Uncommon Indications for Extracorporeal Toxin Removal (ECTR) Robert S. Hoffman, MD Director, Division of Medical Toxicology NYU School of Medicine

Transcription

1 Uncommon Indications for Extracorporeal Toxin Removal (ECTR) Robert S. Hoffman, MD Director, Division of Medical Toxicology NYU School of Medicine

2 Disclosure I have no financial or academic conflicts of interest to report I will NOT be discussing toxins either currently reviewed or anticipated to be reviewed by the EXTRIP Workgroup

3 Objectives Fundamental principles of ECTR Assessment of ECTR Does it work Application of principles to real scenarios

4 Principles of ECTR

5 3 Toxin Specific Governing Principles Molecular weight Volume of distribution Protein binding

6 Molecular weight The size of the molecule must be small enough to fit through the pores of the filter Volume of distribution Protein binding

7 Volume of distribution Only the blood compartment gets filtered 0.08 L/kg A traditionally small Vd = 1 L/kg or less Utility may improve for toxins with a large Vd if ECTR is performed before distribution Molecular weight Protein binding

8 Protein binding As protein binding increases available free toxin decreases Pharmacokinetic parameters are often misleading Consider salicylates of valproate Molecular weight Volume of distribution

9 4 th Principle Clearance ECTR must improve on endogenous clearance Problem: Published data for clearance rarely apply to the patient in front of you.

10 Seminars in Dialysis 2014:27:362

11 ECTR Conditions Max CL (ml/min) ET 1L whole blood exchanged/hour, HCT = 40% 10 PD TPE CRRT IHD/HF/ HP 2L exchange every hour, 50% equilibration of dialysate compared to plasma QB = 140 ml/min and a plasma removal rate 50 ml/min QB = 180 ml/min, high volume CRRT (effluent flow = 45 ml/hr/kg), weight = 70 kg QB = 400 ml/min, HCT = 40%, ER = 100%

12 Assessing ECTR Terminology Efficiency Effectiveness Cost effectiveness Outcome Is the toxin removed Does removal equate with improved outcome Is the outcome worth the risks, benefits and costs

13 Case In error, a patient receives and intravenous overdose of a toxin known to be associated with delayed, debilitating, and long-term consequences Absorption is complete The event is recognized quickly There are no cases of intravenous overdose of this toxin ever reported in any language There is no known antidote

14 Case (continued) The toxin has a low molecular weight Protein binding and volume of distribution are unknown But assumed to be small by analogy No data are available regarding Endogenous clearance or Clearance during hemodialysis

15 Case (cont) A decision is made to attempt hemodialysis: The consequences of the overdose are assumed to be severe There is no alternative therapy The patient has no contraindications to the procedure The patient undergoes hemodialysis without complications and remains asymptomatic

16 Did Hemodialysis Benefit The Patient?

17 Concentration Time

18 Concentration Comparison of Ins and Outs Time

19 A Mathematical Interlude [ ] Into HD [ ] Out of HD ER % Clearance (ml/min) ER = Extraction ratio = C in -C out C in

20 Why Did Extraction Fall Over Time?? Saturable Protein Binding?

21 How Can We Be Sure What We Did?

22 Measure Dialysate Time (hours) Dialysate Concentration (mcg/l) Dialysate flow constant at 700 ml/min

23 Dialysate [ ] Time

24 Concentration Time

25 Total Collected in Dialysate Integrate the area under the curve of the dialysate concentration vs time graph Total 1.0 mg Less than 1% of the administered dose

26 Assessments (1) Apparent half life during ECTR Ignores distribution Ignores endogenous clearance Comparison of apparent half-life before, during and after ECTR Same concerns as above PLUS Apparent half life before ECTR is often prolonged by ongoing absorption

27 Assessments (2) Extraction ratio with calculation to assume clearance Only tells you what the technique is doing Does not account for endogenous clearance Either normal or during ECTR Very misleading for high Vd toxins that are well filtered (such as digoxin)

28 Assessments (3) Gold standard Directly measure the amount of toxin filtered or otherwise removed by the technique Caution This is only the best determination of efficiency and we still have to evaluate effectiveness and even further cost effectiveness

29 Uncommon Indications for ECTR in the Real World

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32 Methylxanthines By Analogy Parameter Theophylline Caffeine Molecular Mass Protein binding Volume of distribution Da 194 Da 50% 35% 0.5 L/kg 0.7 L/kg

33 A 59 year old woman with ESRD on HD develops a headache 2 hours into each dialysis. She drinks 4-6 cups of coffee each day No mention of the number of cups she drinks before or after HD No caffeine concentrations

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35 50 gram ingestion of caffeine Got very sick Had a very high caffeine concentration 405 mg/l Got many therapies including hemodialysis Got better No clearance data

36 10 month old Ingested 30 x 200mg caffeine pills Caffeine 170 mg/l Seizures, cardiac arrest, aspiration

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41 2014;53(23): gram ingestion

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45 Parameter Amatoxin Facts Result Molecular weights α 990 β 373 γ 994 Protein binding Volume of distribution Clearance Unknown in humans, no binding to albumin in dogs (Faulstich) Unknown in humans; ml/kg in dogs (Faulstich) Approaches creatinine clearance in dogs (Faulstich)

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49 Correction of the water-electrolyte imbalance Gastric lavage and continuous drainage of gastroduodenal fluids Cathartics and activated charcoal every hour Enhancement of toxin removal: peritoneal dialysis, plasmapheresis with plasma exchange, and forced diuresis. Most patients were treated with two techniques and some received three. Pharmacologic therapy included high-dose penicillin and thioctic acid

50 53 patients: 25 males, 20 females, Ages ranged from 4 to 72 years The overall mortality in this series was 11.3%; (6/53) Among the survivors, liver injury was absent to mild in 13 patients, moderate in 21, and severe in 13. All deaths were due to acute liver failure and occurred 6 to 12 days after admission. Only one patient experienced severe kidney failure with anuria.

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52 15 years, 41 patients with Amanita poisoning Treatment consisted of: fluid and electrolyte replacement, oral activated charcoal and lactulose, IV penicillin, combined hemodialysis and hemoperfusion in two 8 hour sessions, some received IV thioctic acid, others IV silibinin, all received a special diet. All patients improved and were discharged from the hospital asymptomatic. We concluded that intensive combined treatment applied is effective

53 Mullins ME, Horowitz ZB: The Futility of Hemoperfusion and Hemodialysis in Amanita phalloides Poisoning. Vet Hum Toxicol 2000 ;42: adults with confirmed Amanita poisoning Treated with hemodialysis immediately (23 h after ingestion) and later with hemoperfusion A series blood samples were taken to determine the clearance of the toxin by each method No amatoxin was detected before treatment, after treatment, or in the HD/HP circuits Neither HD nor HP contributed to the clearance of amatoxin

54 Fluoride Facts Parameter Molecular weight Protein binding Volume of distribution Elimination Result 19 Daltons None 0.6 L/kg Largely kidney; T 1/2 5.5 hours Baselt RC: Disposition of Toxic Drugs and Chemicals in Man

55 YOU CAN DIALYZE FLUORIDE IN!

56 Seminars in Dialysis 2000;13:86 91

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58 THE AMERICAN JOURNAL OF CARDIOLOGY 1983;51; 901

59 Ann lntem Med. 1994; 121:

60 Pediatrics 1976;58:90 Peritoneal dialysis was ineffective as the total amount of fluoride removed by this procedure was less than 0.2 mg over two days. This was less than 1.5% of the fluoride excreted in the urine during the same period.

61 A patient is described who accidentally ingested a hydrofluoric acid-containing substance and who likely benefited from hemodialysis. His fluoride level post-dialysis was reduced by approximately 70% from a level drawn three hours prior to the initiation of hemodialysis.

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64 Manganese Poster 219

65 MW 169 Daltons Low protein binding in animals Vd<0.5L/kg in animals Bad ingestion Had many poor prognostic indicators Got IHD and Extraction ratio 91.8% Clearance 97.5 ml/min

66 Summary Manganese useless Caffeine good analogy but limited data Amatoxin I wish I knew, but think not Fluoride makes good sense we need more data Glyphosaste I think you can remove the glyposate but have no idea about surfactant

67 A Plea For Better Data, Please 2014 Jul-Aug;27(4):407