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Drug Overdoses and

Toxic Ingestions

Pia Chatterjee  n  Jeanmarie Perrone

Successful management of patients after a life-threatening drug overdose depends on emergency medical system (EMS) and emergency department (ED) personnel (1) initiating the critical inter-ventions of airway management and cardiovascular stabilization, (2) simultaneously obtaining a thorough history, and (3) targeting specific therapies based on the suspected exposure Communica-tion between the ED and the intensive care unit (ICU) will be paramount for continuing successful resuscitations in the ICU

Not all “drug overdoses” are intentional Toxic ingestions may be accidental or result from the ingestion of products stored inappropriately—for example, lye stored in a soda bottle Iatrogenic dosing errors and excess self-medication of drugs with narrow therapeutic:toxic ratios (salicylates, lithium, digoxin) also occur Occasionally, chronic medications precipitate acute toxicity caused by

a drug interaction or a change in drug metabolism Acute management of poisoned patients will depend on the ingestion; however, disposition of patients following ICU care depends on whether

or not the overdose was intentional

Although deep sedation and coma in patients admitted to the ICU may be attributed to a drug ingestion, patients with unclear histories should undergo evaluation for other causes of altered mental status Intracranial pathologic conditions should be excluded by computed tomographic (CT) scan of the head, and lumbar puncture should be considered in febrile patients

The regional poison center is an additional important resource in the management of any pected poisoning, including those resulting from “new” recreational drugs with serious toxic side effects, such as “bath salts” or synthetic cannabinoids (“K2/Spice”), and new therapies including use of lipid therapy for hemodynamically significant poisonings

sus-Mechanisms of Injury

DIRECT DRUG EFFECTS

Nearly all drugs produce harmful effects if taken in excessive amounts Systemic toxicity is due to selective effects of the toxin or a metabolite on specific targets, such as binding to specific recep-tors (therapeutic drugs), disruption of metabolic pathways (cyanide, salicylates, iron), cellular production of toxic metabolites (acetaminophen in the liver, methanol in the retina, ethylene glycol in the kidney), and enzymatic inhibition (Na+/K+-ATPase by digoxin; anticholinesterase

by organophosphates) Some toxins produce effects by several mechanisms For example, zid causes both hepatotoxicity via a cytochrome P-450 pathway metabolite and neurotoxicity via the inhibition of pyridoxal 5′-phosphate Pathologic effects may also occur at the site of exposure

isonia-as a result of cytotoxic chemical reactions (e.g., caustic acid or alkali ingestions) that damage exposed tissue

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COMPLICATIONS

Aspiration occurs in poisoned patients as a complication of vomiting, orogastric lavage, cheal intubation, or loss of airway reflexes because of obtundation Early assessment and defini-tive airway management are critical in diminishing the risk of aspiration Acute lung injury may complicate recovery following life-threatening ingestions Hyperthermia may occur for several reasons: increased motor activity that occurs with agitation or seizures, direct drug effects on the hypothalamus (sympathomimetics), or aspiration and pneumonia Rhabdomyolysis (see Chapter 81) can occur in patients after prolonged periods of immobilization because of obtundation, pro-tracted agitation or seizures, or cocaine or amphetamine use Under these circumstances, aggressive hydration and maintenance of urine output are important Acute renal failure (see Chapter 81) may occur directly, for example, from ethylene glycol direct toxic effects on the kidneys or secondarily, for example, from drug-induced hypotension Acute hepatic failure (see Chapter 59) most com-monly results from acetaminophen poisoning but may also occur because of the multiorgan effects

endotra-of diffuse toxins such as mercury or iron

Management

DIAGNOSTIC APPROACH

Initial assessment of the airway, breathing, and circulatory status (ABCs) and frequent ment are critical to monitoring the dynamic status of ongoing toxicity Empty pill bottles or discussions with family members regarding medicines available in the home are helpful in focus-ing the diagnostic workup Physical examination should screen for manifestations of common toxic syndromes (“toxidromes”)—for example, anticholinergic, opioid, or salicylate toxicity An electrocardiogram can screen for conduction defects associated with cyclic antidepressants, cal-cium channel antagonists, beta-blockers, or digoxin QR and QT prolongation herald impending cardiotoxicity and should be followed serially Toxicology screening should be performed if the results will be available in a sufficiently short time frame to be clinically relevant All patients with intentional ingestions should have an acetaminophen level checked to exclude a clinically silent, potentially overlooked but treatable acetaminophen ingestion

reassess-THERAPEUTIC APPROACH

After initial stabilization of the ABCs, certain therapies should be considered in all poisoned patients Suspected hypoglycemia should be treated with an intravenous (IV) bolus of concen-trated dextrose solution (50 mL of 50% dextrose) Patients with the triad of signs suggesting opi-oid toxicity (respiratory depression, pinpoint pupils, and coma) warrant treatment with the opioid antagonist naloxone IV fluid therapy is important in many patients with overdoses to compensate for volume losses associated with vomiting Parenteral benzodiazepine sedation is indicated for agitated or uncooperative patients because it may prevent rhabdomyolysis, hyperthermia, and injuries to the patient or staff as well as decrease the risk of seizures

Gastrointestinal (GI) decontamination is no longer routinely recommended for most overdose patients but may have a limited role in some patients with serious toxicity admitted to the ICU Orogastric lavage via a large-bore tube (Ewald tube) may be critical in patients ingesting large quantities of drugs not bound by activated charcoal, such as iron or lithium It can be life saving in serious calcium channel antagonist overdoses by removing a clinically significant fraction of drug, decreasing toxicity Orogastric lavage should only be considered in patients manifesting signs of toxicity following a potentially life-threatening ingestion, and only perform it after the judging the patient’s airway to be protected, often necessitating endotracheal intubation

57—DRUG OVERDOSES AND TOXIC INGESTIONS 559

Oral activated charcoal can diminish the absorption of many drugs and can enhance drug excretion for some agents via GI dialysis (the diffusion of high plasma drug levels back into the gut lumen to be bound to activated charcoal and excreted) or interruption of enterohepatic circulation

of active metabolites Sustained release preparations (e.g., calcium channel blockers) and drugs not bound to activated charcoal (e.g., lithium, iron) may be cleared from the gut using whole bowel irrigation Bowel irrigation is performed with polyethylene glycol–electrolyte lavage solutions (e.g., GoLYTELY, CoLYTE) administered via nasogastric tube at a rate of 1 to 2 L/h in adults.The regional poison control center should be consulted to obtain general management and toxin-specific therapeutic advice, as many common toxins have specific therapies or antidotes (Table 57.1)

Common Toxic Ingestions

ACETAMINOPHEN

Acetaminophen is one of the most commonly ingested medications Few patients become ously ill from acetaminophen overdose because of early diagnosis and antidote treatment with

seri-N-acetylcysteine (NAC) Life-threatening hepatotoxicity, however, occurs in the few who present

late after their ingestions or in whom clinicians fail to recognize acetaminophen when it is ingested with other drugs

co-TABLE 57.1 n  Antidotes and Adjuncts in the Therapy of Selected Poisonings

Acetaminophen N-acetylcysteine Orally 140 mg/kg × 1; followed by 70 mg/kg every

4 hours × 17 doses IV: 150 mg/kg IV over 60 minutes, followed by an infusion of 12.5 mg/kg/h over a 4-hour period, and finally an infusion of 6.25 mg/kg/h over a 16-hour period

Anticholinergic

agents

Physostigmine 1–2 mg IV over 5 minutes; use with caution

for severe delirium (may cause seizures, bronchospasm, asystole, cholinergic crisis) Beta-adrenergic

antagonists Glucagon 2–5 mg IV; titrate repeat doses; may use infusion of 2–10 mg/h Calcium channel

blockers Calcium gluconate 1 g (10 mL of 10% solution) IV over 5 minutes with electrocardiographic monitoring; repeat as

needed, check serum calcium after third dose Insulin Bolus dose of 0.1 U/kg followed by an infusion of 0.5

mg/kg/h; can be titrated up to a rate of 1 U/kg/h with a dextrose infusion to maintain euglycemia Cyclic

antidepressants Sodium bicarbonate 1–2 mEq/kg IV; titrate to arterial pH of 7.5 or electrocardiographic alterations (see text)

Digoxin Digoxin antibodies

(Digibind) Vials (number) = (digoxin level [ng/mL] × weight [kg])/100 or

10–20 vials for a life-threatening arrhythmia Methanol

Ethylene glycol

Fomepizole Loading dose of 15 mg/kg IV over 30 minutes;

subsequent 4 doses every 12 hours at 10 mg/kg; further dosing per poison center

Opioids Naloxone 0.05–0.4 mg IV, repeat as needed; infusion: two thirds

of reversal dose/h, titrate to effect

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Patients with a history of acetaminophen ingestion should have a > 4-hour post ingestion aminophen level obtained and interpreted using the Rumack-Matthew nomogram (Figure 57.1) Nausea, vomiting, and sometimes right upper quadrant abdominal pain are associated with toxic hepatitis from ingestions a day or two earlier Patients with jaundice or coagulopathy or those reporting a large acetaminophen ingestion 1 to 3 days previously should be presumed to have hepa-totoxicity and should have treatment initiated immediately When presentations are delayed more than 24 hours after ingestion, acetaminophen levels may be low or zero, but significant elevations

acet-in transamacet-inases and prothrombacet-in time reflect severe acetamacet-inophen poisonacet-ing

Therapeutic doses of acetaminophen are metabolized in the liver by glucuronidation (60%), sulfation (30%), or by the P-450 cytochrome oxidase system (4%) The last pathway results in a toxic intermediate, N-acetyl-p-benzoquinoneamine (NAPQI) NAPQI is then normally reduced

by glutathione, which prevents toxicity With increasing dose or overdose, more acetaminophen metabolism is shunted into the P-450 system, depleting glutathione As a result, NAPQI accumu-lates and induces centrilobular necrosis of the liver The antidote NAC replenishes the glutathione and prevents hepatic necrosis (Chapter 59)

Patients with toxic acetaminophen levels require a loading dose of NAC (140 mg/kg) and sequent dosing every 4 hours (70 mg/kg) for an additional 17 doses over 72 hours NAC can also

sub-be given parenterally with a loading dose of 150 mg/kg IV over 60 minutes then by continuous

Figure 57.1 The Rumack-Matthew nomogram (solid line) estimates the likelihood of hepatotoxicity in acute

acet-aminophen overdose N-acetylcysteine (NAC) therapy is recommended if the acetacet-aminophen plasma level at

4 hours (or later) after ingestion plots above the broken line For example, patients with levels greater than or equal

to approximately 150 μg/mL at 4 hours or greater than or equal to approximately 35 μg/mL at 12 hours after tion should be treated with NAC (see text) The broken line allows a 25% variability below the solid line to take into

inges-account inaccuracies in estimated time of ingestion or measurement of plasma level (Adapted from Rumack BH, Matthew H: Acetaminophen poisoning and toxicity Pediatrics 44:871-876, 1975.)

57—DRUG OVERDOSES AND TOXIC INGESTIONS 561

IV infusion over 20 hours (see Table 57.1) Although most effective within the first 8 hours after overdose, NAC therapy is effective up to 24 hours after overdose as well as in patients with ful-minant hepatic failure secondary to acetaminophen The current recommended dose and route of administration (orally versus IV) in these situations can be obtained via the local poison center NAC should be continued until the acetaminophen level is zero and the liver function tests are trending down

ALCOHOLS

The clinical effects of ethanol intoxication can range from giddiness to coma and is affected by

time and quantity ingested, tolerance, and co-ingestants When presented with patients with presumed ethanol-induced altered mental status, although debated in the literature, measurement

of ethanol levels may confirm the clinical correlation as well as prevent inappropriate tions that high ethanol levels are the etiology of the altered mental status in any one patient The initial evaluation of any patient acutely intoxicated with alcohol should address whether signifi-cant co-ingestants may be present and add to impending morbidity Such considerations include ingestion of other central nervous system (CNS) depressants that may add to eventual respiratory depression such as benzodiazepines or other sedatives, as well as the ingestion of toxic alcohols as ethanol substitutes

assump-The toxic alcohols to consider include methanol, ethylene glycol, and isopropanol Methanol

is found in Sterno, windshield washer fluids, and industrial solvents Ethylene glycol is the cipal ingredient in most antifreeze preparations and is also used in deicing agents Isopropanol

prin-is commonly used as rubbing alcohol and as a solvent in home products These substances are readily available to ingest as an alcohol substitute in patients who are made abstinent from alco-hol or, in other cases, secondary to suicidal intention The presence of an anion gap acidosis in

a patient with suspected ethanol intoxication should promote a diagnostic search for the ence of methanol or ethylene glycol The findings of an osmolar gap or anion gap acidosis can

pres-be helpful when making the diagnosis but must pres-be interpreted with caution depending on the time since ingestion and the amount of metabolism that may have occurred Soon after inges-tion, either ethanol or a toxic alcohol will cause an elevated osmolar gap because all alcohols are osmotically active Over several hours, this osmolar gap will diminish, whereas an anion gap acidosis will develop if methanol or ethylene glycol were ingested instead of ethanol These toxic alcohols will undergo metabolism to an organic acid (formic acid in methanol poisoning and glycolic acid and oxalic acid in ethylene glycol poisoning) This acidosis, as well as the exclusion of other causes of metabolic acidosis (lactic acid, salicylate ingestion), helps confirm the suspicion of toxic alcohol ingestion while confirmatory methanol and ethylene glycol levels are obtained

Other clinical symptoms that suggest toxic alcohol ingestion are alcohol specific Methanol exposure is characterized by visual symptoms that develop within 12 to 24 hours of exposure Patients complain of “snow field” vision that occurs from formic acid–mediated retinal toxicity Ethylene glycol may cause acute tubular necrosis and acute renal failure 12 to 48 hours after inges-tion because of calcium oxalate precipitants in the kidneys The principal toxicity of isopropanol ingestion is CNS depression, lethargy, and coma as well as ketosis but not a metabolic acidosis because isopropanol is metabolized to acetone contributing to an osmolar gap but not an anion gap acidosis

Laboratory testing should include finger-stick glucose, electrolytes, ethanol level with other hols, and serum osmolarity Urine fluorescence with a Wood’s lamp can detect the presence of anti-freeze (and presumably ethylene glycol) shortly after ingestion; however, this finding is not always present An electrocardiogram (EKG) may show QT prolongation secondary to hypocalcemia from calcium oxalate precipitation in the kidneys

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Fomepizole, like ethanol, blocks metabolism of the toxic alcohols by competitively inhibiting the enzyme alcohol dehydrogenase and is the recommended treatment for suspected ethylene glycol and methanol poisoning When available, fomepizole is preferred to an ethanol infusion because it does not require following serum ethanol levels and increases safety by not adding syn-ergistic respiratory depression Hemodialysis still has a role in toxic alcohol ingestions and should

be discussed with the nephrology team Traditional indications for hemodialysis include severe acidosis, renal failure, or inability to obtain fomepizole or ethanol therapy If an elevated level of ethylene glycol or methanol is discovered, administer fomepizole, but if an acidosis is not yet pres-ent, some patients can be managed expectantly with fomepizole and not dialysis

CALCIUM CHANNEL AND BETA-ADRENERGIC ANTAGONISTS

Accidental or intentional ingestion of the potent calcium channel blockers or beta-adrenergic antagonists can result in significant morbidity and fatalities Patients present with bradycardia and hypotension The mental status may be normal or reflect obtundation, seizures, or coma following beta-blocker poisoning, and it typically remains normal despite significant hypotension in the set-ting of calcium channel blocker poisoning Poisoning with these drugs must be considered in any young person with unexplained bradycardia and may be misdiagnosed as a complicated myocar-dial infarction or conduction defect in older patients Sustained release preparations may produce delayed onset of toxicity and profound decompensation may occur after a period of relative stability.Because beta-adrenergic antagonists decrease intracellular cyclic adenosine monophosphate,

a specific therapeutic role has been demonstrated for the hormone glucagon Glucagon increases myocardial cyclic adenosine monophosphate via a non–beta-adrenergic receptor mediated mech-anism Following a trial of atropine, glucagon should be given (3 to 10 mg IV bolus followed by

a 2 to 5 mg/h IV infusion)

Calcium channel antagonists block slow inward calcium channels on vascular smooth muscle and myocardial cells, causing conduction defects, negative inotropic and chronotropic effects, and peripheral vasodilation Intravenous calcium competitively antagonizes these effects and may work synergistically with atropine and catecholamine pressors Norepinephrine, as an alpha and beta agonist, antagonizes both the negative inotropic effects as well as the peripheral vasodila-tion that are concomitantly contributing to hypotension The use of hyperinsulinemic euglycemic therapy has demonstrated efficacy in moribund calcium channel antagonist poisoned patients.Following acute management and stabilization, GI decontamination must address the sus-tained release preparations and their potential for prolonged toxicity Appropriate management includes orogastric lavage, activated charcoal administration, and whole bowel irrigation Therapy for bradycardia begins with atropine (0.5 to 1 mg IV bolus), followed by 10% calcium chloride or calcium gluconate Calcium therapy may be repeated to a total dose up to several grams if there

is a clinical response High-dose insulin infusion has been described as a novel treatment for calcium channel poisoning Insulin has several proposed mechanisms of action including increas-ing plasma levels of ionized calcium, improving myocardial utilization of carbohydrates, and a positive inotropic effect Insulin therapy can be initiated with a bolus dose of 0.1 U/kg followed

by an infusion of 0.5 mg/kg/h This infusion can be titrated up to a rate of 1 U/kg/h, with a trose infusion to maintain euglycemia In isolated cases with massive ingestion and poor response

dex-to pharmacologic therapy, placement of a transvenous pacer, an intra-aortic balloon pump and extracorporeal membrane oxygenation (ECMO) have each been successful

COCAINE

Cocaine is a potent sympathomimetic drug commonly abused either by nasal insufflation of cocaine hydrochloride or smoked in the form of “crack” cocaine Cocaine readily crosses the

57—DRUG OVERDOSES AND TOXIC INGESTIONS 563

blood-brain barrier and has a rapid onset of action Patients with acute intoxication may plain of chest pain or agitation and may be hypertensive, tachycardic, hyperthermic, and agitated Seizures are not uncommon Pulmonary toxicity may result in bronchospasm, pneumothorax, or pneumomediastinum as well as diffuse alveolar hemorrhage “Crack lung” is the combination of diffuse alveolar infiltrates, eosinophilia, and fevers Upper airway injuries can occur secondary to thermal effects including uvulitis and epiglottitis Wide complex dysrhythmias occur secondary to QRS and QT prolongation mediated by sodium channel blockade comparable to types IA and IC antidysrhythmic drugs Case reports have illustrated successful treatment with sodium bicarbon-ate therapy Rhabdomyolysis is also common, and a creatine phosphokinase (CPK) level should

com-be checked and trended Treatment of acute overdose includes supportive care, rapid cooling for hyperthermia, and benzodiazepines for treatment of seizures and agitation

Special consideration should be given to body stuffers and body packers Body stuffers tend to ingest drugs hastily because of a fear of arrest Body packers ingest large quantities of drugs that are carefully packaged for drug trafficking and face greater potential toxicity in the presence of package leakage or rupture The onset of altered mental status, seizures, or hypertension heralds rapid absorption of “pure” cocaine, and emergent surgery for gut decontamination is indicated Asymptomatic body packers can be identified by abdominal radiographs or contrast abdominal computed tomography (CT) scans Asymptomatic body stuffers and packers should be given multiple doses of activated charcoal to decrease potential cocaine absorption followed by whole bowel irrigation for body packers until all of the packets have been passed A follow-up contrast study can help confirm that the gut has been cleared of retained packets

OPIOIDS: HEROIN, FENTANYL, AND METHADONE

Heroin overdoses are a frequent cause of EMS calls as well as ED visits requiring the opioid antagonist naloxone to reverse life-threatening respiratory depression When faced with the triad

of respiratory depression, pinpoint pupils, and lethargy or coma, the administration of small doses

of naloxone starting at 0.05 to 0.4 mg IV will induce reversal of respiratory depression and can

be followed by larger doses if a desired response (arousal, increased respirations) occurs Caution should be used in patients deemed opioid tolerant such as heroin users or chronic pain patients in that abrupt reversal may precipitate withdrawal (vomiting, agitation) and in some cases may not improve mental status when other CNS depressants (alcohol, benzodiazepines) are co-ingested Thus, vomiting can occur while the patient remains sedated and aspiration can result

Long-acting opioids such as methadone or sustained release morphine or oxycodone may result

in recurrent opioid toxicity In these cases, a continuous naloxone infusion can be initiated because a bolus dose of naloxone will not sustain reversal relative to the longer duration of action of the opioid These patients will need ICU admission and should be observed for recurrent toxicity for a period after the naloxone infusion is stopped Patients who are unresponsive and cyanotic after an opioid overdose and then revived with naloxone are at some risk for acute lung injury Dyspnea may develop within a few minutes to few hours, and a chest radiograph will show pulmonary edema This can

be treated with supplemental oxygen, non-invasive ventilation (Chapter 3), or, rarely, intubation

DIGOXIN

Although the mortality rate of digoxin poisoning has dramatically improved with the use of digoxin-specific antibody fragments (Digibind), both acute and chronic digoxin poisoning con-tinues to occur Patients with acute digoxin poisoning may present with emesis and brady- or tachydysrhythmias Chronic digoxin toxicity often occurs when a patient develops a decrease in renal function, decreasing digoxin clearance by the kidneys GI symptoms are less prominent, and, instead, slight changes in mental status and visual disturbances as well as bradycardia may occur

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Following acute stabilization of a patient with potential digoxin toxicity, oral-activated charcoal should be administered Immediate serum potassium and digoxin levels should be obtained and electrocardiographic monitoring should be initiated Bradycardia, conduction defects, ventricular ectopy, bidirectional ventricular tachycardia, and atrial tachycardia or atrial fibrillation (but without rapid ventricular response) may be seen with digoxin poisoning Any dysrhythmia is an indication for Digibind therapy If Digibind is not immediately available, atropine can be given for bradycardia Potassium elevations > 5 mEq/L indicate significant toxicity and reflect digoxin-induced inhibition of the Na+/K+-ATPase pump This is used as a surrogate marker for toxicity, and treatment with Digibind is indicated as well In the setting of

an unknown overdose with bradycardia when the differential diagnosis includes calcium

chan-nel blockers, beta-blockers, and digoxin, patients should be treated with Digibind before they

are treated with calcium because calcium can significantly and sometimes lethally exacerbate digoxin poisoning

acetylcholines-an exposure that presents with muscle weakness without cholinergic findings

The diagnosis of organophosphate poisoning depends on the clinical symptoms and history Usually, serum tests are not available in a clinically relevant time frame Treatment consists of airway control, supportive measures and decontamination These patients have excessive airway secretions and bronchospasm and may require endotracheal intubation Use only nondepolarizing neuromuscular antagonists (such as rocuronium) to prevent prolonged paralysis Atropine, a com-petitive antagonist of acetylcholine, is used to reverse the excessive cholinergic state The dose is titrated to drying of bronchial secretions, and large doses may be necessary Atropine will not reverse muscle weakness Following atropine therapy, consider pralidoxime as an adjunct therapy

in severe organophosphate poisoning

PSYCHOTROPIC MEDICATIONS

Cyclic Antidepressants

Cyclic antidepressants continue to produce significant toxicity in overdose Screen all overdose patients by electrocardiography for possible cyclic antidepressant ingestion Prolongation of QRS duration (> 100 msec) is associated with serious toxicity In one early study, one third of patients with QRS duration > 100 msec had a seizure, and half of those with a QRS greater than 160 msec had a dysrhythmia A positive deflection of the R wave in lead aVR and an S wave in leads I and aVL are also clues to the presence of a cyclic antidepressant

Patients with cyclic antidepressant ingestions may present with lethargy and anticholinergic signs such as tachycardia, dry mouth, dilated pupils, decreased bowel sounds, and urinary retention Seizures, dysrhythmias, or both signify serious cyclic antidepressant ingestion Patients with recent ingestions (within the prior 30 to 90 minutes) may be asymptomatic initially but rapidly deterio-rate in the first hour in the emergency department Initiate orogastric lavage and activated charcoal early Obtundation often mandates endotracheal intubation If the QRS is > 100 msec, give a trial

57—DRUG OVERDOSES AND TOXIC INGESTIONS 565

of sodium bicarbonate (IV bolus followed by infusion) with a goal of alkalinization of the serum

to pH 7.45 to 7.55 Alkalinization decreases drug binding to the myocardium, expands the plasma volume, and overcomes the sodium channel blocking type IA cardiotoxic effects induced by the cyclic antidepressant Use benzodiazepines to treat seizures because a resultant lactic acidosis will exacerbate the cardiotoxicity If hypotension persists despite sodium bicarbonate and other fluid therapy, a direct vasoconstrictor such as norepinephrine will be more effective than indirectly acting vasopressors

Lithium

Lithium toxicity differs from other psychotropic drug toxicity Acute lithium ingestions duce considerable vomiting and diarrhea As dehydration ensues, renal lithium excretion decreases because lithium, a cation, is reabsorbed with sodium in the proximal tubule Measure lithium levels, serum electrolytes, and renal function Because lithium does not bind to acti-vated charcoal, consider orogastric lavage for recent ingestions, followed by whole bowel irri-gation to limit distal GI absorption Vigorous volume expansion with normal saline enhances lithium excretion Although sodium polystyrene sulfonate (SPS), Kayexalate, has been pro-posed as a binder of lithium, concerns about inducing hypokalemia limit its use Patients on chronic lithium therapy can become ill with elevated lithium levels after a new medication (especially diuretics) or an intercurrent GI illness induces dehydration and a change in renal lithium clearance

pro-The principal toxicity of lithium is to the CNS in both acute and chronic exposures Patients with acute ingestions will have some GI symptoms initially, followed by neuromus-cular manifestations such as hyperreflexia, fasciculations, choreoathetosis, nystagmus, clonus, and lethargy to coma as toxicity progresses Acute ingestions manifest elevated serum lev-els, reflecting rapid absorption yet slow distribution to intracellular compartments and the CNS Therefore, patients may initially be asymptomatic despite high serum levels During this time, lithium is most accessible to dialysis Any patient with lithium levels > 4 mEq/L should undergo hemodialysis, as renal elimination is insufficient to prevent significant neu-ral accumulation of lithium Any patient with serious neurologic symptoms (altered mental status, seizures, or coma) from lithium should also undergo hemodialysis A lithium level immediately after hemodialysis and 6 hours later should be measured because some patients may need a second treatment after lithium redistributes into the serum from the intracellular space Unfortunately, not all patients with elevated levels and neurologic signs recover fully, even with hemodialysis

SALICYLATES

Salicylates are commonly found in many over-the-counter analgesics and combination cold arations Other agents such as methyl salicylate (oil of wintergreen), liniments, and products used for vapor rubs all contain salicylates

prep-Acute salicylate toxicity often manifests with vomiting and auditory disturbances (tinnitus, hearing loss) Hyperpnea or tachypnea may contribute to the classic mixed acid-base disturbance

of a primary respiratory alkalosis and a metabolic acidosis (Chapter 83) Severe hyperthermia and diaphoresis may occur Agitation or confusion may occur and progress to seizures with higher salicylate levels A serum salicylate level should be obtained early and followed serially to determine the extent and course of the ingestion

GI decontamination of salicylate-poisoned patients may include orogastric lavage, but most can be effectively treated with multiple doses of activated charcoal Urinary alkaliniza-tion should be performed in any symptomatic patient until the salicylate level is less than 30 to

40 mg/dL Alkalinization effectively traps the salicylate ion away from the CNS and preserves

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availability for renal excretion Adding three ampules of sodium bicarbonate (44 mEq/ampule)

to 1 L of 5% dextrose in water (D5W) infused IV at a rate of 200 to 300 mL/h alkalinizes the urine Hypokalemia commonly complicates alkalinization and should be corrected prior

to initiating Because salicylate poisoning is commonly accompanied by fluid losses (vomiting, sweating, tachypnea), the saline load is usually well tolerated However, cerebral edema and salicylate-induced acute lung injury may complicate alkalinization therapy, especially in elderly patients

In general, levels > 100 mg/dL mandate hemodialysis Rapidly rising levels, severe acid-base disturbances, neurologic complications, or volume overload precluding alkalinization may also require hemodialysis Early consultation with a nephrologist is advisable in any significant salicylate poisoning

SEDATIVES

Benzodiazepines

Benzodiazepines are a surprisingly safe drug for sedation, causing dose-dependent CNS sion Unlike barbiturates, however, first-generation benzodiazepines (diazepam, chlordiazepoxide) have only rarely been associated with significant respiratory or cardiovascular depression However, all benzodiazepines may produce life-threatening CNS and respiratory depression when ingested along with large amounts of ethanol or other sedative-hypnotic agents As with barbiturates, benzodiazepine dependence is also common, and withdrawal may present as a severe delirium tremens–like syndrome

depres-Laboratory testing by qualitative immunoassay is widely available Many rapid screens use oxazepam as the immunoreagent, and therefore some of the newer benzodiazepines that are not metabolized to oxazepam go undetected Management of benzodiazepine toxicity is supportive, with no proven benefit for enhanced elimination The role of a specific antagonist, flumazenil, in overdose management is controversial Because its effect is brief (1 to 2 hours) and its use may precipitate seizures (in a benzodiazepine-dependent patient or with concomitant cocaine or cyclic antidepressant ingestion), avoid flumazenil in patients admitted to the ICU

GHB ( γ-Hydroxybutyrate)

γ-Hydroxybutyrate (GHB) has been used as an anesthetic, a therapy for narcolepsy, and a ment for ethanol and opioid withdrawal; however, it has also been abused as a recreational drug GHB is usually abused in the setting of dance parties or nightclubs After ingestion, GHB is rapidly absorbed and acts in the CNS at gamma aminobutyric acid (GABA) and opioid recep-tors The hallmark of poisoning is deep sedation, followed by unusually fast resolution to normal mental status Significant respiratory depression may require ventilatory support; modest brady-cardia is often present Myoclonic motion of the face and extremities is sometimes noted Reversal agents such as naloxone and flumazenil are not effective Treatment is supportive, and patients usually recover within a few hours without sequelae

treat-SEROTONERGIC AGENTS

Serotonin syndrome (SS) is a complication of serotonergic agents, which are most commonly able as the newer, safer antidepressants and increase serotonin in the CNS Although SS may occur after an overdose of such an agent, more often SS occurs soon after an increase in dose of a primary serotonergic agent or the addition of a second agent Serotonergic drugs are legion, including selec-tive serotonin reuptake inhibitors, such as fluoxetine, tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, amphetamines such as “Ecstasy” (3,4-methylenedioxymethamphetamine or MDMA), and opioids such as meperidine, tramadol, and dextromethorphan

avail-57—DRUG OVERDOSES AND TOXIC INGESTIONS 567

SS is a challenge to diagnose because it has no confirmatory laboratory tests, and signs and symptoms vary in diversity and severity Common clinical manifestations include one or more

of the following: (1) altered mental status, from restlessness to agitation, or unresponsiveness; (2) autonomic nervous system dysfunction, such as hyperthermia, tachycardia, diaphoresis, and hypo- or hypertension; and (3) neuromuscular dysfunction, such as myoclonus, muscle rigidity, and hyperreflexia (especially of the lower extremities) SS can result in lactic acidosis, rhabdomy-olysis, renal and hepatic dysfunction, or the acute respiratory distress syndrome, but generally it has a good prognosis Treatment remains supportive with aggressive cooling and sedation with benzodiazepines All serotonergic agents should be discontinued

Boyer EW: Management of opioid analgesic overdose N Engl J Med 367:146-155, 2012.

The review decscribes the toxicokinetics, manifestations and management of opioid overdose.

Boyer EW, Shannon M: The serotonin syndrome N Engl J Med 352:1112-1120, 2005

This comprehensive review describes serotonin physiology and psychopharmacology, as well as the pathophysiology, clinical features, and therapy of the serotonin syndrome.

Brent J: Fomepizole for ethylene glycol and methanol poisoning N Engl J Med 360:2216-2223, 2009

This case discussion and review highlights fomepizole therapy for ethylene glycol poisoning The clinical evidence supporting the use of fomepizole follows a discussion of the pathophysiology of methanol and ethylene glycol poisoning.

Deroos F: Calcium channel blockers In: Nelson, Lewin, Howland, et al (eds): Goldfrank’s Toxicologic gencies 9th ed NY: McGraw-Hill, 2010

Emer-This textbook and chapter is the authoritative resource for the management of complicated poisonings, including the cardiovascular collapse associated with calcium channel blocker poisoning The review of life-threatening calcium channel blocker overdoses includes the newer modality of high dose insulin therapy.

Engebretsen KM, Kaczmarek KM, Morgan J, et al: High-dose insulin therapy in beta-blocker and calcium channel-blocker poisoning Clin Toxicol (Phila) 49(4):277-283, 2011

A review of high-dose insulin therapy for the treatment of both beta-blocker and calcium channel-blocker poisonings, including discussion of the mechanism of action and treatment protocols, is provided.

Fertel BS, Nelson LS, Goldfarb DS: Extracorporeal removal techniques for the poisoned patient: a review for the intensivist J Intensive Care Med 25:139-148, 2010

This is a review of the indications for toxin removal by extracorporeal means, and the advantages and vantages for individual techniques.

disad-Heard KJ: Acetylcysteine for acetaminophen poisoning N Engl J Med 359:285-292, 2008

This review highlights the latest proposed mechanisms and indications for N-acetylcysteine therapy in acute and late acetaminophen poisoning as well as special circumstances such as pregnancy.

Heard K, Palmer R, Zahniser NR: Mechanisms of acute cocaine toxicity Open Pharmacol J 2:70-78, 2008

A review of the various mechanisms that contribute to the cardiovascular, cerebrovascular, and other complications

of cocaine use is provided.

Jamaty C, Bailey B, Larocque A, et al: Lipid emulsion in the treatment of acute poisoning: a systematic review

of human and animal studies Clin Toxicol 48:1-27, 2010

This is a systematic review of intravenous fat emulsion of the management of the poisoned patient, including the evidence regarding efficacy and safety.

Kerns W: Management of beta-adrenergic blocker and calcium channel antagonist toxicity Emerg Med Clin North Am 25:309-331, 2007

This review highlights the spectrum of therapies to manage bradycardia and hypotension related to overdoses of calcium channel blockers and beta adrenergic antagonists, including a review of catecholamine pressors and novel approaches such as hyperinsulinemic euglycemia.

Rosenbaum CD, Carreiro SP, Babu KM: Here today, gone tomorrow and back again? A review of herbal marijuana alternative (K2, Spice), synthetic cathinones (bath salts), Kratom, Salvia divinorum, methoxetamine, and piperazines J Med Toxicol 8:15-32, 2012

The paper discusses the background, pharmacology, clinical effects and management of these drugs of abuse.

Smilkstein MJ, Knapp GL, Kulig KW, et al: Efficacy of oral N-acetylcysteine in the treatment of

acetamino-phen overdose: analysis of a national multicenter study (1976–1985) N Engl J Med 319:1557-1562, 1988

This is a summary analysis of the efficacy of oral N-acetylcysteine (NAC) in the treatment of acetaminophen poisoning in 2540 patients over a 10-year period.

Traub SJ, Hoffman RS, Nelson LS: Body packing—The internal concealment of illicit drugs N Engl J Med 349:2519-2526, 2003

This review describes the diagnosis and management of patients ingesting large quantities of illict drugs The use

of contrast imaging, whole bowel irrigation, surgery and antidotal therapy are discussed.

Acute Pancreatitis

Douglas O Faigel  n  Laura Wolfe  n  Faten N Aberra

Acute pancreatitis (i.e., acute inflammation of the pancreas) has multiple causes and may manifest

as mild disease or a life-threatening disorder that can result in multiple organ system failure, sepsis, and death Acute pancreatitis typically presents as abdominal pain, in association with elevated blood levels of pancreatic enzymes It may occur as an initial or recurrent attack The pathogenesis

is considered to be pancreatic autodigestion caused by intraparenchymal activation and release

of proteolytic enzymes from zymogen granules The resultant destruction and inflammation can produce a variety of local complications for which a clinically based system of classification and terminology has been developed (Table 58.1)

Etiology

More than 90% of cases of acute pancreatitis are due to ethanol abuse or cholelithiasis or are pathic A variety of other agents, including medications and toxins, account for the remaining 10% (Box 58.1 and Table 58.2) Biliary microlithiasis (which is bile containing small crystals of cholesterol monohydrate, calcium bilirubinate, or calcium carbonate) is also recognized as a cause of acute and recurrent pancreatitis, accounting for up to 30% of pancreatitis previously considered idiopathic.Clinical Presentation

idio-The hallmark of acute pancreatitis is abdominal pain associated with elevated blood levels of pancreatic enzymes The pain generally comes on suddenly and rises to a peak within a few hours

It is steady, typically midepigastric, and bores through to the back The patient prefers to remain still in bed and may assume a hunched-over or semifetal position in an attempt to release tension

on the retroperitoneum; exaggerating the lumbar lordosis exacerbates the pain Nausea and ing are present in more than 80% of patients The presence of bluish discolorations of the flanks (Grey Turner sign) or periumbilical area (Cullen sign) is rare and does not occur at presentation but rather may develop several days into the illness because of dissection of peripancreatic bleeding into the subcutaneous tissues Bowel sounds are diminished, or absent if a paralytic ileus is pres-

vomit-ent An abdominal radiograph may reveal a sentinel loop, which is a paralyzed air-filled segment of

proximal small bowel in close proximity to the inflamed pancreas The abdomen is typically soft but with exquisite tenderness to deep palpation Peritoneal signs may be present in complicated cases Subcutaneous fat necrosis may be present and resembles erythema nodosum or panniculitis Altered mental status may be due to shock or complications of chronic alcoholism (e.g., alcohol withdrawal syndrome [AWS; Chapter 31], delirium tremens, and Wernicke-Korsakoff syndrome)

The serum amylase level rises in acute pancreatitis within 2 to 12 hours of the onset of symptoms and remains elevated for 3 to 5 days Persistently raised levels suggest local complications The lipase level may remain elevated longer than the amylase level Elevation of both enzymes to levels greater

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58—ACUTE PANCREATITIS 569

than 10 times the upper limit of normal is highly specific but only 80% to 90% sensitive for acute pancreatitis Levels less than 3 times the upper limit of normal should be considered non-specific.Differential Diagnosis

There are multiple causes for an elevated pancreas enzyme level other than acute pancreatitis (Box 58.2) Several deserve special comment Perforated peptic ulcer may present with pain and elevated pancreatic enzymes resulting from spillage into the peritoneal cavity Abrupt onset of pain,

TABLE 58.1 n  Classification System for Acute Pancreatitis

Severe acute

pancreatitis

Acute pancreatitis associated with organ

failure, certain local complications (necrosis, abscess, or pseudocyst), or both Most often it represents the development of

pancreatic necrosis.

Early prognostic signs for severe disease: three or more Ranson criteria (see Table 58.4 ) or eight

or more points in the APACHE II system *

Acute fluid

collections

These collections, localized in or near the

pancreas, occur early in the course of acute pancreatitis and always lack a defined wall.

They are common, occurring in 30%–50% of patients with severe pancreatitis, and most regress spontaneously Those persisting represent an early stage in the development of acute pseudocysts and pancreatic abscesses.

Pancreatic

necrosis Diffuse or focal area(s) of nonviable pancreatic parenchyma, typically associated with

peripancreatic fat necrosis Pancreatic necrosis may be sterile or become infected (the latter triples the risk of death).

Dynamic contrast-enhanced computed tomography shows

a well-marginated zone of nonenhancement.

Acute

pseudocysts

Collections of pancreatic fluid, enclosed by a

defined wall of fibrous or granulation tissue, arising from acute pancreatitis They are usually rich in pancreatic enzymes and most often sterile.

Sometimes palpable but most often discovered by imaging studies, which show a well-defined wall They form 4 or more weeks from the onset of acute pancreatitis Pancreatic

abscesses Circumscribed intra-abdominal collections of pus, in or near the pancreas, but containing

little or no pancreatic necrosis Do not use this term to describe infected pancreatic necrosis (the latter has twice the mortality risk of a pancreatic abscess).

These occur 4 or more weeks after the onset of acute pancreatitis and likely arise as a result of limited necrosis with subsequent liquefaction and infection.

Pancreatic

ascites

The presence of free fluid with pancreatic

enzymes inside the peritoneal cavity.

Pancreatic ascites may be sterile or infected.

Infected

pseudocyst

Variably used to describe infected pancreatic

necrosis or pancreatic abscesses.

Avoid use of this ambiguous term Hemorrhagic

pancreatitis

Defined by direct visualization of hemorrhage

in the gland.

Incorrectly used as a synonym for

pancreatic necrosis, which may not be hemorrhagic.

Pancreatic

phlegmon Originally referred to a palpable mass of sterile edematous tissues, but later used to

describe pancreatic necrosis with infection.

Avoid use of this ambiguous term.

*Knaus WA, Draper EA, Wagner DP, et al: APACHE II: severity of disease classification system Crit Care Med 12:818-829, 1985.

Modified from Bradley EL III: A clinically based classification system for acute pancreatitis Arch Surg 128:586-590, 1993.

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TABLE 58.2 n  Medications and Toxins Associated with Acute Pancreatitis

Methyldopa Anti-inflammatory and analgesic

agents

Acetaminophen Corticosteroids Mesalamine NSAIDs Salicylates Anti-infective agents Didanosine (ddI)

Pentamidine Sulfonamides Tetracyclines

Erythromycin Metronidazole Nitrofurantoin Chemotherapeutic agents 6-MP, azathioprine

l -Asparaginase

Hydrochlorothiazide

Chlorthalidone Ethacrynic acid

Methanol Others Estrogens (via hyperlipidemia)

Intravenous lipid infusions Valproic acid

6-MP, 6-mercaptopurine; NSAIDs, nonsteroidal anti-inflammatory drugs; ACE, angiotensin-converting enzyme.

BOX 58.1 n Selected Causes of Acute Pancreatitis

Major Causes (~90% of cases)

Ethanol abuse

Gallstones, including microlithiasis

Idiopathic

Other Causes (~10% of cases)

Medications and toxins (see Table 58.2)

—Postoperative (especially after intra-abdominal surgery or cardiopulmonary bypass)

—Endoscopic retrograde cholangiopancreatography (ERCP)

58—ACUTE PANCREATITIS 571

peritoneal signs, and free air on radiography differentiates this entity from pancreatitis Acute cystitis may sometimes be associated with mild hyperamylasemia The pain of cholecystitis is typi-cally right-sided, and ultrasonography or computed tomography can suggest the diagnosis A stone

chole-in the bile duct (choledocholithiasis) may cause cholangitis with biliary colic, elevated liver-associated enzymes, and jaundice with or without concomitant pancreatitis Bowel ischemia and infarction result-ing from mesenteric vascular occlusion, volvulus, and hernia are important considerations because of the need for prompt surgical treatment Salpingitis and ruptured ectopic pregnancy may cause abdomi-nal pain and elevated amylase levels and may occasionally be confused with acute pancreatitis.Diagnostic Evaluation

A diagnosis of acute pancreatitis is supported by elevated serum amylase or lipase (≥ 3× upper limit of normal) and abdominal pain Contrast-enhanced computed tomography (CT) of the pancreas is recommended in patients with severe pancreatitis at 72 hours from admission to evalu-ate for complications By contrast-enhanced CT scan, nonenhancing areas within the pancreas correlate with the presence of necrosis Fluid collections and evidence of inflammation around the pancreas are well seen A contrast-enhanced CT performed before 72 hours after admission may underestimate the severity of disease, but it can confirm acute pancreatitis in patients where there

is clinical uncertainty Dynamic CT during bolus intravenous (IV) injection of contrast may both provide a diagnosis (by demonstrating inflammation and ruling out other entities) and help with prognosis (by assessing the degree of inflammation and necrosis)

As part of the evaluation for risk factors of acute pancreatitis, laboratory measurements of serum calcium, liver chemistries, and triglycerides should also be obtained Abdominal ultrasound is recom-mended to evaluate for underlying cholelithiasis and choledocholithiasis as a cause for pancreatitis Contrast-enhanced CT scan or endoscopic ultrasound is also recommended in patients over the age

of 40 years and without an explanation for acute pancreatitis to evaluate for malignancy

Prognosis

Severity of disease and prognosis can also be gauged by clinical scoring systems Ranson and worker s introduced the first such system in 1974, often referred to as Ranson’s criteria (Table 58.3), based on findings on admission to the hospital and at 48 hours after admission This system has proven to be useful specifically to define those with severe acute pancreatitis (see Table 58.1) and their

co-BOX 58.2 n Selected Nonpancreatitis Causes of Hyperamylasemia

—Metabolic, diabetic ketoacidosis

—Acute and chronic liver disease

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Management

Patients with severe acute pancreatitis require admission to the intensive care unit (ICU) for agement by a multidisciplinary team, including an intensivist, a gastroenterologist, and a surgeon

man-TABLE 58.3 n  Ranson’s Criteria for Severity and Prognosis *  in Acute Pancreatitis

Age > 55 years Decrease in hematocrit > 10% (absolute) WBC > 16,000/ μL BUN increase > 5 mg/dL (1.79 mmol/L) Glucose > 200 mg/dL [11.1 mmol/L] Calcium < 8 mg/dL (2 mmol/L)

Gastrointestinal Bowel obstruction (mechanical versus paralytic)

Gastrointestinal hemorrhage Ulceration

Gastric varices Hematologic Coagulopathy (disseminated intravascular coagulation)

Hypocalcemia

Right-sided hydronephrosis Respiratory Acute respiratory distress syndrome

58—ACUTE PANCREATITIS 573

Determining which patients will develop severe acute pancreatitis may be difficult and the scoring systems used to predict mortality—such as Ranson, APACHE (Acute Physiology and Chronic Health Evaluation), and Glasgow criteria—require at least 48 hours of observation to be accurate Thus, the Atlanta Symposium has identified clinical factors to define the severity of acute pancre-atitis primarily examining for evidence of organ failure and complications Risk factors for severity include age > 55, obesity (body mass index [BMI] > 30), organ failure at admission, and pleural effusions or pulmonary infiltrates

Initial management requires supportive care with aggressive intravenous hydration titrating to

a normal hematocrit, in an effort to prevent pancreatic necrosis, as well as careful monitoring for organ failure and other systemic complications The hematocrit should be drawn on admission and 12 hours and 24 hours postadmission Potential offending medications (see Table 58.2) should

be discontinued, and reintroduction should be avoided, as it can lead to fulminant disease Initially, patients should receive nothing by mouth Nasogastric suction should be instituted for persistent vomiting, ileus, or obstruction but otherwise does not alter ultimate outcome Nutritional support should be started when it becomes clear the patient will not be taking oral food for more than

7 days Studies looking at parenteral versus nasojejunal feeding demonstrate that enteral feeds

do not exacerbate pancreatitis and they can decrease the inflammatory response, complications

of vascular catheter infections, and episodes of hyperglycemia compared to parenteral nutrition Elemental or semielemental enteral diets are recommended (Chapter 15) Adequate opioid anal-gesia is required There is no benefit of one opioid over another (Chapter 87), but avoid high doses

of meperidine (previously felt to be the agent of choice), which may result in seizures, particularly

in patients with renal failure

Primary and prophylactic medical and surgical therapies have been largely unsuccessful, with the exception of gallstone pancreatitis Therapies designed to rest the pancreas by inhibiting pancreatic secretion with nasogastric suction, histamine H2-receptor blockers, atropine, glucagon,

somatostatin, or fluorouracil do not change the course of the disease Studies have found no

benefit in using prophylactic antibiotics When infected pancreatic necrosis is suspected, ing a CT-guided fine-needle aspirate (FNA) is recommended to guide appropriate antibiotic therapy Early surgical therapies such as peritoneal lavage and pancreatic resection provide no benefit Surgical treatment of gallstone pancreatitis is not beneficial and when performed in the early acute phase may have a mortality rate as high as 48% Endoscopic retrograde cholangio-pancreatography (ERCP) with sphincterotomy and stone extraction is indicated upon evidence

obtain-of biliary obstruction caused by a stone (e.g., increasing jaundice) or obtain-of acute cholangitis ever, in patients with biliary pancreatitis without signs of obstruction or cholangitis, ERCP and sphincterotomy confer no benefit

How-Supportive treatment addresses the systemic and local complications that may occur (see

Table 58.3) Shock is a combination of hypovolemic shock from massive third spacing of fluid (as evidenced by hemoconcentration), and distributive shock due to severe systemic inflamma-tory response syndrome (SIRS) Cardiovascular collapse may cause early death in patients with severe pancreatitis, and it requires aggressive volume replacement and vasopressors Hypox-emia, occurring in a majority of patients during the first 2 days, is generally asymptomatic with a normal chest radiograph and resolves as the pancreatitis improves However, up to 20%

of patients with severe pancreatitis develop the acute respiratory distress syndrome (ARDS; see Chapter 73) requiring mechanical ventilation, portending greater than 50% mortality Pleural effusions are usually left-sided and exudative, with high amylase levels; they resolve as the pancreatitis improves Persistent and large plural effusions may indicate a pancreaticopleural fistula Coagulopathy, generally from disseminated intravascular coagulation (DIC), has no spe-

cific treatment, but factor replacement may be required for active bleeding or planned invasive

procedures Acute renal failure is generally due to acute tubular necrosis from renal sion; the need for dialysis also predicts greater than 50% mortality Hyperglycemia transiently

hypoperfu-5—PRESENTING PROBLEMS FOR INTENSIVE CARE UNIT ADMISSION

574

occurs in 50% of patients and, if severe, requires insulin therapy Hypocalcemia is multifactorial

because of the saponification of calcium salts in areas of fat necrosis, hypoalbuminemia, magnesemia, and abnormalities of glucagon, calcitonin, and parathyroid hormone secretion

hypo-or responsiveness The ionized calcium level should guide treatment of hypocalcemia den blindness, which occurs rarely but may be permanent, arises from Purtscher’s angiopathic retinopathy (discrete flame-shaped hemorrhages with cotton-wool spots) Idiopathic pancreatic encephalopathy with confusion, delirium, and coma may be due to the effects of brain hypoperfu-

Sud-sion and metabolic abnormalities It must be differentiated from other causes of altered mental status, including the sequelae of alcoholism

The most common gastrointestinal complication is paralytic ileus, treated by nasogastric decompression and observation Occasionally, mechanical bowel obstruction occurs from bowel

involvement by the inflammatory process Mechanical obstruction can also be managed

conser-vatively, although persistence may warrant surgical resection of the affected loop Gastrointestinal hemorrhage may occur from stress ulcerations, bleeding from gastric varices, or a ruptured pseu-

doaneurysm Stress ulcerations can be managed endoscopically and with proton pump inhibitors

Gastric varices develop as a consequence of splenic vein thrombosis, which may complicate either

acute or chronic pancreatitis Treatment options include endoscopic cyanoacrylate glue injection

or splenectomy Erosion of major peripancreatic arteries, usually in association with a pseudocyst,

can produce pseudoaneurysm formation Bleeding from a ruptured pseudoaneurysm reaches the

gastrointestinal tract via the pancreatic duct or directly via the rupture of the pseudocyst into the

bowel lumen Intra- or retroperitoneal hemorrhage can also occur Treatment of this unusual

condi-tion is by angiographic embolizacondi-tion or surgery Extension of pancreatic inflammcondi-tion may cause splenic rupture or right-sided hydronephrosis

Local pancreatic complications include the development of fluid collections, pseudocysts, and localized infection (see Table 58.1), primarily in patients with necrotizing pancreatitis Sterile fluid collections can be managed expectantly because most will resolve Ten percent to 15% of patients will acquire pseudocysts, and two thirds of these will resolve spontaneously, generally within 6 weeks Complications of pseudocysts include pain, bleeding, infection, bowel obstruction, and rupture Endoscopic, percutaneous, or surgical therapy is indicated for symptomatic matured (may take at least 4 weeks) pseudocysts Traditional treatment of pancreatic abscesses and infected pancreatic necrosis with surgical drainage and systemic anti-biotics is being supplanted with endoscopic transgastric drainage and/or percutaneous drain-age In patients with acute pancreatitis who improve with supportive treatment, no further therapy is needed However, with no clinical improvement or further deterioration, consider severe sterile or infected necrosis absent obvious local or systemic complications Both ster-ile and infected necrosis may produce fever and leukocytosis (> 20,000/μL) Although no consensus exists for the role of surgery in severe sterile necrosis, most experts recommend extensive surgical debridement for infected necrosis However, differentiating sterile from infected necrosis may be challenging Intrapancreatic air on CT indicates the presence of gas-forming organisms and the need for surgery CT-guided fine-needle aspiration for Gram stain and culture is both highly sensitive and specific for infection, with Gram stain by itself being 98% sensitive

58—ACUTE PANCREATITIS 574.e1

resuscita-  n   In patients with necrotizing pancreatitis who do not improve or deteriorate while on medical therapy, the presence of infected necrosis should be considered, and CT-guided aspiration should be contemplated

  n   Patients with infected necrosis should receive antibiotics and undergo debridement or another drainage procedure

  n   Those with sterile necrosis who do not improve despite prolonged medical therapy may benefit from late drainage or surgery

Banks PA, Freeman ML: Practice guidelines in acute pancreatitis Am J Gastroenterol 101:2379-2400, 2006.

This is a practice guideline for the diagnostic evaluation and treatment of acute pancreatitis.

Dellinger EP, Tellado JM, Soto NE, et al: Early antibiotic treatment for severe acute necrotizing pancreatitis:

a randomized, double-blind, placebo-controlled study Ann Surg 245:674-683, 2007

This clinical trial of meropenem for the treatment of necrotizing pancreatitis showed no clinical benefits.

Forsmark CE: Complications of pancreatitis Semin Gastrointest Dis 2:165-176, 1991

This is an extensive literature review of the diagnostic evaluation and management of acute pancreatitis.

Freeman ML, Werner J, van Santvoort HC, et al: Interventions for necrotizing pancreatitis: summary of a multidisciplinary consensus conference Pancreas 41:1176-1194, 2012

This consensus statement concluded that the step-up approach or per-oral endoscopic necrosectomy were the emerging treatments of choice.

Gardner TB, Vege SS, Pearson RK, Chari ST: Fluid resuscitation in acute pancreatitis Clin Gastroenterol Hepatol 6:1070-1076, 2008

This review of the literature evaluated the importance of fluid resuscitation in acute pancreatitis.

Isenmann R, Runzi M, Kron M, et al: Prophylactic antibiotic treatment in patients with predicted severe acute pancreatitis: a placebo-controlled, double-blind trial Gastroenterology 126:997-1004, 2004

This clinical trial of prophylactic ciprofloxacin and metronidazole showed no reduced risk for infected necrotizing pancreatitis.

Kim DH, Pickhardt PJ: Radiologic assessment of acute and chronic pancreatitis Surg Clin North Am 87:1341-1358, 2007

This is a thorough review of imaging modalities in the diagnosis, severity, and evaluation of complications of pancreatitis.

Sainio V, Kemppainen E, Puolakkainen P, et al: Early antibiotic treatment in acute necrotising pancreatitis Lancet 346:663-667, 1995

This is one of the initial clinical trials showing that prophylactic antibiotics for necrotizing pancreatitis reduced the risk of infectious complications and possibly mortality All patients in this study had alcohol-induced pancreatitis.

Tse F, Yuan Y: Early routine endoscopic retrograde cholangiopancreatography strategy versus early tive management strategy in acute gallstone pancreatitis Cochrane Database Syst Rev 5:CD009779, 2012

conserva-This Cochrane Database review of 5 randomized controlled trials in 644 patients with suspected gallstone creatitis of early ERCP vs conservative therapy, found no evidence that early routine ERCP significantly affects mortality, and local or systemic complications of pancreatitis, regardless of predicted severity However, they did find evidence of benefit for patients with co-existing cholangitis or biliary obstruction.

pan-Van Santvoort HC, Besselink MG, Bakker OJ, et al: A step-up approach or open necrosectomy for ing pancreatitis N Engl J Med 362:1491, 2010

necrotiz-In this multicenter study, a step approach for the treatment of suspected or confirmed infected pancreatic necrosis consisting of percutaneous drainage followed, if necessary, by minimally invasive retroperitoneal necrosectomy, was compared to traditional open necrosectomy The step-up approach reduced the compositie end point of major com- plications or death.

Windsor AC, Kanwar S, Li AG, et al: Compared with parenteral nutrition, enteral feeding attenuates the acute phase response and improves disease severity in acute pancreatitis Gut 42:431-435, 1998

This clinical trial demonstrated that total enteral nutrition decreased acute phase response and disease severity scores, compared to no significant change in patients receiving total parenteral nutrition for the treatment of acute pancreatitis.

Wu BU, Hwang JQ, Gardner TH, et al: Lactated Ringer’s solution reduces systemic inflammation compared with saline in patients with acute pancreatitis Clin Gastro Hepatol 9:710, 2011

This randomized controlled study in 40 patients concluded that lactated Ringer’s solution had a reduced incidence

of systemic inflammatory response syndrome (SIRS) and lower C-reactive protein (CRP) levels compared to patients treated with saline.

The presentation of ALF is rapid, dramatic, and frequently leads to coma and death from cerebral edema and multiorgan failure over the course of a few days There are approximately 2000 cases of ALF in the United States on a yearly basis It is a rare indication for liver transplantation, accounting for only 6% of all liver transplants One-year survival after liver transplantation is 82%, which is lower than the 88% 1-year survival rate seen in all other recipients, probably owing to the higher severity of illness at the time of transplant Once listed for a liver transplant, patients will wait an average of 3.5 days and 22% of patients will die waiting for a transplant With only medical management in an intensive care unit (ICU) there is a 25% to 43% transplant-free and spontaneous recovery rate For this reason, when there is concern for ALF, patients should be immediately transferred to a transplant center where an evaluation for a transplant can begin.Etiology of Acute Liver Failure

The prognosis of ALF is dependent on its etiology, so every effort should be made to look for the underlying cause of the liver injury (Table 59.1) However, up to 20% of cases will have no discern-able cause The most common cause of ALF in the United States is acetaminophen toxicity, most recently accounting for approximately 39% to 50% of all cases of ALF Idiosyncratic drug reactions account for 13% of cases of ALF Viral hepatitis (acute hepatitis A and B combined) has become a less frequent cause of ALF in the United States, accounting for only 12% of all cases Acute hepatitis

C does not appear to lead to ALF Hepatitis E is a significant cause of liver failure in endemic tries (Russia, Pakistan, Mexico, and India) and should be considered in any patient who travels to these countries and in any pregnant woman, as hepatitis E has a more severe course during pregnancy.Wilson disease and autoimmune hepatitis account for 3% and 4% of all cases of ALF, respec-tively, and are unique in that patients can still be considered as having ALF even though there

coun-is a preexcoun-isting chronic liver dcoun-isease if the dcoun-isease previously had been unrecognized Mushroom

toxicity (usually Amanita phalloides) may cause ALF, and the initial history should always include

recent mushroom ingestion Acute fatty liver of pregnancy and hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome (Chapter 72) typically occur during the third trimester, and prompt delivery of the fetus is essential to achieve good outcomes

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Diagnosis and Initial Evaluation

All patients with clinical or laboratory evidence of moderate to severe acute hepatitis should have

a prothrombin time measured and be assessed for subtle alterations in mentation An INR ≥ 1.5 and evidence of encephalopathy mandate a hospital admission, preferably to an ICU given the potential for rapid clinical deterioration

History taking should include a careful review of possible medication overdoses (especially acetaminophen and acetaminophen-containing products), medications newly started within the

last 6 months, toxins (Amanita phalloides mushrooms in particular), herbal supplements, and risk

factors for exposure to an acute viral hepatitis Physical examination should focus on any mata of chronic liver disease; the prognosis is improved in a patient with acute on chronic liver injury compared to a patient with ALF alone Observe patients frequently for the development

stig-of hepatic encephalopathy; once grade I or II encephalopathy has developed, transfer patients to

a transplant center as they may deteriorate rapidly (Table 59.2)

Initial laboratory examination must be extensive and include tests to evaluate for the severity and etiology of the ALF (Table 59.3) Plasma ammonia (venous or arterial), although not very useful in patients with chronic liver disease, can help determine the risk for cerebral herniation in patients with ALF Although no definite threshold ammonia level has been established, patients with arterial ammonia levels > 200 mcg/dL have a significant risk (close to 100%) of developing severe hepatic encephalopathy and a 55% risk of developing increased intracranial pressure The utility of a liver biopsy is marginal, as it will usually not change therapy; if indicated, it is typically done via the transjugular approach because of a patient’s coagulopathy

Hepatic cross-sectional imaging or Doppler ultrasound is important in the diagnosis of ALF Not only will it look at the hepatic parenchyma and give some information as to the presence of any chronic liver disease (nodular liver, presence of varices, splenomegaly), but it also will look at the patency of the hepatic veins to exclude Budd-Chiari syndrome

Wilson disease requires special consideration, as it may be difficult to diagnose because the low ceruloplasmin levels that are characteristic of the disease are present in most patients with ALF, regardless of etiology Kaiser-Fleischer rings are not uniformly present and serum copper levels require several days to obtain In these cases, a very low alkaline phosphatase with a marked hyper-bilirubinemia resulting from profound hemolytic anemia is relatively specific for Wilson disease

An alkaline phosphatase-to-total bilirubin concentration less than 4 is consistent with Wilson disease and may aid in the diagnosis Rapid diagnosis is essential; these patients will require a liver transplant as spontaneous recovery is estimated at 0%

TABLE 59.1 n  Causes of Acute Liver Failure

Drugs Acetaminophen, halothane, phenytoin

Miscellaneous Acute fatty liver of pregnancy, Reye syndrome, Wilson disease, malignant infiltration,

autoimmune hepatitis Toxins Amanita phalloides, carbon tetrachloride

Vascular Budd-Chiari syndrome, cocaine, heat stroke, ischemia (“shock liver”),

veno-occlusive syndrome Viral hepatitis Hepatitis A, B, D, E, C, * G, * CMV, HSV, EBV, varicella

*Uncertain cause of acute liver failure.

CMV, cytomegalovirus; HSV, herpes simplex virus; EBV, Epstein-Barr virus.

59—ACUTE LIVER FAILURE 577

Predicting Prognosis in Acute Liver Failure

Accurate prognosis of ALF is a paramount goal The traditional King’s College Hospital criteria have been the most commonly used and most frequently validated prognostic criteria for ALF (Table 59.4) Several studies have shown a positive predictive value from 70% to 100% and a negative predictive value of 25% to 94% for the King’s College Hospital criteria for determining mortality An Acute Physiology and Chronic Health Evaluation (APACHE) II score greater than

15 on admission has a specificity of 92% and sensitivity of 81% for predicting a patient’s mortality.Other prognostic criteria have been proposed, including alpha-fetoprotein (a rising level over the first 3 days is a predictor of survival) and serum phosphate levels (hyperphosphatemia is found

in nonsurvivors) The Model for End-stage Liver Disease (MELD) score, now widely used to predict mortality among patients with chronic liver disease, has been studied to predict mortality

in ALF As a predictor of death from ALF, the MELD score does not provide more information

TABLE 59.2 n  Grading Scale for Hepatic Encephalopathy

I Subtle change in mental status, difficulty in

computation, emotional lability No asterixis Normal or symmetric slowing, triphasic waves

II Drowsy, unequivocal loss of computation,

memory loss Asterixis Abnormal symmetric slowing, triphasic waves III Sleepy but arousable, can answer simple

questions only Asterixis (if able to comply) Abnormal symmetric slowing, triphasic waves IVa Coma, no response to commands,

responds to pain Unable to comply for asterixis testing,

Babinski reflex is present

Abnormal slow delta waves (2–3/min)

IVb Coma, no response to commands or pain Same as in IVa Same as in IVa

TABLE 59.3 n  Initial Laboratory Analysis

Acetaminophen level

Ammonia level

Arterial blood gas

Autoimmune markers: ANA, ASMA, immunoglobulin levels

Type and screen

Viral hepatitis serologies: anti-HAV IgM, HepBsAg, anti-HepBcore IgM, HCV Ab

ANA, anti-nuclear antibody; anti-HepBcore, antihepatitis B core antibody; ASMA, anti-smooth muscle antibody; CBC, complete blood count; HAV, hepatitis A virus; HCV Ab, hepatitis C virus antobody; HepBsAg, hepatitis B surface antigen; HIV, human immunodeficiency virus; IgM, immunoglobulin M.

5—PRESENTING PROBLEMS FOR INTENSIVE CARE UNIT ADMISSION

578

than the King’s College Hospital criteria Overall, all current scores miss accuracy in predicting mortality from ALF In general, the clinical course of encephalopathy is regarded as the most informative datum in a particular patient—the deeper the coma, the worse the outcome.The etiology of the ALF is the most significant predictor of outcome Patients with ALF resulting from acetaminophen, hepatitis A, shock liver, or pregnancy-related disease have a > 50% transplant-free survival rate, whereas all other etiologies have a < 25% transplant-free survival rate Renal failure and acidosis (particularly in acetaminophen-induced ALF) are particularly ominous signs

Management of Patients with Acute Liver Failure

All patients with ALF should be transferred to an ICU at a liver transplant center early in their

disease course Early transfer of patients with any degree of encephalopathy is crucial.

SPECIFIC­THERAPY

Patients with ALF who have ingested acetaminophen should receive a full course of N-acetylcysteine

(NAC) Treatment with NAC should be instituted even if 24 to 36 hours have elapsed since the ingestion of acetaminophen (Chapter 57) NAC can be administered intravenously or orally The intravenous dose is a loading dose of 150 mg/kg in 5% dextrose over 15 minutes, followed by

a maintenance dose of 50 mg/kg given over 4 hours followed by 100 mg/kg administered over

16 hours The oral dose is 140 mg/kg by mouth or via nasogastric tube, followed by 70 mg/kg by mouth every 4 hours for a total of 17 doses In addition, some studies suggest that NAC may have beneficial effects on ALF from causes other than acetaminophen

Penicillin G and silibinin (silymarin or milk thistle) are accepted antidotes for Amanita phalloides

poisoning, although there is no controlled trial establishing their efficacy Silymarin has been given

in average doses of 30 to 40 mg/kg/day (either intravenously or orally) for an average duration of

3 to 4 days

Pregnancy-related ALF is treated by prompt delivery of the fetus

HYPOGLYCEMIA

ALF, especially when caused by acetaminophen or one of the microvesicular fat deposition disorders

(acute fatty liver of pregnancy), is often complicated by hypoglycemia Patients should have their

TABLE 59.4 n  Prognostic Criteria Predicting Need for Liver Transplantation

Acetaminophen Toxicity

pH < 7.3 (irrespective of grade of encephalopathy) or prothrombin time > 100 sec and serum creatinine

level > 3.4 mg/dL (300 μmol/L) in patients with grade III or grade IV encephalopathy

All Other Causes

Prothrombin time > 50 sec (irrespective of encephalopathy) or any three of the following variables

(irrespective of grade of encephalopathy):

—Age > 40 years

—Liver failure because of drug idiosyncrasy or idiopathic hepatitis previously called NANB

—Duration of jaundice prior to encephalopathy > 7 days

—Prothrombin time > 25 sec

—Serum bilirubin > 17.5 mg/dL (300 μmol/L)

NANB, non-A, non-B.

59—ACUTE LIVER FAILURE 579

glucose level checked at least every 2 hours An intravenous glucose infusion (1.5 to 2 g/kg/day) is recommended in patients who develop hypoglycemia

COAGULOPATHY

Do not give fresh frozen plasma simply to correct a prolonged prothrombin time The uncorrected prothrombin time is a useful parameter to monitor recovery or deterioration of hepatic synthetic function; along with a patient’s mental status, the prothrombin time is the most significant marker Correct coagulopathy by fresh frozen plasma before invasive procedures, such as placement of central venous catheters or an intracranial pressure (ICP) monitor, or whenever there is evidence

of serious hemorrhage

HEPATIC­ENCEPHALOPATHY­AND­HYPERAMMONEMIA

Lactulose is given to all patients with hepatic encephalopathy Its benefit is maximal when the patient is passing three to four soft stools per 24 hours Nonabsorbable antibiotics (Flagyl, neo-mycin, rifaximin), like lactulose, have never been proven to be beneficial in ALF but now are prescribed widely to aid in the treatment of encephalopathy Avoid neomycin because of the risk

of renal injury

ALF is a catabolic state No convincing controlled clinical trials support withholding protein completely or administering specially formulated oral or parenteral amino acid feedings

INFECTION­PROPHYLAXIS­AND­SURVEILLANCE

Infection is one of the principal causes of death in patients with ALF The most common site

of infection is the lung, followed by the urine and bloodstream The most commonly isolated organisms are gram-positive cocci and enteric gram-negative bacilli, but fungal infections are present in up to 30% of patients with ALF Prophylactic antibiotics have not been shown to improve outcome or survival in patients with ALF Consider empiric antibiotics in patients with stage IV encephalopathy, the presence of systemic inflammatory response syndrome, persistent hypotension, or upon listing for a liver transplant Which antibiotic to choose is always difficult

to determine, but a broad-spectrum antibiotic, like a third-generation cephalosporin, is a

reason-able option Add vancomycin in patients colonized with methicillin-resistant Staphylococcus aureus

or indwelling catheters Start an antifungal agent in any patient whose signs of infection do not promptly improve after starting an antibacterial agent

SEDATION

Psychomotor agitation and pain both can contribute to an increase in intracranial pressure and should be avoided There are insufficient data to recommend one standard agent for sedation in patients with ALF Propofol, though, has a shorter half-life than commonly used benzodiazepines and decreases cerebral blood flow (thereby lowering intracranial pressure [see Chapter 41]), so it

is the recommended agent Fentanyl is the agent of choice to treat pain as it has a short half-life

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Epinephrine has been shown to decrease mesenteric blood flow and hence may compromise hepatic blood flow in patients with ALF Vasopressin is not recommended as it directly causes cerebral vasodilation and may exacerbate intracranial hypertension

RENAL­FAILURE

Acute renal failure is a frequent complication in patients with ALF especially in patients with aminophen overdose because of the direct toxic effect of the drug on the kidneys Aminoglycosides, radiographic dye, and other potentially nephrotoxic agents should be used cautiously If dialysis is needed, use continuous rather than intermittent modes of renal replacement therapy; continuous venovenous hemodialysis has been shown in randomized trials to result in improved stability in cardiovascular and intracranial parameters when compared with intermittent hemodialysis

acet-CEREBRAL­EDEMA­AND­INTRACRANIAL­HYPERTENSION

Cerebral edema is the single most dangerous early complication of ALF Patients may have rapid and extreme changes in cerebral perfusion pressure (CPP), especially precipitated by positional changes and movement At their most severe, acute elevations in intracranial pressure (ICP) may present with seizures, changes in pupillary responses, and decerebrate or decorticate posturing.Because ICP is subject to rapid changes, ICP monitoring may be used in the management of severely ill patients with ALF Monitoring ICP serves two purposes: first, it facilitates attempts

to reduce ICP and restore CPP whenever ICP rises; second, it enables the caregivers to recognize persistently elevated ICP and reduced CPP, which may cause irreversible brain injury before the patient undergoes liver transplantation Unfortunately, the specific thresholds that infallibly pre-dict irreversible brain injury are unknown In the absence of ICP monitoring, frequent evaluation for signs of ICH are needed to identify early evidence of uncal herniation

The placement of an ICP monitor in a patient with ALF is one of the most contentious issues in managing these patients No clinical trials demonstrate that ICP monitoring improves clinical outcomes in this disorder (i.e., that the benefits of ICP monitoring outweigh its risks) ICP monitoring is not advised before the patient is transferred to a liver transplant center Most members of the acute liver failure study group recommend placing an ICP monitor in patients with stage III/IV encephalopathy who are listed for liver transplantation, and those patients not listed in whom intensive medical management offers a reasonable likelihood of recovery (i.e.,

in patients with acetaminophen-induced ALF) Bleeding diathesis should be corrected prior to placing an ICP monitor ICP should be maintained below 20 to 25 mm Hg, and the CPP should

be maintained above 50 to 60 mm Hg

In general, patients with intracranial hypertension should be in a quiet environment with limited stimulation, including endotracheal suctioning Hyperventilation-induced hypocapnia induces cerebral vasoconstriction and decreases ICP Do not treat spontaneous hyperventilation

in ALF, but conversely inducing hyperventilation is not recommended except as emergent rescue therapy in patients with evidence of diencephalic herniation; maintaining a PCO2 of 25 to 35 mm

Hg is reasonable Dexamethasone or other corticosteroids are of no value in treating increased ICP Maintenance of euthermia is recommended

The only treatment of demonstrated therapeutic benefit in the syndrome of elevated ICP

in ALF is intravenous mannitol Administer mannitol, dosed at 0.5 to 1 g/kg, when the ICP is greater than 25 mm Hg for longer than 10 minutes Assess serum osmolality every 6 hours, and then repeat mannitol boluses if the ICP remains greater than 25 mm Hg and the serum osmolality

is less than 320 mOsm/L

59—ACUTE LIVER FAILURE 580.e1

Bibliography

Auzinger G, Wendon J: Intensive care management of acute liver failure Curr Opin Crit Care 14:179-188,

2008

This is a general approach to ICU care of patients with acute liver failure (ALF).

Harrison PM, Keays R, Bray GP, et al: Improved outcome of paracetamol-induced fulminant hepatic failure

by late administration of acetylcysteine Lancet 335:1572-1583, 1990

This describes a landmark trial demonstrating that N-acetyl-cysteine (NAC) is treatment of choice for acetaminophen-induced hepatic failure, even if given late in the course.

Kramer DJ, Canabal JM, Arasi LC: Application of intensive care medication principles in the management of the acute liver failure patient Liver Transpl(14 Suppl 2):S85-S89, 2008

This is a guide to the general critical care management of patients with ALF.

Lee WM, Hynan LS, Rossaro L, et al: for Acute Liver Failure Study Group: Intravenous N-acetylcysteine

improves transplant-free survival in early stage nonacetaminophen acute liver failure Gastroenterology 137:856-864, 2009

This is a multicenter trial demonstrating that NAC therapy confers a survival benefit in patients with ALF from etiologies other than acetaminophen.

Mindikoglu AL, Magder LS, Regev A: Outcome of liver transplantation for drug-induced acute liver failure

in the United States: analysis of the United Network for Organ Sharing database Liver Transpl 15: 719-729, 2009

This is a review of outcomes following liver transplant for ALF.

Ostapowicz G, Fontana RJ, Schiødt FV, et al: Results of a prospective study of acute liver failure at 17 tertiary care centers in the United States Ann Intern Med 137:947-954, 2002

This large multicenter study examined outcomes of ALF in patients in the USA.

Polson J, Lee W: AASLD (American Association for the Study of Liver Disease) Position Paper: the agement of Acute Liver Failure Hepatology 41:1179-1197, 2005

Man-Guidelines published and supported by the main hepatology society for the treatment of ALF are provided.

Schmidt LE, Larsen FS: MELD score as a predictor of liver failure and death in patients with induced liver injury Hepatology 45:789-796, 2007

acetaminophen-MELD score can be used to predict outcomes in ALF, although King’s College Criteria are also used.

Smilkstein MJ, Knapp GL, Kulig KW, Rumack BH: Efficacy of oral N-acetylcysteine in the treatment of

acetaminophen overdose N Engl J Med 319:1557-1562, 1988

Landmark trial demonstrating NAC is treatment of choice for acetaminophen-induced hepatic failure.

Stravitz RT, Kramer AH, Davern T, et al: Intensive care of patients with acute liver failure: recommendations

of the U.S Acute Liver Failure Study Group Crit Care Med 35:2498-2508, 2007

Management of patients with ALF as recommended by a multi-center expert panel is explained.

Trotter JF: Practical management of acute liver failure in the intensive care unit Curr Opin Crit Care 15:163-167,

2009

This is a summary of ICU management of patients with ALF.

Lower Gastrointestinal Bleeding

and Colitis

Stephen Kim  n  Nuzhat A Ahmad

Lower Gastrointestinal Bleeding (LGIB)

Gastrointestinal bleeding (GIB) is a common clinical problem, accounting for ~1% of acute pital admissions Most cases require the intensive care unit (ICU) The ICU management goals of all GIB, upper (UGIB) or lower (LGIB), are stabilization of the patient, prompt diagnosis of the etiology of bleeding, and definitive therapy when possible This chapter provides an overview for recognizing and treating the most common causes of LGIB

hos-LGIB is intestinal bleeding that occurs from a source distal to the ligament of Treitz Various terms to describe LGIB include hematochezia, rectal bleeding, and bright red blood per rectum These terms fail to indicate the acuity or severity of bleeding, localize the bleeding source, and exclude bleeding from beyond the ligament of Treitz For example, when all cases of suspected acute LGIB are thoroughly investigated, 10% to 15% are actually bleeding from upper gastroin-testinal sources

Approximately 80% of all patients with acute LGIB cease bleeding spontaneously, but a ter of these individuals will have recurrent bleeding The overall mortality of 10% to 15% in LGIB

quar-is increased in patients with recurrent or persquar-istent bleeding In up to 8% to 12% of suspected cases of LGIB, no bleeding source is identified

HISTORY AND CAUSES

Initial assessment of patients with all GIB should begin with the measurement of vital signs including heart rate and blood pressure (Figure 60.1) Concomitantly with resuscitation, a directed history and a focused physical examination relevant to LGIB should be performed

The diverse causes of acute LGIB (Table 60.1) can be broadly divided among anatomic, cular, inflammatory, and neoplastic etiologies In patients younger than 50 years of age, hemor-rhoids are the most common cause, whereas in older patients, diverticulosis and angiodysplasia (arteriovenous malformations) are most frequent Rectal pain may indicate an anal fissure or hemorrhoids Abdominal pain may indicate inflammatory bowel disease, ischemia of small or large bowel, or infectious colitis Painless LGIB, especially in an elderly patient, should increase suspicion of diverticulosis or angiodysplasia Pain exacerbated with meals can suggest chronic mesenteric ischemia, whereas pain exacerbated by defecation suggests an anal fissure

vas-The characteristics and color of the patient’s stool in acute LGIB also provide clues about the site of bleeding Blood from the left side of the colon is typically bright red, whereas blood from the right colon is darker and mixed with stool Blood on the outside of well-formed stool likely represents an anal canal or rectosigmoid lesion such as hemorrhoids or fissures A change in bowel habits or stool caliber suggests neoplastic causes If the patient has bloody diarrhea, consider

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inflammatory bowel disease or infectious colitis Although hematochezia, the passage of bright red blood or blood clots per rectum, usually indicates an LGIB source, patients with massive UGIB may also present with hematochezia due to rapid transit of blood through the colon Hematoche-zia, in combination with hemodynamic instability, should always raise the possibility of a UGIB Similarly, LGIB from the distal small bowel or proximal colon can present as melena, or black, tarry stools, a finding typically associated with UGIB and thus an absolute diagnosis of the exact site or etiology of bleeding cannot be made based on the color and characteristics of stool

Figure 60.1  Schematic flow diagram of diagnostic evaluation and initial management, including triage, for 

a patient who presents with a history or signs suggesting lower gastrointestinal bleeding (LGIB) (see text). 

GI, gastrointestinal; EGD, esophagogastroduodenoscopy; IV, intravenous; CBC, complete blood count; ICU,  intensive care unit.

60—LOWER GASTROINTESTINAL BLEEDING AND COLITIS 583

PHYSICAL EXAMINATION

Physical examination may be helpful in determining the cause of LGIB Pain out of proportion

to the physical findings is suspicious for ischemia of the small bowel, colon, or both In tion with a history of atrial fibrillation, recent myocardial infarction, pressor administration, or systemic hypotension, disproportionate abdominal pain suggests inadequate perfusion of the mes-enteric arteries Stigmata of chronic liver disease may indicate the existence of varices anywhere along the gastrointestinal tract, including the small intestine, colon, and rectum Rectal examina-tion may reveal a palpable rectal mass or visible fissures

combina-MANAGEMENT

Patients with LGIB should be admitted to the ICU if they meet appropriate clinical criteria of severity or concomitant disease (Table 60.2) Appropriate resuscitation efforts should be initiated, including large bore intravenous line placements, isotonic intravenous fluid infusions, and red blood cell transfusions The target hemoglobin level depends on the patient’s age and comorbid condi-tions such as coronary artery disease, emphysema, and chronic kidney disease For an elderly patient with significant comorbidities, the hemoglobin level should be maintained at 10 g/dL If a patient has a coagulopathy (International Normalized Ratio [INR] > 1.5) or thrombocytopenia (platelets

< 50,000/μL), these should be quickly addressed with transfusions of fresh frozen plasma and lets, respectively Vitamin K should be given to patients on warfarin in the setting of active GIB Early in the management of these patients, a nasogastric lavage should be attempted at bedside

plate-to evaluate for a possible UGIB An upper endoscopy should be considered in patients when a UGIB cannot be definitively excluded based on nasogastric lavage or other clinical information

TABLE 60.1 n Potential Sources for Lower Gastrointestinal Bleeding (LGIB)

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This is particularly important in patients with hematochezia and hemodynamic instability The surgical and interventional radiology services should be consulted if the patient has massive bleeding (requiring more than 6 units of blood) or develops signs of an acute surgical abdomen

DIAGNOSTIC EVALUATION

Colonoscopy

In general, colonoscopy is the initial examination of choice in the evaluation of suspected LGIB, for the advantages of being both diagnostic and potentially therapeutic Although cleansing of the colon is usually necessary to allow complete mucosal examination, a colonoscopy can also be performed in an unprepared colon, because blood acts as a cathartic After adequate preparation

of the bowel, the diagnostic accuracy of emergent colonoscopy is high (70% to 92%)

For the purpose of colon cleansing, a balanced electrolyte solution is administered orally or via a nasogastric tube at the rate of 240 mL every 15 minutes This provides reasonably satisfac-tory cleansing of the bowel in 4 to 6 hours Once the rectal effluent becomes clear of stool and blood, colonoscopy is performed There is no evidence that a rapid bowel purge in the setting of active LGIB will reactivate or increase the rate of bleeding The only absolute contraindications to colonoscopy in the acute setting are hemodynamic instability or suspicion of a perforated viscus

techne-99 mTc pertechnetate-labeled red cell scan, images are obtained during the first 30 minutes after injection, and then every few hours for up to 24 hours, hence providing further opportunities for identification of intermittent bleeding

The major disadvantage of radionuclide scans is erroneous localization of the site of bleeding, which can occur in up to 25% of cases In addition, these tests are purely diagnostic and do not

TABLE 60.2 n Criteria for Admission to the Intensive Care Unit with Acute Lower Gastrointestinal Bleeding (LGIB)

Patients Should Be Admitted to the ICU If They Have Any of the Following:

ICU, intensive care unit; GI, gastrointestinal.

60—LOWER GASTROINTESTINAL BLEEDING AND COLITIS 585

have the potential for therapeutic intervention Radionuclide imaging is most helpful in ing if patients are bleeding vigorously enough to permit visualization of the site by angiography

assess-Angiography

Angiography can be both a diagnostic and therapeutic intervention The advantage of raphy is that it does not require a bowel preparation and can accurately localize a bleeding site, thus allowing hemostasis or selective surgical resection Angiography permits hemostasis with intra-arterial vasopressin infusion or arterial embolization Instillation of vasopressin should be considered a temporizing maneuver and a bridge to surgical resection, because rebleeding occurs

angiog-in up to 50% of cases after cessation of the vasopressangiog-in angiog-infusion Selective embolization of enteric arteries offers a definitive means of controlling the bleeding, but the success rate varies between 44% and 91%

mes-A significant disadvantage of angiography is that bleeding rates of 0.5 to 1 mL/min are required for localization of the bleeding site Also, angiography carries a 10% complication rate that includes arterial thrombosis and embolization, renal failure from radiocontrast exposure, and the risk of bowel infarction when attempting embolization “Superselective” catheterization tech-niques are currently being employed in an attempt to reduce the infarction risk Angiography

is considered, usually with a therapeutic intent, in patients who have a positive bleeding scan, persistent and recurrent bleeding with a nondiagnostic colonoscopy, or severe bleeding when

co lonoscopy is not possible

Computed Tomographic (CT) Angiography

Advances in computed tomography (CT) technology, with shorter scanning times and improved resolution, have led to an increasing role for CT angiography in the initial evaluation of acute GIB Serial CT scans are performed to localize the source of bleeding An unenhanced CT is performed first as a baseline image for comparison with later scans After intravenous injection

of a contrast agent, CT angiography can detect GIB when high-attenuation contrast material is visualized within the bowel lumen Although early experience with multidetector CT angiogra-phy has demonstrated promise as a first-line modality for sensitive and accurate diagnosis of acute UGIB, its precise role in the management of LGIB is still evolving

Small Bowel Investigations

Investigation of the small bowel is warranted in patients in whom a bleeding site is not identified

in the colon or upper GI tract Limited evaluation of the small bowel can be performed with push enteroscopy When available, wireless video capsule endoscopy should be utilized as the first-line test, which has a high diagnostic yield (up to 60%) for obscure GIB Capsule endoscopy has the advantage of being a non-invasive test with a low complication rate The disadvantages are that

it does not always provide precise localization of the bleeding site and has no therapeutic tial Double balloon enteroscopy, an endoscopic technique that allows visualization of the entire gastrointestinal tract, can be used for both diagnostic and therapeutic interventions on the small bowel However, the procedure is invasive and can take up to 3 hours to complete The gold stan-dard for evaluating the small bowel is the intraoperative enteroscopy, an invasive test that should only be considered when other diagnostic tests have been exhausted A specific radionuclide scan

poten-to detect a bleeding Meckel’s diverticulum may be performed in selected patients at high risk for this disorder, such as adolescents and young adults

SURGICAL INTERVENTIONS

Surgical therapy for LGIB should be recommended for patients who are exsanguinating from uncontrolled hemorrhage An emergent endoscopy is indicated in these patients to rule out a

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CLOSTRIDIUM DIFFICILE COLITIS

Clostridium difficile is a gram-positive, spore-forming anaerobic bacillus that produces two toxins, toxin A, an enterotoxin, and toxin B, a cytotoxin, that mediate colitis and diarrhea C dif- ficile is a common pathogen in hospitalized patients In this setting, C difficile spores are readily

exo-available for transmission, leading to nosocomial outbreaks because they can survive on surfaces

for months The normal human colon resists colonization by C difficile by virtue of its normal endogenous bacteria However, use of antibiotics can alter this environment so that C difficile may predominate and express toxins Additional risk factors for developing C difficile infection include

advanced age, severe illness, and gastric acid suppression

Typical clinical features of C difficile infection include watery diarrhea and crampy lower

abdominal pain with or without low-grade fever The symptoms may begin during antibiotic therapy or 5 to 10 days following antibiotic administration Laboratory evaluation may show

an elevated white blood cell count, electrolyte abnormalities consistent with diarrhea-induced volume depletion, and white blood cells in the stool Flexible sigmoidoscopy, without a bowel preparation, may reveal pseudomembranes However, the absence of these membranes on sig-moidoscopy does not exclude the diagnosis Endoscopy is not warranted in patients with classic clinical findings and a positive stool toxin assay

C difficile infection is diagnosed using an enzyme immunoassay (EIA), which allows direct detection of C difficile toxin Cytotoxicity assay (also known as tissue culture assay) is the gold standard for diagnosis of C difficile However, this test is not performed routinely because of

expense and a 48-hour turnaround time

Worsening abdominal pain and distention, fever, diarrhea, hypovolemia, and marked

leukocy-tosis herald severe or fulminant C difficile infection Diarrhea usually resolves as the colon dilates and becomes atonic The diagnosis of toxic megacolon is made based on imaging studies that dem-

onstrate the largest colon diameter to be greater than 6 cm Serial abdominal examinations and radiographs are indicated under these circumstances Severe localized abdominal pain with signs

of peritonitis may represent the development of a perforation When perforation or severe sepsis develops, a subtotal colectomy with ileostomy is usually necessary

Metronidazole or vancomycin should be used for the treatment of C difficile colitis (see

Chap-ter 38 for details) If possible, other antibiotics should be discontinued As a rule, antidiarrheal agents should be avoided Oral metronidazole or oral vancomycin for 10 to 14 days usually suffices for most cases In critically ill patients, metronidazole may be given intravenously in addition to oral vancomycin administered via a nasogastric tube Response to therapy with resolution of diar-rhea can be expected in the first 72 hours in more than 95% of patients However, 10% to 20% of patients will relapse after discontinuation of the therapy In the ICU setting and in cases of severe

infection, patients should be observed diligently for signs and symptoms of fulminant C difficile

infection, which mandate an urgent surgical evaluation for a possible colectomy

60—LOWER GASTROINTESTINAL BLEEDING AND COLITIS 587

TYPHLITIS

Typhlitis is a life-threatening enterocolitis occurring primarily in immunocompromised patients, typically during or following chemotherapy The exact etiology and pathogenesis are uncertain, with no single pathogenic organism implicated Gram-positive rods and cocci, gram-negative

bacilli and enterococci, and Candida have all been identified in the bowel wall The cecum is

almost always affected, and the process often involves the ascending colon and terminal ileum.Typhlitis should be suspected when a profoundly neutropenic patient (absolute neutrophil count < 500/μL) presents with fever and right lower quadrant abdominal pain Other symptoms include abdominal distention, nausea, vomiting, and watery or bloody diarrhea The abdomen may be tender, and the cecum may be palpable as a boggy mass in the right lower quadrant Abdominal radiograph may reveal a right-sided soft tissue density or an ileus with complete or partial obstruction Although barium enema may demonstrate nodular mucosa, it is not the test

of choice because of the perforation risk The preferred test is the abdominal CT scan, which demonstrates a thickened, distended, fluid filled cecum, a right lower quadrant soft tissue mass,

or cecal pneumatosis Typhlitis mimics acute appendicitis, and distinguishing between the two is important because of their different management strategies

Initial treatment is supportive with complete bowel rest, intravenous hydration, trum antibiotic administration, and consideration of addition of antifungal agents if the patient fails to improve within 72 hours The abdominal examination must be followed closely to monitor for the development of peritoneal signs The surgical service should be alerted if such signs develop or if the patient continues to deteriorate despite intensive medical therapy Any decision

broad-spec-to operate must consider the patient’s overall prognosis from the underlying neoplastic disease,

as well as some studies demonstrating no improvement in outcome despite surgical intervention The surgical procedure of choice is a right hemicolectomy with removal of all necrotic debris.Typhlitis carries a high mortality rate, with overall survival of only 50% Early recognition and institution of prompt treatment are only speculated to improve morbidity and mortality

ISCHEMIC COLITIS

Ischemic colitis is caused by a reduction in intestinal blood flow and most commonly arises from occlusive or nonocclusive causes (Table 60.3) Although intestinal ischemia can affect both the small and the large bowel, ischemic colitis is the most frequent form of intestinal ischemia Most

of the affected patients are elderly and develop transient, self-limited ischemia, which resolves without sequelae A precipitating event is rarely identified The feared complication of colon

is chemia is gangrene, which can be catastrophic if missed

TABLE 60.3 n Causes of Ischemic Colitis

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Patients with acute colonic ischemia typically present with mild abdominal pain Patients may also develop rectal bleeding or bloody diarrhea within 24 hours after the onset of symptoms The blood loss is usually mild and does not require transfusions Physical exam may demonstrate mild tenderness over the affected segment of the colon In contrast, patients with mesenteric ischemia involving the small bowel appear ill, with abdominal pain that is typically out of proportion to the abdominal exam

The majority of patients with ischemic colitis will resolve their symptoms with conservative measures, without complications or long-term sequelae In 10% to 20% of cases, however, patients may develop progressive disease, with increasing abdominal distention and tenderness, worsen-ing ileus, development of necrotic bowel, and ultimately septic shock usually requiring emergent surgical intervention

Ischemic colitis should be suspected in elderly patients with comorbid conditions such as betes, end-stage renal disease on hemodialysis, or peripheral vascular disease who present with lower abdominal pain or rectal bleeding The differential diagnosis includes infectious colitis, inflammatory bowel disease, diverticulitis, and carcinoma There are no specific laboratory mark-ers, though leukocytosis (> 20,000/μL) and an anion-gap metabolic acidosis are highly indicative

dia-of intestinal ischemia with infarction Abdominal radiographs and computed tomography scans may demonstrate nonspecific thickening of the affected bowel segment The definitive diagnosis

of ischemic colitis is made based on sigmoidoscopy or colonoscopy findings; and endoscopy should

be performed without the delay associated with a bowel preparation Angiography is indicated when small bowel ischemia cannot be excluded

Treatment of ischemic colitis is generally supportive with strict bowel rest and intravenous ids to optimize circulation Empiric broad-spectrum antibiotics should be instituted in moderate and severe cases The patient should be monitored for signs of progressive ischemia, which include worsening abdominal pain and distention, fever, leukoytosis, and metabolic acidosis Colonic infarction requires urgent surgical intervention

This is a recent review of the clinical syndrome of typhlitis, also known as neutropenic enterocolitis.

Davila RE, Rajan E, Adler DG, et al: ASGE Guidelines: the role of endoscopy in the patient with lower GI bleeding Gastrointest Endosc 62:656-660, 2005

This is another society guideline of endoscopy practice standards, including the roles of radiology, angiography, and surgery in the evaluation and management of LGIB.

Fisher L, Lee Kinsky M, Anderson MA, et al: ASGE Guideline: the role of endoscopy in the management of obscure GI bleeding Gastrointest Endosc 72(3):471-479, 2010

This is a society guideline to evaluate patients with obscure GIB, including techniques of push enteroscopy, video capsule endoscopy, and deep enteroscopy The guideline also provides two separate diagnostic algorithms for overt and occult GIB.

Feuerstadt P, Brandt LJ: Colon ischemia: recent insights and advances Curr Gastroenterol Rep

Kelly CP, LaMont JT: Clostridium difficile: more difficult than ever N Engl J Med 359:1932-1940, 2008

This is a review of the changing epidemiology, increasing bacterial virulence, and worsening severity of Clostridium difficile infections (CDI), including discussion of new approaches to treatment.

Marti M, Artigas JM, Garzon G, et al: Acute lower intestinal bleeding: feasibility and diagnostic performance

of CT angiography Radiology 262(1):109-116, 2012

This is a prospective study of CT angiography in 47 patients with LGIB, compared to emergency colonoscopy, standard angiography, and surgery to determine its sensitivity, specificity, and positive and negative predictive values CT angiography identified 100% (19 of 19) of patients with active or recent bleeding, with a specificity of 96% (27 of 28) The positive and negative predictive values were 95% (19 of 20) and 100% (27 of 27), respectively Concordance of CT angiography findings and the standard of reference in identifying the potential cause of bleeding was 93% (44 of 47 patients).

Strate LL, Naumann CR: The role of colonoscopy and radiological procedures in the management of acute lower intestinal bleeding Clin Gastroenterol Hepatol 8(4):333-343, 2010

This is a review of the different strategies to manage and treat LGIB, emphasizing early initial colonoscopy The complementary role of radiologic options including angiography, radionuclide scintigraphy, and CT angiography

Upper Gastrointestinal Bleeding

Junsuke Maki  n  Faten N Aberra

Upper gastrointestinal bleeding (UGIB) is defined as bleeding from a source proximal to the ligament of Treitz (Table 61.1), associated with melena, hematemesis, coffee ground emesis, or

aspiration of red blood from a nasogastric tube Severe UGIB results in shock, orthostatic

hypo-tension, decreased hemoglobin concentration (Hgb) by 3 to 4 g/dL, or a transfusion of at least two units of packed red blood cells (pRBCs) Severe UGIB generally necessitates admission to an intensive care unit (ICU) (Box 61.1) Although UGIB occurs more commonly in men, the overall mortality rate of 5% to 10% is similar for both sexes

Assessment

When a patient presents with gastrointestinal bleeding (GI) bleeding, regardless of the source (upper or lower; see also Chapter 60), the initial management should focus on two main aspects: (1) volume resuscitation with appropriate intravenous (IV) fluids and blood products and (2) identification of the bleeding source, to allow selective therapy The rapid initial assessment should include determination of vital signs and postural blood pressure changes, a focused history and physical examination, and gastric lavage

FOCUSED HISTORY

In addition to the presenting symptoms, one should solicit any prior history of GI bleeding, peptic ulcer disease, bleeding diathesis or chronic anticoagulation, renal or liver disease, alcohol abuse,

or nonsteroidal anti-inflammatory drug (NSAID) use It is important to assess the possibility

of cirrhosis or other causes of portal hypertension, because management of variceal bleeding remains distinct from that resulting from other UGIB causes The history may suggest bleeding etiologies Retching or vomiting episodes immediately preceding the onset of UGIB suggest a Mallory-Weiss tear A prior abdominal aortic aneurysm repair should prompt consideration of

an aortoenteric fistula Recent instrumentation of the pancreas, liver, or biliary tract should raise the suspicion of hemobilia or hemosuccus pancreaticus Chronic epistaxis and skin telangiecta-sias indicate potential hereditary hemorrhagic telangiectasia (HHT, also known as Osler-Weber-Rendu syndrome)

With a clear history of vomiting bright red blood or “coffee grounds” (blood present in the stomach long enough to be acidified by gastric acid turns brown), the localization of UGIB is straightforward However, occasional bleeding from the posterior pharynx or the lung may be

confused with UGIB (see also Chapter 79) Unfortunately, a history of melena, resulting from

bacterial degradation of hemoglobin, remains nonspecific Melena commonly arises from brisk UGIB, as well as from a small bowel source (distal of the ligament of Treitz) or a slow bleeding from the right colon

5—PRESENTING PROBLEMS FOR INTENSIVE CARE UNIT ADMISSION

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FOCUSED PHYSICAL EXAMINATION AND LABORATORY EVALUATION

The physical examination begins with evaluating the patient’s hemodynamic status In addition to directing immediate resuscitation, initial vital signs have prognostic importance: 50% of patients presenting with shock have rebleeding episodes An orthostatic pulse rise of more than 20 beats per minute implies an acute blood loss of at least 500 mL, whereas an accompanying fall in dia-stolic pressure of 10 mm Hg or more implies a loss of at least 1000 mL

The initial examination should survey for stigmata of chronic liver disease (such as spider angiomas, gynecomastia, palmar erythema, ascites, and splenomegaly) or findings suggestive of an underlying malignancy Cutaneous manifestations of diseases associated with GI bleeding, such as perioral petechiae in HHT, may also be detected

Initial laboratory evaluation should include a complete blood count (CBC) with a platelet count, coagulation studies (prothrombin time [PT] and partial thromboplastin time [PTT]), and the determination of serum electrolytes, creatinine, blood urea nitrogen (BUN), bilirubin, and liver-associated enzyme levels The initial blood draw should include a sample to be sent to the blood bank for immediate typing and cross matching

Intestinal metabolism of blood raises serum BUN so that a BUN:creatinine ratio > 20 (with both BUN and creatinine expressed in mg/dL) supports the diagnosis of UGIB However, this nonspecific finding can be seen in hypovolemia alone

BOX 61.1 n Indications for Admission to the Intensive Care Unit for Upper

Gastrointestinal Bleeding

Active bleeding

Hemodynamically unstable

Known or suspected portal hypertension

Significant comorbid disease

Coagulopathy (e.g., prothrombin time elevated with INR > 2)

Possible sentinel bleed (previous abdominal aortic graft)

INR, international normalized ratio.