Toxicology

Initial hx:

• what/when ingested, how much
• medical history and prescription meds they have access to (meaning, people cohabitating are rx'd)
• EtOH and recreational drug use
• Hx of self harm? Or prior attempts?

All patients get:

• abc, BMP, LFTs
• ASA, APAP, EtOH
• UDS if going to psych
• UPT
• EKG (often every 15-30 minutes if they're sick)

Consider: VBG, CK, UA, Osm/Toxic alcohols, Specific Drug levels, Ammonia, INR, CXR, CT head

Osm gap is not useful. (Se and Sp not good) [ ] image.

UDS/Urine Drug Screen:

• specific for MJ, Cocaine, Barbituates in last 3-5 days.
• Not specific: benzos (librium and diazepam are good), opioids, amphetamine (ranitidine, bupropion), TCA (lots of false positive - carbamazepine, diphenhydramine, quetiapine)

Tox EKG:

Phase 0 (Na flowing in to cell) and Phase 3 (K flowing out) are what we are worried.

Na channel blockade causes: (es-)citalopram, propranolol, HCQ also causes this

• wide QRS (phase 3)
• progressing toward ventricular tachycardia
• terminal R in AVR (= preferential effect at the R bundle branch, just happens to be more sensitive to Na ); AVR is reciprocal of II

##Case 1: Confused and Hyperthermic

30 F w unknown past medical history is brought in to the ED by EMS after an unknown ingestion. She is agitated, tachycardic, tachypneic, and hyperthermic 39c. In the ED she goes berserk and the ED provider intubates. He calls you "I'm not sure what this patient took but they need an ICU". You accept the patient.

###Differential Diagnosis?

1. Stimulants: Cocaine, methamphetamine, MDMA, spice, BUPROPION etc. ALSO withdrawal from a CNS depressant (clinically, essentially indistinguishable - benzos, alcohol, barbiturate- Think of these as synonymous from here on out.)
2. Serotonin syndrome (SSRI - including trazodone, lithium, MAOi - including linezolid, triptans, antiemetics, tramadol, methadone and fentanyl, MDMA, LSD).
3. Neuroleptic Malignant Syndrome (NMS)- note that neuroleptic overdose will often cause hypotension up to the point of causing hypertension. NMS = mental status change, rigidity (general), fever, and dysautonomia. Antipsychotics and anti-emetics (all drugs that block dopamine can cause). Note: baclofen withdrawal is a mimic.
4. Tricyclic Antidepressant (includes Benadryl, citalopram - Na channel blockade is the receptor level interaction that causes this). Risk is of seizure and VT.
5. Anticholinergic
6. ASA - AMS that varies from agitation to somnolence. Hyperthermia. Nausea and vomiting. Respiratory alkalosis and metabolic acidosis.

Note: NMS and Malignant catatonia overlap: What is malignant catatonia? Fulminant/severe catatonia (a behavioral syndrome of motor disturbance that is manifested from an underlying psychiatric or medical disorder such as bipolar, depression, psychotic d/o's, and delirium) that is not necessarily related to drugs. Has behavioral prodrome, more prominent motor symptoms than NMS.

vs acute dystonic reaction? contraction of a single muscle group or area (e.g. torticollis, oculogyric crisis) vs widespread rigidity.

What would you expect on exam?

Exam: Pupils, armpit, tone/reflexes

• Stimulants: pupils large, armpit sweaty, tone normal to mildly increase. Agitated
• Serotonin: pupils large, armpit sweaty, myoclonus. Quicker onset than NMS
• Neuroleptic: pupils ?, armpit sweaty, rigid (often extreme). Fever is often extreme (40% over 40c).
• TCA/Anticholinergic: pupils large, armpit dry, normal tone. (note: how is TCA diff from Anticholinergic in presentation? TCA: cardiotoxicity/hypotension. AC: urinary retention
• ASA: pupils normal, armpit sweaty, normal tone.

###Treatment

• Stimulants: benzos
• Serotonin syndrome: cyprohepatidine, benzo vs dexmetodomidine (directly lowers serotonin via alpha inhibition)
• Neuroleptic Malignant: benzos
• TCA, anticholinergic: bicarb, benzo. (maybe physostigmine if anticholinergic, never for TCA). Get an EKG to look for QRS width and terminal R-ward qrs axis = big r in AVR
• ASA: blood+urine alkalinization (gets ASA out of the tissue esp brain), volume, dialysis, glucose control

"Treatment of salicylate intoxication is directed toward decreasing the fraction of uncharged (protonated) molecules, which is accomplished by increasing the systemic pH (ie, lowering the H+ ion concentration). "

Acetaminophen

APAP -CYP2E1-> NAPKE = toxic via oxidative damage. Usually not eliminated by this pathway unless large ingestion (sulfating w glutathione and glucuronation = the normal breakdown).

Note: 5-oxoproline is primarily a result of chronic ingestion, thus consider that in GOLDMARK as an indicator of chronic overdose primarily

Potentially toxic if more than 7g ingestion

Normal peak effect = 45 minutes, elimination in 2-3 hours -> slower in overdose (generally true, and especially in co-ingestion)

Stages

When to treat

Rumack - Matthew nomogram predicts development of hepatotoxicity after acute (1x ingestion) within 24h (known time of ingestion).

"4h level" is the most common reference point. 150 = treatment line.

Does not predict chronic ingestion or other outcomes.

Treatment

NAC = makes more glutathione and directly reverses oxidant damage

Must be given within 6-8h to entirely work (takes that long to overwhelm sulfating and glucuronidation pathways) => push to get it on that quick.

Treat (or give) until APAP level is 0 AND transaminases (particularly AST) below 1K and downtrending, INR<2, absence of encephalopathy.

Risk of anaphylACTOID reaction - just slow the rate by 50% and give benadryl (or switch to PO NAC)

If ingested more than 30g (=250-300+ level at 4h, 2x the treatment line), use higher dose of NAC (because there is some evidence of breakthrough toxicity)

Occasionally need Dialysis (APAP is cleared by dialysis): indications - sick and presenting with 800-900 level.

Note: EXTRIP = a group of nephrologists and toxicologists figuring out guidelines for when to dialyze toxic ingestions.

Transplant: King's College criteria (or APACHE over 12 actually a bit better) predicts death or need for transplant. Practically, a lactate that is EITHER normal OR clears with IVF has a good NPV for survival without transplant (80%)

Toxic Alcohols

All potentially lethal without treatment with a full gulp.

• Ethanol - beer. -> acetyl-CoA

• Ethylene glycol - antifreeze. T0.5 - 3-8h -> glycolic and oxalic acid. Nephrotoxicity in 12-24h, occ ca ox deposition in other tissues, hypocalcemia. UA with ca ox is 65% sensitive = not good enough to add info.

• Methanol - wiper fluid, occasionally in fuel line antifreeze. T0.5 4-8h -> formic acid. Optic nerve and retina toxicity (snow-storm vision). Can also cause neurotoxicity / parkinsonism. Maybe some rhabdo

• Isopropanol - rubbing alcohol, occasionally in automotive products. -> acetone (no acid = no gap). Not toxic, causes ketosis without acidosis (and drunkenness). Don't need to treat it - though hemorrhagic gastritis.. mostly in textbook.

• Propylene glycol - 'safe antifreeze', and diluent in some meds

• Diethylene glycol - brake fluid.

KEY POINT: Initially, osmotically active but not acid = elevated osmolality gap. Normal anion gap Middle - ambig Late, metabolized to acids = normal osmol gap and high anion gap

[ ] image

However, osmolal gap is non-specific (just measures total things in the blood). The 'gap' makes so many assumptions that it's clinical utility is low (baseline gap is unknown, normal is -15 to +10). Only useful to rule in with +20-30 or higher.

Lab pitfalls: Need to know ethanol level = are they blocked. Need toxic alcohol labs to be sent as stat. Volatile alcohol panforgoes not include ethylene glycol.

Some lactate analyzers will misinterpret glycolic acid (ethylene glycol) as lactate - can lead to very large lactic acidosis in someone who doesn't look toxic. = 'lactate gap'. (Contrast, formic acid can actually cause a lactic acidosis by mitochondria tox.)

If unclear, can give a dose of fomepizole and block for 12 hours.

Treatment:

• concentration above 20-25 mg/dl = pretty low (wouldn't make you drunk). This is based on natural experiments.

• no reason for charcoal or lavage due to quick absorbtion

• slow alcohol dehydrogenase by either ethanol (competitive inhibition) or fomepizole (safe. Loading dose then 4 follow-up doses. Have to adjust with dialysis)

• dialysis - ExTRIP recommends iHD > Crrt. Do it if acidosis (pH 7.15), methanol > 70, AG 24+, impaired renal function.

• can temporize with bicarb (less acid form = less toxic)

[ ] image summary

Other drugs of abuse

Methamphetamine

[ ] image

Indistinguishable from severe schizophrenia.

Fear hyperthermia (40-41+) - suggests need for cooling (get them wet and with fan > better than ice packs in axilla or cooling blankets) and possibly intubation/sedation.

HTN/Tachy - sedate first. However, if coronary ischemia - treat as real due to risk of dissecting.

Unapposed alpha from beta blocker first? It IS a concern with cocaine, probably also with meth though it's less prone to vasospastic.

Treat with benzodiazepine (or other GABA-ergic). Antipsychotics are not so helpful (no anti-epileptic effect). Maybe precedex (central sympatholytic)

MJ

Plain ol' MJ doesn't come to ICU (sometimes ER due to anxiety and paranoia)

Spice = synthetic cannabinoids (large bucket category)

add agitation, psychosis, seizures, sometimes AKI/coagulopathy with negative UDS.

[ ] surveillance?

Psychedelics

Not just hallucinations (also emphathogens, entactogens) -> act on serotonin

Rarely will end up in ICU - it's probably something else.

MDMA

Bruxism, hyponatremia, Serotonin syndrome

Ayahuasca

Contains DMT and harming (an MAOi).

Mescaline

Aka peyote

Psilocybin

Aka magic mushrooms.

##Toxidromes

Features with good diagnosticity

Anticholinergic - if not tachycardia, very unlikely; except Seroquel will have dilated pupils (Seroquel also has alpha 1)

Cholinergic - v rare. B's - bradycardia, bradypnea, bronchorrhea. (SLUDGE)

Opioids - duh

Sympathomimetic - tachycardia is sensitive. Sweatiness differentiates from anti-Ch. Temperature is most predictive for morbidity.

Sedative-hypnotics

Febrile toxidromes

• sympathomimetic
• serotinergic: clonus, hyperreflexivity
• anticholinergic: dry
• NMS: decreased reflexes. Gradual onset
• Malig Hyperthermia: identical to NMS but rapid onset and after succinylcholine.

Activated charcoal

Review https://bpspubs.onlinelibrary.wiley.com/doi/full/10.1111/bcp.12793

Adsorbs substances.

Does NOT work for metals, hydrocarbons, toxic alcohols, or caustics.

MUST have good enough mental status for a gag reflex -> vomit into bag.

• Isbister -> Aspiration Pneumonitis in an overdose population suggests that if they were going to vomit anyway. https://pubmed.ncbi.nlm.nih.gov/14707564/

Within 1h from ingestion requirement is not legit.

Gastric lavage and whole bowel irrigation

Rarely useful, except in massive ingestion due to meds with poor treatment options. E.g. Lead, iron, lithium, digoxin, propranolol, bupropion

Alkalinization

Intralipid

Lidocaine, TCA, bupropion. Better if given up front

Dialysis

Check extra guidelines

ECMO

Hypoglycemic / Diabetic Medications

Sulfonylureas

Glipizide, glimepiride, glyburide -> long acting and renal clearance.

Q1h BG, Given glucose/meal. Get octreotide if recurrent

Flozins

Volume depletion, euglycemic DKA, UTIs (?), vaginiti

Metformin

Byguanides. Hyperlactatemia (inhibits mitochondria and thus pyruvate is shunted to lactate instead of Krebs).

Needs to be a massive overdose (<5g well tolerated) causes hypoglycemia, hypothermia, CV collapse, and Coma.

MILA (induced), MALA (associated), MULA (unrelated) - spectrum of how much the acidosis is actually caused by the metformin vs some other acute illness.

Can dialyze off if needed.

Hypoglycemia - symptoms correlation.

Physiologic range - down to 82.8 Hypoglycemia < 70 Glucagon released at 68.4 Adrenaline at GH 66.6 Cortisol release 57.6 Neurophysiological dysfunction around 50.