Week 28: Tox Quarterly Round 3

This patient is suffering from an anticholinergic toxidrome secondary to a tricyclic antidepressant (TCA) overdose. The 12-lead ECG shows sinus tachycardia at 117 beats per minute with a wide QRS complex (149 msec) and a terminal R wave in aVR. TCA medications inhibit neurotransmitter uptake at peripheral anticholinergic receptors, leading to a number of physiologic effects. Patients will experience both central and peripheral anticholinergic effects manifested by the anticholinergic toxidrome (dry skin, tachycardia, mydriasis, elevated temperature, and altered mental status); inhibition of central sympathetic reflexes; and inhibition of alpha-1-adrenergic receptors (leading to peripheral vasodilation and hypotension). TCAs also have multiple effects on the cardiovascular system. They impair phase 0 depolarization, leading to prolongation of the QRS interval, and slow phase 4 repolarization, leading to QT interval prolongation. And they can cause hypotension by both direct myocardial depression and peripheral vasodilation. Because of its longer refractory period, the right bundle branch is more effected in TCA overdose manifested by the terminal R wave in aVR, which is pathognomonic for a sodium channel blocking drug overdose. QRS and QT interval prolongation places patients at risk of developing lethal ventricular tachydysrhythmias (ventricular tachycardia, torsades de pointes, ventricular fibrillation). Sodium bicarbonate infusion is the treatment of choice. Infusion leads to alkalinization, leading to a reduction in the pharmacologically active unbound fraction of TCA components and thereby their effects on myocardial contractility. The sodium can overwhelm channel blockade by the drug. The recommended dose of sodium bicarbonate is 1–2 mEq/kg IV bolus, followed by an infusion of 150 mEq in 1,000 cc of D5W administered IV at twice maintenance.

Although the patient does have a wide-complex tachydysrhythmia, neither cardioversion (D) nor amiodarone (A) is indicated for treatment because they do not focus on the underlying pathophysiology. Physostigmine (B) is the antidote for an anticholinergic overdose (e.g., diphenhydramine) but can worsen TCA overdose because it lowers the seizure threshold.

This patient is exhibiting signs and symptoms of valproic acid toxicity. These include nausea, vomiting, sedation, ataxia, respiratory depression, and cerebral edema. Laboratory testing will frequently reveal hyperammonemia while other liver function tests remain normal, which is nearly pathognomonic in overdose patients for valproic acid. Other laboratory abnormalities include hypernatremia, hypocalcemia, and metabolic acidosis. Management of valproic acid toxicity includes symptomatic and supportive care. Naloxone has been reported to be successful in some cases. The antidote to valproic acid toxicity is L-carnitine as this will improve the hyperammonemia induced by the drug.

Fomepizole (A) is the antidote to ethylene glycol or methanol poisoning which present with anion gap metabolic acidosis and either renal toxicity or ocular toxicity, respectively. N-acetylcysteine (C) is the antidote to acetaminophen toxicity, which often presents asymptomatically early on in the disease process but then patients develop signs and symptoms of hepatic toxicity, including elevated liver transaminases. Sodium bicarbonate (D) is used to alkalinize the urine and promote excretion of salicylates in cases of overdose. It is also used in sodium channel blocker toxicity to shorten the QRS and QT interval duration and prevent seizures.

In an actively seizing patient, attention is always directed to the airway first. A patient having a generalized tonic-clonic seizure has a suppressed gag reflex and is prone to aspiration of gastric contents. Therefore, patients should be placed in the left lateral decubitus position. First-line pharmacologic management for an actively seizing patient is a parenteral benzodiazepine. Benzodiazepines directly enhance GABA-mediated neuronal inhibition, affect clinical and electrical manifestations of seizures, and are highly effective at terminating seizure activity. Benzodiazepines have been shown to be more effective than phenytoin at terminating status epilepticus. They are as effective as parenteral phenobarbital, but phenobarbital is associated with a higher risk of hypoventilation and hypotension. The intravenous route is the preferred route to administer an antiepileptic because this has the quickest onset of action. Therefore, intravenous midazolam is the preferred agent from the choices listed above. Midazolam’s onset of action is within 1 minute. In addition to the intravenous preparation, it is available in both intranasal and buccal formulations. It also has the least cardiovascular effects among benzodiazepines.

Fosphenytoin (A) is a water-soluble prodrug form of phenytoin. Unlike phenytoin, fosphenytoin can be administered intramuscularly. Although fosphenytoin can be infused more rapidly than phenytoin can, the time to a therapeutic concentration of the active drug is the same as for intravenous phenytoin. Lorazepam (C) is considered a first-line agent for an actively seizing patient and is the most popular agent used. However, oral medications are contraindicated in an actively seizing patient due to the prolonged onset of action and risk of aspiration. Diazepam (D) is also a first-line agent for an actively seizing patient and is most commonly used as a rectal preparation in the pediatric population where intravenous access is not readily available.

D. The patient presents with life-threatening bleeding and an elevated INR from warfarin use requiring immediate anticoagulant reversal regardless of the indication for anticoagulation. Warfarin acts by inhibiting vitamin K recycling thus limiting the effectiveness of vitamin K dependant clotting factors (factors II, VII, IX and X). The effect of warfarin can be measured using the prothrombin time or the INR. Warfarin is indicated for anticoagulation for a number of disorders including the presence of a metal valve. Patients with metal valves are at a higher 1-year risk of clot formation around the valve and subsequent embolic stroke. The therapeutic goal of warfarin in a patient with a metallic valve is usually between 2.5 – 3.5 or 3.0 – 4.0. Despite the increased stroke risk, patients with life-threatening bleeding should always have their warfarin reversed by administration of vitamin K and fresh frozen plasma (FFP). Alternatively, prothrombin complex concentrates can be given instead of FFP.

A. Disopyramide
Disopyramide is a Class 1A sodium channel blocker and is contraindicated in tricyclic overdose because like TCA’s, it depresses phase 0 depolarization of cardiac tissue and thus can worsen the QRS widening.

B. Flecainide
Flecainide is a Class 1C antiarrhythmic and is contraindicated in tricyclic overdose because like TCA’s, it depresses phase 0 depolarization of cardiac tissue and thus can worsen the QRS widening.

C. Lidocaine
This patient is suffering from QRS prolongation due to TCA overdose. Lidocaine, which is a Class 1B antiarrhythmic, can be used to counteract the effects of the TCA if the patient is refractory to bicarbonate therapy. This occurs because lidocaine does not depress phase 0 depolarization and dissociates fairly quickly from the sodium channels, effectively displacing the TCA. 1A and 1C medications (quinidine, disopyramide, procainamide) and (flecainide, propafenone) respectively are contraindicated and may worsen the sodium blockade as they all do depress phase 0 depolarization. Sources: 1. Foianini et al, What is the role of lidocaine or phenytoin in tricyclic antidepressant-induced cardiotoxicity? Clin Toxicol (Phila). 2010 May;48(4):325-30. PMID: 20507243. 2. Pentel et al, Tricyclic antidepressant poisoning. Management of arrhythmias, Med Toxicol. 1986;1(2):101. PMID 3784839.

D.Quinidine
Quinidine is a Class 1A antiarrhythmic and is contraindicated in tricyclic overdose because like TCA’s, it depresses phase 0 depolarization of cardiac tissue and thus can worsen the QRS widening.

Warfarin is an oral anticoagulant that interferes with the normal synthesis of vitamin K dependent clotting factors (II, VII, IX and X) and proteins C and S. It has a half-life of 36 hours and its activity is measured via INR. Reversal of warfarin involves treatment with fresh frozen plasma (FFP), vitamin K and prothrombin concentrate complex (PCC). Vitamin K will reverse blockade of vitamin K dependent factors, but it will take several hours. FFP restores factor levels to greater than 30% of normal and PCC allows for factor replacement and immediate complete reversal of anticoagulation. The decision to reverse warfarin takes into consideration the presence or absence of bleeding, and the INR. Patients that are at high risk for a thrombotic event if warfarin is reversed are people with mechanical valves or defective native valves with atrial fibrillation. Patients with deep vein thromboses and atrial fibrillation with normal native valves are at low risk for an adverse event.

A. Administer fresh frozen plasma (FFP)
FFP administration is used in cases of bleeding secondary to coumadin anticoagulation. This patient has no signs of bleeding and as such FFP is not indicated

B. Administer vitamin K
The INR will not be elevated in an acute ingestion as it takes days to work. Giving vitamin K or FFP is contraindicated at this time as it prevents monitoring for at least several days.

C. Check baseline INR and arrange for INR check in 2-3 days
The correct answer is to arrange for INR check in 2-3 days. The INR will not be elevated in an acute ingestion as it takes days to work. Giving vitamin K or FFP is contraindicated at this time as it prevents monitoring for at least several days.

D. Administer recombinant factor VII
This patient ingested coumadin, which inhibits factors 10, 9, 7 and 2. Giving factor 7 alone is unlikely to make a significant difference, and this patient is not bleeding so does not require treatment at this time.

A. Desmopressin acetate
Desmopressin is useful for bleeding due to platelet dysfunction such as uremic platelets. It does not reverse heparin.

B. Platelets
Heparin does not inhibit platelets and platelet transfusion is unlikely to help in this case.

C. Protamine Sulfate
Enoxaparin (Lovenox) is a low molecular weight heparin that binds to antithrombin III (like heparin), but the resultant complex inactivates Xa and not thrombin (unlike heparin). The half-life is 3-4 hours and its activity is monitored via Xa levels. Heparin’s activity is monitored via PTT. Like Heparin, enoxaparin’s antidote is protamine sulfate, but protamine only reverses about 60% of enoxaparin’s activity. The maximum dose of protamine is 50mg and the dose depends on the time that enoxparen was given, along with the amount given. Interestingly, xabans (oral factor Xa inhibitors) cannot be reversed with protamine, nor can they be dialyzed as with dabigatran.

D.Vitamin K
Vitamin K would be useful for coumadin/warfarin but not for bleeding secondary to heparin.

A. Administer acetaminophen and if condition stable restart transfusion after 30 minutes
The patient has experienced a febrile non-hemolytic transfusion reaction that is defined as a fever during or within 4 hours after a blood transfusion without hypotension, pain, hematuria, urticaria or airway involvement. The management is controlling the fever and if clinically stable without other signs or symptoms, restarting the transfusion after 30 minutes.

B. Administer antibiotics IV
This patient is having a febrile non-hemolytic transfusion reaction. Antibiotics are not indicated as this is not an infectious process.

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C. Administer epinephrine IM
This patient is having a febrile non-hemolytic transfusion reaction. Epinephrine is not indicated as there is no evidence of anaphylactic reaction.

D. Immediately send Coomb’s test
This patient is having a febrile non-hemolytic transfusion reaction. Coomb’s tests are used for ABO incompatibility and hemolytic reactions.

• Potassium iodine for nuc weapon detonation or reactor breach- prevents radioiodine from accumulating in thyroid. take shortly after exp to be effective- if give too much get iodism
• Dose- 130mg adults, 65mg 3- 18ys, 32mg 1mo- 3yr, 16mg for age< 1mo
• Chelators- calcium, zinc, only for plutonium or americium