Alcohol Related Disorders Simon Pulfrey MSc, MD, CCFP December 5, 2002
Jan 13, 2016
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