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Hemodialysis International 2010; 14:158–167

Review Article in the poisoned patient

George BAYLISS Division of 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 or their toxic metabolites if native renal is not sufficient because of , acuity of symptoms, or burden of . 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 , and dialysate flow rates). The choice of extracorporeal therapy and hemodialysis prescriptions for specific poisonings are discussed.

Key words: Dialysis, poisoning,

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 (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 Urine 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 bicarbonate infusion. A re- trates or pleural effusions. Nurses placed a Foley 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 , 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] 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 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 , specific , 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 , 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 , 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 . 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 . 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 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 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 , 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 effectively dur- face area than either alone, although the addition of con- ing dialysis. In general, the volume of distribution of a vection, which is more important for larger molecules, drug increases as its protein binding decreases.6 reduces diffusive clearance, which is more significant for Knowledge of whether renal clearance can be made to smaller molecules, when replacement fluid is added to become a major component of total clearance may help blood prefilter to compensate for increased water perme- in the management of drug overdoses.10 The native clear- ability of the membrane.13 Older research has shown that ance of poisons may be affected by reductions in glomer- blood contact with high-flux membranes can decrease the ular filtration rate (GFR) as a result of hypotension or sieving coefficient in symmetric membranes, like the volume depletion, the large volume of distribution of the AN69, through protein adsorption to the membrane sur- drug or toxin, its charge, size, and binding characteristics. face.14 Increased use is being made of convection to re- Renal drug clearance is also influenced by tubular se- move middle and high molecular weight solutes. But cretion and re-absorption as well as renal epithelial cell while high-flux membranes have high mid- metabolism. Highly protein-bound drugs have either re- dle molecular weight solute clearance, they also contrib- duced clearance or are secreted into the tubules by active ute to significant loss of albumin.15 Work is under way transport, which is dependent on renal blood flow but to develop a high-flux membrane that does not lead to not on GFR. Most drugs and their metabolites are elim- albumin loss.16 inated by first-order kinetics, and the amount of drug eliminated over time is a fixed proportion of the total body store. The half-life of a drug thus increases as the 6 Modalities of extracorporeal toxin renal function decreases. removal Many toxins and drugs that can build up to toxic levels are weak acids, like salicylates, barbiturates, and chlori- Hemodialysis is the modality of choice for low molecular nated acid herbicides. In theory, maintaining them in the weight, water-soluble molecules, especially those that ionized state decreases their re-absorption across have small volumes of distribution and are not protein phospholipid cell membranes and potentially increases bound or lipid bound. It is ideal for molecules that diffuse their rate of excretion in the urine if the substance is easily across dialysis membranes. Its use is limited in pa- cleared by the kidneys. Increasing the urinary pH should tients who are hypotensive because dialysis, even without in theory increase the ionized fraction of the substance, volume removal, may reduce the blood pressure further. which is expressed in terms of the pKa or dissociation The use of dialysis is further limited to drugs and toxins constant. Weak acids have a high pKa. Ionic and nonionic that reach plasma concentrations that are high enough to forms are in equilibrium when pH=pKa. Most drugs are establish a sufficient concentration gradient like alcohols, in the nonionized phase at the physiologic pH=7.4. lithium, and salicylates.17 Thus, in those cases where alkalinization is indicated, Continuous renal replacement therapies have a theo- experts recommend that the goal should be a urine retical advantage in patients who have ingested sub- pH 7.5 and be maintained at or above that level to stances that are highly lipid bound and have large maximize elimination. The same experts distinguish uri- volumes of distribution with slow intercompartmental nary alkalization from forced diuresis, whose goal is transit times from the extravascular to the intravascular merely to increase urine output.11 space. In theory, CRRT is ideal in cases in which serum Mechanical aspects of dialysis also have an important levels of toxins rebound after rapid removal as toxins re- effect on the clearance of toxic substances and drugs. In equilibrate in the vascular space over time from body general, dialytic clearance of a substance is determined by stores such as lipid-bound molecules in fat stores. CRRT the intrinsic clearance of the dialyzer membrane, the is also useful in hemodynamically unstable patients who length of time of treatment, blood, and dialysis flow rates. are unable to tolerate high blood flow rates. Clearance is Thus, a high-efficiency dialyzer will provide more sur- achieved through the longer total dialysis time, rather face-area contact for blood and dialysate, allowing greater than per unit time, given the slower blood flow rates.7 diffusion of substances down the concentration gradient Some researchers have suggested adding albumin to the

160 Hemodialysis International 2010; 14:158–167 Dialysis in the poisoned patient dialysate to remove highly protein-bound drugs like val- Trends in extracorporeal toxin removal proic acid and carbamezapine during CRRT.18 Hemodialysis has increased sharply as the main modality Hemoperfusion uses a cartridge similar to a dialysis for extracorporeal removal of toxins. Cases of poisoning membrane in which toxins are removed from the blood requiring hemodialysis increased to 707 per million calls by binding to activated charcoal or resin rather than to poison control centers from 231 per million over the diffusing out of the blood down a concentration gradi- time period 1985–2005.22 In the same period, the number ent. The procedure is run on a dialysis machine using of cases of poisoning requiring hemoperfusion declined to regular dialysis pumps but without a dialysate. It is useful 12 from 53 per million calls, while cases of poisoning re- with highly protein-bound and lipid-bound molecules. quiring peritoneal dialysis declined to 1.6 from 2.2 per Disadvantages include saturation of the cartridge and the million calls. Lithium and ethylene glycol remained the need to change it every 2–3 hours. Hemoperfusion car- most common toxins removed by hemodialysis over the tridges can be run in series with hemodialysis membranes 20 years, followed by salicylates and valproic acid. Carb- in patients who also need solute and fluid removal for amazepine has replaced theophylline as the toxin removed .2 most frequently by hemoperfusion (Table 2). Peritoneal dialysis has fallen out of favor as a modality in the poisoned patient because of its low effectiveness in removing toxins. It is useful in small children in whom a Technical aspects and complications peritoneal can be inserted relatively quickly and in cases of overdoses further complicated The technical aspects of toxin removal by extracorporeal by hypothermia, in which core rewarming is required.2 means are largely related to access and equipment. In Therapeutic has a theoretical advantage over hemodialysis, CRRT, and hemoperfusion, access is through dialysis or hemoperfusion in removing substances that a 10–11.5 French dual-lumen dialysis catheter in a central are protein-bound or lipid-bound and in the intravascular because smaller are unable to support the space (4300 Da).19 But there have been no controlled necessary blood flows of 200–450 mL/min. Except where trials, and recommendations for its use are based on case contra-indicated, should be used to anticoagulate reports and series. The American Society for Apheresis the system to improve dialyzer clearance and prevent rates toxin removal as a class III indication (suggestion of blood loss and the loss of time in replacing the dialysis benefit but insufficient evidence to establish efficacy or circuit if it clots. Heparin should not be used, for example, risk vs. benefit). An exception is for in dialyzing patients with . High-flux, phalloid intoxication after ingestion of poisonous mush- high-efficiency dialysis membranes should be used to rooms, particularly .20 The ASFA gives maximize pore size and surface area for toxin removal by this a class II indication (generally accepted but consid- both diffusion and convection, as discussed above.2 ered adjunct therapy). Some consider plasmapheresis at Complications from toxin removal by hemodialysis in- least as effective as hemoperfusion in reducing mortality clude and alkalosis due to diffusion of po- following phalloid mushroom ingestion, but there is not tassium into the dialysate and diffusion of bicarbonate enough evidence to say that it is superior21 (Table 1). from the dialysate, particularly given the need for high-

Table 1 Drugs, toxins amenable to extracorporeal removal by extracorporeal modality

Hemodialysis CRRT Pertitoneal Hemoperfusion Plasmapheresis Lithium Lithiumab Carbamezapine Phalloids Ethylene glycol Theophyllinea Theophylline Methanol Valproic acida Paraquat Salicylates Metformina Valproic acid Metformin Theophylline aHemodialysis preferred method when blood pressure permits. bNo demonstrated advantage for removal of a particular toxin. CRRT=continuous renal replacement therapy.

Hemodialysis International 2010; 14:158–167 161 Bayliss

Table 2 Hemodialysis vs. hemoperfusion and CRRT in acute intoxication. (Adopted with permission from aBorkan SC. Ex- tracorporeal therapies for acute intoxication. Crit Care Clin 2002; 18: 393–420; Goodman JW and Goldfarb DS. The role of continuous renal replacement therapy in the treatment of poisoning. bSemin Dial 2006; 19:402–407; Mulder J et al. Platelet loss across the hemofilter during continuous hemofiltration. bInt J Artif Organs 2003; 96:206–212.)

Parameter aHemodialysis aHemoperfusion bCRRT Renal replacement therapy Yes No Yes Restores electrolyte balance Yes No Yes Corrects volume status Yes No Yes Risk of thrombocytopenia Unusual Yes Yes Removes drugs 4300 Da No Yes No Removes protein-bound drugs No Yes Limited Removes water-soluble drugs Yes No Yes Removes lipid-bound drugs No Yes Theoretical Rapid QB improves drug removal Yes Yes Yes Cartridge saturation No Yes No Can be used in hypotensive patient No No Yes

CRRT=continuous renal replacement therapy; QB =blood flow; SBP=systolic blood pressure.

efficiency dialysis membranes. The complications of Renal replacement therapy is recommended when: CRRT include hypocalcemia, particularly when using ci- trate anticoagulation. Hemoperfusion has been associated the serum lithium level is 43.5 mmol/L; with lymphopenia and thrombocytopenia, although the 2 the serum lithium level is 42.5 mmol/L with symp- mechanism is not clear. toms and a depressed GFR; there is moderate intoxication with the expectation Dialysis prescription for specific drugs that the lithium levels will increase or that they will and toxins not decline to the therapeutic range within 36 hours.2 The following section discusses the characteristics of se- lected drugs and toxins most commonly seen as causes of Both hemodialysis and CRRT provide far superior overdoses, and the dialysis prescriptions recommended clearance to native renal function even when there is no in the literature for their removal. evidence of acute kidney injury, with an extraction ratio during hemodialysis of 90%.17 At blood flows of 250 mL/ min, hemodialysis provides 70–170 mL/min of clearance Lithium compared with 10–40 min/mL in patients with normal Lithium carbonate is a highly effective mood stabilizer; this renal function. Hemodialysis is superior to CRRT, which low molecular weight cation (MW LiHCO3=74 Da) is wa- provides a clearance of around 48–62 mL/min at blood ter soluble, with a volume of distribution of 0.7–0.9 L/kg. flows of 200 mL/min and is thus not recommended in the It is highly dialyzable.2 Most intoxication is chronic in the literature as first-line therapy.2 The literature recommends setting of renal failure and volume depletion while the pa- dialysis for 6–8 hours with repeat sessions until the level tient is also taking diuretics, nonsteroidal anti-inflamma- declines to below 1 mmol/L.2 Other experts suggest, how- tory drugs, or angiotensin-converting enzyme inhibitors.2 ever, that CRRT may be used as the first-line therapy in Mild intoxication occurs at a serum lithium concentra- the event the physician is concerned about rebound tox- tion of 1.5–2.5 mmol/L, while moderate intoxication oc- icity, envisions a long treatment, or is concerned about curs at a serum lithium concentration of 2.5–3.5 mmol/L the effects of fluid removal on patient . (therapeutic is o0.6 mmol/L). Both are characterized by The two modalities may be used together: CRRT may be neuromuscular irritability, nausea, and diarrhea. Severe followed by hemodialysis if hypotension resolves, or lithium intoxication occurs at a serum concentration hemodialysis may be followed by a longer, slower ses- 43.5 mmol/L and is characterized by seizure, stupor, sion of CRRT. But there have been no head-to-head ran- and permanent neurologic damage. domized trials to resolve the issue definitively.23

162 Hemodialysis International 2010; 14:158–167 Dialysis in the poisoned patient

Ethylene glycol and methanol acute kidney injury or electrolyte imbalances that do Ethylene glycol and methanol are volatile alcohols with not respond to conventional therapy; and volumes of distribution equal to that of total body water. deteriorating vital signs despite intensive care. Both ethylene glycol (MW 62 Da) and methanol (MW 32 Da) are metabolized by alcohol dehydrogenase to their The guidelines also indicate dialysis for an alcohol level toxic metabolites—glycolic acid in the case of ethylene 450 mg/dL unless fomepizole is administered, the pa- glycol and formic acid in the case of methanol. Glycolic tient is asymptomatic, and the pH is normal. Further me- acid is further metabolized to oxalate, which deposits in tabolism of the toxic metabolites to nontoxic byproducts renal tubules as envelope and needle-shaped crystals. The should be enhanced by giving pyridoxine and thiamine to exact cause of acute kidney injury is not known. Some patients with ethylene glycol poisoning and folate or 28,29 argue that it is related to glycolic acid;24 others argue that folinic acid to patients with methanol poisoning. calcium oxalate is the causative agent.25 In the case of ethylene glycol, dialysis is undertaken Co-ingestion with ethanol, which binds competitively to with a bicarbonate dialysate bath until the toxic alcohol alcohol dehydrogenase, slows the metabolism of the other level is o20 mg/dL. If one is unable to obtain an alcohol alcohols to their toxic metabolites, but can also conceal level, then dialysis should be carried out for at least 8 2 their presence, particularly because all 3 can present with hours and repeated in another 12 hours. Glycolic acid central nervous system depression and an anion gap has a long half-life and a slow elimination rate. But it also metabolic acidosis.19 Acute kidney injury can delay has a low molecular weight (76 Da), is water soluble, and native clearance of glycolic acid, leading to coma and has a limited volume of distribution (0.55 L/kg). Thus, cardiac toxicity, and of formic acid, leading to CNS even in the event of a low ethylene glycol level, an in- depression and blindness from oxidative damage to the creased anion gap correlates with glycolic acid levels; di- retina. Patients initially develop an osmolar gap and then, alysis should be undertaken because it increases clearance 30 as the alcohol is metabolized to an acid, an anion gap.26 considerably. Hemodialysis provides a clearance of Thus, a normal osmolar gap in the presence of an anion 200–250 mL/min for ethylene glycol and 170 mL/min gap may indicate that the alcohol has been metabolized, for glycolate at blood flow rates of 250–400 mL/min. while a normal anion gap in the presence of an osmolar The elimination half-life of glycolic acid on dialysis is gap may indicate that the ingestion is recent. 155 min compared with 626 min in patients not treated 30 The first line of treatment in the case of ethylene glycol by dialysis. or methanol poisoning is to block the metabolism of the With very high methanol levels, dialysis may need to alcohols to their toxic metabolites. The 4-methyl- be undertaken for 18–21 hours and the procedure re- pyrazole (fomepizole) has emerged as the primary peated after 24 hours if there is rebound toxicity. Most inhibitor of alcohol dehydrogenase.27 The American experts recommend against using heparin anticoagulation Academy of Toxicology recommends treatment with during dialysis because of the risk of intracranial hemor- 31,32 fomepizole rather than ethanol unless fomepizole is not rhage, particularly in the basal ganglia. Hemodialysis available or causes an allergic reaction. The guidelines for provides a clearance of 200 mL/min for methanol and starting fomepizole are similar for both alcohols: 223 mL/min for formate at blood flows of 100–400 mL/ min. But the endogenous elimination half-life of formate documented ingestion of the alcohol and a concen- was not found to be statistically different from the elim- tration of 420 mg/dL; ination half-life on dialysis (205 90 vs. 150 37 min) documented recent ingestion of the alcohol with an in one study. This may be in part due to other treatments osmolar gap 410 mOsm/L; given to patients—folate or folinic acid—to increase the strong clinical suspicion of ingestion of the alcohol metabolism of formic acid to carbon dioxide and water.33 and two of the following—arterial pHo7.3, serum Other researchers, however, have found that hemodialy- HCO3 o20 mEg/L, or an osmolar gap 420 mOsm/L sis significantly reduced formate elimination half-life (or urinary oxalate crystals in the case of ethylene compared with endogenous elimination and question 28,29 glycol). the role of folate.34 Some experts suggest that early intervention with Despite the use of fomepizole, dialytic removal of fomepizole and supportive care like methanol or ethylene glycol may be necessary in the administration to correct the acidosis may lessen the need event of: for hemodialysis in selected cases of methanol intoxica- severe metabolic acidosis with the pHo7.25; tion—those who present late with acidemia and no

Hemodialysis International 2010; 14:158–167 163 Bayliss detectable methanol level—because elimination of for- development of a respiratory acidosis, which led to over- mate through dialysis is not significantly different from all worsening of neurologic toxicity by allowing more endogenous clearance with supportive care.19 Others ar- salicylate to pass into the CNS.41 On the other hand, the gue that dialysis can be avoided in stable patients with older literature cites the case of a child with salicylate less metabolic acidosis and no visual symptoms who can poisoning who was successfully treated with intermittent be treated with fomepizole alone.35 But fomepizole ther- positive pressure ventilation after he was paralyzed,42 and apy should be continued even after extracorporeal re- animal experiments on acute respiratory failure following moval has begun and for several hours after treatment has salicylate-induced hyperventilation found no pulmonary been completed to account for rebound.28 or arterial blood gas abnormalities in 5 sheep that were Very little data exist to show how CRRT compares with paralyzed and ventilated at normal tidal volume and re- hemodialysis in clearing volatile alcohols. A series of 3 spiratory rate.43 patients with methanol ingestion found CRRT clearance Alkalinization of the urine is paramount if the patient is of 45 and 48 mL/min at a blood flow rate of 150 mL/min still making large amounts of urine to prevent reabsorp- over 37 and 27 hours in two patients compared with tion of salicylates,44 and potassium administration pre- clearance on hemodialysis of 237 mL/min at a blood flow vents hypokalemia and acidification of the urine.9 At a rate of 350 mL/min over 4 hours.36 low pH, more salicylate crosses the blood–brain barrier One group has developed an equation to estimate the and increases CNS intoxication.45 How urinary alkali- time required on dialysis to reduce the levels of methanol nization increases salicylate excretion is not entirely clear. and ethylene glycol to 5 mmol/L. The equation is based The conventional view is that weak acids like salicylates on the assumption that toxic alcohols have a dialysis become more ionized in an alkaline environment, and clearance similar to that of urea37: urine alkalinization is recommended for salicylate intox- ication unless there are contraindications (renal failure t ¼½Vlnð5=AÞ=0:06k; and heart disease).6 Given its high dissociation constant where t is time, V is the Watson estimate of total body as a weak acid, a small increase in urinary pH should water,38 A is the initial toxin concentration in mmol/L, produce a large increase in the ionized fraction of salicy- and k is equal to 80% of the manufacturer-specified di- late. But at a urine pH=5, salicylate is already almost completely ionized so that increasing pH further would alyzer urea clearance in milliliters per minute at the initial 46 observed blood flow rate. Validated in a small study of 13 not increase its ionization further. patients, the equation requires only 3 measurements of Dialysis is recommended in the event of: the toxic alcohol: an initial toxin level, 1 drawn 2 hours CNS depression at a level 450 mg/dL; before dialysis is due to stop, and a level drawn 1–2 hours salicylate level 480 mg/dL; after dialysis.39 salicylate-induced pulmonary edema.47 Salicylates have a molecular weight of 38–180 Da and a Salicylates volume of distribution of 0.17 L/kg. At therapeutic levels, Acute salicylate intoxication is characterized in adults by 90% of salicylates are protein bound, but the unbound a respiratory alkalosis as salicylates stimulate the respira- fraction increases as the total concentration increases, as tory center in the medulla and then a metabolic acidosis in the case of intentional overdose. Intermittent hemodi- as lactic acid builds up from interruption by salicylates of alysis is preferred over CRRT unless the patient is hypo- the mitochondrial electron transport chain.40 CNS symp- tensive because 50% of protein-bound aspirin is removed toms indicate severe poisoning. by hemodialysis. The volume of distribution may be diffi- An immediate goal of treatment is to reverse the aci- cult to calculate when salicylate is ingested as enteric- dosis and alkalosis to prevent respiratory collapse: pa- coated aspirin.48,49 tients with salicylate intoxication do very poorly on Dialysis is undertaken against a high-flux membrane at because of the ventilator’s inabil- high blood flow rates with continued additional sodium ity to keep up with the patient’s respiratory rate and bicarbonate infusion because patients are often intravas- the development of respiratory dys-synchronization, al- cularly depleted and require volume replacement, not though there is little empiric evidence to support this in volume removal. Dialysis is continued until the serum the opinion of some experts. One retrospective review of salicylate level is o10 mg/dL if there is concern for re- patients with salicylate intoxication who had been placed bound toxicity, a possibility if the patient has developed a on mechanical ventilation at conventional settings found bezoar.45

164 Hemodialysis International 2010; 14:158–167 Dialysis in the poisoned patient

Acetaminophen 160 140 Acetaminophen is a moderately water-soluble 151 Da 134.4 molecule that is only slightly protein bound. The treat- 120 ment of choice remains activated charcoal if the patient is 100 able to take food and fluids by mouth and N-acetyl 80 cysteine either orally or intravenously if the patient is 60 unable to swallow. N-acetyl cysteine delivered according 40

Salicylate (mg/dL) 30.5 to the Rumack-Matthew nomogram for hepatotoxicity 20 14.5 10.5 11 10.1 helps replete stores of glutathione. Case reports suggest 0 the possibility of using single-pass albumin dialysis using 9/2/2008 9/2/2008 9/2/2008 9/3/2008 9/3/2008 9/3/2008 0020 1441 2220 0020 0112 0312 a high-flux membrane and dialysate to treat the resulting Time liver failure.50 Figure 1 Serum salicylate levels as a function of time in a 51-year-old woman presenting after an intentional aspirin CONCLUSION overdose. Initial measurement is from an earlier presentation to the same emergency room. Dialysis can be a life-saving therapy in the case of acci- dental or intentional overdoses of toxins that are amena- output of 2.2 L over her first hospital night. The dialysis ble to extracorporeal removal such as salicylates, lithium, catheter was removed, and the patient was transferred to and volatile alcohols, with most authorities recommend- a general medical floor in stable condition. ing intermittent hemodialysis with high-efficiency, high- flux membranes, except in cases of hypotension, when CRRT may be necessary because of lower blood flow Manuscript received August 2009; revised October 2009 rates. Use of sustained low-efficiency dialysis has also been reported in a case of acute aspirin overdose.51 The patient in the clinical vignette suffered from the REFERENCES acute effects of aspirin overdose and was at a risk of re- 1 Brent J. Fomepizole for ethylene glycol and methanol spiratory collapse if aggressive measures were not taken poisoning. N Engl J Med. 2009; 360:2216–2213. to reduce salicylate levels. A temporary dialysis catheter 2 Winchester JF, Boldur A, Oleru C, Kitiyakara C. Use of was placed in the emergency department, and the patient dialysis and hemoperfusion in treatment of poisoning. was transferred to the medical . She In: Daugirdas JT, et al., ed. Handbook of Dialysis. 4th ed. underwent 8 hours of hemodialysis with a blood flow of Philadelphia: Walters Kluwer; 2007:300–319. 350–400 mL/min and a dialysate flow rate of 500 mL/min 3 Cohen DL, Post J, Ferroggiaro AA, Perrone J, Foster MH. against a 35 mEq/L bicarbonate bath. She continued to Chronic salicylism resulting in pulmonary edema requir- receive an infusion of isotonic sodium bicarbonate in 5% ing hemodialysis. Am J Kidney Dis. 2000; 36:E20. 4 Rauschka H, Aboul-Enein F,Bauer J, et al. Acute cerebral dextrose in water during dialysis.52 She was never intu- white matter damage in lethal salicylate intoxication. bated. Her breathing improved as hemodialysis pro- Neurotoxicology. 2007; 28:33–37. gressed, and she was maintained with supplemental 5 Kaplan AA. Extracorporeal blood purification in the oxygen, first by a face mask and then by a nasal cannula. treatment of acute renal failure with multi-organ involve- Tachycardia also resolved. ment. Blood Purif. 1996; 14:86–93. Roughly 6 hours after initiation of hemodialysis, the 6 Olyaei AJ, De Mattos AM, Bennett WM. Use of drugs salicylate level was 30 mg/dL, and at 8 hours, it was in patients with renal failure. In: Schrier RW, et al., ed. o10 mg/dL, undetectable (see Figure 1), and dialysis was Diseases of the Kidney and Urinary Tract. Philadelphia: stopped as the patient became hypotensive. The salicylate Lippincot Williams & Wilkins; 2007:2765–2807. level rebounded slightly but declined to undetectable lev- 7 Goodman JW, Goldfarb DS. The role of continuous renal els and remained there without further dialysis. The pa- replacement therapy in the treatment of poisoning. Semin Dial. 2006; 19:402–407. tient became more alert and acknowledged having taken 8 Clark WR, Henderson LW. Renal versus continuous ver- 200 aspirin tablets in a suicide attempt. Her course was sus intermittent therapies for the removal of uremic tox- complicated by upper gastrointestinal tract bleeding, ins. Kidney Int. 2001; 59(Suppl 78):S298–S303. found to be due to erosive gastritis, and requiring trans- 9 Daugirdas JT. Physiologic principles and urea kinetic mod- fusion of 2 U of packed red blood cells. Nevertheless, her eling. In: Daugurdas JT, et al., ed. Handbook of Dialysis. renal function returned to baseline, with a total urine 4th ed. Philadelphia: Walters Kluwer; 2007:25–58.

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