Teaching Shift: Toxicology

Small cation, alters serotonin and norepi uptake via a complex mechanism in which it substitutes for Na+ and K+ and alters cell signaling.

Toxic serum dose – very narrow therapeutic index, toxic effects can be seen as low as 1.5 mEq/L – in rare instances even at 1.2 mEq/L 

Two types of formulations – standard release and sustained/extended-release.

1) With standard release preparations, absorption is nearly complete within 6-8 hours with peak plasma levels occurring within 4 hours.

2) With sustained/extended-release preparations, peak levels are reached after up to 12 hours

Absorption: Lithium is rapidly absorbed and slowly redistributed, so concentration right after ingestion can be elevated but then may drop after reaching steady-state

Immediate-release formulations: 6-hour concentration is more accurate with serial levels until the peak is reached.

Excreted only (no metabolism) – entirely via kidneys, so any decrease in GFR can lead to toxicity even at low doses – dehydration and hypovolemia can also affect it

Anything that increases salt reabsorption in the kidneys can elevate serum levels, because Li has a similar structure to Na but with a higher affinity for renal tubule cells

A lithium level is useful here because it correlates to the severity of toxicity and you can monitor excretion accurately

A lithium level can help confirm the diagnosis, but does not correlate to severity – plasma levels can’t tell you how much is in the tissue compartments, particularly CNS. This is also why patients receiving lithium are supposed to get their levels checked periodically.

Acute tox: Initially it is GI – vomiting, diarrhea, abdominal pain/cramping, as it is a salt and causes direct irritation. Generally, neurologic sequelae are later findings. The worsening danger comes from volume loss secondary to diarrhea and vomiting.

Chronic tox: Acute on chronic toxicity can present as renal failure or neurotoxicity (AMS, seizures, hypertonicity, extrapyramidal side effects, clonus, fasciculations)

Others – Hypothyroidism, nephrogenic DI, ECG changes (QT prolongation, T inversions across the precordial leads, sinoatrial dysfunction, bradycardia, complete heart block, or unmasking of a Brugada pattern) are possible. However, the evidence behind cardiac toxicity is very limited and at this time, lithium isn’t known to be significantly cardiotoxic (compared to its other effects)

GI decontamination: Consider in setting of sustained-release with minimal vomiting

Fluids – For mild toxic levels with normal renal function, maintain and resuscitate volume status with normal saline (0.9% NaCl) at 1.5 – 2x maintenance rates. Monitor urine output – >1ml/kg/hr.

Exclude potential contestants – Consider all the other meds that your patient could be on 

Avoid any other renally-cleared drugs or anything that can interfere with the clearance of lithium

Renal replacement therapy is the mainstay of treatment for Lithium toxicity. Always check out the EXTRIP guidelines when considering renal replacement therapy for toxicologic exposures. For Lithium the indications are:

1) [Li+].>5.0 mEq/L

2) Kidney function is impaired and the [Li+].>4.0 mEq/L

3) Decreased level of consciousness, seizures, or life-threatening dysrhythmias irrespective of [Li+]

4) Confusion

5) Expected time to obtain a [Li+]<1.0 mEq/L with optimal management is >36 h (Generally patients who can’t tolerate large fluid volumes such as patients with heart failure)

ICU: renal impairment or altered mental status; monitor until stable

Floor: Elevated lithium level but asymptomatic or mild symptoms: supportive care (fluids, antiemetics, monitoring of lithium level and creatinine) until both GI symptoms have resolved and lithium level has normalized

1. 1. Rotella J. Lithium, Vomiting And Diarrhoea. Life In the Fast Lane. https://litfl.com/lithium-vomiting-and-diarrhoea/. Published 2019.
2. 2. Mehus B, LeRoy J. Acute and Chronic Lithium Toxicity. ACEP Toxicology Section. https://www.acep.org/how-we-serve/sections/toxicology/news/august-2016/acute-and-chronic-lithium-toxicity/.
3. 3. Grellar HA. Lithium. In: Hoffman RS, Howland MA, Lewin NA, Nelson LS, Goldfrank LR, eds. Goldfrank’s Toxicologic Emergencies, 10e. 10th ed. New York, NY: McGraw-Hill Education; 2015.
4. 4. Decker BS, Goldfarb DS, Dargan PI, et al. Extracorporeal Treatment for Lithium Poisoning: Systematic Review and Recommendations from the EXTRIP Workgroup. Clin J Am Soc Nephrol. 2015;10(5):875-887. doi:10.2215/CJN.10021014

Like benzodiazepines, barbiturates are agonists at the GABA-A channel.

Unlike benzodiazepines which directly open GABA-A channels allowing chloride ions to pass increasing channel opening frequency, barbiturates keep the channel open longer, increasing the periodicity or duty cycle. When combined with benzos the effect is synergistic.

1) Definitive diagnosis of EtOH withdrawal

2) No other active neurologic problems (especially no hepatic encephalopathy)

3) Not on essential medications that interact with phenobarbital (esp. HIV medications)

4) No history of porphyria

5) Not on phenobarbital chronically

1) If you haven’t given a large dose of benzos, you can give phenobarbital loading dose of 10 mg/kg over 30 mins as monotherapy; this shouldn’t cause somnolence on its own.

2) However, if you have given a large amount of benzodiazepines, don’t give the loading dose and give:

Critically ill – 130 mg IV q15min PRN anxiety/agitation OR 260mg IV q30min PRN moderate to severe agitation. Get phenobarb levels. 

Mild/moderate symptoms – 100 mg PO q60 mins prn mild symptoms, or 200 mg PO q60 min prn for moderate symptoms 

3) Limit total cumulative dose of phenobarb to 20-30mg/kg

1. 1. Farkas J. Phenobarbital monotherapy for alcohol withdrawal: Simplicity and power. PulmCrit(EMCrit). https://emcrit.org/pulmcrit/phenobarbital-monotherapy-for-alcohol-withdrawal-simplicity-and-power/. Published 2015.
2. 2. Farkas J. Treating delirium tremens: Pharmacokinetic engineering with diazepam and phenobarbital. PulmCrit(EMCrit). https://emcrit.org/pulmcrit/treating-delirium-tremens-pharmacokinetic-engineering-with-diazepam-and-phenobarbital/. Published 2014.