INTERESTING CASE ROUNDS Alyssa Morris Emergency Medicine R3

Objectives DDX for toxin induced seizures DDX for toxin induced seizures DDX for toxin induced status epilepticus DDX for toxin induced status epilepticus Indications for pyridoxine Indications for pyridoxine Review methylxanthine toxicity Review methylxanthine toxicity Review MDAC Review MDAC

CASE 19M took an unknown ingestion and had a seizure. 19M took an unknown ingestion and had a seizure. What is your quick ddx for drugs that cause seizure? What is your quick ddx for drugs that cause seizure?

DDX Drug induced Seizure OTIS CAMPBELL O- organophosphates O- organophosphates T- TCA T- TCA I- Isoniazid, insulin I- Isoniazid, insulin S- sympathomimetics S- sympathomimetics C- camphor, cocaine A- anticholinergic, amphetamines, anticholinergic, antidepressants M- Methylxanthines P- PCP B- Benzo w/d E- EtOH w/d L- Lithium, lidocaine L- lead, lindane

DDx-Toxin induced Status INH INH Insulin/hypoglycemic agents Insulin/hypoglycemic agents TCA TCA Theophylline Theophylline Wellbutrin Wellbutrin CO CO

Pyridoxine Indications INH INH Ethylene glycol Ethylene glycol Gyromitra Mushrooms Gyromitra Mushrooms Methylxanthines* Methylxanthines*

CASE 19M who ingested 112 caffeine tablets (100mg/tab) who was brought in by friend for intractable nausea and vomiting 19M who ingested 112 caffeine tablets (100mg/tab) who was brought in by friend for intractable nausea and vomiting Total ingestion >11g (175mg/kg) Total ingestion >11g (175mg/kg) O/E: P=131,BP= 164/67, T= 37.6, 02= 98%, agitated, vomiting ++ O/E: P=131,BP= 164/67, T= 37.6, 02= 98%, agitated, vomiting ++

CASE Labs: Labs: APAP/ASA – APAP/ASA – CK 14 CK 14 Na 140, K 2.2, Cl 101, CO2 17, AG: 22 Na 140, K 2.2, Cl 101, CO2 17, AG: 22 Lactate 8.8 Lactate 8.8 pH 7.23 pH 7.23 Caffeine level 429mmol/L Caffeine level 429mmol/L ECG: Sinus tach, no dysrhythmias ECG: Sinus tach, no dysrhythmias

CASE CONT Continued to be tachy, ++ vomitting, no seizure and no dysrhythmias Continued to be tachy, ++ vomitting, no seizure and no dysrhythmias Course in ED: Course in ED: zofran 12mg zofran 12mg Maxeran 10g (still vomiting) Maxeran 10g (still vomiting) Stemitil 10mg (still vomiting) Stemitil 10mg (still vomiting) MDAC MDAC Central line to replace K+ Central line to replace K+ Zantac 50mg Zantac 50mg Ativan 2mg IV x 2 Ativan 2mg IV x 2

CASE CONT Labs in am Labs in am CK CK PO PO K- 3.1 K- 3.1 Caffeine level 295mmol/L Caffeine level 295mmol/L Lactate 3.9 Lactate 3.9 Still vomiting and agitated Still vomiting and agitated

CAFFEINE Methylxanthine Methylxanthine  Similar to theophylline Cause release of endogenous catecholamines Cause release of endogenous catecholamines  Stimulates B1 and B2 R Structural analogue of Adenosine Structural analogue of Adenosine  NE and epinephrine release Inhibit phosphodiesterase (degrades cAMP) Inhibit phosphodiesterase (degrades cAMP)  Effects like adrenergic stimulation

PHARMACOKINETICS Routes: oral, IV, SC, IM, rectal Routes: oral, IV, SC, IM, rectal Oral almost 100% bioavailability Oral almost 100% bioavailability Peak concentration 30-60min Peak concentration 30-60min Diffuses readily into total body water and all tissues Diffuses readily into total body water and all tissues Readily crosses BBB Readily crosses BBB Metabolized by Cytochrome P450 system Metabolized by Cytochrome P450 system Active metabollite is theophylline Active metabollite is theophylline

TOXICOKINETICS Range of toxicity varies greatly Range of toxicity varies greatly No definite conclusions from serum levels can be drawn No definite conclusions from serum levels can be drawn Lethal dose estimated: mg/kg or 5-10g Lethal dose estimated: mg/kg or 5-10g Death associated serum levels >80mm0l/L Death associated serum levels >80mm0l/L  Fatalities <200mmol/L  Survivial >400mmol/L OUR PT: 175mg/kg, serum 429mmol/L

CLINCIAL EFFECTS Occur as a result of: Occur as a result of: 1 Adenosine antagonism 2 Release of endogenous catecholamines 3 Phosphodiesterase inhibiton Toxicity affects: Toxicity affects:  GI system  Cardiovascular system  CNS  MSK

GI Nausea and protracted emesis Nausea and protracted emesis Severe and difficult to control despite use of multiple anti-emetics Severe and difficult to control despite use of multiple anti-emetics Increase in gastric acid secretion and smooth muscle relaxation Increase in gastric acid secretion and smooth muscle relaxation Gastritis and esophagitis (more common with chronic use) Gastritis and esophagitis (more common with chronic use) Transiently elevated liver enzymes Transiently elevated liver enzymes

CARDIOVASCULAR Tachydysrhythmias Tachydysrhythmias  Sinus tach  SVT  MAT  Afib  PVCs  VT MI MI Peripheral vasodilation (wide pulse pressure) Peripheral vasodilation (wide pulse pressure) Hypertension or hypotension Hypertension or hypotension

PULMONARY Stimulates CNS respiratory centre Stimulates CNS respiratory centre  Increased RR  Resp Alkalosis Respiratory failure Respiratory failure Acute lung injury Acute lung injury

CNS H/A H/A Anxiety Anxiety Agitation Agitation Insomnia Insomnia Tremor Irritability Hallucinations Seizures*

MSK Increases intracellular Ca++ Increases intracellular Ca++ Smooth muscle relaxation Smooth muscle relaxation Tremor Tremor Fasiculations Fasiculations Myoclonus Myoclonus Rhabdomyolysis Rhabdomyolysis

METABOLIC HypoK HypoK  Shift into cells from B2 stimulation HypoMg HypoMg HypoPO4 HypoPO4 HypoNa HypoNa Hyperglycemia Hyperglycemia AGMA (lactate) AGMA (lactate)

MANAGEMENT Basics: IV, monitored bed Basics: IV, monitored bed Labs to follow Labs to follow extended electrolytes extended electrolytes Lactate Lactate CK CK +/- Serum caffeine level +/- Serum caffeine level CXR, ECGs CXR, ECGs

TREATMENT MDAC* MDAC* Emesis Emesis  Zofran, maxeran Dysrhythmias Dysrhythmias  Benzos  Esmolol  Lidocaine Rhabdo Rhabdo  Fluids and monitor u/o

TREATMENT Electrolytes Electrolytes  Replace, but careful b/c will become hyperK when shift back out of cell Hypotension Hypotension  Fluids  Not dopamine Seizures Seizures  Benzos  Phenobarb  Pyridoxine

MDAC Definition: more than 2 sequential doses of AC Definition: more than 2 sequential doses of AC In many cases, the number of doses administered is substantially greater In many cases, the number of doses administered is substantially greater MDAC serves 2 purposes: MDAC serves 2 purposes: 1 Prevent ongoing absorption of a drug that persists in the GIT 1 Enhance elimination by either disrupting enterohepatic recirculation or by enteroenteric recirculation

General Indications GI decontamination for drug or poison ingestion associated with significant risk of toxicity, where supportive care/antidote alone is insufficient to ensure a satisfactory outcome GI decontamination for drug or poison ingestion associated with significant risk of toxicity, where supportive care/antidote alone is insufficient to ensure a satisfactory outcome The toxin must be able to bind to AC The toxin must be able to bind to AC Must believe that a significant amount of agent is unabsorbed and is amenable to removal Must believe that a significant amount of agent is unabsorbed and is amenable to removal

AACT Position Statement Position statement states use MDAC only for ingestions of Position statement states use MDAC only for ingestions of Carbamazepine Carbamazepine Dapsone Dapsone Phenobarbital Phenobarbital Quinine Quinine Theophylline /Methylxanthines Theophylline /Methylxanthines

Other Drugs Shown to increase elimination of: Shown to increase elimination of: Digoxin Digoxin Phenobarbital Phenobarbital Carbamazepine Carbamazepine Phenylbutazone Phenylbutazone Dapsone Dapsone Nadolol Nadolol Theophylline Salicylate Quinine Cyclosporine Propoxyphene Nortriptyline Amitriptyline

Contraindications Any contraindication to single-dose activated charcoal Any contraindication to single-dose activated charcoal AC known not to adsorb AC known not to adsorb Airway protective reflexes are absent or expected to be lost and pt is not intubated Airway protective reflexes are absent or expected to be lost and pt is not intubated GI perf (esp caustic ingestion) GI perf (esp caustic ingestion) Increases severity of injury (hydrocarbons) Increases severity of injury (hydrocarbons) Endoscopy for dx/mx anticipated Endoscopy for dx/mx anticipated Presence of ileus Presence of ileus

Administration Initial dose Initial dose 1g/kg or 10:1 ratio of ACT:toxin, whichever is > 1g/kg or 10:1 ratio of ACT:toxin, whichever is > Repeat dose Repeat dose mg/kg every 1-6hrs mg/kg every 1-6hrs Procedure Procedure Can be administered with cathartic for the 1st dose only Can be administered with cathartic for the 1st dose only If pt vomits, repeat the dose If pt vomits, repeat the dose Can use oral, NG or OG route Can use oral, NG or OG route *Sxn tube before removal to reduce aspiration risk

SUMMARY DDX for toxin induced seizures DDX for toxin induced seizures OTIS CAMPBELL OTIS CAMPBELL Refractory seizures in toxic ingestion Refractory seizures in toxic ingestion Think about pyridoxine Think about pyridoxine Caffeine is a methylxanthine Caffeine is a methylxanthine Adrenergic stimulation Adrenergic stimulation Can get refractory seizures Can get refractory seizures MDAC is indicated MDAC is indicated