Substances Included Synonyms

Therapeutic Toxic Class

A)

Specific Substances

1) Cafeine
2) Caffeine
3) Coffeinum
4) Guaranine
5) Guarunine
6) Methyltheobromine
7) Theine
8) 1,3,7-trimethyl xanthine
9) 1,3,7-trimethyl-2,6-dioxopurine
10) 7,methyltheophylline
11) 1,3,7-TRIMETHYLXANTHINE
12) METHYLXANTHINES (CAFFINE)

1.2.1) MOLECULAR FORMULA
1) CAFFEINE CITRATE: C14H18N4O9

Available Forms Sources

A)

1) Caffeine is found in a wide variety of common beverages, foods, and pharmaceuticals. For example, some approximate concentrations of caffeine are (FDA News, 1984; Anon, 1984):

a) SOFT DRINKS (Note: The maximum allowable caffeine content is 0.02% which amounts to 72 mg/12 ounces (oz)). All amounts are per 12-oz can (Prod Info, 1988).

Cola-Caffeine Free	0 mg
Cola, Decaffeinated	trace to 0.18 mg
Coca-Cola(R)/Coca-Cola Classic(R)	46 mg
Caffeine-Free Coca-Cola(R)	0 mg
Cherry Coca-Cola(R)	46 mg
Diet Coke(R)	46 mg
Caffeine Free Diet Coke(R)	0 mg
Diet Cherry Coca-Cola(R)	46 mg
Dr. Pepper(R)	39.6 mg
Dr. Pepper(R), Sugar free	39.6 mg
Fresca(R)	0 mg
Ginger Ale	0 mg
Jolt(R) Cola	70.8 mg
Mello Yellow(R)	52 mg
Mountain Dew(R)	54 mg
Diet Minute Maid(R) Lemon-Lime	0 mg
Diet Minute Maid(R) Orange	0 mg
Mr. Pibb(R)	40 mg
Orange	0 mg
Other Citrus	0 to 54 mg
Pepsi Cola(R)	38.4 mg
Diet Pepsi(R)	36 mg
Root Beer	0 mg
Soda, Seltzer	0 mg
Sprite(R)	0 mg
Diet Sprite(R)	0 mg
TAB(R)	46 mg
Caffeine-Free TAB(R)	0 mg
Tonic Water	0 mg

2) Another source determined caffeine content of energy drinks, carbonated sodas, and other beverages (McCusker et al, 2006):

BEVERAGE	SERVING SIZE (OUNCE)	CAFFEINE (MG/SERVING)
ENERGY DRINKS
Red Devil(R)	8.4	41.8
SoBe(R) Adrenaline Rush	8.3	76.7
SoBe(R) No Fear	16	141.1
Hair of the Dog(R)	8.4	none detected
Red Celeste(TM)	8.3	75.2
E Maxx(TM)	8.4	73.6
Amp(TM)	8.4	69.6
Red Bull(R) Sugar-free	8.3	64.7
Red Bull(R)	8.3	66.7
KMX(TM)	8.4	33.3
CARBONATED SODAS
Coca-Cola Classic(R)	12	29.5
Diet Coke(R)	12	38.2
Diet Coke(R) with Lime	12	39.6
Caffeine Free Diet Coke(R)	12	none detected
Vanilla Coke(R)	12	29.5
Pepsi(R)	12	31.7
Diet Pepsi(R)	12	27.4
Mountain Dew(R)	12	45.4
Mountain Dew(R) Live Wire(TM)	12	48.2
Dr Pepper(R)	12	36
Diet Dr Pepper(R)	12	33.8
Sierra Mist(TM)	12	none detected
Celeste(TM) Cola	12	19.4
Sprite(R)	12	none detected
Seagram's(R) Ginger Ale	12	none detected
Barq's(R) Root Beer	12	18
Pibb Xtra(R)	12	34.6
A&W(R) Root Beer	12	none detected
7-UP(R)	12	none detected
OTHER BEVERAGES
Nestea(R) Cool Lemon Iced Tea	12	11.5
Lipton(R) Brisk Lemon Iced Tea	12	6.5
Yoohoo(R) Chocolate Drink	9	less than 2.7
Starbucks Doubleshot(TM)	6.5	105.7
Starbucks Frappuccino(R) Mocha	9.5	71.8
Starbucks Frappuccino(R) Vanilla	9.5	63.8
Velda Farms(R) chocolate milk	16	less than 3.8

CAFFEINE CONTENT OF FOUNTAIN COCA-COLA
LOCATION	SERVING SIZE (OUNCE)	CAFFEINE (MG/SERVING)
Burger King(R)	16	41.5
Wendy's(R)	16	41.5
McDonald's(R)	16	44
Chick-fil-A(R)	16	48.4
Fast Track	16	45.5
Steak N Shake(R)	16	43.5
Atlanta Bread Company(R)	16	40.9
Checkers(R)	16	46.9
Citgo(R) Food Mart	16	48.4

DRUGS
Anacin(R)		32 mg
Anacin(R) Maximum Strength		32 mg
Appedrine(R), Maximum strength		100 mg
Aqua-Ban(R)		100 mg
Aspirin-Free Excedrin(R)		65 mg
Cafergot(R) (all forms)		100 mg
Cope(R)		32 mg
Coryban-D(R)		30 mg
Darvon(R) compound		32.4 mg
Dexatrim(R)		200 mg
Dexatrim(R) Extra Strength		200 mg
Dristan(R) cap, tab		16.2 mg
Excedrin(R)		65 mg
Fiorinal(R)		40 mg
Midol(R)		32.4 mg
NoDoz(R)		100 mg
Prolamine(R)		140 mg
Synalgos DC(R)		30 mg
Triaminicin(R) tab		30 mg
Vivarin(R)		200 mg
Wigraine(R) (all forms)		100 mg
NATURAL PRODUCTS
Guarana	3% to 5% (24 to 40 mg per 800 mg tablet) one brand (Zoom(R)) states 20.8 mg per 800 mg tablet
Coffee beans	1% to 2%

CAFFEINE CONTENT OF FOUNTAIN COCA-COLA
LOCATION	SERVING SIZE (OUNCE)	CAFFEINE (MG/SERVING)
Burger King(R)	16	41.5
Wendy's(R)	16	41.5
McDonald's(R)	16	44
Chick-fil-A(R)	16	48.4
Fast Track	16	45.5
Steak N Shake(R)	16	43.5
Atlanta Bread Company(R)	16	40.9
Checkers(R)	16	46.9
Citgo(R) Food Mart	16	48.4

DRUGS
Anacin(R)		32 mg
Anacin(R) Maximum Strength		32 mg
Appedrine(R), Maximum strength		100 mg
Aqua-Ban(R)		100 mg
Aspirin-Free Excedrin(R)		65 mg
Cafergot(R) (all forms)		100 mg
Cope(R)		32 mg
Coryban-D(R)		30 mg
Darvon(R) compound		32.4 mg
Dexatrim(R)		200 mg
Dexatrim(R) Extra Strength		200 mg
Dristan(R) cap, tab		16.2 mg
Excedrin(R)		65 mg
Fiorinal(R)		40 mg
Midol(R)		32.4 mg
NoDoz(R)		100 mg
Prolamine(R)		140 mg
Synalgos DC(R)		30 mg
Triaminicin(R) tab		30 mg
Vivarin(R)		200 mg
Wigraine(R) (all forms)		100 mg
NATURAL PRODUCTS
Guarana	3% to 5% (24 to 40 mg per 800 mg tablet) one brand (Zoom(R)) states 20.8 mg per 800 mg tablet
Coffee beans	1% to 2%

DRUGS
Anacin(R)		32 mg
Anacin(R) Maximum Strength		32 mg
Appedrine(R), Maximum strength		100 mg
Aqua-Ban(R)		100 mg
Aspirin-Free Excedrin(R)		65 mg
Cafergot(R) (all forms)		100 mg
Cope(R)		32 mg
Coryban-D(R)		30 mg
Darvon(R) compound		32.4 mg
Dexatrim(R)		200 mg
Dexatrim(R) Extra Strength		200 mg
Dristan(R) cap, tab		16.2 mg
Excedrin(R)		65 mg
Fiorinal(R)		40 mg
Midol(R)		32.4 mg
NoDoz(R)		100 mg
Prolamine(R)		140 mg
Synalgos DC(R)		30 mg
Triaminicin(R) tab		30 mg
Vivarin(R)		200 mg
Wigraine(R) (all forms)		100 mg
NATURAL PRODUCTS
Guarana	3% to 5% (24 to 40 mg per 800 mg tablet) one brand (Zoom(R)) states 20.8 mg per 800 mg tablet
Coffee beans	1% to 2%

3) GUARANA: To achieve a potential toxic caffeine concentration of 20 mg/L, a 70-kg person would need to consume the caffeine content of 17 g of guarana (containing 5% weight/weight caffeine) (Drew & Dawson, 2000).
4) CHEWING GUM: A 13-year-old boy became agitated and aggressive, and developed sinus tachycardia, tachypnea, hypertension, increased diuresis, dysuria, and paresthesia of the legs following consumption of 2 packets of stimulant ("energy") chewing gum within a 4-hour period. Each packet reportedly contained 160 mg caffeine (0.57% caffeine per gum pellet) (Natale et al, 2009).
5) LOOK-ALIKE PRODUCTS

a) AVAILABILITY: Caffeine was formerly available in combination with phenylpropanolamine and ephedrine in formulations designed to mimic controlled stimulants. (This combination was removed from the market in 1982 by the US Food and Drug Administration (FDA). Caffeine alone is still available.)
b) COMBINATIONS: Caffeine with either ephedrine, pseudoephedrine, or phenylpropanolamine is no longer being produced.
c) DOSAGE LIMIT: Since 1989, over-the-counter products labeled as stimulants may not contain more than 200 mg per dose (FDA, 1988).

B)

1) Caffeine 250 mg/mL and sodium benzoate 250 mg/mL injection has been used intramuscularly as an analeptic, a stimulant in acute circulatory failure, a diuretic, and intravenously to alleviate headaches following spinal puncture (Kastrup, 1988).
2) Caffeine has been used in the treatment of prolonged apnea in preterm infants (Gilman et al, 1985).

Overview

Life Support

A)

Clinical Effects

0.2.1)

A) USES: Caffeine (1,3,7-trimethylxanthine) is present in coffee, tea, colas, and chocolate. It is also utilized in over-the-counter cough and cold therapies, and in many dietary supplement products used as anorexiants, diuretics, and stimulants. Botanical sources of caffeine include: guarana, yerba mate, and kola nuts. Caffeine is used medicinally for neonatal apnea and postlumbar puncture headache.
B) PHARMACOLOGY: Caffeine is a trimethylxanthine closely related to theophylline. It acts through nonselective inhibition of adenosine receptors and phosphodiesterase. There is also beta-1 and beta-2 adrenergic stimulation secondary to catecholamine release.
C) TOXICOLOGY: Caffeine is an adenosine analog and functions primarily as an adenosine antagonist lowering the seizure threshold. It also inhibits phosphodiesterase, resulting in accumulation of cAMP and calcium, causing organ-specific downstream effects such as smooth muscle relaxation, or muscle/cardiac/CNS excitation. Caffeine overdoses result in surges in circulating catecholamines and rennin, as well as increased levels of norepinephrine, dopamine, and serotonin in the brain.
D) EPIDEMIOLOGY: Caffeine is commonly used; however, severe manifestations of toxicity are rare, and most exposures result in mild toxicity.
E) WITH POISONING/EXPOSURE

1) MILD TO MODERATE TOXICITY: The earliest symptoms of acute caffeine poisoning include: anorexia, tremor, and restlessness, followed by nausea, vomiting and tachycardia. Chronic high-dose caffeine intake can lead to "caffeinism" which includes nervousness, twitching, anxiety, tremulousness, insomnia, palpitations, and hyperreflexia.
2) SEVERE TOXICITY: With serious ingestions hypokalemia, hyperglycemia, metabolic acidosis, rhabdomyolysis, hypotension, confusion, seizures, tachycardia, and nonfatal dysrhythmias may occur.

0.2.3)

A) WITH POISONING/EXPOSURE

1) Fever has been reported following caffeine overdoses.

0.2.20)

A) Caffeine is classified as FDA pregnancy category B. Aspirin/butalbital/caffeine, butalbital/acetaminophen/caffeine/codeine phosphate, and butalbital/aspirin/caffeine/codeine phosphate have been classified as FDA pregnancy category C. Human studies do not implicate caffeine as a major teratogen, especially at moderate doses. While studies have not identified an increased incidence of infant malformation associated with caffeine use, an increase in stillbirths and low birth weight infants have been associated with caffeine, but not confirmed. Caffeine may potentiate the teratogenic effects of tobacco, alcohol, ergotamine, and propranolol. Caffeine has been shown to be excreted in human breast milk.

0.2.21)

A) In one study, caffeine consumption was higher in cancer patients with basal cell carcinoma. Studies have failed to find an association between breast cancer and caffeine.

0.2.22)

A) WITH POISONING/EXPOSURE

1) Symptomatic withdrawal may occur (headache, fatigue, anxiety, and impaired psychomotor performance).

Laboratory Monitoring

A)

B)

C)

Treatment Overview

0.4.2)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Mild to moderate exposures usually respond to fluid repletion and antiemetic therapy. Electrolyte replacement should be performed as indicated.

B) MANAGEMENT OF SEVERE TOXICITY

1) There is potential for seizures, vomiting, and dysrhythmias, so consider early airway management. Monitor ECG and vital signs for at least 6 hours after any concerning oral ingestion. Treat agitation and seizures with benzodiazepines. If unsuccessful, phenobarbital or propofol may be utilized. Follow patients for hyperthermia or rhabdomyolysis. Treat hypotension with IV fluid boluses and vasopressin or phenylephrine if hypotension persists; drugs with significant beta-adrenergic effects should be avoided. Hypokalemia usually resolves without aggressive treatment because it is due to an intracellular shift of potassium ions; however, severe hypokalemia should be treated. Beta-blockers effectively reverse cardiotoxic effects mediated by beta-adrenergic stimulation. Treat severe tachyarrhythmias with hypotension not responsive to fluid boluses or pressors with esmolol 50 to 200 mcg/kg/min beginning with low doses and titrating to effect. Follow advanced cardiac life support (ACLS) and pediatric advanced life support (PALS) guidelines for malignant dysrhythmias.

C) DECONTAMINATION

1) PREHOSPITAL: Decontamination should be avoided. Mild exposures do not require treatment, and severe overdose can result in seizures and aspiration.
2) HOSPITAL: Activated charcoal adsorbs caffeine effectively. Administration of activated charcoal should be considered on an individual basis; it should be reserved for patients with the potential for significant toxicity and a recent ingestion who are alert or in whom the airway is protected. Gastric lavage is rarely utilized, but might be considered in the rare patient with a recent, life threatening ingestion.

D) AIRWAY MANAGEMENT

1) Because seizures and vomiting are common after severe overdose, it is important to manage the airway early.

E) ANTIDOTE

1) There is no antidote for caffeine.

F) ENHANCED ELIMINATION

1) Hemodialysis is effective and indicated in patients with severe toxicity (eg, seizures, ventricular dysrhythmias or hypotension).

G) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with nontoxic ingestions with minimal symptoms can be managed at home.
2) OBSERVATION CRITERIA: Intentional self-harm attempts should be referred to a health care facility. Observe all patients with mild symptoms (ie, nausea, vomiting, and palpitations) until resolution of symptoms.
3) ADMISSION CRITERIA: Patients with moderate symptoms including palpitations and mild electrolyte disturbances can be observed on telemetry. Any patient showing signs of severe toxicity (ie, seizures, ventricular dysrhythmias or hypotension) should be admitted to the ICU.
4) CONSULT CRITERIA: Involve a poison center or toxicologist with any questions, concerns, or cases of moderate to severe toxicity. If you are considering dialysis, a nephrologist should be involved.

H) PITFALLS

1) Administration of activated charcoal inappropriately can increase a patient's risk of aspiration.

I) PHARMACOKINETICS

1) Caffeine is rapidly absorbed orally (30 to 60 minutes) with peak plasma levels occurring 30 minutes to 2 hours after ingestion. Its volume of distribution is small (0.61 L/kg; higher in neonates). Caffeine's elimination half-life is 3 to 6 hours (can be much longer in neonates, up to 100 hours). It is metabolized primarily in the liver by CYP450, primarily the CYP1A2 isoenzyme, following Michaelis-Menton Kinetics (first order at lower doses, that become saturated and zero order at higher doses).

J) TOXICOKINETICS

1) After an acute ingestion, onset of action usually is reached within 3 hours. Half-life can change in overdose and may be as long as 16 hours.

K) PREDISPOSING CONDITION

1) Neonates, patients in third trimester pregnancy, and those with liver disease are predisposed to toxicity. Caffeine is subject to multiple drug interactions with inhibition by estrogens, cimetidine, and alcohol.

L) DIFFERENTIAL DIAGNOSIS

1) Poisoning with theophylline, herbal remedies, other methylxanthines, albuterol, or sympathomimetics.

Range Of Toxicity

A)

B)

Clinical Effects

Summary Of Exposure

A)

B)

C)

D)

E)

1) MILD TO MODERATE TOXICITY: The earliest symptoms of acute caffeine poisoning include: anorexia, tremor, and restlessness, followed by nausea, vomiting and tachycardia. Chronic high-dose caffeine intake can lead to "caffeinism" which includes nervousness, twitching, anxiety, tremulousness, insomnia, palpitations, and hyperreflexia.
2) SEVERE TOXICITY: With serious ingestions hypokalemia, hyperglycemia, metabolic acidosis, rhabdomyolysis, hypotension, confusion, seizures, tachycardia, and nonfatal dysrhythmias may occur.

Vital Signs

3.3.1)

A) WITH POISONING/EXPOSURE

1) Fever has been reported following caffeine overdoses.

3.3.3)

A) WITH POISONING/EXPOSURE

1) FEVER

a) Fever has been noted following large doses (Perrin et al, 1987).
b) CASE REPORT: A 5-week-old infant presented with a temperature of 39.5 degrees C within several hours of a caffeine overdose (Rivenes et al, 1997).

3.3.4)

A) WITH THERAPEUTIC USE

1) INCREASES IN BLOOD PRESSURE: In a study of normotensive, healthy, nonsmoking adults (women, n=42; men, n=35) with no history of medication use that had a cardiovascular or metabolic effect, the effects of caffeine on blood pressure were measured. Of those patients who received 3.3 mg/kg of caffeine (equivalent to 2 to 3 cups of brewed coffee), almost identical systolic and diastolic blood pressure (BP) elevations were found in both men (4.1 and 3.8 mmHg, respectively) and women (4.5 and 3.3 mmHg, respectively). Despite similar increases in BP readings among men and women, the BP response arises from different hemodynamic mechanisms (eg, men showed an increase in vascular resistance and women had an increase in cardiac output) (Hartley et al, 2004).

B) WITH POISONING/EXPOSURE

1) INCIDENCE: According to a retrospective analysis of clinical data from adult patients who presented to the Royal Infirmary of Edinburgh from January 2000 to December 2008 with acute caffeine poisoning (n=38), systolic blood pressure greater than 140 mmHg occurred in 34.2% of patients. The median amount of caffeine ingested was 1040 mg (range, 600 to 1500 mg) (Waring et al, 2009).

3.3.5)

A) WITH POISONING/EXPOSURE

1) INCIDENCE: According to a retrospective analysis of clinical data from adult patients who presented to the Royal Infirmary of Edinburgh from January 2000 to December 2008 with acute caffeine poisoning (n=38), heart rate greater than 100 beats per minute occurred in 52.6% of patients. The median amount of caffeine ingested was 1040 mg (range, 600 to 1500 mg) (Waring et al, 2009).

Heent

3.4.3)

A) WITH POISONING/EXPOSURE

1) MIOSIS

a) Miosis has occurred following large doses.

2) MYDRIASIS

a) Mydriasis was noted in an adult who overdosed on a large amount of caffeine and ephedrine (Nagesh & Murphy, 1988).

Cardiovascular

3.5.2)

A) CONDUCTION DISORDER OF THE HEART

1) WITH POISONING/EXPOSURE

a) Bigeminy, paroxysmal atrial tachycardia, premature ventricular contractions (PVCs), ventricular tachycardia, and fibrillation have been reported (Schmidt et al, 2015; Ishigaki et al, 2014; Vaglio et al, 2011; Nagesh & Murphy, 1988; Price & Fligner, 1990; Forman et al, 1997). A study of newborns concluded that those children born to mothers who consumed greater than 500 mg/day of caffeine were more likely to have cardiac dysrhythmias than those who consumed less than 250 mg/day of caffeine (Hadeed & Siegel, 1993).
b) RETROSPECTIVE STUDY/CAFFEINATED ENERGY DRINKS: According to a retrospective review of data from the NSW Poisons Information Centre in Australia over a 7-year period (2004 to 2010), there were 117 cases (median age 17 years; range 11 to 60 years) of recreational ingestion of caffeinated energy drinks without coingestants. Of those 117 cases, palpitations/tachycardia were reported in 33 patients. The number of energy drinks consumed in one session varied (median, 5 units; range, 1 to 80 units) (Gunja & Brown, 2012)

1) According to the same study, palpitations/tachycardia were reported in 2 of 14 pediatric patients (mean age 38 months, range 7 to 120 months) who unintentionally ingested caffeinated energy drinks (Gunja & Brown, 2012).

c) CASE REPORTS

1) Supraventricular tachycardia with a ventricular rate between 130 and 150 bpm and hypertension were detected in a 28-year-old man after he intentionally ingested an estimated 500 mg of caffeine within a 4-hour period. The caffeine he consumed was contained in 6 cans of energy drink and some coffee. His medical history was complicated with drug abuse, chronic hepatitis C, severe mitral valve insufficiency, postinfectious endocarditis, and cerebral vascular accident but no history of head trauma. He presented to the emergency department with sudden onset of tonic-clonic seizures and became hypoxic and unresponsive 15 minutes later. He was intubated and placed on ventilation. Laboratory analyses showed acidosis, leukocytosis, and hyperglycemia. He was treated with anticonvulsants, sodium bicarbonate, and digoxin. Twenty-four hours later he was extubated and within 1 week was discharged to a recovery center.(Trabulo et al, 2011).
2) A 41-year-old woman made a complete recovery following a 50 g overdose. Initially, the patient was hemodynamically unstable and developed several different dysrhythmias (eg, wide complex tachydysrhythmia, ventricular fibrillation, bradyarrhythmia, and asystole) and hypotension (systolic blood pressure in the 50s by doppler only), but responded to supportive care, vasopressin infusion and hemodialysis. Within 24 hours of admission, the patient was hemodynamically stable with a normal sinus rhythm. The patient had a protracted ICU course after developing bilateral pneumonia, rhabdomyolysis, and multisystem organ failure (Holstege et al, 2003).
3) Following an acute overdose of 20 g of caffeine and 500 mg of dimenhydrinate, a 38-year-old man developed chaotic rhythm disturbances with variable supraventricular tachycardia with aberrancy and a ventricular rate of 190 with frequent multifocal ventricular premature beats and short runs of ventricular tachycardia with no hemodynamic compromise. Procainamide infusion converted the rhythm to a narrow complex regular tachycardia (Chopra & Morrison, 1995).
4) Following the ingestion of 80 tablets of an unknown strength of caffeine, a 15-year-old girl developed a sinus tachycardia with multiple premature ventricular contractions and occasional bigeminy. She subsequently developed seizures and cardiac arrest (Shum et al, 1997).
5) A 5-week-old infant was brought to the emergency department with sinus tachycardia (heart rate up to 237 beats/min), right axis deviation, and non-specific ST-T wave changes. An elevated CK-MB fraction of 8.6 nanograms/mL was reported and indicative of myocardial ischemia. It was subsequently learned that the infant was intentionally given about 600 mg caffeine orally (Rivenes et al, 1997).
6) A 31-week gestation neonate developed tachycardia (180 to 200 beats/min) and ST depression after receiving 300 mg of caffeine parenterally. Respiratory distress syndrome and cardiac failure developed. Cardiac failure was managed with furosemide. The neonate recovered with no sequelae evident at a 6-month follow-up (Anderson et al, 1999).
7) A 25-year-old woman with preexisting mitral valve prolapse presented to the emergency department with intractable ventricular fibrillation after consuming 55 mL of a guarana health drink containing 10 to 19 g of caffeine/L. No spontaneous cardiac output resulted following lengthy resuscitation. A postmortem caffeine aortic blood concentration of 19 mg/L was reported. This lower concentration may reflect postmortem changes or an enhanced sensitivity to caffeine (Cannon et al, 2001).
8) An 18-year-old man developed severe cardiac instability, including hypotension, episodes of irregular narrow complex tachycardia and severe sinus bradycardia (30 to 40 beats/min), and a pulseless wide complex rhythm, that auto-converted, after ingesting approximately 10 to 20 g of caffeine. An ECG also indicated QTc interval prolongation (greater than 600 msec) and inferolateral ST segment abnormalities. Following continuous infusions of phenylephrine and lidocaine, the patient's condition stabilized with significant improvement of the QTc interval and partial resolution of the ST segment changes (Kapur & Smith, 2009).
9) A 13-year-old, 45-kg boy presented to the emergency department with restlessness, sinus tachycardia (147 beats per min (bpm), tachypnea (25 breaths/min), and hypertension (145/90 mmHg). Prior to presentation, the patient had been agitated and aggressive, and complaining of abdominal pain, increased diuresis, dysuria, and paresthesia in his legs. Toxicologic analysis was negative for cocaine, heroin, and amphetamine. Following overnight observation, the patient recovered and was discharged with sinus bradycardia (40 bpm). Investigation by the mother revealed two empty packets of stimulant ("energy") chewing gum, with each packet containing 160 mg of caffeine (0.57% caffeine per gum pellet). A few days after the first incident, at a follow-up appointment, the patient presented with drowsiness. An ECG demonstrated sinus bradycardia (45 bpm) and low left-ventricular ejection fraction (55%). Over the next 5 days, the patient recovered without sequelae. An interview with the patient, who typically did not ingest caffeine-rich beverages or food, revealed that he had consumed two packets of chewing gum (320 mg caffeine) in 4 hours (equivalent to approximately 10 cups of tea in a 70 kg adult) (Natale et al, 2009).
10) A 20-year-old woman presented with severe agitation, tremors, diaphoresis, and vomiting approximately 1 to 2 hours after ingesting an unknown amount of concentrated caffeine powder and tablets in a suicide attempt. A few minutes after presentation, the patient developed ventricular fibrillation that was successfully cardioverted. Vital signs indicated hypotension (80/62 mmHg) and tachycardia (124 beats/minute), and an ECG revealed junctional tachycardia. For approximately the next hour, the patient experienced a total of 25 separate episodes of pulseless ventricular tachycardia (VT), with successful cardioversion after each episode. Between episodes of VT, an echocardiogram was performed indicating normal left ventricular ejection fraction (55% to 60%) and normal right ventricle global systolic function, with trace regurgitation of the mitral and tricuspid valves. The VT episodes stopped approximately 80 minutes post-presentation and her blood pressure stabilized. Following transfer to an intensive care setting, she received hemodialysis and multi-dose activated charcoal; however, she continued to experience premature ventricular contractions approximately 24 hours post-presentation. On hospital day 7, she was transferred to an inpatient psychiatric facility, where she recovered neurologically. Her serum caffeine concentrations were 240.8 mcg/mL and 150.7 mcg/mL approximately 4 hours (pre-hemodialysis) and 16 hours (post-hemodialysis) post-presentation, respectively (Laskowski et al, 2015).

B) HYPOTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Cardiovascular collapse following massive overdose has been reported in adults (Schmidt et al, 2015; Josephson & Stine, 1976; Rouse et al, 1999), but may not occur in infants due to their ability to better tolerate tachycardia with decreased propensity to cardiac ischemia (Anderson et al, 1999).
b) CASE REPORT: A massive caffeine overdose (50 g) resulted in refractory hypotension (systolic rate in the 50s obtained by doppler only) about 3 hours after ingestion. ECG revealed wide complex tachycardia, which degenerated into multiple dysrhythmias including ventricular fibrillation. After no response following dopamine and norepinephrine infusions, vasopressin infusion was initiated with good response (Holstege et al, 2003).
c) CASE REPORT: An 18-year-old man developed severe cardiac instability, including hypotension (58/43 mmHg), episodes of irregular narrow complex tachycardia and severe sinus bradycardia, and a pulseless wide complex rhythm, that auto-converted, after ingesting approximately 10 to 20 g of caffeine. An ECG also indicated QTc interval prolongation (greater than 600 msec) and inferolateral ST segment abnormalities. Following continuous infusions of phenylephrine and lidocaine, the patient's condition stabilized with significant improvement of the QTc interval and partial resolution of the ST segment changes (Kapur & Smith, 2009).

C) HYPERTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) Individuals with a predisposition to hypertension or those who have borderline hypertension may be at increased risk of caffeine induced elevations in blood pressure (Pincomb et al, 1996).

2) WITH POISONING/EXPOSURE

a) CASE REPORT: After ingesting an estimated 500 mg of caffeine within a 4-hour period, a 28-year-old man presented to the emergency department with tonic-clonic seizures, hypertension (160/70 mmHg), and supraventricular tachycardia. The caffeine he consumed was contained in 6 cans of energy drink and some coffee. He was intubated, ventilated, and treated with anticonvulsants, sodium bicarbonate for acidemia, and digoxin. Twenty-four hours later he was extubated and within 1 week was discharged to a recovery center (Trabulo et al, 2011).

D) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) CASE REPORT: A 20-year-old bulimic woman was admitted to the emergency department with ECG changes and a diagnosis of subendocardial infarction following an overdose of caffeine (20 g). ECG changes included a ventricular rate of 50 and T-wave inversion. Creatine kinase concentration was 492 Units/L, with myoglobin concentration of 15.9 nanograms/mL. Frequent bigeminy and premature ventricular contractions were evident on telemetry. Serum potassium level was 3 mEq/L. Treatment included magnesium sulfate and potassium chloride (Forman et al, 1997).
b) CASE SERIES: A case control study of nonfatal myocardial infarction in 858 women 45 to 69 years of age revealed a positive association with heavy coffee drinking (Palmer et al, 1995).

E) TACHYPHYLAXIS

1) WITH THERAPEUTIC USE

a) Continued administration of caffeine resulted in complete tolerance to blood pressure and heart rate changes in 1 to 4 days (Ellenhorn & Barceloux, 1988). Some studies maintain that caffeine does not produce a persistent increase in blood pressure (Myers, 1988; Newcombe et al, 1988).

F) CARDIAC ARREST

1) WITH POISONING/EXPOSURE

a) Cardiac arrest, occurring within one hour of massive ingestions, has been reported. In 2 cases, a 20-year-old man and a 40-year-old man ingested 18 g and 22 g, respectively, and developed cardiac arrest within an hour (Rouse et al, 1999).
b) CASE REPORT: A 21-year-old woman developed cardiac arrest after ingesting approximately 100 tablets of 100 mg caffeine (total amount ingested 10,000 mg caffeine). An initial ECG of the patient showed ventricular fibrillation. Despite aggressive cardiopulmonary resuscitative efforts, the patient continued to have episodes of ventricular fibrillation until she received a continuous infusion of amiodarone (37.5 mg/hr). Over the course of 3 days, the patient also developed severe metabolic acidosis, hypokalemia, and myoclonus, which was refractory to medical treatment. A neurological exam demonstrated irreversible anoxic brain damage and, at hospital day 5, all treatment was discontinued. The patient eventually died from pneumonia 11 days post-caffeine ingestion (Rudolph & Knudsen, 2010).
c) CASE REPORT: Ventricular fibrillation and subsequent cardiac arrest occurred in a 44-year-old man after intentionally ingesting 10 grams of pure anhydrous caffeine. Following 30 minutes of cardiopulmonary resuscitation, the patient remained in refractory ventricular fibrillation, and arterio-venous extracorporeal membrane oxygenation (ECMO) was started approximately 2 hours later. Despite efforts, the patient died 13 hours post-ingestion (approximately 4 hours after ECMO) (Poussel et al, 2013).

G) ENDOTHELIAL DYSFUNCTION

1) WITH POISONING/EXPOSURE

a) In a cohort study involving 50 healthy individuals, the effects of consuming caffeinated energy drinks on endothelial function and platelet aggregation were assessed. Based on peripheral arterial tonometry hyperemia index (RHI) results, endothelial function significantly decreased among 15 subjects 1 hour after ingesting a sugar-free energy drink (250 mL) containing 80 mg caffeine, 1000 mg taurine, and 600 mg glucuronolactone, although a causal relationship between a specific component of the energy drink and the development of endothelial dysfunction was not established. No effect on endothelial function was observed in 10 control subjects 1 hour after ingesting 250 mL of carbonated water (Worthley et al, 2010).

H) CHEST PAIN

1) WITH POISONING/EXPOSURE

a) RETROSPECTIVE STUDY/CAFFEINATED ENERGY DRINKS: According to a retrospective review of data from the NSW Poisons Information Centre in Australia over a 7-year period (2004 to 2010), there were 117 cases (median age 17 years; range 11 to 60 years) of recreational ingestion of caffeinated energy drinks without coingestants. Of those 117 cases, 6 patients reported chest pain. The number of energy drinks consumed in one session varied (median, 5 units; range, 1 to 80 units) (Gunja & Brown, 2012).

Respiratory

3.6.2)

A) APNEA

1) WITH POISONING/EXPOSURE

a) Acute ingestions of a large quantity of caffeine has been associated with respiratory arrest and subsequent death (Turner & Cravey, 1977).
b) CASE REPORT: Acute respiratory failure occurred following ingestion of 200 to 300 mg/kg of caffeine in a 1-year-old child (Dietrich & Mortensen, 1990).

B) HYPERVENTILATION

1) WITH POISONING/EXPOSURE

a) CASE REPORT (INFANT): Hyperventilation (60 breaths/min) was reported in a 5-week-old infant following an overdose of 600 mg caffeine orally (Rivenes et al, 1997).
b) CASE REPORT: A 17-year-old girl developed a consistent tremor, anxiety, and hyperventilation after intentionally ingesting 12 g of caffeine (266 mg/kg) (Schmidt & Karlson-Stiber, 2008).

C) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Following an estimated IV overdose of 300 mg, a 31-week gestation neonate developed tachycardia, respiratory distress syndrome, and cardiac failure. The neonate was managed with furosemide and positive end-expiratory pressure; respiratory function improved over a 5-day period (Anderson et al, 1999).

D) RESPIRATORY DISTRESS

1) WITH POISONING/EXPOSURE

a) RETROSPECTIVE STUDY/CAFFEINATED ENERGY DRINKS: According to a retrospective review of data from the NSW Poisons Information Centre in Australia over a 7-year period (2004 to 2010), there were 117 cases (median age 17 years; range 11 to 60 years) of recreational ingestion of caffeinated energy drinks without co-ingestants. Of those 117 cases, respiratory distress was reported in 5 patients. The number of energy drinks consumed in one session varied (median, 5 units; range, 1 to 80 units) (Gunja & Brown, 2012).

Neurologic

3.7.2)

A) RESTLESSNESS

1) WITH POISONING/EXPOSURE

a) Large doses can produce insomnia, restlessness, and tinnitus.
b) INCIDENCE: According to a retrospective analysis of clinical data from adult patients who presented to the Royal Infirmary of Edinburgh from January 2000 to December 2008 with acute caffeine poisoning (n=38), dizziness, tremor, and headaches were each reported in 3 patients (7.9%), and agitation was reported in 1 patient (2.6%). The median amount of caffeine ingested was 1040 mg (range, 600 to 1500 mg) (Waring et al, 2009).
c) CASE REPORT: A 5-week-old infant was brought to the emergency department with agitation, crying and moving all 4 extremities vigorously following an overdose of 600 mg caffeine (Rivenes et al, 1997).
d) CASE REPORT: A 17-year-old girl developed a consistent tremor, anxiety, and hyperventilation after intentionally ingesting 12 g of caffeine (266 mg/kg) (Schmidt & Karlson-Stiber, 2008).
e) CASE SERIES: A group of 71 patients who consumed between 200 and 1000 mg/day of caffeine were studied. Overnight caffeine deprivation produced dysphoric symptoms consistent with caffeine withdrawal that were reduced with longer-term abstinence. Acute caffeine intake caused jitteriness, decreased tiredness, and headache (Richardson et al, 1995).
f) CASE REPORT: Mental status changes, including agitation, sedation, and inappropriate behavior (not specified), occurred in an 18-year-old man with hemodynamic instability following ingestion of approximately 10 to 20 g of caffeine (Kapur & Smith, 2009).
g) CASE REPORT: Agitation and aggressiveness were reported in a 13-year-old boy following consumption of two packets of stimulant ("energy") chewing gum over a 4-hour period. Each packet reportedly contained 160 mg of caffeine (Natale et al, 2009).
h) RETROSPECTIVE STUDY/CAFFEINATED ENERGY DRINKS: According to a retrospective review of data from the NSW Poisons Information Centre in Australia over a 7-year period (2004 to 2010), there were 117 cases (median age 17 years; range 11 to 60 years) of recreational ingestion of caffeinated energy drinks without coingestants. Of those 117 cases, 29 patients reported agitation/restlessness and 5 patients reported insomnia. The number of energy drinks consumed in one session varied (median, 5 units; range, 1 to 80 units) (Gunja & Brown, 2012)

1) According to the same study, agitation/restlessness was reported in 9 of 14 pediatric patients (mean age 38 months, range 7 to 120 months) who unintentionally ingested caffeinated energy drinks (Gunja & Brown, 2012).

B) SEIZURE

1) WITH THERAPEUTIC USE

a) ELECTROCONVULSIVE THERAPY (ECT): Caffeine has been used to prolong ECT seizures; however, hypertension and tachycardia appeared to be adverse effects (Acevedo & Smith, 1988).

2) WITH POISONING/EXPOSURE

a) Seizures may occur with large doses (Ishigaki et al, 2014; Rouse et al, 1999; Shum et al, 1997).
b) A 28-year-old man with a history of drug abuse, cardiac disease, and cerebral vascular accident but no history of head trauma presented to the emergency department with sudden onset tonic-clonic seizures after intentionally ingesting an estimated 500 mg of caffeine within a 4-hour period. The caffeine he consumed was contained in 6 cans of energy drink and some coffee. On presentation he was in a postictal state with a Glasgow Coma Scale (GCS) score of 8. Upon examination he was found to be hypertensive and tachycardic with an O2 saturation of 48% and a tympanic temperature of 38.4 degrees C. Fifteen minutes after presentation he became unresponsive and seized again for several minutes. He was intubated and placed on ventilation. Laboratory analyses showed acidosis, leukocytosis, and hyperglycemia. Urine drug screening and blood screening for phenytoin, carbamazepine, tricyclics, valproic acid, and phenobarbital were negative. ECG showed supraventricular tachycardia. Brain CT showed chronic vascular encephalopathy with corticosubcortical atrophy without lesions. He was treated with midazolam and valproate infusions, sodium bicarbonate, and digoxin. Twenty-four hours later he was extubated and within 1 week he was discharged to a recovery center. At 3-month follow-up, he denied further seizure activity (Trabulo et al, 2011).
c) CASE REPORT: Following the ingestion of 80 tablets of an unknown strength of caffeine, a 15-year-old adolescent developed abrupt onset of seizures with subsequent cardiac arrest (Shum et al, 1997).
d) CASE REPORT: A 32-year-old woman ingested 20 g caffeine and developed multiple seizures during gastric lavage therapy with subsequent cardiac arrest and death (Shum et al, 1997).
e) CASE REPORT: A 38-year-old woman presented to the emergency department with nystagmus and blurred vision, followed by a grand mal seizure. Laboratory findings were all within normal limits except for a potassium concentration of 2.9 mEq/L. An MRI demonstrated possible atrophy in the right frontal lobe, indicating a possible association with epilepsy; however, an outpatient EEG was normal. A review of her current medications included sertraline 100 mg daily, zolpidem 10 mg as needed, hydrocodone 5/500 rarely, and Zantrex-3(TM) 2 capsules 3 times daily for 2 months. Zantrex-3(TM) is a dietary supplement, indicated for weight loss, containing niacin, and greater than 300 mg/ 2 capsules of caffeine and caffeine-like stimulants (guarana seed, green tea, cocoa nut, kola nut, yerba mate, and thea sinensis complex). It was estimated that the patient had been consuming between 22.2 and 27.8 mg/kg of caffeine daily for 2 months. Following discontinuation of the dietary supplement, the patient did not experience any more seizure activity (Pendleton et al, 2012).

C) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache has been reported following ingestion of large doses of caffeine (Waring et al, 2009).
b) RETROSPECTIVE STUDY/CAFFEINATED ENERGY DRINKS: According to a retrospective review of data from the NSW Poisons Information Centre in Australia over a 7-year period (2004 to 2010), there were 117 cases (median age 17 years; range 11 to 60 years) of recreational ingestion of caffeinated energy drinks without coingestants. Of those 117 cases, 4 patients reported headaches. The number of energy drinks consumed in one session varied (median, 5 units; range, 1 to 80 units) (Gunja & Brown, 2012).

D) OPISTHOTONUS

1) WITH POISONING/EXPOSURE

a) Opisthotonus has been reported in a premature infant after a 10-fold overdose (Perrin et al, 1987).

E) DIZZINESS

1) WITH POISONING/EXPOSURE

a) Dizziness may occur (Waring et al, 2009; Price & Fligner, 1990).
b) RETROSPECTIVE STUDY/CAFFEINATED ENERGY DRINKS: According to a retrospective review of data from the NSW Poisons Information Centre in Australia over a 7-year period (2004 to 2010), there were 117 cases (median age 17 years; range 11 to 60 years) of recreational ingestion of caffeinated energy drinks without coingestants. Of those 117 cases, 6 patients reported dizziness/syncope. The number of energy drinks consumed in one session varied (median, 5 units; range, 1 to 80 units) (Gunja & Brown, 2012).

F) PARESTHESIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Prickling sensations of the legs was reported in a 13-year-old boy following consumption of two packets of stimulant ("energy") chewing gum over a 4-hour period. Each packet reportedly contained 160 mg caffeine (Natale et al, 2009).
b) RETROSPECTIVE STUDY/CAFFEINATED ENERGY DRINKS: According to a retrospective review of data from the NSW Poisons Information Centre in Australia over a 7-year period (2004 to 2010), there were 117 cases (median age 17 years; range 11 to 60 years) of recreational ingestion of caffeinated energy drinks without coingestants. Of those 117 cases, paresthesias occurred in 6 patients. The number of energy drinks consumed in one session varied (median, 5 units; range, 1 to 80 units) (Gunja & Brown, 2012).

G) TREMOR

1) WITH POISONING/EXPOSURE

a) RETROSPECTIVE STUDY/CAFFEINATED ENERGY DRINKS: According to a retrospective review of data from the NSW Poisons Information Centre in Australia over a 7-year period (2004 to 2010), there were 117 cases (median age 17 years; range 11 to 60 years) of recreational ingestion of caffeinated energy drinks without coingestants. Of those 117 cases, 30 patients reported tremors/shaking. The number of energy drinks consumed in one session varied (median, 5 units; range, 1 to 80 units) (Gunja & Brown, 2012).

Gastrointestinal

3.8.2)

A) GASTRITIS

1) WITH POISONING/EXPOSURE

a) Excessive consumption produces marked gastric irritation, nausea, and emesis (Schmidt & Karlson-Stiber, 2008; Price & Fligner, 1990; Dietrich & Mortensen, 1990). In very severe caffeine intoxication, gastrointestinal hemorrhage can develop.
b) CASE REPORT: Severe nausea, vomiting and diarrhea was reported in a 20-year-old bulimic woman after an acute caffeine overdose of 20 g (Forman et al, 1997).
c) CASE REPORT: Gastric dilatation and intolerance to nasogastric milk feeding, necessitating total parenteral nutrition, was reported in a 31-week gestation neonate following an estimated 300 mg IV caffeine overdose (Anderson et al, 1999).
d) RETROSPECTIVE STUDY/CAFFEINATED ENERGY DRINKS: According to a retrospective review of data from the NSW Poisons Information Centre in Australia over a 7-year period (2004 to 2010), there were 117 cases (median age 17 years; range 11 to 60 years) of recreational ingestion of caffeinated energy drinks without co-ingestants. Of those 117 cases, 29 patients reported gastrointestinal upset. The number of energy drinks consumed in one session varied (median, 5 units; range, 1 to 80 units) (Gunja & Brown, 2012)

1) According to the same study, gastrointestinal upset was reported in 4 of 14 pediatric patients (mean age 38 months, range 7 to 120 months) who unintentionally ingested caffeinated energy drinks (Gunja & Brown, 2012).

B) NAUSEA AND VOMITING

1) WITH POISONING/EXPOSURE

a) INCIDENCE: According to a retrospective analysis of clinical data from adult patients who presented to the Royal Infirmary of Edinburgh from January 2000 to December 2008 with acute caffeine poisoning (n=38), nausea and vomiting was the most common adverse event, occurring in 63.2% of patients. The median amount of caffeine ingested was 1040 mg (range, 600 to 1500 mg) (Waring et al, 2009).
b) CASE REPORT: Repeated vomiting was reported in an 18-year-old man who ingested approximately 10 to 20 g of caffeine (Kapur & Smith, 2009).

C) ABDOMINAL PAIN

1) WITH POISONING/EXPOSURE

a) INCIDENCE: According to a retrospective analysis of clinical data from adult patients who presented to the Royal Infirmary of Edinburgh from January 2000 to December 2008 with acute caffeine poisoning (n=38), abdominal pain was reported in 42.1% of patients. The median amount of caffeine ingested was 1040 mg (range, 600 to 1500 mg) (Waring et al, 2009).

Hepatic

3.9.2)

A) LIVER ENZYMES ABNORMAL

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Transiently elevated liver enzyme levels (AST, 1079; ALT, 578; LDH, 2157) were reported in a 5-week-old infant following an oral overdose of 600 mg caffeine (Rivenes et al, 1997).
b) CASE REPORT: Elevated liver enzyme levels (ALT 367 units/L, AST 694 units/L) were reported in a 42-year-old man who ingested 24 g of caffeine in a suicide attempt 4 days earlier (Campana et al, 2014).

Genitourinary

3.10.2)

A) POLYURIA

1) WITH THERAPEUTIC USE

a) Caffeine is a mild diuretic in low to moderate doses.

2) WITH POISONING/EXPOSURE

a) CASE REPORT: Increased diuresis and dysuria were reported in a 13-year-old boy following consumption of two packets of stimulant ("energy") chewing gum over a 4-hour period. Each packet reportedly contained 160 mg caffeine (Natale et al, 2009).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Acute renal failure secondary to rhabdomyolysis was reported in a 21-year-old man who ingested 3.57 g of caffeine (Wrenn & Oschner, 1989).
b) CASE REPORT: A 36-year-old man, with a history of schizophrenia, developed acute renal failure secondary to rhabdomyolysis and hyponatremia following massive ingestion (15 L) of oolong tea daily for approximately one week. The patient recovered following hemodialysis, hypertonic saline, and supportive care (Kamijo et al, 1999).
c) CASE REPORT: Acute renal failure, secondary to rhabdomyolysis, was reported in a 42-year-old man after intentionally ingesting 24 g of caffeine 4 days earlier. Laboratory data revealed a BUN of 167 mg/dL, a serum creatinine concentration of 10.2 mg/dL, and a creatinine phosphokinase concentration of 59,360 units/L. With supportive therapy, including daily hemodialysis sessions for 9 days, the patient's condition improved and he was transferred for inpatient psychiatric therapy (Campana et al, 2014).

Acid-Base

3.11.2)

A) LACTIC ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Lactic acidosis may occur secondary to seizures, hypotension, and a generalized hyperadrenergic state produced by catecholamine release.
b) CASE REPORT: A lactic acid level greater than 15 mmol/L was detected in a 28-year-old man after he intentionally ingested an estimated 500 mg of caffeine within a 4-hour period. The caffeine consumed was contained in 6 cans of energy drink and some coffee. He presented to an emergency department with sudden onset tonic-clonic seizures and was intubated. One hour later his lactic acid level was 12 mmol/L. He received supportive care and was discharged within 1 week to a recovery center (Trabulo et al, 2011).
c) CASE REPORT: A plasma lactate level of 7 mmol/L with a concomitant pH decrease from 7.42 to 7.33 occurred in a 17-year-old girl 9 hours after intentionally ingesting 12 g of caffeine (266 mg/kg). Following supportive care, the patient recovered with normalization of her lactate level, and was subsequently discharged to a psychiatric facility (Schmidt & Karlson-Stiber, 2008).

B) ACIDOSIS

1) WITH POISONING/EXPOSURE

a) Metabolic acidosis and respiratory alkalosis are typical following acute caffeine poisonings (Laskowski et al, 2015; Schmidt et al, 2015; Ishigaki et al, 2014; Vaglio et al, 2011; Rudolph & Knudsen, 2010; Anderson et al, 1999; Rouse et al, 1999).
b) CASE REPORT: After intentionally ingesting an estimated 500 mg of caffeine within a 4-hour period, a 28-year-old man with a history of drug abuse, cardiac disease, and cerebral vascular accident but no history of head trauma presented to the emergency department with sudden onset tonic-clonic seizures. The caffeine he consumed was contained in 6 cans of energy drink and some coffee. Fifteen minutes after presentation he became hypoxic and unresponsive and seized again for several minutes. Arterial blood gas (ABG) analysis revealed PaCO2 of 90 mmHg, PaO2 of 40 mmHg, pH of 6.8. He was intubated and placed on ventilation. One hour later ABG analysis showed PaCO2 48 mmHg, pO2 217 mmHg, pH 6.95, HCO3 12 mmol/L and lactic acid of 12 mmol/L. ECG revealed supraventricular tachycardia. He was treated with anticonvulsants, sodium bicarbonate, and digoxin. Twenty-four hours later he was extubated and within 1 week was discharged to a recovery center (Trabulo et al, 2011).

Hematologic

3.13.2)

A) LEUKOCYTOSIS

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Leukocytosis of 23,200/mcL was detected in a 28-year-old man with a history of drug abuse, heart disease, and hepatitis C after he intentionally ingested an estimated 500 mg of caffeine within a 4-hour period. The caffeine he consumed was contained in 6 cans of energy drink and some coffee. He presented to an emergency department with sudden onset tonic-clonic seizures and was intubated. He received supportive care and was discharged within 1 week to a recovery center (Trabulo et al, 2011).
b) CASE REPORT: A case report described an elevated WBC count of 12 x 10(9)/L following an acute overdose of 20 g caffeine in a 20-year-old bulimic woman (Forman et al, 1997).
c) CASE REPORT: Leukocytosis of 18,500/mm(3) was reported in a 38-year-old man after ingestion of 20 g (Chopra & Morrison, 1995).
d) CASE REPORT: An 18-year-old man developed mild leukocytosis (17,220/mcL) after ingesting approximately 10 to 20 g of caffeine (Kapur & Smith, 2009).

B) BLOOD COAGULATION DISORDER

1) WITH POISONING/EXPOSURE

a) In a cohort study involving 50 healthy individuals, the effects of consuming caffeinated energy drinks on endothelial function and platelet aggregation were assessed. Based on responses to adenosine diphosphate, platelet aggregation increased significantly among 15 subjects 1 hour after ingesting a sugar-free energy drink (250 mL) containing 80 mg caffeine, 1000 mg taurine, and 600 mg glucuronolactone. although a causal relationship between a specific component of the energy drink and the development of increased platelet aggregation was not established. No effect on platelet aggregation was observed in 10 control subjects who ingested 250 mL of carbonated water (Worthley et al, 2010).
b) CASE REPORT: A D-dimer result of 430 ng/mL was detected in a 28-year-old man after he intentionally ingested an estimated 500 mg of caffeine within a 4-hour period. The caffeine he consumed was contained in 6 cans of energy drink and some coffee. He developed sudden onset tonic-clonic seizures after ingesting the caffeine and presented to an emergency department where he was intubated and received supportive care. He was discharged within 1 week to a recovery center (Trabulo et al, 2011).

Dermatologic

3.14.2)

A) URTICARIA

1) WITH POISONING/EXPOSURE

a) Urticaria was reported in a 48-year-old woman after ingestion of caffeine (Pola et al, 1988).

B) SKIN NECROSIS

1) WITH POISONING/EXPOSURE

a) Skin necrosis developed in a 31-week-gestation neonate who received an estimated 300 mg of caffeine by an IV line that extravasated (Anderson et al, 1999).

Musculoskeletal

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) Massive caffeine overdose may result in rhabdomyolysis and secondary renal failure.
b) CASE REPORT: Rhabdomyolysis was reported in a 21-year-old man who ingested 3.57 g of caffeine. Acute renal failure ensued (Wrenn & Oschner, 1989).
c) CASE REPORT: A 38-year-old man developed a peak CPK of 1820 International Units/L after ingesting 20 g of caffeine and 500 mg of dimenhydrinate (Chopra & Morrison, 1995).
d) CASE REPORT: A 5-week-old infant developed a peak CPK of 1413 International Units/L after he was intentionally given 600 mg caffeine by an abusive parent (Rivenes et al, 1997).
e) CASE REPORT: A 31-week gestation neonate was reported to develop rhabdomyolysis (creatine kinase, 907 Units/L) on day 4 following an inadvertent IV overdose of an estimated 300 mg (Anderson et al, 1999).
f) CASE REPORT: A 36-year-old man developed severe rhabdomyolysis (CPK, 227,200 International Units/L), acute renal failure with hyponatremia (serum sodium, 118 mEq/L) and delirium following massive ingestion (15 L) of oolong tea daily for approximately one week. The patient recovered following therapy with hypertonic saline, hemodialysis, and supportive care. The authors speculated that caffeine toxicity injured muscle cells, which were fragile as a result of potassium depletion, resulting in rhabdomyolysis (Kamijo et al, 1999).
g) CASE REPORT: Rhabdomyolysis (creatine kinase 46,298 international units/L) occurred in a 39-year-old man after ingestion, over a 3-day period, of ibuprofen 14,400 mg, codeine 922 mg, and caffeine 1920 mg (Ernest et al, 2010).
h) CASE REPORT: Rhabdomyolysis and acute renal failure developed in a 42-year-old man after intentionally ingesting 24 g of caffeine 4 days earlier. Laboratory data revealed a BUN of 167 mg/dL, a serum creatinine concentration of 10.2 mg/dL, and a creatinine phosphokinase concentration of 59,360 units/L. With supportive therapy, including daily hemodialysis sessions for 9 days, the patient's condition improved and he was transferred for inpatient psychiatric therapy (Campana et al, 2014).
i) CASE REPORT: A 44-year-old woman presented to the emergency department with nausea, vomiting, palpitations, chest tightness, muscle twitching, and tea-colored urine approximately 6 hours after ingesting 4 cups of black coffee (approximately 1000 mL). Monitoring of vital signs indicated a heart rate of 110 beats/min, blood pressure of 136/92 mmHg, a respiration rate of 20 breaths/minute, temperature of 36.2 degrees C, and an oxygen saturation of 99% on room air. Initially, her laboratory values were normal, with the exception of a mild elevation of hepatic enzymes (AST 45 units/L [reference range 0 to 40 units/L], ALT 108 units/L [reference range 0 to 41 units/L]). However, after 4 hours of observation and administration of IV fluids, repeat laboratory analysis revealed creatine kinase (CK) and CK-MB concentrations of 7315 units/L (reference range 26 to 308 units/L) and 266 units/L (reference range 0 to 25 units/L), respectively. Her initial plasma caffeine concentration was estimated to be 16 mcg/mL (taking into account that the actual plasma caffeine concentration, obtained 10 hours post-ingestion was 4 mcg/mL and the average half-life of caffeine is 5 hours). With continued supportive care for 5 days, the patient completely recovered without neuromuscular sequelae (Chiang et al, 2014).

Endocrine

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) CASE REPORT: Hyperglycemia was reported in an adult with an admission serum caffeine level of 200 mg/dL and a theophylline level of 17.2 mcg/mL (Benowitz et al, 1982).
b) CASE REPORT: Hyperglycemia was reported in 2 cases, each following an acute overdose of 20 g caffeine (Chopra & Morrison, 1995; Forman et al, 1997).
c) CASE REPORT: Hyperglycemia (220 mg/dL) was detected in a 28-year-old man after he intentionally ingested an estimated 500 mg of caffeine within a 4-hour period. The caffeine he consumed was contained in 6 cans of an energy drink and some coffee. He presented to an emergency department with sudden onset tonic-clonic seizures, was intubated, and placed on ventilation. With supportive care he was discharged within 1 week to a recovery center (Trabulo et al, 2011).
d) CASE REPORT: Hyperglycemia (plasma glucose 23.2 mmol/L at 16 hours post-caffeine dose) was reported in a 31-week gestation neonate following an estimated overdose of 300 mg IV over 40 minutes. The neonate was treated with a 5-day insulin infusion titrated to achieve a plasma glucose of 3.5 to 7 mmol/L (Anderson et al, 1999).

Reproductive

3.20.1)

A) Caffeine is classified as FDA pregnancy category B. Aspirin/butalbital/caffeine, butalbital/acetaminophen/caffeine/codeine phosphate, and butalbital/aspirin/caffeine/codeine phosphate have been classified as FDA pregnancy category C. Human studies do not implicate caffeine as a major teratogen, especially at moderate doses. While studies have not identified an increased incidence of infant malformation associated with caffeine use, an increase in stillbirths and low birth weight infants have been associated with caffeine, but not confirmed. Caffeine may potentiate the teratogenic effects of tobacco, alcohol, ergotamine, and propranolol. Caffeine has been shown to be excreted in human breast milk.

3.20.2)

A) OBESITY

1) A prospective study of the offspring of 615 women who followed up for up to 15 years reported that the in utero exposure to high amounts of caffeine (150 mg of more per day) was associated with a significant more than twice the risk of childhood obesity, while the exposure to low amounts (less than 150 mg a day) was associated with a significant 77% increased risk of childhood obesity. There was a dose-response correlation between amount of daily maternal caffeine intake and childhood obesity risk: Every one unit increase (log10 scale) in caffeine intake was associated with a nonsignificant 23% increased risk of persistent obesity (evidenced by at least 50% of BMI measurements being above the 95th percentile) in female but not male offspring after at least 11 years of follow-up (Li et al, 2015).

B) LACK OF EFFECT

1) SUMMARY: Human studies do not implicate caffeine as a major teratogen, especially at moderate doses (Schardein, 1985). Caffeine may potentiate the teratogenic effects of tobacco, alcohol, ergotamine, and propranolol (Nehlig & Debry, 1994).

C) ANIMAL STUDIES

1) Caffeine (as a caffeine base) administered to pregnant mice as sustained release pellets at a dose of 50 mg/kg (less than the maximum recommended intravenous loading dose for infants on a mg/m(3) basis) during organogenesis caused a low incidence of cleft palate and exencephaly (Prod Info caffeine citrate intravenous injection, 2014)
2) CONGENITAL ANOMALY

a) In experimental animals, caffeine did not have any detrimental effects on reproductive performance (Abbott, 1986). Teratogenic effects have been observed in both rats and mice administered caffeine in high doses (greater than 40 mg/kg/day) (Abbott, 1986). Digital defects, cleft palate, extra embryonic structures, and urogenital and musculoskeletal abnormalities have been produced in experimental animals (Schardein, 1993; RTECS , 2001). Caffeine had an adverse effect on mouse oocytes and embryos (Scott & Smith, 1995).
b) Other findings in whole animal reproductive studies or embryonic culture include inhibition of neurogenesis in whole mouse embryo (Marret et al, 1997), reduced cerebral weight in rats (Tanaka, 1997), and cardiovascular, lens, and thymic changes in rats (Matsuoka et al, 1987). Behavioral changes are reported in rat studies (Peruzzi et al, 1985; West et al, 1986) and monkey studies (Gilbert & Rice, 1994), with some rat studies suggesting a multi-generational effect of caffeine exposure (Sinton, 1989; Pollard et al, 1987). Caffeine is also associated with reduced fetal weight in monkeys (Gilbert & Rice, 1991) and also induced stillbirths and miscarriages (Gilbert et al, 1988). Caffeine is positive in the Frog Embryo Teratogenesis (FETAX) developmental toxicity assay (Fort et al, 1998).

3.20.3)

A) STILLBIRTHS

1) While studies have not identified an increased incidence of infant malformation associated with caffeine use (Abbott, 1986; Aaronson & Macnee, 1989), an increase in stillbirths and low birth weight infants has been associated with caffeine, but not confirmed (Aaronson & Macnee, 1989; AMA, 1985; Leviton, 1988).
2) The largest prospective study to date to measure preconception caffeine consumption and the risk of spontaneous abortion, comprising the Snart-Gravid cohort of 5132 Danish women, reported that preconception caffeine consumption (300 mg/day or more vs less than 100 mg/day) was not associated with spontaneous abortion, whereas that during early pregnancy was associated with a small increased risk of spontaneous abortion. However, there was little evidence of a dose-response correlation, and these results may have been impacted by other factors such as smoking (Hahn et al, 2015)
3) In a retrospective study, there was a greater incidence of spontaneous abortion and stillbirths in women who consumed 600 mg/day or greater of caffeine (Aaronson & Macnee, 1989).

a) Similar effects were noted when the same amounts were consumed by the father (Aaronson & Macnee, 1989).
b) POPULATION STUDY: Based on a prospective study of 18,478 pregnant Danish women using a self-reported questionnaire to determine coffee consumption, the overall risk of stillbirth (based on a review of death records) was increased in women drinking 8 or more cups of coffee daily during pregnancy, but no increased risk in infant death was observed. The overall risk of stillbirth was 4.4/1000 (n=82), and the risk of infant death was 4/1000 (n=74). Women who drank 4 to 7 cups of coffee per day had an 80% increased risk of stillbirth, and women who drank 8 or more cups per day had a 300% increased risk compared with women who were non-coffee drinkers. It was also noted that women drinking 8 or more cups were more likely to also smoke and have a higher alcohol intake, and the risk of stillbirth decreased slightly when controlled for smoking and alcohol consumption. Further adjustments for maternal age, parity, and education did not significantly produce any change in association (Wisborg et al, 2003).
c) Caffeine rapidly crosses the placenta and its half-life increases by 3 times during the last trimester of pregnancy. Women who drink 10 cups of coffee per day could develop near-pharmacologic plasma levels during the third trimester (Aaronson & Macnee, 1989).

4) CASE SERIES: A case control study of 331 women with fetal loss and 993 controls showed that the incidence of fetal loss was strongly associated with caffeine intake during pregnancy, and moderately associated with caffeine use before pregnancy (Infante-Rivard et al, 1993). The validity of the results of this study have been questioned (Wei, 1994; Kline et al, 1994; Parazzini et al, 1994).
5) CASE SERIES: A cohort study of 431 women enrolled within 21 days of conception found no evidence that moderate caffeine use increased the risk of spontaneous abortion, intrauterine growth retardation, or microcephaly after accounting for other risk factors (Mills et al, 1993).
6) CASE SERIES: In a population-based, case control study of 562 women with reported spontaneous abortions at 6 to 12 completed weeks of gestation compared with a control group with no spontaneous abortions, it was found that caffeine ingestion may increase the risk of early spontaneous abortion among nonsmoking women carrying fetuses with normal karyotypes (Cnattingius et al, 2000).
7) CASE SERIES: In a nested case-control study of 591 women who had spontaneous abortions at less than 140 days of gestation, compared with women with no spontaneous abortions, it was found that only extremely high serum paraxanthine (a caffeine metabolite) concentrations were associated with spontaneous abortion. The authors suggested that moderate caffeine consumption is not likely to result in an increased risk of spontaneous abortion (Klebanoff et al, 1999).
8) Overall, a very large number of studies have addressed the effect of caffeine consumption (generally in the form of coffee) and various human reproductive parameters including preterm birth, spontaneous abortion, reduced fetal weight, fecundability, and delay in time to conception. It is difficult to find consistent evidence of any particular effect among these studies. Furthermore, effects seen may be due to other substances ingested rather than caffeine itself or may be associated with lifestyle factors such as smoking.
9) A recent analysis looking at spontaneous abortion and fetal growth found a small, but statistically significant, increase in the risk of spontaneous abortion and low birth weight with consumption of caffeine in excess of 150 mg/day. The authors comment that confounders (smoking, ethanol, maternal age) could not be excluded as causing these effects (Fernandes et al, 1998).
10) In a case-control study surveying parents of 393 SIDS victims and parents of 1592 control infants, a significant increased risk for SIDS was found among infants whose mothers had heavy caffeine consumption throughout pregnancy (Ford et al, 1998).

B) FERTILITY DECREASED FEMALE

1) A retrospective study of 1430 parous women not using contraceptives concluded that high levels of caffeine consumption may result in delayed conception among women who do not smoke cigarettes (Stanton & Gray, 1995).

C) BIRTH WEIGHT SUBNORMAL

1) Heavy maternal coffee drinking has also been associated with low birthweight in the neonate (AMA, 1985). In a study of 453 women from Seattle, caffeine use during pregnancy was not significantly related to infant size (Leviton, 1988).
2) CASE SERIES: In a retrospective study of 7025 women, caffeine intake was not related to preterm delivery or low birth weight. Caffeine intake during pregnancy was a risk factor for intrauterine growth retardation (Fortier et al, 1993).
3) CASE SERIES: In a prospective study of 712 women, there was not a relationship between caffeine consumption during pregnancy and fetal growth or birth weight (Shu et al, 1995).

D) BIRTH PREMATURE

1) CASE SERIES: In a prospective study of 1860 women, there was no relationship between caffeine consumption and risk of preterm delivery (Peacock et al, 1995).

E) FETAL DISTRESS

1) CASE SERIES: A prospective study of normal third trimester pregnancies compared 10 women who were high caffeine consumers (greater than 500 mg/day) with women who were low caffeine consumers (less than 200 mg/day). The authors concluded that fetal behavior, primarily manifested by increased arousal, may be influenced by the level of maternal caffeine consumption (Devoe et al, 1993).
2) Children born to mothers who consumed greater than 500 mg/day of caffeine were more likely to have cardiac dysrhythmias (supraventricular tachycardia, atrial flutter, premature atrial contractions), fine tremors, and tachypnea (Hadeed & Siegel, 1993).

F) PREGNANCY CATEGORY

1) The manufacturer has classified caffeine as FDA pregnancy category B (Briggs et al, 1998).
2) The manufacturers have classified the combination products of aspirin/butalbital/caffeine, butalbital/acetaminophen/caffeine/codeine phosphate, and butalbital/aspirin/caffeine/codeine phosphate as FDA pregnancy category C (Prod Info caffeine citrate intravenous injection, 2014; Prod Info Fiorinal(R) oral capsules, 2014; Prod Info Fioricet(R) with Codeine C-III oral capsules, 2011; Prod Info Fiorinal(R) with Codeine oral capsule, 2009)
3) While studies have not identified an increased incidence of infant malformation associated with caffeine use (Abbott, 1986a; Aaronson & Macnee, 1989a), an increase in stillbirths and low birth weight infants has been associated with caffeine but not confirmed (Aaronson & Macnee, 1989a; AMA, 1985a; Leviton, 1988a). Caffeine consumption in moderate amounts during pregnancy is not associated with teratogenic effects. Caffeine may potentiate the teratogenic effects of tobacco, alcohol, ergotamine and propranolol (Nehlig & Debry, 1994). The ingestion of high doses of caffeine (greater than 300 milligrams/day) may be associated with a higher incidence of low birth weight infants and therefore such use in pregnant women should be discouraged.

G) LACK OF EFFECT

1) Epidemiological studies of pregnant women have shown no increase in malformations in infants of women who are heavy coffee drinkers (Abbott, 1986).
2) In more than 700 matched pairs of women who had children with and without congenital malformations, no differences in maternal coffee consumption were found (Aaronson & Macnee, 1989).
3) A systematic review of 7 studies of the effect of maternal caffeine intake on teratogenesis found no evidence to support a teratogenic effect of caffeine in humans (Browne, 2006).

3.20.4)

A) BREAST MILK

1) SERUM/MILK: Caffeine is excreted in breast milk in small amounts (Prod Info Fiorinal(R) oral capsules, 2014). Caffeine is considered to be compatible with breastfeeding by the American Academy of Pediatrics (Anon, 2001). A linear relationship exists between serum and milk concentrations of caffeine. Caffeine binds to fat in the milk; the butter fat content correlates with the amount of caffeine in the milk (Tyrala & Dodson, 1979).
2) Caffeine is commonly contained in combination drug products, beverages, and foodstuffs, and thus is likely to be consumed by nursing mothers. Maternal caffeine consumption in moderate amounts during breastfeeding is not associated with any side effects in breastfeeding infants; however, maternal consumption of large amounts of caffeine has been associated with infant irritability and poor sleeping patterns (Bailey et al, 1982).

3.20.5)

A) FERTILITY DECREASED FEMALE

1) Studies give conflicting reports on the relationship between caffeine consumption and infertility in women (Weinberg & Wilcox, 1990).
2) In a prospective, observational study of fertility in 124 women, caffeine consumption did NOT appear to affect the probability of conception. However, caffeine consumption appeared to potentiate the decreased fertility induced by alcohol when both were used concurrently (Hakim et al, 1998).

Carcinogenicity

3.21.1)

A) IARC Carcinogenicity Ratings for CAS58-08-2 (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004):

1) IARC Classification

a) Listed as: Caffeine
b) Carcinogen Rating: 3

1) The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

3.21.2)

A) In one study, caffeine consumption was higher in cancer patients with basal cell carcinoma. Studies have failed to find an association between breast cancer and caffeine.

3.21.3)

A) SKIN CARCINOMA

1) CASE SERIES: In a case control study of patients with basal cell carcinoma, caffeine consumption was higher in the cancer patients (Sahl et al, 1995).

B) BREAST CARCINOMA

1) CASE SERIES: In a study of 34,388 women in Iowa, there was no association between postmenopausal breast cancer and caffeine intake (Folsom et al, 1993).
2) Caffeine was not associated with breast cancer in a study of 5984 women (Tavani et al, 1998).

Genotoxicity

A)

B)

C)

D)

E)

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) No studies are needed in patients with minimal symptoms. Electrolytes should be checked in patients with mild to moderate symptoms. If there is any concern for rhabdomyolysis, CPK should be checked.
B) An ECG should be performed with continuous cardiac monitoring in moderate to severe poisoning.
C) Caffeine levels are obtainable, but not routinely available in general hospital laboratories and not useful to guide therapy. Serum concentrations greater than 80 mg/L have been associated with mortality.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Quantitative values for caffeine reported in the literature as toxic or lethal vary so widely that no accurate generalizations can be made from laboratory values. Qualitative testing may be of value in confirming an exposure.
2) Monitor fluid and electrolyte balance carefully in symptomatic patients. Hypokalemia, metabolic acidosis, ketonuria, and hyperglycemia may all be noted.
3) Monitor plasma lactate concentrations in symptomatic patients following overdose.

B) LABORATORY INTERFERENCE

1) Falsely elevated serum theophylline levels were measured in 2 children who overdosed on caffeine. Although caffeine is metabolized to theophylline to some degree, the enzyme immunoassay (EMIT) procedure overestimated theophylline levels by 142% to 383% and a high performance liquid chromatography (HPLC) method overestimated levels by 225% to 517% (Fligner & Opheim, 1988).

4.1.3)

A) OTHER

1) Monitor urinary ketones in symptomatic patients.

4.1.4)

A) OTHER

1) ECG

a) Obtain an ECG and institute continuous ECG monitoring in symptomatic patients and those with large overdoses.

Methods

A)

1) Caffeine can be detected readily by ultraviolet spectrophotometry.

B)

1) A high performance liquid chromatography (HPLC) method for the detection and quantification of caffeine in body fluids and tissues was described in one report (Riesselmann et al, 1999).

Treatment

Life Support

A)

Patient Disposition

6.3.1)

6.3.1.1) ADMISSION CRITERIA/ORAL

A) Patients with moderate symptoms including palpitations and mild electrolyte disturbances can be observed on telemetry. Any patient showing signs of severe toxicity (ie, seizures, ventricular dysrhythmias, or hypotension) should be admitted to the ICU.

6.3.1.2) HOME CRITERIA/ORAL

A) Patients with nontoxic ingestions with minimal symptoms can be managed at home.

6.3.1.3) CONSULT CRITERIA/ORAL

A) Involve a poison center or toxicologist with any questions, concerns, or cases of moderate to severe toxicity. If you are considering dialysis, a nephrologist should be involved.

6.3.1.5) OBSERVATION CRITERIA/ORAL

A) Intentional self-harm attempts should be referred to a health care facility. Observe all patients with mild symptoms (ie, nausea, vomiting, and palpitations) until resolution of symptoms.

Monitoring

A)

B)

C)

Oral Exposure

6.5.1)

A) EMESIS NOT RECOMMENDED

1) Pre-hospital decontamination should be avoided. Mild exposures do not require treatment, and severe overdose can result in seizures and aspiration.

B) ACTIVATED CHARCOAL

1) PREHOSPITAL ACTIVATED CHARCOAL ADMINISTRATION

a) Consider prehospital administration of activated charcoal as an aqueous slurry in patients with a potentially toxic ingestion who are awake and able to protect their airway. Activated charcoal is most effective when administered within one hour of ingestion. Administration in the prehospital setting has the potential to significantly decrease the time from toxin ingestion to activated charcoal administration, although it has not been shown to affect outcome (Alaspaa et al, 2005; Thakore & Murphy, 2002; Spiller & Rogers, 2002).

1) In patients who are at risk for the abrupt onset of seizures or mental status depression, activated charcoal should not be administered in the prehospital setting, due to the risk of aspiration in the event of spontaneous emesis.
2) The addition of flavoring agents (cola drinks, chocolate milk, cherry syrup) to activated charcoal improves the palatability for children and may facilitate successful administration (Guenther Skokan et al, 2001; Dagnone et al, 2002).

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.2)

A) ACTIVATED CHARCOAL

1) CHARCOAL ADMINISTRATION

a) Consider administration of activated charcoal after a potentially toxic ingestion (Chyka et al, 2005). Administer charcoal as an aqueous slurry; most effective when administered within one hour of ingestion.

2) CHARCOAL DOSE

a) Use a minimum of 240 milliliters of water per 30 grams charcoal (FDA, 1985). Optimum dose not established; usual dose is 25 to 100 grams in adults and adolescents; 25 to 50 grams in children aged 1 to 12 years (or 0.5 to 1 gram/kilogram body weight) ; and 0.5 to 1 gram/kilogram in infants up to 1 year old (Chyka et al, 2005).

1) Routine use of a cathartic with activated charcoal is NOT recommended as there is no evidence that cathartics reduce drug absorption and cathartics are known to cause adverse effects such as nausea, vomiting, abdominal cramps, electrolyte imbalances and occasionally hypotension (None Listed, 2004).

b) ADVERSE EFFECTS/CONTRAINDICATIONS

1) Complications: emesis, aspiration (Chyka et al, 2005). Aspiration may be complicated by acute respiratory failure, ARDS, bronchiolitis obliterans or chronic lung disease (Golej et al, 2001; Graff et al, 2002; Pollack et al, 1981; Harris & Filandrinos, 1993; Elliot et al, 1989; Rau et al, 1988; Golej et al, 2001; Graff et al, 2002). Refer to the ACTIVATED CHARCOAL/TREATMENT management for further information.
2) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).

6.5.3)

A) ANTACID

1) Gastrointestinal irritation can be treated with an appropriate demulcent or antacid.

B) MONITORING OF PATIENT

1) No studies are needed in patients with minimal symptoms. Electrolytes should be checked in patients with mild to moderate symptoms, and if there is any concern for rhabdomyolysis, CPK should be checked.
2) An ECG should be performed with continuous cardiac monitoring in moderate to severe poisoning. Caffeine levels are obtainable, but not routinely available in general hospital laboratories and not useful to guide therapy.
3) Serum concentrations greater than 80 mg/L have been associated with mortality.

C) SEIZURE

1) SUMMARY

a) Attempt initial control with a benzodiazepine (eg, diazepam, lorazepam). If seizures persist or recur, administer phenobarbital or propofol.
b) Monitor for respiratory depression, hypotension, and dysrhythmias. Endotracheal intubation should be performed in patients with persistent seizures.
c) Evaluate for hypoxia, electrolyte disturbances, and hypoglycemia (or, if immediate bedside glucose testing is not available, treat with intravenous dextrose).

2) DIAZEPAM

a) ADULT DOSE: Initially 5 to 10 mg IV, OR 0.15 mg/kg IV up to 10 mg per dose up to a rate of 5 mg/minute; may be repeated every 5 to 20 minutes as needed (Brophy et al, 2012; Prod Info diazepam IM, IV injection, 2008; Manno, 2003).
b) PEDIATRIC DOSE: 0.1 to 0.5 mg/kg IV over 2 to 5 minutes; up to a maximum of 10 mg/dose. May repeat dose every 5 to 10 minutes as needed (Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
c) Monitor for hypotension, respiratory depression, and the need for endotracheal intubation. Consider a second agent if seizures persist or recur after repeated doses of diazepam .

3) NO INTRAVENOUS ACCESS

a) DIAZEPAM may be given rectally or intramuscularly (Manno, 2003). RECTAL DOSE: CHILD: Greater than 12 years: 0.2 mg/kg; 6 to 11 years: 0.3 mg/kg; 2 to 5 years: 0.5 mg/kg (Brophy et al, 2012).
b) MIDAZOLAM has been used intramuscularly and intranasally, particularly in children when intravenous access has not been established. ADULT DOSE: 0.2 mg/kg IM, up to a maximum dose of 10 mg (Brophy et al, 2012). PEDIATRIC DOSE: INTRAMUSCULAR: 0.2 mg/kg IM, up to a maximum dose of 7 mg (Chamberlain et al, 1997) OR 10 mg IM (weight greater than 40 kg); 5 mg IM (weight 13 to 40 kg); INTRANASAL: 0.2 to 0.5 mg/kg up to a maximum of 10 mg/dose (Loddenkemper & Goodkin, 2011; Brophy et al, 2012). BUCCAL midazolam, 10 mg, has been used in adolescents and older children (5-years-old or more) to control seizures when intravenous access was not established (Scott et al, 1999).

4) LORAZEPAM

a) MAXIMUM RATE: The rate of intravenous administration of lorazepam should not exceed 2 mg/min (Brophy et al, 2012; Prod Info lorazepam IM, IV injection, 2008).
b) ADULT DOSE: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist (Manno, 2003; Brophy et al, 2012).
c) PEDIATRIC DOSE: 0.05 to 0.1 mg/kg IV over 2 to 5 minutes, up to a maximum of 4 mg/dose; may repeat in 5 to 15 minutes as needed, if seizures continue (Brophy et al, 2012; Loddenkemper & Goodkin, 2011; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sreenath et al, 2010; Chin et al, 2008).

5) PHENOBARBITAL

a) ADULT LOADING DOSE: 20 mg/kg IV at an infusion rate of 50 to 100 mg/minute IV. An additional 5 to 10 mg/kg dose may be given 10 minutes after loading infusion if seizures persist or recur (Brophy et al, 2012).
b) Patients receiving high doses will require endotracheal intubation and may require vasopressor support (Brophy et al, 2012).
c) PEDIATRIC LOADING DOSE: 20 mg/kg may be given as single or divided application (2 mg/kg/minute in children weighing less than 40 kg up to 100 mg/min in children weighing greater than 40 kg). A plasma concentration of about 20 mg/L will be achieved by this dose (Loddenkemper & Goodkin, 2011).
d) REPEAT PEDIATRIC DOSE: Repeat doses of 5 to 20 mg/kg may be given every 15 to 20 minutes if seizures persist, with cardiorespiratory monitoring (Loddenkemper & Goodkin, 2011).
e) MONITOR: For hypotension, respiratory depression, and the need for endotracheal intubation (Loddenkemper & Goodkin, 2011; Manno, 2003).
f) SERUM CONCENTRATION MONITORING: Monitor serum concentrations over the next 12 to 24 hours. Therapeutic serum concentrations of phenobarbital range from 10 to 40 mcg/mL, although the optimal plasma concentration for some individuals may vary outside this range (Hvidberg & Dam, 1976; Choonara & Rane, 1990; AMA Department of Drugs, 1992).

6) OTHER AGENTS

a) If seizures persist after phenobarbital, propofol or pentobarbital infusion, or neuromuscular paralysis with general anesthesia (isoflurane) and continuous EEG monitoring should be considered (Manno, 2003). Other anticonvulsants can be considered (eg, valproate sodium, levetiracetam, lacosamide, topiramate) if seizures persist or recur; however, there is very little data regarding their use in toxin induced seizures, controlled trials are not available to define the optimal dosage ranges for these agents in status epilepticus (Brophy et al, 2012):

1) VALPROATE SODIUM: ADULT DOSE: An initial dose of 20 to 40 mg/kg IV, at a rate of 3 to 6 mg/kg/minute; may give an additional dose of 20 mg/kg 10 minutes after loading infusion. PEDIATRIC DOSE: 1.5 to 3 mg/kg/minute (Brophy et al, 2012).
2) LEVETIRACETAM: ADULT DOSE: 1000 to 3000 mg IV, at a rate of 2 to 5 mg/kg/min IV. PEDIATRIC DOSE: 20 to 60 mg/kg IV (Brophy et al, 2012; Loddenkemper & Goodkin, 2011).
3) LACOSAMIDE: ADULT DOSE: 200 to 400 mg IV; 200 mg IV over 15 minutes (Brophy et al, 2012). PEDIATRIC DOSE: In one study, median starting doses of 1.3 mg/kg/day and maintenance doses of 4.7 mg/kg/day were used in children 8 years and older (Loddenkemper & Goodkin, 2011).
4) TOPIRAMATE: ADULT DOSE: 200 to 400 mg nasogastric/orally OR 300 to 1600 mg/day orally divided in 2 to 4 times daily (Brophy et al, 2012).

D) TACHYARRHYTHMIA

1) Monitor for cardiac dysrhythmias. Sinus tachycardia is common and usually does not require any specific antidysrhythmic therapy. Life-threatening dysrhythmias or those that compromise hemodynamic status should be treated aggressively. Dysrhythmias often respond to treatment with beta blockers. Dysrhythmias should be treated using standard advanced cardiac life support (ACLS) and pediatric advanced life support (PALS) protocols.
2) If severe tachycardia is complicated by hemodynamic instability, beta blockers are the agents of choice in controlling caffeine-induced dysrhythmias. Beta blockers can antagonize both the cardiac and peripheral effects of beta-receptor stimulation caused by caffeine. There is a theoretical concern that unopposed alpha-stimulation may lead to vasoconstriction and hypertension, but this has not been proven clinically. If beta blocking drugs are used, a short acting cardioselective beta blocker, like esmolol, is advised. Patients have been successfully managed with propranolol.

E) ESMOLOL

1) TACHYCARDIA SUMMARY

a) Evaluate patient to be sure that tachycardia is not a physiologic response to dehydration, anemia, hypotension, fever, sepsis, or hypoxia. Sinus tachycardia does not generally require treatment unless hemodynamic compromise develops.
b) If therapy is required, a short acting, cardioselective agent such as esmolol is generally preferred (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
c) ESMOLOL/ADULT LOADING DOSE

1) Infuse 500 micrograms/kilogram (0.5 mg/kg) IV over 1 minute (Neumar et al, 2010a).

d) ESMOLOL/ADULT MAINTENANCE DOSE

1) Follow loading dose with infusion of 50 mcg/kg per minute (0.05 mg/kg per minute) (Neumar et al, 2010a).
2) EVALUATION OF RESPONSE: If response is inadequate, infuse second loading bolus of 0.5 mg/kg over 1 minute and increase the maintenance infusion to 100 mcg/kg (0.1 mg/kg) per minute. Reevaluate therapeutic effect, increase in the same manner if required to a maximum infusion rate of 300 mcg/kg (0.3 mg/kg) per minute (Neumar et al, 2010a).
3) The manufacturer recommends that a maximum of 3 loading doses be used (Prod Info BREVIBLOC(TM) intravenous injection, 2012).
4) END POINT OF THERAPY: As the desired heart rate or blood pressure is approached, omit loading dose and adjust maintenance infusion as required (Prod Info BREVIBLOC(TM) intravenous injection, 2012).

e) CAUTION

1) Esmolol is a short acting beta-adrenergic blocking agent with negative inotropic effects. Esmolol should be avoided in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excited atrial fibrillation (wide complex irregular tachycardia) or atrial flutter (Neumar et al, 2010a).

F) PROPRANOLOL

1) PROPRANOLOL/ADULT DOSE

a) INTRAVENOUS: 0.5 mg to 1 mg per dose IV over 1 minute. May repeat dose up to a total of 0.1 mg/kg, if needed (Neumar et al, 2010). A second dose may be repeated in 2 minutes, if necessary; however, any additional drug administration should be given at least 4 hours later (Prod Info propranolol HCl IV injection, 2008).
b) The maximum dose is 3 mg; the rate should not exceed 1 mg/min (Prod Info propranolol HCl IV injection, 2008).

2) PROPRANOLOL/PEDIATRIC DOSE

a) INTRAVENOUS: 0.01 to 0.15 mg/kg IV every 6 to 8 hours (Luedtke et al, 1997).

3) MONITORING

a) The drug should be administered with cardiac monitoring or central venous pressure monitoring. Monitor for bradycardia, hypotension and congestive heart failure (Prod Info propranolol HCl IV injection, 2008).

G) VENTRICULAR ARRHYTHMIA

1) VENTRICULAR DYSRHYTHMIAS SUMMARY

a) Obtain an ECG, institute continuous cardiac monitoring and administer oxygen. Evaluate for hypoxia, acidosis, and electrolyte disorders (particularly hypokalemia, hypocalcemia, and hypomagnesemia). Lidocaine and amiodarone are generally first line agents for stable monomorphic ventricular tachycardia, particularly in patients with underlying impaired cardiac function. Amiodarone should be used with caution if a substance that prolongs the QT interval and/or causes torsades de pointes is involved in the overdose. Unstable rhythms require immediate cardioversion.

2) LIDOCAINE

a) LIDOCAINE/INDICATIONS

1) Ventricular tachycardia or ventricular fibrillation (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010a; Vanden Hoek et al, 2010).

b) LIDOCAINE/DOSE

1) ADULT: 1 to 1.5 milligrams/kilogram via intravenous push. For refractory VT/VF an additional bolus of 0.5 to 0.75 milligram/kilogram can be given at 5 to 10 minute intervals to a maximum dose of 3 milligrams/kilogram (Neumar et al, 2010a). Only bolus therapy is recommended during cardiac arrest.

a) Once circulation has been restored begin a maintenance infusion of 1 to 4 milligrams per minute. If dysrhythmias recur during infusion repeat 0.5 milligram/kilogram bolus and increase the infusion rate incrementally (maximal infusion rate is 4 milligrams/minute) (Neumar et al, 2010a).

2) CHILD: 1 milligram/kilogram initial bolus IV/IO; followed by a continuous infusion of 20 to 50 micrograms/kilogram/minute (de Caen et al, 2015).

c) LIDOCAINE/MAJOR ADVERSE REACTIONS

1) Paresthesias; muscle twitching; confusion; slurred speech; seizures; respiratory depression or arrest; bradycardia; coma. May cause significant AV block or worsen pre-existing block. Prophylactic pacemaker may be required in the face of bifascicular, second degree, or third degree heart block (Prod Info Lidocaine HCl intravenous injection solution, 2006; Neumar et al, 2010a).

d) LIDOCAINE/MONITORING PARAMETERS

1) Monitor ECG continuously; plasma concentrations as indicated (Prod Info Lidocaine HCl intravenous injection solution, 2006).

e) CASE REPORT: An 18-year-old man developed severe cardiac instability, including hypotension, episodes of irregular narrow complex tachycardia and severe sinus bradycardia (30 to 40 beats/min), and a pulseless wide complex rhythm that auto-converted, after ingesting approximately 10 to 20 g of caffeine. An ECG also indicated QTc interval prolongation (greater than 600 msec) and inferolateral ST segment abnormalities. Following continuous infusions of phenylephrine and lidocaine, the patient's condition stabilized with significant improvement of the QTc interval and partial resolution of the ST segment changes (Kapur & Smith, 2009).

3) AMIODARONE

a) AMIODARONE/INDICATIONS

1) Effective for the control of hemodynamically stable monomorphic ventricular tachycardia. Also recommended for pulseless ventricular tachycardia or ventricular fibrillation in cardiac arrest unresponsive to CPR, defibrillation and vasopressor therapy (Link et al, 2015; Neumar et al, 2010a). It should be used with caution when the ingestion involves agents known to cause QTc prolongation, such as fluoroquinolones, macrolide antibiotics or azoles, and when ECG reveals QT prolongation suspected to be secondary to overdose (Prod Info Cordarone(R) oral tablets, 2015).

b) AMIODARONE/ADULT DOSE

1) For ventricular fibrillation or pulseless VT unresponsive to CPR, defibrillation, and a vasopressor therapy give an initial dose of 300 mg IV followed by 1 dose of 150 mg IV. For stable ventricular tachycardias: Infuse 150 milligrams over 10 minutes, and repeat if necessary. Follow by a 1 milligram/minute infusion for 6 hours, then a 0.5 milligram/minute. Maximum total dose over 24 hours is 2.2 grams (Neumar et al, 2010a).

c) AMIODARONE/PEDIATRIC DOSE

1) Infuse 5 milligrams/kilogram as a bolus for pulseless ventricular tachycardia or ventricular fibrillation; may repeat twice up to 15 mg/kg. Infuse 5 milligrams/kilogram over 20 to 60 minutes for perfusing tachycardias. Maximum single dose is 300 mg. Routine use with other drugs that prolong the QT interval is NOT recommended (Kleinman et al, 2010).

d) ADVERSE EFFECTS

1) Hypotension and bradycardia are the most common adverse effects (Neumar et al, 2010a).

4) PROCAINAMIDE

a) PROCAINAMIDE/INDICATIONS

1) An alternative drug in the treatment of PVCs or recurrent ventricular tachycardia when lidocaine is contraindicated or not effective. It should be avoided when the ingestion involves agents with quinidine-like effects (e.g. tricyclic antidepressants, phenothiazines, chloroquine, antidysrhythmics) and when the ECG reveals QRS widening or QT prolongation suspected to be secondary to overdose(Neumar et al, 2010a; Vanden Hoek,TLet al,null).

b) CASE REPORT: Massive overdose resulting in supraventricular tachycardia and frequent multifocal ventricular premature beats was successfully treated with a 400-mg loading dose of procainamide followed by procainamide infusion at 2 mg/min. After a total of 6 hours, the patient returned to normal sinus rhythm (Chopra & Morrison, 1995).

5) PROPRANOLOL

a) PROPRANOLOL/INDICATIONS

1) Nonselective beta-adrenergic receptor blocking agent (Prod Info propranolol HCl IV injection, 2008). May be used to treat stable, narrow-complex tachycardia if rhythm is not controlled or converted by adenosine or vagal maneuvers or if SVT is recurrent; to control ventricular rate in patients with atrial fibrillation or atrial flutter; or certain types of polymorphic ventricular tachycardia (ie, catecholaminergic, or rate associated with acute ischemia). Avoid in patients with asthma, obstructive airway disease, decompensated heart failure and pre-excitation related atrial fibrillation or flutter (Neumar et al, 2010). Propranolol is also used in the treatment of life-threatening digitalis-induced dysrhythmias, although digitalis immune Fab is the treatment of choice (Prod Info propranolol HCl IV injection, 2008).

6) LIPID EMULSION THERAPY

a) CASE REPORT: A 50-year-old woman developed hypokalemia, severe hypotension refractory to vasopressor administration, and ventricular tachycardia progressing to ventricular fibrillation (VF) refractory to resuscitative efforts, including cardioversion, after intentionally ingesting an unknown amount of caffeine tablets. At admission, her caffeine plasma level was 311 mg/L. Due to the patient's severe hemodynamic instability, IV lipid emulsion therapy was started, 4 hours-post admission, with an infusion of 565 mL of 20% intralipid over 2 hours. Approximately 60 minutes after beginning the infusion, continuous veno/venous hemodiafiltration (CVVHDF) was also started, at a dose of 25 mL/kg/hour, with potassium supplementation. After initiation of lipid emulsion therapy, the patient's hemodynamic status improved with an increase in her arterial blood pressure to 50; however, she developed VF refractory to cardioversion and did not spontaneously revert to sinus rhythm until 7 hours after beginning CVVHDF (12 hours post-admission). Twenty-four hours post-admission, the patient's caffeine plasma level decreased to 115 mg/L, however she became hyperkalemic, necessitating continuation of CVVHDF for 6 days. She gradually became hemodynamically stable without evidence of neurologic sequelae, and was transferred 12 days post-admission to a psychiatric facility (Schmidt et al, 2015).

1) It is suspected that IV lipid emulsion therapy may have targeted the lipophilic moiety of the caffeine molecule, contributing to the effective resolution of signs and symptoms following caffeine overdose(Schmidt et al, 2015).

H) HYPOTENSIVE EPISODE

1) SUMMARY

a) Infuse 10 to 20 milliliters/kilogram of isotonic fluid and keep the patient supine. If hypotension persists, administer dopamine or norepinephrine. Consider central venous pressure monitoring to guide further fluid therapy.

2) DOPAMINE

a) DOSE: Begin at 5 micrograms per kilogram per minute progressing in 5 micrograms per kilogram per minute increments as needed (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). If hypotension persists, dopamine may need to be discontinued and a more potent vasoconstrictor (eg, norepinephrine) should be considered (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).
b) CAUTION: If ventricular dysrhythmias occur, decrease rate of administration (Prod Info dopamine hcl, 5% dextrose IV injection, 2004). Extravasation may cause local tissue necrosis, administration through a central venous catheter is preferred (Prod Info dopamine hcl, 5% dextrose IV injection, 2004).

3) NOREPINEPHRINE

a) PREPARATION: 4 milligrams (1 amp) added to 1000 milliliters of diluent provides a concentration of 4 micrograms/milliliter of norepinephrine base. Norepinephrine bitartrate should be mixed in dextrose solutions (dextrose 5% in water, dextrose 5% in saline) since dextrose-containing solutions protect against excessive oxidation and subsequent potency loss. Administration in saline alone is not recommended (Prod Info norepinephrine bitartrate injection, 2005).
b) DOSE

1) ADULT: Dose range: 0.1 to 0.5 microgram/kilogram/minute (eg, 70 kg adult 7 to 35 mcg/min); titrate to maintain adequate blood pressure (Peberdy et al, 2010).
2) CHILD: Dose range: 0.1 to 2 micrograms/kilogram/minute; titrate to maintain adequate blood pressure (Kleinman et al, 2010).
3) CAUTION: Extravasation may cause local tissue ischemia, administration by central venous catheter is advised (Peberdy et al, 2010).

4) CASE REPORT: In one case of refractory hypotension due to a massive caffeine overdose, vasopressin infusion was effective in titrating the blood pressure to an acceptable level (Holstege et al, 2001).

I) RHABDOMYOLYSIS

1) SUMMARY: Early aggressive fluid replacement is the mainstay of therapy and may help prevent renal insufficiency. Diuretics such as mannitol or furosemide may be added if necessary to maintain urine output but only after volume status has been restored as hypovolemia will increase renal tubular damage. Urinary alkalinization is NOT routinely recommended.
2) Initial treatment should be directed towards controlling acute metabolic disturbances such as hyperkalemia, hyperthermia, and hypovolemia. Control seizures, agitation, and muscle contractions (Erdman & Dart, 2004).
3) FLUID REPLACEMENT: Early and aggressive fluid replacement is the mainstay of therapy to prevent renal failure. Vigorous fluid replacement with 0.9% saline (10 to 15 mL/kg/hour) is necessary even if there is no evidence of dehydration. Several liters of fluid may be needed within the first 24 hours (Walter & Catenacci, 2008; Camp, 2009; Huerta-Alardin et al, 2005; Criddle, 2003; Polderman, 2004). Hypovolemia, increased insensible losses, and third spacing of fluid commonly increase fluid requirements. Strive to maintain a urine output of at least 1 to 2 mL/kg/hour (or greater than 150 to 300 mL/hour) (Walter & Catenacci, 2008; Camp, 2009; Erdman & Dart, 2004; Criddle, 2003). To maintain a urine output this high, 500 to 1000 mL of fluid per hour may be required (Criddle, 2003). Monitor fluid input and urine output, plus insensible losses. Monitor for evidence of fluid overload and compartment syndrome; monitor serum electrolytes, CK, and renal function tests.
4) DIURETICS: Diuretics (eg, mannitol or furosemide) may be needed to ensure adequate urine output and to prevent acute renal failure when used in combination with aggressive fluid therapy. Loop diuretics increase tubular flow and decrease deposition of myoglobin. These agents should be used only after volume status has been restored, as hypovolemia will increase renal tubular damage. If the patient is maintaining adequate urine output, loop diuretics are not necessary (Vanholder et al, 2000).
5) URINARY ALKALINIZATION: Alkalinization of the urine is not routinely recommended, as it has never been documented to reduce nephrotoxicity, and may cause complications such as hypocalcemia and hypokalemia (Walter & Catenacci, 2008; Huerta-Alardin et al, 2005; Brown et al, 2004; Polderman, 2004). Retrospective studies have failed to demonstrate any clinical benefit from the use of urinary alkalinization (Brown et al, 2004; Polderman, 2004; Homsi et al, 1997).

J) EXPERIMENTAL THERAPY

1) ANIMAL STUDIES: Rats with caffeine-induced toxicity and ventricular ectopia leading to fibrillation were successfully treated with repeated doses of IV propranolol (1 mg/kg) or verapamil (1 mg/kg). Survival time was prolonged in these rats as opposed to rats treated with shorter acting antiarrhythmic agents such as quinidine, phenytoin, or lidocaine (Strubelt & Diederich, 1999).

Eye Exposure

6.8.1)

A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).

6.8.2)

A) IRRITATION SYMPTOM

1) Concentrated caffeine can cause eye irritation, but exposure from drinks normally does not produce irritation.

B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Enhanced Elimination

A)

1) Hemodialysis may be the safest and most widely available extracorporeal method for enhancing caffeine elimination. Increased availability, operator familiarity, and a lower complication rate for hemodialysis make it preferable to charcoal hemoperfusion when managing the most severe overdoses.
2) CASE REPORT: A 20-year-old woman developed severe agitation, tremors, and hypotension, and experienced a total of 25 separate episodes of pulseless ventricular tachycardia, with each episode successfully cardioverted, after an intentional ingestion of an unknown amount of concentrated caffeine powder and tablets. Following her ventricular tachycardia episodes, the patient received hemodialysis for 3 hours as well as multi-dose activated charcoal. Her serum caffeine concentration pre- and post-dialysis were 240.8 mcg/mL and 150.7 mcg/mL, respectively. With continued supportive care, her hemodynamic status stabilized and, on hospital day 7, she was transferred to an inpatient psychiatric facility, where she recovered neurologically (Laskowski et al, 2015).

B)

1) Exchange transfusion is not considered the first line treatment for caffeine toxicity even in neonates.
2) Exchange transfusion has been used in a premature infant with a very high serum caffeine level (160 mcg/mL). Two exchange transfusions 16 hours apart decreased the serum level by about 40 mcg/mL with each transition (Perrin et al, 1987).

C)

1) SUMMARY: Successful use of charcoal hemoperfusion has been reported in adults and infants to reduce caffeine levels.

a) In one case charcoal hemoperfusion was given for 5 hours, during which the serum caffeine level decreased from 297 mcg/mL to 43 mcg/mL. Clinical improvement was noticed after 3 hours (Nagesh & Murphy, 1988).
b) Two 4-hour charcoal hemoperfusion procedures were performed at 11 hours and 24 hours post-ingestion in an 1-year-old child with severe cardiac and neurologic symptoms (Dietrich & Mortensen, 1990).
c) Serum caffeine concentrations dropped from 186 mcg/mL to 123 mcg/mL during 3 hours of charcoal hemoperfusion in a 40-year-old man with severe caffeine intoxication complicated by ventricular tachycardia, seizures, and hypotension (Rouse et al, 1999). Dysrhythmias, hypotension, and seizures did not recur.

D)

1) CASE REPORT: A 32-year-old man intentionally ingested 156 caffeine tablets (15.6 g of caffeine) and presented to the emergency department, approximately 1.5 hours later, with sinus tachycardia (116 beats/min). Arterial blood gas revealed mild metabolic acidosis, and his plasma caffeine level was 237 mg/L. Approximately 2 hours postingestion, he developed tonic-clonic seizures, managed with benzodiazepines, and, 0.5 hours later, ventricular tachycardia occurred. Despite administration of lidocaine and magnesium, his ventricular tachycardia persisted, and combined hemodialysis and hemoperfusion therapy was performed approximately 4 hours postingestion. Within 0.5 hours of initiating the combined therapy, his ventricular tachycardia improved with complete resolution within 2 hours. At the end of therapy, the patient's caffeine plasma level was 150 mg/L. Following observation, the patient made a complete recovery without further cardiac symptoms (Ishigaki et al, 2014).

E)

1) CASE REPORT: A 50-year-old woman developed hypokalemia, severe hypotension refractory to vasopressor administration, and ventricular tachycardia progressing to ventricular fibrillation (VF) refractory to resuscitative efforts, including cardioversion, after intentionally ingesting an unknown amount of caffeine tablets. At admission, her caffeine plasma level was 311 mg/L. Due to the patient's severe hemodynamic instability, IV lipid emulsion therapy was started, 2 hours-post admission, with an infusion of 565 mL of 20% intralipid over 2 hours. Approximately 60 minutes after beginning the infusion, continuous veno/venous hemodiafiltration (CVVHDF) was also started, at a dose of 25 mL/kg/hour, with potassium supplementation. After initiation of lipid emulsion therapy, the patient's hemodynamic status improved with an increase in her arterial blood pressure to 50; however, she developed VF refractory to cardioversion and did not spontaneously revert to sinus rhythm until 7 hours after beginning CVVHDF (12 hours post-admission). Twenty-four hours post-admission, the patient's caffeine plasma level decreased to 115 mg/dL, however she became hyperkalemic, necessitating continuation of CVVHDF for 6 days. She gradually became hemodynamically stable without evidence of neurologic sequelae, and was transferred 12 days post-admission to a psychiatric facility (Schmidt et al, 2015).

Abstracts

Case Reports

A)

1) In one fatal case of caffeine toxicity, postmortem examination revealed a congested liver and lungs; the gastrointestinal tract was dilated but showed no irritation or other pathologic alteration (Alstott et al, 1973). In another fatal case, a generalized congestion of the lungs, liver and brain stem was reported; death was attributed to pulmonary edema (Turner & Cravey, 1977).
2) CASE REPORT: A 16-year-old boy ingested approximately 6 to 8 g of caffeine (100 to 130 mg/kg). Initial signs and symptoms included nervousness, agitation, irritability, chest pain, hypokalemia (2.2 mEq/L), and tachycardia (140 beats/min) with occasional bigeminy, hyperglycemia (182 mg/dL) and respiratory alkalosis. He was treated with syrup of ipecac followed by activated charcoal. At 20 hours postingestion, his heart rate was 90 beats/min, blood glucose was 146 mg/dL with bigeminy and chest pain remaining. The serum caffeine level at that time was 91 mcg/mL. All manifestations had resolved by 45 hours postingestion. A prolonged elimination half-life of 16 hours was calculated (Leson et al, 1988).
3) CASE REPORT: A 21-year-old woman was reported to ingest 106 g of caffeine and 10.6 g of ephedrine. Upon examination, she was comatose and had premature atrial and ventricular contractions, ventricular tachycardia, and ventricular fibrillation requiring cardioversion. Mydriasis, decerebrate posturing, and hypokalemia were present. The initial caffeine level was 297 mcg/mL, which decreased to 43 mcg/mL after 5 hours of charcoal hemoperfusion with resolution of both coma and dysrhythmias (Nagesh & Murphy, 1988).
4) CASE REPORT: A 41-year-old woman with a history of drinking 20 or more cups of coffee per day for 25 years presented with syncope and a profound hypokalemia. Without specific therapy other than abstinence from caffeine, the serum potassium level rose to normal within 4 days (Rudy & Lee, 1988).

B)

1) Overdoses have been reported in several neonates after receiving 36 to 136 mg/kg of caffeine for respiratory depression. The overdose of caffeine produced a clinical picture that suggested neonatal seizures (Banner & Czajka, 1980).
2) CASE REPORT (PREMATURE NEONATE): A premature neonate received an oral dose of 200 mg/kg followed by 50 mg/kg the following day in a 10-fold dosing error. Three hours after the first dose, fever, agitation, tremor, and distended abdomen were noted. The following day, hypertonia, opisthotonus, seizure activity on EEG, and hyperglycemia occurred. A serum level of 16 mg/100 mL (160 mcg/mL) and a cerebrospinal fluid level of 115 mcg/mL were obtained 66 hours after the first dose. Exchange transfusion reduced the level from 130 to 95 mcg/mL with rapid resolution of symptoms. No permanent sequelae were observed (Perrin et al, 1987).
3) CASE REPORT (PREMATURE NEONATE): A low birthweight premature infant received 500 mg ampules instead of the prescribed 50 mg ampules. A serum level of 60 mcg/mL caffeine was obtained at the time the error was discovered which was 10 days after beginning caffeine therapy. No adverse neurological or cardiovascular effects occurred. Profound hyponatremia (107 mEq/L) was the only abnormal finding (Zaoui et al, 1988).
4) CASE REPORT (PREMATURE NEONATE): A premature infant receiving therapeutic caffeine was found to have a level of 346 mg/L after a medication dosing error (goal concentration was 5 to 20 mg/L). This level was associated with tachypnea, tachycardia, poor perfusion, vomiting, and seizures. Symptoms resolved after caffeine therapy was discontinued (van der Anker et al, 1992).
5) CASE REPORT (INFANT): A 4-month-old infant ingested 1.96 to 3.92 g of caffeine (455.8 to 911.6 mg/kg). At 2.5 hours postingestion, she was tremulous, irritable, tachypneic, and tachycardic. She also had nystagmus, hyperreactivity to stimuli, increased muscle tone, and ankle clonus. Ipecac was given and resulted in coffee ground emesis. Symptoms persisted for 54 hours postingestion (Fligner & Opheim, 1988).
6) CASE REPORT (CHILD): A 14-month-old child ingested an unknown amount of Dexatrim-ES(R), containing caffeine 200 mg and phenylpropanolamine 75 mg per capsule. Six hours postingestion, decreased responsiveness, teeth grinding, stiffening, tachypnea, tachycardia, opisthotonus, and oliguria were noted. Hypertonia resolved within 12 hours and she recovered uneventfully. (Fligner & Opheim, 1988).
7) CASE REPORT (CHILD): A 14-month-old child died after ingestion of an unknown dose of caffeine. Postmortem results included a blood caffeine level of 117.3 mg/L, healing fractures of the ribs, bruises and contusions, and severe dehydration. The author reported this as a case of child abuse (Morrow, 1987).
8) CASE REPORT (INFANT): Ventricular fibrillation, which resolved with defibrillation and lidocaine, developed 90 minutes after an ingestion of an unknown quantity of caffeine tablets in a 1-year-old child (Dietrich & Mortensen, 1990).

Range Of Toxicity

Summary

A)

B)

Therapeutic Dose

7.2.1)

A) ROUTE OF ADMINISTRATION

1) ORAL

a) Stimulant: The recommended dose is 100 to 200 mg every 3 to 4 hours as needed (Prod Info No Doz(R), Maximum Strength, caffeine, 1999).

7.2.2)

A) PARENTERAL

1) Apnea in premature infants (between 28 and less than 33 wks gestation), short-term: The recommended one-time, initial loading dose is 1 mL/kg (equivalent to 20 mg/kg) infused over 30 minutes followed by a maintenance dose of 0.25 mL/kg (equivalent to 5 mg/kg) infused over 10 minutes or given orally. The maintenance dose should be started 24 hours after the initial loading dose, and repeated every 24 hours as needed (Prod Info Cafcit, 2001).
2) Because preterm infants can metabolize theophylline to caffeine, baseline serum caffeine levels should be obtained in infants previously treated with theophylline. Caffeine levels should be periodically monitored during therapy (Prod Info Cafcit, 2001).

Minimum Lethal Exposure

A)

1) A single 1-g dose of caffeine may cause confusion, tremors, tachycardia, pyrexia, vomiting and diarrhea; whereas a lethal dose in an adult is estimated to range between 150 to 210 mg/kg (Peters, 1967; Holmgren et al, 2004). Death was reported after ingestion of 6.5 g in an adult (Alstott et al, 1973) , 18 g in a 19-year-old woman (McGee, 1980), and 10 g in a 21-year-old woman (Rudolph & Knudsen, 2010).
2) Blood caffeine levels in excess of 80 mcg/mL (8 mg/100 mL) have been associated with death; however, the minimum toxic or lethal dose is not well-established due to inter-patient variability, tolerance, and/or preexisting disease states (Rehrig, 1982).
3) CASE REPORT: Following an overdose of 20 g of caffeine, a 32-year-old woman experienced multiple seizures during gastric lavage with subsequent cardiac arrest; resuscitation was unsuccessful (Shum et al, 1997).
4) CASE REPORT: A 20-year-old man ingested 18 g of caffeine and experienced cardiac arrest within one hour of the ingestion. Following resuscitation, his condition declined over the next 8 hours with resultant recurrent ventricular fibrillation refractory to therapy. A normal myocardium was seen on autopsy (Rouse et al, 1999).
5) CASE REPORT: Ventricular fibrillation and subsequent cardiac arrest occurred in a 44-year-old man after intentionally ingesting 10 grams of pure anhydrous caffeine. Following 30 minutes of cardiopulmonary resuscitation, the patient remained in refractory ventricular fibrillation, and arterio-venous extracorporeal membrane oxygenation (ECMO) was started approximately 2 hours later. Despite efforts, the patient died 13 hours post-ingestion (approximately 4 hours after ECMO) (Poussel et al, 2013).
6) CASE REPORT: A 25-year-old woman died after consuming 0.7 liters of vodka and approximately 4 to 5 cans of an energy drink containing caffeine. An empty bottle containing dietary supplement capsules, with each capsule consisting of 300 mg caffeine, as well as a variety of natural sources of caffeine, including green tea leaves, yerba mate fruits, guarana seeds, and kola nut seeds, was also found at her bedside. An autopsy revealed internal organ congestion, pulmonary and cerebral edema, degeneration of the liver, and aspiration of gastric contents. Analysis of the patient's blood and body tissues estimated the ingested dose of caffeine to be 8.3 grams (Jantos et al, 2013).
7) CASE REPORT: A 39-year-old man was found dead at the front door of his residence. A dried white fluid was observed on the man's shirt as well as inside of his vehicle, and an opened container of caffeine anhydrous powder and an empty plastic drink container were also found in the vehicle. Autopsy results revealed pulmonary edema and congestion, and his blood caffeine level was 350 mg/L. Following analysis of the bag contents, it was believed that 22 g of 100% pure anhydrous caffeine had been mixed with a drink for consumption, and that, given the amount of white fluid found on the man and in his vehicle, approximately 50% to 60% of the initial oral dose had been retained after ingestion, suggesting an oral dose of 10 to 12 grams of pure caffeine had been ingested (Jabbar & Hanly, 2013).

B)

1) CASE REPORT: A 15-year-old girl experienced sinus tachycardia with multiple premature ventricular contractions and occasional bigeminy after ingestion of 80 tablets of an unknown strength of caffeine. Seizures developed abruptly with subsequent cardiac arrest and death (Shum et al, 1997).

Maximum Tolerated Exposure

A)

1) SUMMARY: Patients have survived after ingestion of 1 g to 105 g of caffeine (Holstege et al, 2003; Stillner et al, 1978; Benowitz et al, 1982; Nagesh & Murphy, 1988). Two separate individuals, each ingesting 20 g caffeine, survived, but one suffered from myocardial infarction and the other developed complex dysrhythmias (Forman et al, 1997; Chopra & Morrison, 1995).
2) CASE REPORT: A 41-year-old woman made a complete recovery following a 50 g overdose. Initially, the patient developed several different dysrhythmias (eg, wide complex tachydysrhythmia, ventricular fibrillation, bradyarrhythmia, and asystole) and hypotension (systolic blood pressure in the 50s by doppler only), but responded to vasopressin infusion and hemodialysis. Within 24 hours of admission, the patient was hemodynamically stable, but had a protracted ICU course after developing bilateral pneumonia, rhabdomyolysis, and multisystem organ failure (Holstege et al, 2003).
3) CASE REPORT: A 40-year-old man survived a 22 g caffeine overdose. Within an hour of ingestion, he experienced seizures and pulseless ventricular tachycardia, which responded to cardiac resuscitation. He recovered following symptomatic therapy and was discharged 6 days postingestion (Rouse et al, 1999).
4) CASE REPORT: After ingesting 10 to 20 g of caffeine, an 18-year-old man developed irregular narrow complex tachycardia, sinus bradycardia, and pulseless wide complex rhythm that auto-converted (Kapur & Smith, 2009).
5) CASE REPORT: A 39-year-old man developed severe hypokalemia (1.8 mmol/L) and rhabdomyolysis after ingesting, over a 3-day period, 14,400 mg ibuprofen, 922 mg codeine, and 1920 mg caffeine. The patient recovered with potassium replacement and supportive care (Ernest et al, 2010).
6) CASE REPORT: A 27-year-old man, with schizophrenia successfully controlled with antipsychotics, developed irritability and recurrent paranoid thoughts after consuming 2 60-mL energy drinks. Each energy drink contained 200 mg of caffeine plus 48 mg guarana (another source of caffeine). One week later, after consuming 3 60-mL energy drinks (at least 600 mg caffeine [4.8 mg/kg]) within 15 minutes, he developed mood swings (initially laughing and talkative, followed by restlessness, withdrawn, and argumentative), tachycardia, insomnia, and paranoid thoughts that continued for the next several hours. The patient recovered with supportive care and remained stable after discontinuing consumption of energy drinks (Menkes, 2011).
7) According to a retrospective analysis of clinical data from adult patients who presented to the Royal Infirmary of Edinburgh from January 2000 to December 2008 with acute caffeine poisoning (n=38), nausea and vomiting, abdominal pain, dizziness, tremors, headache, agitation, tachycardia, and hypertension occurred after a median ingestion of 1040 mg of caffeine (range, 600 to 1500 mg) (Waring et al, 2009).
8) CASE REPORT: Acute renal failure, rhabdomyolysis, and elevated liver enzymes were reported in a 42-year-old man after intentionally ingesting 24 g of caffeine 4 days earlier. Laboratory data revealed a BUN of 167 mg/dL, a serum creatinine concentration of 10.2 mg/dL, a creatinine phosphokinase concentration of 59,360 units/L, an ALT of 367 units/L, and an AST of 694 units/L. With supportive therapy, including daily hemodialysis sessions for 9 days, the patient's condition improved and he was transferred for inpatient psychiatric therapy (Campana et al, 2014).
9) CASE REPORT: A 32-year-old man intentionally ingested 156 caffeine tablets (15.6 g of caffeine) and presented to the emergency department, approximately 1.5 hours later, with sinus tachycardia (116 beats/min). Arterial blood gas revealed mild metabolic acidosis, and his plasma caffeine level was 237 mg/L. Approximately 2 hours postingestion, he developed tonic-clonic seizures, managed with benzodiazepines, and, 0.5 hours later, ventricular tachycardia occurred. Despite administration of lidocaine and magnesium, his ventricular tachycardia persisted, and combined hemodialysis and hemoperfusion therapy was performed approximately 4 hours postingestion. Within 0.5 hours of initiating the combined therapy, his ventricular tachycardia improved with complete resolution within 2 hours. At the end of therapy, the patient's caffeine plasma level was 150 mg/L. Following observation, the patient made a complete recovery without further cardiac symptoms (Ishigaki et al, 2014).
10) CASE REPORT: A 44-year-old woman presented to the emergency department with nausea, vomiting, palpitations, chest tightness, muscle twitching, and tea-colored urine approximately 6 hours after ingesting 4 cups of black coffee (approximately 1000 mL). Monitoring of vital signs indicated a heart rate of 110 beats/min, blood pressure of 136/92 mmHg, a respiration rate of 20 breaths/minute, temperature of 36.2 degrees C, and an oxygen saturation of 99% on room air. Initially, her laboratory values were normal, with the exception of a mild elevation of hepatic enzymes (AST 45 units/L [reference range 0 to 40 units/L], ALT 108 units/L [reference range 0 to 41 units/L]). However, after 4 hours of observation and administration of IV fluids, repeat laboratory analysis revealed creatine kinase (CK) and CK-MB concentrations of 7315 units/L (reference range 26 to 308 units/L) and 266 units/L (reference range 0 to 25 units/L), respectively. Her initial plasma caffeine concentration was estimated to be 16 mcg/mL (taking into account that the actual plasma caffeine concentration, obtained 10 hours post-ingestion was 4 mcg/mL and the average half-life of caffeine is 5 hours). With continued supportive care for 5 days, the patient completely recovered without neuromuscular sequelae (Chiang et al, 2014).

B)

1) Patients have survived after ingestions ranging from 78 mg/kg up to 912 mg/kg. Symptoms included arrhythmias, seizures, pulmonary edema, hypertension, and metabolic disturbances (Mace, 1978; Rowland & Mace, 1976; Perrin et al, 1987; Dietrich & Mortensen, 1990; Fligner & Opheim, 1988).
2) CASE REPORT: A 17-year-old girl developed nausea, vomiting, tremor, anxiety, hyperventilation, hypokalemia (2.4 mmol/L), and an elevated plasma lactate level of 7 mmol/L with a concomitant decrease in pH to 7.33 after intentionally ingesting 12 g of caffeine (266 mg/kg). The patient recovered with supportive care (Schmidt & Karlson-Stiber, 2008).
3) CASE REPORT: A 13-year-old boy became agitated and aggressive, and developed sinus tachycardia, tachypnea, hypertension, increased diuresis, dysuria, and paresthesia of the legs following consumption of 2 packets of stimulant ("energy") chewing gum within a 4-hour period. Each packet reportedly contained 160 mg caffeine (0.57% caffeine per gum pellet). With supportive care, the patient recovered (Natale et al, 2009).

C)

1) CAFFEINE CITRATE

a) GENERAL: Premature infants receiving caffeine citrate have developed toxicity following inadvertent excessive exposure. Following overdose, serum caffeine levels have ranged from approximately 24 mg/L (increased irritability and poor feeding reported) to 350 mg/L, and serious toxicity has been associated with serum levels greater than 50 mg/L (Prod Info Cafcit, 2001).
b) CASE REPORT: A premature infant received 600 mg caffeine citrate (approximately 322 mg/kg) over 40 minutes, and developed tachycardia, ST depression, respiratory distress, heart failure, gastric distention, acidosis, and a severe extravasation burn with tissue necrosis at the peripheral intravenous injection site (Prod Info Cafcit, 2001).
c) CASE REPORT: A 32-week premature male (born at 28 weeks) received an inadvertent 300 mg/kg dose (intended dose 3 mg/kg) of caffeine, and developed typical symptoms of acute toxicity (ie, dehydration, tachycardia, electrolyte disturbances, and metabolic acidosis). Following supportive care, laboratory and clinical symptoms normalized within 96 hours; no permanent sequelae was reported (Ergenekon et al, 2001).
d) CASE REPORT: An IV overdose of 160 mg/kg occurred in a 31-week gestation, 1860-g neonate (estimated dose, 300 mg over 40 minutes) with clinical effects of hyperglycemia, cardiac failure, and gastric dilatation. Resolution of toxic symptoms occurred on days 6 and 7 and were correlated with a drop in serum caffeine concentrations to 60 to 70 mg/L (Anderson et al, 1999).

D)

1) COINGESTION

a) The combination of caffeine and phenylpropanolamine will result in pharmacologic additive action of each drug (Ekins & Spoerke, 1983).
b) A 5-month study of 19 patients aged 9 months to 2 years reported that an average total dose of 460 mg (40 mg/kg) caffeine resulted in symptoms; all of these cases involved coingested phenylpropanolamine (average 10.5 mg/kg) (Ekins & Spoerke, 1983).

Serum Plasma Blood Concentrations

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) GENERAL

a) Serum levels and reported associated signs and symptoms are listed below:

ADULTS
SERUM LEVEL	SIGNS/SYMPTOMS	REF
greater than 100 mcg/mL	potentially lethal exposure	Holmgren et al, 2004
74.6 mcg/mL	vomiting, tachycardia	May, 1981
42 mcg/mL	vomiting, combativeness	May, 1981
405 mcg/mL	hypotension, multiple dysrhythmias	Holstege et al, 2003

NEONATES
SERUM LEVEL	SIGNS/SYMPTOMS	REF
60 mcg/mL	hyponatremia	Zaoui, 1988
160 mcg/mL	agitation, tremor, opisthotonus, seizures, hyperglycemia	Perrin, 1987
55 mcg/mL	jitteriness, tachypnea, tremors	Kulkarni, 1979
210 mcg/mL	cardiac failure, hyperglycemia, gastric dilatation	Anderson et al, 1999

INFANTS AND CHILDREN
AGE	SERUM LEVEL	SIGNS/SYMPTOMS	REF
5 wk	117 mcg/mL	tachycardia, agitation, fever, elevated liver enzymes	Rivenes, 1997
4 mo	176 mcg/mL	clonus, hyperexcitability, tachycardia	Fligner, 1988
12 mo	385 mcg/mL	ventricular arrhythmias, seizures, metabolic disturbances, pulmonary edema	Dietrich & Mortens, 1990
14 mo	128 mcg/mL	tachypnea, tachycardia, opisthotonus	Fligner, 1988
12 yr	46 mcg/mL	tachycardia, seizures	Sullivan, 1977

NEONATES
SERUM LEVEL	SIGNS/SYMPTOMS	REF
60 mcg/mL	hyponatremia	Zaoui, 1988
160 mcg/mL	agitation, tremor, opisthotonus, seizures, hyperglycemia	Perrin, 1987
55 mcg/mL	jitteriness, tachypnea, tremors	Kulkarni, 1979
210 mcg/mL	cardiac failure, hyperglycemia, gastric dilatation	Anderson et al, 1999

INFANTS AND CHILDREN
AGE	SERUM LEVEL	SIGNS/SYMPTOMS	REF
5 wk	117 mcg/mL	tachycardia, agitation, fever, elevated liver enzymes	Rivenes, 1997
4 mo	176 mcg/mL	clonus, hyperexcitability, tachycardia	Fligner, 1988
12 mo	385 mcg/mL	ventricular arrhythmias, seizures, metabolic disturbances, pulmonary edema	Dietrich & Mortens, 1990
14 mo	128 mcg/mL	tachypnea, tachycardia, opisthotonus	Fligner, 1988
12 yr	46 mcg/mL	tachycardia, seizures	Sullivan, 1977

INFANTS AND CHILDREN
AGE	SERUM LEVEL	SIGNS/SYMPTOMS	REF
5 wk	117 mcg/mL	tachycardia, agitation, fever, elevated liver enzymes	Rivenes, 1997
4 mo	176 mcg/mL	clonus, hyperexcitability, tachycardia	Fligner, 1988
12 mo	385 mcg/mL	ventricular arrhythmias, seizures, metabolic disturbances, pulmonary edema	Dietrich & Mortens, 1990
14 mo	128 mcg/mL	tachypnea, tachycardia, opisthotonus	Fligner, 1988
12 yr	46 mcg/mL	tachycardia, seizures	Sullivan, 1977

2) ADULT

a) SUMMARY: Patients with serum caffeine levels ranging from 19.9 mg/100 mL (199 mcg/mL) to 40 mg/100 mL (400 mcg/mL) have survived (Zimmerman et al, 1985; Benowitz et al, 1982; Nagesh & Murphy, 1988; Tisdell et al, 1986; Holstege et al, 2003). In general, a caffeine blood concentration greater than 100 mcg/mL is considered potentially lethal (Holmgren et al, 2004).
b) Patients with serum levels ranging from 4.2 mg/100 mL to 7.46 mg/100 mL experience variable levels of symptoms including cramps, vomiting, anxiety, and combativeness (May et al, 1981).
c) Blood levels in patients with ultimately fatal ingestion ranged from 10.6 mg/100 mL to 156 mg/100 mL (Turner & Cravey, 1977; McGee, 1980; Mrvos et al, 1989).
d) Caffeine serum levels of 99 mcg/mL have been reported following a 20-g overdose in a nonfatal case which resulted in myocardial infarction (Forman et al, 1997).
e) A postmortem serum caffeine level of 30 mcg/dL was reported in a 32-year-old female following ingestion of 100 tablets of caffeine (200 mg each). Multiple seizures with subsequent cardiac arrest preceded death (Shum et al, 1997).
f) A postmortem caffeine concentration of 1560 mcg/mL was observed in a 22-year-old female (Mrvos et al, 1989).
g) Postmortem femoral blood concentrations of 220 and 190 mg/L were reported in a 19-year-old female and an 81-year-old female, respectively (Riesselmann et al, 1999).
h) CASE REPORT: A 34-year-old woman developed ventricular tachycardia, severe hypokalemia, and metabolic acidosis after ingesting an unknown amount of caffeine tablets. She recovered with supportive care. Laboratory analysis of the patient's blood revealed a caffeine concentration of 128 mcg/mL (reference range, 6 to 20 mcg/mL) (Vaglio et al, 2011).

3) PEDIATRIC

a) In a 12-year-old girl, acute intoxication was reported at a serum level of 4.6 mg/100 mL serum. In this patient, both hyperglycemia and glucosuria were observed (Sullivan, 1977).
b) A postmortem serum caffeine level was reported to be 108 mcg/dL in a 15-year-old female following an overdose of 80 tablets of an unknown strength of caffeine (Shum et al, 1997).
c) A blood caffeine level of 15.8 mg/100 mL was noted in a 5-year-old child 4 hours after ingestion of an unknown quantity. The child died (Diamaio & Garriott, 1974).
d) A serum caffeine concentration of 500 mcmol/L (97 mcg/mL) was reported in a 17-year-old girl 8 hours after intentionally ingesting 12 g of caffeine (266 mg/kg) (Schmidt & Karlson-Stiber, 2008).

4) INFANT

a) One patient with a peak serum caffeine level of 16 mg/100 mL (160 mcg/mL) survived after exchange transfusion (Perrin et al, 1987).
b) Premature infants with caffeine serum levels of 125 to 160 mcg/mL have developed tachycardia, hyperexcitability, and seizures (Perrin et al, 1987); Zaoui et al, 1988). One with a serum level of 60 mcg/mL developed severe hyponatremia, but no adverse CNS or cardiac effects (Zaoui et al, 1988).
c) A 31-week gestation neonate with maximum serum caffeine level of approximately 210 mcg/mL developed cardiac failure, hyperglycemia, and gastric dilatation. She recovered following symptomatic therapy (Anderson et al, 1999).

Workplace Standards

A)

1) Not Listed

B)

1) Not Listed

C)

1) ACGIH (American Conference of Governmental Industrial Hygienists, 2010): Not Listed
2) EPA (U.S. Environmental Protection Agency, 2011): Not Listed
3) IARC (International Agency for Research on Cancer (IARC), 2016; International Agency for Research on Cancer, 2015; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010a; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2008; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2007; IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2006; IARC, 2004): 3 ; Listed as: Caffeine

a) 3 : The agent (mixture or exposure circumstance) is not classifiable as to its carcinogenicity to humans. This category is used most commonly for agents, mixtures and exposure circumstances for which the evidence of carcinogenicity is inadequate in humans and inadequate or limited in experimental animals. Exceptionally, agents (mixtures) for which the evidence of carcinogenicity is inadequate in humans but sufficient in experimental animals may be placed in this category when there is strong evidence that the mechanism of carcinogenicity in experimental animals does not operate in humans. Agents, mixtures and exposure circumstances that do not fall into any other group are also placed in this category.

4) NIOSH (National Institute for Occupational Safety and Health, 2007): Not Listed
5) MAK (DFG, 2002): Not Listed
6) NTP (U.S. Department of Health and Human Services, Public Health Service, National Toxicology Project ): Not Listed

D)

1) Not Listed

Toxicity Information

7.7.1)

A) LD50- (INTRAPERITONEAL)MOUSE:

1) 168 mg/kg (RTECS, 2004)

B) LD50- (ORAL)MOUSE:

1) 127 mg/kg (RTECS, 2004)

C) LD50- (SUBCUTANEOUS)MOUSE:

1) 242 mg/kg (RTECS, 2004)

D) LD50- (INTRAPERITONEAL)RAT:

1) 240 mg/kg (RTECS, 2004)

E) LD50- (ORAL)RAT:

1) 192 mg/kg (RTECS, 2004)

F) LD50- (SUBCUTANEOUS)RAT:

1) 170 mg/kg (RTECS, 2004)

Pharmacology Toxicology

Pharmacologic Mechanism

A)

B)

C)

D)

E)

F)

G)

Toxicologic Mechanism

A)

B)

C)

D)

1) Vasodilation is a result of a direct effect on the media of the vessels. Simultaneously, the sympathetic nervous system is causing a stimulation of the vasomotor centers of the medulla resulting in vasoconstriction. An exception to this mixed response is the cerebral vasculature, which responds with a purely vasoconstrictive effect. The overall result of an acute overdose is an elevation of blood pressure (Lewin, 1994).

Physicochemical

Physical Characteristics

A)

Molecular Weight

A)

Animal Toxicology

Clinical Effects

11.1.5)

A) HORSE - Signs include anorexia, diarrhea, violent excitement, and death (Beasley et al, 1988).

11.1.13)

A) OTHER

1) PRIMATES - Caffeine appears to have an abnormally long half-life, about 11 hours, in the squirrel monkey (Saimiri sciureus)(HSDB , 1990).
2) OTHER SMALL ANIMALS - In general, small animals exhibit vomiting, diarrhea, diuresis, restlessness, hyperactivity, tachycardia, PVCs, tachypnea, ataxia, tremors, seizures, weakness, coma, cyanosis, and hypertension. They may be dehydrated or hyperthermic. Hypokalemia commonly develops; death results from cardiac arrhythmias or respiratory failure.

Treatment

11.2.1)

A) GENERAL TREATMENT

1) GOALS - Maintain basic life support; prevent absorption of caffeine; and supportively treat seizures, arrhythmias, and respiratory difficulties.
2) BEGIN TREATMENT IMMEDIATELY - Keep animal warm; sample vomitus, blood, and urine.
3) ANIMAL POISON CONTROL CENTERS

a) National Animal Poison Control Center, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL 61801
b) NAPCC toll-free number is available to callers in the United States, Puerto Rico, and the Virgin Islands 24 hours a day: 1-800-548-2423. A fee is applied to non-subscribers. Consultations to human poison control centers are free of charge.

11.2.2)

A) GENERAL

1) MAINTAIN VITAL FUNCTIONS: Secure airway, supply oxygen, and begin supportive fluid therapy if necessary.

11.2.4)

A) GASTRIC DECONTAMINATION

1) SMALL ANIMALS

a) EMESIS -

1) If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs can have syrup of ipecac or one tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL -

1) Administer repeated doses of activated charcoal at 0.5 grams/kilogram per os or via stomach tube every three hours for up to 72 hours. Give the course of activated charcoal even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).

c) ORAL CATHARTICS -

1) Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram) per os or via stomach tube at 0 and 3 hours to hasten evacuation. Due to the slow absorption of caffeine, give the cathartic even if exposure occurred several hours before.

2) LARGE ANIMALS

a) EMESIS -

1) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).

b) ACTIVATED CHARCOAL -

1) Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube. Give the course of activated charcoal even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).

c) ORAL CATHARTICS -

1) Administer mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon); magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram); or Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os). Give these solutions via stomach tube and monitor for aspiration. Give the cathartic even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).

11.2.5)

A) SMALL ANIMALS

1) SUMMARY - MAINTAIN VITAL FUNCTIONS - as necessary.
2) SEIZURES - Seizures may be controlled with diazepam or barbiturate anticonvulsants. Dose of diazepam: 0.5 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 1 to 2 minutes. Phenobarbital may be used as adjunct treatment at 6 milligrams/kilogram 2 to 4 times daily as needed.
3) EKG must be monitored.

a) BRADYCARDIA can be treated with atropine at 0.02 milligram/kilogram intravenously.
b) PREMATURE VENTRICULAR CONTRACTIONS -

1) Dogs can be treated with lidocaine (without epinephrine) at a dose of 1 to 2 milligrams/kilogram as an intravenous bolus followed by an intravenous drip of a 0.1 percent solution at 30 to 50 micrograms/kilogram per minute. Propranolol or metaprolol, beta blockers, can be used in dogs refractory to lidocaine. Either is dosed in dogs at 0.04 to 0.15 milligram/kilogram intravenously over 1 to 2 minutes three times daily.
2) CATS - DO NOT USE LIDOCAINE IN CATS. Use propranolol instead of lidocaine; dose at 0.25 milligram diluted in 1 milliliter saline and give 0.2 milliliter boluses intravenously to effect. Monitor for hypotension and decrease in cardiac output. Metaprolol is the preferred beta-blocker, despite difficulty in obtaining it, since propranolol has been shown to reduce clearance of theophylline, another methylxanthine, in humans.

4) Urinary catheterization to prevent absorption of caffeine from urine in the bladder.
5) Avoid erythromycin and corticosteroids (they interfere with the excretion of methylxanthines) (Beasley et al, 1989).

B) LARGE ANIMALS

1) SUMMARY - Maintain vital functions, secure airway, supply oxygen if cyanotic, and begin supportive fluid therapy.
2) SEIZURES - Seizues may be controlled with diazepam or barbiturate anticonvulsants. Dose of diazepam: 1 milligram/kilogram intravenous bolus; may repeat dose every ten minutes for four total doses. Give slowly over 5 to 10 minutes.
3) EKG - Monitor if possible. Bradycardias can be treated with atropine at 0.04 milligram/kilogram intravenously. PVCs can be treated with lidocaine (without epinephrine). Horses: dose of 1 to 1.5 milligrams/kilogram lidocaine as an intravenous bolus followed by an intravenous drip of a 0.1 percent solution at 25 to 80 micrograms/kilogram per minute.
4) Avoid erythromycin and corticosteroids (they interfere with the excretion of methylxanthines) (Beasley et al, 1989).

Range Of Toxicity

11.3.1)

A) DOG

1) A "therapeutic dose" of caffeine is 0.1 to 0.5 gram intramuscularly (Kirk, 1989).

11.3.2)

A) SUMMARY -

1) Deaths due to caffeine ingestion in small animals are rare (Kirk, 1986).

B) DOGS/CATS

1) LD50 of caffeine is 140 milligrams/kilogram and the half-life is about 4.5 hours (Kirk, 1986).
2) Diet pills and stimulants often contain 100 to 200 milligrams caffeine. A medium sized, 20 kilogram dog could receive a toxic dose by swallowing as few as 10 to 14 pills.

C) BIRD

1) WILD BIRDS - Oral LD50 is 316 milligrams/kilogram (RTECS , 1990).

D) RODENT

1) Rat LD50 is approximately 200 mg/kg; hamster and guinea pig LD50 is approximately 230 mg/kg (Sax & Lewis, 1989).

E) RABBIT

1) Rabbit LD50 is approximately 224 mg/kg (Sax & Lewis, 1989).

Continuing Care

11.4.1)

11.4.1.2) DECONTAMINATION/TREATMENT

A) GENERAL TREATMENT

1) GOALS - Maintain basic life support; prevent absorption of caffeine; and supportively treat seizures, arrhythmias, and respiratory difficulties.
2) BEGIN TREATMENT IMMEDIATELY - Keep animal warm; sample vomitus, blood, and urine.
3) ANIMAL POISON CONTROL CENTERS

a) National Animal Poison Control Center, University of Illinois at Urbana-Champaign, 2001 S. Lincoln Avenue, Urbana, IL 61801
b) NAPCC toll-free number is available to callers in the United States, Puerto Rico, and the Virgin Islands 24 hours a day: 1-800-548-2423. A fee is applied to non-subscribers. Consultations to human poison control centers are free of charge.

11.4.2)

11.4.2.2) GASTRIC DECONTAMINATION

A) GASTRIC DECONTAMINATION

1) SMALL ANIMALS

a) EMESIS -

1) If within 2 hours of exposure, induce emesis with 1 to 2 milliliters/kilogram syrup of ipecac per os. Dogs can have syrup of ipecac or one tablet (6 milligrams) apomorphine diluted in 3 to 5 milliliters water and instilled into the conjunctival sac or per os. Do not use an emetic if the animal is hypoxic. In the absence of a gag reflex or if vomiting cannot be induced, place a cuffed endotracheal tube and begin gastric lavage. Pass large bore stomach tube and instill 5 to 10 milliliters/kilogram water or lavage solution, then aspirate. Repeat 10 times (Kirk, 1986).

b) ACTIVATED CHARCOAL -

1) Administer repeated doses of activated charcoal at 0.5 grams/kilogram per os or via stomach tube every three hours for up to 72 hours. Give the course of activated charcoal even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).

c) ORAL CATHARTICS -

1) Administer a dose of a saline cathartic such as magnesium or sodium sulfate (sodium sulfate dose is 1 gram/kilogram) per os or via stomach tube at 0 and 3 hours to hasten evacuation. Due to the slow absorption of caffeine, give the cathartic even if exposure occurred several hours before.

2) LARGE ANIMALS

a) EMESIS -

1) Do not attempt to induce emesis in ruminants (cattle) or equids (horses).

b) ACTIVATED CHARCOAL -

1) Give 250 to 500 grams activated charcoal in a water slurry per os or via stomach tube. Give the course of activated charcoal even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).

c) ORAL CATHARTICS -

1) Administer mineral oil (small ruminants and swine, 60 to 200 milliliters; equids and cattle, 0.5 to 1 gallon); magnesium sulfate (ruminants and swine, 1 to 2 grams/kilogram; equine, 0.2 to 0.9 grams/kilogram); or Milk of Magnesia (small ruminants, up to 0.25 gram/kilogram in 1 to 3 gallons warm water; adult cattle up to 1 gram/kilogram in 1 to 3 gallons warm water or 2 to 4 boluses MgOH per os). Give these solutions via stomach tube and monitor for aspiration. Give the cathartic even if exposure occurred several hours before; this has been proven to shorten the half-life of methylxanthines in the body (Kirk, 1986).

11.4.3)

11.4.3.5) SUPPORTIVE CARE

A) GENERAL

1) Ongoing treatment is symptomatic and supportive.

11.4.3.6) OTHER

A) OTHER

1) GENERAL

a) LABORATORY - Submit serum, plasma, tissue, urine or stomach contents for HPLC. Methylxanthines and their metabolites are stable in serum or plasma at room temperature for 7 days, in the refrigerator for 14 days, and frozen for 4 months (Kirk, 1986).

Kinetics

11.5.1)

A) GENERAL

1) Absorption is rapid after oral or parenteral exposure (Beasley et al, 1989).

11.5.2)

A) GENERAL

1) Methylxanthines are excreted in the bile and then undergo enterohepatic recirculation (Beasley et al, 1989).

11.5.3)

A) GENERAL

1) Liver microsomal enzymes promote the metabolism of caffeine, which also undergoes N-demethylation and phase II conjugation reactions (Beasley et al, 1989).

11.5.4)

A) GENERAL

1) Caffeine is excreted in the bile, urine, and a trace in the feces. Half-life is 4.5 hours in the dog (Kirk, 1986).

Pharmacology Toxicology

A)

1) Caffeine competitively antagonizes cellular adenosine receptors, inhibits phosphodiesterase, stimulates catecholamine release, and increases free calcium.

Sources

A)

1) Caffeine is the second most prevalent methylxanthine poisoning (to chocolate) reported in small animals. The usual sources are diet pills or stimulant pills, many of which contain 100 to 200 milligrams caffeine each. Street drugs containing varying amounts of caffeine or other stimulants may be another source.

B)

1) Due to their finicky eating habits, cats are not as often poisoned by methylxanthines as dogs (Beasley et al, 1989).

C)

1) Caffeine is sometimes used to "hype" racehorses. Horses may also ingest cocoa bean hulls or waste that is used as bedding. Hulls contain theobromine (0.5 to 0.85%).

Other

A)

1) GENERAL

a) POSTMORTEM LESIONS - Few are seen; usually gastroenteritis and congestion of organs. A degenerative fibrotic cardiomyopathy was found in the right atrial appendage of several dogs chronically dosed with theobromine (Kirk, 1986).

References

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FeedBack

CAFFEINE

Classification | Detailed evidence-based information

Therapeutic Toxic Class

Specific Substances

Available Forms Sources

Life Support

Clinical Effects

Laboratory Monitoring

Treatment Overview

Range Of Toxicity

Summary Of Exposure

Vital Signs

Heent

Cardiovascular

Respiratory

Neurologic

Gastrointestinal

Hepatic

Genitourinary

Acid-Base

Hematologic

Dermatologic

Musculoskeletal

Endocrine

Reproductive

Carcinogenicity

Genotoxicity

Monitoring Parameters Levels

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Eye Exposure

Enhanced Elimination

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Workplace Standards

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Molecular Weight

Clinical Effects

Treatment

Range Of Toxicity

Continuing Care

Kinetics

Pharmacology Toxicology

Sources

Other

General Bibliography