikely to offer benefit at the expense of an increase in circulatory volume. Current consensus is that transfusion is indicated if platelet counts are < 50,000 in these patients, but should not delay endoscopy.

Fibrinogen/Cryoprecipitate

Fibrinogen is a critical protein for hemostasis and clot formation. Along with platelets, Fibrinogen levels decrease as cirrhosis advances, leading to deficiencies we can measure on Thromboelastography.30 Current recommendations suggest transfusing Cryoprecipitate to maintain a fibrinogen level >150-200 mg/dL in these patients. 

TXA

From our experiences with trauma and the CRASH-2 trial, we know that early administration of the antifibrinolytic drug TXA safely reduces the risk of death in bleeding trauma patients and is highly cost-effective. Specifically, TXA reduces the risk of bleeding to death by about one third in trauma, with no increase in side effects. 

Increased fibrinolysis occurs in up to 50% of patients with end stage liver disease due to decreased clearance of proteins involved in fibrinolysis through the liver leading to increased circulating serum concentrations of these proteins.34 Despite knowledge of the theoretical benefit of TXA in this population, literature addressing its use is lacking.

So, what do we know so far?

Bennett, 201435

    • Cochrane review of eight randomized controlled trials from 1973-2011 on TXA for upper gastrointestinal bleeding
    • Results:
      • Possible mortality benefit suggested (RR 0.6). However, this was not statistically significant when only studies using anti-ulcer drugs or endoscopy were included
      • Less re-bleeding (RR 0.80)
      • No difference between TXA and control interventions regarding the risk of thromboembolic events.
      • Reduced risk of surgery (RR 0.73)
      • No difference between TXA and placebo in the for transfusion (RR 1.02)

Study Conclusion: TXA appears to offer some benefit in patients with acute upper GI bleed, but larger randomized controlled trials need to be done.

Molenaar, 200736

    • Systematic review and meta-analysis of efficacy and safety endpoints in all published controlled clinical trials on the use of TXA in liver transplantation.
    • 23 studies totaling 1407 patients included
    • Intraoperative red blood cell and fresh frozen plasma requirements, the perioperative incidence of hepatic artery thrombosis, venous thromboembolic events and mortality were analyzed.
    • Results:
      • TXA reduced transfusion requirements compared with controls.
      • No increased risk for hepatic artery thrombosis, venous thromboembolic events
      • No increased risk of perioperative mortality.

Study Conclusion: This systematic review and meta-analysis does not provide evidence for an increased risk of thromboembolic events associated with antifibrinolytic drugs in liver transplantation.

Tavakoli, 201837

    • Double-blind randomized clinical trial of 410 patients with proven acute gastrointestinal bleeding.
    • Study was not specific to cirrhosis or variceal bleeding.
    • All patients enrolled received conventional therapy.
    • Randomized to three groups: (A) intravenous TXA (1 g q6h vs topical TXA (1 g single dose by nasogastric tube) plus systemic TXA; and (C) vs placebo (sodium chloride 0.9%) for 24 hours.
    • Subgroup statistical analyses were conducted for urgent endoscopy, mortality, re-bleeding, blood transfusion, endoscopic and/or surgical intervention rates, and health status.
    • Results:
      • No thromboembolic event was documented during the 1-week follow up
      • TXA decreased need for urgent endoscopy
      • No difference in rate of re-bleeding, need for blood transfusion

Study Conclusion: TXA appears to be safe and may be beneficial at decreasing need for urgent endoscopy in patients with upper GI bleed. However, this should not change management in variceal bleeds, as endoscopy is indicated within 12 hours. TXA does not appear to change mortality, rate of re-bleeding or transfusion requirements. The biggest flaw of this study, at least pertaining to our discussion, is that it is not specific to cirrhotic variceal bleeding.

HALT-IT Trial

    • The HALT-IT trial is currently ongoing and aims to assess whether early administration of tranexamic acid in people with acute gastrointestinal bleeding can reduce their risk of hospital mortality,
    • Secondary outcomes include rates of re-bleeding, non-fatal vascular events, blood transfusion, surgical intervention and general health status.
    • The HALT-IT trial began recruitment on 4 July 2013 and is aiming to recruit 12,000 patients from hospitals worldwide by 31 May 2019.
    • More information on trial progress can be found here

Bottom Line: ACOG does not give specific recommendations on the use of TXA for acute GI bleeds given the lack of evidence. However, its safety has some good backing at this point and clinicians should consider its use in these patients. Especially if increased fibrinolysis is suggested on TEG. Hopefully, with completion of the HALT-IT Trial, more insight will be given in which a change in practice can be confirmed.

Antibiotics

Up to 20% of cirrhotic patients who are hospitalized due to GI bleeding present with bacterial infections and an additional 50% will develop an infection while hospitalized.38 This risk is highest in those with more severe liver disease (Child B and C). Short-term prophylactic antibiotics in patients with cirrhosis and GI bleeding has been shown to decrease the rate of bacterial infections and also decrease mortality.

Bernard, 199939

    • Meta-analysis of 5 trials including 534 patients
    • Assessed efficacy of antibiotic prophylaxis in the prevention of infections and its effect on survival rate in cirrhotic patients with gastrointestinal bleeding.
    • Four end points were assessed:
        • infection
        • bacteremia and/or spontaneous bacterial peritonitis (SBP)
        • incidence of SBP
        • death.
    • Results:
      • Infection decrease: 32%
      • Survival increase: 9.1%

Study Conclusion: In cirrhotic patients with GI bleeding, short-term antibiotic prophylaxis significantly increases the mean percentage of patients free of infection and significantly increases short-term survival rate.

Soares-Weiser, 200238

    • Cochrane review of 8 randomized clinical trials including 864 patients
    • Assessed different types of antibiotic prophylaxis with placebo, no intervention, or another antibiotic to prevent bacterial infections in cirrhotic patients with gastrointestinal bleeding.
    • Results:
      • Significant beneficial effect on decreasing mortality (RR 0.73, 95% CI 0.55 to 0.95)
      • Reduced incidence of bacterial infections (RR 0.40, 95% CI 0.32 to 0.51)
      • No serious adverse events were reported.

Study Conclusion: Antibiotic prophylaxis for cirrhotic inpatients with gastrointestinal bleeding is efficacious in reducing the number of deaths and bacterial infections, are well tolerated, and should be advocated.

Hou, 200440

    • Randomized controlled trial of 120 patients with cirrhosis and acute variceal bleed but no evidence of bacterial infection.
    • Assessed benefit of antibiotic prophylaxis on rate of re-bleeding
    • Clinical and endoscopic characteristics of the gastroesophageal varices, time to endoscopic treatment, and period of follow-up were not different between the two groups.
    • Results:
      • Antibiotic prophylaxis decreased infections (2/59 vs. 16/61)
      • Rate of re-bleeding higher in patients without prophylactic antibiotics (P =.0029).
      • Blood transfusion was also reduced in the prophylactic group (1.40 +/- 0.89 vs. 2.81 +/- 2.29 units, P <.05).
      • There was no difference in survival between the two groups.

Study Conclusion: Antibiotic prophylaxis can prevent infection and re-bleeding as well as decrease the amount of blood transfused for patients with acute GEVB following endoscopic treatment.

Does infection increase risk of Variceal bleeding?

Patients with cirrhosis express increased plasma concentrations of endothelium derived endogenous heparinoids due to increased production and decreased hepatic clearance.30

Stravitz, 201230

    • Prospective cohort study of decompensated cirrhotics admitted to the hospital
    • 36% developed an infection
    • Thromboelastography findings
        • Infected patients:
            • TEG parameters became more hypo-coagulable in patients who developed an infection
            • Resolution of infection was associated with improvement in TEG parameters to pre-infection levels
            • Persistence of infection was associated with continued deterioration of hemostasis as measured by TEG, but not by standard laboratory tests of hemostasis.
        • Non-infected patients:
            • TEG parameters remained unchanged

Papatheodoridis, 199941

    • Prospective analysis of 84 patients with cirrhosis admitted to the hospital for non-bleeding indications.
    • 30 patients had infection (15 on admission, 15 developed after admission)
    • Results:
      • r-time, α-angle, and maximum amplitude were hypo-coagulable in those who developed infection compared to those who did not develop an infection
      • The same parameters significantly improved in patients whose infection resolved
      • The r-time, α-angle, k parameters significantly worsened in those with persistent infection.

Study conclusion: Bacterial infections frequently impair hemostasis in decompensated cirrhotic patients. Successful treatment of infection usually restores hemostasis parameters to preinfection levels in 5 days. Thus, infection may have a role in the bleeding diathesis of cirrhosis.

Bottom Line: Short-term antibiotic prophylaxis should be considered standard practice in all patients with cirrhosis and acute variceal hemorrhage with or without ascites as they have been shown to decrease re-bleeding and improve mortality. ACOG recommends IV Ceftriaxone (1 gram every 24 hours) for patients with advanced cirrhosis. Antibiotics should be continued for a maximum of 7 days and cover gram-negative organisms (Class I, Level B evidence).

Erythromycin

Erythromycin is a prokinetic and theoretically may help improve gastric visualization during endoscopy.

So, does it?

Barkun, 201043

    • Meta-analysis of 3 fully published randomized trials and 2 abstracts assessing a total of 316 patients
    • Assessed prokinetic agents in acute UGIB (Erythromycin and Metoclopramide
    • Primary outcome was the need for a repeat EGD.
    • Secondary outcomes included endoscopic visualization, blood transfusions, duration of hospitalization, and surgery.
    • Results:
      • Erythromycin significantly reduced the need for repeat EGD (OR 0.55; 95% CI, 0.32-0.94). In subgroup analysis, Metroclopramide did not. 
      • The number of units of blood was not significantly altered (WMD, -0.40; 95% CI, -0.86 to 0.06)
      • Hospital stay was not significantly altered (WMD, -1.04; 95% CI, -2.83 to 0.76)
      • Need for surgery was not significantly altered (OR 1.11; 95% CI, 0.27-4.67).
      • Endoscopic visualization was not analyzed because the disparate definitions across studies did not allow for meaningful clinical

Study Conclusion: IV erythromycin immediately before EGD in acute UGIB patients decreases the need for a repeat EGD, but does not improve other clinically relevant measurable outcomes.Endoscopic visualization was not analyzed.

Bai, 201144

    • Meta-analysis of 4 randomized controlled trials of patients with acute upper GI bleed
    • Results:
      • incidence of empty stomach was significantly increased in patients receiving erythromycin (active group 69%, control group 37%, P<0.00001).
      • Need for second endoscopy, amount of blood transfusion and the length of hospital stay were also significantly reduced (all P<0.05).
      • A trend for shorter endoscopic procedure time and decreased mortality rate was observed.

Study Conclusion: Erythromycin is useful for patients with upper gastrointestinal bleeding to decrease the amount of blood in the stomach and reduce the need for second endoscopy, amount of blood transfusion. It may shorten the length of hospital stay, but its effects on mortality need further larger trials to be confirmed.

Bottom Line: Current literature suggests that a single dose of IV Erythromycin given 20-120 minutes before endoscopy is relatively safe and can improve gastric visibility, shorten endoscopy time and reduce the need for a second endoscopy in upper GI bleeding. While the literature does not specifically address variceal bleeding…if recommended by the endoscopist…just give it.

NG Tube Lavage

NGT lavage has traditionally been used to help confirm gastrointestinal bleeding in patients whose diagnosis is questionable and serve as an adjunct to aid with endoscopy. It’s use is somewhat controversial The question is: is NG placement safe to do in suspected varices and does NGT lavage actually improve endoscopy outcomes?

Let’s take look at the evidence…

Singer, 199945

    • Prospective, observational, cross-sectional study conducted at a university-based ED
    • Assessed patient perspectives of the most painful procedures done in the emergency department
    • A total of 1, 171 procedures were evaluated for the 15 most common procedures performed.
    • Results: The most painful procedures according to patients (in descending order)
        • Nasogastric intubation
        • Abscess drainage
        • Fracture reduction
        • Urethral catheterization.

Study Conclusion: Nasogastric tube insertion is the most painful procedure done in the emergency department.

Paterson, 201146

    • Prospective, randomized, multicenter study across 6 emergency departments
    • 253 patients with acute upper gastrointestinal bleeding presenting with hematemesis or melena.
    • Patients randomized into 3 groups:
        • (1) IV erythromycin infusion without nasogastric tube placement (erythromycin group)
        • (2) nasogastric tube placement without erythromycin (nasogastric group)
        • (3) IV erythromycin infusion combined with nasogastric tube placement (nasogastric-erythromycin group).
    • Results:
        • Stomach visualization: Satisfactory in 85% with no significant difference
        • Duration of endoscopic procedure: No significant difference
        • Re-bleeding: No significant difference
        • Need for second endoscopy: No significant difference
        • Number of transfused blood units: No significant difference
        • Mortality at 2, 7 and 30 days: No significant difference

Study Conclusion: In acute upper gastrointestinal bleeding, administration of intravenous erythromycin provides satisfactory endoscopic conditions, without the need for a nasogastric tube and gastric lavage.Nasogastric tube insertion was not associated with an increased risk of re-bleeding frequency, number of transfused blood units or changes in mortality out to 30 days.

Huang, 201147

    • University-based Veterans Affairs medical center retrospective analysis of 632 patients admitted with GI bleeding.
    • Assessed whether NGL is associated with improved process measures and outcomes in GI bleeding
    • Main outcomes measured include 30 mortality rate, length of hospital stay, transfusion requirements, surgery, and time to endoscopy.
    • Results:
        • Mortality: no difference (OR 0.84; 95% CI, 0.37-1.92)
        • length of hospital stay: no difference (7.3 vs 8.1 days, P= .57)
        • Need for surgery: no difference (OR 1.51; 95% CI, 0.42-5.43)
        • Transfusions: no difference (3.2 vs 3.0 units, P= .94)
        • Time to endoscopy: NGL was associated with earlier time to endoscopy (hazard ratio 1.49; 95% CI, 1.09-2.04)

Study Conclusion: Performing NGL is associated with the earlier performance of endoscopy, but does not affect clinical outcomes.

Rockey, 201748

    • Single-blind, randomized, prospective, non-inferiority study of 280 patients with GI bleed
    • Comparing NG placement (with aspiration and lavage) to no NG placement (control).
    • Assessed the usefulness of NG tube placement in patients with UGIB
    • Primary outcome was the probability that physicians could predict the presence of a high-risk lesion (ie, requiring endoscopic therapy) based on NG tube output.
    • Baseline clinical features were similar in each group.
    • Results:
        • Physicians predicted the specific culprit lesion in 38% in the control group and 39% in the NG placement group
        • The presence of coffee grounds or red blood in the NG aspirate did not change physician assessments
        • Pain, nasal bleeding, or failure of NG occurred in 34% patients
        • There were no differences in re-bleeding rates
        • No difference in mortality

Study Conclusion: In patients with acute UGIB, the ability of physicians to predict culprit bleeding lesions and/or the presence of high-risk lesions was poor. Routine NG placement did not improve physician’s predictive ability, did not affect outcomes, and was complicated in one-third of patients.

Palamadessi, 201049

    • Cochrane database review of 3 retrospective studies
    • Assessed if does nasogastric aspiration and lavage in patients with melena or hematochezia and no hematemesis differentiate an upper from lower source of bleeding
    • Results:
        • The prevalence of an upper GI source for patients with melena or hematochezia without hematemesis was 32% to 74%.
        • Sensitivity ranged from 42% to 84%
        • Specificity ranged from 54% to 91%
        • Negative likelihood ratios ranged from 0.62 to 0.20.
        • Only one study reported the rate complications associated with nasogastric aspiration and lavage at 1.6%

Study Conclusion: Nasogastric aspiration, with or without lavage, has a low sensitivity and poor negative likelihood ratio, which limits its utility in ruling out an upper GI source of bleeding in patients with melena or hematochezia without hematemesis.

Bottom Line: NGT lavage may be of benefit in patients when it is unclear if there is ongoing bleeding and to identify patients who pay require early endoscopy, but cannot be used to rule out an upper GI bleed. NG tube has been associated with a decreased time to initial endoscopy, but there is no improvement in rates of re-bleeding, mortality, transfusion requirement, duration of endoscopy or adequacy of stomach visualization. Not to mention, it is the most painful procedure we have to offer patients in the Emergency Department. While the exact risk of hemorrhage from insertion of a nasogastric tube in suspected variceal bleed is unknown, we can extrapolate from the data above that Nasogastric tube insertion is not associated with an increased risk of re-bleeding frequency, number of transfused blood units or changes in mortality out to 30 days. There is a general consensus among endoscopists that suspected rupture of esophageal/gastric varices probably does not contraindicate nasogastric intubation.50

Balloon Tamponade

The use of balloon tamponade is quite effective at temporarily controlling bleeding temporarily with immediate control of hemorrhage with success rates ranging anywhere from 30-90% in literature.51 Most of this data on success is derived between the 1970’s through the early 1990’s. While considered beneficial it is not without potentially catastrophic risk. Apiration, asphyxia and esophageal perforation are associated with its 20% mortality. Further, re-bleeding is seen in 50% of cases. Therefore, balloon tamponade should only be used for massive bleeding as a rescue therapy to bridge to endoscopy or TIPS. An airway should be secured and the tube should be removed within 24 hours of placement to decrease complication risks.5

EMCrit has a nice summary on how these tubes are placed that you can find here…

Treatments that don't help (at least not acutely)

Vitamin K

ACOG guidelines do not recommend Vitamin K for the acute treatment of Variceal hemorrhage. Vitamin K therapy does not cause significant improvements in the majority of coagulation parameters and hence does not seem to be routinely indicated in patients with liver disease.In a 2013 study of 89 cirrhotics administered a single 10 mg dose of subcutaneous Vitamin K. Prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, FVII, protein C, total and free protein S were measured at baseline and 72 h after vitamin K administration. Compared to baseline, vitamin K administration did not cause significant improvements in the majority of coagulation parameters.55  

Further, a 2015 Cochrane review found no randomized controlled trials in which to provide evidence to recommend or refute the use of vitamin K for upper gastrointestinal bleeding in people with liver diseases.Plus, with its very slow onset of action, it is unlikely to offer benefit before endoscopy.  

Beta Blockers

ACOG guidelines state that Beta-blockers should not be used in the acute setting as they will decrease blood pressure and will blunt a physiologic increase in heart rate associated with bleeding.

Factor VII

Recombinant activated factor VII (rFVIIa) has been shown to transiently correct prothrombin time in cirrhotics (Child-Pugh A, B and C) for up to 2-4 hours. It costs about $11,000 per dose, and again, we are just chasing a number here. It’s use has been assessed in 2 randomized controlled trials looking at 501 cirrhotic patients presenting with an acute upper GI bleed receiving a protocol of 8 separate doses of rFVIIa (that’s $11,000 x 8 doses = money). While these studies described relatively safety with no increased adverse effects in regards to thromboembolic event, it failed to show any advantage in regards to control of bleeding, rate of re-bleeding or mortality. However, after exploratory analyses of these studies in cirrhotic patients with Child-Pugh B and C, administration of rFVIIa significantly decreased the proportion of patients who failed to control variceal bleeding. But at the cost, there just isn’t enough proof of evidence to justify its use…and did I mention the cost??? ACOG guidelines state that confirmatory studies are needed before this expensive therapy can be recommended in patients with coagulopathy and variceal bleeding.

DDAVP

Desmopressin (DDAVP), is a drug that decreases bleeding time in cirrhosis. However, it has shown no clinical benefits in the setting of variceal bleeding. In fact, one study assessing the benefit of DDAVP in 46 cirrhotics with acute variceal hemorrhage was halted early because treatment with DDAVP was associated with significantly higher treatment failure when combined with vasoactive medicaations.54

References

  1. D’Amico G, De Franchis R. Upper digestive bleeding in cirrhosis. Post-therapeutic outcome and prognostic indicators. 2003;38:599–612. [PubMed]
  2. AugustinS,GonzálezA, GenescàJ, Acute esophageal variceal bleeding: Current strategies and new perspectives. World J Hepatol. 2010 Jul 27; 2(7):261-274.
  3. D’Amico G, Pagliaro L, Bosch J. Pharmacological treatment of portal hypertension: an evidence-based approach. Semin.Liver Dis. 1999;19:475–505. [PubMed] 
  4. Austin MJ, Shawcross DL. Outcome of patients with cirrhosis admitted to intensive care.Curr Opin Crit Care. 2008;14:202–207. [PubMed] 
  5. Garcia-Tsao G, Sanyal A., at al. Prevention and Management of Gastroesophageal Varices and Variceal Hemorrhage in Cirrhosis. the Practice Guidelines Committee of the American Association for the Study of Liver Diseases and the Practice Parameters Committee of the American College of Gastroenterology. American Journal of Gastroenterology.2007;102(9):2086-2102.
  6. de Franchis R. Evolving Consensus in Portal Hypertension Report of the Baveno IV Consensus Workshop on methodology of diagnosis and therapy in portal hypertension.J Hepatol 2005;43:167–176.PubMed
  7. Kravetz D, Sikuler E, Groszmann RJ. Splanchnic and systemic hemodynamics in portal hypertensive rats during hemorrhage and blood volume restitution. 1986;90:1232–1240. [PubMed] [Google Scholar]
  8. Bosch J, Garcia-Pagan JC. Complications of cirrhosis. I. Portal hypertension. J Hepatol. 2000;32:141–156. [PubMed] [Google Scholar]
  9. Moitinho E, Escorsell A, Bandi JC, Salmeron JM, Garcia-Pagan JC, Rodes J, Bosch J. Prognostic value of early measurements of portal pressure in acute variceal bleeding. Gastroenterology1999;117:626–631.
  10. Castañeda B, Morales J, Lionetti R, Moitinho E, Andreu V, Pérez-Del-Pulgar S, Pizcueta P, Rodés J, Bosch J. Effects of blood volume restitution following a portal hypertensive-related bleeding in anesthetized cirrhotic rats. 2001;33:821–825. [PubMed] [Google Scholar]
  11. Villanueva C, Colomo A, et al. Transfusion strategies for acute upper gastrointestinal bleeding. N Engl J Med. 2013 Jun 13;368(24):2341.
  12. D’Amico G, Pietrosi G, Tarantino I, Pagliaro L. Emergency sclerotherapy versus vasoactive drugs for variceal bleeding in cirrhosis: a Cochrane meta-analysis. 2003;124:1277–1291.[PubMed] [Google Scholar]
  13. Bañares R, Albillos A, Rincon D, Alonso S, Gonzalez M, Ruiz-del-Arbol L, Salcedo M, Molinero LM. Endoscopic treatment versus endoscopic plus pharmacologic treatment for acute variceal bleeding: A meta-analysis. Hepatology2002;305:609–615.
  14. Escorsell A, Bandi JC, Moitinho E, Feu F, Garcia-Pagan JC, Bosch J. Time profile of the haemodynamic effects of terlipressin in portal hypertension. J Hepatol. 1997;26:621–627. [PubMed] [Google Scholar]
  15. Ioannou GN, Doust J, Rockey DC. Systematic review: terlipressin in acute oesophageal variceal haemorrhage. Aliment Pharmacol Ther. 2003;17:53–64. [PubMed] [Google Scholar]
  16. Escorsell A, Ruiz del Arbol L, Planas R, Albillos A, Bañares R, Calès P, Pateron D, Bernard B, Vinel JP, Bosch J. Multicenter randomized controlled trial of terlipressin versus sclerotherapy in the treatment of acute variceal bleeding: the TEST study. 2000;32:471–476. [PubMed] [Google Scholar]
  17. Moreau R, Soubrane O, Hadengue A, Sogni P, Gaudin C, Kleber G, Lebrec D. [Hemodynamic effects of the administration of terlipressin alone or combined with nitroglycerin in patients with cirrhosis] Gastroenterol Clin Biol. 1992;16:680–686.[PubMed] [Google Scholar]
  18. Burroughs AK, McCormick PA, Hughes MD, Sprengers D, D’Heygere F, McIntyre N. Randomized, double-blind, placebo-controlled trial of somatostatin for variceal bleeding. Emergency control and prevention of early variceal rebleeding. 1990;99:1388–1395. [PubMed] [Google Scholar]
  19. Escorsell A, Bandi JC, Andreu V, Moitinho E, García-Pagán JC, Bosch J, Rodés J. Desensitization to the effects of intravenous octreotide in cirrhotic patients with portal hypertension. 2001;120:161–169. [PubMed] [Google Scholar]
  20. Burroughs AK. Double blind RCT of 5 day octreotide versus placebo, associated with sclerotherapy for trial/failures. 1996;24:A352. [Google Scholar]
  21. Bajaj JS, Sanyal AJ. Methods to achieve hemostasis in patients with acute variceal hemorrhage. UptoDate. 2015.
  22. Gotzsche PC, Hrobjartsson A. Somatostatin analogues for acute bleeding oesophageal varices. Cochrane Database Syst Rev. 2008;(3):CD000193. doi(3):CD000193.
  23. Corley DA, Cello JP, Adkisson W, Ko WF, Kerlikowske K. Octreotide for acute esophageal variceal bleeding: a meta-analysis. 2001;120:946–954.[PubMed] [Google Scholar]
  24. Hshieh T, Kaung A, et al. The International Normalized Ratio does not Reflect Bleeding Risk in Esophageal Variceal Hemorrhage. Saudi J Gastroenterol. 2015 Jul-Aug; 21(4): 254–258. doi: 4103/1319-3767.161646
  25. Rout G, Shalimar G, et al. Thromboelastography-guided Blood Product Transfusion in Cirrhosis Patients With Variceal Bleeding: A Randomized Controlled Trial. J Clin Gastroenterol.2019 Apr 17. doi: 10.1097/MCG.0000000000001214.
  26. Wells M, Chande N, et al. Meta-analysis: vasoactive medications for the management of acute variceal bleeds. Aliment Pharmacol Ther. 2012 Jun;35(11):1267-78. Epub 2012 Apr 8. 
  27. Hayashi H, Beppu T, et al. Management of thrombocytopenia due to cirrhosis: a review. World J Gastroenterol. 2014 Mar 14:20(10): 2595-2605. doi: 3748/wjg.v20.i10.2595
  28. Tripodi A, Primignani M, Chantarangkul V, et al. Global hemostasis tests in patients with cirrhosis before and after prophylactic platelet transfusion. Liver Int 2013;33:362-7.
  29. Tripodi A, Primignani M, Chantarangkul V, et al. Thrombin generation in patients with cirrhosis: the role of platelets. Hepatology 2006;44: 440-5.
  30. Stravitz R. Potential applications of thromboelastography in patients with acute and chronic liver disease. Gastroenterol Hepatol (NY). 2012; 8(8): 513-520.
  31. Noval-Padillo JA, León-Justel A, et al. Introduction of fibrinogen in the treatment of hemostatic disorders during orthotopic liver transplantation: implications in the use of allogenic blood. Transplant Proc.2010 Oct;42(8):2973-4. doi: 10.1016/j.transproceed.2010.08.011.
  32. Abraldes JG, Villanueva C, Banares R. et al. Hepatic venous pressure gradient and prognosis in patients with acute variceal bleeding treated with pharmacologic and endoscopic therapy. J Hepatol 2008;48:229–36. [PubMed] 
  33. Hag I, Tripathi D. Recent advances in the management of variceal bleeding. Gastroenterol Rep (Oxf). 2017; 5(2):113-126. doi: 1093/gastro/gox007
  34. Leebeek F, Rijken D. The Fibrinolytic Status in Liver Diseases. Semin Thromb Hemost.2015 Jul;41(5):474-80. doi: 10.1055/s-0035-1550437. Epub 2015 Jun 6.
  35. Bennett C, Klingenberg SL, Langholz E, Gluud LL. Tranexamic acid for upper gastrointestinal bleeding.Cochrane Database of Systematic Reviews2014, Issue 11. Art. No.: CD006640.DOI: 10.1002/14651858.CD006640.pub3.
  36. Molenaar IQ, Warnaar N, Groen H, et al.Efficacy and safety of antifibrinolytic drugs in liver transplantation: a systematic review and meta-analysis. Am J Transplant 2007;7:185–94. 10.1111/j.1600-6143.2006.01591.x [PubMed] [CrossRef] [Google Scholar]
  37. Tavakoli N, Mokhtare M, et al. Comparison of the efficacy of intravenous tranexamic acid with and without topical administration versus placebo in urgent endoscopy rate for acute gastrointestinal bleeding: A double-blind randomized controlled trial. United European Gastroenterol J. 2018 Feb; 6(1): 46–54. doi: 1177/2050640617714940
  38. Soares-Weiser K, Brezis M, Tur-Kaspa R, Leibovici L. Antibiotic prophylaxis for cirrhotic patients with gastrointestinal bleeding. Cochrane Database Syst Rev. 2002:CD002907.[PubMed] 
  39. Bernard B, Grange JD, Khac EN, Amiot X, Opolon P, Poynard T. Antibiotic prophylaxis for the prevention of bacterial infections in cirrhotic patients with gastrointestinal bleeding: a meta-analysis. 1999;29:1655–1661. PubMed
  40. Hou MC, Lin HC, Liu TT, Kuo BI, Lee FY, Chang FY, Lee SD. Antibiotic prophylaxis after endoscopic therapy prevents rebleeding in acute variceal hemorrhage: a randomized trial. Hepatology2004;39:746–753.
  41. Papatheodoridis GV, Patch D, Webster GJ, Brooker J, Barnes E, Burroughs AK. Infection and hemostasis in decompensated cirrhosis: a prospective study using thrombelastography. 1999;29:1085–1090. [PubMed] 
  42. Montalto P, Vlachogiannakos J, Cox DJ, Pastacaldi S, Patch D, Burroughs AK. Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study. J Hepatol. 2002;37:463–470. [PubMed] 
  43. Barkun AN, Bardou M, et al,. Prokinetics in acute upper GI bleeding: a meta-analysis. Gastrointest Endosc. 2010;72(6):1138. 
  44. Bai Y, Guo JF, Li SZ. Meta-analysis: erythromycin before endoscopy for acute upper gastrointestinal bleeding. Aliment Pharmacol Ther. 2011;34(2):166. Epub 2011 May 25. 
  45. Singer, A.J., Richman, P.B., Kowalska, A. et al. Comparison of patient and practitioner assessments of pain from commonly performed emergency department procedures. Ann Emerg Med. 1999; 33: 652–658
  46. Pateron D, Vicaut E, et al,.  Erythromycin infusion or gastric lavage for upper gastrointestinal bleeding: a multicenter randomized controlled trial. Ann Emerg Med. 2011;57(6):582. Epub 2011 Feb 17.
  47. Huang, E.S., Karsan, S., Kanwal, F. et al. Impact of nasogastric lavage on outcomes in acute GI bleeding. Gastrointest Endosc. 2011; 74: 971–980
  48. Rockey DC, Ahn C, de Melo SW Jr. Randomized pragmatic trial of nasogastric tube placement in patients with upper gastrointestinal tract bleeding. J Investig Med. 2017;65(4):759. Epub 2017 Jan 9.
  49. Palamidessi N, Sinert R, Falzon L, Zehtabchi S. Nasogastric aspiration and lavage in emergency department patients with hematochezia or melena without hematemesis.Acad Emerg Med. 2010;17:126–132. doi: 10.1111/j.1553-2712.2009.00609.x. [PubMed]
  50. Osman D, Djibre M, et al,. Management by the intensivist of gastrointestinal bleeding in adults and children. Ann Intensive Care. 2012; 2: 46.Published online 2012 Nov 9. doi: 1186/2110-5820-2-46
  51. Avgerinos A, Armonis A. Balloon tamponade technique and efficacy in variceal haemorrhage. Scand J Gastroenterol Suppl1994;207:11–6.
  52. Bosch J, Thabut D, Albillos A, Carbonell N, Spicak J, Massard J, D’Amico G, Lebrec D, de Franchis R, Fabricius S, et al. Recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: A randomized, controlled trial. 2008;47:1604–1614. [PubMed] 
  53. Bosch J, Thabut D, Bendtsen F, D’Amico G, Albillos A, González Abraldes J, Fabricius S, Erhardtsen E, de Franchis R. Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial. 2004;127:1123–1130. [PubMed] 
  54. de Franchis R, Arcidiacono PG, Carpinelli L, Andreoni B, Cestari L, Brunati S, Zambelli A, Battaglia G, Mannucci PM. Randomized controlled trial of desmopressin plus terlipressin vs. terlipressin alone for the treatment of acute variceal hemorrhage in cirrhotic patients: a multicenter, double-blind study. New Italian Endoscopic Club. 1993;18:1102–1107. [PubMed]
  55. Saja MF, Abdo AA, et al,. The coagulopathy of liver disease: does vitamin K help? Blood Coagul Fibrinolysis.2013 Jan;24(1):10-7. doi: 10.1097/MBC.0b013e32835975ed.
Want updates in your inbox?
I agree to have my personal information transfered to MailChimp ( more information )
Subscribe and receive email alerts when new topics are published.
We hate spam. Your email address will not be sold or shared with anyone else.
Nicholas McManus
Latest posts by Nicholas McManus (see all)

Share this post

Share on facebook
Share on google
Share on twitter
Share on print
Share on email