Transcript Alcohol Related Disorders

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
• 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?
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Other ingestion and/or WD syndrome
Intracranial pathology
Infection
Hypoglycemia
Electrolyte abnormalities
Hypoxia
Organ failure
Denver Man Case
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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 contraindications
2. 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
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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
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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
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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
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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
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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?
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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
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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
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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
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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
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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?
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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
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Smell
Acidosis with ketonuria/emia
Osmol gap
Mild or non-existant acidemia
Management
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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