Hemodialysis International 2010; 14:158–167 Review Article Dialysis in the poisoned patient George BAYLISS Division of Kidney Disease and Hypertension, Alpert School of Medicine, Brown University, Providence, Rhode Island, USA Abstract Patients who ingest toxic substances may require extracorporeal removal of the poisons or their toxic metabolites if native renal clearance is not sufficient because of acute kidney injury, acuity of symptoms, or burden of toxin. Here, a case is presented, and the literature on renal replacement therapy in the event of acute intoxication is reviewed. Extracorporeal therapy efficacy is examined in terms of the characteristics of the toxin (molecular size, charge, protein, or lipid binding); the patient (body habitus and volume of distribution); and the process (membrane effects on extraction ratios and sieving, role of blood, and dialysate flow rates). The choice of extracorporeal therapy and hemodialysis prescriptions for specific poisonings are discussed. Key words: Dialysis, poisoning, hemoperfusion A CASE 1.4 L of urine over 4 hours as she was volume resuscitated with isotonic fluid. A 51-year-old woman with a history of depression and Serum chemistries showed elevated serum creatinine chronic pancreatitis from Valproic acid (Depakote) expo- (1.7 mg/dL, up from her baseline of 0.7 mg/dL), mild sure was brought to the emergency department by EMS hyperkalemia (potassium=5.3 mEq/L), serum bicarbon- after her 11-year-old daughter found her unresponsive on ate of 14 mEq/L, and an anion gap of 24. An arterial blood the bathroom floor. In the emergency department, the gas showed pH=7.38 and pCO =18 mmHg, indicating patient was tachycardic, with an initial heart rate of 2 both a metabolic acidosis and respiratory alkalosis. 129 beats/min, but normotensive, with blood pressure Urine toxicology screen was positive for salicylates, and ranging from 139/65 to 135/65 mmHg. She was tachyp- the serum salicylate level was 134 mg/dL (therapeutic neic, with a respiratory rate of 44 breaths/min. Oxygen o30 mg/dL). saturation by pulse oximetry was 97% on 3 L of oxygen The patient’s initial electrocardiogram revealed sinus by nasal cannula. She was minimally responsive with di- tachycardia, left axis deviation, a narrow QRS complex, lated, minimally responsive pupils. Cardiac exam re- and no prolongation of PR or QT intervals. She subse- vealed normal heart sounds and no murmurs, rubs, or quently developed supraventricular tachycardia at a heart gallops. Her clear lungs were clear to auscultation. Her rate of 145–160 beats/min that did not respond to abdomen was soft, her mucus membranes were dry, and adenosine. her skin was damp. She had no lower extremity edema. A A toxicology consultation was obtained, and the pa- chest X-ray showed a normal-sized heart and no infil- tient was started on a sodium bicarbonate infusion. A re- trates or pleural effusions. Nurses placed a Foley catheter nal consult was requested. in the emergency department, and the patient voided DISCUSSION Correspondence to: G. Bayliss, MD, Division of Kidney Disease and Hypertension, Alpert School of Medicine, Brown This patient appeared critically ill and at risk of needing University, Rhode Island Hospital, Providence, RI 02903, intubation for airway protection. Her case illustrates the USA. key circumstances under which extracorporeal removal of E-mail: [email protected], [email protected] toxins is required to prevent extreme morbidity and r 2010 The Authors. Journal compilation r 2010 International Society for Hemodialysis 158 DOI:10.1111/j.1542-4758.2009.00427.x Dialysis in the poisoned patient death. In such cases, experts recommend immediate con- brane, while large, protein-bound or lipid-bound mole- sultation with a medical toxicologist or poison control cules are more difficult to remove because of their size center to optimize medical management of patients while and difficulty in breaking those bonds, thus requiring the need for and feasibility of extracorporeal therapy is dialysis membranes with larger pores (like b2 microglob- evaluated, based on the molecular size of the toxin, its ulin, MW 11,800 Da). volume of distribution, water solubility, and protein- The pharmacokinetics of a drug or a toxin depends on binding characteristics.1 several factors.6 The first is absorption, with the bioavail- The use of hemodialysis, continuous renal replacement ability of the drug defined as the percentage of the ad- therapy (CRRT), or hemoperfusion is important in the ministered drug that reaches systemic circulation. management of certain drug overdoses and toxic inges- Next, the volume of distribution, Vd, of a toxin repre- tions when other measures such as activated charcoal, sents the theoretical dispersion of the substance in the gastric lavage, specific antidotes, and respiratory support patient’s body and is defined as the amount of drug in the have failed or are not feasible because of the patient’s body divided by the concentration of the drug in plasma. condition.2 Such extracorporeal procedures should be This depends on both the characteristics of the patient considered adjunctive, and not substitutes for other mea- and the toxin. Water-soluble molecules will remain more sures and supportive care. Furthermore, certain measures accessible and toxic levels can be more easily reduced such as gastric lavage, forced alkaline diuresis, or admin- when the toxin has a small Vd in the patient. Lipid-sol- istration of chemical inhibitors may be critical in the early uble molecules have a larger Vd, and toxic levels are more phases of drug ingestion, obviating the need for extracor- difficult to reduce because the intravascular levels repre- poreal therapy or supplementing it. sent only a small fraction of the total body burden of the The circumstances that in this case point to the need toxin. for extracorporeal drug removal include progressive de- A related concept is rebound. Intravascular levels of terioration of the patient’s status despite intensive sup- lipid-soluble molecules may decline quickly after an ini- portive therapy; decreased level of consciousness with tial session of dialysis, but increase again as serum levels suppression of midbrain functions; the risk of complica- re-equilibrate from the extravascular space. Patient char- tions of coma like aspiration pneumonia; impaired native acteristics that affect a drug’s Vd include obesity, extracel- clearance of drugs and toxins in the setting of reduced lular fluid volume status, age, gender, thyroid function, glomerular filtration as a result of acute kidney injury; the renal function, and cardiac output. In general, a drug’s 6 amount of toxin ingested; and faster clearance of the toxin plasma concentration correlates inversely with its Vd. by extracorporeal means than normal native clearance Clearance of a substance is the theoretical volume of would provide.2 In the case of salicylate intoxication, blood from which the substance is removed per unit of aggressive volume expansion and forced diuresis could time.7 Native clearance depends on the ability of a mol- prove harmful with complications that include pulmonary3 ecule to pass across the glomerular basement membrane or cerebral edema.4 into the urinary space, a function of molecular size and Extracorporeal techniques include dialysis and hemo- charge, and the urine flow rate [U]V/[P], expressed in perfusion; dialysis therapies include intermittent hemo- milliliters per minute. Solute removal occurs first by fil- dialysis, CRRT, and peritoneal dialysis. Each has tration (convection), but is also influenced by modifica- advantages, depending on the properties of the toxin be- tion in the tubules, the continuous nature of native renal ing removed, the total burden of toxin in the patient, and clearance, and stable serum concentrations in the steady the rate at which the extracorporeal method removes tox- state.8 ins from the blood. Therapeutic plasma exchange has also In dialysis, clearance is achieved through diffusion and been used to remove protein-bound drugs as well as convection via ultrafiltration and is defined as the product endotoxin.5 of the extraction ratio—the percentage of the substance removed from the blood as it passes over the membrane— 9 Key principles and the blood flow rate [(Cinitial À Cfinal)/Cinitial][QB]. It is also expressed in terms of milliliters per minute. Intrinsic Molecular size, charge, and binding characteristics help characteristics of the dialysis membrane that affect clear- determine the ease with which toxic substances and ance across the membrane include the size and number of drugs in overdose can be removed from the patient. dialysis membrane pores (flux), membrane composition Low molecular weight substances (like urea, MW 60 Da) and thickness, and the total surface area of the dialysis that are water-soluble pass easily across a dialysis mem- membrane (efficiency). The intermittent nature of the ther- Hemodialysis International 2010; 14:158–167 159 Bayliss apy means that solute clearance, mass removal rate, and from blood to effluent. Larger pores will allow greater serum concentration are not constant.8 convective solute clearance, or sieving, during ultrafiltra- Protein binding considerably affects a drug’s pharma- tion via solvent drag.12 cokinetics, with only unbound drugs or active drug me- The combination of diffusive and convective clearance tabolites able to exert a pharmacologic effect. Drugs that provides more total clearance per unit of membrane sur- are highly protein bound are not removed