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CLINICAL APPROACH TO TOXIN-INDUCED HYPOTENSION

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Hypotension has been broadly defined as a systolic blood pressure of 90 mm Hg or less. Some patients (especially those of small stature or with hypothermia) may have normal perfusion with a systolic blood pressure less than 90 mm Hg. Patients with chronic hypertension may have inadequate perfusion despite a blood pressure of greater than 90 mmHg systolic. Clinically, hypotension is defined as inadequate tissue perfusion, as assessed by vital signs, skin color, capillary refill, mentation, urine output and concentration, and acid-base balance. This management focuses on toxin-induced hypotension, as it relates to common clinical features, diagnostic studies, and treatment .

Specific Substances

    1) Toxin-induced low blood pressure
    2) BLOOD PRESSURE, LOW
    3) DECREASED BLOOD PRESSURE
    4) HYPOTENSION
    5) LOW BLOOD PRESSURE
    6) TOXIN-INDUCED HYPOTENSION

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) WITH POISONING/EXPOSURE
    1) Many toxins have the ability to produce hypotension. Toxin-induced hypotension may occur in numerous settings, and is usually due to four major mechanisms: decreased peripheral resistance, decreased myocardial contractility, dysrhythmia, and intravascular volume depletion. This topic is limited to common adverse effects which may occur following an exposure of an unknown agent. If an agent is known or suspected, refer to that specific management.
    2) In the setting of toxin-induced hypotension, physical signs and symptoms may help to reveal the poison involved. The following is a selection of drugs or chemicals that are frequently associated with hypotension and the clinical features commonly seen with acute exposure.
    a) BETA-RECEPTOR BLOCKER agents - bradycardia and hypotension are common with frequent conduction disturbances and dysrhythmias (ie, AV blocks, intraventricular conduction delays, ventricular dysrhythmias and cardiac arrest). CNS depression and seizures (especially propranolol) are common with severe cardiac toxicity. Complications of profound hypotension include: acute renal failure, respiratory failure, and acute lung injury.
    b) CALCIUM ANTAGONISTS (calcium channel blockers) - Hypotension, bradycardia and AV nodal depression are characteristic. Junctional, atrial and ventricular dysrhythmias, asystole, sinus tachycardia and myocardial ischemia may also occur. Other possible effects include: CNS depression, syncope, acute lung injury, hyperglycemia, and reduced bowel motility.
    c) CLONIDINE or IMIDAZOLINE agents (similar presynaptic alpha-2 stimulant effect) - mild hypertension may develop initially followed by hypotension. Other clinical features in overdose (oral ingestion or excessive topical administration) can include: miosis, CNS depression (severe drowsiness with diaphoresis), hypotension or shock, bradycardia, respiratory depression, and coma.
    d) CARDIAC GLYCOSIDES (eg, digitalis) - nausea and vomiting are characteristic of acute or chronic toxicity. Psychosis (ie, visual hallucinations, confusion, agitation), hyperkalemia (acute toxicity), and conduction disturbances (atrial and ventricular dysrhythmias common) along with hypotension are also frequently observed.
    e) CHOLINERGIC AGENTS - (eg, organophosphates, carbamate insecticides, bromocriptine, acetylcholine, physostigmine, pyridostigmine) commonly have muscarinic (salivation, lacrimation, diarrhea, miosis) and nicotinic (weakness, fasciculations) effects.
    f) IRON - Hypotension can develop within 2-6 hours of severe poisoning secondary to vomiting, diarrhea, blood loss or vasodilation. Major clinical findings can include: stupor, shock, acidosis, hematemesis, bloody diarrhea, or coma. Minor findings: vomiting, mild lethargy and hyperglycemia.
    g) OPIOIDS - Overdose can result in CNS and respiratory depression with hypoxia, hypotension, shock, gastric hypomotility with ileus, and acute lung injury. An opiate intoxication syndrome has been described as a triad of depressed level of consciousness, miotic pupils, and decreased respirations.
    h) SEDATIVES - (eg, barbiturates, benzodiazepines, chloral hydrate) can produce CNS and respiratory depression along with hypothermia. Cardiac collapse and cardiac arrest can occur.
    i) SYMPATHOMIMETICS - (eg, direct-acting {amphetamines, cocaine}, direct-acting, alpha-agonists{ergot alkaloids, epinephrine}, direct-acting, beta-agonists {albuterol) - usually initially produce hypertension followed by hypotension in severe cases. Other clinical features: tachycardia, agitation, seizures and rhabdomyolysis (eg, cocaine, amphetamines).
    j) THEOPHYLLINE - Acute effects of overdose are characterized by nausea, vomiting, abdominal pain, mild metabolic acidosis, hyperkalemia, hyperglycemia, and tachycardia. Severe overdose can result in hypotension, seizures, and dysrhythmias.
    k) TRICYCLIC ANTIDEPRESSANTS (eg, amitriptyline, doxepin, clompramine) - cardiovascular toxicity is the leading cause of death in overdose. Severe overdoses can result in sinus tachycardia, conduction disturbances (ie, QRS widening, QTc prolongation), ventricular dysrhythmias (ie, ventricular tachycardia and fibrillation) and hypotension. Other effects can include CNS depression, coma, and seizures.
    0.2.3) VITAL SIGNS
    A) WITH POISONING/EXPOSURE
    1) Tachycardia, bradycardia, hyperthermia or hypothermia may develop depending on the agent involved.
    0.2.5) CARDIOVASCULAR
    A) WITH POISONING/EXPOSURE
    1) Toxin-induced heart rate and cardiac rhythm abnormalities can worsen or promote hypotension.
    0.2.14) DERMATOLOGIC
    A) WITH POISONING/EXPOSURE
    1) Intravascular volume depletion leading to hypovolemia and alterations in blood pressure can be attributed to agents that produce diaphoresis following acute exposure.

Laboratory Monitoring

    A) Treatment is based more on clinical presentation. Some specific laboratory data, are indicated to rule out other possible sources (eg, myocardial infarction, bleeding, etc) of hypotension.
    B) Monitor blood pressure and heart rate frequently. Obtain orthostatic blood pressures, if possible to assess for volume depletion. Monitor temperature and oxygen saturation (pulse oximetry).
    C) CBC, electrolytes, urinalysis, renal function test should be obtained in patients with significant hypotension.
    D) Institute continuous cardiac monitoring and obtain an ECG. Obtain serial serum troponin levels if myocardial ischemia is a concern.
    E) Evaluate for dehydration (assess skin color and turgor, mucous membranes, neuro status, urine output, and pulse pressure) which can occur with toxins that produce volume depletion. Monitor urine output.

Treatment Overview

    0.4.2) ORAL/PARENTERAL EXPOSURE
    A) Gastric lavage if performed within the first hour of ingestion may be beneficial for large overdoses of life-threatening ingestions.
    B) Monitor ECG and vital signs frequently. Continuous cardiac monitoring is indicated. CVP and Swan-Ganz monitoring may be indicated to guide fluid replacement and use of vasopressors following a significant exposure.
    C) Establish immediate intravenous access. For mild/moderate asymptomatic hypotension, pharmacologic intervention may not be necessary. However, immediate and potentially aggressive supportive care is required in symptomatic patients.
    D) FLUID REPLACEMENT - Fluid replacement with isotonic crystalloids is the first line therapy for hypotension to improve circulating volume and cardiac output. Infuse 10 to 20 mL/kg isotonic fluid. Fluids may not completely reverse the hypotensive effects, and further drug therapies may be indicated.
    E) VASOPRESSORS/VASOCONSTRICTORS - If a toxin remains unknown and fluid replacement therapy is inadequate to maintain blood pressure, a vasopressor or vasoconstrictor is indicated. These agents should be used until a specific antidotal (if appropriate) therapy is determined (Hessler, 2002). Begin with dopamine (10 to 20 mcg/kg/min) or norepinephrine (0.1 to 0.2 mcg/kg/min), and titrate to desired response.
    1) Naloxone administration should be considered for patients that present with CNS depression.
    2) ANTIDOTES - Glucagon may be effective in stimulating heart rate and improving cardiac output following beta-adrenergic blocker or calcium channel blockers. Calcium can improve depressed cardiac contractility following calcium antagonist exposure. Digibind may be used for digoxin overdose.
    F) BRADYCARDIA - Atropine should be administered to patients with bradycardia and hypotension, although it may not be effective in patients with toxin induced bradycardia. Isoproterenol may be indicated if heart rate or blood pressure is unresponsive to atropine. Cardiac pacing may be required in some settings.
    G) SEIZURES (eg, sympathomimetic, tricyclic antidepressant exposure) - If present, treat aggressively as acidosis may worsen cardiovascular toxicity.
    1) SEIZURES: Administer a benzodiazepine; DIAZEPAM (ADULT: 5 to 10 mg IV initially; repeat every 5 to 20 minutes as needed. CHILD: 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) or LORAZEPAM (ADULT: 2 to 4 mg IV initially; repeat every 5 to 10 minutes as needed, if seizures persist. CHILD: 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).
    a) Consider phenobarbital or propofol if seizures recur after diazepam 30 mg (adults) or 10 mg (children greater than 5 years).
    b) Monitor for hypotension, dysrhythmias, respiratory depression, and need for endotracheal intubation. Evaluate for hypoglycemia, electrolyte disturbances, and hypoxia.
    2) REFRACTORY SEIZURES: Consider continuous infusion of midazolam, propofol, and/or pentobarbital. Hyperthermia, lactic acidosis and muscle destruction may necessitate use of neuromuscular blocking agents with continuous EEG monitoring.
    I) CNS DEPRESSION and/or RESPIRATORY DEPRESSION - Early intubation is advised in patients with significant mental status changes or respiratory depression/insufficiency to protect the airway and provide adequate oxygenation and ventilation.

Range Of Toxicity

    A) Because of the numerous agents that may be associated with toxin-induced hypotension, a minimum toxic dose cannot be delineated. Coadministration of multiple agents and coexisting conditions (eg, acidosis, hypoxia, volume depletion, etc) may produce refractory symptoms or potentiate the clinical effects observed.
    B) Refer to a specific management if a toxin is known or suspected to determine potential toxicity.

Clinical Effects

Summary Of Exposure

    A) WITH POISONING/EXPOSURE
    1) Many toxins have the ability to produce hypotension. Toxin-induced hypotension may occur in numerous settings, and is usually due to four major mechanisms: decreased peripheral resistance, decreased myocardial contractility, dysrhythmia, and intravascular volume depletion. This topic is limited to common adverse effects which may occur following an exposure of an unknown agent. If an agent is known or suspected, refer to that specific management.
    2) In the setting of toxin-induced hypotension, physical signs and symptoms may help to reveal the poison involved. The following is a selection of drugs or chemicals that are frequently associated with hypotension and the clinical features commonly seen with acute exposure.
    a) BETA-RECEPTOR BLOCKER agents - bradycardia and hypotension are common with frequent conduction disturbances and dysrhythmias (ie, AV blocks, intraventricular conduction delays, ventricular dysrhythmias and cardiac arrest). CNS depression and seizures (especially propranolol) are common with severe cardiac toxicity. Complications of profound hypotension include: acute renal failure, respiratory failure, and acute lung injury.
    b) CALCIUM ANTAGONISTS (calcium channel blockers) - Hypotension, bradycardia and AV nodal depression are characteristic. Junctional, atrial and ventricular dysrhythmias, asystole, sinus tachycardia and myocardial ischemia may also occur. Other possible effects include: CNS depression, syncope, acute lung injury, hyperglycemia, and reduced bowel motility.
    c) CLONIDINE or IMIDAZOLINE agents (similar presynaptic alpha-2 stimulant effect) - mild hypertension may develop initially followed by hypotension. Other clinical features in overdose (oral ingestion or excessive topical administration) can include: miosis, CNS depression (severe drowsiness with diaphoresis), hypotension or shock, bradycardia, respiratory depression, and coma.
    d) CARDIAC GLYCOSIDES (eg, digitalis) - nausea and vomiting are characteristic of acute or chronic toxicity. Psychosis (ie, visual hallucinations, confusion, agitation), hyperkalemia (acute toxicity), and conduction disturbances (atrial and ventricular dysrhythmias common) along with hypotension are also frequently observed.
    e) CHOLINERGIC AGENTS - (eg, organophosphates, carbamate insecticides, bromocriptine, acetylcholine, physostigmine, pyridostigmine) commonly have muscarinic (salivation, lacrimation, diarrhea, miosis) and nicotinic (weakness, fasciculations) effects.
    f) IRON - Hypotension can develop within 2-6 hours of severe poisoning secondary to vomiting, diarrhea, blood loss or vasodilation. Major clinical findings can include: stupor, shock, acidosis, hematemesis, bloody diarrhea, or coma. Minor findings: vomiting, mild lethargy and hyperglycemia.
    g) OPIOIDS - Overdose can result in CNS and respiratory depression with hypoxia, hypotension, shock, gastric hypomotility with ileus, and acute lung injury. An opiate intoxication syndrome has been described as a triad of depressed level of consciousness, miotic pupils, and decreased respirations.
    h) SEDATIVES - (eg, barbiturates, benzodiazepines, chloral hydrate) can produce CNS and respiratory depression along with hypothermia. Cardiac collapse and cardiac arrest can occur.
    i) SYMPATHOMIMETICS - (eg, direct-acting {amphetamines, cocaine}, direct-acting, alpha-agonists{ergot alkaloids, epinephrine}, direct-acting, beta-agonists {albuterol) - usually initially produce hypertension followed by hypotension in severe cases. Other clinical features: tachycardia, agitation, seizures and rhabdomyolysis (eg, cocaine, amphetamines).
    j) THEOPHYLLINE - Acute effects of overdose are characterized by nausea, vomiting, abdominal pain, mild metabolic acidosis, hyperkalemia, hyperglycemia, and tachycardia. Severe overdose can result in hypotension, seizures, and dysrhythmias.
    k) TRICYCLIC ANTIDEPRESSANTS (eg, amitriptyline, doxepin, clompramine) - cardiovascular toxicity is the leading cause of death in overdose. Severe overdoses can result in sinus tachycardia, conduction disturbances (ie, QRS widening, QTc prolongation), ventricular dysrhythmias (ie, ventricular tachycardia and fibrillation) and hypotension. Other effects can include CNS depression, coma, and seizures.

Vital Signs

    3.3.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Tachycardia, bradycardia, hyperthermia or hypothermia may develop depending on the agent involved.
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) HYPOTHERMIA may indicate exposure to sedatives (Hurlbut, 2000).
    2) HYPERTHERMIA suggests exposure to sympathomimetics (eg, cocaine, amphetamines) along with tachycardia (Hurlbut, 2000; Cortes-Belen et al, 1998; Chan et al, 1994; Ginsberg et al, 1970) .
    3.3.4) BLOOD PRESSURE
    A) WITH POISONING/EXPOSURE
    1) Initial hypertension and tachycardia followed by hypotension may indicate exposure to clonidine, imidazoline drugs or sympathomimetics (Hurlbut, 2000). Hypotension that is preceded by hypertension is often a sign of severe toxicity, and may progress to cardiovascular collapse in some cases (Prod Info Catapres(R), clonidine hydrochloride, 2001; Chan et al, 1994).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) BRADYCARDIA
    a) Sinus bradycardia may develop following calcium antagonist(s) (eg, verapamil) or beta adrenergic antagonist exposure. Heart rates below 60 beats/min with accompanying hypotension at presentation are common with these agents (Vadlamudi & Wijdicks, 2002; Schwab et al, 2002; Meyer et al, 2001; Snook et al, 2000).
    2) TACHYCARDIA
    a) Exposure to vasodilators (eg, nitroglycerin), can result in reflex TACHYCARDIA (Hurlbut, 2000; Schlafer & Stork, 2000).
    b) Tachycardia may also occur following sympathomimetic (eg, cocaine, amphetamines) (Anon, 1989; Lan et al, 1998)or tricyclic antidepressant exposure (Braden et al, 1986).

Cardiovascular

    3.5.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Toxin-induced heart rate and cardiac rhythm abnormalities can worsen or promote hypotension.
    3.5.2) CLINICAL EFFECTS
    A) ELECTROCARDIOGRAM ABNORMAL
    1) WITH POISONING/EXPOSURE
    a) Agents that produce hypotension can also produce specific cardiac conduction abnormalities (eg, various heart blocks or prolonged intervals). Classes of compounds have been observed to produce common alterations in cardiac conduction following overdose. The lists below describe the characteristic ECG abnormalities that can occur following a specific exposure and the effect on heart rate.
    b) PULSE AND ECG CHANGES BY AGENTS PRODUCING HYPOTENSION
    1) In the setting of toxin-induced hypotension, physical signs and symptoms may help to reveal the poison involved. The following is a selection of drugs or chemicals that are frequently associated with hypotension and the clinical features commonly seen with acute exposure.
    2) AGENTS PRODUCING BRADYCARDIA AND ECG CHANGES
    1) Antipsychotic drugs (eg, thioridazine, haloperidol) - QTc prolongation (Chong et al, 2001)
    2) Beta-Adrenergic antagonists - Bradycardia with PR and QRS prolongation possible; first degree AV block; hypotension is due to negative inotropic effects (Love, 1994; Love & Elshami, 2002)
    3) Calcium channel antagonists - sinus bradycardia, AV block {common}, complete heart block, junctional rhythm, QT prolongation, moderate S-T segment depression, low amplitude T-waves, prominent U-waves (Henrikson & Chandra-Strobos, 2003; Moroni et al, 1980; McMillan, 1988)
    4) Carbamazepine - AV conduction delay may be observed in the elderly (Chong et al, 2001)
    5) Cholinergic Agonists-direct - bradycardia occurs at large doses because of nicotinic effects; left bundle branch block and third-degree AV block with a slow idioventricular escape rate has occurred with pilocarpine (Cordner et al, 1986)
    6) Digoxin - all degrees of heart block, PAT with block, bundle branch block, nodal tachycardia with A-V dissociation, atrial and ventricular ectopy, and ventricular tachycardia and fibrillation; any or all may occur in the same patient (Rodensky & Wasserman, 1961)
    7) Lithium - T wave depression, AV block (Chong et al, 2001)
    8) Magnesium - bradycardia and conduction delays with heart block may occur with severe hypermagnesemia (Kulkarni et al, 1999)
    9) Propafenone - prolongation of PR interval and QRS duration have occurred in overdose (Hartel, 1985; Rambourg-Schepens et al, 1999)
    10) Sotalol - QTc prolongation; fusion of the T and U waves (Gottlieb et al, 1997; Link et al, 1997; Pellinen et al, 1981)
    a) In the setting of toxin-induced hypotension, these agents can produce either prolonged intervals or heart block along with bradycardia(Hessler, 2002):
    3) AGENTS PRODUCING TACHYCARDIA AND ECG CHANGES
    1) Anticholinergic agents (eg, antihistamines) - QRS widening; wide complex tachycardia possible (Danze & Langdorf, 1991)
    2) Antidysrhythmic agents - initially reflex tachycardia; PR and QRS interval(s) prolonged (Denaro & Benowitz, 1989)
    3) Cocaine - sinus tachycardia most common finding; associated dysrhythmias include supraventricular tachycardia (Merigian et al, 1994), PVCs, and bigeminy (Orr & Jones, 1968)
    4) Cyclic antidepressants - sinus tachycardia, QRS widening, QTc prolongation; flattened T waves (Braden et al, 1986)
    5) Phenothiazines - QTc prolongation; late onset (ie, 10 hours after overdose) of ventricular dysrhythmias is possible (Smolinske & Larson, 2000; Blaye et al, 1993)
    6) Antimalarial agents (quinine/chloroquine) - increased PR interval; widened QRS, increased U wave (Jaeger et al, 1987; Marshall & Forker, 1982)
    a) In the setting of toxin-induced hypotension, these agents can produce ECG changes along with tachycardia (Hessler, 2002):
    b) PSYCHOTROPIC AGENTS (eg, tricyclic antidepressants, antipsychotic agents (eg, more likely with first-generation agents - clozapine), mood stabilizers (eg., valproate) - exert their effects on the heart (primarily tachycardia and hypotension) by the blockade of muscarinic receptors (type-2 muscarinic receptors are responsible for vagal inhibition through increased potassium conductance and inhibition of calcium channels - blockade leads to tachycardia), and alpha-1 adrenoreceptors, which results in constriction of veins and blockade of these receptors leads to vasodilation. The vasodilation results in reflex tachycardia (Chong et al, 2001).
    B) CONDUCTION DISORDER OF THE HEART
    1) WITH POISONING/EXPOSURE
    a) AGENTS PRODUCING BRADYCARDIA AND DYSRHYTHMIA
    1) Digoxin - multiple types of dysrhythmias have been associated with digoxin (eg, atrial flutter, suppression of AV conduction, AV dissociation with atrial flutter and nonparoxysmal junctional and ventricular fibrillation)
    2) Plant toxins
    a) Aconitine - multifocal premature ventricular contractions, ventricular tachycardia, torsades de pointes and ventricular fibrillation may occur in severe poisoning (Tai et al, 1992a; Tomlinson et al, 1993; Fitzpatrick et al, 1994)
    b) Andromedotoxin - conduction defects and bradydysrhythmias can occur; occasional tachydysrhythmias are also possible(Biberoglu et al, 1988; Yavuz et al, 1991)
    c) Veratrine - bradyarrhythmias and A-V node dissociation have occurred (Festa et al, 1996)
    3) Propafenone - ventricular dysrhythmias have been observed in some cases (Podrid, 1985)
    4) Propoxyphene - ventricular extrasystoles, bigeminy, or ventricular tachycardia may be seen (McCarthy & Keenan, 1964; Sloth-Madsen et al, 1984)
    5) Sotalol - torsades de pointes has been reported following therapeutic use (Laakso et al, 1981; Kontopoulos et al, 1981; McKibbin et al, 1984) and may occur in acute exposure
    1) In the setting of toxin-induced hypotension, these agents can produce dysrhythmias along with bradycardia (Hessler, 2002):
    b) AGENTS PRODUCING TACHYCARDIA AND DYSRHYTHMIAS
    1) Anticholinergic agents - wide complex tachycardia has occurred (Danze & Langdorf, 1991)
    2) Antidysrhythmic agents - (eg, mexiletine, tocainide) can produce torsades de pointes, ventricular fibrillation (Denaro & Benowitz, 1989)
    3) Antihistamines - supraventricular and ventricular dysrhythmias have occurred (Tenley & Friedman, 1966; Bobik & McLean, 1976)
    4) Antimalarial agents (eg, quinine, chloroquine) - ventricular tachycardia, ventricular fibrillation (Jaeger et al, 1987)
    5) Antipsychotics (eg, haloperidol) - torsades de pointes has occurred in overdose (Wilt et al, 1993; Perrault et al, 2000; Buckley & Sanders, 2000)
    6) Arsenic - ventricular tachycardia, ventricular bigeminy, and ventricular fibrillation have been described after acute arsenic ingestion (Peterson & Rumack, 1977; Goldsmith, 1980)
    7) Chloral hydrate - cardiac dysrhythmias (ranging from sinus tachycardia to multifocal PVCs, ventricular tachycardia, ventricular fibrillation, AV block and asystole) are frequently reported following overdose (Graham et al, 1988; Ludwigs et al, 1996)
    8) Cocaine - unstable supraventricular dysrhythmias; ventricular tachycardia
    9) Cyclic antidepressants - supraventricular and ventricular dysrhythmias, ventricular fibrillation (Marshall & Forker, 1982)
    10) Methylxanthines (Hessler, 2002)
    11) Noncyclic antidepressants (Hessler, 2002)
    12) Phenothiazines - ventricular tachycardia or torsades de pointes which may terminate spontaneously or degenerate into ventricular fibrillation (Krikler & Curry, 1976; Keren et al, 1981)
    13) Sympathomimetics - initial tachycardia, followed by bradycardia, heart block and eventually asystole following massive overdoses(Hessler, 2002)
    1) In the setting of toxin-induced hypotension, these agents can produce tachycardia along with dysrhythmias:
    c) ANTIPSYCHOTIC AGENTS
    1) Although these agents (eg, clozapine, haloperidol, lithium, risperidone) are structurally and pharmacologically diverse, they commonly produce adverse cardiovascular effects through both direct and indirect stimulation. The effects can include postural hypotension, tachycardia, palpitations, heart failure and dysrhythmias (Buckley & Sanders, 2000).
    d) CALCIUM CHANNEL ANTAGONISTS
    1) Calcium channel blockers (eg, diltiazem, verapamil, nifedipine) can produce vasodilatation, and depress myocardial contractility and sinus and atrioventricular nodal conduction by blocking the inward movement of calcium into cells through "slow channels" from extracellular sites (Proano et al, 1995).
    2) SIGNS/SYMPTOMS - Hypotension with systolic blood pressures less than 100 mmHg is common following significant overdose with all agents but particularly VERAPAMIL; syncopal episodes secondary to impaired perfusion may occur (Ramoska et al, 1993; Welch et al, 1992; Luscher et al, 1994; Cavagnaro et al, 2000; Ori et al, 2000; Herbert et al, 2001; Meyer et al, 2001; Vadlamudi & Wijdicks, 2002; Schwab et al, 2002). Hypotension is prominent in cases of verapamil toxicity (Hofer et al, 1993).
    3) ONSET - Common within 1 to 5 hours postingestion, although delayed onset (more than 24 hours) and prolonged duration of symptoms can occur following sustained-release dosage forms (Krick et al, 1990; Quezado et al, 1991; Luscher et al, 1994; Spiller et al, 1991; Buckley et al, 1993; Morimoto et al, 1999).
    e) TRICYCLIC ANTIDEPRESSANTS
    1) Tricyclic antidepressant overdose should be suspected in patients with signs of anticholinergic poisoning, coma or hypotension. Hypotension may develop secondary to a dysrhythmia, myocardial depression and/or alpha adrenergic blockade (Braden et al, 1986).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) DECREASED RESPIRATORY FUNCTION
    1) WITH POISONING/EXPOSURE
    a) In the setting of toxin-induced hypotension, respiratory depression may occur. Numerous agents (eg, antiarrhythmic agents, opioids, tricyclic antidepressants, sedatives) may precipitate respiratory depression and respiratory arrest (eg., antiarrhythmics) in some cases (Denaro & Benowitz, 1989; Braden et al, 1986).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) SEIZURE
    1) WITH POISONING/EXPOSURE
    a) In the setting of toxin-induced hypotension, seizures may occur. Numerous agents (eg, antiarrhythmic agents, beta-receptor blockers, theophylline, tricyclic antidepressants, sympathomimetics) may result in the development of seizures following acute exposure(Love, 1994; Denaro & Benowitz, 1989; Braden et al, 1986).
    B) CENTRAL NERVOUS SYSTEM DEFICIT
    1) WITH POISONING/EXPOSURE
    a) In the setting of toxin-induced hypotension, CNS depression and coma may occur. Numerous agents (eg, antimalarial agents, antiarrhythmic agents, beta-receptor blockers, calcium antagonists, clonidine/imidazoline, tricyclic antidepressants, sedatives) may result in the development of CNS depression, coma and/or seizures following acute exposure (Jaeger et al, 1987; Denaro & Benowitz, 1989; Love, 1994; Hofer et al, 1993).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) VOLUME DEPLETION, GASTROINTESTINAL LOSS
    1) WITH POISONING/EXPOSURE
    a) Acute exposure to a number of different agents (eg, drugs, plants, chemicals) may result in the development of hypotension due to potentially severe gastrointestinal loss. Symptoms can include profuse vomiting and/or diarrhea, which may be hemorrhagic in some agents (eg, iron).
    b) In the setting of toxin-induced hypotension the following list describes agents (drugs or chemicals) that may produce gastrointestinal loss (ie, vomiting, and/or diarrhea) (Hessler, 2002):
    1) DRUGS
    a) Antibiotics - vomiting and/or diarrhea possible
    b) Cholinergic Agents (drugs or chemicals {organophosphates, carbamates pesticides, bromocriptine, acetylcholine, physostigmine, pyridostigmine}) - may produce vomiting, diarrhea, lacrimation, and increased salivation (Hurlbut, 2000)
    c) Colchicine - marked volume depletion possible (Valenzuela et al, 1995; Berlin et al, 1997; Kubler, 2000)
    d) Iodine - severe corrosive gastroenteritis possible (Kurt et al, 1996)
    e) Iron - vomiting, diarrhea, blood loss possible after exposure (Wu et al, 1998)
    f) Laxatives and cathartics - vomiting and diarrhea frequent in overdose (Hendrickse et al, 1977)
    g) Lithium - vomiting and diarrhea can occur following acute toxicity (Bosinski et al, 1998)
    h) Nonsteroidal anti-inflammatory agents - vomiting can be severe; hematemesis has also occurred (Joubert, 1982; Fredell & Strand, 1977)
    i) Opioid withdrawal (eg, heroin) - vomiting and diarrhea has been reported in adults and children (O'Connor & Fiellin, 2000)
    j) Theophylline (Shannon, 1993)
    1) CHEMICALS
    a) Arsenic salts - vomiting; diarrhea may be profuse and gastroenteritis common (Moore et al, 1994; Brayer et al, 1997; Bartolome et al, 1999)
    b) Cholinergic Agents (drugs or chemicals {organophosphates, carbamates pesticides, bromocriptine, acetylcholine, physostigmine, pyridostigmine}) - may produce vomiting, diarrhea, lacrimation, and increased salivation (Hurlbut, 2000; Lifshitz et al, 1994)
    c) Mercury salts - vomiting and diarrhea can occur following an acute exposure (Nascimento et al, 1990)
    d) Methylxanthines {caffeine} - severe intoxication produces vomiting; gastrointestinal hemorrhage possible
    e) Plants-toxalbumins (ricin) - hemorrhagic diarrhea (Malizia et al, 1977; Kopferschmitt et al, 1983)
    f) Podophyllium (cytotoxic agent) (Hessler, 2002)
    g) Zinc phosphate (Hessler, 2002)

Genitourinary

    3.10.2) CLINICAL EFFECTS
    A) URINARY LOSS
    1) WITH POISONING/EXPOSURE
    a) TOXINS ASSOCIATED WITH VOLUME LOSS
    1) Acute or chronic exposure (eg, lithium) to a number of different agents (eg, drugs, plants, chemicals) may result in the development of hypotension due to urinary loss. Symptoms can include polyuria (eg, chronic lithium toxicity) (Dyson et al, 1987; Corbett et al, 1989; Jaeger et al, 1993) and dehydration.
    2) DRUGS/AGENTS COMMONLY ASSOCIATED WITH URINARY LOSS
    1) Diuretics
    2) Ethanol
    3) Lithium
    4) Mercury salts
    5) Salicylates
    6) Methylxanthines (caffeine)
    7) Vacor
    8) Reference: (Hessler, 2002)

Acid-Base

    3.11.2) CLINICAL EFFECTS
    A) METABOLIC ACIDOSIS
    1) WITH POISONING/EXPOSURE
    a) Sustained hypotension from any cause may lead to metabolic acidosis from inadequate tissue perfusion.
    1) Anion gap metabolic acidosis observed soon after exposure, may be suggestive of a significant iron ingestion (Schonfeld & Haftel, 1989; Wu et al, 1998). Mild metabolic acidosis is also common with acute intoxication or acute on chronic (therapeutic use) intoxication with theophylline exposure(Shannon, 1993). Metabolic acidosis has also developed following tricyclic antidepressant exposure (Braden et al, 1986), and was observed as the terminal event following a verapamil overdose (Hofer et al, 1993).

Dermatologic

    3.14.1) SUMMARY
    A) WITH POISONING/EXPOSURE
    1) Intravascular volume depletion leading to hypovolemia and alterations in blood pressure can be attributed to agents that produce diaphoresis following acute exposure.
    3.14.2) CLINICAL EFFECTS
    A) EXCESSIVE SWEATING
    1) WITH POISONING/EXPOSURE
    a) Dehydration can lead to alterations in volume status. Increased diaphoresis which may occur with some agents can contribute to insensible fluid losses and can result in orthostatic hypotension. The following is a list of agents which may produce increased diaphoresis (Hessler, 2002).
    b) INCREASED DIAPHORESIS
    1) Adrenergic (alpha and beta) agents
    2) Cholinergic (muscarinic, nicotinic) agents
    a) Carbamate insecticides
    b) Chlorophenoxy herbicides
    3) Dinitrophenol
    4) Ethanol withdrawal
    5) Methylxanthines
    6) Opioid withdrawal
    7) Organic phosphorus insecticides
    8) Salicylates
    9) Sedative-hypnotic withdrawal
    10) Reference: (Hessler, 2002)

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) RHABDOMYOLYSIS
    1) WITH POISONING/EXPOSURE
    a) In the setting of toxin-induced hypotension, rhabdomyolysis may develop. Intoxication with sympathomimetics (eg, cocaine, amphetamines) can result in rhabdomyolysis secondary to agitation (Lombard et al, 1988; Menashe & Gottlieb, 1988), and are frequently associated with hyperthermia and seizures.

Endocrine

    3.16.2) CLINICAL EFFECTS
    A) HYPERGLYCEMIA
    1) WITH POISONING/EXPOSURE
    a) In the setting of toxin-induced hypotension, hyperglycemia has occurred following acute exposure with several agents. Hyperglycemia is a consistent finding in acute theophylline overdose (Biberstein et al, 1984; Tsiu et al, 1990). Hyperglycemia is common with significant iron overdose (Mann et al, 1989). Hyperglycemia has also been reported following acute calcium antagonist(s) exposure (Howarth et al, 1994).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Treatment is based more on clinical presentation. Some specific laboratory data, are indicated to rule out other possible sources (eg, myocardial infarction, bleeding, etc) of hypotension.
    B) Monitor blood pressure and heart rate frequently. Obtain orthostatic blood pressures, if possible to assess for volume depletion. Monitor temperature and oxygen saturation (pulse oximetry).
    C) CBC, electrolytes, urinalysis, renal function test should be obtained in patients with significant hypotension.
    D) Institute continuous cardiac monitoring and obtain an ECG. Obtain serial serum troponin levels if myocardial ischemia is a concern.
    E) Evaluate for dehydration (assess skin color and turgor, mucous membranes, neuro status, urine output, and pulse pressure) which can occur with toxins that produce volume depletion. Monitor urine output.
    4.1.2) SERUM/BLOOD
    A) BLOOD/SERUM CHEMISTRY
    1) CBC, electrolytes, and CPK or troponin levels are indicated in moderate to severe poisoning cases.
    4.1.3) URINE
    A) URINALYSIS
    1) A urinalysis should be obtained in all patients.
    B) URINE OUTPUT
    1) Insert a foley catheter to monitor urine output hourly or as determined. Note color and concentration.
    4.1.4) OTHER
    A) OTHER
    1) PULSE RATE
    a) Many toxins that produce hypotension can also alter the heart rate (bradycardia or tachycardia).
    1) Monitor pulse rate and quality frequently.
    2) ECG MONITORING
    a) Many toxins (eg, anticholinergic, sympathomimetics, cyclic antidepressants, cardiac agents) that produce hypotension can also produce ECG abnormalities (ie, heart block, prolonged intervals or dysrhythmias).
    1) Obtain a baseline ECG and institute continuous cardiac monitoring.
    3) TILT TEST
    1) Obtain blood pressure and pulse after the patient has been resting supine for 2 minutes.
    2) Stand the patient up for at least 1 minute and recheck blood pressure and pulse, and observe for orthostatic signs (ie, dizziness, light-headedness). If the patient is unable to stand, have them sit up right for at least 2 minutes and recheck blood pressure and pulse.
    3) The test is considered positive if any of the following occur:
    a) Systolic BP decreases by greater than 20 mm Hg
    b) Diastolic BP decreases by greater than 10 mm Hg
    c) Pulse increases by greater than 10 beats/minute
    d) Development of clinical symptoms of hypovolemia (dizziness, syncope, light-headedness)
    1) Reference: (Hessler, 2002)
    a) ORTHOSTATIC VITAL SIGNS can help to assess a patient's volume status. This is not advised in patients with persistent hypotension or clinical evidence of decreased tissue perfusion. Volume depletion that occurs with gastrointestinal losses or urinary losses can produce orthostatic changes. Functional volume depletion can also occur secondary to peripheral vasodilatation (Hessler, 1994).
    4) CONTINUOUS VENOUS PRESSURE (CVP) MONITORING
    a) CVP and/or right heart catheter monitoring may be indicated to guide fluid replacement and cardiac output, if unresponsive to initial fluid replacement or as indicated with significant co-morbidity.

Radiographic Studies

    A) CHEST RADIOGRAPHY
    1) Obtain a chest x-ray in patients with persistent hypotension.

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Monitoring

    A) Treatment is based more on clinical presentation. Some specific laboratory data, are indicated to rule out other possible sources (eg, myocardial infarction, bleeding, etc) of hypotension.
    B) Monitor blood pressure and heart rate frequently. Obtain orthostatic blood pressures, if possible to assess for volume depletion. Monitor temperature and oxygen saturation (pulse oximetry).
    C) CBC, electrolytes, urinalysis, renal function test should be obtained in patients with significant hypotension.
    D) Institute continuous cardiac monitoring and obtain an ECG. Obtain serial serum troponin levels if myocardial ischemia is a concern.
    E) Evaluate for dehydration (assess skin color and turgor, mucous membranes, neuro status, urine output, and pulse pressure) which can occur with toxins that produce volume depletion. Monitor urine output.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) SUMMARY
    1) Prehospital care should include IV access and administration of isotonic crystalloid fluids and immediate transport to a healthcare facility.
    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) PREVENTION OF ABSORPTION
    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.
    B) CHARCOAL DOSE
    1) 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).
    a) 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).
    2) ADVERSE EFFECTS/CONTRAINDICATIONS
    a) 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.
    b) Contraindications: unprotected airway (increases risk/severity of aspiration) , nonfunctioning gastrointestinal tract, uncontrolled vomiting, and ingestion of most hydrocarbons (Chyka et al, 2005).
    C) GASTRIC LAVAGE
    1) Gastric lavage is indicated if it can be performed soon after ingestion, and a significant exposure is suspected.
    2) Some toxins that produce hypotension can also produce significant bradycardia (eg, beta blocking agents), and it is suggested that atropine be made available because gastric lavage can alter vagal tone (Soni et al, 1983). However, pretreatment with atropine is NOT routinely recommended.
    3) INDICATIONS: Consider gastric lavage with a large-bore orogastric tube (ADULT: 36 to 40 French or 30 English gauge tube {external diameter 12 to 13.3 mm}; CHILD: 24 to 28 French {diameter 7.8 to 9.3 mm}) after a potentially life threatening ingestion if it can be performed soon after ingestion (generally within 60 minutes).
    a) Consider lavage more than 60 minutes after ingestion of sustained-release formulations and substances known to form bezoars or concretions.
    4) PRECAUTIONS:
    a) SEIZURE CONTROL: Is mandatory prior to gastric lavage.
    b) AIRWAY PROTECTION: Place patients in the head down left lateral decubitus position, with suction available. Patients with depressed mental status should be intubated with a cuffed endotracheal tube prior to lavage.
    5) LAVAGE FLUID:
    a) Use small aliquots of liquid. Lavage with 200 to 300 milliliters warm tap water (preferably 38 degrees Celsius) or saline per wash (in older children or adults) and 10 milliliters/kilogram body weight of normal saline in young children(Vale et al, 2004) and repeat until lavage return is clear.
    b) The volume of lavage return should approximate amount of fluid given to avoid fluid-electrolyte imbalance.
    c) CAUTION: Water should be avoided in young children because of the risk of electrolyte imbalance and water intoxication. Warm fluids avoid the risk of hypothermia in very young children and the elderly.
    6) COMPLICATIONS:
    a) Complications of gastric lavage have included: aspiration pneumonia, hypoxia, hypercapnia, mechanical injury to the throat, esophagus, or stomach, fluid and electrolyte imbalance (Vale, 1997). Combative patients may be at greater risk for complications (Caravati et al, 2001).
    b) Gastric lavage can cause significant morbidity; it should NOT be performed routinely in all poisoned patients (Vale, 1997).
    7) CONTRAINDICATIONS:
    a) Loss of airway protective reflexes or decreased level of consciousness if patient is not intubated, following ingestion of corrosive substances, hydrocarbons (high aspiration potential), patients at risk of hemorrhage or gastrointestinal perforation, or trivial or non-toxic ingestion.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should be initiated as clinically indicated. The causative agent may often be unknown at the start of therapy. Hypotension caused by reduced systemic resistance and lowered cardiac output may require fluid replacement, and vasoconstriction with high dose dopamine or norepinephrine.
    2) Correct any underlying electrolyte or metabolic disturbances, hypoxia, and treat any concomitant condition (eg, seizures).
    3) If the agent is known or suspected, refer to the specific topic for further information.
    B) MONITORING OF PATIENT
    1) Monitor blood pressure frequently along with continuous cardiac monitoring. Orthostatic vital signs may be indicated. Serial ECGs should be performed.
    2) Obtain baseline renal function, CBC, serum electrolytes, and urinalysis; repeat as indicated.
    3) Serum and urine toxicology studies should be performed to help guide therapy.
    4) Monitor fluid status frequently. Rapid and aggressive fluid replacement may lead to fluid overload, congestive heart failure, or pulmonary edema in some patients. Neck vein distension, chest x-ray, ECG, or other studies may suggest other causes of cardiopulmonary insufficiency (eg, myocardial infarction, cardiac tamponade, pulmonary embolism, valvular heart disease) unrelated to a toxin. (Hessler, 2002)
    5) CVP measurement can be useful. Patients that fail to respond to initial therapy may require the insertion of a pulmonary artery catheter (eg, Swan-Ganz catheter) to more accurately assess the cause of hypotension (potentially non-toxin induced), as well as, monitor and adjust therapeutic interventions based on cardiac filling pressures and cardiac output.
    C) HYPOTENSIVE EPISODE
    1) FLUID REPLACEMENT
    a) INDICATIONS - Fluid replacement is the first line of therapy for hypotension and is indicated to increase circulating volume especially if fluid loss is suspected (eg, gastrointestinal loss, urinary losses, etc). Administer isotonic fluids.
    b) Vasopressors or vasoconstrictors may be indicated when fluid replacement is ineffective or if the toxin remains unknown. Selection of the most appropriate inotropic agent may be complicated by the type of toxin ingested (Hessler, 2002). Hypotension caused by some toxins may be refractory to dopamine but may respond to direct-acting agents such as norepinephrine, epinephrine, or phenylephrine.
    c) SUMMARY
    1) 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.
    d) VASOPRESSOR AGENTS
    1) 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).
    2) 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).
    e) EPINEPHRINE
    1) ADULT
    a) BOLUS DOSE: 1 mg intravenously/intraosseously every 3 to 5 minutes to treat cardiac arrest (Link et al, 2015).
    b) INFUSION: Prepare by adding 1 mg (1 mL of 1:1000 (1 mg/mL) solution) to 250 mL D5W, yielding a concentration of 4 mcg/mL, and infuse this solution IV at a rate of 1 mcg/min to 10 mcg/min (maximum rate) (Lieberman et al, 2010). Used primarily for severe hypotension (systolic blood pressure 70 mm Hg), or anaphylaxis associated with hemodynamic or respiratory compromise, may also be used for symptomatic bradycardia if atropine and transcutaneous pacing are unsuccessful or not immediately available (Peberdy et al, 2010).
    2) PEDIATRIC
    a) CARDIOPULMONARY RESUSCITATION: INTRAVENOUS/INTRAOSSEOUS: OLDER INFANTS/CHILDREN: 0.01 mg/kg (0.1 mL/kg of 1:10,000 (0.1 mg/mL) solution); maximum 1 mg/dose. May repeat dose every 3 to 5 minutes (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008; Sorrentino, 2005). ENDOTRACHEAL: OLDER INFANTS/CHILDREN: 0.1 mg/kg (0.1 mL/kg of 1:1000 (1 mg/mL) solution). Maximum 2.5 mg/dose (maximum total dose: 10 mg). May repeat every 3 to 5 minutes (Kleinman et al, 2010; Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008). Follow ET administration with saline flush or dilute in isotonic saline (1 to 5 mL) based on the child's size (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    b) INFUSION: Used for the treatment of refractory hypotension, bradycardia, severe anaphylaxis. DOSE: 0.1 to 1 mcg/kg/min, titrate dose; start at lowest dose needed to reach desired clinical effects. Doses as high as 5 mcg/kg/min may sometimes be necessary. High dose epinephrine infusion may be useful in the setting of beta blocker poisoning (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008).
    3) CAUTION
    a) Extravasation may cause severe local tissue ischemia (Hegenbarth & American Academy of Pediatrics Committee on Drugs, 2008); infusion through a central venous catheter is advised.
    f) PHENYLEPHRINE
    1) MILD OR MODERATE HYPOTENSION
    a) INTRAVENOUS: ADULT: Usual dose: 0.2 mg; range: 0.1 mg to 0.5 mg. Maximum initial dose is 0.5 mg. A 0.5 mg IV dose can elevate the blood pressure for approximately 15 min (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011). PEDIATRIC: Usual bolus dose: 5 to 20 mcg/kg IV repeated every 10 to 15 min as needed (Taketomo et al, 1997).
    2) CONTINUOUS INFUSION
    a) PREPARATION: Add 10 mg (1 mL of a 1% solution) to 500 mL of normal saline or dextrose 5% in water to produce a final concentration of 0.2 mg/mL.
    b) ADULT DOSE: To raise blood pressure rapidly; start an initial infusion of 100 to 180 mcg/min until blood pressure stabilizes; then reduce infusion to 40 to 60 mcg/min titrated to desired effect. If necessary, additional doses in increments of 10 mg or more may be added to the infusion solution and the rate of flow titrated to the desired effect (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    c) PEDIATRIC DOSE: Intravenous infusion should begin at 0.1 to 0.5 mcg/kg/min; titrate to the desired effect (Taketomo et al, 1997).
    3) ADVERSE EFFECTS
    a) Headache, reflex bradycardia, excitability, restlessness and rarely dysrhythmias may develop (Prod Info phenylephrine HCl subcutaneous injection, intramuscular injection, intravenous injection, 2011).
    g) DOBUTAMINE
    1) DOSE: ADULT: Infuse at 5 to 10 micrograms/kilogram/minute IV. PEDIATRIC: Infuse at 2 to 20 micrograms/kilogram/minute IV or intraosseous, titrated to desired effect (Peberdy et al, 2010; Kleinman et al, 2010).
    2) CAUTION: Decrease infusion rate if ventricular ectopy develops (Prod Info dobutamine HCl 5% dextrose intravenous injection, 2012).
    h) ANTIDOTES
    1) SUMMARY - Glucagon may be effective in stimulating heart rate and improving cardiac output following beta-adrenergic blocker or calcium antagonist exposure. Likewise, calcium can improve depressed cardiac contractility following calcium antagonist overdose. Insulin and glucose infusions have been effective in reversing hypotension unresponsive to other modalities in patients with calcium antagonist overdose. Digoxin immune Fab may be used for the treatment of potentially life-threatening digoxin intoxication.
    i) GLUCAGON
    1) INDICATIONS: Glucagon is indicated for cardiac toxicity from BETA ADRENERGIC BLOCKER or CALCIUM CHANNEL BLOCKER overdoses that produce severe bradycardia, AV block, and hypotension. Treatment of symptomatic bradycardia with glucagon in 3 patients taking maintenance beta-blocker therapy obviated the need for further treatment (Howland, 2002; Love & Howell, 1997). Following a massive tricyclic antidepressant overdose, a severely hypotensive female responded to intravenous glucagon (bolus followed by an infusion), and her QRS interval on ECG shortened from 129 to 89 msec (Sener et al, 1995). Glucagon is also used when foreign bodies have been ingested and are lodged in the esophagus.
    2) DOSE (Adult): An initial intravenous bolus dose of 2 to 5 milligrams over 1 minute is recommended (may give up to 10 milligrams IV bolus); if no effect within 5 minutes, a repeat dose, up to 10 milligrams, can be given; or an infusion of 2 to 5 milligrams/hour (up to 10 milligrams per hour) may be given (Howland, 2002). When glucagon doses will exceed 2 mg, it is recommended that sterile water for injection be used as a diluent rather than the phenol-containing diluent provided by the manufacturer.
    3) DOSE (Adolescent): Give 50 micrograms/kilogram intravenous bolus over 1 to 2 minutes is recommended; if no response within 5 minutes, a repeat dose, up to 10 milligrams, can be given.
    4) MAINTENANCE INFUSION: Do NOT use phenol diluent when reconstituting for a continuous infusion. Reconstitute glucagon in D5W. Adult dose is 2 to 10 mg/hour, titrated to the desired effect on heart rate and blood pressure. Pediatric dose is 0.07 mg/kg/hour, titrated to the desired effect on heart rate and blood pressure (Howland, 2002).
    5) ADVERSE EFFECTS: Therapy is usually well tolerated, but dose-dependent nausea and vomiting are likely to occur; take measures to prevent aspiration. Hyperglycemia with resultant hypokalemia may occur secondary to a reflex release of insulin; monitor serum glucose and potassium during therapy. Hypersensitivity reactions are rare (Howland, 2002; White , 1999).
    j) CALCIUM
    1) CALCIUM ANTAGONIST EXPOSURE - Calcium has been used to reverse the hypotension and conduction defects observed following calcium antagonist exposure. It has been successful in mild overdoses, but its usefulness following a massive overdose is less predictable (Clark & Hanna, 1993; Pearigen & Benowitz, 1991; Krenzelok, 1991).
    2) DRUG OF CHOICE - Calcium chloride is thought to produce more predictable increases in extracellular ionized calcium and a greater positive inotropic response (Haynes et al, 1985; White et al, 1976). Calcium chloride is given through a central line.
    3) ADULT DOSE - Optimal dosing is not established; in one series, doses varied from 4.5 milliequivalents to 95.2 milliequivalents, with no evidence of a dose-response relation (Ramoska et al, 1993).
    a) CALCIUM CHLORIDE recommendations are 1 gram given over 5 minutes, repeated every 10 to 20 minutes for 3 to 4 more doses (Pearigen & Benowitz, 1991).
    b) CALCIUM GLUCONATE recommendations are 3 grams given over 5 minutes, repeated every 10 to 20 minutes for 3 to 4 more doses (Luscher et al, 1994; Pearigen & Benowitz, 1991) .
    k) INSULIN/DEXTROSE
    1) Insulin and dextrose infusions have been effectively used in patients with refractory hypotension secondary to calcium antagonist overdose. In adults, a bolus dose 10 units insulin and 25 grams dextrose was followed by an insulin infusion, with a dose ranging from 0.1 unit/kilogram/hour to 1.0 unit/kilogram/hour, and dextrose (50% w/v) infusion, the dose ranging from 5 grams/hour to 15 grams/hour, via a central venous catheter. (Yuan et al, 1999; Boyer et al, 2002).
    D) BRADYCARDIA
    1) ATROPINE
    a) ATROPINE/DOSE
    1) ADULT BRADYCARDIA: BOLUS: Give 0.5 milligram IV, repeat every 3 to 5 minutes, if bradycardia persists. Maximum: 3 milligrams (0.04 milligram/kilogram) intravenously is a fully vagolytic dose in most adults. Doses less than 0.5 milligram may cause paradoxical bradycardia in adults (Neumar et al, 2010).
    2) PEDIATRIC DOSE: As premedication for emergency intubation in specific situations (eg, giving succinylchoine to facilitate intubation), give 0.02 milligram/kilogram intravenously or intraosseously (0.04 to 0.06 mg/kg via endotracheal tube followed by several positive pressure breaths) repeat once, if needed (de Caen et al, 2015; Kleinman et al, 2010). MAXIMUM SINGLE DOSE: Children: 0.5 milligram; adolescent: 1 mg.
    a) There is no minimum dose (de Caen et al, 2015).
    b) MAXIMUM TOTAL DOSE: Children: 1 milligram; adolescents: 2 milligrams (Kleinman et al, 2010).
    b) ISOPROTERENOL
    1) ISOPROTERENOL INDICATIONS
    a) Used for temporary control of hemodynamically significant bradycardia in a patient with a pulse; generally other modalities (atropine, dopamine, epinephrine, dobutamine, pacing) should be used first because of the tendency to develop ischemia and dysrhythmias with isoproterenol (Neumar et al, 2010).
    b) ADULT DOSE: Infuse 2 micrograms per minute, gradually titrating to 10 micrograms per minute as needed to desired response (Neumar et al, 2010).
    c) CAUTION: Decrease infusion rate or discontinue infusion if ventricular dysrhythmias develop(Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    d) PEDIATRIC DOSE: Not well studied. Initial infusion of 0.1 mcg/kg/min titrated as needed, usual range is 0.1 mcg/kg/min to 1 mcg/kg/min (Prod Info Isuprel(TM) intravenous injection, intramuscular injection, subcutaneous injection, intracardiac injection, 2013).
    2) TRANSVENOUS PACING
    a) Cardiac pacing is indicated if pharmacologic measures are unsuccessful in controlling severe bradycardia or heart block.
    b) PROPAFENONE/CASE REPORT - A healthy 28-year-old male ingested 8.1 g propafenone (a class IC antiarrhythmic, which exhibits beta-adrenergic and calcium channel blocking activities) and developed profound bradycardia and hypotension along with seizures and coma. Initial therapy included fluid resuscitation, but persistent bradycardia and hypotension improved with only transvenous pacing (which would not capture until 1 mg of epinephrine was given; settings, 15 MA and rate of 100) and a constant epinephrine infusion. Glucagon, dopamine, and dobutamine were initiated without any change in heart rate or blood pressure. Mild cardiomyopathy was reported 4 months after exposure (Kerns et al, 1994).
    E) SEIZURE
    1) Seizure in the setting of toxin-induced hypotension (eg, tricyclic antidepressants) can be associated with deterioration of hemodynamic status, and should be treated aggressively (Ellison & Pentel, 1989).
    2) 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).
    3) 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 .
    4) 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).
    5) 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, 2009; Chin et al, 2008).
    6) 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).
    7) 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).
    8) RECURRING SEIZURES
    a) If seizures are not controlled by the above measures, patients will require endotracheal intubation, mechanical ventilation, continuous EEG monitoring, a continuous infusion of an anticonvulsant, and may require neuromuscular paralysis and vasopressor support. Consider continuous infusions of the following agents:
    1) MIDAZOLAM: ADULT DOSE: An initial dose of 0.2 mg/kg slow bolus, at an infusion rate of 2 mg/minute; maintenance doses of 0.05 to 2 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: 0.1 to 0.3 mg/kg followed by a continuous infusion starting at 1 mcg/kg/minute, titrated upwards every 5 minutes as needed (Loddenkemper & Goodkin, 2011).
    2) PROPOFOL: ADULT DOSE: Start at 20 mcg/kg/min with 1 to 2 mg/kg loading dose; maintenance doses of 30 to 200 mcg/kg/minute continuous infusion dosing, titrated to EEG; caution with high doses greater than 80 mcg/kg/minute in adults for extended periods of time (ie, longer than 48 hours) (Brophy et al, 2012); PEDIATRIC DOSE: IV loading dose of up to 2 mg/kg; maintenance doses of 2 to 5 mg/kg/hour may be used in older adolescents; avoid doses of 5 mg/kg/hour over prolonged periods because of propofol infusion syndrome (Loddenkemper & Goodkin, 2011); caution with high doses greater than 65 mcg/kg/min in children for extended periods of time; contraindicated in small children (Brophy et al, 2012).
    3) PENTOBARBITAL: ADULT DOSE: A loading dose of 5 to 15 mg/kg at an infusion rate of 50 mg/minute or lower; may administer additional 5 to 10 mg/kg. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusion dosing, titrated to EEG (Brophy et al, 2012). PEDIATRIC DOSE: A loading dose of 3 to 15 mg/kg followed by a maintenance dose of 1 to 5 mg/kg/hour (Loddenkemper & Goodkin, 2011).
    4) THIOPENTAL: ADULT DOSE: 2 to 7 mg/kg, at an infusion rate of 50 mg/minute or lower. Maintenance dose of 0.5 to 5 mg/kg/hour continuous infusing dosing, titrated to EEG (Brophy et al, 2012)
    b) Endotracheal intubation, mechanical ventilation, and vasopressors will be required (Brophy et al, 2012) and consultation with a neurologist is strongly advised.
    c) Neuromuscular paralysis (eg, rocuronium bromide, a short-acting nondepolarizing agent) may be required to avoid hyperthermia, severe acidosis, and rhabdomyolysis. If rhabdomyolysis is possible, avoid succinylcholine chloride, because of the risk of hyperkalemic-induced cardiac dysrhythmias. Continuous EEG monitoring is mandatory if neuromuscular paralysis is used (Manno, 2003).

Range Of Toxicity

Summary

    A) Because of the numerous agents that may be associated with toxin-induced hypotension, a minimum toxic dose cannot be delineated. Coadministration of multiple agents and coexisting conditions (eg, acidosis, hypoxia, volume depletion, etc) may produce refractory symptoms or potentiate the clinical effects observed.
    B) Refer to a specific management if a toxin is known or suspected to determine potential toxicity.

Pharmacology Toxicology

Toxicologic Mechanism

    A) Toxin-induced hypotension may be due to several mechanisms: intravascular volume depletion (ie, gastrointestinal, urinary or insensible losses, interstitial redistribution {"third spacing"}) and alterations in venous tone (agents can produce an increase in venous capacitance, a decrease in venous pressure and relative hypovolemia). Changes in venous tone can be caused by centrally- mediated effects on the sympathetic nervous system (eg, clonidine) or direct effects on the peripheral vasculature (eg, tricyclic antidepressant agents, theophylline) (Hessler, 2002). Other mechanisms associated with persistent toxin-induced hypotension can include alpha- or beta-adrenergic receptor blockade. Dysrhythmias and vasodilatation can be produced by blockade of myocardial calcium channels (Hurlbut, 2000). In addition, coexisting hypoxia, acidosis and/or electrolyte abnormalities, myocardial infarction, anaphylaxis, and hypothermia can result in hypotension (Hessler, 2002; Hurlbut, 2000).

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