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Alcohol Related Disorders. Simon Pulfrey MSc, MD, CCFP December 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 36 o , 145/90, 92 reg, 97% RA Contusion R forehead

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alcohol related disorders

Alcohol Related Disorders

Simon Pulfrey MSc, MD, CCFP

December 5, 2002

denver man 46 yo passenger in mvc 2 hours ago
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
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
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
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
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
Classic Signs of Minor EtOH Withdraw
  • 6 to 36hrs
  • Mild autonomic hyperactivity
  • Nausea, anorexia, tremor, tachycardia, hypertension, hypereflexia, anxiety, disturbed sleep…
major withdraw sx
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
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
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
Denver Man Case
  • Stopped drinking 24 hours ago.
  • 6 rye/day several years
  • EtOH withdraw…Delirium tremens
  • Treatment?
management of aws dt
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
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
slide15
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
Butyrophenones
  • Haloperidol and droperidol
  • May have synergistic effect with BDZ
  • IV, IM, PO
others
Others
  • Beta-blockers
  • AWS increased noradrenergic activity
  • BDZ no direct na affects
  • Consider obvious contraindications

2. Alpha agonists

adjunctive therapy
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
EtOH Related Seizures
  • Differentiate between alcohol related seizures and alcohol withdraw seizures
  • Underlying and non-EtOH related seizure disorder?
etoh and seizures causes
EtOH and Seizures Causes
  • AWS
  • Neurotoxic effects
  • Metabolic brain disorder
  • Cerebral trauma
  • Precipitating seizures with underlying epilepsy
  • Cerebral compromise – infection, bleed
management issues
Management Issues
  • Glucose, thiamine, MgSO4,
  • Anticonvulsants?
slide24
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!!
slide26
The case 1 clinical clerk
  • What drug would you use?
what is zero order kinetics
What is Zero-Order Kinetics?
  • Elimination at a constant rate regardless of concentration. Linear
what is first order kinetics
What is first-order kinetics?
  • Rate of elimination is proportional to concentration.
who cares
Who Cares?
  • Alcohols largely zero-order therefore, t1/2 can be difficult to predict
  • ASA and phenytoin at high concentrations
case 2 father tito
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
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
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
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
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 metabolites are responsible for methanol’s toxic effects?
  • What B-Vitamin is necessary for methanol metabolism?
why is it important to know what time pt ingested ww fluid
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
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
Methanol Pathophysiology
  • Peak absorption 30-90min post GI
  • Transdermal and pulmonary possible
  • Toxic metabolites 14h-30h depending upon dose and co-ingestants
clinical features
Clinical Features
  • Wary of delayed presentation
  • CNS depression, HA, seizures
  • Visual disturbances – variable, “snowstorm”
  • Abdominal pain, N, Vx
  • Anion-gap metabolic acidosis
ophthalmologic exam
Ophthalmologic exam
  • Dilated pupils
  • Sluggish or absent reaction to light
  • Poor accomadation
  • Hyperemia of optic disc
  • Retinal edema
other findings in methanol toxicity
Other Findings in Methanol Toxicity
  • CT head – basal ganglia infarction –”Parkinsonian-like”
  • GI - N, Vx, severe epigastric pain
  • Acute pancreatitis
harbringer of poor outcomes
Harbringer of poor outcomes
  • Hypotension
  • Bradycardia
  • Outcome is better correlated to severity of metabolic acidosis rather than methanol level
slide44
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
Anion-gap metabolic acidosis
  • Strong and relatively consistent finding in methanol toxicity
father tito
“Father Tito”
  • Methanol level 24 mmol/l
  • EtOH 19 mmol/l
  • Aspiration pneumonitis
  • Hemodialysis recommended > 7.8mmol/L
disposition
Disposition
  • ICU
  • EtOH therapy
  • Hemodialysis
  • FIFE
  • D/C ICU after 3 days
  • F/U ophthalmology
what makes you the most drunk
What makes you the most drunk?
  • Isopropanol, methanol, ethylene glycol, or EtOH
  • Isopropanol, ethelyen glycol, EtOH, methanol
case 3 19 yo man suicide attempt with ingestion of 250ml antifreeze 6 hours ago
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
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 31
Case 3
  • EtOH, methanol, ethylene glycol levels
  • Urinalysis
    • What are you expecting to see on urinalysis?
case 3 urinalysis
Case 3 Urinalysis
  • Crystalluria
  • Calcium oxalate monohydrate crystals more specifically
  • Markers of tubular dysfunction may also be present
what products contain ethylene glycol
What products contain Ethylene glycol?
  • Antifreeze/coolant
  • Deicing fluid
  • Brake fluid
  • Solvents
  • Component of some paints, cosmetics and laquers
pathophysiology of eg
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
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
Three phases of EG intoxication?
  • CNS depression 1h-12h
  • Cardiopulmonary 12h-24h
  • Nephrotoxicity 24h – 72h
cns phase 1
CNS – Phase 1
  • Inebriation
  • Hallucinations
  • Coma
  • Seizures
  • Of Note – optic fundi normal but nystagmus and opthalmoplegia possible
cardiopulmonary phase 2
Cardiopulmonary – Phase 2
  • Tachycardia/pnea and hypertension
  • CHF – ARDS and subsequent CVS collapse
  • Rarely myositis
hallmarks of eg toxicity
Hallmarks of EG Toxicity
  • Inebriation but no scent of alcohol
  • Anion- gap metabolic acidosis
  • Crystalluria
nephrotoxixity phase 3
Nephrotoxixity – Phase 3
  • Flank pain & CVA tenderness
  • Oliguric RF and ATN
  • Crystal and direct nephrotoxic effect
delayed neurological sequelae phase 4
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 32
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
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
Treatment
  • Correction of metabolic acidosis
  • Prevent formation of toxic metabolites through ADH blockade
  • Removal of parent alcohol
metabolic acidosis correction
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
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
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
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
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
Disposition Issues
  • EtOH infusion/ hemodialysis – ICU
  • Nephrology
  • F/U ophthalmology
  • Neurology
prevention
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
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
What products contain isopropyl alcohol?
  • Rubby
  • Solvent
  • Disinfectants
  • Hair products
  • Jewelry cleaners
pathophysiology1
Pathophysiology
  • 2 x as potent and 2-4x longer acting than EtOH
  • Onset 30 mins
  • T1/2 7h
  • First-order kinetics
slide77
Isopropanol

ADH

NAD -NADH

Acetone

Acetate and Formate

CO2

clinical features1
Clinical Features
  • Hallmark ketonemia and ketonuria without elevated blood glucose or glycosuria
  • GI irritant – gastritis – hemorrhagic…
  • Peripheral vasodilation
  • Hypotension
  • Hypoglycemia
ia ingestion
IA Ingestion
  • Classically
    • Smell
    • Acidosis with ketonuria/emia
    • Osmol gap
    • Mild or non-existant acidemia
management
Management
  • Rarely dangerous
  • Supportive
  • Inotropes for severe hypotension
  • Most can be discharged once positive sobering trend after 6-8hrs
  • Wary vitamins and electrolytes
summary
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