1. Intoxication

2. Rupesh Raina MD,FAAP,FACP, FASN and FNKF
Consultant Nephrologist
Adult-Pediatric Kidney Disease/Hypertension Department of Nephrology
Director of Medical Research in Internal Medicine Akron General Medical Center Associate of Cleveland Clinic Foundation
&
Akron Children's Hospital, Cleveland Ohio. Council Member for University Council of Deans
Northeast Ohio Medical University Assistant Professor and Faculty Staff at Case Western Reserve University School of Medicine Cleveland Ohio.

3. What is Poisoning
Poisoning is when cells are injured or destroyed by the inhalation, ingestion, injection or absorption of a toxic substance
Key factors that predict the severity and outcome
Nature, dose and formulation
Route of exposure of the poison
Co-exposure to other poisons
State of nutrition of the child
Age and pre-existing health conditions
Bornstein A, et al. Clin Toxicology ;47:

4. Epidemiology
2004 greater than deaths in children and youth <20 yrs.: 13% of all fatal accidental poisonings worldwide
Highest for children < 1 year with another slight peak around 15 years
Fatal poisoning rates in low-income and middle-income countries are 4x that of high-income countries
Am J Emerg Med 23:589–666
Curr Opin Crit Care 13:668–673

5. Toxic ingestions with the use of RRT
65% of these intoxications occur <20 yr. with 11% of the fatalities
Between ( ) >19,000 cases required extracorporeal therapy
Change in both the etiology (an increase AED) and the therapy [a trend away charcoal hemoperfusion (CH)]
Require therapy in ICU due to respiratory, metabolic or cardiac compromise
Pediatr Nephrol (2011) 26:535–541

6. General Principle
Kinetics of drugs are based on therapeutic not toxic levels (therefore kinetics may change)
Choice of extracorporeal modality is based on availability, expertise of people & the properties of the intoxicant in general
It may be necessary to switch modalities during therapy (combined therapies inc: endogenous excretion/detoxification methods)
Apher Dial. 2006;10:118–24
Crit Care Med 31:2794–2801

7. Enhancing Toxin Elimination
GI tract elimination
Gastric emptying or lavage
Activated charcoal
Cathartics
Renal elimination
Urinary alkalinization
Forced diuresis
Extracorporeal methods
Hemodialysis
Hemoperfusion

8. General Pharmacokinetic Concepts and Principles of Extracorporeal Therapy
Volume of Distribution
Protein Binding
Membrane Transport
Lipid Solubility
Ionization
Intercompartmental Transfer
Drug Removal
AJKD volume 3;issue 3;1984; B.A.
Warady et al. (eds.), Pediatric Dialysis ,

9. Volume of Distribution
Estimate of extent to which a drug will migrate from vascular space into extravascular tissues
Increased volume of distribution  drug stays in interstitium  subtherapeutic intravascular drug concentrations
An important source of pharmacokinetic variability in critically ill patients with AKI
Eyler RF, Mueller BA, 2011, Nat Rev Nephrol

10. Viability in Antibiotic Volume of Distribution (Vd) in Critically Ill Patients
Dynamic volume shifts – volume resuscitation, third spacing, TPN
Acid base disturbances  altered protein binding
Individual patient characteristics – Vd may vary over time
Decreasing albumin
Cachexia and muscle mass depletion
Capillary leak syndrome
Malnutrition
Heart failure
Acute kidney injury
Burn injuries (>30-40% TBSA)
Use of drugs such as vasopressors
Post-surgical drains with high drainage volumes
Fish DN, Pharmacy Practice, 2002;15(2):85-95
Pea F, et al. Clin Pharmacokinet, 2005;44:
Boucher BA, et al. Crit Care Clin, 2006;22:

11. Intercompartmental Transfer
18 yr old 70 Kg. ( 154 lbs) Patient (60% Water = 42 Liters (44 qts)
INTRACELLULAR FLUID VOLUME
2/3 OF WATER
EXTRACELLULAR
FLUID VOLUME
1/3 of WATER
28 Liters – 29.5 qts
14 Liters – 15 qts
ISF-V
10.5 Liters – 12 qts
DIALYSIS ACCESS
PLASMA VOLUME
3.5Liter – 3.7 qts

12. Potential PK Alterations Related to Physiochemical Properties of Drugs
Hydrophilic Lipophilic
Volume of distribution Small Large
Area of distribution Extracellular Intracellular
Elimination (clearance) Primary renal Primary liver
Changes in volume ↕ depending on Not highly
of distribution with fluid shifts affected by
critical illness volume status
Adapted from Roberts JA, Lipman J: Crit Care Med 2009;37(3):

13. Drug Removal Clearance (C) for hemodialysis is expressed as:
C= Qb x Q (A- V)/A
(A – V)/A is termed (E x ) that represents the solute removed as a fraction of the maximum it is theoretically possible to remove
J Pediatr. 2006;148:770–778

14. Calculations
If ammonia level does not fall as expected calculate recirculation ratio and ammonia clearance (ClNH4). 
RR = (systemic NH4 – access NH4)  x 100
(systemic NH4 – return NH4)
Recirculation ratio goal <10 %.
ClNH4 = QB(ml/min) x (access line NH4 – return line NH4)
access line NH4
ClNH4 (ml/min) should be = Qb
RR >10% and ClNH4 low, consider repositioning or replacing dialysis access
Pediatric Nephrol. June 2013, Volume 28, issue 6,p 983–986

15. CRRT Clearance is =E/P x Qe E- effluent concentration
P -plasma concentration toxic substance,
Qe is the effluent flow rate (Quf or Qd or Quf + Qd)
E/P -sieving coefficient = E x - that represents the solute removed as a fraction of the maximum it is theoretically possible to remove

16. CRRT Clearance on Sieving Coefficient (SC)
Clearance total = ClCRRT + Cl residual renal + Cl non-renal
ClCRRT =Qe( effulent rate=Quf+Qd) x Ce/Cp
Since we assume at the CRRT Ce=Cp if sieving coefficient is 1 then
ClCRRT =Qe (Quf+Qd) x unbound fraction of drug
Semin Nephrol. 2008;28:488–492

17. Calculations Drug X has large Vd~20 L/kg.
1 gm dose given 30 kg child with a plasma concentration of mg/mL ( 42.2 )
E x at Qb 200 mL/min, theoretically be 200 mL/min, which is equivalent to drug removal of 0.32 mg/min or 76.8 mg in 4 h
<10% of the total given dose.

18. Mueller BA, Pasko DA. Artif Organs 2003;27:808-14.

19. Hemodialysis –Favorable Pharmacokinetic Profile
Low molecular weigh <300 Da, high-efficacy dialyzers up to 2,000 Da
Volume of distribution <1 L/kg
Water soluble
Nonionized
Low protein binding
Rapidly equilibrate between the tissue and the blood compartments
Pediatr Nephrol (2011) 26:535–541

20. HD Prescription High flux dialyzer (unless MW is very small)
High surface area
Highest blood flow rate possible

21. Drugs/Toxins Efficiently Removed by HD
Molecular Weight (daltons)
Volume of Distribution
Water Soluble
Ethylene glycol 62
0.6
Yes
Isopropanol 60
Lithium 7
Methanol 32
0.7
Salicylate
138
0.2
Theophylline
180
0.5

23. 6 yr. old girl present to ED with 4hrs history's of nausea, vomiting, salivation, headache, blurred vision, and acidotic “Kussmaul” breathing
She severe mixed acidosis, metabolic and respiratory with high anion gap
The family gave us new information that the girl regularly took a drink called Kola Ingles. They stated that the patient had found a 250mL pink perfume bottle and that she had ingested 200mL of its contents, thinking it was the cola drink.

24. Metabolic Pathways for Ethylene Glycol, Ethanol and Methanol

25. Treatment of Ethylene Glycol and Methanol Intoxications

26. Osmolal Gap and Its Application in Screening for Ethylene Glycol or Methanol Poisoning
Osmolal gap = measured serum osmolality − calculated serum osmolarity
Calculation of serum osmolarity (traditional units)Serum osmolarity = ([2 × sodium] + [BUN ÷ 2.8] + [glucose ÷ 18.1])
Osmolal gap = 355 mOsm/kg – 330 mOsm/liter = 25†
Thus, 25 mOsm/liter are unaccounted for, so if the contribution of methanol to the osmolal gap is: methanol (mg/dl) ÷ 3.2, the value for methanol is 3.2 × 25 = 80 mg/dl
Ethanol ÷ 4.6, Ethylene glycol ÷ 6.2, and Methanol ÷ 3.2.

27. Methanol:Toxiderm Absorption/metabolism
Absorbed rapidly via GI tract
Peak levels in minutes
Latent period of ~ 24 hrs before development of symptoms or AGMA
75-85% metabolized via alcohol dehydrogenase in liver & 10-20% excreted unchanged by lungs
ADH metabolizes methanol to formaldehyde  oxidized to formic acid  AGMA & retinal toxicity

28. Management of Poisoning
Supportive care
ABCs – intubation/vent & pressors if needed
Low index of suspicion in unexplained coma, ARF, or other metabolic disorders – do some quick screening:
ABG
Blood chemistries
Figure out acid/base status
pay close attention if resp alkalosis and met acidosis
Calculate AG and osmolar gap
Prevent absorption & enhance elimination

29. General Measure
Fomepizole (4-methylpyrazole), Alcohol dehydrogenase was approved in 1997 for patients at least 12 years old with suspected or confirmed EG poisoning
Ld of 15 mg/kg with maint. doses of 10 mg/kg with total dose of 25 mg/kg
Fomepizole Treatment of Ethylene Glycol Poisoning in an Infant
Ethylene glycol – thiamine & pyridoxine
Thiamine
Shunts metabolism of glycolic acid towards non-toxic compound (alpha-hydroxy-beta ketoadipic acid)
Pyridoxine
Shunts metabolism of glycolic acid towards glycine
Methanol – folate
Enhance elimination of formic acid
Clin Toxicol (Phila) 2010 Jun;48(5):401-6); Pediatrics; Dec Vol 106-6

30. Indications for HD in Ethylene Glycol or Methanol Intoxication
Severe metabolic acidosis (pH 7.25 – 7.3)
Renal failure
Visual symptoms/signs
Deteriorating vital signs despite intensive supportive care
Ethylene glycol or methanol levels >50 mg/dl, unless fomepizole is being administered and patient is asymptomatic with a normal pH
Barceloux et al. J Toxicol Clin Toxicol 1999; 37;
Barceloux et al. J Toxicol Clin Toxicol 2002; 40;

31. Hemodialysis Choose High efficiency, High flux dialysis
Saline, Cool dialysate and vasoconstrictors for hypotension
Adjust Dialysate composition (K/HCO3
Heparin Anticoagulation unless contraindicated (Methanol)
Phosphorus supplement
Ther Apher Dial. 2006;10:118–24.

32. Hemoperfusion
Blood is passed over a cartridge packed with charcoal or carbon
Carbon/charcoal competes with plasma proteins as a binding site for toxin
Drug adsorbs to charcoal/carbon & removed from circulation
More efficient clearance/elimination of lipid soluble & highly protein-bound toxins compared to hemodialysis
Adv Ren Replace Ther. 2002;9(1):26–30
Clin Toxicol ;17:493–500.

33. Hemoperfusion

34. Drugs/Toxins Efficiency Removed by HP
Molecular Weight (daltons)
Volume of Distribution
Water Soluble
Theophylline
180
0.5
Yes
Carbamazepine
236
1.4 No
Disopyramide
340
0.6
Phenobarbital
232
Phenytoin
252

35. Hemodialysis vs Hemoperfusion
Parameter
Hemodialysis
Hemoperfusion
Treats renal failure
Yes No
Corrects electrolyte abnormalities
Corrects volume status
Risk of thrombocytopenia
Unusual
Removes drugs >300 Da
Removes protein-bound drugs
Removes water-soluble drugs
Removes lipid-soluble drugs
Rapid QB increases drug removal
Cartridge saturation

36. Hemoperfusion - Complications
Mild thrombocytopenia
If > 30% decrease, consider adding prostacyclin Rx
Mild leukopenia
Low fibrinogen – adsorption
Hypothermia
Hypocalcemia
Hypoglycemia
Clotting of cartridge – heparin adsorbed also
Trans Am Soc Artif Intern Organs. 1977;23:762–842.

37. Serum Concentrations of Common Poisons In Excess of Which HD or HP Should be Considered

38. Drugs/Toxins Not Amenable to Extracorporeal Treatments
Tricyclic antidepressants (high Vd, high lipid solubility)
Short-acting barbiturates
Acetaminophen
Narcotics
Non-barbiturate hypnotics, sedatives, tranquilizers (high Vd, high lipid solubility)

39. CRRT
CRRT removal of drugs that distribute in multiple compartments with slow equilibration
Continuous removal of the drug from the vascular compartment maintains a favorable gradient
Facilitates its release from the inaccessible compartments into the vascular compartment
Rebound phenomenon resulting in high serum levels due to redistribution seen after HD is not seen with CRRT modalities
Hemodynamic instability may benefit t from CRRT

40. Factors Affecting Drug Removal During CRRT
Elimination pathway Renally eliminated drugs more readily removed
Volume of distribution (Vd) <0.7 L/kg: “small’ Vd, readily removed
Molecular weight <500 daltons: readily removed
Plasma protein-binding <80%: not highly protein-bound, more readily removed
Dialysis membrane Membrane material Membrane surface area Membrane permeability
Dialyzer system Type of dialysis Filter age Prefilter vs. postfilter replacement fluids Flow rate of dialysate Duration of dialysis

41. Hybrid Theory Continuous Detoxification methods
CAVHF, CAVHD, CAVHP, CVVHF, CVVHD, CVVHP
Indicated in cases where removal of plasma toxin is then replaced by redistributed toxin from tissue
Can be combined with acute high flux HD

42. HD Rx of Ammonemia NH4 rebound with reinstitution of HD
NH4 micromoles/l
Time (Hrs)
Gregory et al, Vol. 5,abst. 55P,1994

43. HD to CRRT (prevention of the rebound)
Transition from HD to CVVHD
NH4 micromoles/l
Time (Hrs)

44. HD Prescription Blood flow rate: 30-50 ml/min
Dialysis flow rate: ≥ 300ml/min
Duration maximum of 4 hours or until ammonia level μmol/L whichever comes first; (goal KT/V ammonia = 2 at 2 hrs).
Patient will then be transitioned to regular CRRT.
Filter surface area to approximate body surface area
HD machine will be cooled down to 340C in patients randomized to cooling
Replace phosphorus.
Measure ammonia level at 30 minutes, and then at least every 2 hours.
Measure RFP, Mg, ABG, cbc at least every 4 hours.
Follow routine lab orders for anticoagulation (Cai or ACT)

45. Step-down CRRT
Initiated after HD to prevent rebound of ammonia above 200 μmol/l.
Clearance (replacement and/or dialysate flow rate will be total at least 2500 ml/1.73m2/hour).
CRRT will be continued at least until serum ammonia level is < 100 μmol/l during at least 4 hours on at least two measurements.
Net ultrafiltration rate will be matched to or below the patient’s intake since these patients are often polyuric and dehydrated.

46. Lithium Narrow therapeutic window Rapid GI absorption
Peak levels in 2-4 hrs
Large Vd ( L/kg)
Excreted by kidney

47. Hybrid Therapy for Lithium Toxicity
Readily diffusible, IHD followed by CVVHD because of the risk of a post-dialysis rebound concentration due to large Vd
CVVHD following HD for Lithium poisoning L i m E q /
HD started
Li Therapeutic range
mEq/L
CT-190 (HD)
Multiflo-60
both patients
BFR-pt #1 200 ml/min
HD & CVVHD
-pt # ml/min
HD & 200 ml/min
CVVHD
PO4 Based dialysate at
2L/1.73m2/hr
CVVHD started
Hours
Slide from pCRRT :Bunchamn et al

48. Plasmapheresis
1 plasma volume (3 L for a 70-kg patient) removes approximately 63% of all solutes & 1.5 plasma volume removes about 78%
40–60 mL of plasma/kg over 2–3 h
Plasma protein binding >80% and Vd <0.2 L/kg
Phalloid mushroom/ TCA (amitriptyline)/L-thyroxin/ phenbromate/ verapamil/diltiazem/ carbamazepine poisoning,
Can be used heavy metals such as mercury
Artif Cells Blood Biotechnol. 2000;28:429–40
Journal of Clin Apheresis. 2009;24:21–4.
NDT 2003;18(Suppl 5):v56–8

49. Albumin-Enhanced Continuous Venovenous Hemodialysis
Valproic acid (80–90%), Carbamazepine (~75%) and phenytoin (∼90%) protein bound
Dialysate-side albumin acts as a ‘sink’ to bind any free toxin that crosses the dialyzer membrane with a concentration gradient from the blood to the dialysate side
Concentration gradient is restored and more blood-side toxin will disassociate from blood-side albumin, cross the membrane into the dialysate and then bind to dialysate-side albumin
Askenazi et al, Pediatrics 2004

50. Albumin Hemofiltration
Novel Approaches to facilitating intoxicant removal during hemofiltration
Addition of albumin to dialysate
Enhancement of Valproic Acid removal during CVVHD by the addition of albumin to dialysate
A 6-1/2 month old infant was hospitalized with a serum valproic acid level of 1043 mcg/mL.
He received CVVHD (blood flow 80 mL/min; prefilter replacement fluid: 400mL/hr; dialysate: 450 mL/hr) without and with albumin 45 gm/L) in the dialysate.
Serial serum levels were obtained before and during dialysis. (PRISMA- M60)
V Chadha et al. pCRRT- Orlando 2002

51. Carbamazepine Clearance
T-1/2 for acute 25-60hrs vs chronic 12 to 20 hours vs 7 to 8 hrs albumin-enhanced CVVHD
Natural
Decay
Clearance with
Albumin Dialysis
Askenazi et al, Pediatrics 2004

52. Vancomycin Toxicity N= 167 children (age: 1 week–19 years)
Nephrotoxicity rate ~ 14% (28% versus 7.3% with > vs < serum trough above 15mcg/mL).
MW~1448 Daltons:Vd - average: 0.7 L/kg
HD high-flux hemodialysis 6 hours at Qb 180ml/min the URR ~75% (213.2mcg/mL to 51.8mcg/mL) with Qb/Qd 1:1.5
Rebound 30% in 22 hrs
Furosemide continuous infusion to promote urine output and decrease intrarenal vancomycin accumulation
Charcoal hemoperfusion can only remove 40%
Journal of Pediatrics, vol. 158, no. 3, pp. 422–426, 2011
Hindwai -Neph case reports Volume 2011, 4 pages

54. Synthetic Cannabinoids (synthetic marijuana, “spice”)
Designer drugs of abuse typically dissolved in a solvent, applied to dried plant material, and smoked
16 cases of AKI following exposure to SCs identified in six sates from March-December 2012
Presented with nausea/vomiting, abdominal or flank pain
Median serum creatinine 6.7 mg/dl
Variable urinalyses:6/8 pts with ATN, 3/8 had AIN
New SC, XLR-11, associated with some cases
Management is supportive; no existing antidote
Recovery within 3 days of peak Cr, though some patients may require HD
CDC. MMWR Morb Mort Wkly Rep Feb 15; 62(6);93-8

55. Not only Drugs to Worry About
Animal, plant, chemical poisons are all common
ARF occurs with 5-25% of all snake bites
Viper bites: DIC, bleeding, hypotension, ARF
Sea snakes: rhabdo, ARF
Bee, wasp, hornet stings can cause rhabdo, ARF
Mushrooms (Amanita, Galerina, & Cortinorius) cause GI sxs followed by hypotension/ARF.