Alcohol Related Disorders

1
Alcohol Related Disorders

• Simon Pulfrey MSc, MD, CCFP
• December 5, 2002

2
(No Transcript)
3
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

4
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

5
4 hours later

• 37.50, 150/100, 98, 98RA
• 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

6
5 hour post arrival ED

• 7 hours post MVC generalized seizure x 3 mins,
  then 15 mins then 15 minsand 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

7
Alcohol Withdraw Syndrome

• Incomplete understanding of neuropathophysiology
• State of CNS excitation
• Develops 6 to 36 hours after cessation or
  reduction of EtOH intake

8
Classic Signs of Minor EtOH Withdraw

• 6 to 36hrs
• Mild autonomic hyperactivity
• Nausea, anorexia, tremor, tachycardia,
  hypertension, hypereflexia, anxiety, disturbed
  sleep

9
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

10
Delirium Tremens

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

11
This guy is in EtOH withdrawWhat do you have to
rule out?

• Other ingestion and/or WD syndrome
• Intracranial pathology
• Infection
• Hypoglycemia
• Electrolyte abnormalities
• Hypoxia
• Organ failure

12
Denver Man Case

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

13
Management of AWS - DT

• Provide relief from anxiety and hallucinations
• Help prevent seizures
• Allow detection of psychiatric illness
• Prepare for long-term treatment!

14
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
  

15
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,

16
Butyrophenones

• Haloperidol and droperidol
• May have synergistic effect with BDZ
• IV, IM, PO

17
Others

• Beta-blockers
• AWS increased noradrenergic activity
• BDZ no direct na affects
• Consider obvious contraindications
• 2. Alpha agonists

18
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

19
EtOH Related Seizures

• Differentiate between alcohol related seizures
  and alcohol withdraw seizures
• Underlying and non-EtOH related seizure disorder?

20
EtOH and Seizures Causes

• AWS
• Neurotoxic effects
• Metabolic brain disorder
• Cerebral trauma
• Precipitating seizures with underlying epilepsy
• Cerebral compromise infection, bleed

21
DIMS
22
Management Issues

• Glucose, thiamine, MgSO4,
• Anticonvulsants?

23
EtOH. 7 min generalized seizure, 1st time. N CT,
Lytes, glucose

• Do you start phenytoin?

24
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!!

25
EtOH. Status epileptcus.Management? Would you
still use dilantin?

• ABC
• BDZ
• Phenytoin

26

• The case 1 clinical clerk
• What drug would you use?

27
What is Zero-Order Kinetics?

• Elimination at a constant rate regardless of
  concentration. Linear

28
What is first-order kinetics?

• Rate of elimination is proportional to
  concentration.

29
Who Cares?

• Alcohols largely zero-order therefore, t1/2 can
  be difficult to predict
• ASA and phenytoin at high concentrations

30
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

31
Case 2

• LOC declines rapidly
• Intubated en route to FMC for GCSlt8 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

32
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?

33
Common sources of methanol?

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

34
Can methanol be absorbed via transdermal and the
respiratory routes?

• Yes
• What toxic alcohol doesnt work for huffing?

35
What metabolites are responsible for methanols
toxic effects?

• What B-Vitamin is necessary for methanol
  metabolism?

36
Methanol Metabolism
37
Why is it important to know what time pt ingested
WW fluid?

• Methanols 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

38
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

39
Methanol Pathophysiology

• Peak absorption 30-90min post GI
• Transdermal and pulmonary possible
• Toxic metabolites 14h-30h depending upon dose and
  co-ingestants

40
Clinical Features

• Wary of delayed presentation
• CNS depression, HA, seizures
• Visual disturbances variable, snowstorm
• Abdominal pain, N, Vx
• Anion-gap metabolic acidosis

41
Ophthalmologic exam

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

42
Other Findings in Methanol Toxicity

• CT head basal ganglia infarction
  Parkinsonian-like
• GI - N, Vx, severe epigastric pain
• Acute pancreatitis

43
Harbringer of poor outcomes

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

44
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 glucoseurea
• Freezing point depression

45
Anion-gap metabolic acidosis

• Strong and relatively consistent finding in
  methanol toxicity

46
Father Tito

• Methanol level 24 mmol/l
• EtOH 19 mmol/l
• Aspiration pneumonitis
• Hemodialysis recommended gt 7.8mmol/L

47
Disposition

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

48
What makes you the most drunk?

• Isopropanol, methanol, ethylene glycol, or EtOH
• Isopropanol, ethelyen glycol, EtOH, methanol

49
What alcohol causes long QT?

• Why?

50
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

51
Case 3

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

52
Case 3

• EtOH, methanol, ethylene glycol levels
• Urinalysis
• What are you expecting to see on urinalysis?

53
Case 3 Urinalysis

• Crystalluria
• Calcium oxalate monohydrate crystals more
  specifically
• Markers of tubular dysfunction may also be present

54
What products contain Ethylene glycol?

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

55
What are EGs toxic metabolites?
56
Pathophysiology of EG

• Colorless, odorless and sweet
• Rapid GI absorption peak 1-4hrs
• T1/2 increased from 3-5hrs to gt15hrs with EtOH gt
  17mmol/l
• Toxic metabolites- aldehydes, gylcolate, oxalate,
  and lactate- effect lungs, kidney, heart and
  brain
• Vit B2 B6 deficiency increase toxic metabolite
  production

57
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

58
Three phases of EG intoxication?

• CNS depression 1h-12h
• Cardiopulmonary 12h-24h
• Nephrotoxicity 24h 72h

59
CNS Phase 1

• Inebriation
• Hallucinations
• Coma
• Seizures
• Of Note optic fundi normal but nystagmus and
  opthalmoplegia possible

60
Cardiopulmonary Phase 2

• Tachycardia/pnea and hypertension
• CHF ARDS and subsequent CVS collapse
• Rarely myositis

61
Hallmarks of EG Toxicity

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

62
Nephrotoxixity Phase 3

• Flank pain CVA tenderness
• Oliguric RF and ATN
• Crystal and direct nephrotoxic effect

63
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

64
Case 3

• APAP, ASA, methanol negative
• EtOH 25 mmol/L
• EG level 12 mmol/L
• Hemodialysis gt 4.03 mmol/L
• Lethal cases reported gt 5.69 mmol/L

65
Treatment for EG and Methanol Toxicity

• Is there a role for gastric lavage?
• Is there a role for activated charcoal?
• What about forced diuresis?

66
Treatment

1. Correction of metabolic acidosis
2. Prevent formation of toxic metabolites through
   ADH blockade
3. Removal of parent alcohol

67
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

68
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 methanols and
  100 x EGs
• Wary level, glucose and vitamins
• Monitor q1-4h

69
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
• Doesnt replace dialysis!!

70
Hemodialysis

• Cornerstone of therapy
• EG gt 4.03 mmol/L
• Methanol gt 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?

71
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

72
Disposition Issues

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

73
Prevention

• Bittering agents?
• Less toxic alcohols such as propylene glycol?

74
Case 4 42 yo man in YK. Cut head after 12 beers
and 2 hair sprays

• What toxic alcohol?
• So very drunk

75
What products contain isopropyl alcohol?

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

76
Pathophysiology

• 2 x as potent and 2-4x longer acting than EtOH
• Onset 30 mins
• T1/2 7h
• First-order kinetics

77

• Isopropanol
• 
  ADH
• NAD -NADH
• Acetone
• Acetate and Formate
• CO2

78
Clinical Features

• Hallmark ketonemia and ketonuria without elevated
  blood glucose or glycosuria
• GI irritant gastritis hemorrhagic
• Peripheral vasodilation
• Hypotension
• Hypoglycemia

79
IA Ingestion

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

80
Management

• Rarely dangerous
• Supportive
• Inotropes for severe hypotension
• Most can be discharged once positive sobering
  trend after 6-8hrs
• Wary vitamins and electrolytes

81
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