Read Overdoses_Oct 2010 text version

DIALYSIS AND DRUG OVERDOSES Nephrology Fellows' Academic Half-Day R. Suri Objectives:

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To understand the general management of overdoses To understand the properties of toxins which make them amenable to hemodialysis To understand the pathophysiology and recognize the clinical features of common overdoses for which nephrology is consulted: including ASA, alcohols, and lithium. To understand the specific management of ASA, methanol, ethylene glycol, and lithium overdose, and the indications for hemodialysis.

Articles: Zimmerman JL. Poisonings and overdoses in the intensive care unit: General and specific management issues. Crit Care Med 2003. (Read first part on general management of overdoses, as well as Li, alcohols, and ASA) Tyagi TK, Winchester JF, Feinfeld DA. Extracorporeal removal of toxins. Kidney Int 2008. Sood MM, Richardson R. Negative anion gap and elevated osmolar gap due to lithium overdose. CMAJ 2007. Megarbane B, Borron SW, Baud FJ. Current recommendations for treatment of severe toxic alcohol poisonings. Intensive Care Med 31:189-95, 2005. Darga PI, Wallace CI, Jones AL. An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose. Emerg Med J 19:206-9, 2002.

Cases: #1 ­ Mrs. MC -60 yo female brought to emergency by son because of confusion and tachypnea -PMH: chronic arthritis, headaches, depression -Meds: Entrophen 325 mg "prn" -O/E: drowsy, somewhat confused and restless, RR30, BP 120/80, euvolemic, temp 38.5, sweaty -Labs: Hgb 129, plts 349, WBC 15.6 Na 133, K 2.8, Cl 96, HCO3 17, creat 98, urea 7 pO2 78, pCO2 23, HCO3 17 pH 7.46 1) 2) 3) 4) 5) 6) What acid-base disorders are present? What is the most likely diagnosis? What other symptoms would you ask about? What other features on physical exam would you look for? What other lab tests you would order? What is your management plan?

#2 ­ Mrs. LV -33 yo female presented to emergency after admitted to "taking some pills" (50-100 pills of her current medications) including lithium -initially normal LOC " decreased in ER and intubated -PMH: Bipolar Disorder, DM, GERD -Meds: lithium, quetiapine (Seroquel), nitrazepam, metformin, losec -O/E: CNS ­ not rousable to pain or verbal stimuli (GCS 8), reflexes normal RESP ­ intubated, saO2 100% on 100% O2, chest clear CV ­ BP 90/60, HR 120 SR, heart sounds normal, JVP flat ABD ­ soft GU ­ u.o. 200 cc/hour -Labs: Hgb 144, plts 331, WBC 10.4 Na 138, K 3.8, Cl 109, HCO3 23, creat 59, urea 5, glu 5 pO2 73, pCO2 39, HCO3 23, pH 7.39 (on room air) lithium level 3.0 1) What are the clinical features of lithium overdose? 2) What other lab tests you would order? 3) What is your management plan?

#3 ­ Mr. SH -23 yo male brought to ER by a friend with generalized abdo pain, N/V, and decr. LOC -PMH: smoker 1ppd, EtOH 6-12 beer/wk + binges, ?occasional marijuana use rest unkwown none known CNS ­ very drowsy, rouses to voice but unable to answer questions, moves all 4 limbs, reflexes normal, PR's down Resp ­ RR 28, saO2 99% R/A, chest clear CV ­ BP 180/11, HR 106 SR, HS normal, flow murmur LSB, extremities warm GI ­ abdo tender to deep palpation in region of left costo-vertebral angle GU ­ urine output 30cc Foley last hour since arrival Temp ­ 37.5 Hgb 120, MCV 104, plts 120, WBC 14, 90% PMN's, INR 1.0, PTT 30 Na 140, K 4.5, Cl 105, HCO3 14, creat 188, urea 14, glu 6 Alb 30, Ca 1.5, PO4 1.0, Mg 0.8 pH 7.31, pO2109, pCO2 17, HCO3 9 CXR normal, ECG normal, CT head normal 1) 2) 3) 4) 5) What are the acid-base abnormalities? What is the differential diagnosis? What other labwork would you like to order? What is the most likely diagnosis based on these additional labs? What is your management?

-Meds: -O/E:


#4 ­ Mr. GT -75 yo male brought to ER by paramedics after witnessed grand-mal seizure -PMH: COPD, HTN -Meds: Atrovent, Ventolin, theophylline, Biaxin and prednisone (started 5 d ago), ramipril -O/E: obtunded, intubated, saO2 100% on 100%, hemodynamically stable, afebrile -Labs: Hgb 150, plts 130, WBC 10 Na 140, K 3.5, Cl 100, HCO3 28, creat 70, urea 8, liver enz's normal theophylline level 160 umol/L

1) What is the "normal" therapeutic range for theophylline in SI units? 2) At what range and/or clinical picture should one consider extracoporeal therapy?

Concise Definitive Review

R. Phillip Dellinger, MD, Section Editor

Poisonings and overdoses in the intensive care unit: General and specific management issues

Janice L. Zimmerman, MD, FCCM

Objective: To provide current information on general and specific interventions for overdoses likely to require intensive care. Design: Review of literature relevant to selected interventions for general management of overdoses and specific poisons. Results: The benefit of interventions to decrease absorption or enhance elimination of toxins is limited to a relatively small number of specific agents. Antidotes and certain interventions may be helpful in preventing or treating toxicity in specific poisonings when used appropriately. Intensive supportive care is also necessary to achieve good outcomes. Conclusion: Knowledge of the indications and limitations of current interventions for poisonings and overdoses is important for care of the critically ill poisoned patient. (Crit Care Med 2003; 31:2794 ­2801) KEY WORDS: overdose; poisoning; critical care; acetaminophen; -blockers; calcium channel blockers; ethylene glycol; methanol; cocaine; cyclic antidepressants; lithium; carbon monoxide salicylates; alternative medicines

"Poison and medicines are oftentimes the same substance given with different intents."--Peter Latham


oisoning may result from intentional or unintentional exposures, recreational drug use, and therapeutic use of drugs or other agents. Although mortality and serious morbidity in poisonings are uncommon, patients requiring hospitalization often require intensive care. The appropriate management of poisoned patients should improve outcome and decrease complications. Evidence-based information is minimal in toxicology because the variety of drugs and doses that patients are exposed to limits the ability to conduct clinical trials of specific interventions. Current recommendations for severely poisoned patients are based on limited data from animal and human studies, case reports, pharmacokinetic information, known pathophysiology, and often consensus opinion. Studies in animal models and human volunteers do not replicate clinical situations commonly encountered in patients. Therapeutic guidelines can be suggested but may not be supported by definitive evidence. The management of a poisoned patient often involves emergency physicians, primary care physicians, and inten-

sivists. Table 1 summarizes some management issues before intensive care unit (ICU) admission (1­7), and additional material can be consulted for more information (8, 9). This review will focus on interventions likely to be used in the ICU.

drug packets (8). Although some volunteer studies show decreased bioavailability of ingested drugs, the impact of whole bowel irrigation on clinical outcomes has not been assessed. Currently, whole bowel irrigation is not indicated for ingestions other than those mentioned here.


Whole bowel irrigation is a technique to prevent absorption of drugs that can be initiated in the emergency department or ICU. Large volumes of a polyethylene glycol electrolyte solution (1­2 L/hr for adults) are administered until the rectal effluent is clear or toxin elimination is confirmed. A nasogastric tube is often necessary to effectively administer the electrolyte solution. The airway must be protected in patients with depressed level of consciousness or respiratory depression. In addition, the head of the bed should be elevated to 45° to decrease the likelihood of vomiting and aspiration. Whole bowel irrigation is contraindicated in patients with ileus, gastrointestinal (GI) obstruction or perforation, hemodynamic instability, or intractable vomiting. This technique has been suggested for enhancing elimination of substances not well adsorbed by activated charcoal such as iron, lithium, sustained-released or enteric-coated medications, and illicit


Several techniques use hepatic and renal mechanisms to eliminate toxins. Most of these interventions are initiated in the ICU setting. Multiple-dose activated charcoal (MDAC) enhances elimination of drugs by repeated oral administration of activated charcoal. MDAC adsorbs drugs or metabolites that are actively secreted into the bowel following hepatic metabolism. Drugs or metabolites also are adsorbed after active or passive diffusion into the GI tract (GI dialysis). Clinical studies have not established the optimum dosing regimen. Following the initial dose of activated charcoal, subsequent doses of 0.5­1 g/kg every 4 hrs or an infusion via nasogastric tube of 12.5 g/hr can be administered (10). Smaller doses administered more frequently may decrease the incidence of vomiting. Factors that should be assessed before considering this technique include patient cooperation, level of consciousness, gasCrit Care Med 2003 Vol. 31, No. 12

From the Department of Medicine, Baylor College of Medicine, Houston, TX. Copyright © 2003 by Lippincott Williams & Wilkins DOI: 10.1097/01.CCM.0000100123.50896.F0


Table 1. Management issues before arrival in the intensive care unit Resuscitation and stabilization Assess airway Intubation and mechanical ventilation for airway protection, hypoventilation, or hypoxemia Assess hemodynamic status Isotonic fluids for hypotension Treat significant arrhythmias Interventions for altered mental status (1) 50% glucose (25­50 g intravenously) Thiamine (100 mg intravenously) Naloxone (0.4­2.0 mg intravenously, intramuscularly) Flumazenil (not routinely administered) History Type of drug and quantity Time of ingestion/exposure Available drugs in environment Physical examination Vital signs Neurologic findings Patterns of response (toxidromes) As indicated by presentation Electrolytes, renal function Arterial blood gas Plasma osmolarity Electrocardiogram Qualitative toxicology screen (urine) Quantitative drug concentrations (serum) Gastric emptying (2­4) Ipecac not recommended Gastric lavage: consider only for life-threatening drug within 1 hr of ingestion Adsorption of poisons (5) Activated charcoal (1 g/kg) Decreased transit time in gastrointestinal tract (6, 7) Cathartics (no evidence to support routine use) Whole bowel irrigation (see text)

may be attractive in hemodynamically unstable patients who cannot tolerate hemodialysis or hemoperfusion (15). Although significant drug clearance has been reported, no data are currently available on the effect of these techniques on clinical outcomes.


Acetaminophen. Acetaminophen is one of the most common drugs in overdoses, and knowledge of appropriate management is important to prevent hepatic failure and death. Liver damage can occur with ingestions of 7.5­10 g in adults, but lower doses may be toxic in chronic alcohol users or malnourished individuals with low glutathione reserves (16). Activated charcoal adsorbs acetaminophen and many coingestants and should be administered (17). Activated charcoal interferes only slightly with the effectiveness of N-acetylcysteine (NAC), and the NAC dose does not require adjustment. An acetaminophen concentration should be obtained 4 hrs after ingestion and compared to the RumackMatthew nomogram to determine the need for NAC therapy. The nomogram is useful only for single acute ingestions. NAC should be administered orally (140 mg/kg loading dose, then 70 mg/kg every 4 hrs for 72 hrs) if the concentration falls above the lower "possible hepatic toxicity" line. NAC therapy is most effective when initiated in the first 8 hrs following ingestion, but it is recommended to be initiated as late as 24 hrs after a significant ingestion (18). It is reasonable and appropriate to administer NAC 24 hrs after ingestion if toxic concentrations of acetaminophen are present or hepatic enzymes are elevated (19). Late administration of NAC has demonstrated beneficial effects on mortality rate in fulminant hepatic failure due to acetaminophen toxicity (20). No firm guidelines are established for administration of NAC in chronic ingestions or multiple ingestions over time. NAC administration should be strongly considered if hepatic enzymes are elevated at presentation. Antiemetics frequently are required to improve tolerance of oral NAC. An intravenous formulation of NAC is not available in the United States, but the oral preparation has been given intravenously (21, 22, 23). Shorter courses of therapy with NAC recently have been proposed (24). The local Poison Control Center should be contacted for assistance with intravenous


Initial clinical evaluation

Laboratory evaluation

Gastrointestinal decontamination

tric emptying, and presence of vomiting. Following the initial dose, subsequent doses of activated charcoal should not contain a cathartic because of the potential for persistent diarrhea, dehydration, electrolyte abnormalities, and abdominal discomfort. Evidence that MDAC reduces morbidity or mortality rates in poisoned patients is lacking (11). Studies suggest that elimination of carbamazepine, dapsone, phenobarbital, quinine, and theophylline is enhanced with MDAC (11, 12). Use of MDAC for other drug overdoses is not recommended. Forced diuresis by administration of large volumes of isotonic fluids and diuretics to increase renal excretion of drug or metabolite is of limited clinical value. It is not recommended because of potential volume overload and electrolyte abnormalities. Urinary alkalinization to enhance excretion of weak acids is beneficial only for salicylates and phenobarbital/primidone. Sodium bicarbonate should be administered to achieve a urine pH 7.5. Hypokalemia often results and must be corrected to achieve adequate urinary alkalinization.

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Invasive techniques such as hemodialysis and hemoperfusion are reserved for elimination of specific life-threatening toxins. Hemodialysis is particularly suited for drugs or metabolites that are water soluble, have a low volume of distribution, have a molecular weight 500 Da, and have low plasma protein binding. Hemodialysis may be difficult to initiate in the hemodynamically unstable patient. Hemodialysis can be considered for poisonings with methanol, ethylene glycol, salicylates, and lithium. Hemoperfusion involves the passage of blood through an absorptive-containing cartridge (usually charcoal). This technique removes substances that have a high degree of plasma protein binding. Charcoal hemoperfusion may be indicated for intoxications with carbamazepine, phenobarbital, phenytoin, and theophylline. There is limited experience with continuous hemofiltration techniques (arteriovenous and venovenous) as new modalities for drug removal in poisonings (13, 14). Smaller drugs are transported across a semipermeable membrane in response to hydrostatic pressure gradients. These techniques

NAC regimens and short course therapy. Extended-release forms of acetaminophen may result in delayed elevations of acetaminophen concentrations. Concentrations should be determined 4 and 8 ­10 hrs after ingestion and NAC initiated if either concentration is possibly toxic (25). Alcohols (Ethylene Glycol and Methanol). Poisonings with ethylene glycol and methanol are infrequent but can result in significant morbidity and mortality rates. Cardiopulmonary and neurologic symptoms include pulmonary edema, hypotension, ataxia, central nervous system depression, seizures, and coma. Nausea, vomiting, and abdominal pain are frequent. Visual disturbances (blurred vision, blindness, optic disc hyperemia) are hallmarks of methanol toxicity, and urinary calcium oxalate crystals may suggest ethylene glycol ingestion. Symptoms may be delayed if ethanol is also consumed. Both ingestions are classically characterized by an anion gap metabolic acidosis and an osmolar gap. However, other patterns of metabolic disturbance may be present (26, 27). In early presentations, sufficient time may not have elapsed for metabolism to toxic acids (glyoxylic acid, oxalic acid, formic acid), or high concentrations of ethanol may prevent metabolism of other alcohols leading to an osmolar gap without an anion gap metabolic acidosis. Late presentations may not manifest an osmolar gap if the alcohol already has been metabolized to acid metabolites, but an anion gap acidosis will be prominent. Practice guidelines based on available literature have been proposed for treatment of ethylene glycol and methanol poisonings (28, 29). Aggressive supportive care is needed in these ingestions. A secure airway must be maintained, and thiamine, folate, and multivitamin supplements usually are indicated. Folinic acid (leucovorin) in a dose of 1 mg/kg up to 50 mg every 4 ­ 6 hrs for 24 hrs is suggested in methanol poisoning to provide the cofactor for formic acid elimination. Hypertonic glucose may be necessary to treat hypoglycemia. Gastric lavage may be considered within 1 hr of ingestion. Although activated charcoal does not adsorb alcohols, administration may be appropriate if other drugs are suspected. Fluids should be administered to maintain adequate urine output especially since ethylene glycol is excreted by the kidneys. Some clinicians recommend


aggressive use of bicarbonate, but benefit has not been confirmed. Two interventions can prevent metabolism of these alcohols to toxic metabolites. Ethanol can be administered orally or intravenously to maintain a blood concentration of 100 ­150 mg/dL. Ethanol is preferentially metabolized by alcohol dehydrogenase. Fomepizole (4-methylpyrazole) is an inhibitor of alcohol dehydrogenase that also prevents metabolism to acid metabolites (30, 31). The potential advantages of fomepizole are the ease of administration (intravenous bolus), the lack of central nervous system depression, and no requirement for monitoring blood concentrations. The high cost is a disadvantage, and cost-effectiveness analyses are lacking. If the alcohol has been completely metabolized to acid, the use of ethanol or fomepizole is unlikely to benefit the patient. Hemodialysis is necessary to remove the alcohol and toxic metabolites. Indications for hemodialysis include significant or refractory acidosis, visual impairment, renal failure, and pulmonary edema. Hemodialysis for elevated concentrations of the specific alcohol often is recommended, but most laboratories are unable to provide concentrations in a timely manner. Hemodialysis is continued until the acidosis is resolved. Hemodialysis may not be necessary in patients without acidosis who are treated with fomepizole, but this approach is controversial and requires further study. Amphetamines and Related Drugs. Amphetamines, methamphetamines, and related agents increase central and peripheral catecholamine concentrations, which result in a sympathomimetic syndrome. Clinical manifestations often include tachycardia, hyperthermia, agitation, hypertension, and mydriasis. Hallucinations and acute psychosis are also common. The adverse consequences of these drugs include myocardial ischemia, arrhythmias, seizures, intracranial hemorrhage, stroke, rhabdomyolysis, necrotizing vasculitis, and death. A commonly abused drug in this class is 3,4methylenedioxymethamphetamine, a designer drug associated with rave parties (32). It is commonly known as ecstasy, XTC, E, or MDMA. It is ingested orally and acts as a stimulant and hallucinogen by stimulating serotonin release and inhibiting serotonin reuptake in the brain. Bruxism and jaw clenching are clues to use of ecstasy. In addition to the previously mentioned complications, hyponatremia and liver injury progressing to ful-

minant failure have been reported (33, 34). ICU care for patients with amphetamine intoxication is primarily supportive. Gastric lavage has little role since most drug is absorbed at the time of presentation. A careful clinical assessment should be made for potential complications. Intravenous hydration for possible rhabdomyolysis may be warranted in individuals with known exertional activities, hyperthermia, or evidence of intravascular volume depletion pending creatine kinase results. Benzodiazepines are used for control of agitation, and haloperidol is reserved for patients who do not adequately respond to benzodiazepines. -Blockers. The clinical effects of -blockers vary with lipid solubility, oral availability, metabolism, membranestabilizing activity, and intrinsic sympathomimetic activity (35, 36). Significant toxicity manifests as bradycardia, atrioventricular or intraventricular block, and/or hypotension. Negative inotropy contributes more to hypotension than rate-related decreases in cardiac output, and bradycardia may not be present in symptomatic patients (37). Lipid soluble -blockers such as propranolol, metoprolol, acebutolol, and timolol can cause delirium, coma, and seizures. Toxicity usually occurs within the first 6 hrs of ingestion, but delayed toxicity may result from extended-released preparations. The initial treatment of bradycardia and hypotension usually consists of atropine and isotonic fluids. However, the response to atropine is frequently inadequate, and additional therapy usually is warranted. Despite variable success rates, glucagon is considered to be the antidote for -blocker toxicity because it increases cyclic adenosine monophosphate concentrations intracellularly resulting in inotropic and chronotropic effects (38). The initial dose is 2­5 mg intravenously followed by a dose of 10 mg if needed. The goal of treatment is improvement in blood pressure and perfusion rather than an increase in heart rate. For responsive patients, a continuous infusion can be initiated at 2­10 mg/hr. Adverse effects of glucagon include nausea, vomiting, hyperglycemia, and hypocalcemia. There are reports of benefit of calcium chloride (1 g of 10% solution) in this setting (39, 40). Ventricular pacing (transthoracic or transvenous) may be considered in refractory cases if bradycardia is assessed to significantly contribute to hypotension. Adrenergic drugs such as dobutamine,

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dopamine, norepinephrine, and epinephrine are often ineffective at usual doses, but some patients respond to higher doses. Phosphodiesterase inhibitors such as milrinone, intra-aortic balloon pump, and cardiopulmonary bypass may be considered as salvage therapy for refractory cases. Recently, high-dose insulin infusions together with glucose to maintain euglycemia have been shown to promote recovery in an animal model (41). Insulin has been postulated to improve inotropy by increasing carbohydrate uptake in myocytes or increasing cytoplasmic calcium concentrations. Calcium Channel Blockers. Calcium channel blockers produce varying degrees of negative inotropy, vasodilation, bradycardia, and atrioventricular conduction block. Verapamil is most commonly associated with serious morbidity and mortality (42). Toxic manifestations include bradycardia, hypotension, and, less commonly, central nervous system findings such as lethargy, confusion, and coma. Calcium chloride (10-mL intravenous bolus of a 10% solution) should be administered as the initial intervention provided that digoxin toxicity has been excluded. A continuous infusion of calcium chloride (20 ­50 mg·kg 1·hr 1) is required to sustain increases in blood pressure. Ionized calcium concentrations should be assessed regularly (43). In patients unresponsive to calcium, glucagon has been reported to be beneficial (44, 45). Vasopressors, often in high doses, may reverse refractory vasodilation, and ventricular pacing may be necessary. Insulin-glucose infusions are reported to be beneficial, but the optimum doses are not defined (insulin 0.1­10 units·kg 1·hr 1, glucose 10 ­75 g/hr) (46). Intra-aortic balloon pump or cardiopulmonary bypass can be considered for hypotensive patients unresponsive to other interventions (47). Carbon Monoxide (CO). CO poisoning is a common cause of morbidity and mortality in the United States (48). Due to its affinity for hemoglobin, CO toxicity results in impaired transport and release of oxygen causing cellular hypoxia and possibly direct damage at the cellular level. Cellular hypoxia can result in altered mental status, angina, arrhythmias, and seizures. Diagnosis requires a high level of suspicion. Pulse oximetry inaccurately reflects oxygen saturation because it cannot distinguish carboxyhemoglobin from oxyhemoglobin (49). Venous or arterial carboxyhemoglobin concentrations

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should be measured by spectrophotometer and interpreted carefully. Carboxyhemoglobin concentrations as high as 10% may occur in smokers and in urban areas. In addition, a normal carboxyhemoglobin concentration may not reflect prior exposure of the patient. High-flow oxygen by nonrebreather mask or intubation with administration of 100% oxygen should be initiated as soon as possible while confirmatory tests are obtained. An electrocardiogram, chest radiograph, and arterial blood gas measurement should be obtained to assess severity of exposure. A metabolic acidosis implies significant exposure with tissue hypoxia. Hyperbaric oxygen therapy shortens the half-life of carboxyhemoglobin to 15­30 mins compared with 40 ­ 80 mins with 100% oxygen. The indication for and benefits of use of hyperbaric oxygen in CO poisoning continue to be debated (50, 51). Table 2 lists indications that have been proposed. A recent clinical trial suggests that hyperbaric oxygen decreases the incidence of postexposure cognitive deficits (52). Cocaine. Cocaine use can result in a typical sympathomimetic syndrome with findings of tachycardia, dilated pupils, hypertension, hyperthermia, and agitation. Benzodiazepines are used liberally for control of agitation. Haloperidol is reserved for overt psychosis in patients who are unresponsive to benzodiazepines. Cardiovascular complications include hypertension, arrhythmias (ventricular or supraventricular), myocardial ischemia, and rarely aortic dissection (53). Chest pain thought to be ischemic usually responds to nitroglycerin and/or benzodiazepines (54, 55). Aspirin should be administered due to increased platelet aggregation and possible thrombosis (56). Phentolamine, an -adrenergic antagonist that may affect vasoconstriction, is considered a second-line agent for chest pain (57). Thrombolysis for myocardial infarction may be considered when other interventions have failed and invasive reperfusion options are not availTable 2. Carbon monoxide poisoning: Proposed indications for hyperbaric oxygen therapy Any loss of consciousness Depressed level of consciousness Neurologic findings other than headache Cardiac ischemia or arrhythmia Carboxyhemoglobin level 25­40% Pregnancy and carboxyhemoglobin level 15% Persistent symptoms after normobaric oxygen treatment for 4­6 hrs

able. Severe sustained hypertension may be treated with labetalol or other vasodilators such as nitroprusside. Neurovascular complications include seizures, cerebral infarction, intracranial hemorrhage (intracerebral, intraventricular, subarachnoid), and rarely cerebral vasculitis (58). Patients with subarachnoid hemorrhage should be evaluated for underlying vascular lesions amenable to surgery. Seizures respond best to benzodiazepines and not to phenytoin. Other supportive care is based on the underlying lesion. Pulmonary complications of cocaine are less frequent and include barotrauma, noncardiogenic pulmonary edema, bronchospasm, interstitial pneumonitis, and alveolar hemorrhage (59). Hyperthermia and rhabdomyolysis can occur and are exacerbated by environmental hyperthermia. It is reasonable to institute vigorous hydration to increase urine output pending results of creatine kinase values. Bowel ischemia has been described and may require surgical intervention. Cyclic Antidepressants. Antidepressants are responsible for the third largest number of deaths from overdose in the United States, with the majority due to cyclic antidepressants (60). Principle toxicities include depressed level of consciousness, wide complex arrhythmias, seizures, and hypotension. Anticholinergic effects include mydriasis, fever, dry skin, delirium, tachycardia, ileus, and urinary retention. Life-threatening complications usually occur within 6 hrs of ingestion. Serum alkalinization and sodium loading with sodium bicarbonate should be instituted for a prolonged QRS and wide complex arrhythmias (61). However, the exact threshold for instituting therapy based on QRS duration has not been definitively established. Proposals have included a QRS 0.10 secs or 0.16 secs and an R wave in AVR 3 mm (62, 63). A QRS that is prolonging over time also should prompt consideration of therapy. Bicarbonate is administered in 50 ­100 mEq boluses (1­2 mEq/kg) to alkalinize the blood pH to 7.45­7.55. Hyperventilation to achieve alkalinization may be less effective but useful in patients who do not tolerate the sodium and volume load (64). The optimum pH is probably best determined by clinical end points such as narrowing of the QRS or reversal of arrhythmia. Following bolus administration of sodium bicarbonate, continuous infusion can be maintained for 4 ­ 6 hrs and tapered. Hypertonic saline also has been reported to be effective


in treating cardiac toxicity, but clinical experience is limited (65, 66). If torsade de pointes develops, magnesium sulfate should be administered. Hypotension may be secondary to altered adrenergic receptor response or myocardial depression. Hypotension refractory to volume expansion is best treated with an -agonist such as norepinephrine or phenylephrine, rather than dopamine, which is less effective (67). Sodium bicarbonate should be administered if conduction abnormalities are present. Forced diuresis, hemodialysis, and hemoperfusion are ineffective in cyclic antidepressant overdoses. Physostigmine is not recommended for treatment of altered mental status due to potential cholinergic toxicity of seizures and arrhythmias. Seizures are best treated with benzodiazepines, and sodium bicarbonate therapy is not expected to be of any benefit. Patients should remain in the ICU for 12 hrs after symptoms resolve and therapeutic interventions have been discontinued before transfer (68). Lithium. Lithium has a narrow therapeutic index, and toxicity may occur with acute, acute on chronic, or chronic ingestions. The significance of a lithium concentration must be considered in conjunction with clinical findings because of variability in development of toxicity. Chronic ingesters of lithium have a high total body lithium burden that results in toxicity at lower serum concentrations. In acute ingestions, GI symptoms may occur early with central nervous system symptoms developing later after tissue distribution. In chronic ingestions, neurologic abnormalities are the major manifestations and include tremor, clonus, agitation, lethargy, dysarthria, delirium, seizures, and coma. Myocardial dysfunction and arrhythmias occur rarely. If lithium toxicity is suspected, lithium concentration should be assessed immediately and 2 hrs later to evaluate for increasing concentrations. Many preparations of lithium are sustainedrelease forms, and absorption may continue over a long period (69). Lithium is excreted by the kidneys, so renal function must be assessed. A decreased anion gap suggests a severely elevated lithium concentration. Volume status should be assessed and isotonic saline administered as indicated. Forced diuresis is not effective in enhancing lithium excretion, but adequate urine output should be maintained. Whole bowel irrigation has been proposed as the technique of choice for GI


decontamination, since lithium is not adsorbed by charcoal (8, 70). This technique is best instituted in the ICU with close monitoring. Diuretics worsen lithium toxicity by causing salt and water depletion and increased resorption of lithium. Hemodialysis is effective in removing lithium, but controversy exists on the indications for treatment and duration of therapy (71). Proposed indications for dialysis include renal dysfunction, severe neurologic dysfunction, inability to tolerate fluid replacement, and lithium concentration 4 mmol/L in acute ingestion and 2.5 mmol/L in chronic ingestion. The risks of hemodialysis for an individual patient must be weighed against the lithium concentration and severity of symptoms. Redistribution between intracellular and extracellular compartments can result in a rebound increase in lithium concentration 6 ­ 8 hrs after dialysis. A lithium concentration should be assessed immediately after hemodialysis and 6 ­ 8 hrs later. Repeat dialysis and prolonged sessions (4 ­ 6 hrs) may be indicated if the concentration is increasing or neurologic toxicity is not improving. It is important to recognize that improvement of neurologic toxicity lags behind the decrease in serum concentration. Continuous arteriovenous and venovenous hemodiafiltration has been used to remove lithium and may be associated with less rebound, but further study is required to assess benefit (72). Although animal studies document decreased lithium concentrations with use of sodium polystyrene sulfonate resin, the large doses are not feasible in humans and may result in hypokalemia, hypernatremia, and fluid overload. No evidence supports the use of low-dose dopamine in lithium toxicity (71). Opioids. Opioid toxicity produces a classic syndrome characterized by depressed level of consciousness, respiratory depression, and miosis. Additional toxicities may include hypotension, noncardiogenic pulmonary edema, aspiration pneumonitis, ileus, nausea, vomiting, and pruritis. Seizures may be associated with meperidine and propoxyphene. Heroin abuse is responsible for most fatal overdoses, especially with intravenous administration. Respiratory and hemodynamic stabilization of the patient usually is accomplished before ICU admission. Intubation and mechanical ventilation along with intravenous fluids may be necessary. Naloxone, a competitive opioid antagonist, can be administered intrave-

nously, intramuscularly, by sublingual injection, or via endotracheal tube to reverse toxic effects. Higher doses of naloxone (10 ­20 mg) may be required to reverse effects of synthetic opioids such as propoxyphene, codeine, methadone, hydrocodone, oxycodone, and fentanyl. If initial doses of naloxone restore adequate respiration and further therapy is needed, repeat boluses or a continuous infusion of naloxone can be used. The infusion dose is typically one half to two thirds of the initial amount of naloxone that reversed the respiratory depression administered on an hourly basis (73). If the patient has been intubated, a naloxone infusion is not necessary. Nalmefene, a long-acting opioid antagonist, has been used to treat overdoses but may result in prolonged withdrawal symptoms (74). Noncardiogenic pulmonary edema is usually self-limited (24 ­36 hrs) and managed with supportive care (75). Organophosphates/Carbamates/Nerve Agents. Organophosphates and carbamates are acetylcholinesterase inhibitors used in insecticides. Carbamates do not enter the central nervous system, and enzyme inhibition is reversible in minutes to hours resulting in limited toxicity. Organophosphates permanently inactivate acetylcholinesterase and penetrate the central nervous system leading to greater toxicity and need for antidote administration. Nerve agents such as sarin and VX that may be used in terrorist attacks are potent organophosphates that produce cholinergic poisoning (76). Cholinergic poisoning due to accumulation of acetylcholine at synapses exerts deleterious effects on three systems: muscarinic, nicotinic, and central nervous system (Table 3). The diagnosis of cholinergic poisoning is primarily clinical although low plasma acetylcholinesterase concentrations may be helpful for confirmation. The most life-threatening concerns are bronchorrhea, bronchospasm, and respiratory insufficiency (77). The airway is best protected by early endotracheal intubation, and only nondepolarizing neuromuscular blockers should be used due to prolonged paralysis with succinylcholine (78). After decontamination and control of the airway, the initial intervention is the intravenous administration of atropine 2­ 4 mg, which is repeated every 2­5 mins as needed for control of respiratory secretions. Glycopyrrolate, which does not cross the blood-brain barrier, may be considered instead of atropine if no central nervous system symptoms are

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present. Large doses of atropine (40 ­1000 mg/day) may be needed over a prolonged period of time especially for the more lipidsoluble organophosphate insecticides. Lower doses are usually adequate for nerve agent poisoning (79). A continuous infusion of atropine can be initiated at 0.05 mg·kg 1·hr 1 and titrated. After stabilization, atropine should be withdrawn slowly and respiratory secretions monitored closely. Atropine does not reverse nicotinic effects, and pralidoxime (2-PAM) is required in patients with significant muscle weakness. Pralidoxime allows for reactivation of cholinesterases if it is given before irreversible binding of toxin occurs (usually 24 ­ 48 hrs depending on the specific agent). The usual recommended dose is 1­2 g intravenously over 10 ­20 mins followed by 200 ­500 mg/hr infusion (76). The World Health Organization-sponsored dose recommendations are a bolus of 30 mg/kg followed by 8 mg·kg 1·hr 1 infusion (80). Delayed neurotoxicity and polyneurorapthy may occur 1­3 wks after exposure, and recovery is variable. An intermediate syndrome that occurs 24 ­96 hrs after resolution of the severe cholinergic crisis also has been described (81). In this syndrome, patients may develop respiratory paralysis, weakness, and depressed reflexes. Treatment is primarily supportive with resolution in 1­3 wks. Salicylates. Clinical manifestations of salicylate toxicity include tinnitus, nausea/vomiting, fever, seizures, depressed level of consciousness, respiratory alkalosis, anion gap metabolic acidosis, hypoglycemia, coagulopathy, hepatic toxicity, and noncardiogenic pulmonary edema (82). Patients with chronic rather than acute ingestions of salicylates are more likely to develop toxicity and require intensive care. A salicylate concentration should be measured initially and reassessed for continued absorption, especially with enteric-coated products. A salicylate concentration 35 mg/dL 6 hrs after acute ingestion or significant symptoms with a lower concentration should be treated with administration of sodium bicarbonate to alkalinize the urine to pH 7.5. Urinary alkalinization increases renal clearance of salicylate, and alkalemia promotes the movement of salicylate from brain and tissue to the blood. Hypokalemia often develops or worsens as the acidosis resolves and must be corrected (83). The use of MDAC has been proposed but remains controversial (11).

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Volume status should be assessed and optimized because many patients have increased insensible losses. Hemodialysis may be required for concentrations 100 mg/dL in acute ingestions, seizures, persistent alteration of mental status, refractory acidosis, or persistent electrolyte abnormalities. Hemodialysis also may be necessary if patients develop fluid overload from bicarbonate therapy or they are unable to tolerate bicarbonate therapy. Alternative Medicines. Herbal medicines and dietary supplements are the most common forms of alternative therapy in the United States and are marketed without testing for safety or efficacy. Significant toxicity may result from product misuse, contamination of the product, or interaction with other medications. Table 4 lists toxicities of some alternative medicines or agents found in some products that might require ICU care (84 ­ 87). Care is primarily supportive depending on the clinical manifestations. In aconitine toxicity, atropine may be considered for bradycardia or hypersalivation (88). If cardiac glycoside toxicity is suspected, a digoxin concentration should be obtained but many glycosides are not detected in the radioimmune assay. The patient's symptoms and serum potassium concentration should be used to guide intervention. Significant toxicity should be treated with digoxin-specific antibodies (89). After these antibodies have been administered, digoxin concentrations are

Table 3. Effects of cholinergic poisoning Muscarinic Miosis Bradycardia Salivation Lacrimation Urination Diarrhea Nausea, vomiting Bronchorrhea Bronchospasm Nicotinic


nowledge of the indications and limitations of

current interventions for poisonings and overdoses is important for care of the critically ill poisoned patient.

no longer useful. Products also have been found to contain undeclared medications and lead, arsenic, and mercury in concentrations above limits established by the U.S. Pharmacopoeia (90). Unusual symptoms or toxidromes in ICU patients ingesting such products may require assistance of the local health department or a toxicologist to identify a potential toxin. Additional information about specific herbs can be found at or


Intensive care plays an important role in the management of patients with severe poisonings and overdoses. After resuscitation, stabilization, and initial evaluation and management, interventions

Central Nervous System Headache Confusion Ataxia Delirium Coma Psychosis Dysarthria Respiratory depression Seizures

Mydriasis Weakness Diaphragmatic failure Tachycardia Hypertension

Table 4. Toxicities of alternative medicines Ephedrine (ma huang) Ginkgo Ginseng Garlic Kava Aconite Cardiac glycosides (digoxin-like factors) Sympathomimetic syndrome, intracranial hemorrhage, seizures, arrhythmias, myocardial infarction, stroke, hepatic failure, death (87­89) Bleeding (cerebral or extracerebral) (88) Hypoglycemia, potential bleeding (88) Bleeding (88) Hepatic failure (90), potentiation of anesthetics Bradycardia, ventricular tachycardia and fibrillation, hypersalivation, gastrointestinal disturbances (84) Arrhythmias, gastrointestinal disturbances, visual disturbances (85)


that can be used in the ICU to decrease toxin absorption or enhance elimination include whole bowel irrigation, multipledose activated charcoal, and invasive techniques such as hemodialysis and hemoperfusion. Specific interventions or antidotes may be indicated in certain poisonings, but supportive care that includes attention to airway and monitoring is also important to improve outcomes. Critical care practitioners should be familiar with the evaluation of these patients and knowledgeable about beneficial interventions.






1. Hoffman RS, Goldfrank LR: The poisoned patient with altered consciousness. JAMA 1995; 274:562­569 2. Pond SM, Lewis-Driver DJ, Williams GM, et al: Gastric emptying in acute overdose: A prospective randomized controlled trial. Med J Aust 1995; 163:345­349 3. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position statement: Ipecac syrup. J Toxicol Clin Toxicol 1997; 35:699 ­709 4. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position statement: Gastric lavage. J Toxicol Clin Toxicol 1997; 35:711­719 5. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position statement: Single-dose activated charcoal. J Toxicol Clin Toxicol 1997; 35:721­724 6. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists. Position statement: Whole bowel irrigation. J Toxicol Clin Toxicol 1997; 35:753­762 7. American Academy of Clinical Toxicology, European Association of Poisons Centres and Clinical Toxicologists: Position statement: Cathartics. J Toxicol Clin Toxicol 1997; 35: 743­752 8. Zimmerman JL, Rudis M: Poisonings. In: Critical Care Medicine. Second Edition. Parrillo JE, Dellinger RP (Eds). St. Louis, MO, Mosby, 2001, pp 1501­1524 9. Goldfrank LR, Flomenbaum NE, Lewin NA, et al (Eds): Goldfrank's Toxicologic Emergencies. Seventh Edition. New York, McGraw-Hill, 2002 10. Ilkhanipour K, Yealy DM, Krenzelok EP: The comparative efficacy of various multiple-dose activated charcoal regiments. Am J Emerg Med 1992; 10:298 ­300 11. American Academy of Clinical Toxicology, European Association of Poison Centres and Clinical Toxicologists. Position statement and practice guidelines on the use of multidose activated charcoal in the treatment of 16.











acute poisoning. J Toxicol Clin Toxicol 1999; 37:731­751 Bradberry SM, Vale JA: Multiple-dose activated charcoal: A review of relevant clinical studies. J Toxicol Clin Toxicol 1995; 33: 407­ 416 Golper TA, Bennett WM: Drug removal by continuous anteriovenous haemofiltration: A review of the evidence in poisoned patients. Med Toxicol 1998; 3:341­349 Van Bommel EF, Kalmeijer MD, Ponssen HH: Treatment of life-threatening lithium toxicity with high-volume continuous venovenous hemofiltration. Am J Nephrol 2000; 20:408 ­ 411 Christiansson LK, Kaspersson KE, Kulling PE, et al: Treatment of severe ethylene glycol intoxication with continuous arteriovenous hemofiltration dialysis. J Toxicol Clin Toxicol 1995; 33:267­270 Makin AJ, Wendon J, Wiliams R: A 7-year experience of severe acetaminophen-induced hepatotoxicity. Gastroenterology 1995; 109: 1907­1916 Buckley NA, Whyte IM, O'Connell DL, et al: Activated charcoal reduces the need for N-acetylcysteine treatment after acetaminophen (paracetamol) overdose. J Toxicol Clin Toxicol 1999; 37:753­757 Smilkstein MJ, Knapp GL, Kulig KW, et al: Efficacy of oral N-acetylcysteine in the treatment of acetaminophen overdose. N Engl J Med 1988; 319:1557­1562 Bizovi KE, Smilkstein MJ: Acetaminophen. In: Goldfrank's Toxicologic Emergencies. Seventh Edition. Goldfrank LR, Flomenbaum NE, Lewin NA, et al (Eds). New York, McGraw-Hill, 2002, pp 480 ­501 Keays R, Harrison PM, Wendon JA, et al: Intravenous acetyl-cysteine in paracetamol induced fulminant hepatic failure: A prospective controlled trial. BMJ 1991; 303: 1026 ­1029 Yip L, Dart BC, Hurlbut KM: Intravenous administration of oral N-acetylcysteine. Crit Care Med 1998; 26:40 ­ 43 Buckley NA, Whyte IM, O'Connell DL, et al: Oral or intravenous N-acetylcysteine: Which is the treatment of choice for acetaminophen (paracetamol) poisoning? J Toxicol Clin Toxicol 1999; 37:759 ­767 Dribben WH, Porto SM, Jeffords BK: Stability and microbiology of inhalant N-acetylcysteine used as an intravenous solution for the treatment of acetaminophen poisoning. Ann Emerg Med 1003; 42:9 ­13 Woo OF, Mueller PD, Olson KR, et al: Shorter duration of oral N-acetylcysteine therapy for acute acetaminophen overdose. Ann Emerg Med 2000; 35:363­368 Cetaruk EW, Dart RC, Hurlbut KM, et al: Tylenol extended relief overdose. Ann Emerg Med 1997; 30:104 ­108 Ammar KA, Heckerling PS: Ethylene glycol poisoning with a normal anion gap caused by concurrent ethanol ingestion: Importance of the osmolal gap. Am J Kidney Dis 1996; 27:130 ­133

27. Glaser DS: Utility of the serum osmol gap in the diagnosis of methanol or ethylene glycol ingestion. Ann Emerg Med 1996; 27:343­346 28. American Academy of Clinical Toxicology: Practice guidelines on the treatment of ethylene glycol poisoning. J Toxicol Clin Toxicol 1999; 37:537­560 29. American Academy of Clinical Toxicology: American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol 2002; 40:415­ 446 30. Brent J, McMartin K, Phillips S, et al: Fomepizole for the treatment of ethylene glycol poisoning. N Engl J Med 1999; 340:832­ 838 31. Brent J, McMartin K, Phillips S, et al: Fomepizole for the treatment of methanol poisoning. N Engl J Med 2001; 344:424 ­ 429 32. Kalant H: The pharmacology and toxicology of "ecstasy" (MDMA) and related drugs. CMAJ 2001; 165:917­928 33. Ajaelo I, Koenig K, Snoey E: Severe hyponatremia and inappropriate antidiuretic hormone secretion following ecstasy use. Acad Emerg Med 1998; 5:839 ­ 840 34. Andreic V, Mas A, Bruguera M, et al: Ecstasy: A common cause of severe acute hepatotoxicity. J Hepatol 1998; 29:394 ­397 35. Reith DM, Dawson AH, Epid D, et al: Relative toxicity of beta blockers in overdose. J Toxicol Clin Toxicol 1996; 34:273­278 36. Love JN, Howell JM, Litovitz TL, et al: Acute beta blocker overdose: Factors associated with the development of cardiovascular morbidity. J Toxicol Clin Toxicol 2000; 38: 275­281 37. Love JN, Enlow B, Howell JM, et al: Electrocardiographic changes associated with -blocker toxicity. Ann Emerg Med 2002; 40:603­ 610 38. Taubolet P, Cariou A, Berdeaux A, et al: Pathophysiology and management of selfpoisoning with -blockers. J Toxicol Clin Toxicol 1993; 31:531­551 39. Brimacombe JR, Scully M, Swainston R: Propanolol overdose--A dramatic response to calcium chloride. Med J Aust 1991; 155: 267­268 40. Pertoldi F, D'Orlando L, Mercante WP: Electromechanical dissociation 48 hours after atenolol overdose: Usefulness of calcium chloride. Ann Emerg Med 1998; 31:777­781 41. Kerns W, Schroeder D, Williams C, et al: Insulin improves survival in a canine model of acute -blocker toxicity. Ann Emerg Med 1997; 29:748 ­757 42. Ramoska EA, Spiller HA, Myers A: Calcium channel blocker toxicity. Ann Emerg Med 1990; 19:649 ­ 653 43. Kerns W, Kline J, Ford MD: -blocker and calcium channel blocker toxicity. Emerg Med Clin N Am 1994; 12:365­390 44. Mahr NC, Valdes A, Lamas G: Use of glucagon for acute intravenous diltiazem toxicity. Am J Cardiol 1997; 79:1570 ­1571 45. Papadopoulos J, O'Neill MG: Utilization of a glucagon infusion in the management of a


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massive nifedipine overdose. J Emerg Med 2000; 18:453­ 455 Yuan TH, Kerns WP, Tomaszewski CA, et al: Insulin-glucose as adjunctive therapy for severe calcium channel antagonist poisoning. J Toxicol Clin Toxicol 1999; 37:463­ 474 Holzer M, Sterz F, Schoerkhuber W, et al: Successful resuscitation of a verapamilintoxicated patient with percutaneous cardiopulmonary bypass. Crit Care Med 1999; 27:2818 ­2823 Ernst A, Zibrak JD: Carbon monoxide poisoning. N Engl J Med 1998; 339:1603­1608 Hampson NB: Pulse oximetry in severe carbon monoxide poisoning. Chest 1998; 114: 1036 ­1041 Scheinkestel CD, Bailey M, Myles PS, et al: Hyperbaric oxygen or normobaric oxygen for acute carbon monoxide poisonings: A randomized controlled clinical trial. Med J Aust 1999; 170:203­210 Hawkins M, Harrison J, Charters P: Severe carbon monoxide poisoning: Outcome after hyperbaric oxygen therapy. Br J Anaesth 2000; 84:584 ­586 Weaver LK, Hopkins RO, Chan KJ, et al: Hyperbaric oxygen for acute carbon monoxide poisoning. N Engl J Med 2002; 347: 1057­1067 Lange RA, Hillis LD: Medical progress: Cardiovascular complications of cocaine use. N Engl J Med 2001; 345:351­358 Baumann BM, Perrone J, Hornig SE, et al: Randomized, double-blind placebo-controlled trail of diazepam, nitroglycerin, or both for treatment of patients with potential cocaine-associated acute coronary syndromes. Acad Emerg Med 2000; 7:878 ­ 885 Honderick T, Williams D, Seaberg D, et al: A prospective, randomized, controlled trial of benzodiazepines and nitroglycerine or nitroglycerine alone on the treatment of cocaineassociated with acute coronary syndromes. Am J Emerg Med 2003; 21:39 ­ 42 Heesch CM, Wilhelm CR, Restich J, et al: Cocaine activates platelets and increases the formation of circulating platelet containing microaggregates in humans. Heart 2000; 83: 688 ­ 695 Hollander JE, Coates WA, Hoffman RS: Use of phentolamine for cocaine-induced myocardial ischemia. N Engl J Med 1992; 327:361 Daras M, Tuchman AJ, Koppel BS, et al: Neurovascular complications of cocaine. Acta Neurol Scand 1994; 90:124 ­129 Haim DY, Lippman ML, Goldberg SK, et al: The pulmonary complications of crack cocaine. A comprehensive review. Chest 1995; 107:233­240 Litovitz TL, Klein-Schwartz W, Rodgers GC, et al: 2001 Annual report of the American















Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med 2002; 20:391­ 452 Liebelt EL: Targeted management strategies for cardiovascular toxicity from tricyclic antidepressant overdose. The pivotal role for alkalinization and sodium loading. Pediatr Emerg Care 1998; 14:293­298 Boehnert M, Lovejoy FH Jr: Value of the QRS duration versus the serum drug level in predicting seizures and ventricular arrhythmias after an acute overdose of tricyclic antidepressants. N Engl J Med 1985; 313:474 ­ 479 Liebelt EL, Francis PD, Woolf AD: ECG lead aVR versus QRS interval in predicting seizures and arrhythmias in acute tricyclic antidepressant toxicity. Ann Emerg Med 1995; 26:195­201 Pentel PR, Benowitz NL: Tricyclic antidepressant poisoning--Management of arrhythmias. Med Toxicol 1986; 1:101­121 McCabe JL, Cobaugh DJ, Menegazzi JJ, et al: Experimental tricyclic antidepressant toxicity: A randomized, controlled comparison of hypertonic saline solution, sodium bicarbonate, and hyperventilation. Ann Emerg Med 1998; 32:329 ­333 McKinney PE, Rasmussen R: Reversal of severe tricyclic antidepressant-induced cardiotoxicity with intravenous hypertonic saline solution. Ann Emerg Med 2003; 42:20 ­24 Tran TP, Panacek EA, Rhee KJ, et al: Response to dopamine vs norepinephrine in tricyclic antidepressant-induced hypotension. Acad Emerg Med 1997; 4:864 ­ 868 Tokarski GF, Young MJ: Criteria for admitting patients with tricyclic antidepressant overdose. J Emerg Med 1988; 6:121­124 Dupuis RE, Cooper AA, Rosamond LJ, et al: Multiple delayed peak lithium concentrations following acute intoxication with an extended-release product. Ann Pharmacother 19967; 30:356 ­360 Smith SW, Ling LJ, Halstenson C: Wholebowel irrigation as a treatment for acute lithium overdose. Ann Emerg Med 1991; 20: 536 ­539 Scharman EJ: Methods used to decrease lithium absorption or enhance elimination. J Toxicol Clin Toxicol 1997; 35:601­ 608 LeBlanc M, Raymond M, Bonnardeaux A, et al: Lithium poisoning treated by highperformance continuous arteriovenous and venovenous hemodiafiltration. Am J Kidney Dis 1996; 27:365­372 Goldfrank L, Weisman RS, Errick JK, et al: A dosing nomogram for continuous infusion intravenous naloxone. Ann Emerg Med 1986; 15:566 ­570 Kaplan JL, Marx JA, Calabro JJ, et al: Doubleblind, randomized study of nalmefene and

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DISCLOSURE The author declared no competing interests. REFERENCES

1. Giachelli CM, Jono S, Shioi A et al. Vascular calcification and inorganic phosphate. Am JKidney Dis2001; 38(Suppl 1): S34­S37. Kurz P Monier-Faugere MC, Bognar Bet al. Evidence , for abnormal calcium homeostasis in patients with adynamic bone disease. Kidney Int 1994; 46: 855­861. London GM, Marty C, Marchais SJet al. Arterial calcifications and bone histomorphometry in endstage renal disease. JAm Soc Nephrol 2004; 15: 1943­1951. Price P Roublick AM, Williamson MK. Artery A, calcification in uremic rats is increased by a low protein diet and prevented by treatment with ibandronate. Kidney Int 2006; 70: 1577­1583.









Neves KR, Graciolli FG, dos Reis LM et al. Vascular calcification: contribution of parathyroid hormone in renal failure. Kidney Int 2007; 71: 1262­1270. Coen G, Manni M, Mantella D et al. Are PTH serum levels predictive of coronary calcifications in haemodialysis patients?Nephrol Dial Transplant 2007; 22: 3262­3267. KawataT, Nagano N, Obi M et al. Cinacalcet suppresses calcification of the aorta and heart in nephrectomized uremic rats. Kidney Int 2008; 74: 1270­1277. Lopez I, Mendoza F Aguilera-Tejero Eet al. The J, effect of calcitriol, paricalcitol, and a calcimimetic on extraosseous calcifications in uremic rats. Kidney Int 2008; 73: 300­ 307. Molostvov G, James S, Fletcher Set al. Extracellular calcium-sensing receptor is functionally expressed in human artery. Am JPhysiol R enal Physiol 2007; 293: F946­F955.

see original article on page 1327

Extracorporeal removal of toxins

Pallavi K.Tyagi1, James F Winchester1 and Donald A. Feinfeld1 .

Holubek et al. reviewed data on extracorporeal removal (ECR) of toxins from the Toxic Exposure Surveillance System (TESS) from 1985 to 2005. Hemodialysis use increased, but hemoperfusion nearly disappeared. Lithium, ethylene glycol, salicylate, and, increasingly, acetaminophen still often necessitate hemodialysis; ECR for theophylline has disappeared. TESS data do not separate continuous renal replacement therapy from hemodialysis, and not all poisonings were reported in this system. Nonetheless, these trends are useful to the nephrology community.

Kidney International (2008) 74, 1231­1233. doi:10.1038/ki.2008.476

Extracorporeal removal (ECR) techniques used for clearance of toxins can be a critical step in the management of chemical or drug poisoning. e use of these techniques for removal of toxins can be justied if there is evidence of severe toxicity and if the total-body elimination of the toxin can be increased by 30% or more by the extracorporeal technique.1 Large randomized controlled trials of ECR in toxicology are hard to come by and, for obvious reasons, difficult to perform.

1Division of Nephrology and Hypertension, Department of Medicine, Beth Israel Medical Center, New Y New Y US ork, ork, A Correspondence: Donald A. Feinfeld, Division of Nephrology and Hypertension, Beth Israel Medical Center, 350 E 17 th S ast treet, New Y New Y ork, ork 10003, US A. E-mail: [email protected]

Speci c extracorporeal techniques and their indications remain a matter of debate. Application of extracorporeal modalities requires a thorough knowledge of drug pharmacokinetics and of the techniques available. e technology of choice for the removal of a particular toxin, however, may not be immediately available to physicians in clinical practice. Holubek et al.2 (this issue) describe trends in the use of ECR for removal of toxins in the United States over a 21-year period of poison-center data recorded in the Toxic Exposure Surveillance System (TESS) database from 1985 to 2005. TESS is a uniform data set of cases reported from poison centers in the United States. Categories of information include the patient, caller, route of exposure, substance or substances,

clinical picture, treatment, and medical outcomes. e trend was an increase in hemodialysis (HD) use with a decrease in hemoperfusion (HP) over the nal 10 years. is may be attributed to a change in the technology itself as well as a change in the pro les of drugs causing overdose. Improvement in HD technologies over the years, with use of newer synthetic membranes at greater blood ow rates, has resulted in drug elimination rates similar to that achieved through HP.3 HP cartridges are expensive and have limited shelf life, and some require sterilization. It is technically more di cult to perform, cannot correct the acid­base uid and electrolyte abnormalities associated with intoxications, and can cause thrombocytopenia, leukopenia, and hypocalcemia. According to TESS data from 2004, only 27 of the almost 2.5 million exposures reported to United States poison control centers were managed with charcoal HP.4 Shalkham et al. reported the availability of charcoal HP cartridges in only approximately one-third of hospitals receiving emergency patients in New York City, and only three in-hospital HD units had performed HP in the past ve years, on three cases.5 e use of theophylline and barbiturate drugs, which were traditionally removed by HP, has declined, leading to a decline in the use of HP for their elimination.6 e role of continuous renal replacement therapy (CRRT), available since the late 1970s, in the treatment of poisoning is still under debate and is not currently reported in the TESS database. e use of continuous veno-venous hemo ltration (CVVH) and continuous veno-venous hemodia ltration (CVVHD) have been reported in poisonings with salicylates, barium, lithium, carbamazepine, phenobarbital, methanol, iodine, pilsicainide, mercury, metformin, valproic acid, and tetramine. CVVH and CVVHD are considered continuous therapies because they are applied for a longer time (24­48 hours) than HD (usually 4­6 hours). An advantage of CVVH and CVVHD is that they are better tolerated than HD in hemodynamically unstable patients. CVVH achieves solute clearance by convection (solvent drag e ect) through the membrane, with pore dimensions larger


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than those of conventional HD membranes. In CVVHD, di usive transport of molecules is combined with ltration in order to increase the solute clearance. Drugs and chemicals must meet given criteria in order to reach a high extraction ratio, that is, low molecular weight, low volume of distribution, and weak protein binding. Compared with HD, the properties of the membranes used for CVVH and CVVHD allow the removal of poisons with higher molecular weights (up to 40,000 da for CVVH and CVVHD compared with less than 500 da for HD). However, the toxicokinetic requirements for an e cient toxin removal do not differ between the two techniques: small volume of distribution (<1 liter per kg), low endogenous clearance (<4 ml/min/kg), and an extraction ratio exceeding endogenous elimination.7 e phenomenon of rebound must be considered in the evaluation of removal of drugs. Depending on the volume of distribution of a particular drug, a large quantity may be protein bound or stored intracellularly, as in muscle or adipose tissue. A er cessation of ECR, any drug removed from the extracellular space can have a concentration gradient that causes drugs to move from their intracellular stores to the extracellular space, leading to a rebound increase in the plasma levels. CRRT can prevent rebound because of its constant clearance of substances with the clinical advantage of preventing rebound, for example, of lithium.8 Disadvantages of CRRT include that it requires patients to be sedentary for a long period of time; the need for anticoagulation; and that it may not be available at many smaller hospitals. e debate over CRRT versus HD continues, and the decision should be made on a case-by-case basis, keeping in mind that one modality can be followed by the other should the clinical status of the patient warrant such change. In cases in which the blood level of the toxin is very high, HD would be the preferred treatment if the patient can tolerate it.9 Figure 1 shows the percentage of all ECR treatments that were performed for 10 toxins during each of the four quinquennia reviewed by Holubek et al.2 Lithium, ethylene glycol, and salicylate remained the major toxins for which HD



40 35

Percent of reported treatments

30 25 20 15 10 5 0

1985­1990 1991­1995 1996­2000 2001­2005


Ethylene glycol





Percent of reported treatments





1985­1990 1991­1995 1996­ 2000 2001­ 2005


0 Methanol Barbiturate Theophyll Isopropanol Carbamazepine

Figure 1 | Trends in toxin-removal treatments. (a) Percentage of treatments reported for toxins with increasing use of ECR.2 (b) Percentage of treatments reported for toxins with decreasing or AP steady use of ECR.2 AP , acetaminophen.

was performed, while ECR for acetaminophen and valproic acid poisoning has increased dramatically in recent years (Figure 1a), re ecting their increased use and hence likelihood of overdose. While theophylline and isopropanol have largely disappeared as indications for ECR (Figure 1b), HD and even HP continue to be used to treat ethanol poisoning. Since 1989, acetaminophen has been the sixth most common reason for HD, and in 2001 it became the h most common exposure, replacing theophylline. Toxic exposures to acetaminophen (paracetamol) have increased in other countries as well. In November 2003, paracetamol was made available in non-pharmacy outlets in Norway. In 2004, there was a considerable increase in inquiries to poison centers regarding acute and chronic paracetamol exposures. e number of

severe paracetamol exposures presented to poison centers nearly doubled from 2003 to 2006. 10 The Swedish Poisons Information Centre has observed a continuously increasing number of inquiries related to paracetamol overdose in adolescents and young women.11 Although the possible bene t in terms of toxin removal from HD or HP late in acetaminophen poisoning has been questioned, a series of patients dialyzed more than 14 hours a er ingestion of the drug had a smaller rise in hepatic enzymes than those with a similar overdose who were not dialyzed.12 e data of Holubek et al.2 were collected from the TESS database, which has a number of limitations. Reporting to TESS is not regulated or required; instead, callers are seeking diagnostic or treatment assistance or information. As a result, the incidence of certain subsets of poisoning

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is underreported in TESS, most notably substance abuse and poisoning fatalities. During the quinquennium 1985­1990, about one- h of the calls to poison centers were not included in TESS,4 so the trends in the report might not be as robust as they might have been if data collection had been more universal. TESS data are collected during telephone consultations; thus, bedside con rmation and data collection are not necessarily conducted by specialists in poison information. However, because calls are initiated by the general public, health-care professionals, and emergency rst responders, the data collected provide a broader narrative of poisoning exposures than those from traditional health-care databases. Data quality may improve as data are collected and documented by specialists in poison information during the evaluation of the exposure and determination of the potential toxicity and therapeutic needs. It is also worth bearing in mind that the trend of the use of ECR in the United States may not necessarily re ect trends in Europe and the rest of the world. Newer techniques for removal of toxins, such as Molecular Adsorbent Recirculating System (MARS), although still not widely available, may eventually become more common and replace HD as the modality of choice for removal of certain toxins. E cacy of MARS in the removal of protein-bound drugs such as phenytoin, diltiazem, and theophylline has been described in case reports, but its availability remains limited. e epidemiological trend of extracorporeal toxin removal in the United States has been changing, as has the pro le of drugs removed by these techniques. With the use of newer techniques and change in drugs used in medical therapy, the trends will continue to evolve, with nephrologists playing a central role in the use of these therapeutic modalities.

DISCLOSURE The authors declared no competing interests. REFERENCES

1. 2. 3. Maher JF Schreiner GE. The dialysis of poisons and , drugs. TransAm Soc Artif Intern Organs 1968; 14: 440­453. Holubek WJ, Hoffman RS, Goldfarb DSet al. Use of hemodialysis and hemoperfusion in poisoned patients. Kidney Int 2008; 74: 1327­1334. Tapolyai M, Campbell M, Dailey K, Udvari-Dagy





S. Hemodialysis is as effective as hemoperfusion for drug removal in carbamazepine poisoning. Nephron 2002; 90: 213­215. Watson WA, Litovitz TL, Rodgers GCet al. 2004 Annual report of the American Association of Poison Control CentersToxic Exposure Surveillance System. Am JEmerg Med 2005; 23: 589­666. Shalkham AS, Kirrane BM, Hoffman RSet al. The availability and use of charcoal hemoperfusion in the treatment of poisoned patients. Am JKidney Dis 2006; 48: 239­241. Lenhardt R, Malone A, Grant EN, Weiss KB. Trends in emergency department asthma care in metropolitan Chicago: results from the Chicago Asthma Surveillance Initiative. Chest 2003; 124: 1774­1780. Jaeger A, Sauder P Kopferschmitt Jet al. , Toxicokinetics in clinical toxicology. Acta Clin Belg

1990; 45: 1­12. Goodman JW, Goldfarb DS. The role of continuous renal replacement therapy in the treatment of poisoning. Semin Dial 2006; 19: 402­407. 9. Feinfeld DA, Rosenberg JW, Winchester JF Three . controversial issues in extracorporeal toxin removal. Semin Dial 2006; 19: 358­362. 10. Ziesler TA, Lorentzen HR, Knapstad SE, Muan B. Has increased availability of paracetamol had any effects on inquiries received by the National Poisons Information Centre in Norway?Clin Toxicol 2007; 45: 368 (abstr.). 11. Rafstedt K, Swanhagen A, Irestedt B. Poisonings with paracetamol among adolescents in Sweden. Clin Toxicol 2007; 45: 349­350 (abstr.). 12. Winchester JF Gelfand MC, Helliwell M et , al. Extracorporeal treatment of salicylate or acetaminophen poisoning: is there a role?Arch Intern Med 1981; 141: 370­374. 8.

see original article on page 1262

Interstitial fibrosis: tubular hypothesis versus glomerular hypothesis

E I. Christensen1 and Pierre J. Verroust 1 rik

The pathogenesis of renal interstitial fibrosis leading eventually to renal failure is highly debatable. Whereas the so-called tubular hypothesis, involving an increased tubular uptake of potentially toxic substances that induce a variety of cytokines, growth factors, and profibrogenic factors, is based to a large extent on cell-culture studies, the glomerular hypothesis is based mainly on careful morphological observations. Unraveling the pathways appears to be extremely complex, but in vivo studies appear to offer the most reliable results.

Kidney International (2008) 74, 1233­1236. doi:10.1038/ki.2008.421

Most if not all glomerular diseases involving extracapillary injury progressively develop extensive brotic processes, leading to nephron destruction and terminal renal failure. Two hypotheses have been put forward to account for this evolution. e rst proposes that the primary event is tubular: the increased amount of protein that gains access to the proximal tubule,

1Department of Cell Biology, Institute of Anatomy,

University of Aarhus, Aarhus, Denmark Correspondence: Erik I. Christensen, Department of Cell Biology, Institute of Anatomy, Wilhelm MeyersAllé, Building 234, University of Aarhus, DK-8000 AarhusC, Denmark. E-mail: [email protected]

which results in increased protein tra cking in the proximal tubule cells, is toxic for the cells, thus triggering a number of in ammatory and brotic pathways. e second proposes that the primary event is glomerular: the formation of glomerular crescents leads to encroachment on the glomerular­tubular junction and subsequent tubular degeneration. Two recent studies provide additional data in this context. Motoyoshi et al.1 (this issue) induced massive glomerular proteinuria in a mouse model, mating mosaic megalin kidney knockout mice with a transgenic mouse, NEP25, in which podocytes


Kidney International (2008) 74

Teach i ng Case Repor t Negative anion gap and elevated osmolar gap due to lithium overdose

The case: A 65-year-old man was found in a state of clouded consciousness of unknown duration. At hospital his Glasgow Coma Scale score was 9. Naloxone and thiamine were administered. A CT head scan showed no acute injury. The serum anion gap was 1 mmol/L, and the osmolar gap 12.8 mOsmol/kg (Table 1). The patient was normoglycemic, and

Table 1: Result s of laborat ory t est s

results of urine and serum toxicology screens were positive for lithium; no other toxins were present. The lithium level was above 6 mmol/L, and the patient was subsequently transferred to our hospital for acute hemodialysis. On arrival, the patient's blood pressure was 91/64 mm Hg, heart rate 111 beats/min, respiratory rate 22 and temperature 35.6°C; the jugular venous pressure was not visible. His urine output over 6 hours was 2.4 L and dilute in appearance. Repeat blood work revealed an anion gap of ­2 mmol/L, an osmolar gap of 36 mOsmol/kg, a serum creatinine level of 89 µmol/L, a serum calcium level of 2.64 mmol/L

Pr act ice

and a lithium level of 14.5 mmol/L. The patient had a history of suicidal ideation, bipolar affective disorder and hypertension. His medications included hydrochlorothiazide and longterm lithium therapy. Aggressive rehydration was begun with 3 L of normal saline, as was conventional hemodialysis using a 1.8-m2 high-flux dialyzer at a blood pump speed of 300 mL/min and a dialysate flow rate of 750 mL/min. A bicarbonate bath dialysate was used. The lithium level rapidly fell to 4.7 mmol/L over

Box 1: Adverse effects of lithium Central nervous system · · · · · · · · · Alt ered level of consciousness Dysart hria Psychomot or ret ardat ion Vert igo Nyst agmus Tremor Parkinsonian movement s Seizures Pseudot umour cerebri

Test (normal range) Sodium, mmol/ L (135­145) Pot assium, mmol/ L (3.2­5.0) Chloride, mmol/ L (100­110) Bicarbonat e, mmol/ L (23­29) Creat inine, µmol/ L (< 99) Calcium, mmol/ L (2.20­2.62) Albumin, g/ L (35­45) Anion gap, mmol/ L (7­13) Lit hium, mmol/ L (0.6­1.2) Urea, mmol/ L (2­8) Plasma glucose, mmol/ L (3.8­7) Plasma osmolalit y, mOsm/ kg (275­295) Calculat ed osmolalit y, mOsm/ kg (275­295) Osmolar gap, mOsm/ kg (< 20) Phosphat e, mmol/ L (0.8­1. 4) Hemoglobin, g/ L (110­145) pH (7.35­7.45) Part ial pressure of carbon dioxide, mm Hg (35­45) Part ial pressure of oxygen, mm Hg (80­100)


Result s available from t ransferring hospit al 143 3.6 109 36 95 2.68 40 ­2 > 6* 5.2 4.0 308 295.2 12.8 -- -- -- -- -- Posit ive for lit hium only

Result s at present at ion 142 3.8 115 26 89 2.64 40 1 14.5 6.6 4.9 324 295.5 28.5 < 0.5 138 7.38 47 80 Posit ive for lit hium only

Dermatologic · Folliculit is · Alopecia Cardiovascular · · · · · · · · · · · · · · · · · · Cardiac arrhyt hmia Hypotension Bradycardia Syncope Hypo- or hypert hyroidism Goit er Hyperglycemia Hypercalcemia Hyperparat hyroidism Anorexia Nausea or vomit ing Diarrhea Met allic t ast e Excessive salivat ion Nephrogenic diabet es insipidus Glucosuria Chronic renal failure Prot einuria



Serum and urine t oxicology screen


Not e: The elect rolyt es were measured using t he Badebehring Dimension (colorimet ric).The osmolal it y was measured using t he freezing point , and t he plasma sample f or lit hium levels was collect ed using a nonheparized t ube. About 12 hours elapsed bet ween values obt ained at t he referring hospit al and t hose obt ained at our inst it ut ion. Toxicology t est s performed included screening for t oxic alcohols, acet ylsalicylic acid, acet aminophen, t heophylline, digoxin, opiat es, benzodiazepines and cocaine. *Exact value unavailable.



Mar ch 27, 2007





© 2007 Canadian Medical Association or its licensors

Pr act i ce

4 hours. Hemodialysis was continued for a total of 24 hours, and the patient's level of consciousness improved. Fortyeight hours after discontinuing dialysis, the lithium levels rebounded to more than 4 mmol/L, and the patient's speech became slurred. Continuous venovenous hemodiafiltration was performed at a blood flow rate of 100 mL/min, a dialysate flow rate of 1500 mL/min and a replacement fluid (75 mmol/L saline) flow rate of 1000 mL/min. Dialysis was continued for 40 hours. During this period, the patient's urine output was more than 4 L/d, and his speech returned to normal. After discontinuation of dialysis, the patient rapidly recovered. He was discharged from hospital 2 weeks later with no detected neurologic deficits. Lithium is highly effective in the treatment of bipolar disease, with success rates approaching 70%. However, because of the drug's narrow therapeutic window, toxic effects are common (Box 1). The most common manifestation of toxicity is altered mental status. Our patient also had a high urine output of 2.4 L in 6 hours, which suggests polyuria due to a concentrating defect. Depending on the length of lithium use, toxic effects can occur with levels as low as 2.5 mmol/L. Severe toxic effects have been reported in acute overdoses with levels of 5­ 9 mmol/L. Risk factors for lithium toxicity include the use of thiazide diuretics, renal insufficiency, congestive heart failure and volume depletion. The principles of management of lithium intoxication are outlined in Box 2. The mortality is as high as 25%, and 10% of survivors will have permanent neurologic deficits.1 The anion gap is a key diagnostic clue when approaching the differential diagnosis of toxidromes and metabolic acidosis. The formula is given in Box 3. Lithium is a positive charged ion with valence of 1 and electrochemical properties similar to those of sodium and potassium. Large quantities of positive cations in the plasma are balanced by the anions bicarbonate and chloride and can cause a negative anion gap because sodium, but not lithium, is included in the calculation. Our patient had only a mildly elevated calcium level with a normal albumin level. Of note, the severe lithium intoxication in this case resulted in a negative anion gap that was corrected with dialysis (Fig. 1). The osmolar gap is another useful diagnostic clue in cases of overdose. Common causes of an elevated osmolar gap and the formula are outlined in Box 4. In our patient, the osmolar gap was elevated at 36 mOsmol/kg. Other causes of elevation were excluded since the results of the toxicology screen were negative for alcohols, serum ketones and lactate and the patient had a normal lipid profile. We postulate that the high level of lithium with its anion, bicarbonate (from lithium carbonate), contributed to an increase in plasma osmolality. This is further supported by the patients' elevated bicarbonate level of 36 on presentation. The expected increase in osmolar gap would be 2 times the lithium level, or about 28 mOsmol/kg, which is similar to the level in our patient. Lithium has never been previously reported to lead to an elevation in the osmolar gap and should be included in the list of currently known causes. The combination

15 11 Anion gap 9 Lithium level 12

Box 2: Principles of management of lithium intoxication · Recognize clinical and biochemical feat ures of int oxicat ion · Decrease gast ric absorpt ion by means of whole-bowel irrigat ion · St op all furt her use of lit hium, diuret ics and nonst eroidal ant iinflammat ories · Begin aggressive rehydrat ion · Begin hemodialysis · Maint ain wat er balance

Box 3: Anion gap Calculation Anion gap = Na -- (chloride + bicarbonat e) The anion gap is the difference between measured cations and anions, with normal values falling between 7 and 13 mmol/ L. This difference is due to charges on plasma proteins, part icularly albumin, and must be adj ust ed downward in pat ient s with hypoalbuminemia. For every decrease in albumin of 10 g/ L, the anion gap decreases by about 2.5 mmol/ L. Differential diagnosis of a low anion gap · Hypercalcemia · Hypermagnesemia · Hyperkalemia · Cat ionic immunoglobulins (as in plasma cell dyscrasias) · Bromide int oxicat ion · Nit rat es · Lit hium

7 9 5 3 1 3 -1 -3 0 24 48 72 96 0 6

Time, h

Fig. 1: Inverse correlation between lithium level and anion gap over time. Of note, the initial anion gap of ­2 mmol/L corresponded to a lithium level of 14.5 mmol/L.



Mar ch 27, 2007





Lithium level, mmol/L

Anion gap, mmol/L

Pr act i ce


Int ermit t ent hemodialysis Cont inuous venovenous hemodiafilt rat ion

Box 4: Osmolar gap Calculation Osmolar gap = measured osmolalit y -- calculat ed osmolalit y = plasma osmolalit y --[(2 × Na) + plasma glucose + urea] Differential diagnosis of an elevated osmolar gap · · · · · · · · · · Isopropanolol N-propanolol Propylene glycol Et hylene glycol* Met hanol* Formaldehyde* Paraldehyde* Mannit ol Diet hyl et her ingest ion Lit hium overdose

Lithium level, mmol/L





0 0 24 48 72 96 120

Time, h

Fig. 2: Effects of intermittent hemodialysis and continuous venovenous hemodiafiltration on lithium levels. Time zero was arrival at our centre. Arrow indicates rebound in lithium levels that required initiation of continous venovenous hemodiafiltration.

*Denot es causes associat ed wit h an elevat ed anion gap met abolic acidosis.

of an elevated osmolar gap and decreased anion gap without metabolic acidosis should be considered highly suggestive of severe lithium intoxication after exclusion of severe hyperproteinemia, hyperlipidemia and mannitol ingestion. Lithium is absorbed through the gastrointestinal tract, with peak plasma levels occurring within 1­4 hours and steady state levels in 6 days. Lithium has a large volume of distribution of 0.6­ 0.9 L/kg, and its primary route of excretion is through the kidneys. Because of its large volume of distribution, lithium shifts into the intracellular compartment of cells. With long-term use, the intracellular concentration of lithium increases, which thereby results in an increased total body lithium load. The intracellular concentration is not reflected by the plasma level, which measures only the extracellular fluid concentration. In our case, assuming a volume of distribution close to 1 L/kg and complete gastric absorption, each 300-mg tablet will increase the plasma lithium level by 0.1 mmol/L. Therefore, a plasma lithium level of 14.5 mmol/L correlates with the ingestion of about 145 tablets.2 Intermittent hemodialysis is the treatment of choice for lithium intoxication in patients who are hemodynamically stable. In our case, hemodialysis was initiated at a high blood pump speed

of 300 mL/min, which achieved a measured lithium clearance of 262 mL/min (lithium clearance = blood pump speed [Qb] × [(lithium level arterial side ­ lithium level venous side)/ lithium level arterial side]). This high rate of clearance resulted in a dramatic decrease in the plasma lithium levels, from 14.5 to 4.7 mmol/L, in 4 hours (Fig. 2). Previous reports of intermittent hemodialysis for lithium removal achieved clearances of 94­170 mL/min with lower blood and dialysate flow rates.3,4 We stopped intermittent hemodialysis after 24 hours because our patient's cognitive status improved and his plasma lithium level fell to 1.8 mmol/L. Discontinuation of hemodialysis often results in a rebound of plasma lithium levels as intracellular lithium shifts to the extracellular space. Three days after the ingestion of lithium and 48 hours after hemodialysis was stopped, our patient's lithium level rebounded to more than 4 mmol/L. Continuous venovenous hemodiafiltration was then started, because of hemodynamic instability, and continued for 40 hours. Hazouard and associates previously demonstrated that lithium elimination with continuous renal replacement therapy linearly correlated with the volume of hemofiltration plus dialysate flow rate.5 Of note, lithium levels fell rapidly with the use of intermittent hemodialysis, whereas the use of continuous venCMAJ Mar ch 27, 2007 176(7) | 923

ovenous hemodiafiltration, with its slower blood flow rates, resulted in much slower lithium clearance. Unfortunately, our patient's hemodynamic status did not allow us to safely use intermittent hemodialysis, but it is much more effective at removing lithium from the blood in cases of intoxication. Manish M. Sood Robert Richardson Department of Medicine Division of Nephrology Toronto General Hospital University Health Network Toronto, Ont.

This article has been peer reviewed. Competing interests: None declared.


1. 2. Adityanjee, Munshi RK, Thanmpy A. The syndrome of irreversible lithium-effectuated neurotoxicty. Clin Neuropharmacol 2005;28:38-49. Henry GC. Lithium. In: Goldfrank LR, Flomenbaum NE, Lewin NA, et al, editors. Goldfrank's toxicologic emergencies. 6th ed. Stamford (CT): Appleton & Lange; 1998. p. 894. Fenves AZ, Emmett M, White MG. Lithium intoxication associated with acute renal failure. South Med J 1984;77:1472-4. Clendeninn NJ, Pond SM, Kaysen G, et al. Potential pitfalls in the evaluation of the usefulness of hemodialysis for the removal of lithium. J Toxicol Clin Toxicol 1982;19:341-52. Hazouard E, Ferrandiere M, Rateau H, et al. Continous veno-venous haemofiltration versus continous veno-venous haemodialysis in severe lithium selfpoisoning: a toxicokinetics study in an intensive care unit. Nephrol Dial Transplant 1999;14:1605-6.

3. 4.





retically, therefore, an elevated lactate concentration should not elevate the osmolar gap because the osmolar gap calculation accounts for sodium. However, elevations in the osmolar gap with lactic acidosis and shock have been consistently reported in both human and animal studies.2­4 There are 3 likely explanations for these observations. First, many reports have described elevations in the osmolar gap in patients who have prolonged stays in the intensive care unit with sepsis or organ hypoperfusion. Medications such as lorazepam, multivitamin preparations and nitroglycerin are often stored in propylene glycol, a solvent that is known to increase the osmolar gap and lead to lactic acidosis.5 Second, in alcoholic patients without detectable serum ethanol levels, endogenous compounds such as glycerol, acetone and acetone's metabolic by-products have been shown to elevate the osmolar gap.6 If these patients have concurrent liver damage, a type 2 lactic acidosis may be present because the liver fails to clear lactate. These 2 examples illustrate situations in which an elevated osmolar gap and elevated lactate concentration may be detected concurrently; this may explain the confusion in the literature. Lastly, in experimental settings, Schelling and colleagues found that the osmolar gap in a cohort of hospitalized patients with lactic acidosis was elevated (10.3 ± 2.0 mmol/kg) compared with that of control patients.2 It is felt that with lactic acidosis, cell breakdown leads to the release of other products of glycogen breakdown that contribute to the elevation of the osmolar gap. This contribution is relatively minor (generally leading to an osmolar gap of less than 25 mOsmol/kg), but it is detectable. Thus, we feel that an elevated lactate concentration does make a contribution to increasing the osmolar gap. Manish M. Sood MD Robert Richardson MD Department of Medicine Division of Nephrology Toronto General Hospital Toronto, Ont.

Competing interests: None declared.


1. 2. 3. 4. Sood MM, Richardson R. Negative anion gap and elevated osmolar gap due to lithium overdose. CMAJ 2007;176(7):921-3. Schelling JR, Howard RL, Winter SD, et al. Increased osmolar gap in alcoholic ketoacidosis and lactic acidosis. Ann Intern Med 1990;113:580. DiNubile MJ. Serum osmolality. N Engl J Med 1984;310:1609. Linden C, Lovejoy, F. Illnesses due to poisons, drug overdosage and envenomation. In: Harrison's principles of internal medicine. 14th ed. New York: McGraw-Hill; 1998. p. 2523-5. Chicella M, Jansen P, Parthiban A, et al. Propylene glycol accumulation associated with continuous infusion of lorazepam in pediatric intensive care patients. Crit Care Med 2002;30:2752-7. Braden GL, Strayhorn C, Germain M, et al. Increased osmolal gap in alcoholic acidosis. Arch Intern Med 1993;153:2377-80.



Lactate and the osmolar gap

Although the teaching case report in the March 27 issue on a negative anion gap and elevated osmolar gap resulting from lithium overdose1 is interesting, I identified the following concern. In the third paragraph from the end of the report, the authors listed lactate as one of the potential causes of an elevated osmolar gap that they excluded. It is unfortunate that they perpetuated this common misperception of the role of lactate. An elevated lactate concentration does not account for an elevated osmolar gap because the lactate is accounted for in the osmolality calculation by multiplying the sodium concentration by 2. Frances M. Rosenberg MD PhD Pathology and Laboratory Medicine St. Paul's Hospital Vancouver, BC

Competing interests: None declared.



In the July 17 issue of CMAJ, a map accompanying a news story should have identified Afghanistan's eastern and southern neighbour as Pakistan.


1. Kondro W. Afghanistan: Outside the comfort zone in a war zone. CMAJ 2007;177[2]:131-4.


In the Review article 1 in the May 22 issue of CMAJ, there was an error in Table 1. A hemorrhagic effusion should have a negative Gram's staining result and negative bacteria culture, and not positive as indicated.


1. Kherani RB, Shojania K. Septic arthritis in patients with pre-existing inflammatory arthritis. CMAJ 2007;176(11):1605-8.


1. Sood MM, Richardson R. Negative anion gap and elevated osmolar gap due to lithium overdose. CMAJ 2007;176(7):921-3.



[The authors respond:]

We thank Frances Rosenberg for her comment on our paper.1 The contribution of lactic acid to the osmolar gap is complex. Lactic acid ionizes; Rosenberg astutely mentions that the cation accompanying lactate is sodium. Theo-

In a recent article,1 the prevalence estimates for HIV and hepatitis C (HCV) in Canada have been reversed. They should read 0.18% for HIV and 0.8% for HCV.


1. Calzavara L, Ramuscak N, Burchell AN, et al. Prevalence of HIV and hepatitis C virus infections among inmates of Ontario remand facilities. CMAJ 2007;177(3):257-61.


CMAJ · August 28, 2007 · 177(5)

© 2007 Canadian Medical Association or its licensors


Intensive Care Med (2005) 31:189­195 DOI 10.1007/s00134-004-2521-0


Bruno MØgarbane Stephen W. Borron FrØdØric J. Baud

Current recommendations for treatment of severe toxic alcohol poisonings

Received: 2 July 2004 Accepted: 8 November 2004 Published online: 31 December 2004 Springer-Verlag 2004

International congress presentation: presented in part at the 23rd Congress of The European Association of Poisons Centers and Clinical Toxicologists, Rome, Italy, June 2003 B. MØgarbane ()) · F. J. Baud RØanimation MØdicale et Toxicologique, Hôpital Lariboisire, 2 rue Ambroise ParØ, 5010 Paris, France e-mail: [email protected] Tel.: +33-1-49959030 Fax: +33-1-49956578 S. W. Borron Department of Emergency Medicine, George Washington University School of Medicine and International Toxicology Consultants, LLC, Washington, D.C., USA

Abstract Background: Ethylene glycol (EG) and methanol are responsible for accidental, suicidal, and epidemic poisonings, resulting in death or permanent sequelae. Toxicity is due to the metabolic products of alcohol dehydrogenase (ADH) and aldehyde dehydrogenase. Conventional management of these intoxications consists of ethanol and hemodialysis. Fomepizole, a potent ADH inhibitor, has largely replaced antidotal ethanol use in France and two recent prospective U.S. trials definitively established its efficacy. Fomepizole appears safer than ethanol and while no comparative study of efficacy exists, fomepizole is recommended as the first-line antidote. Focus: Fomepizole, administered early in EG intoxication, prevents renal injury. In the absence of renal failure, EG clearance is rapid, avoiding the need for prolonged fomepizole administration. The long elimination half-life of methanol poisonings, with absent hemodialysis,

necessitates prolonged administration of fomepizole. In the U.S. trials, patients were dialyzed when plasma EG or methanol concentrations were 0.5 g/l. However, EG-poisoned patients treated with fomepizole prior to the onset of significant acidosis may not require hemodialysis. Indeed, fomepizole may also obviate the need for hemodialysis in selected methanol-poisoned patients, in the absence of neurological and ocular impairment or severe acidosis. When dialysis is indicated, 1 mg·kg·h continuous infusion of fomepizole should be provided to compensate for its elimination. Conclusions: Fomepizole is an effective and safe first-line recommended antidote for EG and methanol intoxication. In selected patients, fomepizole may obviate the need for hemodialysis. Keywords Methanol · Ethylene glycol · Acute poisoning · Fomepizole · Hemodialysis

Poisonings involving ethylene glycol (EG) and methanol are relatively uncommon, but remain important causes of suicide or epidemic poisonings, resulting in multiple deaths and serious sequelae [1]. Toxicity is related to the production of toxic metabolites by alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (AldDH) (Fig. 1). The accumulation of glycolate (in EG poisoning) or formate (in methanol poisoning) results in an anion gap metabolic acidosis. In addition, methanol may induce irreversible visual impairment, while EG causes acute renal

failure [2, 3]. Either alcohol may cause death. Recommended management includes: 1) supportive care; 2) infusion of sodium bicarbonate to correct metabolic acidosis, to increase renal elimination of glycolate and formate, and to inhibit precipitation of calcium oxalate crystals; 3) antidotes, such as a competitive ADH substrate (ethanol) or inhibitor (fomepizole) to block ADH metabolism of the toxic alcohol; and 4) intermittent dialysis to remove the toxic alcohol and its toxic metabolites, to correct acidosis, and, in the case of methanol


Table 1 European dosage regimen of fomepizole in ethylene glycol poisoning: fomepizole is administered every 12 h, by oral or intravenous route, according to plasma ethylene glycol concentrations.

Ethylene glycol plasma concentration g/l 6 3 1.5 0.75 0.35 0.1­0.3 mmol/l 96 48 24 12 5.6 1.6­5.5

Fomepizole (mg/kg) Loading dose 15 15 15 15 15 15 2nd dose T + 12 h 10 10 10 10 7.5 3rd dose T + 24 h 10 10 10 7.5 4th dose T + 36 h 10 10 7.5 5th dose T + 48 h 7.5 7.5 6th dose T + 60 h 5

poisonings, to shorten the course of hospitalization [4, 5]. Fomepizole [4-methylpyrazole (4MP)] is a potent inhibitor of ADH with limited toxicity. It has been successfully used in France since 1981 in EG [6, 7] and methanol poisonings [8]. No lethality or significant morbidity has occurred with either alcohol when patients were treated before significant toxic metabolism occurred; all patients recovered from their poisonings. Two recent U.S. multi-center prospective clinical trials confirmed fomepizole's efficacy [9, 10]. Rapid resolution of acidosis accompanied clinical improvement, with no new symptoms of poisoning after the initiation of therapy. Renal injury did not occur if fomepizole was administered early in EG intoxication. Treatment with fomepizole resulted in alteration of the toxicokinetics of both EG and methanol, with a prolongation of their elimination and a reduction in glycolate and formate formation. The objectives of this review were to examine the remaining indications for supplementation of fomepizole therapy by hemodialysis in toxic alcohol poisonings.

Fomepizole is a safe and effective antidote

Fomepizole pharmacokinetics have been extensively studied. Although mostly administered by the intravenous route, fomepizole is rapidly and almost completely absorbed orally. Approximately one-third of our published cases of EG and methanol poisoning received this antidote orally [7, 8]. Fomepizole's volume of distribution has been reported to be in the range of 0.6­1.0 l/kg. Its plasma protein binding is low. Fomepizole has three metabolites: 4-hydroxymethylpyrazole, the only active metabolite--with approximately 1/3 the potency of the parent compound--4-carboxypyrazole, and a glucuronide metabolite [11]. Fomepizole is virtually entirely eliminated by saturable hepatic metabolism, with a Km of 6 mol/l, a concentration always markedly exceeded during therapeutic use [12]. Fomepizole's in vitro inhibitory constant for human ADH is 0.2 mol/l. Its affinity for ADH is 500­1,000 times higher than that of ethanol. A plasma concentration of 10 mol/l inhibits formate accumulation in methanol-poisoned monkeys [11]. In the U.S. studies, complete inhibition was reached in each case

[9, 10], with plasma fomepizole concentrations exceeding the target concentration of 10 mol/l. Elimination is characterized by dose-dependent, non-linear zero order kinetics, with a rate of 4­15 mol·l·h [12, 13]. While fomepizole blocks ADH activity, repeated doses induce cytochrome P450, and particularly cytochrome P450 2E1, resulting in an increase in its own elimination rate after 48 h of treatment [12]. Thus, an increase to 15 mg/kg in patients treated over 48 h is currently recommended by practice guidelines developed by the American Academy of Clinical Toxicology, to account for its enhanced metabolism [14, 15]. However, it is noteworthy that fomepizole is expensive and a dosage regimen using the minimal effective cumulative dose remains to be determined. The French dosing regimen consists of a loading dose of 15 mg/k followed by 10 mg/ kg every 12 h until the alcohol concentration is <0.2 g/l. Borron et al. reported on a series of EG poisonings successfully treated with tapering doses of fomepizole [7]. Based on this clinical experience, a different dosage regimen is recommended in Europe (Table 1). During hemodialysis, fomepizole is extracted with a mean extraction coefficient of 5043%, a mean hemodialysis clearance of 9933 ml/min, and a mean hourly extracorporeal extraction of 8331% [16, 17]. Although not systematically validated, two different protocols were proposed to compensate for fomepizole loss in the dialysate. The U.S. manufacturer recommends a reduction in the dosing interval from 12 h to 4 h, while European authors have proposed a continuous IV infusion of 1­ 1.5 mg·kg·h for the entire duration of the hemodialysis session following the initial loading dose [16, 17]. Since the duration of hemodialysis depends on the initial plasma EG or methanol concentration, the continuous infusion protocol appears better adapted than a shortening of the dosing interval. This regimen appears simpler and is sufficient to maintain fomepizole above the minimally effective concentrations (>10 mol/l). However, the dosage of fomepizole during continuous veno-venous hemodiafiltration or continuous arteriovenous hemodialysis and the pharmacokinetics in patients with liver failure are not known. In patients with normal renal function, the renal clearances of EG and methanol are reported to be about 20 ml/min and 1 ml/min, respectively [14, 15].


Fig. 1 Pathogenesis of methanol and ethylene glycol poisonings. The principal symptoms are related to the toxic metabolites resulting from degradation of the alcohol by alcohol (ADH) and aldehyde (AldDH) dehydrogenases.

Fomepizole administration results in first-order elimination of the toxic alcohols with a prolonged half-life, respectively 20 h and 54 h, for EG and methanol [9, 10, 18]. The contraindications of fomepizole administration are previously known allergy to pyrazole derivates (such as phenylbutazone) and pregnancy. Case series and clinical trials indicate that fomepizole is well tolerated at therapeutic doses, although headache (12%), nausea (11%), dizziness (7%), and injection site irritation were reported [9, 10]. Other adverse reactions included rash, lymphangitis, vomiting, diarrhea, abdominal pain, tachycardia, hypotension, vertigo, slurred speech, inebriation, fever, mild transient eosinophilia, and slight increases in hepatic transaminases, none requiring discontinuation of therapy. In human volunteers, therapeutic doses of fomepizole (10­20 mg/kg) caused a 40% reduction in the rate of elimination of ethanol (0.5­0.7 g/kg). Conversely, ethanol was demonstrated to inhibit fomepizole metabolism, consequently increasing its blood concentration [13]. Thus, previous ethanol intake or administration before fomepizole therapy does not decrease the efficiency of the antidotal therapy. However, the clinical relevance of the effect of fomepizole on ethanol elimination remains to be determined. Although not formally studied in children,

several pediatric cases suggest clinical efficacy without severe side effects [19, 20], other than nystagmus [21]. Therapeutic concentrations are reliably achieved with the proposed dosing regimens and no severe central nervous system or liver toxicity or hypoglycemia occurs with fomepizole, in contrast with ethanol therapy. Ethanol therapy requires blood concentration monitoring and intravenous glucose administration in an intensive care unit (ICU), especially for pediatric poisonings [22]. Monitoring of therapeutic concentrations of fomepizole does not appear necessary. Therefore, considering its demonstrated efficacy and safety, we recommend fomepizole as a firstline antidote. In the case of suspicion of toxic alcohol ingestion or metabolic acidosis with elevated anion gap unexplained by an equivalent increase in serum lactate concentration, we suggest the administration of a loading dose of fomepizole while awaiting definitive diagnosis.

Hemodialysis and toxic alcohol poisoning

Hemodialysis is considered to be an integral part of the treatment of toxic alcohol poisonings to expedite removal of the alcohol and its metabolites, thus reducing the duration of antidotal treatment. Ethylene glycol and methanol are efficiently cleared by dialysis (Table 2). The traditional end-point of dialysis is a plasma concentration of the toxic alcohol <0.2 g/l, with resolution of acid-base disturbances and the osmolar gap [14, 15]. More recently, a simple method to estimate the required dialysis time was validated [23]. The required time (RDT) to reach a 5 mmol/l toxicant concentration is estimated as follows: RDT (h) = [V.Ln(5/A)]/0.06 k, with V (l) representing the Watson estimation of total body water, A (mmol/l) the initial toxicant concentration, and k (ml/min) 80% of the manufacturer-specified dialyser urea clearance. In this study, there was no difference between the predicted hemodialysis duration (7.61.9 h) and the actual duration employed using hourly concentration sampling (7.41.9 h).

Table 2 Toxicokinetic parameters of ethylene glycol and methanol and their modifications in relation to hemodialysis or antidotal treatment. Ethylene glycol Lethal dose Molecular weight Distribution volume Elimination Total body clearance Renal clearancea Half-life + fomepizole + ethanol Half-life under dialysis Dialysis clearanceb Main metabolite clearancec

a b c

Methanol 1.2 ml/kg (risk of blindness: 10­15 ml) 32.04 g 0.6­0.77 l/kg Zero order 11 ml/min 1 ml/min ~54 h 30­52 h 197­219 min 95­176 ml/min 223 ml/min

1.4­1.6 ml/kg 62.4 g 0.5­0.8 l/kg Zero or 1st order 70 ml/min 17­39 ml/min ~20 h 11­18 h 150­210 min 192­210 ml/min 254 ml/min

Dependent on renal function Dependent on blood flow during hemodyalisis Glycolate regarding ethylene glycol and formate regarding methanol


Table 3 Revised recommendations for hemodialysis in ethylene glycol and methanol poisoning [10, 11, 16, 17, 27].

Ethylene glycol poisoning: Arterial pH <7.109 or 7.25­7.30 [16] Drop in arterial pH >0.05 resulting in a pH outside the normal range despite bicarbonate infusion Inability to maintain arterial pH >7.3 despite bicarbonate therapy Decrease in bicarbonate concentration >5 mmol/l, despite bicarbonate therapy Renal failure (serum creatinine concentration >265 mol/l or rise in the serum creatinine by >90 mol/l [10]) Deteriorating vital signs despite intensive supportive care Initial plasma e.g., concentration 0.5 g/l (8.1 mmol/l) unless fomepizole is administered in the absence of both renal dysfunction and significant acidosisa Methanol poisoning: Initial arterial pH <7.109 or 7.25­7.30 [16] Drop in arterial pH >0.05 resulting in a pH outside the normal range despite bicarbonate infusion Inability to maintain arterial pH >7.3 despite bicarbonate therapy Decrease in bicarbonate concentration >5 mmol/l, despite bicarbonate therapy Visual impairment Renal failure Deteriorating vital signs despite intensive supportive care Initial plasma methanol concentration 0.5 g/l (15.6 mmol/l)a Rate of methanol decline <0.1 g/l (3.1 mmol/l) per 24 h


The recommendation for routine hemodialysis on the basis of serum concentrations alone has been recently called into question

Hemodialysis and ethylene glycol poisoning

Hemodialysis is typically recommended in case of severe or refractory metabolic acidosis, deteriorating vital signs, and at the onset of acute renal failure (Table 3). A serum EG concentration above 0.5 g/l (8.1 mmol/l) has been considered a symptom-independent indication, although this is debated [14]. In the U.S. study, 17 of 19 EG-poisoned patients treated with fomepizole were hemodialysed [9]. Among them, 18 survived, whereas only one died secondary to a myocardial infarction. All patients who developed renal injury had admission plasma glycolate concentrations >0.98 g/l (12.9 mmol/l). Renal elimination and hemodialysis are the only significant routes of EG elimination, as long as fomepizole concentrations are maintained well above 10 mol/l [18]. Hemodialysis effectively clears glycolate, with an elimination half-life of 155474 min, compared to the spontaneous elimination half-life of 625474 min [24]. In a retrospective study, we demonstrated the lack of requirement for systematic dialysis in the management of EG poisoning treated with fomepizole [7]. We described 11 significantly EG-poisoned patients, among whom 21% presented with coma, 34% metabolic acidosis, and 11% an initial plasma creatinine >110 mol/l. Hemodialysis was performed in only three of these 11 patients, two with renal insufficiency and acidosis and one with a very high EG concentration (8.27 g/l). Among the seven patients with normal renal function, no subsequent deterioration was noted. Only one patient died with severe multiorgan failure, the onset of which preceded fomepizole administration. Patients who were dialyzed were significantly more acidotic than those who were not. In summary, patients treated with fomepizole prior to the onset of

significant acidosis did not require hemodialysis. An EG concentration above 0.5 g/l (8.1 mmol/l) should no longer be considered as an independent criterion for hemodialysis in patients treated with fomepizole [25]. The recommended dialysis criteria are currently significant metabolic acidosis, renal failure, electrolyte imbalances unresponsive to conventional therapy, and deteriorating vital signs despite intensive supportive care [14]. Initial serum glycolic acid concentration appears to be a good indicator for hemodialysis; however, it is not readily available in most hospitals. Initial glycolic acid >10 mmol/l predicts acute renal failure, with a sensitivity of 100%, a specificity of 94% and an efficiency of 98% [26]. In a retrospective study of 41 EG-poisoned patients, dialysis was unnecessary, regardless of EG level, if glycolic acid was 8 mmol/l in patients receiving antidote. Anion gap >20 mmol/l or pH <7.30, but not EG concentration, were predictive of acute renal failure [26].

Hemodialysis and methanol poisoning

In methanol poisonings, due to its long elimination halflife, antidote administration clearly must be prolonged, whereas normal renal clearance of EG appears sufficient to avoid a prolonged course of fomepizole. The usual criteria for hemodialysis include severe acidosis, the presence of visual impairment or a plasma methanol concentration >0.5 g/l (15.6 mmol/l) (Table 3). In an U.S. study, seven of 11 methanol-poisoned patients treated with fomepizole were also hemodialysed [10]. Among these, nine survived, whereas two, with the most elevated formic acid concentrations, died from brain anoxia. Moreover, in other reported methanol poisonings treated


with fomepizole, hemodialysis was systematically employed [27, 28]. Low pH, bicarbonate, and elevated anion gap correlate independently with formate concentration [29]. However, although dialysis clears formate, surprisingly, it may not significantly enhance endogenous elimination (half-life: 15037 min versus 20590 min) [29], although this is debated [30]. We treated an asymptomatic 35-year-old patient who refused dialysis for combined methanol (1.46 g/l) and isopropanol (0.39 g/ l) poisoning [31]. Fomepizole (16 doses, cumulative dose: 96.6 g) appeared effective in blocking the toxic metabolism. In an outbreak of epidemic methanol poisoning in Cambodia, numerous patients were treated with intravenous fomepizole alone, as hemodialysis was not available. While follow-up was limited, no cases of recurrent or worsening toxicity were observed in this series [personal communication, Stephen W. Borron]. In poisonings involving high methanol concentrations, without severe acidosis or visual impairment, patients have been successfully treated by prolonged repeated doses of fomepizole without dialysis. We treated four patients with methanol levels >0.5 g/l with only fomepziole without hemodialysis [8]. They recovered without sequelae. However, in this retrospective analysis of 14 methanolexposed patients, metabolic acidosis was significantly more severe among patients undergoing hemodialysis, suggesting that they were more severely intoxicated. Visual impairment is traditionally considered an absolute indication for dialysis. Two case reports suggest that this recommendation is reasonable. A 42-year-old man, with central blindness completely recovered after combined fomepizole and hemodialysis [32]. A 60-yearold man, with blurred vision and alteration in his evoked potentials examinations, experienced a complete reversal of his visual impairment within 20 h after combined fomepizole and hemodialysis [33]. Moreover, fomepizole appeared safe in patients exhibiting retinal toxicity, despite its potential to inhibit retinol dehydrogenase (ADH isoenzyme, essential to vision) [32]. Recent recommendations limit dialysis indications to severe acidosis, visual signs or symptoms, deteriorating vital signs despite intensive care, renal failure, significant electrolyte disturbance unresponsive to conventional therapy, or serum methanol concentration 0.5 g/l [15]. Additional clinical experience with prolonged fomepizole administration may obviate the need to dialyze patients on the basis of elevated serum methanol concentration alone. After initial hemodialysis, ocular abnormalities may persist and should not thus be considered as an indication for continued dialysis.

plying principles of evidence-based medicine would justify such recommendations now, given the significant experience with fomepizole and dialysis [25]. While a comparison of fomepizole with ethanol (+/ hemodialysis) would be of interest, such a study has not and likely will not be done for a variety of reasons. Nonetheless, until it is demonstrated that ethanol therapy results in equivalent outcomes, it is difficult not to recommend fomepizole. There are frequent references to the minimal cost of parenteral ethanol in comparison with the relatively high cost of fomepizole. Such comparisons ignore the critical issue of laboratory costs for monitoring serum ethanol and blood glucose, the increased nursing care required for inebriated patients, and the requirement for intensive care (which may not be necessary in patients receiving fomepizole, in the absence of extant toxicity). Considering the high cost of fomepizole (about $1,000 per gram), smaller hospital centers that only occasionally see EG or methanol poisoning, might prefer continuing to stock inexpensive and readily available parenteral ethanol. However, it should be kept in mind that the suggested shelf life of fomepizole is 3 years and that, in some cases, the manufacturer will replace it at no charge after this period, rendering it economical even for smaller emergency departments to have this antidote in their armamentarium. Why is it worthwhile to confirm that fomepizole may obviate hemodialysis under certain conditions? First, there is a significant downside to the use of hemodialysis: it is not universally available, rendering it difficult in case of epidemic poisonings. It represents an invasive technique with risks of adverse effects. Moreover, some data suggest that it does not modify formate kinetics (elimination half-life). Furthermore, hemodialysis of poisoned patients often requires hospitalization in an ICU. If sig-

Critical analysis of the role of hemodialysis

Although ethanol and hemodialysis for many years constituted the recommended therapy, it is unlikely that apFig. 2 Proposed algorithm for treatment of EG and methanol-poisoned patients. This algorithm is based on series and case reports.


nificant toxicity and hemodialysis can be avoided by the early administration of fomepizole, ICU admissions may be limited to a relatively brief (24 h) period of observation (Fig. 2). There are also advantages to the use of fomepizole in comparison with ethanol: fomepizole is a more potent ADH inhibitor with a wider therapeutic index, a longer duration of action, easier dosing, and more predictable kinetics. There is no need for blood concentration monitoring. Treatment is well tolerated, even during prolonged administration (up to 8 days), whereas there are no similar data concerning ethanol. Pancreatitis, seen after certain cases of methanol poisoning, has been attributed to prolonged `therapeutic' administration of ethanol [34]. Thus, ethanol, in our estimation, should be administered only when fomepizole is unavailable or contraindicated. Given its safety, especially in patients who may subsequently be found not to be poisoned with toxic alcohols, fomepizole permits a margin of diagnostic error. In selected exposed patients, fomepizole may obviate the need for hemodialysis. However, the risks, costs, and inconvenience of prolonged hospitalization and the cost of fomepizole must be weighed against those of hemodialysis. Keeping patients with high serum methanol concentrations monitored in an ICU for a long period is considered by some authors as untenable [15]. Whether these patients, in the absence of initial toxicity, actually require prolonged intensive care monitoring has yet to be determined, however.

Other experiences with fomepizole in alcohol and glycol poisonings

Fomepizole has been used to treat other toxic alcohol poisonings, including diethylene and triethylene glycols [35], methanol and isopropanol [31], butoxyethanol [36], and 1,4 butanediol [37] poisonings. In one case of diethylene glycol poisoning, a patient was treated with combined fomepizole and hemodialysis [38]. Fomepizole inhibits the accumulation of acetaldehyde in disulfiram reactions [39], attenuating facial flushing, tachycardia, and vasodilatation. These cases serve solely as examples of potential indications for fomepizole. We must underscore that before fomepizole or any other antidote is employed in the case of a toxic alcohol exposure, the metabolism of that alcohol should be understood and the antidote's safety and efficacy for that particular treatment demonstrated. Such an understanding will avoid unintended blockade of detoxifying metabolism or induction of activating metabolism.


Fomepizole appears safe and effective in preventing or diminishing EG and methanol toxicity. While antidotal therapy without hemodialysis appears to be efficacious in a number of cases of uncomplicated poisonings, further experience is needed to clearly define the indications for associated hemodialysis.


1. Watson WA, Litovitz TL, Rodgers GC Jr, Klein-Schwartz W, Youniss J, Rose SR, Borys D, May ME (2003) 2002 annual report of the American Association of poison control centers toxic exposure surveillance system. Am J Emerg Med 21:353­421 2. Hylander B, Kjellstrand CM (1996) Prognostic factors and treatment of severe ethylene glycol intoxication. Intensive Care Med 22:546­552 3. Liu JJ, Daya MR, Carrasquillo O, Kales SN (1998) Prognostic factors in patients with methanol poisoning. J Toxicol Clin Toxicol 36:175­181 4. Jacobsen D, McMartin KE (1997) Antidotes for methanol and ethylene glycol poisoning. J Toxicol Clin Toxicol 35:127­143 5. MØgarbane B, Baud F (2003) Is there a remaining place for hemodialysis in toxic alcohol poisonings treated with fomepizole? J Toxicol Clin Toxicol 41:396­397 [abstr] 6. Baud FJ, Galliot M, Astier A, Bien DV, Garnier R, Likforman J, Bismuth C (1988) Treatment of ethylene glycol poisoning with intravenous 4methylpyrazole. N Engl J Med 319:97­ 100 7. Borron SW, MØgarbane B, Baud FJ (1999) Fomepizole in treatment of uncomplicated ethylene glycol poisoning. Lancet 354:831 8. MØgarbane B, Borron SW, Trout H, Hantson P, Jaeger A, Krencker E, Bismuth C, Baud FJ (2001) Treatment of acute methanol poisoning with fomepizole. Intensive Care Med 27:1370­1378 9. Brent J, McMartin K, Phillips S, Burkhart KK, Donovan JW, Wells M, Kulig K (1999) Fomepizole for the treatment of ethylene glycol poisoning. Methylpyrazole for Toxic Alcohols Study Group. N Engl J Med 340:832­ 838 10. Brent J, McMartin K, Philipps S, Aaron C, Kulig K, Methylpyrazole for Toxic Alcohols Study Group (2001) Fomepizole for the treatment of methanol poisoning. N Engl J Med 344:424­429 11. McMartin KE, Hedström KG, Tolf BR, Ostling-Wintzell H, Blomstrand R (1980) Studies on the meatbolic interactions between 4-methylpyrazole and methanol using the monkey as an animal model. Arch Biochem Biophys 199:606­614 12. Jacobsen D, Barron SK, Sebastian CS, Blomstrand R, McMartin KE (1989) Non-linear kinetics of 4-methylpyrazole in healthy human subjects. Eur J Clin Pharmacol 37:599­604 13. Jacobsen D, Sebastian CS, Dies DF, Breau RL, Spann EG, Barron SK, McMartin KE (1996) Kinetic interactions between 4-methylpyrazole and ethanol in healthy humans. Alcohol Clin Exp Res 20:804­809


14. Barceloux DG, Krenzelok EO, Olson K, Watson W (1999) American Academy of Clinical Toxicology practice guidelines on the treatment of ethylene glycol poisoning. J Toxicol Clin Toxicol 37:537­560 15. Barceloux DG, Bong GR, Krenzelok EP, Cooper H, Vale JA, American Academy of Clinical Toxicology ad Hoc Committee on the Treatment Guidelines for Methanol Poisoning (2002) American Academy of Clinical Toxicology practice guidelines on the treatment of methanol poisoning. J Toxicol Clin Toxicol 40:415­446 16. Faissel H, Houze P, Baud FJ, Scherrmann JM (1995) 4-methylpyrazole monitoring during hemodialysis of ethylene glycol intoxicated patients. Eur J Clin Pharmacol 49:211­213 17. Jobard E, Harry P, Turcant A, Roy PM, Allain P (1996) 4-methylpyrazole and hemodialysis in ethylene glycol poisoning. J Toxicol Clin Toxicol 34:379­ 381 18. Sivilotti MLA, Burns MJ, McMartin KE, Brent J (2001) Toxicokinetics of ethylene glycol during fomepizole therapy: implications for management. Ann Emerg Med 36:114­125 19. Martin Caravati E, Heileson HL, Jones M (2004) Treatment of severe pediatric ethylene glycol intoxication without hemodialysis. J Toxicol Clin Toxicol 42:255­259 20. Brown MJ, Shannon MW, Woolf A, Boyer EW (2001) Childhood methanol ingestion treated with fomepizole and hemodialysis. Pediatrics 108:77­79 21. Benitez JG, Swanson-Biearman B, Krenzelok EP (2000) Nystagmus secondary to fomepizole administration in a pediatric patient. J Toxicol Clin Toxicol 38:795­798

22. Roy M, Bailey B, Chalut D, SenØcal PE, Gandreault P (2003) What are the adverse effects of ethanol used as an antidote in the treatment of suspected methanol poisoning in children. J Toxicol Clin Toxicol 41:155­161 23. Hirsch DJ, Jindal KK, Wong P, Fraser AD (2001) A simple method to estimate the required dialysis time for cases of alcohol poisoning. Kidney Int 60:2021­ 2024 24. Moreau CL, Kerns W II, Tomaszewski CA, McMartin KE, Rose SR, Ford MD, Brent J (1998) Glycolate kinetics and hemodialysis in ethylene glycol poisoining. J Toxicol Clin Toxicol 36:659­666 25. Watson WA (2000) Ethylene glycol toxicity: closing in on rational, evidence-based treatment. Ann Emerg Med 36:139­141 26. Porter WH, Rutter PW, Bush BA, Papas AA, Dunnington JE (2001) Ethylene glycol toxicity: the role of serum glycolic acid in hemodialysis. J Toxicol Clin Toxicol 39:607­615 27. Hantson P, Wallemacq P, Brau M, Vanbinst R, Haufroid V, Mahieu P (1999) Two cases of acute methanol poisoning partially treated by oral 4methylpyrazole. Intensive Care Med 25:528­531 28. Burns MJ, Graudins A, Aaron CK, McMartin K, Brent J (1997) Treatment of methanol poisoning with intravenous 4-methylpyrazole. Ann Emerg Med 30:829­832 29. Kerns W 2nd, Tomaszewski C, McMartin K, Ford M, Brent J, META Study Group (2003) Methylpyrazole for toxic alcohols: formate kinetics in methanol poisoning. J Toxicol Clin Toxicol 41:257­258 30. Yip L, Jacobsen D (2002) Endogenous formate elimination and total body clearance during hemodialysis. J Toxicol Clin Toxciol 40:137­143

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An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose

P I Dargan, C I Wallace and A L Jones Emerg Med J 2002 19: 206-209

doi: 10.1136/emj.19.3.206

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An evidence based flowchart to guide the management of acute salicylate (aspirin) overdose

P I Dargan, C I Wallace, A L Jones


See end of article for authors' affiliations

Emerg Med J 2002;19:206­209


Correspondence to: Dr P Dargan, National Poisons Information Service, Guy's and St Thomas' NHS Trust, Avonley Road, London, SE14 5ER, UK; [email protected] Accepted for publication 29 October 2001


Objective: To develop a flowchart to be used as a tool to guide clinicians step by step through the management of salicylate poisoning. Methods: A comprehensive literature search was carried out. Results: The evidence base was used to develop a management flowchart that guides the clinician through the three main steps in caring for the patient with salicylate poisoning: preventing further absorption, assessing the severity of poisoning and, where appropriate, increasing elimination. Conclusions: Salicylate poisoning can result in severe morbidity and mortality and this flowchart provides an evidence based guideline that will guide clinicians through the management of patients presenting to the emergency department with salicylate poisoning.

lthough the overall mortality in salicylate poisoning is low, such figures can be very deceptive as severe poisoning may cause metabolic acidosis, convulsions, coma, hyperpyrexia, pulmonary oedema, and renal failure.1 Death can occur in 5% of patients who have such features of severe poisoning and is attributable to cardiac arrest or multiple complications after severe brain damage.1­3 Critically, in severe salicylate poisoning, delay in diagnosis was associated with a mortality of 15% compared with a much lower rate in those patients in whom early diagnosis and initiation of treatment was made.4 The current problem is that because salicylate poisoning is not seen so commonly, through lack of familiarity, medical and nursing staff may underestimate the severity of poisoning or fail to administer sufficiently vigorous treatments early enough to prevent morbidity and mortality (NPIS data, not shown). Once the severity of poisoning is recognised, management is a success story for clinical toxicology as over the past 40 years techniques to reduce the absorption of salicylate and increase its elimination have been developed. This evidence based flowchart has been developed to help guide decision making in salicylate poisoning. It is a guide however, not a protocol and individual decisions will still need to be made for each patient. Further advice on the management of salicylate poisoning is also always available from a poisons centre (in the UK the single national number, 0870 600 6266, will connect you to your local poisons centre)



There is no antidote to salicylate poisoning and management is directed towards preventing further absorption and increasing elimination of the drug in patients with features of moderate or severe intoxication. Prevention of further absorption A study on volunteers taking 1.5 g aspirin comparing activated charcoal, emesis, and gastric lavage had several limitations; salicylate elimination was followed up for only 24 hours, the analytical method used underestimated some salicylate metabolites, and plasma salicylate concentrations were not measured.5 Like similar volunteer studies in other drugs it does not accurately reflect the effect of treatment regimens in poisoned patients, but none the less taken with the other evidence shown in figure 1, it provides some rationale to support the use of activated charcoal within one hour of an overdose.6 Repeated doses of activated charcoal may have the added advantage of shortening the elimination half life of salicylates.7 This study is controversial in clinical toxicology because the charcoal administered in this study contained bicarbonate (Medicoal) but in our view its implications have been too readily dismissed.8 9 A study in adult volunteers given 1.9 g of aspirin showed that three, four hourly 50 g doses of charcoal resulted in a significant decrease in salicylate absorption when compared with one or two doses of charcoal.10 Aspirin forms concretions within the stomach 11 12 and it may be important to recoat surfaces of such concretions with charcoal to reduce ongoing absorption. The administration of a second dose of activated charcoal is of particular value in adults who have ingested substantial quantities of an enteric coated or sustained release preparation. Gastric decontamination in salicylate poisoning remains controversial even among toxicologists.13 However, we would advocate that patients with salicylate poisoning are given repeat doses of activated charcoal (four hourly doses of 50 g in adults, 1 g/kg body weight in children) until the salicylate level peaks to minimise delayed absorption of salicylates. Assessing the severity of salicylate poisoning The serum salicylate should be determined on admission provided that more than four hours have elapsed from the time of ingestion of the overdose. Measurements made before this


A literature search was carried out using Medline (1966­4/ 2000), Toxline (1966­4/2000) and EMBASE (1988­4/2000). The following terms were used: (*aspirin OR exp salicylate$.mp) AND (exp poisoning OR *overdose$.mp). No limits were placed. Using this evidence base, an algorithmic flowchart was constructed to guide the clinician through the management of salicylate poisoning in a stepwise fashion.


The results are shown in figure 1, which is a flowchart for management guidance in salicylate poisoning and supporting references from the literature.

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Management of acute salicylate (aspirin) overdose 207

Note: some salicylate preparations contain other agents such as opiates, paracetamol and caffeine. This flowchart deals only with the management of the salicylate component; the other agents need separate consideration


Gastric lavage24 25 if sure of dose and time of ingestion. Ensure that the airway is protected

< 1 hour

When taken?

> 500 mg/kg26 27

Dose taken?

< 125 mg/kg and asymptomatic26 27

Discharge patient if sure of dose Advise to return if develops any symptoms, particularly vomiting, tinnitus, sweating

Before the patient is discharged an assessment of their mental state and risk of repeated episodes of deliberate self harm should be carried out, ideally by a psychiatrist or psychiatric liaison nurse

! 125 mg/kg or unknown26 27 > 1 hour 50 g Oral activated (children 1 g/kg bodyweight) Ensure that the airway is protected charcoal5 6 28­30

Haemodialysis + Give sodium bicarbonate (cautious with volume if anuric)1 11 22


Does the patient have any of the severe clinical features?

Severe clincial features1: Coma, convulsions Acute renal failure Pulmonary oedema If these develop at any stage: 1 Resuscitate i.e airway, breathing, circulation 2 Check ABGs 3 Discuss with local poisons unit and ITU 4 Consider haemodialysis

Conversion factors for plasma salicylate concentration: - to convert mmol/l to mg/l divided by 0.0072 - to convert mg/l to mmol/l multiply by 0.0072

No Rehydrate the patient and take blood for salicylate level, U&E, FBC, INR (at least 4 hours after ingestion) ABG should be checked in symptomatic cases Check blood results

Metabolic acidosis? i) If arterial pH < 7.3, treat with 1 ml/kg 8.4% sodium bicarbonate iv to increase pH to 7.4 ii) If arterial pH < 7.2, consider haemodialysis


Is this the first salicylate level?


Before the patient is discharged an assessment of their mental state and risk of repeated episodes of deliberate self harm should be carried out, ideally by a psychiatrist or psychiatric liaison nurse.

NOTE: · Children (< 12 y and the elderly (> 65 y) are more susceptible to the effects of salicylate poisoning and tend to get more severe clinical effects at lower blood salicylate concentrations · Not all of the features described need to be present for each of the classifications of mild, moderate or severe poisoning. The plasma salicylate concentration needs to be interpreted in the context of the patient's clinical features and degree of metabolic acidosis. Clinical features are more important in grading the severity of salicylate poisoning

No Oral activated charcoal:7 8 10 31 32 - Adults 50 g - Children 1 g/kg

Has the salicylate level peaked? (ie. is the current level less than the previous level)


Discharge patient Advise to return if develops any symptoms, particularly vomiting, tinnitis, sweating


Is the peak level < 300 mg/l (adults) or < 200 mg/l (children/elderly)?


Salicylate level: - Adults < 300 mg/l - Children/elderly < 200 mg/l Clinical features: Patient asymptomatic

Mild poisoning: Salicylate level: - Adults 300­600 mg/l - Children/elderly 200­450 mg/l Clinical features: Lethargy, nausea, vomiting, tinnitus, dizziness

Moderate poisoning2 16: Salicylate level: - Adults 600­800 mg/l - Children/elderly 450­700 mg/l Clinical features: Mild features + tachypnoea, hyperpyrexia, sweating, dehydration, loss of coordination, restlessness

Severe poisoning1 22: Salicylate level: - Adults > 800 mg/l - Children/elderly > 700 mg/l Clinical features: Hypotension, significant metabolic acidosis after rehydration, renal failure (oliguria), CNS features e.g. hallucinations, stupor, fits, coma

Rehydrate with oral fluids

Rehydrate with oral or intravenous fluids

Urinary alkalinisation11 16 22 (see box for details)

Haemodialysis1 11 22 + Give sodium bicarbonate (cautious with volume if anuric)

Monitor urine output and fluid balance carefully Repeat salicylate level every 3 hours until a peak concentration is reached (this can be as late as 12 hours after ingestion, particularly with enteric coated aspirin)17 18 19

Urinary alkalinisation Adults: Give 1 of 1.26% sodium bicarbonate with 20 to 40 mmol potassium as an iv infusion over 3 hours. Children: Dilute 1 ml/kg 8.4% sodium bicarbonate in 10 ml/kg sodium chloride solution and add 1 mmol/kg potassium. This should be given at a rate of 2 ml/kg/h as an iv infusion. Check urinary pH hourly, aiming for a pH of 7.5­8.5; the rate of sodium bicarbonate administration given above will need to be increased if the urine pH remains < 7.5. Check U&E every 3 hours, the serum potassium should be kept in the range 4.0 to 4.5

Figure 1

Flowchart for management guidance in salicylate poisoning (numbers in superscripts relate to the supporting references).

time are difficult to interpret. It is important to repeat the measurement to make sure the salicylate concentration is not continuing to rise because of continued absorption.14 In adults or children, plasma concentrations six hours after an overdose very roughly correlate with toxicity as follows 2 15: 300­500 mg/l (mild toxicity)

500­700 mg/l (moderate toxicity) >750 mg/l (severe toxicity) The presence of symptoms and signs and the degree of acidosis should be considered when interpreting the plasma salicylate concentration and deciding upon management.2 4 The reason that the arterial pH needs to be taken into account

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208 Dargan, Wallace, Jones

when interpreting a plasma salicylate concentration is that in the presence of acidaemia, more salicylic acid crosses the blood brain barrier resulting in greater CNS toxicity. In mild or early poisoning burning in the mouth, lethargy, nausea, vomiting, tinnitus, or dizziness can occur. In moderate poisoning all of the above plus tachypnoea, hyperpyrexia, sweating, dehydration, loss of coordination, and restlessness, can occur.2 16 In severe poisoning hallucinations, stupor, convulsions, cerebral oedema, oliguria, renal failure, cardiovascular failure, and coma may be seen together with metabolic acidosis.1 2 4 After ingestion of enteric coated tablets, plasma salicylate concentrations on admission are unreliable guides to the severity of poisoning.17 Salicylate levels may not peak until more than 12 hours after such an overdose.17­19 The use of gastroscopic and other measures to remove enteric coated tablets requires further evaluation in the future. As well as aspirin tablets, other sources of salicylate poisoning include excessive topical application or ingestion of salicylate containing ointments, keratolytic agents or agents containing methylsalicylate (for example, oil of wintergreen).20 21 These agents contain liquid preparations and many of them are concentrated and lipid soluble and so there is the potential for severe, rapid onset salicylate poisoning.21 We would advise that doctors looking after a patient poisoned with one of these agents contact their local poisons centre for advice on treatment. Methods used to increase the elimination of salicylates The elimination of salicylate may be increased by alkalinisation of the urine (see fig 1 for details).16 There is a 10-fold to 20-fold increase in renal salicylate clearance associated with an increase in urine pH from 5 to 8 and renal excretion of salicylate depends much more on urine pH than flow rate.16 A urine pH of 7.5 or higher is indicated and careful monitoring of the urine pH is necessary. The pH of blood should not exceed pH 7.55 however. The most common recommendation is to continue treatment until the plasma salicylate concentration decreases to the therapeutic range but cessation of the patient's symptoms are also a crucial factor in the decision to discontinue alkalinisation. Although it is prudent to administer supplemental potassium to hypokalaemic patients, it is inappropriate to delay the administration of sodium bicarbonate solution until normokalaemia is achieved. Forced diuresis alone has little effect and is potentially harmful because of the potential for pulmonary oedema, hypernatraemia, and hypokalaemia.16 However, in severe poisoning the renal elimination of salicylate may be very slow as the urine becomes acidic and there may be oliguria.8 This is when haemodialysis needs to be considered.1 11 22 Haemodialysis reduces both the mortality and morbidity of poisoning and should be considered in those with severe salicylate poisoning--that is, systemic metabolic acidosis or plasma concentrations greater than 800 mg/l in adults and 700 mg/l in children or the elderly.1 While the plasma salicylate concentration is undoubtedly a good guide to treatment it should not be the sole determinant of when to consider extracorporeal removal and other factors such as the presence of a severe systemic metabolic acidosis, a young patient or very old patient, CNS features (for example, drowsiness, agitation, coma or convulsions), acute renal failure or pulmonary oedema make it much more likely that haemodialysis will be needed.1 11 17 A recent case has emphasised the importance of continuing urinary alkalinisation in patients who are undergoing haemodialysis in order to reduce plasma concentrations quickly, prevent acidaemia, and promote elimination of as much salicylate as possible via the kidneys.22 Although haemodialysis has been used successfully for many years in the management of severe salicylate poisoning, no controlled trial comparing its efficacy with that of carefully managed urinary alkalinisation and

diuresis has been performed. Nevertheless its use has the advantage of normalising acid base balance and electrolyte abnormalities while removing salicylate, without the thrombocytopenia that frequently accompanies charcoal haemoperfusion.23 The role of haemofiltration remains unproven in salicylate poisoning.


Salicylate poisoning can result in severe morbidity and mortality. It is important that clinicians caring for patients with salicylate poisoning are able to identify patients that are severely poisoned on the basis of clinical features, metabolic acidosis and their plasma salicylate concentrations so that appropriate treatment can be started. This evidence based flowchart will guide the clinician step by step through the management of salicylate poisoning. Contributors Paul Dargan was responsible for the literature review and together with Craig Wallace designed the management flowchart. Alison Jones reviewed the literature review and the management flowchart. All these authors were involved in the writing of the paper and all three authors will act as guarantors


Authors' affiliations

P I Dargan, C I Wallace, A L Jones, National Poisons Information Service, Guy's and St Thomas' NHS Trust, London, UK Funding: none. Conflicts of interest: none.


1 Chapman BJ, Proudfoot AT. Adult salicylate poisoning: deaths and outcome in patients with high salicylate concentrations. Q J Med 1989;72:699­707. 2 Proudfoot AT. Toxicity of salicylates. Am J Med 1983;75:99­103. 3 McGuigan MA. A two-year review of salicylate deaths in Ontario. Arch Intern Med 1987;147:510­12. 4 Thisted B, Krantz T, Stroom J, et al. Acute salicylate self-poisoning in 177 consecutive patients treated in ICU. Acta Anaesthesiol Scand 1987;31:312­16. 5 Danel V, Henry JA, Glucksman E. Activated charcoal, emesis, and gastric lavage in aspirin overdose. BMJ (Clin Res Ed) 1988;296:1507. 6 American Academy of Clinical Toxicology; European Association of Poison Control Centres and Clinical Toxicologists. Position statement: single dose activated charcoal. J Toxicol Clin Toxicol 1997;35:721­41. 7 Hillman RJ, Prescott LF. Treatment of salicylate poisoning with repeated oral charcoal. BMJ (Clin Res Ed) 1985;291:1472. 8 American Academy of Clinical Toxicology; European Association of Poison Control Centres and Clinical Toxicologists. Position statement and practice guidelines on the use of multiple-dose activated charcoal in the treatment of acute poisoning. J Toxicol Clin Toxicol 1999;37:731­51 9 Kirshenbaum LA, Mathews SC, Sitar DS, et al. Does multiple-dose charcoal therapy enhance salicylate excretion? Arch Intern Med 1990;150:1281­3. 10 Barone JA, Raia JJ, Chain Y. Evaluation of the effects of multiple-dose activated charcoal on the absorption of orally administered salicylate in a simulated toxic ingestion model. Ann Emerg Med 1988;17:34­7. 11 Yip L, Dart RC, Gabow PA. Concepts and controversies in salicylate toxicity. Emerg Med Clin North Am 1994;12:351­64. 12 Eppler J, Johnson D. Measurement of serum acetylsalicylic acid in a porcine model of aspirin overdose. Vet Hum Toxicol 1996;38:409­12. 13 Juurlink DN, McGuigan MA. Gastric decontamination for enteric-coated aspirin overdose: what to do depends who you ask. J Toxicol Clin Toxicol 2000;38:465­70. 14 Vale JA, Buckley GM, Meredith TJ. Algorithm for modified alkaline diuresis in salicylate poisoning. BMJ (Clin Res Ed) 1985;290:155. 15 Done AK. Salicylate intoxication: significance of measurements of salicylate in blood in cases of acute intoxication. Pediatrics 1960;26:800­7. 16 Prescott LF, Balali-Mood M, Critchley JA, et al. Diuresis or urinary alkalinisation for salicylate poisoning? BMJ (Clin Res Ed) 1982;285:1383­6. 17 Todd PJ, Sills JA, Harris F, et al. Problems with overdoses of sustained-release aspirin. Lancet 1981;i1:777. 18 Kwong TC, Laczin J, Baum J. Self-poisoning with enteric-coated aspirin. Am J Clin Pathol 1983;80:888­90. 19 Wortzman DJ, Grunfeld A. Delayed absorption following enteric-coated aspirin overdose. Ann Emerg Med 1987;16:434­6

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Management of acute salicylate (aspirin) overdose

20 Brubacher JR, Hoffman RS. Salicylism from topical salicylates: review of the literature. J Toxicol Clin Toxicol 1996;34:431­6. 21 Chan TY. The risk of severe salicylate poisoning following the ingestion of topical medicaments or aspirin. Postgrad Med J 1996;72:109­12 22 Higgins RM, Connolly JO, Hendry BM. Alkalinisation and hemodialysis in severe salicylate poisoning: comparison of elimination techniques in the same patient. Clin Nephrol 1998;50:178­83. 23 Jacobsen D, Wiik-Larsen E, Bredesen JE. Haemodialysis or haemoperfusion in severe salicylate poisoning. Hum Toxicol 1988;7:161­3. 24 American Academy of Clinical Toxicology; European Association of Poison Control Centres and Clinical Toxicologists. Position statement: Gastric lavage. J Toxicol Clin Toxicol 1997;35:711­19. 25 Burton BT, Bayer MJ, Barron L, et al. Comparison of activated charcoal and gastric lavage in the prevention of aspirin absorption. J Emerg Med 1984;1:411­16.


26 Brenner BE, Simon RR. Mangement of salicylate intoxication. Drugs 1982;24:335­40. 27 Temple AR. Acute and chronic effects of aspirin toxicity and their treatment. Arch Intern Med 1981;141:364­9. 28 Dillon EC Jr, Wilton JH, Barlow JC, et al. Large surface area of activated charcoal and the inhibition of aspirin absorption. Ann Emerg Med 1989;18:547­52. 29 Curtis RA, Barone J, Giacona N. Efficacy of ipecac and activated charcoal/cathartic. Arch Int Med 1984;144:48­52. 30 Dawling S, Chand S, Braithwaite RA, et al. In vitro and in vivo evaluation of two preparations of activated charcoal as adsorbents of aspirin. Hum Toxicol 1983;2:211­16. 31 Boldy D, Vale JA. Treatment of salicylate poisoning with repeated oral charcoal. BMJ (Clin Res Ed) 1986;292:136. 32 Mofenson HC, Caraccio TR, Greensher J, et al. Gastrointestinal dialysis with activated charcoal and cathartic in the treatment of adolescent intoxications. Clin Pediatr 1985;24:678­84.


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