Transcript Interesting Case Rounds

Interesting Case Rounds
Chris McCrossin
Special Thanks to Dr Vicas and Paul
Tourigny
Case
• 21 yo M presents to ED at 8:50 AM
• Drank 1 glass of antifreeze at 2am, was “tired
of life”
• Vomited immediately after the ingestion
• Now he wants to live so he thought he should
get checked out in the ED
• Vitals
– T 37.2, HR 129, RR 18, BP 138/96
• O/E
– CVS, Resp, Neuro, Abdo all unremarkable
Case
• Are you worried?
• He tells you he vomited “right away”,
does this change anything?
• What if you are a rural doc with access
only to basic to labs?
Ethylene Glycol
• Pathophysiology
• Diagnostics
• Treatment modalities
~ 30% excreted
unchanged
Stages of Toxicity
1.
Acute CNS
•
Renal Failure
•
Within 12 h
I.
II.
III.
•
3.
Slurred Speech
Ataxia
Altered mental status
AG, Oxalate
crystalluria
4.
Delayed CNS
•
2.
Cardiopulmonary
•
12 - 24 h
I.
II.
III.
HTN
Tachycardia
CHF
24-72 h
I.
Oliguria
II. Flank Pain
III. Azotemia
6-12 days
I.
II.
III.
Cranial neuropathies
Motor deficits
Cognitive deficits
Toxic Levels
• What ingested dose do you start to worry
about EG toxicity?
– Minimum Lethal Dose:
» 1-2 ml/kg (ie 70 cc in 70 kg adult = 1/3 cup)
» 30-60 ml can result in death or severe impairment
• What serum level do you worry about EG
toxicity?
– Not reliable, especially if late presenting;
metabolites that are toxic (EG may be low in
presence of high [metabolites])
– Will talk about more specifics with treatment
Case
• Labs
– Na 141, K 3.6, Cl 107, CO2 21
– EthOH 8.3 mmol/L
– Ethylene Glycol 10 mmol/L
– Isopropanol, methanol undetectable
Case
• What do you want to do?
– More labs?
– Treatment?
• Start ethanol drip?
• Start fomepazole?
• Start dialysis?
Urinalysis
• Crystalluria is only seen in ~ 15-50% of
cases
• Hematuria and proteinuria are more
common
• Helpful if you see oxalate crystals in the
unknown overdose but it doesn’t tell you
anything if you don’t see it
Anion Gap
• Na - [HCO3 + Cl]
• Normal 7 +/- 4
• Detects toxic metabolites; expect it to
be normal in the early period following
ingestion
Anion Gap
• 141 - [107+21] = 13
• What does this tell you?
• What if he had an AG of 28 and an
EthOH level of 40?
Osmol Gap
• To Calculate
– 2 Na + Glu + BUN + [EthOH x 1.2]
– Calculated - Measured
– A difference > 10 suggests a gap is present
• Primary use is as a screening test for the
presence of toxic alcohols
• Detects presence of parent alcohol; toxic
metabolites don’t contribute to the osmol gap
Anion Gap & Osmol Gap
Osmol Gap
• Our patient:
– Calculated Osmol
• 2(141) + 5.3 + 6.4 + 1.2(8.3) = 303
– Measured Osmol
• 321
– Osmol Gap
• 18
– Irrelevant in this case
Osmol Gap
• Limitations
– Only estimates molar quantity of uncharged
molecules (ie measures only the parent
compound, not the toxic metabolites {glycolate,
glyoxylate, and oxalate}) therefore insensitive for
late presentations
– Can see a gap in ketoacidosis, lactic acidosis, and
chronic renal failure*
– Gap is not sensitive enough to rule out small
ingestions*
– Cannot distinguish between the alcohols
– Large quantities of Alcohol raise the gap more
than expected based on its molecular weight
Osmol Gap
• Conclusion
– An abnormal gap may be helpful in
identifying toxic alcohol ingestion, however,
a normal gap does not rule out the
diagnosis, nor does an abnormal gap
confirm the diagnosis.
Treatment
•
Options
1.
2.
3.
4.
5.
6.
•
Gut Decontamination?
Hemodialysis
Bicarb
Cofactors
Ethanol
Fomepazole
Memory Aid:
•
4 A’s: block ADH, Alkalinize, Accelerate, Adjunct
Treatment
• Gastric Lavage or Charcoal?
– EG is very rapidly absorbed
– Activated charcoal does not absorb
significant amounts of alcohol
– Gastric lavage may be beneficial only
within the 1st hour after ingestion and
before toxic symptoms develop
Treatment
• Cofactors
– Thiamine & Pyridoxine
– MOA
• Involved in the metabolism of glyoxylic acid to
non-toxic substrates
– Theoretical benefit with some indirect
evidence
– Cheap therefore use them
Treatment
• NaHCO3?
– Rationale
• EG is metabolized to glycolate, glyoxalate, and oxalate.
Acidemia leads to protonation of these metabolites and
making them more likely to penetrate end-organ tissues
(ie kidney). Tx with bicarb deprotonates metabolites
making them less toxic.
– However
• No clear evidence exists to determine how bicarb should
be given.
Treatment
• NaHCO3
– Recommendations
• UpToDate
– 1-2 meq/kg bolus with maintenance infusion for patients
with pH < 7.3
• Micromedex Poison Index
– “NaHCO3 should NOT be routinely administered
prophylactially…or for the tx of mild to mod acisosis”
– Tx should be reserved for temporizing measure in
manageing cases of severe and life-threatening acidosis
prior to hemodialysis
• CJEM 2002
– “MA should be treated aggressively with NaHCO3 to bring
the serum pH back to within normal limits (7.35-7.45)”
Treatment
• Hemodialysis
– Best method to rapidly remove both parent
alcohols and their toxic metabolites
– May be avoidable with early administration
of an ADH inhibitor
Treatment
• Hemodialysis
– Indications
• Deteriorating vital signs
• Unresponsive significant MA (pH < 7.3)
• Renal failure, fluid, or electrolyte disturbances
not responsive to the usual therapy
• A serum ethylene glycol concentration of greater
than 8 mmol/L is traditionally an indication for
dialysis
» Micromedix, CJEM 2002
Treatment
• Hemodialysis
– Recommendations from European
Conference
Treatment
• Hemodialysis Endpoints
– Serum pH is normal
– Parent alcohol concentration is less than
3.2 mmol/L
– Resolution of the osmolar gap
Treatment
• ADH Inhibitors
– Prevents conversion of parent alcohol into its toxic
metabolites
– Two options:
• EthOH (65 x more affinity for ADH than EG)
• Fomepazole (500-1000 x more affinity for ADH than
EthOH)
– ADH inhibitors do nothing once the toxic
metabolites have formed (other than prevent
further parent alcohol from forming)
– May prevent need for HD even in large ingestions;
same is not true for Methanol
» WHY?
Treatment
• ADH Inhibition: MOA
• N Engl J Med 1999
Treatment
Treatment
• Ethanol
– How to give it (CJEM 2002)
• ADH is effectively saturated at 22-33 mmol/L
• IV loading dose
– 7.6- 10 ml/kg as 10% sol’n
• IV maintenance dose
– 1-2 ml/kg hourly
– Draw levels hourly
– Higher doses required for dialysis
– Continue until EG levels are undetectable (1/2 life
is increased when ADH inhibitor is given)
Treatment
• Fomepazole
– How to give it (CJEM 2002)
• Loading dose
– 15 mg/kg IV (oral is effective but not available in Canada)
• Maintenance
– 10 mg/kg every 12 hours for 4 doses; then 15 mg/kg every
12 hours until EG levels are below 3.2 mmol/L*
– Shortened dosing interval or infusion recommended if
patient is undergoing hemodialysis
– Cost
• $1075 per 1.5 gram vial (avg 4 vials per patient)
– Restricted access to PADIS
Treatment
• How good is Fomepazole?
– Anecdotal cases with ingestions between 100-300
mL presenting 1-12 h post ingestion. All treated
with fomepazole, no dialysis, complete recovery.
– 42 yo M with 1.5 L of antifreeze presented 4.5 h
post ingestion, EG 51 mmol/L. Received initial
loading dose of ethanol, then fomepazole.
Complete recover without dialysis.
» CJEM 2002
Treatment
• Ethanol
– Pros
• Cheap
• Effective
– Cons
• Notoriously difficult to
titrate (easy to
over/under shoot)
• S/E of hypoglycemia
• Risk of aggressive
behaviour
• Peds require ICU Admit
• Need to monitor levels
• Need to be on an
infusion (oral difficult to
titrate)
• Fomepazole
– Pros
•
•
•
•
•
•
Effective
No levels required
Long 1/2 life
Easy dosing
Peds don’t require ICU
Safe, minimal side
effects
– Cons
• Expensive
• Expensive
• Expensive
Treatment
• When to consider Fomepazole over
Ethanol?
– Rural areas without adequate lab support
– Pediatrics (decrease ICU admissions)
– Patients prone to hypoglycemia
– Liver failure
Back to the Case
• His EthOH level was only 8, not
protective
• He doesn’t have an AG
• He does have an osmol gap
• Based on what we’ve reviewed how do
you want to treat him?
Case
• He was started on an EthOH drip and
titrated to a level > 20 mmol/L and
maintained on the drip until his EG level
became undetectable and his Osmol
gap cleared
Proposed Treatment
Algorithm
Summary
• EG is rapidly absorbed and toxic in small
amounts
• A low/neg EG level and osmol gap can be
misleading in late presenters
• Expect AG to be normal in early presenters
• Significant metabolic acidosis suggests
presence of toxic metabolites of which our
only definitive therapy is dialysis
• ADH inhibitors are used to prevent further
metabolization of the parent alcohol
References
•
•
•
•
•
•
Scalley, RD et al. Treatment of ethylene glycol poisoning. Am Fam
Phys 2002; 66(5): 807-12.
Megarbane, B et al. Current recommendations for treatment of severe
toxic alcohol poisonings. Intensive Care Med 2005; 31: 189-95.
Glaser, DS. Utility of the serum osmol gap in the diagnosis of methanol
or ethylene glycol poisoning. Ann Emerg Med 1996; 27(3): 343-46
Hall, T. Fomepazole in the treatment of ethylene glycol poisoning.
CJEM 2002; 4(3): 199-204
Micromedix Poison Index: Ethylene Glycol. Accessed June 29, 2008.
Sivilotti, ML. Methanol and ethylene glycol intoxication. UpToDate
Accessed June 29th, 2008 (updated Feb 14, 2008).