Overdose – Common Medications

Table I.

Effect	Clinical manifestation	Proposed Mechanism
Respiratory Alkalosis	-Tachypnea-Hyperpnea	Direct stimulation of the respiratory center inducing hyperventilation
GI Toxicity	Nausea/Vomiting	-Direct Local Irritation-Stimulation of the chemoreceptor trigger zone-Inhibition of stomach acid production
Metabolic Acidosis	-Anion Gap Acidosis-Increased Lactate	-Bicarb excretion to compensate for primary respiratory alkalosis-Inhibition of oxidative phosphorylation-Increased fatty-acid metabolism generating ketone bodies
CNS Toxicity	-Neuroglycopenia-Altered Mental Status-Lethargy-Coma-Seizures-Hyperthermia	-Direct effect of salicylates-Uncoupling oxidative phosphorylation
Endocrine Toxicity	CSF Hypoglycemia	-Increase glycolysis secondary to uncoupling oxidative phosphorylation-The rate of CSF glucose use exceeds the rate of supply leading to CNS hypoglycemia
Otolaryngologic Effects	-Tinnitus-Hearing Loss	-Direct effect on electrophysiologic changes in the inner ear and 8th cranial nerve impulse transmission-Drug accumulation and vasoconstriction may contribute
Acute Lung Injury	-Clinical and radiographic manifestations of pulmonary edema	-Direct effect of salicylates-Hypoxia resulting in pulmonary arterial hypertension

What caused this disease to develop at this time?

Pathophysiology of Acetaminophen toxicity

Acetaminophen is primarily metabolized by the liver. Nearly 65-80% undergoes sulfation and glucoronidation to non-toxic metabolites. 5-15% of acetaminophen is metabolized in liver by the CYP P450 isoenzyme, 2E1 to a reactive, toxic metabolite, N-acetyl-p-benzoquinoneimine (NAPQI). After therapeutic doses, approximately 5% of acetaminophen is excreted in the urine unchanged.

Under normal conditions and therapeutic dosing, NAPQI is rapidly detoxified by glutathione to non-toxic metabolites. The safety of acetaminophen depends on the presence of glutathione stores. In healthy patients and after therapeutic dosing, glutathione stores are far greater than what is needed to detoxify NAPQI. In overdose and in patients with depleted glutathione stores (e.g., malnourished patients, chronic alcoholics), NAPQI is not detoxified and free NAPQI is then able to bind to hepatocytes and cause cellular damage. NAPQI covalently binds to and acrylates cell proteins and cause cell damage and death. After this covalent binding, a cascade of events occurs with alteration in normal cell function and can cause impaired mitochondrial function, increased cell permeability and inflammatory reactions.

This all results in the final pathway of hepatic cell death and leads to hepatic necrosis. Acetaminophen causes predominantly a centrilobular necrosis (Zone III) because this zone contains the highest concentration of CYP 2E1.

Acetaminophen can also cause an isolated renal injury which is an acute tubular necrosis. This is believed largely to be due to the local metabolism of acetaminophen to NAPQI in the renal tubules by 2E1.

The sequelae of severe toxicity are due to the secondary effects of fulminant hepatic failure as opposed to direct acetaminophen toxicity.

Stages of Acetaminophen toxicity

The clinical course of acetaminophen can be divided into four phases. Although there may be some overlap in these phases, staging can be useful in assessing patients. Early recognition is imperative to minimize morbidity and mortality however, this is difficult because of the lack of early predictive signs.

Stage I is an asymptomatic phase. There has been no hepatic injury at this point and even patients that eventually progress to fulminant hepatic failure can be completely asymptomatic during Phase I. Clinical findings, if any, are often non-specific during phase I. There may be nausea, vomiting, malaise and pallor. Hepatic function tests will be normal in Stage 1. Occasionally, after large overdoses, patients can have altered mental status and/or metabolic acidosis. This is not routine and other causes must be considered to ensure that there were no co-ingestants.

Stage II is heralded by the onset of liver injury. Aspartate aminotransferase (AST) is the most sensitive, widely available way to measure hepatotoxicity. Elevations of AST generally begin within 24 hours, although this increase can begin within 12 hours when there has been a massive overdose.

Stage III is when the maximum hepatotoxicity occurs. Generally, this stage occurs between 72 and 96 hours after ingestion. The clinical manifestations can include: fulminant hepatic failure; coma; coagulopathy; markedly elevated transaminases; hepatorenal syndrome. During this stage, it is critical that a patient be assessed for poor prognostic indicators as these patients may require a liver transplant. Fatalities due to hepatic failure tend to occur between 3 and 5 days after an overdose. With treatment, the mortality rate after acute acetaminophen poisoning is less than 0.5%.

Stage IV is defined as the recovery phase. Generally speaking, the time to recovery is quite variable and is generally dependent on how severely ill the patient was.

Clonidine toxicity – Pharmacology and Pathophysiology

Clonidine and the other centrally acting antihypertensive agents work centrally to reducing the sympathetic outflow by agonizing the central alpha-2 adrenergic receptors in the brain. This causes a reduction of norepinephrine release, resulting in a reduction in heart rate, vascular tone and the arterial blood pressure.

Imidazoline receptors are located in the ventrolateral medulla of the brain as well as other tissues and likely plays a role in the clinical effects/toxicity of these agents. Direct stimulation of these receptors appear to decrease blood pressure independent of the central alpha-2 adrenergic effects.

In therapeutic doses, these agents have little effect on peripheral alpha-2 adrenergic receptors. However, in overdose, peripheral agonism of the alpha-2 adrenergic receptor may occur with a resultant transient increase in blood pressure.

Sulfonylurea toxicity – Pharmacology and Pathophysiology

Sulfonylureas bind to the beta islet cell of the pancreas and close potassium channels. This results in insulin release and therefore, sulfonylureas are referred to as insulin secretagogues. The sulfonylureas may produce delayed hypoglycemia (up to 24 hours) and persistent hypoglycemia for greater than 24 hours after exposure.

The meglitinide class of drugs are structurally dissimilar to sulfonylureas but they bind to the ATP-dependent K+ channels on the beta islet cell and result in the same pharmacologic effect of an increase in insulin release. The meglitinides, repaglinide and nateglinide, have a faster onset and shorter duration of effect when compared to sulfonylureas. Compared to the sulfonylureas, the potential for hypoglycemia is less with the meglitinides, but potentially life-threatening hypoglycemia is still a possibility with these agents.

Beta Blocker and Calcium Channel Blocker toxicity – Pharmacology and Pathophysiology

Beta Blockers (Beta Adrenergic Antagonists):

Three distinct beta adrenergic receptors have been identified: Beta-1, Beta-2 and Beta-3. Approximately 80% of the beta (B) receptors in the healthy heart are B-1. B-2 receptors and possible B-3 receptors are present in the heart but to a lesser degree. Catecholamine binding to Beta-1 receptors stimulates activation of adenylate cyclase through a G-protein coupled process. This results in an increased cyclic AMP (cAMP) which then initiates an entire cascade with the end result being an increase in intracellular calcium and thereby an increase in cardiac contractility. Beta-2 receptors also increase chronotropy although the mechanism is less well elucidated.

Beta-receptor agonists have noncardiac effects which are also important. Beta-receptor stimulation causes smooth muscle relaxation in multiple organs, the most important being in arteriolar smooth muscle relaxation, and bronchodilation in the lungs.

Beta-adrenergic antagonists (Beta Blockers) competitively inhibit the effects of catecholamines at Beta-1 receptors. This results in a decrease in cellular cyclic AMP in the myocardium and a blunting of both the chronotropic and inotropic response to catecholamines.

Calcium Channel Blockers (Calcium Channel Antagonists):

Numerous types of calcium channels have been identified including L, N, P, T, Q and R types. They are found intracellularly on the sarcoplasmic reticulum or on cell membranes in neuronal and secretory tissues. All currently available calcium channel blockers (CCBs) antagonize L-type channels.

There are three structurally different groups of CCBs: phenylaklyamine (verapamil); benzothiazepine (diltiazem) and dihydropyridines (amlodipine; nifedipine). Each of these three bind differently to the subunit on the L-type channels and thereby, each has a different affinity for various L-type channels. Verapamil and diltiazem have profound effects on the SA and AV nodal tissue. In contrast, the dihydropyridines have little myocardial effects but they antagonize peripheral L-type calcium channels with a resultant decline in systemic vascular resistance. Because of their pharmacologic difference, verapamil and diltiazem cause profound bradycardia and hypotension in overdose whereas dihydropyridines cause hypotension with a reflex tachycardia.

Additional Pharmacology of Beta Blockers

Both selective and non-selective beta blockers are commercially available, though in overdose situations the selectivity is lost. Beta blockers also differ in their intrinsic selectivity (ISA), membrane stabilizing effects (MSA) and potassium channel blocking abilities. Beta blockers that inhibit fast sodium channel blockers are said to have MSA; propranolol is the most commonly known beta blocker with MSA.

Beta blockers with ISA act as partial agonists at the Beta-adrenergic receptor thereby decreasing the severe decrease in resting heart rate that occurs with other beta blockers. The clinical benefit of ISA has not been demonstrated and the use of these agents are limited. An example of a beta blocker with ISA is acebutolol. Sotalol is a beta blocker but is better known for its anti-arrhythmic properties because of its effect on blocking the delayed rectifier potassium current resulting in a prolongation of the action potential and prolonged QT interval on the electrocardiogram.

Antidepressant toxicity – Pharmacology and Pathophysiology

Tricyclic Antidepressants (TCAs):

Therapeutically, TCAs decrease presynaptic reuptake of norepinephrine and serotonin. TCAs also have numerous other pharmacologic effects which are responsible for the side effect profile as well as the clinical manifestations of toxicity after overdose. TCAs are competitive antagonists of the muscarinic acetycholine receptors; they are antagonists at the alpha-1 adrenergic receptor in the periphery; they are fast sodium channel blockers in cardiac tissue; they inhibit both central and peripheral histamine receptors and they are GABA antagonists. All of these pharmacologic effects describe the clinical toxicity seen in overdose with a TCA.

Serotonin Reuptake Inhibitors (SSRIs):

SSRIs decrease the reuptake of serotonin and thereby secreted serotonin persists in the neuronal synapse stimulating post-synaptic serotonin receptors. Unlike TCAs, SSRIs have little effect on cholinergic receptors, GABA receptors, sodium channels or peripheral alpha-adrenergic receptors.

Atypical Antidepressants:

Venlafaxine and desvenlafaxine decreases the reuptake of serotonin and norepinephrine. They can also cause inhibition of fast sodium channels and antagonize GABA binding to its receptor.

Bupropion decreases the reuptake of dopamine and to a lesser extent, serotonin and norepinephrine. Additionally, buproprion is a fast sodium channel blocker on cardiac cells and is able to antagonize GABA binding.

Mirtazapine is fairly unique and it causes serotonin reuptake inhibition and increases neuronal norepinephrine. It also blocks some subtypes of serotonin receptors which appear to have antidepressant effects.

Salicylate poisoning – Pharmacology and Pathophysiology

It is important to differentiate that the therapeutic effect of aspirin from the toxicity associated with acute aspirin poisoning. Under normal therapeutic conditions, salicylates inhibit cyclooxygenase thereby decreasing the synthesis of prostaglandins resulting in the antiinflammatory, analgesic, antiplatelet and antipyretic properties of aspirin.

By contrast the toxicity of salicylates is due to their effects on the electron transport chain. Salicylates are metabolic poisons and interfere with aerobic respiration by uncoupling oxidative phosphorylation. The net result is a decrease in aerobic respiration and an increase in anaerobic respiration with an increase in lactate production and inability to create ATP.

What laboratory studies should you request to help confirm the diagnosis? How should you interpret the results?

Acetaminophen toxicity

A serum acetaminophen concentration should be obtained upon initial presentation or 4 hours or more post-exposure. Acetaminophen levels obtained 4 or more hours after a single acute ingestion can help predict the risk of serious hepatotoxicity (defined by an AST >1000 U/L) using the Rumack-Matthew nomogram. This nomogram has been well validated and is available on many reference sites including Micromedex and Lexi-Comp. The nomogram, as first published in 1975, indicates that an acetaminophen concentration of 200 mcg/ml at 4 hours post-ingestion will likely result in hepatotoxicity. In the United States, an acetaminophen level of 150 mcg/ml at 4 hours post ingestion is a more generally accepted value for predicting a high risk of hepatotoxicity and the need for therapeutic intervention.

Depending on the stage of toxicity when the patient presents, additional laboratory studies to consider include: liver function tests; basic metabolic profile; coagulation studies; lactate; phosphate and blood gas analysis.

What are the Poor Prognostic Indicators?

The King’s College Criteria are used to predict liver failure and the need for liver transplantation after acetaminophen poisoning. For acetaminophen induced liver failure, the high risk criteria include a serum pH < 7.3 (after appropriate fluid resuscitation) or all three of the combination of a serum creatinine > 3.3 mg/dL, a prothrombin time > 100 seconds (most usually use an INR > 6.5)], and grade III or IV encephalopathy.

The survival rate for patients who meet these criteria but who do not receive a liver transplant is less than 20%.

In addition to the Kings College Criteria, serum lactate concentration at a median time of 55 hours after overdose of greater than 3.0 mmol/L after fluid resuscitation has been shown to be sensitive and specific to predict mortality. Serum phosphate level of greater than 1.2 mmol/L at 48-96 hours after overdose has been shown in a single study to also be predictive of mortality, although the data supporting this is less rigorous.

Clonidine toxicity

The diagnosis of clonidine or other centrally acting antihypertensive agents is a clinical diagnosis. The physical exam findings and the vital signs, with a good patient history, will quickly guide the diagnosis. These patients may appear to have an opioid-like toxidrome with the CNS depression, respiratory depression and miosis. The hypotension and bradycardia, in addition to these findings, should suggest that these agents be included in the differential diagnosis.

In patients with suspected exposure to clonidine or similar agents, rapid assessment and stabilization of airway, breathing and circulation is essential. A 12-lead electrocardiogram and continuous cardiac and pulse oximetry monitoring should be initiated immediately. Management decisions should be based on the patient’s clinical presentation and exam findings.

Although there are no electrolyte or hematologic abnormalities that occur after clonidine exposure, it is prudent to measure the serum glucose in all patients with acute alterations in mental status.

Sulfonylurea toxicity

Serial blood glucose monitoring is essential following a sulfonurea overdose. If a patient is found to be hypoglycemic by fingerstick blood glucose measurement, it is prudent to confirm that with a venous blood glucose measurement.

Though blood glucose monitoring is accurate, treatment for hypoglycemia should not be solely based on the glucose level. In particular, it is important to remember that patients with diabetes may have symptoms of hypoglycemia despite what seems to be a relatively ‘normal’ blood glucose measurement.

Children can become hypoglycemic after ethanol ingestion because of decreased glycogen stores. Depending on the scenario, a serum ethanol concentration may be warranted.

In a patient with hypoglycemia of unknown etiology, C-peptide and insulin levels can help confirm or differentiate a sulfonylurea overdose from exogenous insulin administration or an insulinoma. These results may take several days to return so treatment of the hypoglycemia cannot await the result. In sulfonylurea overdose, meglitinide overdose and with an insulinoma, the C-peptide and insulin levels will be markedly elevated. In contrast, in cases of exogenous insulin overdose, C-peptide levels will be markedly low and the insulin level will be markedly elevated.

Beta Blockers or Calcium Channel Blockers toxicity

All patients with suspected exposure/toxicity should have a 12 lead electrocardiogram and should be monitored on continuous cardiac monitoring.

Serum glucose should be tested as hyperglycemia is a poor prognostic sign after CCB overdose and hypoglycemia can be present in pediatric BB exposures.

In patients with hypotension and signs of hypoperfusion, an assessment of the serum electrolytes and acid-base status may be helpful. Lactic acid concentration can be performed if metabolic acidosis with an anion gap is present.

As with all intentional overdoses, additional laboratory testing for exposure to acetaminophen and salicylates should be performed.

In an unintentional exposure, a basic metabolic profile should be obtained and repeated depending on how acutely ill the patient is.

Antidepressant toxicity

No specific laboratory test will assist in the diagnosis of the antidepressants. In acutely poisoned patients, particularly those with intentional ingestions, laboratory testing for other medications including acetaminophen and salicylate levels is important.

Basic metabolic profile and close evaluation of electrolytes and acid base status are part of good supportive care. Close monitoring of acid base status and serum potassium is of particular importance when sodium bicarbonate is being given for wide QRS complex durations.

Serum concentrations of TCAs are available however, the levels have not been correlated with clinical toxicity and therefore not generally helpful in the acute management of these patients.

Salicylate poisoning

Basic metabolic profile should be obtained to assess acid-base status particularly determining the presence or absence of an anion gap metabolic acidosis. Arterial or venous blood gas should be obtained to assess the acid base status and followed serially. In a patient without evidence of acute lung injury, venous blood gas monitoring can be done. However, if lung injury is suspected or confirmed, arterial blood gas should be performed to assess the degree of hypoxia.

Venous glucose monitoring should be done in every patient and in particular those patients with altered mental status. However, because of the discordance of venous blood glucose to CSF glucose, any patient with aspirin poisoning should receive supplemental glucose if they have an altered mental status despite a normal peripheral venous glucose.

Salicylate concentrations should be obtained serially every 2-3 hours until the peak has occurred and the level is trending downward. The frequency of obtaining salicylate concentrations can decrease when the level has peaked and is trending downward. It is important to know the units of which your institution reports salicylate levels. Some report in mg/L and others report in mg/dL. The therapeutic range for salicylates is 15-30 mg/dl and patients often complain of symptoms with levels of 30-40 mg/dl. Toxic salicylate concentrations are generally considered those over 30 mg/dl; levels approaching 90 – 100 mg/dL should be considered life-threatening.

Confirming the diagnosis

Acetaminophen toxicity

Acetaminophen levels obtained 4 or more hours after a single acute ingestion can help predict the risk of serious hepatotoxicity (defined by an AST >1000 U/L) using the Rumack-Matthew nomogram. This nomogram has been well validated and is available on many reference sites including Micromedex and Lexi-Comp. The nomogram, as first published in 1975, indicates that an acetaminophen concentration of 200 mcg/ml at 4 hours post-ingestion will likely result in hepatotoxicity. In the United States, an acetaminophen level of 150 mcg/ml at 4 hours post ingestion is a more generally accepted value for predicting a high risk of hepatotoxicity and the need for therapeutic intervention with N-Acetylcysteine.

There is little data to guide therapy after an unintentional intravenous (IV) Acetaminophen overdose. IV acetaminophen is a brand-new dosage formulation in the United States and until we have better data, treatment includes following consensus guidelines. As discussed below, treatment with N-acetylcysteine is recommended in patients that receive a single one time dose of IV acetaminophen greater than 60 mg/kg or a serum acetaminophen level of greater than 50 mcg/mL at the 4 hour line.

If you are able to confirm that the patient has overdosed, what treatment should be initiated?

Acetaminophen toxicity

N-acetylcysteine (NAC) is the most frequently used antidotes for acetaminophen toxicity and its use can be life-saving in the management of severe acetaminophen poisoning. When acetaminophen is still present in the plasma, NAC primarily acts by replenishing glutathione stores and thereby detoxifying N-acetyl-p-benzoquinoneimine (NAPQI) which is the major toxic metabolite in acetaminophen poisoning. NAC also serves as a sulfur donor and potentially increases the metabolism of acetaminophen through sulfation to non-toxic metabolites.

Once fulminant hepatic failure occurs, even when all of the acetaminophen has been metabolized, NAC is still beneficial and has been shown to decrease mortality by 50% in this scenario. It is believed to work through antioxidant and anti-inflammatory properties to improve oxygen delivery and utilization as well as by replenishing glutathione stores.

NAC is available in both oral and intravenous dosage forms. No head-to-head studies compare IV to oral NAC, though, both are believed to be equally efficacious when administered within 8 hours of an acetaminophen overdose and before hepatic failure has occurred. NAC can be beneficial when given after 8 hours, although the incidence of significant hepatotoxicity increases when used later. Of note however, only IV NAC has been shown to be beneficial in patients who have fulminant hepatic failure due to acetaminophen.

Indications for the initiation of NAC include:

A serum acetaminophen concentration on or above the Rumack-Matthew nomogram;

A serum acetaminophen level not available within 8 hours of the ingestion of a potentially toxic dose;

Hepatotoxicity as defined by clinical symptoms or liver enzyme elevations above baseline.

The FDA approved dosing for
IV NACis 150 mg/kg infused over 1 hour followed by 50 mg/kg over 4 hours and then 100 mg/kg over 16 hours. There are specific recommendations available in the package insert for dilution specific for pediatric patients and this should be followed closely.

The FDA approved dosing for
oral NACis 140 mg/kg followed by 70 mg/kg every 4 hours for a total of 17 doses.

Because of the risks associated with IV NAC, it is recommended that oral NAC be used in small children, unless there is a strong indication for IV NAC.

Clonidine toxicity

In patients with suspected exposure to clonidine or similar agents, rapid assessment and stabilization of airway, breathing and circulation is essential. A 12-lead electrocardiogram and continuous cardiac and pulse oximetry monitoring should be initiated immediately. Management decisions should be based on the patient’s clinical presentation and exam findings.

Although there are no electrolyte or hematologic abnormalities that occur after clonidine exposure, it is prudent to measure the serum glucose in all patients with acute alterations in mental status.

Gastrointestinal decontamination with activated charcoal can be effective if given very early after the exposure but because of the rapid onset of symptoms following clonidine ingestion, this often is not employed. In patients who have ingested a clonidine patch, multiple doses of activated charcoal or whole bowel irrigation with poly-ethylene glycol with electrolyte solution can be considered.

Treatment of clonidine overdose is largely supportive. Hypotension generally responds to standard doses of IV crystalloid boluses. Bradycardia is generally mild and self-limited but in severe poisonings bradycardia may respond to standard PALS dosing of atropine. Dopamine has been used in patients with recalcitrant hypotension or bradycardia.

Tactile stimulation is effective in improving the CNS and respiratory depression as well as the hemodynamics. In fact, tactile stimulation has been effective in preventing an intubation in a published case report.

Naloxone has been used and effective in approximately 50% of the cases of clonidine toxicity. Naloxone has been effective in reversing the CNS depression, respiratory rate, heart rate and blood pressure in responsive patients. It remains unclear as to the exact reason for this physiologic response. Clinical improvement may only occur with higher doses of naloxone (up to 10 mg). It remains unclear how effective naloxone is with other centrally acting antihypertensives but because of its relative safety in opioid-naive patients, it is not unreasonable to try this intervention.

The dosing of naloxone, for this scenario, should be an initial dose of 2 mg and titrated upwards to 10 mg. If no effect at 10 mg, naloxone should be considered a treatment failure and other interventions to control heart rate and blood pressure be employed. The duration of effect of naloxone is relatively shorter than the agent ingested and therefore, if effective, a continuous infusion of naloxone at 2/3 the effective dose should be initiated.

Sulfonylurea toxicity

Treatment focuses on the correction of hypoglycemia. Symptomatic patients require immediate dextrose supplementation: 0.5 -1 g/kg of D50W in young adults; D25W in children or D10W in neonates. Re-dosing is often required depending on symptoms and repeat glucose monitoring. Continuous infusions of dextrose are often required and should be employed with the goal of maintaining blood glucose measurements greater than 80 mg/dL. Oral feeding should be attempted as soon as possible if the child is awake and alert.

Octreotide is a long-acting synthetic analog of somatostatin and has been shown to counteract the insulin releasing properties of sulfonylureas and meglitinides. Octreotide decreases intracellular calcium release from the beta islet cell of the pancreas and thereby decreases insulin release. It is used as an adjunct to dextrose and has been shown to decrease the amount of supplemental dextrose to maintain serum glucose concentrations. Octreotide is given subcutaneously at a dose of 1-1.5 mcg/kg/dose (up to the adult dose of 50 mcg) and can be repeated every 6 hours. The utilization of octreotide does not diminish the need for intensive monitoring of blood glucose levels.

We suggest that octreotide be initiated if rebound hypoglycemia occurs after dextrose has been given for treatment of a sulfonylurea exposure/overdose. Side effects associated with several doses of octreotide are minimal and may include diarrhea and abdominal discomfort.

Gastrointestinal decontamination with activated charcoal 1 g/kg without sorbitol can be considered in an asymptomatic patient and an exposure that has occurred within 1 – 2 hours prior to ED arrival.

All patients with exposure to sulfonylureas require blood glucose monitoring for 24 hours, paying particular attention to intensive glucose monitoring when the child is asleep. If sulfonylurea induced hypoglycemia has occurred in a child, we recommend hourly fingerstick glucose measurements when the child is asleep during the initial day. There are several cases reported in the literature describing a delay in the onset of hypoglycemia for 12-18 hours post-exposure.

There is little data to suggest how long to observe a patient with meglitinide exposure; at this point, because of the paucity of data, we recommend the same observation and monitoring as one would for sulfonylureas.

Beta Blockers or Calcium Channel Blockers toxicity

Because of the pathophysiologic similarities between CCBs and BBs, treatment is similar. One must rapidly assess and manage the airway, breathing and circulation. In any a patient with an altered mental status, fingerstick glucose should be obtained.

Initial treatment, particularly in an asymptomatic patient, should focus on gastrointestinal decontamination. Attempts to prevent absorption of drug from the GI tract may mitigate toxicity. This can be a critical intervention. The importance of early GI decontamination even for the well-appearing, asymptomatic patient with exposure to a sustained release product may be life-saving. This is of particular importance in children where it has been described that even a single pill or two of a sustained release CCB results in toxicity.

Orogastric lavage can be considered in large ingestions if the patient is seen within 1-2 hours after ingestion however, but it should be noted that most pill formulations of CCBs and BBs are too large to be removed by even the largest sized orogastric tubes.

Activated charcoal 1 g/kg should be considered in all patients with an exposure to an immediate release product. In patients with bowel sounds, multiple doses of activated charcoal (without sorbitol) should be considered (1 g/kg every 2-4 hours). In patients who have ingested a sustained release formulation, whole bowel irrigation with poly-ethylene glycol with electrolyte solution should be employed.

The pediatric dosing for PEG-ELS is 500 mL/hour orally until the rectal effluent is clear. PEG-ELS can cause nausea, vomiting and abdominal distention; treatment with antiemetics should be employed to minimize this. PEG-ELS can be administered orally though most children will not be able to effectively drink that quantity so nasogastric administration should be considered. PEG-ELS does not cause any electrolyte abnormalities or osmotic shifts and therefore is a relatively safe intervention.

Asymptomatic patients with exposure to an immediate release preparation can be observed for 6-8 hours. Asymptomatic patients with exposure to a sustained release preparation or a preparation with a delayed peak effect (e.g., amlodipine) must be observed for 24 hours. Patients with exposure to sotalol require 24 hour observation.

Pharmacotherapy should focus on maintenance or improvement of the hemodynamic instability. The treatment of patients with hypotension and bradycardia begins with IV crystalloid fluids and atropine. Unfortunately, patients with more than mild poisoning often do not adequately respond to these interventions. Other treatment modalities include calcium; glucagon; hyperinsulinemia/euglycemia therapy; vasopressors; cardiac pacing; 20% fatty acid emulsion; extracorporeal circulatory support and intra-aortic balloon pump.

Each of these interventions will be discussed briefly below.

Calcium:

Calcium is an integral part of myocardial function and is necessary for normal conduction, contraction and vascular tone. Calcium has been used for both CCB and BB toxicity. the administration of exogenous calcium may overcome the already blocked calcium channels or increase calcium entry into the myocardium via non-blocked channels. It should be initiated after atropine and fluids.

Calcium is available in both chloride and gluconate salt forms and the dosing is somewhat empirical. One gram of calcium chloride contains 13.5 mEq (270mg) of elemental calcium compared with 1 gram of calcium gluconate which contains 4.5 mEq (90 mg) of elemental calcium. Calcium gluconate may be preferred for pediatric patients. Calcium chloride should be given cautiously and through a large bore peripheral intravenous line or through a central line to minimize the chance for tissue necrosis associated with extravasation. A reasonable starting dose in children is 0.2 ml/kg of 10% calcium chloride or 0.6 mL/kg of 10% calcium gluconate. The dose can be repeated every 10-15 minutes depending on the response up to a total of approximately 4 doses. Higher doses should only be administered when one can closely monitor blood ionized calcium levels.

Glucagon:

Glucagon can be useful in the management of BB overdose because it can increase cardiac cAMP directly and independently of the beta receptor, resulting in an increase in inotropy and chronotropy and also possibly improving cardiac conduction. Glucagon is used for CCB overdose as well because an increase in cAMP is beneficial regardless of the cause. Glucagon has a relatively quick onset of action and also a short duration of effect. If initially effective, a continuous infusion should be employed.

As with many therapies in toxicology, dosing recommendations are somewhat empirical. Doses of 50 mcg/kg, up to a dose of 10 mg in adults, have been employed. If the glucagon is effective, infusions at the effective dose of glucagon should be started. Glucagon causes nausea and vomiting and therefore needs to be considered prior to administration particularly in a patient with concern for aspiration. Antiemetics should be given because of the near likely induction of nausea and vomiting at the doses that are required.

Hyperinsulinemia/Euglycemia Therapy (HIET):

HIET has changed the management and outcome in patients severely poisoned by CCBs and BBs. HIET was first demonstrated to be effective in managing patients severely poisoned with CCBs and/or BBs in the late 1990s. The exact mechanism for HIET in CCB/BB toxicity remains unknown although the data suggest an improvement in carbohydrate use and the production of energy in myocardial cells with a resultant improvement in contractility.

The beneficial effects of HIET is delayed and generally takes approximately 15-60 minutes. Because of this time delay, it is imperative to initiate HIET early in the course of therapy. We recommend initiating HIET when hypotension and bradycardia persist after IV fluids, atropine, calcium and/or glucagon. HIET is particularly effective at improving myocardial contractility and early administration may avert the need for vasopressors or allow a reduction in their dose and their potential for ischemic consequences. The sicker the patient is from a CCB overdose, the more likely they are to be hyperglycemic before HIET is instituted.

HIET should begin with an IV loading dose of 1 Unit/kilogram of regular insulin followed by an infusion of 0.5 to 1 Unit/Kilogram/hour. The infusion dose can then be increased every 20 to 30 minutes up to 2.5 to 3 Units/kilogram/hour depending on the response. Serum glucose should be monitored and maintained at a level greater than 100 mg/dL during HIET. If the initial blood glucose is less than 400 mg/dL, an IV loading dose of 0.5 g/kg dextrose should be administered along with the insulin. Infusions of 0.5 grams/kilogram/hour of dextrose are given with meticulous and frequent monitoring of serum glucose and potassium levels. A falling glucose concentration should be treated by increasing the glucose delivery rather than decreasing the insulin infusion until the patient is hemodynamically stable.

Vasopressors:

Vasopressors may be necessary to manage hemodynamics in patients poisoned with BBs and/or CCBs. There have been cases with both success and failure of a wide variety of vasopressors including dopamine, norepinephrine, epinehrine, dobutamine and vasopressin.

Norepinephrine is a logical first choice agent in the setting of non-dihydropyridine CCBs and/or BB induced bradycardia and hypotension because of its agonist effects on B-1 receptor as well as its alpha-1 adrenergic effects. Phenylephrine is a more logical choice for dihydropyridine CCBs as they are pure alpha-adrenergic receptors and improve the peripheral vascular resistance. Dopamine is an indirect acting vasopressor and may be less effective in improving hemodynamics in patients poisoned with CCBs and/or BBs because these patients are likely to have presynaptic depletion of catecholamines. Dobutamine is a poor choice as it has B-1 and B-2 agonist properties and the B-2 agonism can result in peripheral vasodilation which may worsen the hemodynamics in CCB and/or BB poisoned patients.

Vasopressin is a V-1 agonist which results in peripheral vasoconstriction and has been described to have beneficial responses in patients poisoned with CCBs or BBs. It may be considered when the patient remains hemodynamically unstable despite appropriate HIET therapy and adequate dosing of norepinephrine or phenylephrine.

20% Fatty Acid Emulsion (IFE):

Despite the promising case reports, IFE therapy as an antidote remains in the discovery phase. IFE should be considered in the setting of a CCB or BB when a patient is refractory to advanced supportive care measures and other accepted antidotal therapy. Verapamil, diltiazem and propropanol are potential toxins that should be considered amenable to IFE.

The dosing of IFE is unclear and remains speculative. Based on the successful reports in the literature, a reasonable dosing strategy is 20 % IFE 1.5 mL/kg over 1-2 minutes IV push; the bolus dose can be repeated. Some reports describe the use of continuous infusion, following the bolus dose with improvement in hemodynamics, at a rate of 0.25-0.5 mL/kg/min for 30-60 minutes. There are little published information about adverse events though it appears to be relatively safe.

Adjunct interventions:

In severely poisoned patients, every pharmacologic intervention may fail. Transcutaneous or transvenous pacing may be required to improve heart rate. Intraaortic balloon pump has been reported to be effective. Intraaortic balloon pump has been shown to improve cardiac output and blood pressure in CCB poisoned patients. Cardiopulmonary surgeons will need to be available to place an intraaortic balloon pump. Small children are likely not candidates for intraaortic balloon pump because of their small size.

Extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass have been described in severe cases. These require special equipment and personnel and likely not available at every institution.

IFE – Mechanism of action

IFE has been used for years to supply calories in the form of free fatty acids to patients requiring parenteral nutrition. A novel use of fatty acid emulsion is its role as an antidote for drug-induced cardiovascular collapse. The first animal models describing its role were in bupivacaine induced cardiac toxicity. Since those early studies, there have been multiple case reports of successful resuscitation of cardiovascular collapse due to local anesthetic toxicity. This led to investigators looking into the role, if any, of IFE for other drug toxicity scenarios caused by lipid soluble drugs including calcium channel blockers, beta blockers and tricyclic antidepressants.

The exact mechanism as to its effectiveness remains speculative but the ‘lipid sink’ theory is foremost at this time. Other actions that might contribute include direct activation of myocardial calcium channels and modulation of myocardial energy by providing the heart with energy in the form of free fatty acids. Regardless of the mechanism, IFE has been successfully used in animal models as well as in humans after exposure to a cardiovascular toxin with toxicity.

Antidepressant toxicity

In all patients presenting to the Emergency Department after an intentional overdose, rapidly obtaining an electrocardiogram (ECG) can provide important diagnostic information. The ECG is helpful, in particular, to predict the incidence of seizures and ventricular dysrhythmias after TCA overdose. There is a 33% incidence of seizures when the QRS complex is greater than 100 milliseconds and 50% incidence of ventricular dysrhythmias when the QRS complex is greater than 160 milliseconds.

As with all presentations in the field of clinical toxicology, close attention and evaluation to airway, breathing and circulation is essential.

TCAs:

Because of the rapid onset of symptoms and potential severity of symptoms, all patients with an exposure to a TCA require immediate cardiac monitoring and good peripheral IV access.

A 12 lead ECG should be obtained as soon as possible.

Early intubation should be considered in patients with CNS depression or hemodynamic instability.

Gastrointestinal decontamination, in particular, orogastric lavage should be considered in patients with symptoms after an overdose of a TCA. Orogastric lavage should only be performed once the patient’s airway has been stabilized and protected. Activated charcoal should be administered in nearly all cases. Because of the anticholinergic properties of TCAs, gastrointestinal decontamination should be considered and employed even outside of the normal time frame of 1-2 hours post ingestion.

Seizures are generally self-limited however, benzodiazepines should be mainstay of therapy for seizures.

Sodium bicarbonate is the mainstay for treating the wide-complex dysrhythmias and for reversing the conduction delays and hypotension. The sodium bicarbonate provides both sodium loading and serum alkalinization. The optimal dose of sodium bicarbonate is variable and the dosing recommendations are based on clinical experience as well as animal models of toxicity.

A bolus of sodium bicarbonate of 1-2 meq/kg should be administered initially. Additional boluses may be necessary until the QRS complex narrows. Blood pH should be maintained to a target pH of 7.45-7.55 and serum potassium should be monitored and replaced to normal range. Once the QRS complex narrows, an infusion of 3 ampules of sodium bicarbonate in 1 L of 5% dextrose in water should be started at 1.5 to 2 times maintenance to maintain serum pH between 7.45-7.55. Alkalinization should be continued for 12-24 hours after the ECG has normalized.

Lidocaine is the anti-dysrhythmic of choice for TCA induced dysrhythmias. Procainamide is a Class Ia antidysrhythmic and is contraindicated in TCA poisoning and could result in catastrophic results. Magnesium can also be administered particularly when there is prolongation of the QT interval.

Hypotension should be managed initially with IV crystalloid fluids. If hypotension is recalcitrant after IV crystalloid and sodium bicarbonate, initiation of a vasopressor is reasonable. Because of the pharmacologic action of TCAs, phenylephrine and/or norepinephrine should be initiated.

In patients with cardiovascular collapse despite the above interventions, 20% fatty acid emulsion (IFE) should be considered (See above: IFE – mechanism of action).

All patients that present with the history of exposure to a TCA or an unknown history, require a minimum of 6 hours of observation, even if asymptomatic.

SSRIs:

Treatment of SSRI overdose is mainly supportive. Most patients will have only mild symptoms and resolve over the first 6-8 hours after ingestion. Patients presenting after overdose with most SSRIs require a 6 hour observation time. Citalopram and escitalopram are the exceptions and require an observation time for 24 hours with continuous cardiac monitoring.

Activated charcoal 1 g/kg should be considered in most cases especially if the ingestion time is within the first 1-2 hours. One study describes the efficacy of multiple doses of activated charcoal reducing the incidence of QT prolongation after citalopram overdose.

If seizures occur due to citalopram or escitalopram, they are generally self-limited however treatment with benzodiazepines are considered first line.

Sodium bicarbonate should be given for wide QRS complex dysrhythmias. A bolus of sodium bicarbonate of 1-2 meq/kg should be administered initially. Additional boluses may be necessary until the QRS complex narrows. Blood pH should be maintained to a target pH of 7.45-7.55 and serum potassium should be monitored and replaced to normal range.

Once the QRS complex narrows, an infusion of 3 ampules of sodium bicarbonate in 1 L of 5% dextrose in water should be started at 1.5 to 2 times maintenance to maintain serum pH between 7.45-7.55. Alkalinization should be continued for 12-24 hours after the ECG has normalized. Magnesium 2 grams IV should be considered in patients with QTc prolongation greater than 500 milliseconds. Replacement of potassium and calcium should occur to normal levels in the setting of a prolonged QTc. If torsades de pointes does occur, standard ACLS management including cardioversion; magnesium and overdrive pacing should be employed.

Though there is little data to support its use, in patients with cardiovascular collapse despite standard aggressive care, IFE should be considered.

Atypical Antidepressants:

Treatment of atypical antidepressants is mainly supportive. Agents with long duration of effect and sustained release dosage forms, require a prolonged observation time.

Activated charcoal 1 g/kg should be considered in most cases. Due to the severity of toxicity due to bupropion and the mainly sustained release and extended release dosage forms, multiple doses of activated charcoal or even whole bowel irrigation with PEG-ELS should be considered in large overdoses.

Benzodiazepines are beneficial and should be employed for seizures; agitation and hyperadrenergic vital signs that can occur secondary to these compounds.

Sodium bicarbonate should be employed, as described above, for wide QRS complex durations and magnesium should be considered for prolongation of the QTc.

Trazodone tends to cause significant hypotension and IV crystalloid should be employed. Rarely, vasopressors such as norepinephrine, may have to be initiated to maintain hemodynamics.

Bupropion can cause delayed onset of toxicity including seizures and wide QRS complex and subsequent ventricular dysrhythmias which may be refractory to standard interventions. The first case of successful use of IFE due to an intentional overdose was a case of cardiovascular collapse secondary to bupropion and lamotrigine. IFE was effective in returning spontaneous circulation after a prolonged resuscitation of 52 minutes after just 1 minute. IFE should be considered in this scenario particularly after bupropion ingestion.

Salicylate poisoning

Close attention to airway, breathing, circulation and dextrose is imperative after suspected salicylate poisoning. In patients who have symptoms of salicylate poisoning upon presentation, particularly those with alterations in mental status, protection of the airway is critical. If mechanical ventilation is needed, it is imperative that the rate and tidal volume be increased to maintain the same degree of hyperventilation as the patient had prior to intubation and to avoid hypoventilation. Deaths have been reported when patients have been intubated and placed on standard ventilatory settings; this causes a worsening, profound metabolic acidosis with salicylate entering the CSF.

Benzodiazepines and sedatives should be used with caution as well because of the same concern of inducing hypoventilation.

Gastrointestinal Decontamination:

As with most toxins, the choice of gastrointestinal decontamination is controversial. Many studies have been done and demonstrate that activated charcoal reduces the absorption of therapeutic doses of aspirin by up to 70-80%. Activated charcoal is effective in adsorbing aspirin from both immediate release preparations and enteric coated formulations.

Multiple doses of activated charcoal likely decreases the amount of absorption, however, the value of this intervention is controversial.

There is theoretical benefit of whole bowel irrigation using PEG-ELS in large ingestions or enteric coated preparations. Salicylates cause pylorospasm thereby potentially increasing the amount of drug in the stomach and therefore may make it more amenable to charcoal for longer than the standard 1-2 hours post ingestion. Salicylates, however, cause gastrointestinal toxicity including nausea and vomiting which may limit the potential of gastrointestinal decontamination.

Glucose supplementation:

In any patient with salicylate poisoning and an altered mental status, we advocate for the use of supplemental dextrose regardless of the serum glucose level, and especially when the venous glucose concentrations are within the normal range.

Serum and urinary alkalinization:

Serum alkalinization with sodium bicarbonate reduces the fraction of un-ionized salicylate. Un-ionized compounds have the ability to cross membranes and therefore, serum alkalinization results in a decrease of salicylate concentration in the brain. Serum alkalinization both prevents salicylate diffusing into the CNS and removes salicylate from the CNS. Salicylate is a weak acid and therefore, urinary alkalinization results in an increased urinary elimination of salicylates.

Alkalinization should be intiated with sodium bicarbonate when a salicylate poisoned patient is symptomatic and whose serum salicylate concentration is greater than 40 mg/dL.

Alkalinization is achieved with a bolus of 1-2 meq/kg sodium bicarbonate followed by an infusion of 3 amps of sodium bicarbonate in 1 L D5W at 1.5 to 2 times maintenance. Serum pH should be maintained between 7.45 and 7.55. Urine pH should be maintained at 7.5 to 8.0. Close attention should be paid to serum potassium concentrations as sodium bicarbonate will cause an intracellular shift of potassium. Hypokalemia makes it nearly impossible to create an alkaline urine because the kidneys will reabsorb potassium in exchange for hydrogen ions.

Extracorporeal removal:

Extracorporeal removal of salicylates using hemodialysis should be employed in severely ill patients, in patients with very high salicylate concentrations despite symptoms, in cases complicated by severe fluid or electrolyte imbalances, in cases where there has been acute lung injury, or if the patient is unable to eliminate salicylates due to renal failure. A salicylate level approaching 90 – 100 mg/dL should be considered life-threatening and is an indication for hemodialysis.

What are the adverse effects associated with each treatment option?

Acetaminophen toxicity

IV NAC:

Anaphylactoid reactions can occur, particularly with the loading dose, making this of concern in the Emergency Department. To minimize the risk of anaphylactoid reactions, the loading dose is given over 60 minutes. In the event that an anaphylactoid reaction occurs, turning off the infusion is the first step. If hypotension, wheezing, shortness of breath, or erythema occurs, standard symptomatic therapy including antihistamines, epinephrine and corticosteroids as necessary should be employed. Once the reaction has abated, the IV NAC can be restarted at a much slower infusion rate.

In patients with severe reactive airway disease, oral NAC, which rarely produces anaphylactoid reactions, should be employed.

Improper dilution and improper dose has resulted in overdose of IV NAC leading to hyponatremia, cerebral edema and death. There are specific guidelines in the package insert for patients weighing less than 40 kilograms and should be followed closely.

Oral NAC:

Nausea and vomiting occur frequently following oral NAC administration. Otherwise, oral NAC is generally well tolerated and has less anaphylactoid reactions associated with it. Mixing oral NAC in a soft drink can improve palatability. Placing the oral NAC in a container with a closed lid and ensuring that it is properly diluted to a 5% solution minimize the adverse effects. Antiemetics may need to be given to ensure that the full oral dose is tolerated and retained.

What is the endpoint of therapy for Acetaminophen toxicity?

Regardless of the route of administration, NAC should not be discontinued until:

the acetaminophen concentration is undetectable and the AST is normal or has significantly improved and,

the synthetic function of the liver has improved as evidenced by an INR < 2 and

there is no evidence of an altered mental status due to hepatic encephalopathy.

What is the evidence?

Acetaminophen toxicity

Gray, T, Hoffman, RS, Bateman, N. “Intravenous paracetamol: an international perspective of toxicity”. Clinical Toxicology. vol. 49. 2011. pp. 150-152.

Oakley, E, Robinson, J, Deasy, C. “Using 0.45% saline solution and a modified dosing regimen for infusing NAC in children with paracetamol poisoning”. Emergency Medicine Australia. vol. 23. 2011. pp. 63-67.

Heard, K, Schaeffer, TH. “Massive acetylcysteine overdose associated with cerebral edema and seizures”. Clinical Toxicology. vol. 49. 2011. pp. 423-425.

Sung, L, Simons, JA, Dayneka, NL. “Dilution of intravenous NAC as a cause of hyponatremia”. Pediatrics. vol. 100. 1997. pp. 389-391.

Harrison, PM, Keays, R, Bray, GP. “Improved outcome of paracetamol-induced fulminant hepatic failure by late administration of acetyclcysteine”. Lancet. vol. 335. 1990. pp. 1572-1573.

Rumack, BH, Matthew, H. “Acetaminophen poisoning and toxicity”. Pediatrics. vol. 55. 1975. pp. 871-876.

Rumack, BH, Peterson, RG. “Acetaminophen overdose: Incidence, diagnosis and management in 416 patients”. Pediatrics. vol. 62. 1978. pp. 898-903.

Clonidine toxicity

Anderson, FJ, Hart, GR, Crumpler, CP. “Clonidine overdose. Report of six cases and review of the literature”. Ann Emerg Med. vol. 10. 1981. pp. 107-112.

Niemann, JT, Getzug, T, Murphy, W. “Reversal of clonidine toxicity by naloxone”. Ann Emerg Med. vol. 15. 1986. pp. 1229-1231.

Rangan, C, Everson, G, Cantrell, FL. “Cental alpha-2 adrenergic eye drops: case series of 3 pediatric systemic poisonings”. Ped Emerg Care. vol. 24. 2008. pp. 197-199.

Seger, D. “Clonidine Toxicity Revisted”. Clin Tox. vol. 40. 2002. pp. 145-155.

Sulfonylurea toxicity

Boyle, PJ, Justice, K, Krentz, AJ. “Octreotide reverses hyperinsulinemia and prevents hypoglycemia induced by sulfonylurea overdoses”. J Clin Endocrinol Metab. vol. 76. 1993. pp. 753-756.

Fasano, CJ, O’ Malley, G, Dominici, P. “Comparison of octreotide and standard therapy versus standard therapy alone for the treatment of sulfonylurea induced hypoglycemia”. Ann Emerg Med. vol. 51. 2008. pp. 400-406.

Calello, DP, Kelly, A, Osterhoudt, KC. “Case files of the medical toxicology fellowship training program at the Children's Hospital of Philadelphia: A pediatric exploratory sulfonylurea ingestion”. J Med Toxicol. vol. 2. 2006. pp. 19-24.

Rath, S, Bar-Zeev, N, Anderson, K. “Octreotide in children with hypoglycemia due to sulfonylurea ingestion”. J Paediatr Child Health. vol. 44. 2008. pp. 383-384.

Pelavin, PI, Abramson, E, Pon, S. “Extended-release glipizide overdose presenting with delayed hypoglycemia and treated with subcutaneous octreotide”. J Pediatr Endocrinol. vol. 22. 2009. pp. 171-175.

Beta Blockers or Calcium Channel Blockers toxicity

Kerns, W. “Management of beta adrenergic blocker and calcium channel antagonist toxicity”. Emerg Med Clin North America. vol. 25. 2007. pp. 309-331.

DeWitt, CR, Waksman, JC. “Pharmacology, pathophysiology and management of calcium channel blocker and beta blocker toxicity”. Toxicol Rev. vol. 23. 2004. pp. 223-238.

Yuan, TH, Kerns, WP, Tomaszewski, CA. “Insulin-glucose as adjunctive for severe calcium channel antagonist poisoning”. J Tox Clin Tox. vol. 37. 1999. pp. 463-474.

Megarbane, B, Karyo, S, Baud, FJ. “The role of insulin and glucose (hyperinsulinaemia/euglycaemia) therapy in acute calcium channel antagonist and beta blocker poisoning”. Toxicol Rev. vol. 23. 2004. pp. 215-222.

Levine, M, Boyer, EW, Pozner, CN. “Assessment of hyperglycemia after calcium channel blocker overdoses involving diltiazem or verapamil”. Crit Care Med. vol. 35. 2007. pp. 2071-2075.

Bania, TC, Chu, J, Perez, E. “Hemodynamic effects of intravenous fat emulsion in an animal model of severe verapamil toxicity resuscitated with atropine, calcium and saline”. Acad Emerg Med. vol. 14. 2007. pp. 105-111.

Tebbutt, S, Harvey, M, Nicholson, T. “Intralipid prolongs survival in a rat model of verapamil toxicity”. Acad Emerg Med. vol. 13. 2006. pp. 134-139.

Antidepressant toxicity

Sirianni, AJ, Osterhoudt, KC, Calello, DP. “Use of lipid emulsion in the resuscitation of a patient with prolonged cardiovascular collapse after overdose of bupropion and lamotrigine”. Ann Emerg Med. vol. 51. 2008. pp. 412-415.

Friberg, LE, Isbister, GK, Duffull, SB. “Pharmacokinetic-pharmacodynamic modelling of QT interval prolongation following citalopram overdoses”. Br J Clin Pharmacol. vol. 61. 2006. pp. 177-190.

Personne, M, Persson, H, Sjoberg, E. “Citalopram toxicity”. Lancet. vol. 350. 1997. pp. 518-519.

Boehnert, M, Lovejoy, FH. “Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants”. NEJM. vol. 313. 1985. pp. 474-479.

Liebelt, EL. “Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose: the pivotal role for alkalinization and sodium loading”. Pediatric Emergency Care. vol. 14. 1998. pp. 293-298.

Liebelt, EL, Ulrich, A, Francis, PD. “Serial electrocardiogram changes in acute tricyclic antidepressant overdoses”. Crit Care Med. vol. 25. 1997. pp. 1721-1726.

Salicylate poisoning

O’ Malley, GF. “Emergency Department Management of the Salicylate-Poisoned Patient”. Emerg Med Clin N Am. vol. 25. 2007. pp. 333-346.

Thurston, JH, Pollock, PG, Warren, SK. “Reduced brain glucose with a normal plasma glucose in salicylate poisoning”. J Clin Invest. vol. 49. 1970. pp. 2139-2144.

“American Academy of Clinical Toxicology and European Association of Poisons Centers and Clinical Toxicologists. Position statement and practice guidelines on the use of multi-dose activated charcoal in the treatment of acute poisoning”. J Tox Clin Tox. vol. 37. 1999. pp. 731-751.

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