Role of r.r.t in toxicology modalities and indications Dr sunil Karanth md, fnb, edic, fcicm Chairman of critical care service Manipal health enterprises (p) ltd Manipal hospital, bangalore Adjunct prof in critical care medicine Manipal university

Poisoning and overdose not uncommon in an intensive care unit Extracorporeal therapy one of the methods of elimination of a toxin First conceptualized in 1950 by doolan Showed elimination of salicylates by dialysis Resulted later in Jorgensen publishing a paper on dialyzable poisons To date 142 dialyzable poisons

Data and evidence on the use of rrt in toxicology Factors affecting dialyzability of drugs and toxins Discuss different extracorporeal treatment modalities Review the role of r.r.t in management of specific poisons

Removal of drugs and toxins by extracorporeal therapies Justified if there is an indication of severe toxicity Determined by different physico-chemical properties

Hemodialysis Hemofiltration Hemoperfusion Molecular weight <500 Da   Hemodialysis Hemofiltration Hemoperfusion Molecular weight <500 Da <40 KDa Protein binding Low (<80%) Low Low or high Volume of distribution <1 L/Kg Solubility Water Water or lipid Endogenous clearance <4 mL/Kg/min

Extracorporeal treatment modalities

INTERMITTENT DIALYSIS CONTINUOUS RENAL REPLACEMENT THERAPY HEMOPERFUSION MOLECULAR ADSORBANT RECIRCULATING SYSTEM

INTERMITTENT HEMODIALYSIS BY DIFFUSION MEMBRANE SURFACE AREA AND TYPE HIGH FLUX OR HIGH EFFICIENCY MAXIMUM MOLECULAR WEIGHT THAT CAN BE CLEARED IS 10 k DALTONS BLOOD FLOW DIALYSATE FLOW RATE PROS AND CONS FACILITATES RAPID REMOVAL OF TOXINS REBOUND TOXICITY AFTER CESSATION DEPENDS ON INTERMITTENT HEMODIALYSIS

CONTINUOUS RENAL REPLACEMENT THERAPY BY CONVECTION LARGELY – CVVHf IF DIFFUSIVE TREATMENT ADDED - CVVHDF MAINSTAY OF RRT IN ICU ALLOWS CLEARANCE OF MOLECULES WITH LARGER MOLECULAR WEIGHT UPTO 40K DALTONS NO REBOUND PHENOMENON SLOWER RATE OF CLEARANCE LESS DRAMATIC DECREASE IN PLASMA LEVELS SLOWER REEQUILIBRATION Does not provide rapidity of elimination like intermittent hemodialysis CONTINUOUS RENAL REPLACEMENT THERAPY

Ihd vs cvvhf diffusion Rapid initial clearance Risk of rebound phenomena Good experience – familiarity and hence preferred Convection Slow initial clearance No rebound phenomena Case reports and series only present

hemoperfusion Passage of anticoagulated blood through a cartridge with adsorbant material Water soluble and lipid soluble 100-40000 daltons Specially useful for highly protein bound drugs

Rrt in specific poisonings

Toxic alcohol ingestion Methanol Formaldehyde Formic acid (toxic) Folic acid Ethylene glycol Glycolaldehyde Glycolic acid Glyoxylic acid Oxalic acid (toxic) Calcium oxalate Alcohol dehydrogenase Aldehyde dehydrogenase Lactate dehydrogenase Glycolate oxidase Glycine Thiamine Alpha-hydroxy- beta-ketoadipate Pyridoxine C O 2 + H O CNS SYMPTOMS Toxic alcohol ingestion Methanol, ethylene glycol High anion gap with increased osmolar gap Later stages only high anion gap – lactate induced RETINAL TOXICITY ACUTE KIDNEY INJURY

Toxic alcohol ingestion Alcohol dehydrogenase + Acetone monooxygenase Glyoxylase Aldehyde dehydroxygenase Isopropyl alcohol Acetone Acetol Methylglyoxal D-Lactate Glucose L-Lactate L-Lactaldehyde Formate+Acetate L-Propane-1, 2-diol Toxic alcohol ingestion Isopropyl alcohol Normal anion gap Increased osmolar gap Ketones positive Rrt rarely needed

Toxic alcohol ingestion Fomipazole or ethanol Competitive blockade of alcohol dehydrogenase Rrt very effective Readily dialyzable Useful in the presence of aki, metabolic acidosis If unstable consider crrt Rrt if levels of parent alcohols > 50mg% In case of ethylene glycol, hd even for glycolic acid clearance Formic acid not cleared by dialysis Monitor osmolality and acid-base balance for 12-36 hours in view of the risk of redistribution

Type of toxic alcohol Core clinical features Core laboratory features General principles of treatment Indications for RRT Methanol CNS depression AMS Seizures Visual changes/retinal toxicity Hemodynamic instability HAGMA High osmolal gap Elevated lactic acid (formic acid mediated inhibition of mitochondrial electron transport chain) Supportive care Fomepizole Ethanol (if fomepizole is unavailable) Folic acid or folinic acid pH < 7.3 Methanol level > 50 mg/dL Visual changes AKI Severe electrolyte derangements Hemodynamic instability and progression despite appropriate care Ethylene glycol Seizures Calcium oxaluria Hypocalcemia Electrolyte abnormalities Calcium oxalate crystals in the urine Falsely elevated lactic acid (glycolic acid can be mistaken for lactic acid) Ethanol (if fomepizole is unavailable) Thiamine Pyridoxine Ethylene glycol level > 50 mg/dL Glycolic acid level > 8 mmol/L Refractory hyperosmolarity Diethylene glycol Gastrointestinal symptoms Peripheral neuropathy Elevated liver enzymes Persistent HAGMA Isopropyl alcohol instability in advanced cases High osmolal gap Increased ketones in the blood and urine Absence of HAGMA Falsely elevated creatinine (due to acetone cross reactivity) Ethanol (if fomepizole is unavailable) Hemodynamic instability and progression despite appropriate care Isopropyl alcohol level > 4000 mg/dL

Salicylate toxicity Aspirin, bismuth salicylate Inhibition of cyclooxygenase pathway – decreased production of prostaglandins Higher doses – uncoupling of oxidative phosphorylation Hemodialysis most appropriate

Other indications for rrt Pulmonary edema Hypoxemia Altered mental status indicating high cns concentration Acute kidney injury

Lithium toxicity Follows sodium kinetics Hemodialysis effective modality despite a large volume of distribution No protein binding Risk of rebound toxicity CVVHF if hemodynamically unstable Rrt to be continued till lithium levels < 1 meq/l Lithium toxicity

Valproic acid poisoning Favourable molecular weight and volume of distribution for hemodialysis High protein binding at therapeutic concentrations Supratherapeutic concentrations – decreased protein binding due to saturation of stores Amenable to hemodialysis Cvvhf can be considered Unstable hemodynamics Hyperammonemia End point for dialysis – valproate levels < 100 mg%

Metformin poisoning Rapid removal by hemodialysis despite large volume of distribution Low protein binding Low molecular weight Rapid transport from cell to serum CVVHF If hemodynamically unstable Lactic acidosis

Dabigatron poisoning Predominantly excreted by the kidneys Intermittent hemodialysis seemed to be superior to crrt Risk of rebound levels Recently role of rrt limited in view of the development of a monoclonal anti- body idarucizumab

Miscellaneous drugs Many other drug toxicities may benefit from hemodialysis – in severe toxicities only Anticonvulsants like Carbamezapine Phenytoin Phenobarbital Calcium channel blockers Beta blockers Theophylline Dapsone Inh Cefipime, metronidazole Hemodialysis may be most appropriate Limited data with other modes Crrt used if unstable hemodynamically

In summary Rrt could be considered Drug toxicity Specially – toxic alcohol, salicylates, lithium, metformin, valproate May have a role in other drugs based on the pharmacokinetic profile Support for organ dysfunction Aki Hepatic dysfunction Most circumstances ihd can be used Crrt is a suitable alternative with limited experience

Thank you