Case of the Month Discussion

In summary this is a 24 yo male with an unknown medical history that presents with rapidly deteriorating mental status, tachycardia, a low grade fever and a seizure while in the ED.  When approaching any differential diagnosis, it is helpful to work within a framework of body systems.  A commonly used mnemonic is: VITAMINS C & E
Vascular
Infectious/Inflammatory
Trauma/Toxicologic
Autoimmune/Allergic
Metabolic/Mental
Idiopathic / Iatrogenic
Neoplastic/Nutritional
Congenital
Environmental

We can limit the differential in this patient to a few on the list:  Infection (meningitis, meningoencephalitis, brain abscess), Trauma (SAH, epidural, subdural) or Toxic (alcohol, illicit drug overdose, prescription drug overdose, poisoning). 

• The physical exam reveals dry mucous membranes, dilated pupils, tachycardia and hypoactive bowel sounds.  This constellation of findings in the setting of deteriorating mental status, makes anticholinergic poisoning and more specifically, tricyclic-antidepressant overdose the leading diagnosis at this point. 

• The EKG further leads us to suspect TCA overdose:  The EKG reveals a sinus tachycardia, a widened QRS (120msec in this patient) and an R wave in avR.  (See below for further discussion).

ED Course:
The patient's mental status continued to deteriorate.  He was intubated for airway protection.  The patients blood pressure began to drop (90/50) and he appeared more tachycardic on the monitor.  A repeat EKG 45 minutes after arrival was done (EKG #2):

EKG #2	EKG #3

The patient was given two amps (100meq) of NaHCO3 IVP (1-2meq/kg bolus), followed by an infusion of 2 amps of NAHCO3 added to 1 liter of .045NS at 200 cc/hr to attain a target serum pH of 7.45-7.55.  Orogastric lavage was done with a 28 french Ewald tube revealing small, non-discernable pill fragments.  The patient was also given multi-dose activated charcoal.  After the initial sodium bicarbonate bolus, the QRS immediately narrowed (see above EKG #3), and his blood pressure normalized.  Results of serum and urine toxicology were negative as was the patient's head CT.  The patient was maintained on a sodium bicarb infusion and transferred to the MICU for further inpatient management.  The patient's vital signs, mental status and EKG normalized during his stay and he was extubated on hospital day #4 and transferred to the psychiatric ward for further evaluation (where he later escaped... another story in itself).  He admitted to a history of depression and the ingestion of 3 grams of Elavil (Amitryptyline) just prior to being apprehended at the grocery store (toxic ingestion

Final Diagnosis:  Tricyclic Antidepressant Overdose

Discussion

Epidemiology
TCA's were first introduced in 1958.  The first fatal overdose reported 1959 and to this day remains the leading cause of poisoning death from antidepressants.  In 2004, there were 12,088 cases of TCA overdoses reported to the American Association of Poison Control Centers' Toxic Exposure Surveillance System (AAPCC-TESS), of which 7,546 were reported as intentional.  Eighty-four (1.1%) of intentional overdoses were fatal.

Pathophysiology
Peak plasma concentration is reached approximately 4-6 hours after an overdose (less for therapeutic doses), and most TCA is rapidly absorbed from the small intestine into tissues (protein bound= large volume of distribution) so serum levels do not reflect toxicity.  Morbidity and mortality of TCA's are caused by the blockade of muscarinic acetylcholine receptors, sodium channels, alpha-adrenergic receptors, GABA receptors and histamine receptors:
• Muscarinic blockade leads to agitation, lethargy, hyperthermia, seizures, mydriasis, tachycardia dry skin, urinary retention and ileus.
• Na Channel Blockade (quinidine like effects (IA). Block fast Na channels / prolong phase 0 depolarization ) leads to arrhythmias and hypotension.
• Alpha blockade leads to hypotension.
• Histamine blockade leads to sedation.
• GABA blockade:  CNS toxicity (agitation, seizures, coma)

Diagnostic Tools
1) Serum levels of TCA's can be obtained but typically can not be run on a STAT basis and help little in the acute setting.

2) EKG findings: Can be used as a screening tool for TCA overdose:
• QRS >100 msec predictive of seizures / >160msec predictive of arrhythmias (our patient had a QRS of >250msec!).  (Medline)
• R wave in aVR>3mm also predictive of seizure / arrhythmia.  (The so called "Rightward terminal 40msec of the QRS" that is often discussed but rarely described).  (Medline)
• Sinus Tachycardia.
• QT prolongation.

General Treatment
• A,B,C's: aggressive airway, hemodynamic and seizure management.
• Gastric Lavage: Indicated only if time from ingestion was less than 1-2 hours and only if the airway has already been secured.
• Activated Charcoal (1-2grams/kg):  Only single dose AC is currently recommended.  The American College of Clinical Toxicologists does not recommend multi dose activated charcoal at this time.  Despite the fact that TCA's have significant enterohepatic circulation, studies have not shown any significant benefit of MDAC.  (Medline).
• Sodium Bicarbonate:  An inital bolus of 1-2meq/kg sodium bicarbonate, followed by an infusion to maintain a serum pH of 7.45-7.55.  Both the sodium and the bicarbonate are important in the mechanism of action of sodium bicarb.  Alkalinization of the serum uncouples Na from myocardium and also enhances elimination by the kidney.  Sodium aids in overcoming the sodium blockade (hypotension / arrhythmias).  A hypertonic saline solution is therefore indicated in treating TCA toxicity.  Each amp of Sodium Bicarb contains 50meq of Na or HCO3.  Adding two amps to a liter of 0.45 NaCl (77meq/L) will result in a final concentration of Na of 177meq/L (if added to D5, would result in a hypotonic solution of only100meq/l). 

•Hemodialysis:  No role is TCA overdose due to large volume of distribution.

Specific Treatment
• Arrhythmias:  Lidocaine (class 1B antiarrhytmic) is the drug of choice in treating TCA induced arrhythmias.  Class 1A (quinidine, procainamide) and class 1C (flecainide and propafenone) are contraindicated due to their worsening of sodium blockade and proarrhythmic effects.
•Hypotension:  Direct alpha agonists (norepinephrine, phenylephrine) are preferred.
•Seizures:  Should be treated aggressively to prevent further acidosis.  Benzo's are first line.  Phenytoin should be avoided due to its potential proarrhythmic effects.

Disposition
•Discharge from ED criteria:  Minimum 6 hour observation period with normal discharge mental status and normal EKG.  (Note: Psych eval/transfer for all intentional overdoses).
•All others: admit to monitored setting.