Intoxication

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.

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. 2009;47:911-1084.

Epidemiology 2004 greater than 45 000 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

Toxic ingestions with the use of RRT 65% of these intoxications occur <20 yr. with 11% of the fatalities Between (1985 -2005) >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

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

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

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;381-84 B.A. Warady et al. (eds.), Pediatric Dialysis ,

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

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;44:1009-1034 Boucher BA, et al. Crit Care Clin, 2006;22:255-271

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

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):840-851.

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

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

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

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

Calculations Drug X has large Vd~20 L/kg. 1 gm dose given 30 kg child with a plasma concentration of 0.0016 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.

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

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

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

Drugs/Toxins Efficiently Removed by HD Molecular Weight (daltons) Volume of Distribution Water Soluble Ethylene glycol 62 0.6 Yes Isopropanol 60 Lithium 7 0.7-0.9 Methanol 32 0.7 Salicylate 138 0.2 Theophylline 180 0.5

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.

Metabolic Pathways for Ethylene Glycol, Ethanol and Methanol

Treatment of Ethylene Glycol and Methanol Intoxications

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.

Methanol:Toxiderm Absorption/metabolism Absorbed rapidly via GI tract Peak levels in 30-60 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

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

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 2000. Vol 106-6

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; 537-560 Barceloux et al. J Toxicol Clin Toxicol 2002; 40; 415-446

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.

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. 1980;17:493–500.

Hemoperfusion

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

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

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.

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

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)

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

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

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

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

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

HD Prescription Blood flow rate: 30-50 ml/min Dialysis flow rate: ≥ 300ml/min Duration maximum of 4 hours or until ammonia level 200 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)

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.

Lithium Narrow therapeutic window Rapid GI absorption Peak levels in 2-4 hrs Large Vd (0.6-0.9 L/kg) Excreted by kidney

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 0.5-1.5 mEq/L CT-190 (HD) Multiflo-60 both patients BFR-pt #1 200 ml/min HD & CVVHD -pt # 2 325 ml/min HD & 200 ml/min CVVHD PO4 Based dialysate at 2L/1.73m2/hr CVVHD started Hours Slide from pCRRT :Bunchamn et al

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

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

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

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

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

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. 2013 Feb 15; 62(6);93-8

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.