HEMATEMESIS & MELENA

June 30, 2005 Glen E. Hastings MD

Definitions: o Hematemesis is the vomitus of bright red blood or coffee-ground material 1 . o Melena is black, tarry stool which is foul smelling1 because of the presence of partially digested blood products. Melena implies that the blood has been in the GI tract for at least 14 hours, & that usually indicates an upper GI source, but melena may also occur with bleeding from the small bowel or the right colon. Table 1: UGI Causes of Hematemesis & Melena Sources % II Introduction: Duodenal Ulcerations 24.3% Hematemesis &/or melena are caused by acute bleeding Gastric Erosions 23.4% from the upper GI tract or the mouth or pharynx. Profuse Gastric Ulcers 21.3% hematemesis is a very common hospital emergency that Gastric or esophageal varices 10.3% Mallory-Weiss tears 7.2% still caries an 8%- 14% hospital mortality 2 . Among adults, Erosive Esophagitis 6.3% hemorrhage from gastric or duodenal ulceration & Erosive Duodenitis 5.8% esophageal varices are the most frequent causes. Other Neoplasms 2.9% common causes & their relative frequency is shown in Stomal Ulcers 1.8% 3 Esophgeal Ulceration 1.7% Table 1. In children mucosal lesions and variceal Miscellaneous 6.8% hemorrhage (commonly secondary to extra hepatic portal venous obstruction) are common & in intensive care settings, ventilator management, infections and drugs predominate as causes for stress ulceration 4 . III Medical History & Physical Examination: In no other situation is the medical history more important than in an acute GI bleed. Not only does the history usually point to the diagnosis, more importantly it determines prognosis because patients rarely die from exsanguinations, but more frequently from co-morbid conditions or complications. The most important items of the physical examination are the vital signs, pulse, blood pressure, respiratory rate & body temperature. The examining physician needs to obtain these measurements personally or to verify their accuracy as well as to evaluate the patient for postural changes in pulse or BP indicative of blood volume depletion. It takes at least 24 hours for a brisk GI bleed to be fully reflected by decreased hematocrit & hemoglobin levels. Differential Diagnosis of the Bleeding Source: o Duodenal Ulcer & Erosive Duodenitis 5 : General Considerations: 10% of UGI bleeding episodes caused by duodenal ulcer (DU) present without prior symptoms. 70% stop spontaneously. Continuous infusion of a proton pump inhibitor (PPI) keeping the gastric pH between 6 & 7 or infusion with octreotide or somatostatin reduces rebleeding risk about 53%. Symptoms & Signs: The pain of DU is characteristically burning in quality & epigastric in location occurring about 2 hours after meals & relieved by antacids & two thirds of DU patients are awakened at night by this symptom between 12 & 3AM. Others describe the pain as gnawing or ill-defined and aching or like a hunger pain. Physical examination usually demonstrates epigastric point tenderness, although this finding does not distinguish between DU gastric ulcer (GU) or non-ulcer dyspepsia (NUD). Diagnostic Testing: Upper endoscopy is the diagnostic modality of choice as it not only provides an avenue for diagnosis but also provides information determining the likelihood of rebleeding as well as an avenue for direct therapeutic intervention. Electrocoagulation or epinephrine injection of an endoscopically visible blood vessel in the ulcer bed reduces the risk of recurrent bleeding from 33% to less than 10%. Patients with a clean be ulcer with no visible vessel enjoy a rebleeding rate approaching 0%, so once stabilized they can be discharged to outpatient care. Both the rapid urease test & tissue biopsy of the ulcer bed are 95% sensitive & 95% specific for H pylori. Serum gastrin levels >200pg/mL suggests Zollinger Ellison (ZE) syndrome.

Hematemesis: Page 2 of 7 Prognosis: About of patients rebleed with 2 years, so long term maintenance deals with the causes of peptic ulceration, which are 3 in number: NSAIDS, H pylori & excessive gastric acid (0.5% to 1% have Zollinger-Ellison syndrome) Long Term Management: 90% of bleeding duodenal ulcers are H pylori related, so H pylori eradication is the hallmark of long term medical management. No matter what the pharmaceutical reps tell you, the most effective H pylori therapy as well as the cheapest is the combination of a PPI, Pepto-Bismol, tetracycline & metronidazole QID for 2 weeks. About 20% of peptic ulcers are NSAID related. NSAID use should be discontinued if at all possible, because 15 to 30% of NSAID users develop ulcers. When this is impossible either a PPI or misoprostol 200g QID provide effective prophylaxis. The question of whether or not to use a COX-2 NSAID must be evaluated alongside the increased risk of CAD associated with these agents. PPIs are far & away the best agents for suppressing gastric acid production. Surgery is reserved for refractory or persistently recurrent situations & is unusual today. Complications & Comorbidities: Post-bulbar DU, multiple DUs or recurrent or refractory disease suggests the possibility of ZE syndrome & is evaluated by testing for basal gastric acid secretion >15mMol/hour, serum gastrin >1000pg/mL of elevated serum gastrin >200pg/mL within 2 minutes of injecting 2U secretin/kG IV. 60% of the gastronomas causing ZE syndrome are malignant. 50% are located in the duodenium, 20% in the pancreas & another 10% in the local area. Gastric Ulcer (GU) presents in an older age group (peaking in the 6th decade) is unlikely to be relieved by food & frequently occurs during meals. The pain is usually epigastric & may be described as burning or aching & much more likely to be accompanied by bloating, anorexia, nausea or vomiting. GU is much less likely related to H pylori & more likely related to NSAIDS & baseline gastric acid is usually normal or decreased. Gastric ulcers that are not located in the prepyloric area & the lesser curvature of the stomach are suspicious for gastric malignancy. Diagnostic testing & management are as in DU. Hemorrhagic Erosive Gastritis: Alcoholic Gastritis typically occurs in binge alcoholics (rarely in chronic continuous alcoholism) after several weeks of heavy binging, frequently with little food intake. Antral gastritis supervenes causing epigastric burning, cramping or aching pain, nausea & vomiting. This usually terminates the drinking binge & the patient frequently arrives at the emergency room sober with a serum ethanol level of zero. The pivitol diagnostic test is upper endoscopy. The degree of hemorrhage is usually minimal unless the patient has an alcohol related coagulopathy. The treatment of the bleeding is medical management with PPI therapy, but the most serious task is to look for & to exclude more life threatening emergencies such as incipient delirium tremens, alcoholic ketoacidosis or incipient hepatic coma induced by breakdown of blood in the GI tract in a patient with borderline liver function, or acute pancreatitis. NSAID Induced Antral Gastritis also may present with hematemesis. The diagnosis is made endoscopically. The bleeding is usually minor & the treatment similar to NSAID induced ulcers. H pylori also produces an antral gastritis which is treated similar to H pylori ulcers. MALT lymphomas of the stomach as well as gastric carcinomas are associated with H pylori. It is uncertain whether eradication of H pylori reduces their incidence. Stress Ulceration with UGI bleeding is a life threatening emergency in the ICU setting that occurs in severely ill patients (often requiring ventilator management). The most effective prophylaxis to prevent stress related GI bleeding is a continuously infused PPI. Sucralfate is less effective than the PPIs but has the advantage of not suppressing gastric acid production. Some pulmonologists believe gastric acid suppression to be an important contributor to bacterial overgrowth in the stomach leading to late-onset ventilator associated pneumonia (a major cause of ventilator-associated mortality). Those pulmonologists prefer sucralfate prophylaxis. Both reduce bleeding, neither reduce overall mortality.

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Esophageal Varices1,6 : General Considerations: When advanced cirrhosis of the liver increases venous pressures within the portal system beyond 12cm/H2O, the result is venous engorgement & owing to the absence of valves within the portal venous system, venous varicosities that may bleed unpredictably. Variceal bleeding usually presents with massive painless hematemesis without apparent precipitating factors in a patient with advanced liver disease. Variceal bleeding is always a medical emergency & should be managed in an ICU setting. Clinical Evaluation & Emergency Management: begins with careful assessment of the circulating blood volume status & careful measurement of blood loss. A postural drop > 15mm/Hg in blood pressure coupled with tachycardia or bradycardia are important signs of blood volume depletion & an indication for emergency transfusion regardless of the hematocrit or hemoglobin. Physical examination will usually reveal other evidence of portal hypertension such as ascites or peripheral edema as well as evidence of impaired hepatocellular function such as spider nevi, paper dollar teleangectasia or erythematous palms (caused by accumulation of estrogens usually detoxified in the liver) or hepatic encephalopathy caused by the accumulation of nitrogenous products. INR, aPTT & platelet count should be obtained & parenteral vitamin K & clotting factors should be replaced as needed. Fresh frozen plasma is the emergency source of vitamin K dependent coagulation factors during an acute bleeding episode & platelet packs are indicated if thrombocytopenia (<20,000) is a contributing factor. Cryoprecipitate has no role in this setting. Octreotide (50g bolus followed by 50g/hour IV drip) has replaced vasopressin as the agent of choice to help control acute bleeding. Esophageal tamponade using a Sengstaken-Blakemore or Minnesota tube is rarely used today because of high complication rates. When used, prior endotracheal intubation is recommended because of the high incidence of aspiration pneumonia. Diagnosis & Interventional Management is best done endoscopically. Variceal banding is superior to sclerotherapy in mortality & morbidity for eradication of bleeding varices. Those in whom bleeding persists or recurs may require a transjugular intrahepatic portosystemic shunt (TIPS) procedure, which reduces variceal pressures more effectively & thereby decreases bleeding more effectively than endoscopic therapy. The trade-off is that TIPS is more likely to precipitate hepatic encephalopathy, the shunt tends to restenose after a year or two & although variceal bleeding is reduced it doesnt change mortality. Distal (splenorenal) shunting is reserved for more compensated milder cases. Long Term Management: Nonselective -blocker therapy with propanolol or nadolol in dosages reducing the hepatic porto-venous gradient (HPVG) to < 12cm/H2O, or to reduce pulse rate 25% reduces bleeding rates 40 to 50% & improves mortality, when combined with variceal banding. Portal Hypertensive Gastropathy is associated with variceal bleeding as it is a congestive gastropathy caused by increased portal pressures in cirrhotic patients. The endoscopic appearance is a friable engorged gastric mucosa & its treatment is -blockade as with esophageal varices. PPIs, H2 antagonists & sucralfate are ineffective & have no role in this setting. Mallory-Weiss Tears1: also occur in the setting of alcoholic gastritis as well as other conditions featuring violent retching or coughing. Hemorrhage, which may quite profuse occurs immediately from a tear at or nearby the squamocolumnar border & resolves spontaneously in 80 to 90% of cases. Rebleeding occurs in less than 5%. Persistent or recurrent bleeding may respond to vasopressin or octreotide infusion & has also been managed by arterial embolization. Surgical oversewing is rarely required. Erosive Esophagitis 7 : is characterized endoscopically as inflamed, friable mucosa with linear ulcers that are usually superficial & exudates. Most patients will have several years history of heartburn, reflux of sour caustic material into the oropharynx, hoarseness & sometimes nocturnal asthma or repeated episodes of aspiration pneumonia (in severe cases) prior to the occurrence of hematemesis or (more frequently) dysphagia. The bleeding is usually not severe & tends to resolve spontaneously. Erosive gastritis, over time however tends to stimulate the development of metaplastic columnar endothelial changes in the distal esophagus (Barretts esophagitis). Barretts esophagitis increases the risk of esophageal cancer by 30 to 125 times that of the

Hematemesis: Page 4 of 7 general population. The rate of cancer development is about 0.5%/year so intensive treatment with PPI therapy is indicated along with periodic surveillance endoscopy. When high grade dysplasia is found the treatment of choice is surgical esophagectomy of the involved mucosal segment. o Malignancies: o Unusual Causes of Hematemesis or Melena: Hemorrhage from the small bowel causes melena or hematochezia & will be discussed in the outline by that title. Other unusual causes of UGI bleeding include teleangectsias such as in hereditary Osler-Weber-Rendu syndrome, gastric antral ectasia (watermelon stomach) or a superficial mucosal Dieulafoy vessel, bleeding from gastric prolapse secondary to violent retching, ruptured aortic aneurism or bleeding from the pancreatic or bile ducts. Common Comorbidities & Complications: Because alcoholism is an increasing pandemic in the developed & developing world & is ubiquitous among most of the patients seen on any medical school hospital service, the potentially lethal comorbidities of alcoholism should always be considered & excluded by appropriate testing or clinical observation. o Alcoholic Ketoacidosis 8,9 occurs among binge drinking alcoholics when antral gastritis causes abdominal pain nausea & vomiting & termination of the drinking binge. By the time of arrival at the ER the patient may be sober with an ethanol level of zero. Hyperglycemia is usually not present or not impressive & the dipstick Acetest for ketones may not be impressive because it detects only acetoacetic acid & the vast majority of the acidosis is because of -hydroxybutyrate. Its presence is detected by a low serum bicarbonate & a markedly elevated anion gap. The problem is severe metabolic acidosis secondary to depleted liver glycogen stores, low serum insulin levels, elevated glucagon levels & starvation ketosis. Vomiting will likely have produced a concomitant metabolic hypokalemic alkalosis. The most serious danger is that, as the ketoacidosis improves & the pH returns toward normal, the resulting intracellular influx of potassium may be so abrupt & profound as to result in a lethal cardiac dysrythmia. Concomitant seizures or delirium tremens may produce a respiratory alkalosis while pneumonia, GI bleeding, thiamin deficiency or pancreatitis may produce lactic acidosis. Treatment is with saline & glucose resuscitation, aggressive potassium, glucose and thiamin replacement. Insulin is not required unless the patient is diabetic. Magnesium or calcium supplementations are sometimes required o Hepatic Encephalopathy5: Gastrointestinal hemorrhage is the most common event precipitating hepatic encephalopathy in previously stable cirrhotic patients. Its onset is heralded by a subtle loss of the ability of the patient to follow a linear train of conversation which progresses to frank confusion & mood lability, then to slurred speech & sundowning, followed by astarixis, lethargy & characteristic triphasic EEG waves, then to coma & death. It is useful to grade the level of hepatic encephalopathy as a guide to monitoring therapy & assessing prognosis. The grades of hepatic coma are shown in Table 2:
Table 2: Stages of Hepatic Coma: Stage I. Symptoms Impaired attention/cognition, Psychiatric/personality changes, "Sundowning". Gross mental confusion, Drowsiness Amnesia, Speech disorders, Inappropriate behavior. Somnolent but arousable, Disoriented; bizarre. Comatose Neurological Changes Tremor, apraxia, poor handwriting. Astarixis, dysarthria, ataxia & hypoactive reflexes Astarixis, hyperactive reflexes, rigidity. Decerebration EEG Triphasic wave activity (5 cps).

II.

Triphasic wave activity (5 cps). Grossly abnormal EEG with theta & 5 cps triphasic waves Delta waves

III. IV.

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Acute alcohol intoxication, delirium tremens, sepsis, head injury or subdural hematoma or Wernicke-Korsakoff syndrome may all mimic hepatic coma, particularly inn its earlier stages. There is no single diagnostic test for hepatic encephalopathy, but an elevated serum ammonia level is helpful in patient with stigmata of advanced liver disease, a prolonged INR, an obvious precipitating event (like a GI bleed), progressive neurological findings as described above, characteristic EEG findings & the exclusion of other diagnostic possibilities. Treatment is with bowel evacuation of blood & other nitrogenous products, treatment of the precipitating event & good supportive care. The Child-Pugh staging classification shown in Table 3 is useful for estimating long term prognosis 10 :
Table 3: Child-Pugh Classification of the Stages of Cirrhosis 3 Points Stage of Encephalopathy Stage 3-4 Ascites Moderate Total Bilirubin (mg/dL) 3.0 mg/dL Exception: Primary Biliary Cirrhosis 10.0mg/dL Serum Albumin (mg/dL) < 2.8mg/dL Prothrombin Time Ratio (International Normalized Ratio) > 2.0 Scoring: Class A (Well Compensated) 5-6 Points. Class B (Mildly Decompensated): 7-9 Points. Class C (Decompensated) 10-15 Points. Assessment Category 1 Point None None 2.0 mg/dL 4.0 mg/dL <3.5mg/dL < 1.4 Assessment Score 2 Points Stage 1-2 Mild 2.1-2.9 mg/dL 4.1-9.9mg/dL 2.8-3.5mg/dL 1.4-2.0

A series of 402 Spanish cirrhotic patients were reported in 2002 after being followed for an average of 73 months following a first episode of GI bleeding. Only about 40% of Class C patients survived 6 weeks. The median survival of Class B patients was about 40 months & the median survival of Class A patients was just short of 100 months9. Alcohol Withdrawal, Seizures & Delirium Tremens 11 : In 90% of cases, alcohol withdrawal is limited to mental confusion, anxiety, tremulousness, anorexia, mood lability visual tactile or auditory hallucinations and agitation which peak at 24-36 hours & gradually subside. Seizures may occur within 8-24 hours of the last drink & generally peak at about 24 hours. About 1% of cases worsen, autonomic instability occurs and about 72-96 hours after the last drink full-blown delirium tremens supervenes. In DTs the patient becomes globally disoriented, autonomic instability manifests itself as fever > 101o, tachycardia >120/minute, diaphoresis, disruption of the sleep/wake cycle and severe agitation. The duration is variable, averaging 2-5 days. Expected mortality is about 10%. Benzodiazepines are the treatment of choice. The advantage of longer acting benzodiazepines is that they are more effective at preventing seizures & produce better symptom control, since their blood levels do not fluctuate as much as shorter acting agents. Their disadvantage is a longer period of sedation in the event of overdose. The shorter acting agents are also safer in patients with liver failure. In patients without evidence of liver failure long acting agents are preferable. The initial dose is established at presentation and decreased by 20% each day thereafter. Some programs administer the drugs on a fixed schedule (such as 50mg chlordiazepoxide or 20mg diazepam every 6 hours). Others tailor the dose to the severity of the withdrawal symptoms & signs. Wernicke-Korsakoff Syndrome10: Wernickes syndrome is a neurological emergency calling for immediate administration of parenteral thiamin. It is a disease of acute onset consisting of a triad of: Cranial Nerve VI palsy (weakness of lateral gaze) accompanied by nystagmus, diplopia, and strabismus, ataxia of gait & stance & global confusion and apathy. As the delirium clears, it may be replaced by an often permanent defect in retentive memory and learning, frequently accompanied by confabulation, Korsakoffs syndrome in which the sensorium is not clouded. Wernicke-Korsakoff Syndrome is caused by profound thiamin deficiency & may be inadvertently precipitated by the administration of intravenous or oral glucose, which accelerates the use of thiamin. To prevent this eventuality all patients treated with parenteral as well as oral thiamin administered before or simultaneously with any IV fluids containing glucose or fructose. Parenteral therapy is especially important in the malnourished. Oral therapy should be continued for several weeks. Korsakoffs syndrome is permanent & irreversible but potentially preventable.

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Acute Alcoholism: Occasionally, acutely intoxicated patients become combative during treatment for UGI bleeding & are sedated with parenteral benzodiazepines, sometimes at doses sufficient to produce profound respiratory depression, once behavioral controls established. It is sometimes difficult to empathize with such patients but it is nonetheless essential to continuously monitor the O2 saturation & respiratory status of during the first few hours. A greater number of anesthetic deaths may well occur on the way to x-ray or to the endoscopy suite than in the OR. Acute Pancreatitis: Many causes of GI bleeding regularly produce mild elevations of serum amylase. In order to be considered indicative of acute pancreatitis the level must be at least 3X the upper limit of normal at the lab doing the test. Even then serum amylase has only a 68% sensitivity & 75% specificity for pancreatitis. Serum lipase is a much better test with a sensitivity of 95% & a specificity of 95%. CT without contrast characteristically shows pancreatic parenchymal & peripancreatic edema & sometimes fluid collections & is virtually 100% accurate for the diagnosis. When pancreatitis coexists it is imparitive that Ransons or the Glascow criteria be determined (see Table 3). When 3 or more of Ransons criteria are present, a mortality in excess of 15% is predicted indicating the need for prophylactic antibiotic therapy & evaluation after the 3rd day after onset, for pancreatic necrosis using rapid bolus CT technique.
Table 3: Prognostic Criteria for Acute Pancreatitis Ransons Criteria Non-gallstone Pancreatitis On Admission: Age > 55 WBC > 16,000 Blood glucose>200 mg/dL Serum LDH > 350 IU/L AST (SGOT) > 250 IU/L Within 48 hours: Hematocrit decrease > 10% BUN increase > 5 mg/dL Serum calcium < 8 mg/dL Arterial pO2 < 60 mm Hg Base deficit > 4 Fluid deficit > 6L Gallstone Pancreatitis On Admission: Age > 70 WBC > 18.5 K Blood glucose> 180 mg/dL LDH > 400 U/dL AST >250 U/dL Within 48 Hours: Hematocrit decrease > 10% BUN increase > 2 mg/dl Serum Calcium < 8 mg/dl Base deficit > 5 mmol/L Fluid deficit > 4 liters Modified Glasgow Criteria Age >55 WBC > 15,000 Blood glucose> 180 mg/dL BUN > 45 (after rehydration) pO2 < 60 mm Hg Ca < 8 mg/dL Albumin < 3.4 gm/dL LHD > 600 IU AST or ALT > 200 IU

Interpretation: 3 or more at any time during the first 48 hours indicates severe pancreatitis.

Interpretation: mild attack: < 0-2 sign (<1% mortality) moderate attack: 3-4 signs (16% mortality) severe attack: 5 or more signs (>40% mortality)

Similar to alcoholism, tobacco habituation, obesity & their attendant risks for atherosclerotic, hypertensive & pulmonary comorbidities need always be considered & excluded in UGI bleeding: o Acute Myocardial Infarction: Coexisting chest pain, new onset dyspnea or (in patients > age 65) a new neurological event or symptom, require exclusion of acute myocardial infarction by serial EKGs & troponin. ST segment elevation in 2 contiguous EKG leads is 45% sensitive & 95% specific for AMI 12 . A baseline EKG is required for all adult patients with GI bleeding. o Respiratory Failure: can occur either because of coexistent community acquired pneumonia, Nosocomial pneumonia, aspiration pneumonia or depression of the respiratory drive. The latter has already been discussed. The diagnosis of aspiration or Nosocomial pneumonia is usually straight forward unless the resident fails to look for it. Aspiration pneumonia evolves in 3 phases: The first, acute aspiration is managed sometimes supplemented with tracheobronchial lavage. The second phase, which occurs within a few hours shows x-ray shadowing caused by the tissue irritant effects of gastric contents. The bacterial phase only occurs about of the time & not until 3 days later. It is only in this last phase that an antibiotic (i.e. clindamycin) is indicated.

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IV Requisite Laboratory Evaluation: o When bleeding is brisk especially if signs of hemodynamic instability are present t is wise to type 4 to 6 units of packed red blood cells stat. o Upper endoscopy is the immediately preferred diagnostic & therapeutic modality. o EKG, comprehensive metabolic profile (CMP), CBC with platelet count & differential, O2 saturation, INR & aPTT are always indicated to screen for serious comorbidities as well as specifically additional laboratory work indicated by the initial workup or preexisting conditions. V Bibliography:
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Laine L. Gastrointestinal Bleeding. Ch. 37 in Harrisons Principles of Internal Medicine 16thEdition. Editors: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL. McGraw-Hill NY,NY 2005 pages 235-8. Meier R, Wettstein AR. Treatment of acute nonvariceal upper gastrointestinal hemorrhage. Digestion. 1999;60 Suppl 2:47-52. Elta, GH, Approach to the patient with gross gastrointestinal hemorrhage. Ch 33 in Textbook of Gastroenterology 4 Edition. Editor: Yamada T. Lippincott, Williams & Wilkins Philadelphia PA 2002; pages 696-723. Arora NK, Ganguly S, Mathur P, Ahuja A, Patwari A. Upper gastrointestinal bleeding: etiology and management. Indian J Pediatr. 2002;69(2):155-68. Valle JD. Peptic Ulcer Disease & Related Disorders. Ch. 274 in Harrisons Principles of Internal Medicine 16thEdition. Eds: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL. McGraw-Hill NY,NY 2005 pages 1746-62. Chung RT, Podolsky DK. Cirrhosis & Its Complications. Ch. 289 in Harrisons Principles of Internal Medicine 16thEdition. Eds: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL. McGraw-Hill NY,NY 2005 pages 1858-69. Goyal RK. Diseases of the Esophagus. Ch. 273 in Harrisons Principles of Internal Medicine 16thEdition. Editors: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL. McGraw-Hill NY,NY 2005 pages 1739-46. Wrenn KD, Slovis CM, Minion .GE, Rutkowski R: The syndrome of alcoholic ketoacidosis. Amer J Med 1991;91:119-28. Fulop M: Alcoholic ketoacidosis. Endocrinol Metab Clin North Am. 1993;22:209-19. del Olmo JA, Pea A, Serra MA, et al. Predictors of morbidity and mortality after the first episode of upper gastrointestinal bleeding in liver cirrhosis. J Hepatol. 2000;32(1):19-24. Mayo-Smith MF, Chapter 2: Management of Alcohol Intoxication and Withdrawal in Schuckit MA Drug and Alcohol Abuse 4 Edition Plenum Medical Book Company, 1995, New York, NY.
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1999 Update: ACC/AHA Guidelines for the management of patients with acute myocardial infarction: A report of the ACC/AHA task force on practice guidelines. J Am Coll Cardiol 1999;34:890-911.