SYMPATHOMIMETICS-PARENTERAL

Classification | Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

Specific Substances

1) CAS 34368-04-2 (dobutamine)
2) CAS 49745-95-1 (dobutamine hydrochloride)

1) 3-Hydroxytyramine
2) 3,4-Dihydroxyphenethylamine
3) CAS 51-61-6 (dopamine)
4) CAS 62-31-7 (dopamine hydrochloride)

1) CAS 86197-47-9 (dopexamine)
2) CAS 86484-91-5 (dopexamine hydrochloride)

1) CAS 299-42-3 (ephedrine)
2) CAS 50906-05-3 (ephedrine hemihydrate)
3) CAS 50-98-6 (ephedrine hydrochloride)
4) CAS 134-72-5 (ephedrine sulfate)

1) Methylaminoethanolcatechol
2) CAS 51-43-4

1) CAS 536-24-3 (ethylnorepinephrine)
2) CAS 3198-07-0 (ethylnorepinephrine hydrochloride)

1) Isoprenaline
2) CAS 7683-59-2

1) CAS 100-92-5 (mephentermine)
2) CAS 6190-60-9 (mephentermine sulfate)

1) Meta-hydroxynorephedrine
2) Metaradrine
3) CAS 54-49-9 (metaraminol)
4) CAS 33402-03-8 (metaraminol bitartrate)

1) CAS 6116-5 (methoxamine hydrochloride)

1) Levarterenol
2) CAS 51-41-2 (norepinephrine)
3) CAS 69815-49-2 (norepinephrine bitartrate)

1) Metaoxedrin
2) CAS 61-76-7 (phenylephrine hydrochloride)

1) D-1959 (reproterol)
2) W-2946M
3) Trihydroxyphenethyl amino propyl theophylline
4) hydrochloride
5) CAS 54063-54-6 (reproterol)
6) CAS 13055-82-8 (reproterol hydrochloride)

1) CAS 26652-09-5 (ritodrine)
2) CAS 23239-51-2 (ritodrine hydrochloride)

1) CAS 23031-25-6 (terbutaline)
2) CAS 23031-32-5 (terbutaline sulfate)

1) PARENTERAL SYMPATHOMIMETICS

1.2.1) MOLECULAR FORMULA
1) PHENYLEPHRINE HYDROCHLORIDE: C9H13NO2.HCl

Available Forms Sources

1) PARENTERAL FORMS AVAILABLE IN THE US

a) Dobutamine: 250 mg in 20 mL vials
b) Dopamine: 40 mg/mL, 80 mg/mL, 160 mg/mL
c) Epinephrine: 1:1000, 1:10,000
d) Isoproterenol: 0.2 mL, 1 mg/5 mL
e) Mephentermine: 15 mg/mL, 30 mg/mL
f) Metaraminol: 10 mg/mL
g) Methoxamine: 20 mg/mL
h) Norepinephrine: 1 mg/mL
i) Phenylephrine: 10 mg/mL
j) Ritodrine: 10 mg/mL, 15 mg/mL
k) Terbutaline: 1 mg/mL

2) As of February 2011, the FDA has warned against the use of oral or injectable terbutaline in pregnant women for the prevention or prolonged treatment (beyond 48 to 72 hours) of preterm labor due to the risk of potentially serious maternal cardiac events (ie, tachycardia, cardiac dysrhythmias, myocardial infarction, hypertension and pulmonary edema) and death (US Food and Drug Administration, 2011; U.S. Food and Drug Administration, 2011).

Overview

Life Support

Clinical Effects

0.2.1)

A) USES: This class of drugs are used to treat hypotension, bradycardia, heart failure, asthma, and anaphylaxis, which includes epinephrine, norepinephrine, dobutamine, dopamine, isoproterenol, terbutaline, and phenylephrine.
B) PHARMACOLOGY: These agents cause stimulation of adrenergic receptors leading to vasoconstriction, increased inotropy and chronotropy.
C) TOXICOLOGY: Primarily from sympathomimetic excess and can either result from vasoconstriction leading to ischemia and hypoxia in end organs, toxic effects from hypertension or hypotension, and cardiac strain from tachycardia.
D) EPIDEMIOLOGY: Uncommon overdose that can lead to significant morbidity and mortality.
E) WITH THERAPEUTIC USE

1) ADVERSE EFFECTS: Tachycardia, nausea, vomiting, hypertension, headache, diaphoresis, and pallor. Ischemic necrosis secondary to local vasoconstriction can result from extravasation of sympathomimetic agents including dobutamine, dopamine, epinephrine, metaraminol and norepinephrine.
2) TERBUTALINE: As of February 2011, the FDA has warned against the use of oral or injectable terbutaline in pregnant women for the prevention or prolonged treatment (beyond 48 to 72 hours) of preterm labor due to the risk of potentially serious maternal cardiac events (ie, tachycardia, cardiac dysrhythmias, myocardial infarction, hypertension and pulmonary edema) and death.

F) WITH POISONING/EXPOSURE

1) OVERDOSE: Overdoses are typically iatrogenic. Home exposure is generally from accidental injection of epinephrine autoinjectors. These drugs have occasionally been injected as drugs of abuse, although this is rare.
2) MILD TO MODERATE TOXICITY: Tachycardia, nausea, vomiting, hypertension, headache, diaphoresis, and pallor.
3) SEVERE TOXICITY: Seizures, stroke, pulmonary edema, hypotension, cyanosis, myocardial ischemia or infarction, dysrhythmias, acidosis, hypokalemia, and tissue necrosis.

0.2.4)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS has been seen following overdoses.

0.2.5)

A) BIPHASIC REACTION: Hypertension, or hypertension followed by profound hypotension, may occur.
B) MYOCARDIAL ISCHEMIA: Myocardial ischemia or infarction may occur.
C) DYSRHYTHMIAS: Supraventricular tachydysrhythmias, bradycardia, or ventricular dysrhythmias may be seen.
D) VASOCONSTRICTION: Unintentional subcutaneous autoinjection of a digit may result in severe vasoconstriction with numbness and paleness.

0.2.6)

A) Pulmonary edema and cyanosis may occur.

0.2.7)

A) WITH POISONING/EXPOSURE

1) Anxiety, diaphoresis, palpitations, tremor, and numbness and tingling of the extremities may occur.

0.2.8)

A) WITH POISONING/EXPOSURE

1) Nausea, vomiting, and abdominal pain may occur in overdose.

0.2.10)

A) WITH POISONING/EXPOSURE

1) Urinary incontinence has been reported with overdose.
2) Acute renal failure following an overdose of epinephrine has also been reported.

0.2.11)

A) Acidemia and lactic acidosis have been reported.

0.2.12)

A) WITH POISONING/EXPOSURE

1) Hypokalemia has been reported in overdose.

0.2.14)

A) WITH POISONING/EXPOSURE

1) Pallor, sweating and erythema have been reported following parenteral sympathomimetics.
2) Injection site reactions from either subQ intentional ("skin pop") or unintentional injections may result in edema, cellulitis, and local ischemia.

0.2.15)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis was reported following an epinephrine overdose.

0.2.16)

A) WITH POISONING/EXPOSURE

1) Hyperglycemia has occurred following an overdose.

0.2.20)

A) Articaine hydrochloride/epinephrine, epinephrine, and phenylephrine are classified as FDA pregnancy category C. Terbutaline is classified as FDA pregnancy category B. Beta sympathomimetic drugs freely cross the placenta and may adversely affect the fetus. Maternal effects, such as hypertension, dysrhythmias, myocardial ischemia and damage, and electrolyte/fluid imbalances, may also occur following the use of beta sympathomimetics for tocolysis during pregnancy. Maternal death and serious cardiovascular events have been reported with terbutaline when used for preterm labor prophylaxis or treatment. As a result of these findings, the FDA warns against use as prophylaxis or for prolonged treatment (beyond 48 to 72 hours) of preterm labor with terbutaline. The risk of serious adverse events outweighs any potential benefit to a pregnant woman.

Laboratory Monitoring

Treatment Overview

0.4.4)

A) Ocular exposure has occasionally caused systemic manifestations including transient hypertension, palpitations, tachycardia, ventricular ectopy, chest pain and in one case a non-ST elevation myocardial infarction.
B) DECONTAMINATION: 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, the patient should be seen in a healthcare facility.

0.4.6)

A) MANAGEMENT OF MILD TO MODERATE TOXICITY

1) Accidental digital or intramuscular injections of epinephrine can usually be managed with warm soaks and compresses. Other treatments are not well studied, but injections of phentolamine, use of nitroglycerin paste, and injections of terbutaline have been reported to be successful. Vital signs should be continuously monitored in other parenteral overdoses. Hypertension without evidence of end organ dysfunction should first be treated with benzodiazepines which can reduce adrenergic tone and treat agitation. Sinus tachycardia generally does not require treatment unless there is evidence of end organ dysfunction.

B) MANAGEMENT OF SEVERE TOXICITY

1) Refractory hypertension or hypertension with evidence of end organ dysfunction should be treated with sodium nitroprusside or phentolamine. Hypotension may develop abruptly following hypertension, so a titratable agent is generally preferred. Hypotension should initially be treated with intravenous fluid boluses. If hypotension persists, a vasopressor such as dopamine or norepinephrine should be used unless they were involved in the overdose. Ventricular tachycardias can be treated with lidocaine or amiodarone, and cardioversion if hemodynamically unstable. If sinus tachycardia results in hemodynamic instability or cardiac strain, a short acting beta-blocker such as esmolol can be used, although care should be used as this may result in unopposed alpha-adrenergic stimulation.

C) DECONTAMINATION

1) PREHOSPITAL: There is no role for prehospital decontamination of a parenterally administered agent. Irrigate eyes and mucous membranes, and wash skin as appropriate.
2) HOSPITAL: There is no role for decontamination of a parenterally administered agent. Irrigate eyes and mucous membranes, and wash skin as appropriate.

D) AIRWAY MANAGEMENT

1) Patients who are comatose or with altered mental status may need orotracheal intubation and mechanical respiratory support.

E) ANTIDOTE

1) Phentolamine can be administered for intravenous extravasation of sympathomimetic agents. Doses of 5 to 10 mg of phentolamine in 10 to 15 mL of normal saline can be infiltrated into the affected area. Phentolamine has also been reportedly used successfully in accidental subcutaneous epinephrine injections that produce digit ischemia. Doses of 0.5 to 1.5 mg injected either as a digital block or into the same site of the epinephrine injection have been reported. Intra-arterial infusion of phentolamine was used in one patient after inadvertent intra-arterial administration of epinephrine, with apparent success in reversing vasospasm and ischemia.

F) ENHANCED ELIMINATION

1) Hemodialysis is generally not useful since these agents have short half-lives.

G) PATIENT DISPOSITION

1) HOME CRITERIA: Patients with accidental injections of epinephrine autoinjectors can generally be managed at home with warm soaks.
2) OBSERVATION CRITERIA: Patients that do not manifest symptoms after 4 to 6 hours can be discharged.
3) ADMISSION CRITERIA: Patients with unstable vital signs or evidence of end organ dysfunction should be admitted to an intensive care unit.
4) CONSULT CRITERIA: Consult a poison center or medical toxicologist for assistance in managing severe poisonings.

H) PITFALLS

1) When administering epinephrine therapeutically, care should be taken in distinguishing the 1:1,000 and 1:10,000 concentrations.
2) Hypertension may be followed abruptly by severe hypotension. If end organ effects necessitate treatment of severe hypertension, a short acting titratable agent is generally preferred (eg; nitroprusside or nitroglycerin).
3) Use of beta blockers may precipitate unopposed alpha effects, including accelerated hypertension and vasoconstriction.

I) PHARMACOKINETICS

1) Varies depending on the agent. The half-life of epinephrine, dobutamine, norepinephrine and dopamine is 1 to 2 minutes. Phenylephrine and isoproterenol have half-lives of approximately 2 to 3 hours, and the half-life of terbutaline is 3 to 4 hours. Onset of action of these agents is fast and is typically 1 to 10 minutes.

J) TOXICOKINETICS

1) Extravasations or subcutaneous injections may have a longer duration of action due to the local vasoconstriction.

K) DIFFERENTIAL DIAGNOSIS

1) Since these overdoses tend to occur primarily in the hospital, the diagnosis is often known. Other sympathomimetic agents including drugs of abuse such as cocaine and amphetamines may cause a similar presentation.

Range Of Toxicity

Clinical Effects

Summary Of Exposure

Vital Signs

3.3.3)

A) WITH THERAPEUTIC USE

1) FEVER has been reported with therapeutic doses of ritodrine (Hankins & Leveno, 1983).

Heent

3.4.1)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS has been seen following overdoses.

3.4.3)

A) WITH POISONING/EXPOSURE

1) MYDRIASIS: Mydriasis may be seen following overdoses (Jarvie et al, 1987) (Woodard & Brent, 1998).
2) OCULAR ABSORPTION may result in systemic effects.

a) DOPAMINE: CASE REPORT: A 32-year-old ICU nurse inadvertently splashed 1 or 2 drops of undiluted (40 mg/mL) dopamine solution into her eye. No decontamination was performed. Several minutes later, she experienced dizziness, palpitations, facial flushing, and xerostomia. An ECG revealed an SVT of 160 beats/minute with nonspecific ST-T changes and a blood pressure of 152/100 mm Hg. Symptoms resolved over the next 48 hours, and she recovered without incident (Strauss, 1985).
b) PHENYLEPHRINE: CASE REPORT: A 57-year-old man developed severe hypertension (260/120 mm Hg) and PVCs minutes after 4 drops of 10% phenylephrine were unintentionally instilled into his eye. Three hours later, he complained of chest pain. Serial electrocardiograms and enzyme quantitation revealed acute, non-Q-wave anterolateral myocardial infarction (Lai, 1989).

Cardiovascular

3.5.1)

3.5.2)

A) CARDIOVASCULAR FINDING

1) WITH THERAPEUTIC USE

a) TERBUTALINE: As of February 2011, the FDA has warned against the use of oral or injectable terbutaline in pregnant women for the prevention or prolonged treatment (beyond 48 to 72 hours) of preterm labor due to the risk of potentially serious maternal cardiac events (ie, tachycardia, cardiac dysrhythmias, myocardial infarction, hypertension and pulmonary edema) and death (US Food and Drug Administration, 2011; U.S. Food and Drug Administration, 2011).
b) OBSTETRIC USE: Serious cardiac events have been reported after prolonged administration of oral or injectable terbutaline to pregnant women (US Food and Drug Administration, 2011; U.S. Food and Drug Administration, 2011).
c) A review of postmarketing reports of adverse events submitted to the United States Food and Drug Administration Adverse Event Reporting System identified 12 maternal cases of serious cardiovascular events associated with terbutaline between January 1998 and July 2009. Events included cardiac dysrhythmias, myocardial infarction, pulmonary edema, hypertension, and tachycardia. Routes of administration of terbutaline included subQ pump (n=3) and oral terbutaline, either alone or in addition to subQ administration in outpatients (n=3) or inpatients (n=2) (U.S. Food and Drug Administration, 2011). Oral terbutaline should not be used for the treatment or prevention of preterm labor (US Food and Drug Administration, 2011; U.S. Food and Drug Administration, 2011). Terbutaline administered by injection or by continuous infusion pump should not be used beyond 48 to 72 hours and should not be used in either the outpatient or home setting (U.S. Food and Drug Administration, 2011).

B) ABNORMAL BLOOD PRESSURE

1) WITH POISONING/EXPOSURE

a) Following parenteral epinephrine overdose, there is an initial hypertension caused by peripheral alpha receptor stimulation with vasoconstriction (Carter et al, 1971).
b) During epinephrine metabolism, blood levels fall and hypotension from residual stimulation of the more sensitive beta receptors causing vasodilation appears (Hall et al, 1987; Lapostolle et al, 2002).

C) HYPERTENSIVE EPISODE

1) WITH POISONING/EXPOSURE

a) Sympathomimetics, especially epinephrine, may cause initial significant increases in blood pressure.
b) CASE REPORTS

1) DOBUTAMINE: A 47-year-old woman with urosepsis became hypertensive (BP=170/80 mmHg compared to baseline of 108/60) for 2 hours when she was inadvertently given dobutamine at a rate more than 130 mcg/kg/min for 30 minutes (Paulman et al, 1990).
2) EPINEPHRINE: An 18-year-old man with septic shock (baseline vital signs; BP 105/28 mmHg, heart rate 106 beats/min, respiratory rate 18 breaths/min) developed hypertension (BP of 250/188 mm Hg) after receiving an excess of 24 mL (10.5 mg) of epinephrine. It was found that electromagnetic interference from a cellular phone triggered the infusion pump to malfunction and deliver excess epinephrine (Hahn et al, 2005).
3) PHENYLEPHRINE: INTRAVENOUS: A 29-year-old man was inadvertently injected with 30,000 mcg of IV phenylephrine instead of 3 mg of neostigmine for residual effects of anesthesia following a cholecystectomy. Shortly after the infusion he became tachycardic and hypertensive (diastolic 150 mmHg; systolic unknown). Mechanical ventilation and sedation were maintained while he received IV infusions of nicardipine and esmolol. Within 10 minutes his arterial pressure was normal, but the tachycardia persisted. He was admitted to the ICU, and diagnosed with cardiac failure and a left ventricular ejection fraction of 30%. By day 2, the patient was transferred to a cardiac unit after being extubated. He recovered fully within 1 week (Dubost et al, 2011).
4) PHENYLEPHRINE: INTRANASAL: A 30-year-old man was undergoing minor surgery to stent a tear duct and inadvertently received 10 vials of 0.5 mL of 10% (total 500 mg) phenylephrine via a nasal pack. Shortly after exposure, his BP rose to 210/146 with a heart rate of 45 beats/min. The nasal pack was removed and labetalol was given. The patient made a complete recovery (Macmillan & Barker, 2008).

D) VENTRICULAR ARRHYTHMIA

1) WITH THERAPEUTIC USE

a) All these drugs result in cardiac stimulation and have the potential to alter rhythm function of the ventricle with ventricular extrasystoles, tachycardia, and even fibrillation (Lee, 1967; Levine & Orkin, 1981; Davis & Wax, 1999; Lapostolle et al, 2002). As a result, patients with angina can have clinical exacerbations.
b) EPINEPHRINE: CASE REPORT: Ventricular tachycardia, progressing to ventricular fibrillation, occurred during anesthesia in a 12-year-old girl following the instillation of 6 mL of 1:1000 epinephrine (240 mcg/kg) in 2 divided doses into the external auditory canal. CPR was initiated. Sinus rhythm was restored after 10 defibrillation attempts. The excess epinephrine solution was suctioned from the ear canals (Bennie & Miyamoto, 1994).

2) WITH POISONING/EXPOSURE

a) EPINEPHRINE: CASE REPORT: Shortly after a 35-year-old woman's cervix uteri was inadvertently injected with 8 mg (instead of 0.08) of epinephrine (1:1000) (instead of an 8 mL solution of 1% lidocaine HCl and 1:100,000 epinephrine), she experienced palpitations, chest pain, headache, fever, abdominal pain, hypotension (80/50 mm Hg), and sinus tachycardia (120 beats/min). She developed reversible myocardial stunning characterized by significant hemodynamic compromise (cardiogenic shock), profound, albeit transient, left ventricular systolic and diastolic dysfunction, and only modestly elevated biochemical markers of myocardial necrosis. Plasma troponin I, creatine phosphokinase myocardial band (CPK-MB) mass, amount, and CPK-MB fraction peaked within 24 hours of injection. Following intensive supportive care, which included intra-aortic balloon pump support over several days, complete reversal of myocardial systolic and diastolic LV function was noted 2 weeks after exposure (Budhwani et al, 2004).
b) EPINEPHRINE/CASE REPORT: A 5-year-old boy inadvertently received 1.75 mg epinephrine subcutaneously, instead of 0.175 mg, and developed junctional bigeminy, premature ventricular contractions, and 2 brief unsustained runs of ventricular tachycardia. One to three mm ST segment depression in leads V1 through V6 was reported on an ECG. His rhythm spontaneously converted to normal sinus rhythm 21 minutes later (Davis & Wax, 1999).

E) ATRIAL TACHYCARDIA

1) WITH POISONING/EXPOSURE

a) EPINEPHRINE/CASE REPORT: A 3-year-old boy with croup was inadvertently given 1 mg epinephrine IV push (approximately 6 times the recommended dose of 0.01 mg/kg body weight via a nebulizer) and developed sudden flushing, tachycardia (187 beats/min), worsening hypoxia (90% O2 saturation on room air) and dyspnea. He developed multifocal atrial tachycardia and an ECG showed a wandering pacemaker (p-waves with different origins and configurations). Treatment included IV furosemide and oxygen supplementation. Tachycardia resolved in about 12 hours, but a wandering pacemaker was confirmed by 24 hour Holter monitoring. The child was discharged at 48 hours with normal vital signs. At follow-up at 2, 12 and 18 months, Holter monitoring continued to show a persistent wandering atrial pacemaker with a normal ventricular rate and QRS duration; no ECG was available for comparison prior to this event (Aburawi et al, 2013).

F) BRADYCARDIA

1) WITH POISONING/EXPOSURE

a) Profound bradycardia with cyanosis has been described in a racemic-epinephrine-overdosed infant (Kurachek & Rockoff, 1985).

G) TACHYARRHYTHMIA

1) WITH POISONING/EXPOSURE

a) Sinus tachycardia is common following epinephrine overdose and was observed with dobutamine overdose (Hahn et al, 2005; Hall et al, 1987; Paulman et al, 1990; Lapostolle et al, 2002).
b) CASE REPORTS

1) EPINEPHRINE: An 18-year-old man with septic shock (baseline vital signs; BP 105/28 mmHg, heart rate 106 beats/min, respiratory rate 18 breaths/min) developed tachycardia (heart rate: 198 beats/min) after receiving an excess of 24 mL (10.5 mg) of epinephrine. It was found that electromagnetic interference from a cellular phone triggered the infusion pump to malfunction and deliver excess epinephrine (Hahn et al, 2005).
2) PHENYLEPHRINE: A 29-year-old man developed tachycardia after he was inadvertently injected with 30,000 mcg of IV phenylephrine instead of 3 mg of neostigmine for residual effects of anesthesia following a cholecystectomy. Tachycardia and hypertension developed shortly after the infusion. Mechanical ventilation and sedation were maintained while he received IV infusions of nicardipine and esmolol. Within 10 minutes his arterial pressure was normal, but the tachycardia persisted (110 beats/min). He was admitted to a cardiac unit with heart failure and bilateral pulmonary embolism and recovered fully within 1 week (Dubost et al, 2011).
3) RITODRINE: Sinus tachycardia was reported in a 22-year-old pregnant woman following administration of 200 mg ritodrine infusion over 12 hours. Acute pulmonary edema with severe hypoxia developed after Caesarean section was completed. On the following 2 days, she had an apicolateral myocardial ischemia, which spontaneously improved by the fourth day (Brosset et al, 1982).
4) TERBUTALINE: Two patients who received inadvertent 2.5 mg subQ doses of terbutaline developed tachycardia (150 beats per minute) and elevated systolic pressures (130 to 150 mmHg) persisting for 6 to 8 hours with subsequent recovery without treatment (Kaul & Stubblefield, 1980).

H) HYPOTENSIVE EPISODE

1) WITH THERAPEUTIC USE

a) TERBUTALINE: CASE REPORT: A 33-year-old, 38-week pregnant woman felt dizzy following administration of 0.25 mg terbutaline subQ. Her heart rate increased from 84 to 132 beats/minute and blood pressure fell from 130/98 mmHg to a palpable 50 mmHg. She responded to fluid replacement without compromise to the fetus. Altered hemodynamic status of the pregnancy combined with a possible lowering of systemic vascular resistance may have contributed to this effect (Margulies & Kallus, 1986).

I) ISCHEMIA

1) WITH POISONING/EXPOSURE

a) Intravenous or subQ epinephrine overdose may produce myocardial ischemia with ECG changes, precordial chest discomfort, or frank myocardial infarction, even in patients with normal coronary arteries (Novey & Meleyco, 1969; Ferry et al, 1986; Hall et al, 1987; Davis & Wax, 1999).
b) Large IV doses of epinephrine are likely to produce coronary artery spasms and may decrease coronary artery perfusion (Karch, 1989).
c) CASE REPORTS

1) EPINEPHRINE: An 18-year-old man with septic shock (baseline vital signs; BP 105/28 mmHg, heart rate 106 beats/min, respiratory rate 18 breaths/min) developed pulmonary edema, ECG changes, and myocardial damage (as evidenced by elevated cardiac enzymes) after receiving an excess of 24 mL (10.5 mg) of epinephrine. His vital signs were BP of 250/188 mm Hg, heart rate 198 beats/min, respiratory rate 60 breaths/min, and SpO2 88% on room air. It was found that electromagnetic interference from a cellular phone triggered the infusion pump to malfunction and deliver excess epinephrine (Hahn et al, 2005).
2) EPINEPHRINE: PEDIATRIC: A 5-year-old boy, unintentionally given 1.7 mg epinephrine subQ instead of 0.17 mg, developed 12 minutes of junctional bigeminy, PVCs, and brief runs of VT. Serial ECGs showed 1 to 3 mm ST segment depression in leads V1 through V6. CPK peaked at 603 IU/L with 3% CK-MB. Over the next 18 hours, ECG changes resolved (Davis & Wax, 1994; Davis & Wax, 1999).
3) PHENYLEPHRINE: INTRANASAL: A 30-year-old man was undergoing minor surgery to stent a tear duct and inadvertently received 10 vials of 0.5 mL of 10% (total 500 mg instead of 100 mg) phenylephrine via a nasal pack. Shortly after exposure, his BP rose to 210/146 with a heart rate of 45 beats/min. An ECG showed significant ST depression. The nasal pack was removed and labetalol was given. BP improved, but ST depression was observed in lateral leads and surgery was stopped. ECG changes normalized within 12 hours; cardiac enzymes and echocardiogram were normal, and work up for pheochromocytoma was negative (Macmillan & Barker, 2008).
4) TERBUTALINE: Inadvertent subQ administration of 2.5 mg terbutaline in a 35-year-old woman, 21 weeks pregnant, was followed in 10 minutes by substernal pressure, tachycardia, ST segment depressions, and inverted T waves consistent with interlateral ischemia. Cardiac effects resolved without specific treatment in 10 hours (Brandstetter & Gotz, 1980).

d) CASE SERIES

1) TERBUTALINE: PEDIATRIC: A case series of 29 children receiving IV terbutaline for the treatment of severe asthma was evaluated to examine cardiac toxicity (measured by elevations in serum cardiac troponin T (cTnT) and compare CK and CK-MB and ECG findings). Twenty patients (69%) were reported to have ischemia on ECG; however, 19 of these had ischemic findings on ECG prior to terbutaline administration. CK and CK-MB elevations and ECG ischemic changes did not correlate with cTnT elevations. It was concluded that no clinically significant cardiac toxicity resulted from intravenous terbutaline in these asthmatic children (Chiang et al, 2000).

J) MYOCARDIAL INFARCTION

1) WITH POISONING/EXPOSURE

a) EPINEPHRINE: CASE REPORT: Acute myocardial infarction resulted in a 29-year-old woman following self injection of a solution extracted from Primatene Mist inhaler. An estimated 82.5 to 124 mg of epinephrine was injected (approximately 25 times a normal dose). The woman experienced atrial fibrillation, acidemia and significant hypotension within an hour of the injection, and developed anterior myocardial infarction by the next day (Woodard & Brent, 1998).
b) EPINEPHRINE: CASE REPORT: Ventricular fibrillation, with myocardial damage (initial CK-MB of 40.3 ng/mL) and acidemia were reported in a 37-year-old man after an intentional injection of Primatene Mist (82.5 mg epinephrine). Marked hypotension requiring continuous pressor infusions were required, but the patient died 26 days after exposure (Scalzo et al, 1995).

K) HEART FAILURE

1) WITH POISONING/EXPOSURE

a) PHENYLEPHRINE: CASE REPORT: A 29-year-old man was inadvertently injected with 30,000 mcg of IV phenylephrine instead of 3 mg of neostigmine for residual effects of anesthesia following a cholecystectomy. Shortly after the infusion he became tachycardic and hypertensive. Mechanical ventilation and sedation were maintained while he received IV infusions of nicardipine and esmolol. Within 10 minutes his arterial pressure was normal, but the tachycardia persisted. He was admitted to the ICU where ultrasonography showed cardiac failure. His left ventricular ejection fraction was approximately 30%. Laboratory analysis showed a transiently elevated troponin level. On the following day he was extubated successfully. Further cardiac studies showed normal coronary arteries, but he was diagnosed with bilateral pulmonary emboli. The pathophysiology was unclear and arterial blood gases remained normal. He was anticoagulated with low molecular weight heparin and transferred to a cardiac unit for 1 week. He recovered fully (Dubost et al, 2011).

L) VASOSPASM

1) Significant vasoconstriction resulting in numbness and paleness of the left index finger occurred following subQ epinephrine autoinjection of the digit (Mol & Gaver, 1992).

M) INJECTION SITE REACTION

1) WITH POISONING/EXPOSURE

a) Arterial vasospasm, leading to poor perfusion of affected extremity, may occur following unintentional intra-arterial injection of epinephrine during resuscitation efforts (Roberts & Krisanda, 1989).
b) Sclerosis of the peripheral veins may occur following repeated injections of contaminated sympathomimetic substances. Two preferred access sites of drug abusers are the femoral vessels ("groin hit") and the great vessels of the neck ("pocket shot"). There are also other likely sites (McCarroll & Roszler, 1991).

Respiratory

3.6.1)

A) Pulmonary edema and cyanosis may occur.

3.6.2)

A) BRONCHIECTASIS

1) WITH POISONING/EXPOSURE

a) The most common desired clinical effect of all these drugs is bronchodilation.

B) ACUTE LUNG INJURY

1) WITH POISONING/EXPOSURE

a) SUMMARY

1) Pulmonary edema with rales, rhonchi, dyspnea, frothy or bloody sputum, and a typical chest x-ray picture may occur (Freedman, 1955; Novey & Meleyco, 1969; Carter et al, 1971; Kurachek & Rockoff, 1985; McCarroll & Roszler, 1991). Following an epinephrine overdose, pulmonary edema usually develops within 20 minutes (Liu et al, 1999).

b) TERBUTALINE

1) As of February 2011, the FDA has warned against the use of oral or injectable terbutaline in pregnant women for the prevention or prolonged treatment (beyond 48 to 72 hours) of preterm labor due to the risk of potentially serious maternal cardiac events (ie, tachycardia, cardiac dysrhythmias, myocardial infarction, hypertension and pulmonary edema) and death (US Food and Drug Administration, 2011; U.S. Food and Drug Administration, 2011).
2) OBSTETRIC USE: Serious cardiac events have been reported after prolonged administration of oral or injectable terbutaline to pregnant women (US Food and Drug Administration, 2011; U.S. Food and Drug Administration, 2011).
3) A review of postmarketing reports of adverse events submitted to the United States Food and Drug Administration Adverse Event Reporting System identified 12 maternal cases of serious cardiovascular events associated with terbutaline between January 1998 and July 2009. Events included cardiac dysrhythmias, myocardial infarction, pulmonary edema, hypertension, and tachycardia. Routes of administration of terbutaline included subQ pump (n=3) and oral terbutaline, either alone or in addition to subQ administration in outpatients (n=3) or inpatients (n=2) (U.S. Food and Drug Administration, 2011). Oral terbutaline should not be used for the treatment or prevention of preterm labor (US Food and Drug Administration, 2011; U.S. Food and Drug Administration, 2011). Terbutaline administered by injection or by continuous infusion pump should not be used beyond 48 to 72 hours and should not be used in either the outpatient or home setting (U.S. Food and Drug Administration, 2011).
4) The FDA has issued a warning concerning use of subcutaneous administration of terbutaline sulfate as a tocolytic agent. Complications of this therapy for prevention of preterm labor have included chest pain, tachycardia, dyspnea and pulmonary edema (Anon, 1998).

c) CASE REPORTS

1) EPINEPHRINE: In one case of an unintentional 10-fold dose increase in an epinephrine-soaked gauze placed over a large area of wound debridement, a delayed-onset (over one hour after dose) pulmonary edema occurred. The authors suggested the delayed onset was due to slow absorption of the applied drug through the damaged skin and a change that may have been related to the drug's local vasoconstrictive effect (Liu et al, 1999).
2) EPINEPHRINE: An 18-year-old man with septic shock (baseline vital signs; BP 105/28 mmHg, heart rate 106 beats/min, respiratory rate 18 breaths/min) developed pulmonary edema, ECG changes, and myocardial damage after receiving an excess of 24 mL (10.5 mg) of epinephrine. His vital signs were BP of 250/188 mm Hg, heart rate 198 beats/min, respiratory rate 60 breaths/min, and SpO2 88% on room air. It was found that electromagnetic interference from a cellular phone triggered the infusion pump to malfunction and deliver excess epinephrine (Hahn et al, 2005).

C) CYANOSIS

1) WITH POISONING/EXPOSURE

a) Cyanosis may occur in epinephrine overdose (Kurachek & Rockoff, 1985).

D) PNEUMOTHORAX

1) WITH POISONING/EXPOSURE

a) "POCKET SHOT": In patients using illicit IV drugs, such as cocaine, pocket refers to the general area of the supraclavicular fossa. Addicts gain access to the jugular, subclavian, and brachiocephalic veins through the pocket. Pneumothorax is a complication of the pocket shot. Since the lung apex is in direct proximity to the vascular structures in the pocket, pneumothorax may result when the needle deviates from its desired course (subclavian injection) (McCarroll & Roszler, 1991).

E) PULMONARY EMBOLISM

1) WITH POISONING/EXPOSURE

a) CHRONIC EXPOSURE: Illicit IV injections, especially chronic repeated ones, have resulted in septic pulmonary emboli. Necrotizing pneumonia may also occur in these patients, probably due to septic embolism or septic infarction if focal (McCarroll & Roszler, 1991).
b) PHENYLEPHRINE: CASE REPORT: A 29-year-old man was inadvertently injected with 30,000 mcg of IV phenylephrine instead of 3 mg of neostigmine for residual effects of anesthesia following a cholecystectomy. Shortly after the infusion, hypertension and tachycardia developed. Mechanical ventilation and sedation were maintained after the surgery while he was treated with IV nicardipine and esmolol. He was admitted to ICU for the night and diagnosed with cardiac failure. The following day he was extubated. Further cardiac studies were normal, but diagnosed with bilateral pulmonary emboli. Pathophysiology was unclear and arterial blood gases remained within normal limits. He was anticoagulated with low molecular weight heparin and transferred to a cardiac unit for 1 week. He recovered fully (Dubost et al, 2011).

Neurologic

3.7.1)

A) WITH POISONING/EXPOSURE

1) Anxiety, diaphoresis, palpitations, tremor, and numbness and tingling of the extremities may occur.

3.7.2)

A) ANXIETY

1) WITH POISONING/EXPOSURE

a) Anxiety, nervousness, palpitations, and numbness of hands and feet are common minor side effects of all these drugs, and are often seen in epinephrine overdose (Freedman, 1955; Hall et al, 1987; Paulman et al, 1990).

B) TREMOR

1) WITH POISONING/EXPOSURE

a) Tremors, which are believed to be due to a peripheral and not a central effect, have been particularly marked with terbutaline (Hall et al, 1987; Paulman et al, 1990) and have been reported following epinephrine overdose (Lapostolle et al, 2002).

C) INSOMNIA

1) WITH POISONING/EXPOSURE

a) Insomnia may also be noted following overdoses of parenteral sympathomimetics (Hall et al, 1987).

D) HEADACHE

1) WITH POISONING/EXPOSURE

a) Headache has been reported following epinephrine overdose (Hahn et al, 2005; Freedman, 1955).

Gastrointestinal

3.8.1)

A) WITH POISONING/EXPOSURE

1) Nausea, vomiting, and abdominal pain may occur in overdose.

3.8.2)

A) GASTRITIS

1) WITH POISONING/EXPOSURE

a) Nausea, vomiting, and abdominal pain are common following an epinephrine overdose (Hahn et al, 2005; Freedman, 1955; Levine & Orkin, 1981).
b) Anorexia may also occur following overdoses.
c) DOBUTAMINE: CASE REPORT: Vomiting occurred twice when a 47-year-old woman with urosepsis was inadvertently given dobutamine at a rate more than 130 mcg/kg/min for 30 minutes (Paulman et al, 1990).

Genitourinary

3.10.1)

A) WITH POISONING/EXPOSURE

1) Urinary incontinence has been reported with overdose.
2) Acute renal failure following an overdose of epinephrine has also been reported.

3.10.2)

A) URINARY INCONTINENCE

1) WITH POISONING/EXPOSURE

a) DOBUTAMINE: CASE REPORT: Urinary incontinence was noted in a 47-year-old woman with urosepsis who inadvertently received dobutamine at a rate more than 130 mcg/kg/min for 30 minutes (Paulman et al, 1990).

B) ACUTE RENAL FAILURE SYNDROME

1) WITH POISONING/EXPOSURE

a) EPINEPHRINE: CASE REPORT: Acute renal failure, accompanied by anterior myocardial infarction and atrial fibrillation, has been reported in a 29-year-old woman following self injection of Primatene Mist inhalant (82.5 to 124 mg epinephrine). Peak serum creatinine and BUN were reported to be 14.2 mg/dL and 105 mg/dL, respectively, and decreased to 7.5 mg/dL and 85 mg/dL, respectively, within 24 hours without dialysis (Woodard & Brent, 1998).

Acid-Base

3.11.1)

A) Acidemia and lactic acidosis have been reported.

3.11.2)

A) ACIDOSIS

1) CASE REPORT: One case of lactic acidosis has been reported following intravenous epinephrine overdose (Kolendorf & Moller, 1974).
2) CASE REPORT: A case of metabolic acidosis was reported in an infant who inadvertently received an IV injection of racemic epinephrine. Therapy with sodium bicarbonate reversed the acidemia (Kurachek & Rockoff, 1985).
3) CASE REPORT: Metabolic acidosis (blood pH, 6.83) was reported in a 29-year-old woman after an intentional intravenous overdose of epinephrine, from Primatene Mist inhalant, of 82.5 to 124 mg (Woodard & Brent, 1998).

Dermatologic

3.14.1)

A) WITH POISONING/EXPOSURE

3.14.2)

A) PALE COMPLEXION

1) WITH POISONING/EXPOSURE

a) Pallor is common following an epinephrine overdose (Hall et al, 1987).

B) EXCESSIVE SWEATING

1) WITH POISONING/EXPOSURE

a) Diaphoresis has been described following an epinephrine overdose (Hall et al, 1987).

C) ERUPTION

1) WITH THERAPEUTIC USE

a) Palmar and plantar erythema have been reported following therapeutic infusions of salbutamol in pregnant women during premature labor (Reygagne et al, 1991).

D) INJECTION SITE REACTION

1) WITH POISONING/EXPOSURE

a) "SKIN POP": Illicit subQ ("skin pop") drug injection injuries may result in abscess formation at the injection site, as well as injection site cellulitis, lymphangitis, or lymphadenopathy. Local ischemia induced by vasoconstriction from these agents may occur. Other effects of illicit subQ injections may include suppurative tenosynovitis, joint space infections, osteomyelitis, gangrene, and bacteremia (Thomas et al, 1995).
b) Unintentional digit injections of epinephrine, often from autoinjector devices, have resulted in intense vasoconstriction leading to tissue ischemia, sometimes irreversible. Rapid onset of local symptoms including pallor, loss of sensation and function, pain and swelling develops (Barkhordarian et al, 2000).
c) CASE SERIES

1) Twenty-eight epinephrine autoinjector exposures were presented, with most of the cases involving injection into digits. Symptoms included swelling, pallor, pain and erythema. Only 6 cases required medical treatment in the emergency department, although 14 patients went to the hospital, 14 other patients were treated at home (Mrvos et al, 2002).

E) EXTRAVASATION INJURY

1) WITH THERAPEUTIC USE

a) Ischemic necrosis secondary to local vasoconstriction can result from extravasation of sympathomimetic agents including dobutamine, dopamine, epinephrine, metaraminol and norepinephrine (Schummer et al, 2005; Brown et al, 1979; Gaze, 1978; Greenlaw & Null, 1977; Heckler, 1989; Hoff et al, 1979; Upton et al, 1979; Weeks, 1966).

Musculoskeletal

3.15.1)

A) WITH POISONING/EXPOSURE

1) Rhabdomyolysis was reported following an epinephrine overdose.

3.15.2)

A) RHABDOMYOLYSIS

1) WITH POISONING/EXPOSURE

a) EPINEPHRINE: CASE REPORT: Rhabdomyolysis (peak CK of 9,646 IU/L, peak creatinine of 3.6 mg/dL) has been reported in a 37-year-old man following the intentional injection of Primatene Mist inhalant containing 82.5 mg epinephrine. The patient died 26 days postexposure after remaining in a persistent vegetative state (Scalzo et al, 1995).
b) EPINEPHRINE: CASE REPORT: A 4-day-old (2400-g) infant developed hypokalemia (potassium 2.2 mEq/L), rhabdomyolysis (peak CPK 4124 Units/L; with 100% CPK-MM isoenzymes), and transient oliguria after receiving epinephrine at 100 times the usual dose (2 mg of epinephrine 1:1000 [1 mg/mL] into a peripheral IV line). She was treated with an infusion of potassium chloride 2 mEq/kg/day over 80 hours. Following supportive therapy, she was extubated on the 9th day of life and was discharged on day 22 (Fang et al, 2005).

B) INCREASED MUSCLE TONE

1) WITH POISONING/EXPOSURE

a) EPINEPHRINE: CASE SERIES: Seven cases of transient, painless contraction of the muscles of the lower extremities (or limb rigidity) have been described following the intrathecal administration of 10 mcg sufentanil and 200 mcg epinephrine. The effect was present within 2 minutes after drug administration, thus not likely a central opioid effect. The authors suggested a reaction mediated by the alpha1-adrenoreceptor system due to epinephrine (Newman et al, 1994).

Endocrine

3.16.1)

A) WITH POISONING/EXPOSURE

1) Hyperglycemia has occurred following an overdose.

3.16.2)

A) HYPERGLYCEMIA

1) WITH POISONING/EXPOSURE

a) Mild elevations in blood sugar have occurred following a parenteral epinephrine overdose (Hall et al, 1987).

B) DIABETES INSIPIDUS

1) WITH THERAPEUTIC USE

a) DOPAMINE: CASE REPORT: An 18-year-old woman developed a nephrogenic diabetes insipidus-like syndrome following the administration of dopamine (12 mcg/kg/min) to maintain blood pressure following a barbiturate-induced coma to control status epilepticus. Polyuria (8 L/day) and urine hypo-osmolarity (urine osmolarity 52 mosm/L, urine sodium 11 mmol/L) occurred, with free water excretion greater than 7 L/day. Within an hour of replacing dopamine infusion with norepinephrine, urine output decreased to less than 100 mL/hr (Oppenheim et al, 1999).

Reproductive

3.20.1)

3.20.2)

A) LACK OF INFORMATION

1) EPINEPHRINE

a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info ADRENACLICK(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN Jr(R) intramuscular injection, subcutaneous injection, 2014).

2) PHENYLEPHRINE

a) At the time of this review, no data were available to assess the teratogenic potential of this agent (Prod Info VAZCULEP intravenous injection, 2014).

B) LACK OF EFFECT

1) In studies of albuterol, bitolterol, metaproterenol, pirbuterol, and terbutaline used during pregnancy, no adverse effects were observed with regard to rates of congenital malformation (Tan & Thomson, 2000; Anon, 2000).
2) TERBUTALINE

a) No adverse growth or developmental effects of terbutaline were observed among 21 eighteen-month-old infants exposed to tocolytic therapy with terbutaline (Karlsson et al, 1980). Terbutaline in tocolysis also decreases the incidence of neonatal respiratory distress (Bergman & Hedner, 1978). This effect has also been demonstrated in a randomized, placebo-controlled double-blind study (Hallak et al, 1992).

C) ANIMAL STUDIES

1) EPINEPHRINE

a) Epinephrine was teratogenic in rabbits at approximately 30 times the maximum recommended daily subQ or IM dose (on a mg/m(2) basis at a maternal dose of 1.2 mg/kg/day for 2 to 3 days), in mice at approximately 7 times the maximum recommended daily subQ or IM dose (on a mg/m(2) basis at a maternal dose of 1 mg/kg/day for 10 days), and in hamsters at approximately 5 times the maximum recommended daily subQ or IM dose (on a mg/m(2) basis at a maternal dose of .5 mg/kg/day for 4 days). There was no teratogenic effects in mice at approximately 3 times the maximum recommended daily subQ or IM dose (on a mg/m(2) basis at a maternal dose of .5 mg/kg/day for 10 days) (Prod Info ADRENACLICK(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN Jr(R) intramuscular injection, subcutaneous injection, 2014).

2) PHENYLEPHRINE

a) Potential teratogenic effects (1 incidence of clubbed feet, partial development of the intestine) were observed in normotensive pregnant rabbits administered subQ doses of 0.33 mg/kg 3 times daily (approximately 1.9-fold the total daily human dose) during gestation (Prod Info VAZCULEP intravenous injection, 2014).

3.20.3)

A) LACK OF INFORMATION

1) EPINEPHRINE

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info ADRENACLICK(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN Jr(R) intramuscular injection, subcutaneous injection, 2014).

2) PHENYLEPHRINE

a) At the time of this review, no data were available to assess the potential effects of exposure to this agent during pregnancy in humans (Prod Info VAZCULEP intravenous injection, 2014).

B) PREGNANCY CATEGORY

1) ARTICAINE HYDROCHLORIDE/EPINEPHRINE is classified as FDA pregnancy category C (Prod Info Septocaine(R) Solution for intraoral submucosal injection, 2009).
2) EPINEPHRINE is classified as FDA pregnancy category C (Prod Info ADRENACLICK(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN Jr(R) intramuscular injection, subcutaneous injection, 2014).
3) PHENYLEPHRINE is classified as FDA pregnancy category C (Prod Info VAZCULEP intravenous injection, 2014).
4) TERBUTALINE is classified as FDA pregnancy category B (Prod Info terbutaline sulfate injection, 2004). NOTE: See FDA warning below of potential maternal risk of terbutaline use for preterm labor (U.S. Food and Drug Administration, 2011).

C) PLACENTAL BARRIER

1) PRETERM LABOR PROPHYLAXIS OR TREATMENT

a) Beta sympathomimetic drugs freely cross the placenta. When used during pregnancy for tocolysis, they have been implicated in causing adverse effects on the fetus including (Katz & Seeds, 1989; Brosset et al, 1982; Hermansen & Johnson, 1984; Lenke & Trupin, 1984; Nuchpuckdee et al, 1986):

1) Heart rate and rhythm disturbances, stillbirth, hydrops, myocardial ischemia and infarction, neonatal cardiac failure, and neonatal death.
2) Interventricular septal thickness changes have been documented in babies exposed to these agents in utero.
3) While these complications are not common, they add enough potential risk such that the therapeutic use of these agents during pregnancy should be carefully weighed.

b) TERBUTALINE

1) FDA WARNING (TERBUTALINE AND PRETERM LABOR): Based on data collected from the Adverse Event Reporting System between 1976 and 2009, the United States Food and Drug Administration (FDA) has identified reports of 16 maternal deaths along with 12 maternal cases in which there was an association between terbutaline use and serious maternal cardiovascular effects. Cardiovascular adverse events included cardiac arrhythmias, myocardial infarction, pulmonary edema, hypertension, and tachycardia. Among the 16 maternal death cases, terbutaline was administered by subQ pump on an outpatient basis in 3 cases and oral alone or in addition to subQ in 9 cases. Of these 9 cases, oral terbutaline was used on an outpatient basis in 2 cases and on an inpatient basis in 7 cases. In the remaining 4 cases, the route of terbutaline administration was subQ, IV, or unknown. Among the 12 cases of serious cardiovascular effects, terbutaline was administered by subQ pump in 3 cases and oral alone or in addition to subQ in 5 cases. Of these 5 cases, oral terbutaline was used on an outpatient basis in 3 cases and on an inpatient basis in 2 cases. As a result of these findings, the FDA warns against use as prophylaxis or for prolonged treatment (beyond 48 to 72 hours) of preterm labor with parenteral terbutaline. In addition, the FDA warns against acute or prolonged oral terbutaline therapy for the prevention or treatment of preterm labor (unapproved use). The risk of serious adverse events outweighs any potential benefit to a pregnant woman (U.S. Food and Drug Administration, 2011).
2) Transient fetal tachycardia or hypoglycemia can occur when terbutaline is administered for tocolysis, and fetal plasma levels have ranged up to 55% of maternal levels following a single IV dose within 90 minutes of delivery, suggesting rapid placental transfer (Cotton & Strassner HT Hill, 1984; Ingemarsson, 1976). The most serious adverse fetal effects have been associated with continuous infusions of terbutaline (Benedetti, 1983).
3) Sudden fetal death 5 hours following initiation of IV terbutaline for preterm labor was reported (Lenke & Trupin, 1984). Uterine, placental, and fetal anomalies were ruled out as contributing to the death. Myocardial necrosis consistent with catecholamine excess culminating in neonatal congestive heart failure was reported in a 37-week-old fetus after exposure to a 12-week course of subcutaneous terbutaline therapy (Fletcher et al, 1991a). Myocardial necrosis following terbutaline tocolysis was also reported by others (Thorkelsson & Loughead, 1991), but the association between these events and terbutaline has been disputed (Bey et al, 1992; Kast & Hermer, 1993).

D) NEONATAL MORTALITY

1) Postnatal effects and long-term sequelae in infants exposed prenatally to betamimetic tocolytics are reported. Hyaline membrane disease (HMD) incidence was similar in both treated and untreated infants at each gestational age. Neonatal (30 day) mortality ranged from 2.5% to 16% in 5 series; two series using matched control groups reported both higher (16% vs 6%) and lower (2.5% vs 10%) mortality in the treated infants. Mortality rates at 18 and 24 months were reported as 7% (5 of 79) and 2% (1 of 55) in 2 series. Sudden infant death was noted in 2 of 79 patients in one series only. Psychomotor disturbances were reported in 2 series (3 of 79 patients at 18 months follow-up and 3 of 54 at 24 months follow up). In the immediate postpartum period, preterm infants exposed to betamimetics may show hypoglycemia (10% to 20%). EKG changes and hypotension may also be more prominent and warrant monitoring. Postmortem examinations in 8 infants revealed no myocardial lipid necrosis attributable to antenatal beta agonist treatment (Svenningsen, 1982).

E) SYSTEMIC EFFECTS

1) Maternal effects following the use of beta sympathomimetics for tocolysis during pregnancy have included hypertension, dysrhythmias, myocardial ischemia and damage, and electrolyte/fluid imbalances (Bendetti, 1983; Katz & Seeds, 1989).

F) MYOCARDIAL ISCHEMIA

1) Myocardial necrosis was seen in a newborn whose mother had used subcutaneous terbutaline infusion for labor suppression. No sequelae were seen at 1 month of age (Fletcher et al, 1991).

G) PULMONARY EDEMA

1) The intravenous use of beta-2 agonists has been associated with pulmonary edema, and should be used with caution during pregnancy (Tan & Thomson, 2000).

H) ERYTHROPOIETIN INCREASED

1) In one study, there were increased erythropoietin levels in newborn infants whose mothers had been administered intravenous infusions of sympathomimetic tocolytic drugs. The authors speculate that decreased fetal oxygenation as a result of the tocolysis stimulates fetal erythropoietin production (Rouse et al, 1993).

I) LACK OF EFFECT

1) In studies of albuterol, bitolterol, metaproterenol, pirbuterol, and terbutaline used during pregnancy, no adverse effects were observed with regard to rates of perinatal mortality, low birth weight, or complications of labor and delivery (Tan & Thomson, 2000; Anon, 2000).

J) ANIMAL STUDIES

1) PHENYLEPHRINE

a) Early onset labor, increased fetal lethality, and adverse placental effects were observed in normotensive pregnant rabbits administered subQ doses of 0.33 mg/kg 3 times daily (approximately 1.9-fold the total daily human dose) during gestation. Decreased uterine blood flow and decreased PaO2 in the fetus were observed in normotensive pregnant sheep administered IV phenylephrine at doses of 4 mcg/kg/min for 30 minutes (1.1 to 1.2 times the human bolus dose based on body surface area) during late gestation (Prod Info VAZCULEP intravenous injection, 2014).

3.20.4)

A) LACK OF INFORMATION

1) EPINEPHRINE

a) At the time of this review, no data were available to asses the potential effects of exposure to this agent during lactation in humans (Prod Info ADRENACLICK(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN Jr(R) intramuscular injection, subcutaneous injection, 2014).

2) PHENYLEPHRINE

a) At the time of this review, no data were available to asses the potential effects of exposure to this agent during lactation in humans (Prod Info VAZCULEP intravenous injection, 2014).

B) BREAST MILK

1) TERBUTALINE

a) Breast milk levels of terbutaline were the same as maternal plasma levels in two patients, with peak milk concentrations found 4 hours after terbutaline ingestion (Lonnerholm & Lindstrom, 1982), although milk levels may fluctuate less than plasma levels during a dosing interval. Using a mean milk level of 3.2 ng/mL and daily ingestion of 125 to 150 mL breast milk/kg, the authors calculated an infant dose not exceeding 0.5 mcg/kg (0.2% of the maternal dose). Therefore, the authors conclude nursing need not be interrupted. Another source calculated distribution of 0.7% of the maternal dose into breast milk (Boreus et al, 1982).
b) In four nursing mothers receiving oral terbutaline 2.5 or 5 mg 3 times daily, blood and milk samples were taken for 8 hours after the morning dose of terbutaline. The highest milk to plasma ratio was 2.9 with breast milk concentrations ranging from 2.5 to 4.6 ng/mL. No terbutaline was detected in infant plasma (Lindberg et al, 1984).

3.20.5)

A) LACK OF INFORMATION

1) EPINEPHRINE

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info ADRENACLICK(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN(R) intramuscular injection, subcutaneous injection, 2014; Prod Info EPIPEN Jr(R) intramuscular injection, subcutaneous injection, 2014).

2) PHENYLEPHRINE

a) At the time of this review, no data were available to assess the potential effects on fertility from exposure to this agent (Prod Info VAZCULEP intravenous injection, 2014).

B) ANIMAL STUDIES

1) TERBUTALINE

a) RATS: There was no impairment of fertility when rats were given oral doses of terbutaline up to 50 mg/kg (approximately 810 times the maximum recommended daily subQ dose for adults on a mg/m(2) basis) (Prod Info terbutaline sulfate injection, 2004).

Laboratory Monitoring

Monitoring Parameters Levels

4.1.1)

A) Drug levels are not clinically useful.
B) Monitor vital signs frequently.
C) Monitor serum electrolytes.
D) Obtain cardiac enzymes for patients with chest pain.
E) Obtain serial ECGs and institute continuous cardiac monitoring.
F) Obtain a chest x-ray if there are signs or symptoms of pulmonary edema.

4.1.2)

A) BLOOD/SERUM CHEMISTRY

1) Hypokalemia and hyperglycemia may occur following epinephrine overdose (Hall et al, 1987). Monitor serum electrolytes and glucose.

B) EXOGENOUS VS ENDOGENOUS EPINEPHRINE

1) The ratio of plasma epinephrine metabolites (metanephrine, MET; normetanephrine, NMET) may be useful to distinguish between exogenous and endogenous epinephrine administration (Yaworsky et al, 2005).

a) In a controlled animal study, 3 different protocols (group 1, the physiologic stress group; group 2, the sub-lethal dose group; group 3; the lethal dose group) were used in rabbits. Group 1 rabbits (n=8) were immobilized for 30 minutes in a restraining tube. Group 2 anesthetized rabbits (n=9) were injected 0.01 mg/kg of epinephrine. Group 3 anesthetized rabbits (n=8) were injected 1.0 mg/kg of epinephrine. Serum cortisol and plasma MET and NMET were measured at regular intervals for up to 480 minutes. In group 1 animals (the endogenous stress model), serum cortisol and plasma MET and NMET levels increased during immobilization. In the group 2 animals (the sub-lethal dose group), plasma MET increased but plasma NMET decreased. In this group, the peak plasma MET levels were similar to the levels observed in group 1; however, the ratio of plasma MET to NMET was significantly different. In group 3 (the lethal dose group), both the plasma MET levels and ratio of metabolites were significantly greater than those observed in the stressed animals (Yaworsky et al, 2005).

4.1.4)

A) OTHER

1) MONITORING

a) Monitor ECG and blood pressure.
b) Monitor chest x-ray and arterial blood gases in patients with pulmonary edema.

Radiographic Studies

1) Obtain a chest x-ray in patients with severe respiratory or CNS depression.

Methods

1) Identification in biological fluids is not readily available.
2) Urine screen by thin layer chromatography is available in some labs for qualitative identification.
3) The enzyme-multiplied-immunoassay technique (EMIT) that is used in the drug analysis laboratory does not differentiate between amphetamine and phenylpropanolamine.
4) Thin layer chromatography followed by gas chromatography can differentiate between amphetamine and phenylpropanolamine (Mueller, 1983).
5) Salbutamol and terbutaline plasma concentration has been determined by ion-pair high-performance liquid chromatography with amperometric detection (Jarvie et al, 1987).
6) Phenylpropanolamine (d,l-norephedrine) and its diastereomer d-norpseudoephedrine are indistinguishable on the Toxilab TLC system. The drugs differ pharmacologically and therapeutically (Gal & Lichtenstein, 1987).

Treatment

Life Support

Patient Disposition

6.3.2)

6.3.2.1) ADMISSION CRITERIA/PARENTERAL

A) Patients with unstable vital signs or evidence of end organ dysfunction should be admitted to an intensive care unit.
B) All patients with parenteral sympathomimetic overdose require evaluation and observation for development of hypertension, hypotension, serious cardiac arrhythmias, and pulmonary edema. Patients who are asymptomatic with normal vital signs and ECG after 4 to 6 hours of observation can be discharged with appropriate follow up.
C) Patients should be admitted to an intensive care unit, particularly if complaints of chest pain or dyspnea are present.

6.3.2.2) HOME CRITERIA/PARENTERAL

A) Patients with accidental injections of epinephrine autoinjectors can generally be managed at home with warm soaks.

6.3.2.3) CONSULT CRITERIA/PARENTERAL

A) Consult a poison center or medical toxicologist for assistance in managing severe poisonings.

6.3.2.5) OBSERVATION CRITERIA/PARENTERAL

A) Patients that do not manifest symptoms after 4 to 6 hours can be discharged.

Monitoring

Oral Exposure

6.5.1)

A) There is no role for prehospital decontamination of a parenterally administered agent. Irrigate eyes and mucous membranes, and wash skin as appropriate.

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) OCULAR ABSORPTION

1) Systemic symptoms have occurred following ocular exposure to undiluted parenteral dopamine solution (Strauss, 1985); ocular exposures should be treated as parenteral exposures.

Abstracts

Case Reports

1) EPINEPHRINE: A 13-month-old child was inadvertently given 0.25 mL of 2.25% racemic epinephrine IV during treatment for croup. Tachycardia occurred, but was rapidly followed by profound bradycardia and pulselessness. Cardiopulmonary resuscitation and administration of atropine, calcium chloride, sodium bicarbonate, and 1:10,000 epinephrine resulted in adequate blood pressure and perfusion. Metabolic acidosis and pulmonary edema developed, but the child recovered fully (Kurachek & Rockoff, 1985).
2) EPINEPHRINE: Renal failure and tachyarrhythmias were reported in a 2 kg newborn of 34 weeks' gestation who accidentally received 1 to 2 mL of 0.25% racemic epinephrine for inhalation via an umbilical artery catheter. Anuria persisted for 20 hours, and oliguria for 12 hours. She eventually recovered with no lasting sequelae. The authors suggested intense constriction of the renal vascular bed as the mechanism of renal failure (Levine et al, 1985).

1) DOBUTAMINE: A 47-year-old woman with urosepsis presented with hypertension, tachycardia, tachypnea, jitteriness, palpitations, chest pains, paresthesia, vomiting, and urinary incontinence when she was inadvertently given dobutamine at a rate more than 130 mcg/kg/min for 30 minutes. Her symptoms resolved after 2 hours but there was no mention of therapy given (Paulman et al, 1990).
2) DOPAMINE: A 32-year-old ICU nurse inadvertently splashed 1 or 2 drops of undiluted (40 mg/mL) dopamine solution into her eye. No decontamination was performed. Several minutes later, she experienced dizziness, palpitations, facial flushing, and xerostomia. An ECG revealed an SVT of 160 beats/minute with nonspecific ST-T changes and a blood pressure of 152/100 mm Hg. Symptoms resolved over the next 48 hours, and she recovered without incident (Strauss, 1985).
3) EPINEPHRINE: A 19-year-old man developed palpitations, precordial chest tightness, pallor, diaphoresis, headache, and numbness and tingling of the hands and feet after self-injecting about 1.1 mg of epinephrine IV. After being given a sublingual nitroglycerin tablet by a bystander, a syncopal episode occurred. Hypotension, mental confusion, mild hypokalemia and hyperglycemia, and depressed ST segments in the precordial leads of the ECG were noted. Cardiac enzymes remained normal, and clearing of most of the ECG changes occurred over the following 19 hours, although mild hypotension was still present. Treatment was supportive with careful cardiac and vital sign monitoring and IV fluid boluses (Hall et al, 1987).
4) EPINEPHRINE: A 37-year-old man experienced diaphoresis, chest pain, vomiting and collapsed after injecting 15 mL of Primatene Mist (82.5 mg epinephrine). Following CPR, he was found to be in ventricular fibrillation. Pupils were dilated and unresponsive, with intact corneal reflexes. Myocardial damage, with initial CK-MB of 40.3 ng/mL, LDH5 isoenzymes of 48% with peak LDH of 4192 IU/L on day 2, and ST elevation in anterior ECG leads, was reported. Marked hypotension followed, requiring continuous pressor infusions. Rhabdomyolysis with peak CK of 9646 International Units/L developed. The patient expired 26 days postexposure (Scalzo et al, 1995).
5) PHENYLEPHRINE: A 57-year-old man developed severe hypertension (260/120 mm Hg) and PVCs minutes after 4 drops of 10% phenylephrine were inadvertently instilled into his eye. Three hours later, he complained of chest pain. Serial electrocardiograms and enzyme quantitation revealed acute, non-Q-wave anterolateral myocardial infarction (Lai, 1989).
6) ISOPROTERENOL: A 45-year-old man was accidentally given 2.5 mg isoproterenol instead of diazepam via IV bolus. Within 30 seconds, his heart rate increased to 190 beats/minute, and a blood pressure was unobtainable. The patient complained of palpitations, faintness, and angina. A supraventricular tachyarrhythmia was diagnosed, and cardioversion was attempted, but was unsuccessful. Reevaluation showed the arrhythmia to be sinus tachycardia. Propranolol 1 mg IV and a fluid bolus were given. Within 2 minutes his heart rate had fallen to 90 beats/minute, and systolic blood pressure rose to 90 mm Hg. No complications developed, and the patient recovered uneventfully (Kosolcharoen et al, 1981).

Range Of Toxicity

Summary

Therapeutic Dose

7.2.1)

A) SPECIFIC SUBSTANCE

1) DOBUTAMINE

a) DOBUTAMINE: The rate usually needed to increase cardiac output usually ranges from 2.5 to 15 mcg/kg/min. Infusion rates up to 40 mcg/kg/min have rarely been required to obtain the desired effect (Prod Info dobutamine injection, 2005).

2) DOPAMINE

a) DOPAMINE: An initial IV infusion rate of 2 to 5 mcg/kg/min; usual rates are up to 20 to 50 mcg/kg/min. If rates exceed 50 mcg/kg/min, it is suggested that urine output be checked frequently (Prod Info dopamine hcl, 5% dextrose injection, 2003).

3) EPINEPHRINE

a) ANAPHYLAXIS

1) AUTOINJECTOR (30 kg and greater): The recommended dose is 0.3 mg; may be repeated if severe anaphylaxis persists (Prod Info EPIPEN(R) intramuscular injection, subcutaneous injection, 2014; Prod Info ADRENACLICK(R) intramuscular injection, subcutaneous injection, 2014).

b) CARDIOPULMONARY RESUSCITATION

1) The recommended dose in cardiac arrest is 0.5 to 1.0 mg (5 to 10 mL of 1:10,000 solution) may be given. During a resuscitation effort, the recommended dose is 0.5 mg (5 mL); should be administered IV every 5 minutes (Prod Info epinephrine IV injection, intracardiac, endotracheal, 2005).

4) ETHYLNOREPINEPHRINE

a) ETHYLNOREPINEPHRINE: A subQ or IM dose of 1 to 2 mg is recommended for bronchodilator action (Prod Info Bronkephrine(R), ethylnorepinephrine, 1995).

5) ISOPROTERENOL HYDROCHLORIDE

a) BRADYCARDIA

1) The recommended dosage for the treatment of symptomatic bradycardia, unresponsive to atropine, is isoproterenol 2 to 10 mcg/min IV and titrate to heart rate and rhythm response (Neumar et al, 2010).

b) ADAMS-STOKES SYNDROME

1) The recommended initial adult dose of isoproterenol for serious attacks of Adams-Stokes syndrome is 0.02 mg to 0.06 mg IV bolus, followed by 0.01 mg to 0.2 mg IV bolus depending on response. The recommended initial infusion rate is 5 mcg/min and titrate to response (Prod Info ISUPREL(R) IV injection, 2004).
2) The recommended initial adult dose of isoproterenol for serious attacks of Adams-Stokes syndrome is 0.2 mg subQ, followed by 0.15 to 0.2 mg subQ, depending on response (Prod Info ISUPREL(R) IV injection, 2004).
3) The recommended initial intracardiac adult dose of isoproterenol for serious attacks of Adams-Stokes syndrome is 0.02 mg (Prod Info ISUPREL(R) IV injection, 2004).

6) METARAMINOL BITARTRATE

a) An IM or subQ dose of 2 to 10 mg may be given for hypotensive emergencies. An intravenous bolus of 0.5 to 5 mg may be given. An IV infusion of 15 to 100 mg in 500 mL in an IV solution may be infused at a rate to maintain adequate blood pressure control (Prod Info Aramine(R), metaraminol bitartrate, 1995).

7) NOREPINEPHRINE

a) HYPOTENSION: The initial dose of norepinephrine is 8 to 12 mcg of base/minute via intravenous infusion. Adjust rate of flow to establish and maintain a low normal blood pressure (usually 80 to 100 mmHg systolic). The usual maintenance dose ranges from 2 to 4 mcg of base per minute. Daily doses as high as 68 mg base may be necessary (Prod Info norepinephrine bitartrate injection, 2005).

1) In previously hypertensive patients, blood pressure should be raised no higher than 40 mmHg below the preexisting systolic pressure (Prod Info norepinephrine bitartrate injection, 2005).

8) PHENYLEPHRINE

a) INJECTION 10 MG/ML

1) HYPOTENSION DURING ANESTHESIA

a) BOLUS: The recommended dose is 40 to 100 mcg administered by IV bolus. Additional boluses may be administered every 1 to 2 minutes as needed. MAX dose: 200 mcg (Prod Info VAZCULEP intravenous injection, 2014).
b) CONTINUOUS INFUSION: Initiate continuous IV infusion at a rate of 10 to 35 mcg/min. MAX dose: 200 mcg/min (Prod Info VAZCULEP intravenous injection, 2014).

b) INJECTION 1%

1) HYPOTENSION

a) MILD TO MODERATE: 0.2 mg IV; dose range, 0.1 mg to 0.5 mg; initial dose not to exceed 0.5 mg; do not repeat dose more often than every 10 to 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
b) MILD TO MODERATE: 2 to 5 mg SUBQ or IM; dose range, 1 to 10 mg; initial dose not to exceed 5 mg (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
c) SEVERE: INITIAL: 100 to 180 mcg/min continuous IV infusion; once blood pressure is stabilized, decrease rate to 40 to 60 mcg/min to maintain blood pressure (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
d) HYPOTENSION PROPHYLAXIS DURING SPINAL ANESTHESIA: 2 to 3 mg SUBQ or IM 3 to 4 min before injection of spinal anesthetic (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
e) HYPOTENSION EMERGENCY DURING SPINAL ANESTHESIA: 0.2 mg IV; subsequent doses should not exceed previous dose by more than 0.1 mg to 0.2 mg; MAX dose, 0.5 mg (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).

2) PAROXYSMAL SUPRAVENTRICULAR TACHYCARDIA

a) Rapid IV injection is recommended (within 20 to 30 seconds) with an initial dose not exceeding 0.5 mg. Subsequent doses should not exceed the initial dose by more than 0.1 to 0.2 mg. MAX dose: 1 mg (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).

9) TERBUTALINE

a) As a bronchodilator, terbutaline may be given in a subcutaneous dose of 0.25 milligrams, with a second dose repeated in 15 to 30 minutes as needed. The total dose should not exceed 0.5 milligrams in 4 hours as a bronchodilator (Prod Info terbutaline sulfate injection, 2004).

1) As a tocolytic agent, terbutaline has been given as a continuous subcutaneous infusion with a maximum basal rate of 0.1 milligram/hour (Sala & Moise, 1990).
2) A continuous intravenous syringe pump has been successfully used with a 3 milliliter syringe for subcutaneous terbutaline tocolytic therapy. Continuous subcutaneous doses are 50 to 100 micrograms/hour with bolus doses of 250 micrograms/dose to control breakthrough periods of increased uterine contractility (Adkins et al, 1993).

7.2.2)

A) SPECIFIC SUBSTANCE

1) DOBUTAMINE

a) DOBUTAMINE: 2 to 20 mcg/kg/minute IV infusion. Begin at a low dose and titrate by monitoring effects (Kleinman et al, 2010; Brierley et al, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Bhatt-Mehta & Nahata, 1989). May also be given by IO route if IV access unavailable (Kleinman et al, 2010).

2) DOPAMINE

a) DOPAMINE: 2 to 20 mcg/kg/minute continuous IV infusion. Begin at a low dose and titrate by monitoring effects (Kleinman et al, 2010; Brierley et al, 2009; Santhanam et al, 2008; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Booker et al, 1995; Bhatt-Mehta & Nahata, 1989). May also be given by the IO route if IV access unavailable (Kleinman et al, 2010).

3) EPINEPHRINE

a) ANAPHYLAXIS

1) INTRAMUSCULAR/SUBCUTANEOUS: 0.01 mg/kg of 1:1000 concentration (MAXIMUM: 0.3 to 0.5 mg) IM/subQ every 5 to 20 minutes as necessary; may give at a more frequent interval if required (Sicherer et al, 2007; Lieberman et al, 2005; Sampson et al, 2005).
2) INTRAVENOUS (not responsive to IM/subQ injection): 0.01 mg/kg (0.1 mL/kg of a 1:10,000 solution) IV. MAXIMUM DOSE: 0.3 mg (Lieberman et al, 2005).
3) AUTOINJECTOR DOSING (Intramuscular): Children: 10 kg to 25 kg: 0.15 mg IM; repeat dose as necessary. Children: 25 kg or greater: 0.3 mg IM; repeat dose as necessary (Sicherer et al, 2007).
4) AUTOINJECTOR (15 to 30 kg): The recommended dose is 0.15 mg; may be repeated if severe anaphylaxis persists (Prod Info EPIPEN Jr(R) intramuscular injection, subcutaneous injection, 2014; Prod Info ADRENACLICK(R) intramuscular injection, subcutaneous injection, 2014)
5) AUTOINJECTOR (30 kg or more): The recommended dose is 0.15 mg; may be repeated if severe anaphylaxis persists (Prod Info EPIPEN(R) intramuscular injection, subcutaneous injection, 2014; Prod Info ADRENACLICK(R) intramuscular injection, subcutaneous injection, 2014)

b) BRONCHIOLITIS

1) RACEMIC EPINEPHRINE: 0.5 mL of 2.25% diluted in 2 to 3 mL normal saline by nebulizer; dose may be repeated as necessary if there is documented clinical response (Grewal et al, 2009; Walsh et al, 2008; Langley et al, 2005).
2) L-EPINEPHRINE (1:1000): 1 to 3 mL diluted in normal saline (up to 5 mL) by nebulizer has been used in clinical trials (Plint et al, 2009; Bentur et al, 2005; Kuyucu et al, 2004; Hariprakash et al, 2003).

c) CARDIOPULMONARY RESUSCITATION (PALS Guidelines)

1) INTRAVENOUS/INTRAOSSEOUS: 0.01 mg/kg (0.1 mL/kg of 1:10,000 concentration) IV/IO. MAXIMUM: 1 mg/dose. May repeat every 3 to 5 minutes (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008). High-dose epinephrine (0.1 mg/kg) is not recommended for routine use during resuscitation. It may be considered in extenuating circumstances such as in beta-blocker poisoning (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sorrentino, 2005).
2) ENDOTRACHEAL: 0.1 mg/kg (0.1 mL/kg of 1:1000 concentration). Maximum 2.5 mg/dose. May repeat every 3 to 5 minutes (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).

d) CROUP, MODERATE/SEVERE

1) RACEMIC EPINEPHRINE: 0.05 mL/kg (MAXIMUM: 0.5 mL) of 2.25% diluted in 2 to 3 mL normal saline by nebulizer, dose may be repeated as necessary (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Cherry, 2008; Weber et al, 2001; Prod Info racepinephrine inhalation solution, USP, 2000; Rizos et al, 1998; Kunkel & Baker, 1996; Ledwith et al, 1995; Waisman et al, 1992; Fogel et al, 1982).
2) L-EPINEPHRINE (1:1000): 0.5 mL/kg (MAXIMUM: 5 mL or 5 mg) in normal saline (up to 5 mL) by nebulizer; dose may be repeated as necessary (Walker, 2009; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Chin et al, 2002; Waisman et al, 1992).
3) Based on a review of clinical trials, there is no clinical advantage for using racemic versus L-epinephrine, or administering nebulized epinephrine alone versus administering it by intermittent positive pressure breathing (Bjornson et al, 2011).

e) VASOPRESSOR SUPPORT

1) INTRAVENOUS: 0.1 to 1 mcg/kg/min continuous IV infusion; adjust to desired response (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008). For septic shock, a dose range of 0.05 to 0.3 mcg/kg/min is recommended (Brierley et al, 2009). Higher doses (2 mcg/kg/min) have been used for septic shock, and doses as high as 5 mcg/kg/min may be necessary (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Ceneviva et al, 1998). Inotropic doses of epinephrine are less than 0.3 mcg/kg/min (or greater than 0.3 mcg/kg/min when used with a vasodilator). Vasopressor doses of epinephrine are greater than 0.3 mcg/kg/min (Ceneviva et al, 1998). May also be given by the IO route, if IV access unavailable (Kleinman et al, 2010).

B) PHENYLEPHRINE

1) INJECTION 10 MG/ML

a) HYPOTENSION DURING ANESTHESIA

1) Safety and effectiveness have not been established in pediatric patients (Prod Info VAZCULEP intravenous injection, 2014).

2) INJECTION 1%

a) HYPOTENSION DURING SPINAL ANESTHESIA

1) The recommended dose is 0.5 to 1 mg per 11.3 kg of body weight administered either subQ or IM (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).

Minimum Lethal Exposure

1) The minimum lethal human epinephrine dose by subcutaneous injection has been estimated to be 4 mg (Freedman, 1955).

1) One patient died immediately after receiving 3 mg of epinephrine intravenously (Freedman, 1955).
2) A 37-year-old man died 26 days after self injecting 82.5 mg of epinephrine, from Primatene Mist, intravenously (Scalzo et al, 1995).
3) A 34-year-old woman was found dead outside her home after apparently self-injecting 2 auto injectors of epinephrine (0.15 mg of epinephrine in 0.3 mL solution); the auto-injectors were found near the body along with 2 skin injection marks. She was reportedly depressed and receiving antidepressant therapy; a suicide note was found. The woman had access to the auto-injectors because one of her children was allergic to bees. The cardiac blood concentration for epinephrine was 79.7 nmol/L. The cause of death was secondary to cardiac dysrhythmias and cardiac arrest (Palmiere et al, 2015).

Maximum Tolerated Exposure

1) The maximum tolerated dose of subcutaneous epinephrine has been estimated to be 7 to 8 mg (Freedman, 1955).
2) Patients have developed ischemic ECG changes or myocardial infarction after receiving inadvertent intravenous epinephrine doses between 0.6 to 1 mg.

1) Shortly after a 35-year-old woman's cervix uteri was inadvertently injected with 8 mg of epinephrine (1:1000) (instead of an 8 mL solution of 1% lidocaine HCl and 1:100,000 epinephrine), she experienced palpitations, chest pain, headache, fever, abdominal pain, hypotension (80/50 mm Hg), and sinus tachycardia (120 bpm). She developed reversible myocardial stunning, characterized by significant hemodynamic compromise (cardiogenic shock), profound, albeit transient, left ventricular systolic and diastolic dysfunction, and only modestly elevated biochemical markers of myocardial necrosis. Plasma troponin I, creatine phosphokinase myocardial band (CPK-MB) mass, amount, and CPK-MB fraction peaked within 24 hours of injection. Following intensive supportive care which included intra-aortic balloon pump therapy for several days, complete reversal of myocardial dysfunction was noted (Budhwani et al, 2004).
2) A 37-year-old man suffered ventricular fibrillation, myocardial ischemia, and refractory hypotension, resulting in death 26 days later following self injection of 82.5 mg of epinephrine from Primatene Mist (Scalzo et al, 1995).
3) Two patients with histories of IV drug abuse have been reported who self-injected 1.1 and 20 mg of epinephrine IV and survived (Hall et al, 1987; Kolendorf & Moller, 1974).
4) An inadvertent IV injection of 0.25 mL of a 2.25% solution of racemic epinephrine resulted in hypotension, tachycardia followed by bradycardia, and pulmonary edema in a 13-month-old, 8.6 kg infant (Kurachek & Rockoff, 1985).

1) A 29-year-old man was inadvertently injected with 30,000 mcg of IV phenylephrine instead of 3 mg of neostigmine for residual effects of anesthesia following a cholecystectomy. He was treated for hypertension, tachycardia and cardiac failure. On day 2, he was diagnosed with bilateral pulmonary emboli with normal blood gases. He was treated with anticoagulation therapy and recovered fully after spending 1 week in a cardiac unit (Dubost et al, 2011).

Serum Plasma Blood Concentrations

7.5.1)

A) THERAPEUTIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) TERBUTALINE: Normal therapeutic plasma concentrations have been reported as 2 to 6 micrograms/liter (Heath & Hulten, 1987).

7.5.2)

A) TOXIC CONCENTRATION LEVELS

1) SPECIFIC SUBSTANCE

a) TERBUTALINE: A plasma terbutaline level of approximately 200 nanograms/milliliter was reported in a patient who developed significant toxicity after ingesting 500 milligrams of terbutaline orally (Heath & Hulten, 1987).
b) EPINEPHRINE: A plasma level of epinephrine and norepinephrine of 641 pg/mL (normal, 20-115) and 438 pg/mL (normal, 150-400), respectively, is reported following the accidental overdose of 1.7 mg subcutaneously in a 5-year-old boy (Davis & Wax, 1994).

Toxicity Information

7.7.1)

A) DOPAMINE
B) EPINEPHRINE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 4 mg/kg (Budavari, 1996)

C) ISOPROTERENOL

1) LD50- (ORAL)RAT:

a) 2,221 mg/kg (Budavari, 1996)

D) MEPHENTERMINE

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 110 mg/kg (Budavari, 1996)

E) METARAMINOL

1) LD50- (INTRAPERITONEAL)MOUSE:

a) 440 mg/kg (Budavari, 1996)

F) PHENYLEPHRINE

1) LD50- (INTRAPERITONEAL)RAT:

a) 17 mg/kg (Budavari, 1996)

2) LD50- (SUBCUTANEOUS)RAT:

a) 33 mg/kg (Budavari, 1996)

Pharmacology Toxicology

Pharmacologic Mechanism

Toxicologic Mechanism

1) Following parenteral epinephrine overdose, there is an initial hypertension caused by peripheral alpha receptor stimulation with vasoconstriction (Carter et al, 1971).
2) During epinephrine metabolism, blood levels fall and hypotension occurs from residual stimulation of the more sensitive beta receptors, causing vasodilation (Hall et al, 1987; Gilman et al, 1985).

Physicochemical

Physical Characteristics

Ph

Molecular Weight

Animal Toxicology

References

General Bibliography

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SYMPATHOMIMETICS-PARENTERAL

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

Genitourinary

Acid-Base

Dermatologic

Musculoskeletal

Endocrine

Reproductive

Monitoring Parameters Levels

Radiographic Studies

Methods

Life Support

Patient Disposition

Monitoring

Oral Exposure

Eye Exposure

Case Reports

Summary

Therapeutic Dose

Minimum Lethal Exposure

Maximum Tolerated Exposure

Serum Plasma Blood Concentrations

Toxicity Information

Pharmacologic Mechanism

Toxicologic Mechanism

Physical Characteristics

Ph

Molecular Weight

General Bibliography