Alcohol Related Disorders

Simon Pulfrey MSc, MD, CCFPDecember 5, 2002

Denver man. 46 yo. Passenger in MVC 2 hours

ago. • Driving with sister. T-boned low speed.

Belted. No airbags. Spinal precautions via EMS

• No LOC• 36o, 145/90, 92 reg, 97% RA• Contusion R forehead• Fracture R 3rd and 4th proximal phalanges • 3 R-sided rib #

Case 1 Continues

• Normal hematocrit, lytes, glucose• Lives with sister. Telemarketer• No meds, no allergies, no

hospitalizations, no insurance…• Not confused. Shaky• States “just nervous”

4 hours later

• 37.50, 150/100, 98, 98%RA• Normal CT head and cervical spines• Anxious and “still recovering from

the shock of the accident”• Sister states “he is a nervous guy”• On casual exam – generalized

tremor

5 hour post arrival ED

• 7 hours post MVC – generalized seizure x 3 mins, then 15 mins then 15 mins…and so on…

• Lorazepam, haloperidol• Seizures abate an hour later• Very confused, agitated, and

delirious• Admitted and required over 800mg

of lorazepam over the next two days

Alcohol Withdraw Syndrome

• Incomplete understanding of neuropathophysiology

• State of CNS excitation• Develops 6 to 36 hours after

cessation or reduction of EtOH intake

Classic Signs of Minor EtOH Withdraw

• 6 to 36hrs• Mild autonomic hyperactivity• Nausea, anorexia, tremor,

tachycardia, hypertension, hypereflexia, anxiety, disturbed sleep…

Major Withdraw Sx?

• Usually 12 – 50 hours post • More pronounced sx as per minor

WD• Major anxiety, auditory and visual

hallucinations, decreased seizure threshold, delirium

Delirium Tremens

• Extreme end of EtOH WD spectrum• Gross tremor, fever, incontinence,

frightening hallucinations

This guy is in EtOH withdraw…

What do you have to rule out?• Other ingestion and/or WD syndrome

• Intracranial pathology• Infection• Hypoglycemia• Electrolyte abnormalities• Hypoxia• Organ failure

Denver Man Case

• Stopped drinking 24 hours ago.• 6 rye/day several years• EtOH withdraw…Delirium tremens• Treatment?

Management of AWS - DT

• Provide relief from anxiety and hallucinations

• Help prevent seizures• Allow detection of psychiatric

illness• Prepare for long-term treatment!

Management of AWS

• More than 150 drugs and combinations reported

• Benzodiazepines considered cornerstone

• No clear superiority of any on BDZ• Consider delivery modality,

bioavailability, t1/2

BDZ

• Lorazepam– Good bioavailability po, im,iv, – T1/2 7-14 hrs– Rel safe in hepatic/renal dysfxn

• Diazepam • Chlordiazepoxide• May require massive doses – eg diazepam

2600mg/48hr, midazolam 75 mg 1 hr,

Butyrophenones

• Haloperidol and droperidol• May have synergistic effect with

BDZ• IV, IM, PO

Others

1. Beta-blockers• AWS increased noradrenergic

activity• BDZ no direct na affects• Consider obvious

contraindications2. Alpha agonists

Adjunctive Therapy

• Thiamine 100 mg IV or PO• MgSO4 2-4g IV (po in non-acute setting

has improved strength, LTs, electrolytes)

• Volume repletion• Electrolyte normalization• Phenothiazines unhelpful

– Hypotension, decrease seizure threshold, extrapyramidal effects

EtOH Related Seizures

• Differentiate between alcohol related seizures and alcohol withdraw seizures

• Underlying and non-EtOH related seizure disorder?

EtOH and Seizures Causes

• AWS• Neurotoxic effects• Metabolic brain disorder• Cerebral trauma• Precipitating seizures with

underlying epilepsy• Cerebral compromise – infection,

bleed

DIMS

Management Issues

• Glucose, thiamine, MgSO4, • Anticonvulsants?

EtOH. 7 min generalized seizure, 1st time. N CT, Lytes,

glucose

• Do you start phenytoin?

EtOH. Multiple past hx seizures. Negative epilepsy w/u in past. N CT, glucose, lytes. Non-adherent

with dilantin.Do you restart it?

• Controversial.• May increase incidence of seizures if

suddenly stopped• Must determine cause and effect- is it

EtOH?, nonadherence?, new etiology? • Rehab!!

EtOH. Status epileptcus.Management? Would you still

use dilantin?

• ABC• BDZ• Phenytoin

• The case 1 clinical clerk

• What drug would you use?

What is Zero-Order Kinetics?

• Elimination at a constant rate regardless of concentration. Linear

What is first-order kinetics?

• Rate of elimination is proportional to concentration.

Who Cares?

• Alcohols largely zero-order therefore, t1/2 can be difficult to predict

• ASA and phenytoin at high concentrations

Case 2 - “Father Tito”

• Found slumped at bottom of stairs at home by fellow priests.

• Empty bottle of beer at feet, multiple empty beer cans

• No obvious trauma• Mumbling incoherently, unable to

stand, c/o headache

Case 2

• LOC declines rapidly• Intubated en route to FMC for GCS<8

Spinal precautions• GCS 8• 80/55 90 370 • PER sluggish 4mm B, Withdraw to pain, N

fundi, R sided crackles, blue fluid on shirt• Foley - anuric

What now?

• Na 141, K 4, Cl 95, HCO3 20, glucose 6, creatinine 90, urea 3, AG 26

• ABG – 7.2/27/112/18/-10• CXR R infiltrate nil else• What are your thoughts on

diagnosis?

Common sources of methanol?

• Sternos, glass cleaners, carburator fluid, antifreeze, window-washer fluid, shallacs, laquers, adhesives, copy fluid, inks

Can methanol be absorbed via transdermal and the respiratory routes?

• Yes• What toxic alcohol doesn’t work for

“huffing”?

What metabolites are responsible for methanol’s toxic effects?

• What B-Vitamin is necessary for methanol metabolism?

Methanol Metabolism

Why is it important to know what time pt ingested WW

fluid?

• Methanol’s toxic effects related to metabolites.

• T1/2 variable, prolonged and increased with co-ingestion of EtOH

• Sx may not appear until 12 –30 hrs post-injestion

• Zero-order kinetics at higher doses

Pathophysiology

• Optic neuropathy and putaminal necrosis two main complications

• Increased lactate production from formate-induced inhibition of mitochondrial respiration exacerbates acidemia

• Formaldehyde – retinal edema and optic papillitis

Methanol Pathophysiology

• Peak absorption 30-90min post GI• Transdermal and pulmonary

possible• Toxic metabolites 14h-30h

depending upon dose and co-ingestants

Clinical Features

• Wary of delayed presentation• CNS depression, HA, seizures• Visual disturbances – variable,

“snowstorm”• Abdominal pain, N, Vx

• Anion-gap metabolic acidosis

Ophthalmologic exam

• Dilated pupils• Sluggish or absent reaction to light• Poor accomadation• Hyperemia of optic disc• Retinal edema

Other Findings in Methanol Toxicity

• CT head – basal ganglia infarction –”Parkinsonian-like”

• GI - N, Vx, severe epigastric pain• Acute pancreatitis

Harbringer of poor outcomes

• Hypotension• Bradycardia

• Outcome is better correlated to severity of metabolic acidosis rather than methanol level

Gaps

• Father Tito had an osmol gap of 8. Does this r/o significant methanol toxicity?– Can have N osmol gap– Wary of lab calculations and

calculated osmol gaps. Consider 2Na +glucose+urea

– Freezing point depression

Anion-gap metabolic acidosis

• Strong and relatively consistent finding in methanol toxicity

“Father Tito”• Methanol level 24 mmol/l• EtOH 19 mmol/l• Aspiration pneumonitis

• Hemodialysis recommended > 7.8mmol/L

Disposition

• ICU• EtOH therapy• Hemodialysis• FIFE• D/C ICU after 3 days• F/U ophthalmology

What makes you the most drunk?

• Isopropanol, methanol, ethylene glycol, or EtOH

• Isopropanol, ethelyen glycol, EtOH, methanol

What alcohol causes long QT?

• Why?

Case 3 - 19 yo man. Suicide attempt with ingestion of

250ml antifreeze 6 hours ago

• Rural community – EMS to FMC• GCS 15• 120/80, 90, 16, SpO2 99%, 36.7• CVS, Resp, CNS, abdo exam

normal• No other ingestions

Case 3

• Na 144, K 3.5, Cl 106, HCO3 20, AG 18• CBC , urea, creatinine N• 7.3/38/90/21/97%RA• APAP, ASA nil• Osmolar gap 10• What are your ingestion concerns?• What else do you want to order?

Case 3

• EtOH, methanol, ethylene glycol levels

• Urinalysis– What are you expecting to see on

urinalysis?

Case 3 Urinalysis

• Crystalluria • Calcium oxalate monohydrate

crystals more specifically• Markers of tubular dysfunction

may also be present

What products contain Ethylene glycol?

• Antifreeze/coolant• Deicing fluid• Brake fluid• Solvents• Component of some paints,

cosmetics and laquers

What are EG’s toxic metabolites?

Pathophysiology of EG• Colorless, odorless and sweet• Rapid GI absorption – peak 1-4hrs• T1/2 increased from 3-5hrs to

>15hrs with EtOH > 17mmol/l• Toxic metabolites- aldehydes,

gylcolate, oxalate, and lactate- effect lungs, kidney, heart and brain

• Vit B2 & B6 deficiency increase toxic metabolite production

EG Pathophysiology

• Glyoxylic acid also metabolized to formic and oxalic acid

• Metabolic acidosis• Oxalic combines with Ca –

crystalluria(50% of cases) and possible clinically significant hypocalcemia

Three phases of EG intoxication?

• CNS depression 1h-12h

• Cardiopulmonary 12h-24h

• Nephrotoxicity 24h – 72h

CNS – Phase 1

• Inebriation• Hallucinations• Coma• Seizures• Of Note – optic fundi normal but

nystagmus and opthalmoplegia possible

Cardiopulmonary – Phase 2

• Tachycardia/pnea and hypertension

• CHF – ARDS and subsequent CVS collapse

• Rarely myositis

Hallmarks of EG Toxicity

• Inebriation but no scent of alcohol• Anion- gap metabolic acidosis• Crystalluria

Nephrotoxixity – Phase 3

• Flank pain & CVA tenderness• Oliguric RF and ATN

• Crystal and direct nephrotoxic effect

Delayed Neurological Sequelae Phase 4

• All associated with RF• 6-12 d later• Facial & auditory nerve oxalosis

• Parkinsonian-like symptoms

• Intervention finding? – dialysis since 1978

Case 3

• APAP, ASA, methanol negative• EtOH 25 mmol/L

• EG level 12 mmol/L

• Hemodialysis > 4.03 mmol/L• Lethal cases reported > 5.69 mmol/L

Treatment for EG and Methanol Toxicity

• Is there a role for gastric lavage?

• Is there a role for activated charcoal?

• What about forced diuresis?

Treatment

1. Correction of metabolic acidosis

2. Prevent formation of toxic metabolites through ADH blockade

3. Removal of parent alcohol

Metabolic Acidosis Correction

• NaHCO3 -bolus and infusion

• Aim to normalize arterial pH• May require large amounts• Definite acute benefits and may be

beneficial in reversing visual defects

• Wary of worsening hypocalcemia

ADH Blockade

• EtOH or fomepizole• What EtOH serum level do you

titrate to?• 20-30 mmol/L• ADH affinity for EtOH is 10-20 x

methanol’s and 100 x EG’s• Wary level, glucose and vitamins• Monitor q1-4h

Fomepizole- Methylprazole

• Affinity for ADH 8000x that of EtOH• Easier administration, minimal CNS

effects, do not need to follow levels, longer t1/2

• $$, pregnant class C, pediatric literature sparse

• Awaiting META trial

• Doesn’t replace dialysis!!

Hemodialysis

• Cornerstone of therapy• EG > 4.03 mmol/L• Methanol > 7.8 mmol/L• Depends on timing and clinical

scenario! • Or recalcitrant metabolic acidosis,

electrolyte abnormalities, renal failure• Decreases t1/2 to 2.5-3.5 hrs• End point?

Cofactors

• Folic acid in methanol toxicity – 50mg

• Thiamine and pyridoxine in hyperoxaluria of EG toxicity – 100 and 50 mg respectively

• Calcium gluconate? Fine balance. Wary in EG

• MgSO4 with thiamine

Disposition Issues

• EtOH infusion/ hemodialysis – ICU• Nephrology• F/U ophthalmology• Neurology•

Prevention

• Bittering agents?

• Less toxic alcohols such as propylene glycol?

Case 4 42 yo man in YK. Cut head after 12 beers and 2 hair

sprays• What toxic alcohol?• So very drunk

What products contain isopropyl alcohol?

• Rubby• Solvent• Disinfectants• Hair products• Jewelry cleaners

Pathophysiology

• 2 x as potent and 2-4x longer acting than EtOH

• Onset 30 mins• T1/2 7h• First-order kinetics

Isopropanol ADH

NAD -NADH

Acetone

Acetate and Formate

CO2

Clinical Features

• Hallmark ketonemia and ketonuria without elevated blood glucose or glycosuria

• GI irritant – gastritis – hemorrhagic…

• Peripheral vasodilation• Hypotension• Hypoglycemia

IA Ingestion

• Classically– Smell– Acidosis with ketonuria/emia– Osmol gap– Mild or non-existant acidemia

Management

• Rarely dangerous• Supportive • Inotropes for severe hypotension• Most can be discharged once

positive sobering trend after 6-8hrs• Wary vitamins and electrolytes

Summary

• Always consider possibility of methanol and/or EG toxicity in the comatose, suicidal and desperate drunk

• Do not be reassured by a normal Osmol gap

• Start ADH blockade early