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Upper Gastrointestinal Bleeding

Audis Bethea, Pharm.D.

Assistant Professor

Therapeutics IV

April 13, 2004

Upper Gastrointestinal BleedingOccurs in approximately 100 cases per 100,000 adults per year

Overall mortality from acute GI bleeding is approximately 6-7%

Mortality rates approach 30% for upper GI bleeds due to varices

Mortality rates may confounded by concomitant diseases present in patients who present with gastrointestinal bleeds

Bleeding occurring from one of the following organsEsophagusStomachDuodenum

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Esophageal Bleeding

Mallory-Weiss tearsMost common cause of all upper GI bleeds Longitudinal tears caused by retching

Erosive esophagitisResult of severe gastroesophageal reflux disease (GERD)

Esophageal varicesResult of portal hypertension

Stomach and Duodenal BleedingGastric varices

Most common cause of gastric bleedingResult of portal hypertension

Peptic ulcersSecond leading cause of gastric bleedingSevere peptic bleeds result in mortality rates of 10-25%

Stress related mucosal lesions (Stress ulcers)Injury to gastric mucosa secondary to elevated physiologic stressGastric erosions are present in approx. 90% of patients by the third ICU day

Duodenal ulcer / duodenitisMost often associated with H. pylori overgrowth/infection

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Upper Gastrointestinal Bleeding

OvertMelenaHematocheziaBloody gastric aspirateHematemesis

Clinically significant bleedingAny or all of the above resulting in significant blood loss requiring clinical intervention

Management of Upper GI Bleed

StabilizationABCsIntubationAssessment of cardiovascular statusIntravenous accessFluid resuscitationLaboratory parameters

• BMP, CBC, coagulation panel

DiagnosisEndoscopic examSedation and/or analgesia

• Benzodiazepines• Opiates

TreatmentDepends on the source of the bleedContinue cardiovascular stabilization Empiric therapy targets ulcer and variceal bleeds

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Management of Upper GI Bleed

LethargicConfusedAgitatedAnxious Mental Status

< 55 – 1520 – 30> 30Urine output (mL/hr)

DecreasedDecreasedNormalNormal Supine blood pressure

> 140> 120> 100< 100 Pulse rate

> 40%30 – 40%15 – 30%< 15%% Loss of volume

Class IVClass IIIClass IIClass IParameter

Management of Upper GI Bleed

Whole blood RV = VDColloid = 1.5 X VD

Crystalloid RV = 4 X VD

Determine resuscitation volume (RV)

VD = BV X % lossCalculate volume deficit (VD)

Refer to previous slideEstimate % loss of blood volume

Whole blood Male = 66 mL/kg, female = 60 mL/kg

Estimate normal blood volume

DescriptionSequence

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Management of Upper GI BleedFluid resuscitation

Crystalloids (Normal saline, lactated ringers)• Isotonic fluids freely distribute; 3:1 extravascular to intravascular space• Requires large amounts of fluid to achieve adequate volume expansion

Colloids (Dextran, albumin, and hetastarch)• Large oncotically active molecules that are relatively impermeable to vasculature• Expand vascular volume 2 to 4 times more than that of crystalloids• Colloids have no advantage over crystalloids in reducing mortality

Blood products• Used only to supplement intravenous fluids

– One unit of packed RBCs increases Hgb by approximately 1 g/dL and Hct by 3%• Usually not necessary for Class I or Class II hypovolemia

Non-variceal Esophageal Lesions

Mallory-Weiss tearsBleeding typically subsides spontaneously after retching stopsPersistent bleeding

• Cauterization via endoscopy• Prevention of acid secretion via H2-antagonist or proton pump

inhibitors (PPI)• Antiemetics to prevent retching / emesis

No formal algorithms or recommendations exist

Erosive esophagitisAntisecretory therapy to increase gastric pH See PUD / GERD lectures

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Variceal LesionsDefinition

Tortuous, collateral vessel that forms in response to ↑ portal pressureVarices divert blood flow from the portal vein, lowering portal pressure

EpidemiologyApproximately 40–60% of patients with cirrhosis develop gastroesophageal varicesEsophageal and gastric varices account for approximately 30 % upper GI bleedsUp to 30% of initial variceal bleeds are fatal70% of patients will have recurrent variceal bleedsOne-year survival rate following variceal bleed is 32-80%

Etiology of Variceal LesionsCirrhosis

Impeded hepatic flowPortal Hypertension

Dilation of portal vascular channelsDilated vascular channels

Portosystemic collateral vessels (varices)Varices

Shunt blood away from portal vein

Risk factors for variceal bleedSeverity of liver diseaseContinued alcohol consumption Varix sizeElastic properties of the vesselIntravariceal pressureVariceal wall tension

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Management of Variceal Bleeds

Fluid resuscitationCrystalloids, colloids, and blood products

Endoscopic therapyInjection sclerotherapy

• 70-80% efficacy for acute bleeds• Numerous complications

Variceal ligation (banding)• Bands wrapped around esophageal

mucosa• 70-80% efficacy for acute bleeds• Fewer complications

Management of Variceal Bleeds

Balloon tamponadeApplies direct pressure to bleeding varixBridge therapy in patients w/ excessive bleeding↑ incidence of complications

• Esophageal laceration or rupture

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Pharmacologic Therapy of Variceal BleedsVasopressin

Endogenous peptide, also known as antidiuretic hormone (ADH)Stimulates V1 receptors in smooth muscle of vasculature

• ↓ splanchnic blood flow of organs feeding into the portal system; ↓ portal pressureSystemic vasoconstriction → myocardial and mesenteric ischemia limits use The addition of nitroglycerin infusion improves efficacy and ↓ side effects

DosingVasopressin → 30-40 units bolus over 30-40 min.; continuous infusion 0.4-0.8 u/minNitroglycerin → initiate infusion at 40-50 mcg/min; titrate up to 400 mcg/min

• *Maintain SBP ≥ 100 mmHg*

Pharmacologic Therapy of Variceal Bleeds

OctreotideSynthetic analogue of the naturally occurring peptide somatostatin

• Secreted by the hypothalamus, pancreas, and gastrointestinal tractInhibits the secretion of numerous hormones:

• Pituitary gland → growth hormone• Pancreas → insulin and glucagon• Gastrointestinal tract → gastrin, gastric acid, pepsin, and cholecystekinin• Nervous system → substance P

Mechanism of actionInhibits variceal bleeding by reducing splanchnic blood flow and portal pressure

• Prevention of postprandial hyperemia• Inhibition of vasodilatory effects of substance P and glucagon

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Pharmacologic Therapy of Variceal BleedsOctreotide

Randomized, controlled trials have found octreotide to be more effective vs. vasopressin with substantially fewer adverse effectsTypically used in conjunction with endoscopic therapy

Dosing50 mcg bolus (IVP); continuous infusion of 25-50 mcg/hr x 24-48 hoursBreakthrough bleeding → additional 50 mcg bolus; ↑ rate to 50 mcg/hour

Adverse effectsHyperglycemia, abdominal cramping, bradycardia, and biliary congestion

IV preparation1200 mcg in 250 mL of diluent (normal saline)Stable for up to 48 hours when stored at room temperature or refrigerated

Surgical Treatment of Variceal Bleeds

Salvage therapy with failure of endoscopic or pharmacologic therapy

Portosystemic shuntCompletely bypasses liver

Transjugular intrahepatic portosystemicshunt (TIPS)

Implanted into the liver bypassing the liverRisk of rebleed is 8-18% per yearIncreases risk of hepatic encephalopathyStenosis occurs in about 50% of patients within 2 years

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Management of Peptic Ulcers

Fluid resuscitation measuresCardiovascular stabilizationAssessment of precipitating cause (ex. NSAIDs)Pharmacological management → identical to treatment for bleeding stress ulcer

Stress Ulcers and GastritisDefinition

Acute superficial inflammatory lesion of the gastroduodenal mucosa • Associated with abnormally elevated physiologic demands

EpidemiologyEndoscopic evidence of stress gastritis is evident within 24 hours of admissionGastric erosions are present in approx. 90% of patients by the third ICU dayGastrointestinal bleeding occurs in up to 50 - 70% of critically ill patientsClinically significant bleeds occur in 5-30% of patients with stress gastritis Mortality rates from clinically significant bleeds approach 50%

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Stress Ulcers and Gastritis

EtiologyAlteration in gastric mucosal defense

• Reduced perfusion of gut mucosalDecreased delivery of bicarbonate and adenosine triphosphate to gut mucosa

• Generation of oxygen-derived free radicalIntraluminal acid

• Impaired perfusion results in impaired removal of gastric acid from the mucosa and back diffusion of hydrogen ions

Breakdown of gastric mucosal barrier

Formation of Stress Ulcers and GastritisGut Mucosal Ischemia

Impaired Protective Mechanisms↓ Prostaglandin Production

↓ Mucous / bicarbonate barrier

↓ H+ back diffusion

↓ Epithelial removal

↓ Mucous / bicarbonate barrier

Gastrointestinal Bleed

Acid Secretion

?? H. Pylori

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Risk Factors for Stress Ulcers and Gastritis

Mechanical ventilation

Sepsis

Coagulopathy / anticoagulation

Burn patients

Renal failure

Age > 65 years

Corticosteroid therapy / NSAIDS

Recent history of gastric ulcers / bleed

Head trauma / bleed

Anaphylaxis

Severe polytrauma

Ileus or other gastroenterologic disease

Renal disease

SBP < 100 mmHg for > 1 hour

Stress ulcers vs. Peptic Ulcer DiseaseStress ulcers

Often asymptomaticSuperficialLocated in acid producing areasRarely perforateUsually produce superficial bleeding

Peptic ulcer diseaseSymptomaticDeep, well definedDuodenal bulb, gastric antrum Commonly perforateExtensive bleeding from exposed vessel(s)

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Stress Ulcers: Preventive Strategies

Preservation of mesenteric blood flowMaintain systemic perfusion and Do2

Enteral nutrition Reduce risk of stress ulcer bleeding

• Maintains functional integrity of gut

PharmacologicCytoprotective agents

• SucralfateAntacidsAntisecretory agents

• H2-antagonists• Proton pump inhibitors

Cytoprotective Agent: Sucralfate

Cytoprotective agent → helps maintain integrity of gastric mucosaComplexes w/ gastric secretions forming a viscous, adhesive paste Viscous paste forms a protective coating from gastric secretions

DosingProphylaxis → 1g PO/per tube q6 hours Treatment → 1g PO/per tube q4-6 hoursMix with 10mL sterile water to administer per tube

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Cytoprotective Agent: SucralfateAdvantages

Lower risk of gastric bacterial colonization → ↓ risk of aspiration pneumoniaInexpensive

DisadvantagesLower rate of clinically significant bleeding with acid suppression vs. sucralfate

Adverse EffectsConstipationAluminum toxicity; CNS manifestations (seizures, encephalopathy, and myoclonus)Requires enteral administrationIncreases in gastric pH decrease efficacyDifficult to administer via feeding tubes with small lumens Drug-drug interactions

The Role of Acid Suppression Therapy

Pepsin destruction8

Clot stabilization (↓ frequency of rebleeding)7

↑ platelet aggregation and polymerization of fibrin5 – 7‡

99.9% neutralization of gastric acid5

Pepsin inactivation> 4†

Decreased frequency of bleeding episodes> 3.5

Clinical effectpH

† Goal of acid suppression therapy for GI prophylaxis‡ Goal of acid suppression therapy for active non-variceal upper GI bleeds

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Acid Suppression Therapy: Antacids

AntacidsNeutralization of gastric acidity resulting in ↑ gastric pH

DosingProphylaxis

• Give 30 mL of antacid formulation and check gastric pH in 1 hour• If pH < 4.0 give 60 mL antacid and check pH in 1 hour• Repeat step 2 until gastric pH is > 4.0• Give maintenance antacid doses every 1-2 hours

Treatment → no role in the treatment of acute non-variceal upper gastrointestinal bleeds

Acid Suppression Therapy: Antacids

AdvantagesAllows quantitative assessment of efficacy via measurement of gastric pHLow cost

DisadvantagesRequires enteral administrationRequires frequent administration of large doses to obtain optimal acid suppressionIncreased risk of aspiration pneumoniaElectrolyte abnormalitiesConstipation / diarrheaDrug - drug interactionsDecreased absorption of quinolones, tetracycline, and thyroid supplements

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Antisecretory Therapy: H2-AntagonistsAntisecretory activity increases gastric pH

Competitive inhibition of histamine-2 receptors of the gastric parietal cells • Reduces gastric acid secretion and hydrogen ion concentration

Dosing

IV → 20 mg bolus, followed by continuous infusion of 1.7 mg/hr

PO/per tube → 20 mg q12 hIV → 20mg q12 h

Famotidine

IV → 50 mg bolus, followed by continuous infusion of 6-8 mg/hr

*PO/per tube → 150 mg q12 hIV → 50 mg IV q 8 hours

Ranitidine

TreatmentProphylaxisAgent

Antisecretory Therapy: H2-Antagonists

AdvantagesIV and enteral administrationAllows quantitative assessment of efficacy via measurement of gastric pH

DisadvantagesIncreased risk of aspiration pneumonia

ToleranceCumulative effect, ↑ exposure results in decreased activity> 24 hours of exposure to treatment doses results in significant tolerance Theorized that tachyphylaxis is due to an increase in histamine activity

Adverse EffectsThrombocytopenia, CNS

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Antisecretory Therapy: PPI

Antisecretory effects increase gastric pH

Activated in the vesiclular compartment of parietal cells

Irreversible binding inactivates Na+/K+

ATPase pumps

Antisecretory Therapy: PPI

Do not use per tube40mg PO BID20mg PO qdayRabeprazole

See Omeprazole administration60mg PO BID30mg PO qdayLansoprazole

Do not use per tube40mg IV bolus, then 8mg/hr 40mgPO/IV QD-BIDPantoprazole

1) Empty pellets into 40mL of an acidic beverage (fruit juice) - NOT plain water -and administer immediately2) Empty pellets into 10mL of 8.4% sodium bicarbonate - NOT plain water – and allow suspension to form (~15 minutes) or crush. Refrigerate and administer within 14 days

40mg PO BID40mg PO QDOmeprazole

Administration per tubeTreatmentProphylaxisAgent

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Antisecretory Therapy: PPI

AdvantagesIV and enteral administrationAllows quantitative assessment of efficacy via measurement of gastric pHMost rapid and potent suppressor of gastric acid (vs. H2-antagonists and antacids)Numerous clinical studies have shown:

• pH > 4 is achieved more quickly; ↑ duration of time with pH > 4 • Few adverse effects

DisadvantagesInactive until they reach the low pH of the vesicular compartments of parietal cells Drug interactions?Inhibitors of CYP450 2C19

• May interact with SSRIs, warfarin, phenytoin, amiodarone, etc.

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