Dr. Bob Hoffman's slides at the UTSW EM GR on 1/8/2015 regarding HD for poisoning.

1. An Evidence-Based Education of
Hemodialysis For Poisoning
Robert S. Hoffman, MD FAACT, FACMT, FRCP Edin, FEAPCCT
Director Division of Medical Toxicology
New York University School of Medicine

2. Disclosure
• I have no financial disclosures
• I am a co-chair of the EXTRIP workgroup

3. Objectives
• Describe the critical parameters of a drug or
toxin that might make in amenable to removal
by hemodialysis.
• Explain the differences between various
modalities of extracorporeal drug elimination
(hemodialysis, hemoperfusion,
plasmapheresis, etc.).

4. Objectives (2)
• Describe the mathematical tools used to
determine the efficacy of extracorporeal drug
removal.
• Explain the EXTRIP (Extracoporeal Treatments
in Poisoning) methods and recommendations
for common poisonings.

5. History
Trans Assoc Am Physicians 1913;58:51-4

6. History
• In 1948, the first reported the use of dialysis in
a human was for a case of salicylate poisoning,
similar to that carried out by Abel in animals
34 years earlier.
– Bywaters EG, Joekes AM. The artificial kidney; its
clinical application in the treatment of traumatic
anuria. Proc R Soc Med 1948;41:420-426.

7. Mardini J, Lavergne V, Roberts D, Ghannoum M. Case reports of extracorporeal
treatments in poisoning: historical trends. Seminars in dialysis. 2014;27(4):402-6.

9. Kidney International (2008) 74, 1327–1334

10. Problem
• Extracorporeal techniques are well accepted
based on limited and antiquated data.
• Not a single RCT exists for the utility of
extracorporeal removal in any of the most
commonly treated toxins

11. This is Why EXTRIP Might Be Helpful
28 members from 12 countries

13. Physiology and Terminology
• Dialysis from Webster
– The separation of crystalloids from colloids in a
solution by diffusion through a membrane.
– The separation of large molecules, as proteins, from
small molecules and ions in a solution by allowing the
latter to pass through a semipermeable membrane.

14. • Hemodialysis is not passive
– Counter current of dialysate keeps concentration
near zero – never reaches equilibrium
– Pump adds pressure – forces flow of water across
the membrane

18. Critical Toxin Parameters
• Molecular size
• Protein binding
• Volume of distribution
• Endogenous clearance
– By which organ(s)

19. Ghannoum M, Roberts DM, Hoffman RS, Ouellet G, Roy L, Decker
BS, et al. A stepwise approach for the management of poisoning
with extracorporeal treatments. Seminars in dialysis.
2014;27(4):362-70.

20. A Word About Protein Binding
• Most published values for protein binding are
at therapeutic concentrations
– There is rarely a desire to remove the last
therapeutic dose in most cases
– Protein binding may decrease with overdose
• Aspirin
• Valproate

21. Volume of Distribution
• Total body water = 0.7 L/kg
• Blood volume = 0.08 L/kg
• We can only dialyze the water compartment
of the blood (1-Hct) = 0.04 L/kg
• A small volume of distribution is considered
<1-2 L/kg

22. A Word About Endogenous Clearance
• Extracorporeal therapies are neither free nor
benign.
• If the body can remove the toxin promptly on
its own, no extracorporeal treatments are
needed.
• Is the organ of elimination poisoned?

24. Other Benefits
• Correction of Acid-Base status
– Aspirin, metformin, methanol, ethylene glycol
• Removal of other complications of toxicity
– Ammonia in valproate poisoning
• Stabilization of fluid status
• Temperature regulation

25. Unintended Complications
• Costs
– Direct
– ICU
– Transfer
• Risks associated with vascular access
• Hemoperfusion specific
– Drop in platelets
– Hemolysis
– Charcoal embolization
• Other rare issues

27. Case
• A young woman sees a chelationist for a
complex medical problem and is prescribed a
long course of therapy
• Magnesium is supposed to be infused IV as
part of the regimen
• Immediately after therapy the doctor realized
that she gave 800 mg of Manganese Chloride
instead of Magnesium
• The patient is sent to my hospital

28. Toxicology Assessment
• We know
–Manganese is bad
–The exposure just happened
–It takes a long time to get symptoms
–There are NO reported cases of IV
manganese overdose ever reported
–Blood concentrations take days to weeks to
get back

29. Rules
• Small molecules don’t stick well to activated
charcoal
• Small molecules are nicely dialyzed IF
– The are not highly protein bound AND
– Have a small volume of distribution
• The Vd and protein binding of manganese are
largely unknown

30. Prove Exposure

31. Consult with friends and agree to
do hemodialysis
Relatively safe and inexpensive
….sense we had to do something

32. 0
20
40
60
80
100
120
140
0 1 2 3 4 5
Time of HD
Concentration
Blood Concentration

33. 15
20
25
30
35
40
45
50
0 1 2 3 4 5
Time of HD
Concentration
Blood Extraction

34. Math Time
Into HD Out of HD ER Clearance
40 29 0.28 45.4
32 27 0.16 25.8
25 22 0.12 19.8
20 18 0.1 16.5

35. Why Did Extraction Fall Over
Time?

36. How Can We Be Sure What We
Did?

37. Measure Dialysate
Time (hours) Dialysate Concentration
(mcg/L)
0 16
1 7
2 3.4
3 1.5
4 1
Dialysate flow constant at 700 mL/min

38. 0
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5
Time
Concentration
Dialysate Concentration

39. Total Mn Collected in Dialysate
• Integrate the area under the curve of the
concentration vs time graph
• Total = 1.2 mg

40. 0
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5
Time
Concentration

41. Did Dialysis Work?
Why Did The Blood Concentration
Fall So Quickly on Hemodialysis?

42. How To Determine A Dialysis Effect
• Quantitative (efficiency)
– Defined as getting the toxin out
• Qualitative (efficacy)
– The patient got better
• Many ongoing processes
–Other therapies
–Endogenous elimination
• Risk-Benefit-Value (cost effective)

43. Quantitative (1)
• The half life on dialysis was shorter than the
half life off of dialysis
– Factors that confuse the analysis
• Pre-dialysis apparent half-life may be prolonged
because of on-going absorption
• Post-dialysis apparent half-life may be
shortened by a change in kinetics (zero order to
first order)

44. Did Dialysis Work
0.1
1
10
100
1000
1 2 3 4 5 6 7
Toxin X
HD
Concentration
Time

45. Did Dialysis Work
0.1
1
10
100
1000
1 2 3 4 5 6 7
Toxin X
HD
Concentration
Time

46. Did Dialysis Work
1
10
100
1000
1 2 3 4 5 6 7 8 9 10 11
Toxin X
HD
Concentration
Time

47. Did Dialysis Work
1
10
100
1000
1 2 3 4 5 6 7 8 9 10 11
Toxin X
HD
Concentration
Time

48. Rebound
• Bad Rebound
– Ongoing absorption
• May be associated with recurrent or continued
toxicity
• Good Rebound
– Blood compartment cleared faster than deep
compartment
– Toxin re-equilibrating with blood compartment
• Becoming available for repeat dialysis

49. From: Amdisen Medical Toxicology 3: 18-32 (1988)
Serum
CSF

50. Extraction Ratio And Clearance
• Extraction ratio (ER)
– Measure of efficiency of the procedure
[in]-[out]
[in]
• Clearance = BFR x (1-HCT) x ER

51. 15
20
25
30
35
40
45
50
0 1 2 3 4 5
Time of HD
Concentration
Blood Extraction

52. Math Time
Into HD Out of HD ER Clearance
40 29 0.28 45.4
32 27 0.16 25.8
25 22 0.12 19.8
20 18 0.1 16.5

53. Problems With ER and Calculated Cl
• No relationship to total body load of the drug
• No relationship to endogenous clearance
• No relationship to total body clearance

54. Gold Standard
• Measure the total amount of drug removed by
the procedure:
– Collect the known volume of waste and measure
the concentration
– Sample the concentration of waste over time,
know the waste flow rate and integrate the area
under the curve
• Compare with known dose or total body load

55. 0
2
4
6
8
10
12
14
16
18
0 1 2 3 4 5
Time
Concentration
Mn Dialysate Concentration

58. Methods
• Get every paper written in every language
• Extract the data
• Evaluate the level of evidence

59. Evaluating The Evidence

61. Predefined Criteria

62. Process

63. Toxin Summaries
• Every Statement has two values
– Strength of recommendation (agreement)
– Strength of evidence
• Not surprisingly we have some strong
recommendations based on some weak
evidence

64. Parachute Analogy
• What is the level of evidence to support that
jumping out of a plane with a parachute
improves survival?
– No RCTs
– No case-controlled trials
– Many people have jumped with parachutes and
survived
– Some have jumped with parachutes and died
– Some have jumped without parachutes and lived

65. Parachute
• Level of evidence D or C at best
• Strength of recommendation:
– All experts would strongly agree that it is best to
have a parachute if you jump out of a plane
• Final recommendation: 1D

66. Fully Published Recommendations
• Thallium
• Tricyclic Antidepressants
• Barbiturates
• Acetaminophen
• Carbamazepine
• Methanol
• On the way soon
– Lithium, Metformin, Salicylates, Theophylline, etc

67. Thoughts
• Thallium
– Test toxin to try the methodology
– Rare toxin, look up (or call Bob) if you see one
• TCAs
– Large volume of distribution
– No role for ECTR for any indication at all
– Risks outweigh the benefits

68. Methanol
• Low molecular weight
• Small volume of distribution
• No protein binding
• Antidotes
– Ethanol: difficult
– Fomepizole: expensive and not always available
– Limitations
• Long elimination half-life after antidotes

69. Methanol
ECTR is recommended in the following circumstances:
1) Severe methanol poisoning (grade 1D), including any
of:
a) Coma (grade 1D)
b) Seizures (grade 1D)
c) New vision deficits (grade 1D)
d) Metabolic acidosis from methanol poisoning
i) Blood pH ≤ 7.15 (grade 1D)
ii) Persistent metabolic acidosis despite adequate supportive
measures and antidotes (grade 1D)
e) Serum anion gap > 24 mmol/L (grade 1D); calculated by
serum [Na+] – [Cl–] – [HCO3
–].

70. 2) Serum methanol concentration
a) > 700 mg/L or 21.8 mmol/L in the context of
fomepizole therapy (grade 1D)
b) > 600 mg/L or 18.7 mmol/L in the context of
ethanol treatment (grade 1D)
c) > 500 mg/L or 15.6 mmol/L in the absence of an
ADH blocker (grade 1D)
d) In the absence of a methanol concentration, the
osmolal/osmolar gap may be informative (grade
1D)

71. 3) In context of impaired kidney function (grade 1D)
To optimize the outcomes from ECTR, we recommend:
4) Intermittent hemodialysis is the modality of choice in
methanol poisoning (grade 1D). Continuous modalities are
acceptable alternatives if intermittent hemodialysis is not
available (grade 1D).
5) ADH inhibitors are to be continued during ECTR for methanol
poisoning (grade 1D) as well as folic acid
6) ECTR can be terminated when the methanol concentration is <
200 mg/L or 6.2 mmol/L and a clinical improvement is
observed (grade 1D)

72. Questions
http://www.extrip-workgroup.org/