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

Disclosure

• I have no financial disclosures

• I am a co-chair of the EXTRIP workgroup

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.).

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.

History

Trans Assoc Am Physicians 1913;58:51-4

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.

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.

Kidney International (2008) 74, 1327–1334

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

This is Why EXTRIP Might Be Helpful

28 members from 12 countries

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.

• 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

Critical Toxin Parameters

• Molecular size

• Protein binding

• Volume of distribution

• Endogenous clearance

– By which organ(s)

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.

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

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

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?

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

Unintended Complications

• Costs– Direct– ICU– Transfer

• Risks associated with vascular access• Hemoperfusion specific

– Drop in platelets– Hemolysis– Charcoal embolization

• Other rare issues

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

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

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

Prove Exposure

Consult with friends and agree to do hemodialysis

Relatively safe and inexpensive

….sense we had to do something

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Into HD Out of HD ER Clearance40 29 0.28 45.432 27 0.16 25.825 22 0.12 19.820 18 0.1 16.5

Why Did Extraction Fall Over Time?

How Can We Be Sure What We Did?

Measure Dialysate

Time (hours) Dialysate Concentration (mcg/L)

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Dialysate flow constant at 700 mL/min

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Total Mn Collected in Dialysate

• Integrate the area under the curve of the concentration vs time graph

• Total = 1.2 mg

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Did Dialysis Work?

Why Did The Blood Concentration Fall So Quickly on Hemodialysis?

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)

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)

Did Dialysis Work

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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

From: Amdisen Medical Toxicology 3: 18-32 (1988)

Serum

CSF

Extraction Ratio And Clearance

• Extraction ratio (ER)

– Measure of efficiency of the procedure

[in]-[out]

[in]

• Clearance = BFR x (1-HCT) x ER

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Into HD Out of HD ER Clearance40 29 0.28 45.432 27 0.16 25.825 22 0.12 19.820 18 0.1 16.5

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

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

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Methods

• Get every paper written in every language

• Extract the data

• Evaluate the level of evidence

Evaluating The Evidence

Predefined Criteria

Process

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

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

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

Fully Published Recommendations

• Thallium

• Tricyclic Antidepressants

• Barbiturates

• Acetaminophen

• Carbamazepine

• Methanol

• On the way soon– Lithium, Metformin, Salicylates, Theophylline, etc

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

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

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 poisoningi) Blood pH ≤ 7.15 (grade 1D)

ii) Persistent metabolic acidosis despite adequate supportivemeasures and antidotes (grade 1D)

e) Serum anion gap > 24 mmol/L (grade 1D); calculated by serum [Na+] – [Cl–] – [HCO3

–].

2) Serum methanol concentrationa) > 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 ofethanol 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 (grade1D)

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 areacceptable alternatives if intermittent hemodialysis is not available (grade 1D).

5) ADH inhibitors are to be continued during ECTR for methanolpoisoning (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)

Questions

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