Ebook The intensive care unit manual (2/E): Part 2

C H A P T E R

57

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 interventions of airway management and cardiovascular stabilization, (2) simultaneously obtaining a
thorough history, and (3) targeting specific therapies based on the suspected exposure. Communication 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 suspected 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.

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 receptors (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, isoniazid 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
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, endotracheal intubation, or loss of airway reflexes because of obtundation. Early assessment and definitive 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, protracted 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 commonly results from acetaminophen poisoning but may also occur because of the multiorgan effects
of diffuse toxins such as mercury or iron.

Management
DIAGNOSTIC APPROACH
Initial assessment of the airway, breathing, and circulatory status (ABCs) and frequent reassessment 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 focusing 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, calcium 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.

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 concentrated dextrose solution (50 mL of 50% dextrose). Patients with the triad of signs suggesting opioid 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.


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

Antidote

Dosing for Adults and Comments

Acetaminophen

N-acetylcysteine

Anticholinergic
agents

Physostigmine

Beta-adrenergic
antagonists
Calcium channel
blockers

Glucagon

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
1–2 mg IV over 5 minutes; use with caution
for severe delirium (may cause seizures,
bronchospasm, asystole, cholinergic crisis)
2–5 mg IV; titrate repeat doses; may use infusion of
2–10 mg/h

1 g (10 mL of 10% solution) IV over 5 minutes
with electrocardiographic monitoring; repeat as
needed, check serum calcium after third dose
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
1–2 mEq/kg IV; titrate to arterial pH of 7.5 or
electrocardiographic alterations (see text)
Vials (number) = (digoxin level [ng/mL] × weight
[kg])/100 or
10–20 vials for a life-threatening arrhythmia
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
0.05–0.4 mg IV, repeat as needed; infusion: two thirds
of reversal dose/h, titrate to effect

Calcium gluconate

Insulin

Cyclic
antidepressants
Digoxin

Sodium bicarbonate

Methanol
Ethylene glycol

Fomepizole

Opioids

Naloxone

Digoxin antibodies
(Digibind)

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 seriously ill from acetaminophen overdose because of early diagnosis and antidote treatment with
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 coingested with other drugs.


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Patients with a history of acetaminophen ingestion should have a > 4-hour post ingestion acetaminophen 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 hepatotoxicity 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
in transaminases and prothrombin time reflect severe acetaminophen poisoning.
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 accumulates 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 subsequent dosing every 4 hours (70 mg/kg) for an additional 17 doses over 72 hours. NAC can also
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 acetaminophen overdose. N-acetylcysteine (NAC) therapy is recommended if the acetaminophen 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 ingestion should be treated with NAC (see text). The broken line allows a 25% variability below the solid line to take into
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.)


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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 fulminant 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 assumptions 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 significant 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.
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 principal ingredient in most antifreeze preparations and is also used in deicing agents. Isopropanol
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 alcohol 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 presence of methanol or ethylene glycol. The findings of an osmolar gap or anion gap acidosis can
be helpful when making the diagnosis but must be interpreted with caution depending on the
time since ingestion and the amount of metabolism that may have occurred. Soon after ingestion, 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 ingestion 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 alcohols, and serum osmolarity. Urine fluorescence with a Wood’s lamp can detect the presence of antifreeze (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 synergistic 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 present, 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 setting 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 myocardial 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 mechanism. 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 vasodilation 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 sustained 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 increasing 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 dextrose infusion to maintain euglycemia. In isolated cases with massive ingestion and poor response
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


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blood-brain barrier and has a rapid onset of action. Patients with acute intoxication may complain 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 bicarbonate therapy. Rhabdomyolysis is also common, and a creatine phosphokinase (CPK) level should
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 continues 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 channel 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.

ORAGANOPHOSPHATES
Organophosphates are commonly used as insecticides, include diazinon, malathion, parathion
and chlorpyrifos. Exposures can occur from occupational exposure in agriculture or military use
in chemical warfare. Organophosphates bind irreversibly to inhibit the enzyme acetylcholinesterase, thereby increasing acetylcholine at nerve synapses and overstimulating the nicotinic and
muscarinic receptors. Clinical presentation depends on the specific agent, dose, and route of
exposure. Poisoned patients present with CNS effects ranging from restlessness to delirium, coma,
and seizures. The classic cholinergic toxidrome includes salivation, lacrimation, diaphoresis, urinary incontinence, emesis, and bradycardia. An intermediate syndrome can occur 1 to 4 days after
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 competitive 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 deteriorate 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


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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 produce 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 activated charcoal, consider orogastric lavage for recent ingestions, followed by whole bowel irrigation to limit distal GI absorption. Vigorous volume expansion with normal saline enhances
lithium excretion. Although sodium polystyrene sulfonate (SPS), Kayexalate, has been proposed 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.
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 neuromuscular manifestations such as hyperreflexia, fasciculations, choreoathetosis, nystagmus, clonus,
and lethargy to coma as toxicity progresses. Acute ingestions manifest elevated serum levels, 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 neural 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 preparations. Other agents such as methyl salicylate (oil of wintergreen), liniments, and products used
for vapor rubs all contain salicylates.
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 alkalinization 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 depression. 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.
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 treatment 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 receptors. The hallmark of poisoning is deep sedation, followed by unusually fast resolution to normal
mental status. Significant respiratory depression may require ventilatory support; modest bradycardia 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.

SEROTONERGIC AGENTS

Serotonin syndrome (SS) is a complication of serotonergic agents, which are most commonly available 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 selective 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.


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, rhabdomyolysis, 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.
An annotated bibliography can be found at www.expertconsult.com.


Bibliography
Boehnert M, Lovejoy FH: Value of the QRS duration versus the serum drug level in predicting seizures and
ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 313:474-479,
1985.
This classic prospective study demonstrated that the QRS duration is the best predictor of serious toxicity in
tricyclic antidepressant toxicity.
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 Emergencies. 9th ed. NY: McGraw-Hill, 2010.
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 disadvantages for individual techniques.
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 acetaminophen 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.

567.e1


C H A P T E R

58

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 idiopathic. 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
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 vomiting 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 present. 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

Additional online-only material indicated by icon.

568

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58—ACUTE PANCREATITIS

TABLE 58.1  n  Classification System for Acute Pancreatitis
Term

Definition

Comments

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.
These collections, localized in or near the
pancreas, occur early in the course of acute
pancreatitis and always lack a defined wall.

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.*

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.
Dynamic contrast-enhanced
computed tomography shows
a well-marginated zone of
nonenhancement.

Acute fluid
collections

Pancreatic
necrosis

Acute
pseudocysts

Pancreatic
abscesses

Pancreatic
ascites
Infected
pseudocyst
Hemorrhagic
pancreatitis

Pancreatic
phlegmon

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).
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.
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).
The presence of free fluid with pancreatic
enzymes inside the peritoneal cavity.
Variably used to describe infected pancreatic
necrosis or pancreatic abscesses.
Defined by direct visualization of hemorrhage
in the gland.
Originally referred to a palpable mass of
sterile edematous tissues, but later used to
describe pancreatic necrosis with infection.

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.
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 may be sterile or
infected.
Avoid use of this ambiguous term.
Incorrectly used as a synonym for
pancreatic necrosis, which may
not be hemorrhagic.
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.

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,

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5—PRESENTING PROBLEMS FOR INTENSIVE CARE UNIT ADMISSION

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)
Metabolic conditions
—Hyperlipidemia
—Hypercalcemia
—End-stage renal failure
—Hypothermia
Infections
—Viral (mumps, Coxsackie virus, hepatitis A or B, echovirus, adenovirus, cytomegalovirus, varicella, Epstein-Barr virus, human immunodeficiency virus)
—Bacterial (Mycoplasma pneumoniae, Salmonella, Campylobacter jejuni, Mycobacterium, Legionella,
Leptospira)
—Intraductal parasites (Ascaris, Clonorchis)
Trauma
—Blunt
—Postoperative (especially after intra-abdominal surgery or cardiopulmonary bypass)
—Endoscopic retrograde cholangiopancreatography (ERCP)

TABLE 58.2  n  Medications and Toxins Associated with Acute Pancreatitis
Category

Definite Association

Antihypertensive agents
Anti-inflammatory and analgesic
agents

Anti-infective agents

Chemotherapeutic agents
Diuretics
Toxins
Others

Didanosine (ddI)
Pentamidine
Sulfonamides
Tetracyclines
6-MP, azathioprine
l-Asparaginase
Furosemide
Hydrochlorothiazide
Ethanol
Methanol
Estrogens (via hyperlipidemia)
Intravenous lipid infusions
Valproic acid

Probable Association
ACE inhibitors
Methyldopa

Acetaminophen
Corticosteroids
Mesalamine
NSAIDs
Salicylates
Erythromycin
Metronidazole
Nitrofurantoin

Chlorthalidone
Ethacrynic acid

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


58—ACUTE PANCREATITIS

571

BOX 58.2  n  Selected Nonpancreatitis Causes of Hyperamylasemia
Intra-abdominal emergencies
—Perforated viscus (stomach, duodenum, jejunum)
—Mesenteric infarction
—Biliary obstruction
—Acute cholecystitis
—Ruptured ectopic pregnancy
—Salpingitis
Salivary adenitis
Poor renal clearance
—Renal insufficiency

—Macroamylasemia
Miscellaneous
—Metabolic, diabetic ketoacidosis
—Acute and chronic liver disease

peritoneal signs, and free air on radiography differentiates this entity from pancreatitis. Acute cholecystitis may sometimes be associated with mild hyperamylasemia. The pain of cholecystitis is typically right-sided, and ultrasonography or computed tomography can suggest the diagnosis. A stone
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 resulting 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 abdominal 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 evaluate 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 recommended 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 coworker­s 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

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5—PRESENTING PROBLEMS FOR INTENSIVE CARE UNIT ADMISSION

TABLE 58.3  n  Ranson’s Criteria for Severity and Prognosis* in Acute Pancreatitis
Criteria on Admission

Criteria within 48 Hours of Admission

Age > 55 years
WBC > 16,000/μL
Glucose > 200 mg/dL [11.1 mmol/L]
LDH > 350 IU/L
AST > 250 U/L

Decrease in hematocrit > 10% (absolute)
BUN increase > 5 mg/dL (1.79 mmol/L)
Calcium < 8 mg/dL (2 mmol/L)
Pao2 < 60 mm Hg
Base deficit > 4 mEq/L (4 mmol/L)
Fluid sequestration > 6 L

*Predicted mortality for patients with nongallstone pancreatitis: < three criteria, 0% mortality; three to five criteria,
10% to 20% mortality; six or more criteria, > 50% mortality.
AST, aspartate aminotransferase; BUN, blood urea nitrogen; LDH, lactic dehydrogenase; WBC, white blood cell
count.
From Ranson JHC, Rifkind KM, Roses DF, et al: Prognostic signs and the role of operative management in
acute pancreatitis. Surg Gynecol Obstet 129:69-81, 1974.

TABLE 58.4  n  Local and Systemic Complications of Acute Pancreatitis
System

Complication

Cardiovascular

Hypotension and circulatory shock
Rupture of pseudoaneurysm
Splenic rupture or hematoma
Psychosis
Bowel obstruction (mechanical versus paralytic)
Gastrointestinal hemorrhage
Ulceration
Gastric varices
Coagulopathy (disseminated intravascular coagulation)
Hyperglycemia
Hypocalcemia
Acute renal failure
Right-sided hydronephrosis
Acute respiratory distress syndrome
Retinopathy

Central nervous system
Gastrointestinal

Hematologic
Metabolic
Renal
Respiratory

Vision

mortality risks. Patients with multiple organ system failure (e.g., hypoxia, renal failure, hypotension)
do poorly.
The disease severity evident on CT correlates well with clinical course and outcome. Patients
with only interstitial edema of the pancreas on CT usually have a mild clinical course with low risk
of local or systemic complications, and recovery is the rule. In contrast, patients with evidence of
pancreatic necrosis usually have a high risk of local and systemic complications (Table 58.4) and
about a 25% risk of death.

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


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 pancreatitis 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 analgesia 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, obtaining 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 cholangiopancreatography (ERCP) with sphincterotomy and stone extraction is indicated upon evidence
of biliary obstruction caused by a stone (e.g., increasing jaundice) or of acute cholangitis. However, in patients with biliary pancreatitis without signs of obstruction or cholangitis, ERCP and
sphincterotomy confer no benefit.
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 inflammatory response syndrome (SIRS). Cardiovascular collapse may cause early death in patients with
severe pancreatitis, and it requires aggressive volume replacement and vasopressors. Hypoxemia, 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 specific 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 hypoperfusion; the need for dialysis also predicts greater than 50% mortality. Hyperglycemia transiently

574

5—PRESENTING PROBLEMS FOR INTENSIVE CARE UNIT ADMISSION

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, hypomagnesemia, and abnormalities of glucagon, calcitonin, and parathyroid hormone secretion
or responsiveness. The ionized calcium level should guide treatment of hypocalcemia. Sudden 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 hypoperfusion 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 conservatively, although persistence may warrant surgical resection of the affected loop. Gastrointestinal
hemorrhage may occur from stress ulcerations, bleeding from gastric varices, or a ruptured pseudoaneurysm. 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 condition is by angiographic embolization or surgery. Extension of pancreatic inflammtion 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 antibiotics is being supplanted with endoscopic transgastric drainage and/or percutaneous drainage. 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 sterile 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.
An annotated bibliography can be found at www.expertconsult.com.


58—ACUTE PANCREATITIS

574.e1

Pearls










nInitial

assessment is aimed at determining the cause and differentiating mild from severe
disease based on prognostic signs and CT findings.

nPatients with severe pancreatitis require admission to the ICU, aggressive fluid resuscitation, treatment of systemic complications, and ERCP if signs of biliary obstruction or acute
cholangitis are present.
nIn 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.
nPatients with infected necrosis should receive antibiotics and undergo debridement or
another drainage procedure.
nThose with sterile necrosis who do not improve despite prolonged medical therapy may
benefit from late drainage or surgery.


Bibliography
Al-Omran M, Albalawi ZH, Tashkandi MF, et al: Enteral versus parenteral nutrition for acute pancreatitis.
Cochrane Database Syst Rev 20:CD002837, 2010.
This meta-analysis of 8 trials in 348 patients found that, compared to parenteral nutrition, enteral nutrition in
patients with acute pancreatitis significantly reduced mortality, multiple organ failure, systemic infections, and the
need for operative interventions.
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 conservative management strategy in acute gallstone pancreatitis. Cochrane Database Syst Rev 5:CD009779, 2012.
This Cochrane Database review of 5 randomized controlled trials in 644 patients with suspected gallstone pancreatitis 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.
Van Santvoort HC, Besselink MG, Bakker OJ, et al: A step-up approach or open necrosectomy for necrotizing pancreatitis. N Engl J Med 362:1491, 2010.
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 complications 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.

574.e2


C H A P T E R

59

Acute Liver Failure
Karen L. Krok

In acute liver failure (ALF) there is rapid deterioration of liver function in a previously healthy
individual. By definition there is evidence of coagulopathy (International normalized ratio,
INR ≥ 1.5) and mental status alteration (encephalopathy) in a patient without preexisting
cirrhosis within 26 weeks of the onset of jaundice. ALF has been subdivided into hyperacute
(illness < 7 days), acute (illness between 7 to 21 days), and subacute (illness between 21 days
and 26 weeks), but these subdivisions have not shown any prognostic significance distinct from
the etiology of the liver failure.
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 discernable 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 countries (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, respectively, and are unique in that patients can still be considered as having ALF even though there
is a preexisting chronic liver disease if the disease 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.

Additional online-only material indicated by icon.

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TABLE 59.1  n  Causes of Acute Liver Failure
Category

Examples

Drugs

Miscellaneous

Acetaminophen, halothane, phenytoin
Acute fatty liver of pregnancy, Reye syndrome, Wilson disease, malignant infiltration,
autoimmune hepatitis
Amanita phalloides, carbon tetrachloride
Budd-Chiari syndrome, cocaine, heat stroke, ischemia (“shock liver”), venoocclusive syndrome
Hepatitis A, B, D, E, C,* G,* CMV, HSV, EBV, varicella

Toxins
Vascular
Viral hepatitis

*Uncertain cause of acute liver failure.
CMV, cytomegalovirus; HSV, herpes simplex virus; EBV, Epstein-Barr virus.

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 stigmata 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
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 hyperbilirubinemia 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%.


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59—ACUTE LIVER FAILURE

TABLE 59.2  n  Grading Scale for Hepatic Encephalopathy
Grade Symptoms

Signs

I

No asterixis

II
III
IVa

IVb

Subtle change in mental status, difficulty in
computation, emotional lability
Drowsy, unequivocal loss of computation,
memory loss
Sleepy but arousable, can answer simple
questions only
Coma, no response to commands,
responds to pain

Coma, no response to commands or pain

Asterixis
Asterixis (if able to
comply)
Unable to comply for
asterixis testing,
Babinski reflex is
present
Same as in IVa

Electroencephalo-­
graphic Findings

Normal or symmetric
slowing, triphasic waves
Abnormal symmetric
slowing, triphasic waves
Abnormal symmetric
slowing, triphasic waves
Abnormal slow delta waves
(2–3/min)

Same as in IVa

TABLE 59.3  n  Initial Laboratory Analysis
Acetaminophen level
Ammonia level
Arterial blood gas
Autoimmune markers: ANA, ASMA, immunoglobulin levels
CBC
Ceruloplasmin level
Comprehensive panel
HIV
Pregnancy test (females)
Prothrombin time/INR
Toxicology screen
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.

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


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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.

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% transplantfree 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.

SPECIFIC THERAPY
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