Scott D. Phillips, MD, FACP, FACMT, FAACT University of Colorado Rocky Mountain Poison & Drug Center Washington Poison Center

Toxicology Dilemmas in Critical Care

› HPI:

– A 70 yr. M presented with slurred speech for 24 hrs. Denies any N/V/D/C, no CP, SOB, DOE, PND, no headache. Has had a NP cough for several days. The patient is sleeping and when woken up, he dozes off. He has slurred speech but no other complaints of weakness at the time of admission. According to his wife, he started having slurred speech the evening prior to admission.

› PMH:

– HTN, DM 2, HCV, questionable CVA, CAD S/P catheterization 3 years ago, with a stent in RCA, hypercholesterolemia, PVD, pneumonia 5 months ago

Case # Chief Co plai t Ge e alized Weak ess

› Medications

– ramipril 10 mg/d, cilostazol 100 mg bid, metformin 500 mg bid, atorvastatin 20 mg/d and aspirin 325 mg/d, no influenza vaccination

› SH:

– Retired, Lives with his wife. Denies any alcohol. Smokes 1 ppd for 30 yrs.

› FMH:

– Denies any CVA or CAD , + for T2DM and COPD

Case #1 (continued)

› PE:

– WD/WN in NAD, VS: T 39.5 RR 38 BP129/60 P 105 Chest: faint bibasilar rales

– CVS: Tachy S1S2 no CRMG

– Abdomen: Soft, NT, ND, +BS

– Ext: no c/c/e

– Neuro: responds to name, some slurring, very lethargic to stuperous, no facial or limb asymmetry, non-focal, Strength: decreased, bulk & to e a e app op iate fo age. Ce e ella : u a le to oope ate, DTR’s 1+

Case #1 (continued)

› In the ER, the admitting doctor felt that the patient had slurred speech and some slight weakness of his left arm and left leg. He had a tremor in his right arm. Otherwise no other focal findings or meningeal signs were noticed. An aspirin was given. He was admitted with a suspected stroke.

Case #1 (continued)

› A — Alcohol/Acidosis

› E — Endocrine

› Epilepsy

› Electrolytes

› Encephalopathy

› I — Infection

› O — Opiates, Overdose

› U — Uremia

› T — Trauma

› I — Insulin

› P — Poisoning/Psychosis

› S — Stroke/Seizure/syncope

AMS Mnemonic

› Plan:

– IV, ? Glucose,

– Labs + ABG

– EKG

– X-rays

Case #1 (continued)

› CBC: – WBC 7.8, Hgb 13, Hct 39, Plat 187

› Chemistries – Na 138, K 3.2, Cl 104, CO2 12, BUN 34, Cr 1.5 eGFR 48, Glu 78, AG 22

› ABG

› 7.36, 30, 68, 12 (1○ Met Acid, 2○ Resp Acid)

› EKG – ST 100, NSST-T wave changes

› X-rays – CXR: Pulm edema, ? CHF: CT head; mild diffuse edema

Case #1 (continued)

Pulm Edema

Mild Cerebral Edema

› Alcoholic Ketoacidosis

› Starvation ketoacidosis

› Ingestions

– Methanol

– Ethylene glycol

– Aspirin (Salicylate) toxicity

– Iron

– INH

› Ingestions

› Lactic Acidosis

› Sepsis, liver disease, CO, CN, metformin, methemoglobin

› Renal Failure/Uremia

› Ketoacidosis

› DKA

Case #1 Differential Diagnosis Anion gap metabolic acidosis

› Confirmatory test?

Case #1 (continued)

2-Acetoxybenzoic acid;

›ALWAYS REMEMBER SALYCILATES – They kill early and often if missed.

– Often die with optimum treatment.

Case #1 Final

› 46 yr. old male presents with altered mental status and agitation. He has a hx of alcohol (EtOH) abuse and has been admitted for alcohol withdrawal syndrome (AWS) 3 times in the past 2 years.

› He has received 240 mg of IV diazepam in the ER and is still very agitated and hard to manage as he is moved into your critical care unit.

› Why is this patient not responding to benzodiazepines?

› How do you control this patient?

Case #2

Refractory Alcohol Withdrawal

› Definition – Poo ly defi ed…you k ow it whe you see it. – > 200 mg diazepam or 40 mg lorazepam in initial 3-4 hours fail

› Etiology – low endogenous GABA levels or

– acquired conformational changes in the GABA receptor

› Refractory AWS Treatment

› Be zo’s PLU“: – Phenobarbital 130-260 mg IV q15 min

– Dexmedetomidine without load, 0.2mcg/kg/hour

– Intubate and Propofol infusion start 5mcg/kg/min Titrate

Management in the Critically Ill

› Severe alcohol withdrawal characterized by – Profound agitation

– Autonomic hyperactivity

– Alcohol withdrawal seizures and delirium

› Lack of validated measurement tool for ICU patients (especially mechanically ventilated) – Options studied in ICU patients CIWA-Ar, SAS, RASS

› Benzodiazepines standard of care to prevent delirium and seizures – RAW e ui es ↑ sedatio a d is asso iated with a ~4 %

mechanical ventilation rate

– Alternative sedation options: phenobarbital, propofol, dexmedetomidine

Resistant Alcohol Withdrawal

› On study: RAW ~ 5% of all ICU admissions, with nearly 40% of patients requiring mechanical ventilation and a mean ICU length of stay of 5.7 days. (Gold 2007)

› Resistant alcohol withdrawal had very high diazepam requirements in first 24 hours: •Mean = 234 mg •Range: 10–1490 mg

Toxicodynamics of RAWS

› Main CNS neurotransmitters (NT) affected

– Inhibitory NT: gamma-aminobutyric acid (GABA) binds to GABA-a receptor

– Excitatory NT: glutamate binds to N-methyl-d-aspartate (NMDA) receptor

Ethanol (EtOH) Receptor Modulation

Acute EtOH

GABA

Glutamate

LOC

Cognition

Chronic EtOH

GABA level

GABAA Receptors & Sensitivity

NMDA

Receptor Tolerance

EtOH required for same effect

Abrupt Cessation

Glutamate binding to NMDA

GABA binding to GABAA

CNS Stimulation

Causes AWS

GABA Receptor

NMDA Receptor

NMDA Receptor in Chronic Use

› Chronic Use and Withdrawal:

– Excessive activity of the NMDAR

– Increase in Ca2+ influx,

› Major cause of neurotoxicity & cell death

› cortical pyramidal cells,

› hippocampal CA1 pyramidal cells,

› granule cells in the dentate gyrus, and amygdala

RAW“ a d ki dli g

› Repeated episodes of alcohol withdrawal leads to persistent and progressive EEG abnormalities,

› Further episodes of withdrawal become increasingly resistant to benzodiazepines.

› Repeated alcohol withdrawal lead to permanent dysregulation of GABA receptors. This understanding may be an explanation for the

› ki dli g phe o e a, – observation of increasing severity of alcohol withdrawal among individual

subjects, and the development of benzodiazepine-resistant alcohol withdrawal.

Delirium Tremens

› (1) disturbance of consciousness (such as reduced clarity of awareness of the environment) with reduced ability to focus, sustain, or shift attention, delirium, confusion,and frank psychosis, or

› (2) a change in cognition (such as memory deficit, disorientation, language disturbance) or the development of a perceptual disturbance that is not better accounted for by a preexisting, established, or evolving dementia.

› Unlike typical alcohol withdrawal, which typically last for 3–5 days, DT’s can last for up to 2 weeks

Barbiturates

• Few controlled studies

• Becoming first line agent

• Add for “RAW”*

• Acts on different GABA-a site

Propofol

• Stimulates GABA-A receptor

• Inhibits glutamate receptors

• Need to intubate

Propofol

• Good choice as a second agent

• Can add when refractory to massive benzodiazepine doses

• Act on different site of GABA-A receptor • Benzodiazepine augmenting agent

› Intoxication

› Alcohol Withdrawal Syndrome (AWS)

› Deli iu T e e s DT’s

› Refractory Alcohol Withdrawal syndrome (RAWS)

Alcohol Syndromes you are Treating

› Failure to consider a diagnosis – Novel chemicals

– Approximately 15 million chemical constituents, › About 30 antidotes

› Everything else is just supportive care

› Failure to appreciate the dynamic nature of overdoses – Changes toxicokinetics and toxicodynamics

› Failure to appreciate the danger – Most overdoses do fine with minimal treatment

– You need to appreciate the ones that are bad.

› Failure to react to the case.

Toxicology Dilemmas

› Analgesics (ASA & APAP)

› Alcohols (IPA, EtOH, MeOH, PgOH)

› Iron

› Opiates + e zo’s et

› Colchicine

› Selenous acid

› Insecticides, rodenticides, avicides, pisicides, moluscosides, Paraquat

› Botulism 1 million times great LD 50 than strychnine.

› Envenomation's

Very Dangerous substances

Thank you

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