Toxicology in the ICU - Part1

DOI 10.1378/chest.10-2548 2011;140;795-806Chest

W. Boyer and Anne-Michelle RuhaMichael Levine, Daniel E. Brooks, Carrie A. Truitt, Brian J. Wolk, Edward Overview and Approach to TreatmentToxicology in the ICU : Part 1: General

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Postgraduate Education CornerCONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

CHEST

CHEST / 140 / 3 / SEPTEMBER, 2011 795www.chestpubs.org

Physicians frequently encounter critically ill patients who were poisoned under a variety of circum-

stances. The wide range of clinical syndromes that occur as a result of overdose or recreational use of an ever-increasing array of available prescription and illicit drugs provides a continuous challenge to the intensive care physician. This article is the fi rst of a three-part series to be published in CHEST and dis-cusses general management, laboratory tests, enhanced elimination, and emerging therapies. The second article will focus on the management of specifi c overdoses;

the last will cover plants, mushrooms, envenomations, and heavy metals.

Toxidromes

Specifi c toxic syndromes (toxidromes) arise from similarities in the pharmacology of many poisons, permitting treatment to be started empirically, based on clinical presentation without defi nitive knowledge of the offending agent. The classic toxidromes include opioid, sedative-hypnotic, anticholinergic, cholinergic, and sympathomimetic ( Table 1 ).

The classic opioid toxidrome results from the stim-ulation of opioid receptors by naturally occurring opi-ates, such as morphine and codeine, or by synthetic opioids, such as oxycodone, hydrocodone, hydromor-phone, and fentanyl. The toxidrome is characterized by bradypnea, depressed mental status, and miosis. 1 , 2 Miosis and a respiratory rate of � 12 breaths/min are both sensitive (88% and 80%, respectively) and specifi c (90% and 95%, respectively) for predicting a response to naloxone. 3 Opioids produce a gen-eral depression in autonomic activity; bradycardia,

Toxicology in the ICU

Part 1: General Overview and Approach to Treatment

Michael Levine , MD ; Daniel E. Brooks , MD ; Carrie A. Truitt , MD ; Brian J. Wolk , MD ; Edward W. Boyer , MD , PhD ; and Anne-Michelle Ruha , MD

Manuscript received October 4 , 2010 ; revision accepted May 23 , 2011 . Affi liations: From the Department of Medical Toxicology (Drs Levine, Brooks, Truitt, and Ruha), Banner Good Samaritan Medical Center, Phoenix, AZ; and the Division of Medical Toxicology (Drs Wolk and Boyer), Department of Emergency Medicine, University of Massachusetts, Worcester, MA . Correspondence to: Michael Levine, MD, Department of Medical Toxicology, Banner Good Samaritan Medical Center, 925 E McDowell Rd, 2nd Floor, Phoenix, AZ 85006; e-mail : [email protected] © 2011 American College of Chest Physicians. Reproduction of this article is prohibited without written permission from the American College of Chest Physicians ( http :// www . chestpubs . org / site / misc / reprints . xhtml ). DOI: 10.1378/chest.10-2548

Poisonings, adverse drug effects, and envenomations continue to be commonly encountered. Patients often present critically ill and warrant ICU admission. Many other patients who are ini-tially stable have the potential for rapid deterioration and require continuous cardiopulmonary and neurologic monitoring. Given the potential for rapid deterioration, and because patients need continuous monitoring, ICU admission is frequently required. This article is the fi rst of a three-part series to be published in CHEST ; it discusses general management, laboratory tests, enhanced elimination, and emerging therapies. The second article will address the management of specifi c overdoses; the last will cover plants, mushrooms, envenomations, and heavy metals. CHEST 2011; 140( 3 ): 795 – 806

Abbreviations : AC 5 activated charcoal ; AG 5 anion gap ; AMS 5 altered mental status ; CCB 5 calcium channel blocker ; CRRT 5 continuous renal replacement therapy ; EET 5 extracorporeal elimination technique ; HD 5 hemodialysis ; HIE 5 hyperinsulinemic euglycemia ; ILE 5 IV lipid emulsion ; NMS 5 neuroleptic malignant syndrome ; OG 5 osmol gap ; UDS 5 urine drug screen ; Vd 5 volume of distribution ; WBI 5 whole bowel irrigation


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796 Postgraduate Education Corner

hypotension, and hypothermia are common. Hypo-active bowel sounds are possible. 4 , 5

This classic toxidrome may be obscured in mixed overdoses, and several opioids have unique clinical features of importance. Meperidine, propoxyphene, and tramadol can cause seizures. 6 - 9 Miosis is not reli-ably present in the setting of tramadol or meperidine toxicity, 10 or with mixed ingestions. Propoxyphene produces sodium channel blockade, which is asso-ciated with QRS prolongation and cardiovascular collapse, 8 , 9 whereas potassium effl ux blockade and QT prolongation are commonly observed with meth-adone toxicity. 11 The rapid administration of high-dose IV fentanyl can induce chest wall rigidity, which can complicate ventilation. 12

The sedative-hypnotic toxidrome also produces a generalized decrease in autonomic activity. Agents that may produce this toxidrome include benzodiaze-pines, benzodiazepine-like agents (eg, zolpidem), barbi-turates, carisoprodol, chloral hydrate, ethanol, and baclofen. In most cases, CNS depression is enhanced via binding at postsynaptic g -aminobutyric acid type A channels , thereby promoting chloride infl ux and neuronal hyperpolarization. 13 Characteristic clinical effects are anxiolysis and, as mentioned earlier, CNS depression. Respiratory depression and hypothermia may also occur.

The sympathomimetic toxidrome is often caused by stimulants such as cocaine and methamphetamine. Several over-the-counter and prescription medica-tions, such as pseudoephedrine, caffeine, and agents used to treat attention defi cit disorders (eg, methyl-phenidate), can also produce this toxidrome. Signs may include tachycardia, hypertension, hyperthermia, tachypnea, CNS excitation, and diaphoresis. Pupils are characteristically dilated but reactive. 14 , 15 Agita-tion and muscular hyperactivity are common and may produce life-threatening hyperthermia. 16

Sympathomimetics produce a general increase in sympathetic tone via several mechanisms, depend-ing on the drug. 17 - 19 These include increased release of catecholamines, inhibition of reuptake, direct recep-tor stimulation, and altered neurotransmitter metab-olism. 18 The differing modes of action may explain why cocaine intoxication responds well to benzodiaz-epines, whereas amphetamine-induced toxicity may be relatively resistant. 20 - 23 Another example of a sym-pathomimetic, clenbuterol, is a long-acting direct b -agonist used for its anabolic and lipolytic properties. Its use may result in tachycardia, hyperglycemia, hypo-kalemia, and myocardial infarction. 19 , 24

Sedative-hypnotic withdrawal syndrome can appear similar to the sympathomimetic toxidrome, and occurs with abrupt discontinuation of a sedative-hypnotic agent following prolonged use. In patients with alcohol withdrawal, seizures may result, with . 90% occurring

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within the fi rst 48 h. 25 Severe alcohol withdrawal occurs in 5% of patients with a history of alcohol depen-dence admitted to the hospital. 26 The most severe presentation of ethanol withdrawal, delirium tremens, is characterized by altered sensorium, abnormal neuro-muscular activity, and autonomic hyperactivity. With aggressive treatment, the mortality from alcohol with-drawal has declined to , 5%. 26

The anticholinergic toxidrome results from a mul-titude of different classes of drugs, including tricyclic antidepressants, antihistamines, antipsychotics, and cyclobenzaprine. It may be more accurately referred to as an antimuscarinic toxidrome, and is character-ized by the combination of mydriasis, dry fl ushed skin, delirium, hyperthermia, tachycardia, urinary retention, and hypoactive bowel sounds. 27 - 30 Mydriasis is not always present, especially if coexisting a antag-onism is present. 31 Progression and severity of anticholinergic effects are often dose related. 29 , 30 At low doses, dryness of the mouth and skin may be noted; moderate doses lead to worsening anhidro-sis, mydriasis, and tachycardia. At higher doses, central anticholinergic effects will occur, including ataxia, agitation, delirium, hallucinations, and coma. 29 , 30 Mumbling, incoherent speech, visual hallucinations, and carphologia (picking at imaginary objects) can be encountered. 29 , 32

The cholinergic toxidrome is characterized by an increase in secretions, with fi ndings of lacrimation, salivation, bronchorrhea, and urinary and fecal incon-tinence. It is classically produced by organophosphate insecticide poisoning, but may also be produced by other medications that affect acetylcholinesterase, such as edrophonium or physostigmine. Bradycardia is common, but tachycardia may result from stimu-lation of nicotinic receptors or hypoxia. Bronchor-rhea, bronchospasm, bradycardia, and hypotension are ominous signs and indicate the need for aggres-sive therapy with atropine. 33 Muscular weakness, including respiratory muscle paralysis, may occur because of nicotinic hyperstimulation 34 , 35 and does not respond to atropine.

Serotonin syndrome describes a combination of symptoms that is precipitated by the interaction or overdose of multiple proserotonergic medications, resulting in an increase in CNS serotonin activity. 36 , 37 Initially, mild symptoms such as tachycardia and tremor may be noted. If the offending drugs are not removed, or in the case of ingestions of multiple serotonergic medications, more severe manifesta-tions may develop, including hyperthermia, myo-clonus, muscle rigidity, opsoclonus, agitation, delirium, and diaphoresis. 36 - 39

Neuroleptic malignant syndrome (NMS) is charac-terized by hyperthermia, altered mental status (AMS), autonomic instability, and lead-pipe rigidity (increased

muscle tone without tremor or cog-wheeling). 40 - 42 Unlike serotonin syndrome, which occurs following a predictable increase in synaptic serotonin con-centrations, 36 NMS is at least partially idiosyncratic. However, it should be noted that commencing neu-roleptic therapy at high doses, or rapidly increasing the dose, can increase the risk of NMS. 42 NMS can present along a spectrum; milder forms manifest simply with AMS and rigidity, whereas more severe forms have autonomic life-threatening autonomic instability, hyperthermia, and rhabdomyolysis. 40 Pro-longed hyperthermia is associated with a poor out-come. 16 The syndrome generally follows therapeutic administration of a typical or atypical antipsychotic, but has also been reported following withdrawal of prodopaminergic medications such as levodopa/carbidopa. 39 , 40 , 43 NMS is a diagnosis of exclusion; the differential diagnosis includes serotonin syndrome, anticholinergic toxicity, lethal catatonia, and malig-nant hyperthermia.

Toxicology Laboratory Studies

Serum or urine assays to detect or quantify specifi c medications or illicit substances have clinical useful-ness in many situations. In cases in which it is unclear whether a patient is intoxicated or whether an alter-native diagnosis exists, these assays can be very helpful in ruling out or confi rming specifi c drug intoxication as a cause of illness. For example, in a patient with delirium, tachycardia, and fever, a urine drug screen (UDS) that is negative for cocaine or methamphet-amine might point the physician toward an infectious cause, whereas a positive UDS might direct him or her toward more specifi c treatment, such as the gen-erous use of benzodiazepines, early intubation, and aggressive cooling measures. Specifi c drug assays will not be useful or affect the management of every patient, however, and when interpreting results, the physician must always consider the limitations of the particular test and whether the results “make sense,” considering the clinical fi ndings.

Most UDS are immunoassays, in which the binding of an antibody to a recognized chemical structure produces a positive result. However, not all drugs in a class have a shared structure, so false-negative results are common. 44 For instance, benzodiazepines, which are not metabolized to oxazepam, such as lorazepam and alprazolam, may be missed in some UDS. 45 The cannabinoid screen detects a metabolite of d -9-tetrahydrocannabinol and thus misses dis-similar compounds with cannabinoid effects, such as JWH-018, the synthetic cannabinoid found in “spice.” 46 , 47 Alternatively, substances in other drug classes may posses a structure similar to that of the targeted substances, yielding a false-positive result.





For example, because of structural similarities with the tricyclics, diphenhydramine, cyclobenzaprine, carbamazepine, and quetiapine may cause a false-positive tricyclic antidepressant screen. 48 - 53 Because of the frequent false-positives from a UDS, results should be considered preliminary until confi rmed by gas chromatography-mass spectrometry. The test specifi city varies, depending on the immunoassay used. A UDS may also remain positive for a prolonged period, so in many cases it will only suggest the his-torical use of an agent ( Table 2 ). 51 , 54 Urinary levels of most drugs do not correlate with intoxication.

Obtaining serum drug concentrations may also be useful in some circumstances. As examples, lithium, digoxin, valproic acid, carbamazepine, phenytoin, salic-ylate, and acetaminophen concentrations may all infl uence management ( Table 3 ). Others, such as tri-cyclic antidepressants, are of less use because spe-cifi c concentrations do not correlate well with clinical fi ndings. However, in some cases they may be useful in confi rming excessive exposure.

Gaps

The anion gap (AG) is the difference between the measured dominant cations and anions, with a nor-mal AG occurring between 4 and 12 mEq/L. An ele-vated AG usually results from increased unmeasured anions and assists in narrowing the differential for metabolic acidosis ( Table 4 ). A low or negative AG may occur with lithium, bromide, or iodide. 55 , 56 Hyper-lipidemia or hypoalbuminemia may also cause a decreased AG. 56 - 58

The osmolal gap (OG) is the difference between the measured osmolality (mOsm/kg water) and the cal-culated osmolarity (mOsm/L) and is used to detect the presence of osmotically active substances ( Fig 1 ). 59 , 60

Concentrations of sodium, BUN, creatinine, glucose, and measured osmolality, which are used in deter-mining the OG, must be obtained simultaneously in order to increase validity. The normal OG ranges from 2 14 to 10. 54 , 60 Ethanol, ethylene glycol, meth-anol, isopropanol, excipients (eg, propylene glycol), ketones, and shock states can raise the OG. 61 , 62 It is important to remember that the large normal range for the OG may allow a patient to have a “normal” value despite a clinically signifi cant gap for that patient.

The arterial oxygen saturation gap is the calculated percentage saturation (based on P o 2 and pH) minus the percentage saturation measured by multiwave-length cooximetry (not simple pulse oximetry). An arterial oxygen saturation gap of . 5% usually results from elevated levels of carboxyhemoglobin, methe-moglobin, or sulfhemoglobin. Cyanide poisoning does not result in an increased oxygen saturation gap. 63

Coma Cocktail

Historically, the initial treatment of patients with undifferentiated AMS included use of a “coma cocktail,” which refers to IV administration of dex-trose, thiamine, and naloxone. Rapid glucose testing is often available, in which case hypoglycemia can be confi rmed and rapidly corrected. If rapid glucose analysis is unavailable, dextrose should be adminis-tered empirically. 64

Thiamine (vitamin B 1 ) is administered routinely with dextrose, in a dose of 100 mg , to prevent precip-itation of Wernicke encephalopathy. This concern is not evidence based and is attributed to a poorly described case series. 65 However, Wernicke encepha-lopathy can complicate other medical conditions, including hyperemesis gravidarum. 66 In suspected hypoglycemia, dextrose should not be withheld if thiamine is not available immediately. 64 Furthermore, for true cases of suspected Wernicke encephalopathy, higher doses of thiamine are recommended. 67

Table 2 — Detection Period of Commonly Detected Drugs on a Urine Drug Screen

DrugApproximate

Detection Period

Amphetamine, methamphetamine 4 d Barbiturate Short acting (eg, pentobarbital) 24 h Long acting (eg, phenobarbital) 3 wk Benzodiazepines Short acting (eg, lorazepam) 3 d Long acting (eg, diazepam) 4 wk Cocaine metabolite (benzoylecgonine) 3 d Marijuana (cannabinoids) Single use 3 d Long-term use 4 wk Opiates (varies by agent) 4 d Phencyclidine 8 d

Modifi ed with permission from Chattergoon et al 51 and McQuillen and Anderson. 54

Table 3 — Specifi c Serum Concentrations That May Affect Management

Acetaminophen Carbamazepine Cooximetry (carboxyhemoglobin, methemoglobin, sulfhemoglobin) Digoxin Selected metals (iron, lead, mercury; based on history and clinical

fi ndings) Lithium Phenytoin Salicylate Theophylline, caffeine Toxic alcohol (ethylene glycol, isopropanol, methanol) Valproic acid




The purpose of administering naloxone, a compet-itive opioid receptor antagonist, is to reverse opioid-induced respiratory depression. An ideal therapeutic goal is to prevent intubation without precipitating withdrawal. As such, a reasonable starting dose is 0.2 to 0.4 mg IV. This can be increased rapidly to a dose of 2 to 10 mg if no effect is achieved. The typical half-life is 30 to 80 min, so additional doses may be required for reversal of resedation. 68 , 69 If multiple doses are administered, a continuous infusion of two-thirds the minimal effective dose may be adminis-tered per hour. 70 Repeated doses of naloxone are often needed for agents with long half-lives, such as methadone or extended-release oxycodone. In addi-tion to precipitation of opioid withdrawal, adverse reactions to naloxone include development of non-cardiogenic pulmonary edema or seizures (with tra-madol or meperidine). 64 , 71 - 77

Table 4 — MUDPILES Mnemonic for Causes of Anion-Gap Acidosis

M ethanol, metformin U remia D iabetic ketoacidosis P araldehyde, propylene glycol, propofol I ron, isoniazid, ibuprofen L actate E thanol (alcoholic ketoacidosis), ethylene glycol S alicylates, starvation ketoacidosis

Figure 1. Osmolal gap calculations . CF 5 correction factor; EtOH 5 ethanol; Glu 5 glucose; Na 5 sodium; OG 5 osmol gap.

In the treatment of mixed opioid agonist-antagonists such as buprenorphine, the reversal with naloxone follows a bell-shaped curve. IV doses . 4 mg are less effective than smaller doses, thus reemphasizing the need for careful titration. 78 , 79 When multiple sedative-hypnotic agents contribute to respiratory depression, naloxone may cause adverse reactions without clin-ical benefi t. 80

GI Decontamination

GI decontamination refers to any measures under-taken to minimize absorption of the toxin from the GI tract. These measures have traditionally included activated charcoal (AC), syrup of ipecac, gastric lavage, and whole-bowel irrigation (WBI). Because of a lack of proven benefi t and undesirable side effects, how-ever, the use of ipecac and gastric lavage are no longer recommended routinely. 80 - 82

AC is most likely to be of benefi t if given within 1 h of ingestion, although patients with certain inges-tions, such as salicylate, may benefi t from delayed administration. 83 , 84 The recommended dose is 0.5 to 1 g/kg in children or 25 to 100 g in adults. Impor-tantly, AC does not bind well to hydrocarbons, alco-hols, or most metals (except thallium). 85 Aspiration is a potential complication and may result in prolonged hospitalization, lung injury, or death. 83 , 86 - 89 There-fore, AC administration is contraindicated unless the





patient is able to protect his or her airway or has been intubated. Common side effects include vomit-ing, abdominal bloating, constipation, or diarrhea. 83 Relative contraindications include anticipated endos-copy or abdominal surgery. Cathartics (eg, sorbitol) should not be used. 90 Importantly, the routine use of AC has not been demonstrated convincingly to reduce morbidity or mortality.

Unlike single-dose charcoal, which is used for gas-tric decontamination, the administration of repeated, scheduled doses of charcoal is a form of enhanced elimination and is referred to as multiple-dose AC. Although multiple-dose AC has been recommended and shown to decrease serum levels for various agents (theophylline, dapsone, phenobarbital, car-bamazepine, and quinine), 91 its use has not been demonstrated to improve patient-oriented outcomes (eg, mortality). Its routine use is not recommended.

WBI involves administering large volumes (1.5-2 L/h) of a polyethylene glycol-based solution to facilitate rapid transit of a toxin through the GI tract. In volun-teer studies, WBI was effective in decreasing absorp-tion of enteric-coated aspirin and sustained-release lithium tablets. 92 , 93 Although it is not recommended routinely, WBI should be considered following inges-tion of highly toxic, extended-release preparations such as verapamil, metals such as iron (especially those preparations with high concentrations of elemental iron), or asymptomatic drug packers. 94 - 98 Contraindi-cations include compromised airway, ileus, and bowel obstruction. 94 As in the case of charcoal, data demon-strating improved clinical outcomes are lacking.

Endoscopy has been used to remove button bat-teries or drug bezoars, whereas laparotomy has been used to remove illicit drug packets (body packers or stuffers). 98 Button batteries lodged in the esophagus or trachea mandate endoscopic removal. 99 Symptom-atic leakage of sympathomimetic drug packets gener-ally mandates immediate laparotomy, whereas leakage of packets of heroin can be managed more conserva-tively. Bowel obstruction due to drug packet inges-tion also requires operative management. 98

Enhanced Elimination

All xenobiotics, or exogenous chemicals, achieve effectiveness and toxicity based on the ability to reach target tissues. Pharmacokinetic variables include absorption, distribution, metabolism, clearance, and elimination. Extracorporeal elimination techniques (EETs) seek to reduce or prevent toxic concentra-tions in target tissue. The ability of EETs to remove a xenobiotic depends on the xenobiotic’s molecular weight, protein binding, and apparent volume of dis-tribution (V d). Substances with a small Vd ( , 1 L/kg) have limited penetration into tissue and maintain

a relatively high intravascular concentration. Low molecular weight, low Vd, high water solubility, and low protein binding allow the xenobiotic to be removed more effectively by hemodialysis (HD) because the xenobiotic can cross the fi ltration mem-brane easier and dissolve into the dialysate.

The main EET used in the management of poison-ing is HD, which can both reduce drug/metabolite concentrations and correct fl uid and electrolyte abnor-malities. A list of xenobiotics that undergo signifi cant clearance by HD is given in Table 5 . Hemoperfusion has advantages over HD for the treatment of some poisonings because of its ability to remove substances with high protein binding, such as carbamazepine, 100 but is no longer available in most US centers.

The advantages of HD are technical ease and avail-ability . Because HD removes xenobiotics only from circulating blood, intercompartmental transfer or prolonged absorption may require prolonged or recur-rent treatments. This scenario commonly occurs with the treatment of lithium toxicity, where levels can rise again because of redistribution many hours after HD is completed. In cases where rebound is a concern, a precartridge level should be obtained before termi-nating HD. Because HD may also remove thera-peutic medications, the dosing interval of some drugs may need to be decreased.

Newer EET techniques include molecular adsor-bent recirculating system, sustained low-effi ciency dialysis, extended daily dialysis, and continuous renal replacement therapy (CRRT). 101 - 103 These techniques may aid in the treatment of poisoned patients but in general should be considered adjunctive therapy. Additionally, several studies have failed to show that CRRT is safer in hypotensive patients. 104 , 105

Specifi c Xenobiotics Removed by HD

Salicylates have a low molecular weight, a relatively small Vd, and signifi cant protein binding, but after overdose, the fraction of unbound drug increases,

Table 5 — Xenobiotics Removed by Hemodialysis

Salicylates Phenobarbital Theophylline Methanol Ethylene glycol Lithium Diethylene glycol Propylene glycol Isopropyl alcohol Valproic acid Carbamazepine

This list contains some of the more common substances for which hemodialysis is effective, but not all cases will require hemodialysis.




allowing for effective HD. 106 There are no specifi c evidence-based guidelines for when to initiate HD in the treatment of salicylate toxicity. Generally, AMS, pulmonary edema, seizures, and elevated and rising salicylate concentrations despite aggressive supportive care, or serum levels nearing 100 mg/dL following an acute overdose, typically require emergent use of HD. 107

Li 1 has a low molecular weight, minimal protein binding, and a small Vd. As with salicylate toxicity, clear, evidence-based guidelines for when to initiate HD do not exist. Furthermore, because HD has not been demonstrated to improve clinical out-comes with Li 1 toxicity, there is some variability in clinical practice and controversy surrounding the best treatment. Many medical toxicologists believe the deci sion as to whether to remove Li 1 via HD should be based more on clinical fi ndings, such as the pres-ence of encephalopathy or neurotoxicity, then on levels alone. 108 Acute Li 1 ingestion may result in predistribution levels well above 4 mEq/L within the fi rst few hours of ingestion, but may produce only minimal clinical effects. Alternatively, some propose that Li 1 should be removed by HD before it reaches the CNS. 106 Newer forms of extracorporeal therapy such as CRRT have been proposed for use in Li 1 toxicity based on the ability to slowly remove lithium and eliminate rebound. However, because of limited evidence supporting CRRT, HD is still the recommended modality for extracorporeal removal of Li 1 . 106

Ethylene glycol and methanol have low molecular weights, limited protein binding, and a small Vd. 109 HD effectively removes both the parent compounds and their toxic metabolites while correcting pH, fl uid status, and electrolytes. 110 Fomepizole, a safe and effective inhibitor of alcohol dehydrogenase, has changed the indications of HD following methanol or ethylene glycol ingestions. Before fomepizole, the threshold for initiating HD was a plasma concentra-tion of 50 mg/dL. 111 Currently, if a patient is treated with fomepizole, elevated concentrations of toxic alcohols alone should not prompt use of HD. 112 How-ever, signifi cant metabolic acidosis or renal dysfunc-tion associated with any specifi c toxic alcohol level is likely to require HD. 111 Although isopropanol may also be removed by HD, it is metabolized to acetone and causes much less toxicity, making HD unneces-sary in the vast majority of cases.

Urinary Alkalinization: Some drugs become ionized and undergo ion trapping in urine at elevated urine pH, limiting reabsorption and enhancing elimina-tion. Table 6 includes xenobiotics in which urinary alkalinization is recommended. 113 A general goal of uri-nary alkalinization is to maintain a urine pH � 7.5, 114

although in the case of salicylate, increased renal sali-cylate clearance occurs up to about pH 8.5. There is no standard method of producing alkaluria. Many physicians infuse 150 mEq NaHCO 3 in 1 L of 5% dextrose in water (D 5 W ) solution. Potassium sup-plementation is usually needed in the absence of hyperkalemia to prevent paradoxical urinary aciduria from distal tubular reabsorption of Na 1 in exchange for protons rather than K 1 .

Emerging Therapies

Several therapies have emerged in recent years for the treatment of poisonings. These include hyperin-sulinemic euglycemia (HIE) therapy for the treatment of severe calcium channel blocker (CCB) toxicity, IV lipid emulsion (ILE) therapy for shock due to lipo-philic drugs, and hydroxocobalamin for the treatment of cyanide toxicity.

Hyperinsulinemia Euglycemia

Toxicity from CCB poisoning is characterized by hypotension, hypokalemia, cardiac dysrhythmias, metabolic acidosis, and hyperglycemia. The hyper-glycemia is multifactorial in origin. First, CCB impair calcium infl ux through the l -type calcium channels in the pancreatic b cells, resulting in impaired insu-lin release. In addition, CCB poisoning results in impaired intracellular signaling and insulin resis-tance. 115 During CCB toxicity, the myocardial cells change their preferred energy substrate from free fatty acids to glucose. 116 High-dose insulin therapy has been shown to promote cellular uptake of glucose into adipose and muscle tissue, reduce cytosolic cal-cium concentration, and promote intracellular potas-sium movement. 116 , 117 The use of HIE may increase

Table 6 — Xenobiotics For Which Urinary Alkalinization Increases Clearance

Salicylates a Chlorpropamide 2,4-dichlorophenoxyacetic acid Difl unisal Fluoride Mecoprop (MCPP, a chlorphenoxy herbicide) Methotrexate Phenobarbital b

a The most recent recommendations of the American Academy of Clinical Toxicology and the European Association of Poison Con-trol Centres and the Clinical Toxicologists Position Statement is that “based on volunteer and clinical studies, urine alkalinization should be considered as fi rst line treatment for patients with moderately severe salicylate poisoning who do not meet the criteria for hemodialysis.” 113 b Phenobarbital is the only barbiturate shown to benefi t from urinary alkalinization.





myocardial contractility and mean arterial pressure, but typically does not reverse bradycardia or conduc-tion defects. 116 - 118 Clinical improvement often begins approximately 30 min after therapy is commenced. 117 Although there is moderate human experience with HIE, its use in CCB toxicity has not been validated prospectively and may be associated with potential adverse effects including hypoglycemia and hypoka-lemia. 117 , 119 However, it is unlikely that a prospec-tive randomized controlled trial on HIE will ever be conducted. 118

Although various guidelines for the use of HIE exist, one approach involves giving an IV bolus of 1 unit/kg of insulin, followed by a maintenance insu-lin infusion of 0.5 to 1 unit/kg/h. 120 Glucose should be monitored frequently. Unless the patient is signif-icantly hyperglycemic, an initial bolus of 1.0 g/kg of glucose should be given followed by a continuous glucose infusion of 0.5 g/kg/h. This infusion should be titrated based on the patient’s blood sugar level. Hyperinsulinemic euglycemic therapy is most likely to be of benefi t in patients who are hyperglycemic and in those with decreased cardiac contractility.

The exact timing as to when to start HIE is some-what controversial. Given the lack of controlled trials, its use certainly cannot be recommended as fi rst-line therapy. 117 However, because its use as a “last ditch” effort seems to be associated with failure, 116 , 118 it seems reasonable to start HIE shortly after a patient fails to improve with standard therapies including vasopressors. Hyperinsulinemic euglycemic therapy is most likely to be of benefi t in patients who are hyperglycemic and in those with decreased cardiac contractility.

IV Lipid Emulsion

Based on limited data, the use of ILE has been cited as standard of care for treating neurotoxicity or cardiotoxicity due to local anesthetics. 121 In 2006, the fi rst cases of ILE use in humans were reported and involved successful resuscitation after cardiac arrest following local anesthetic toxicity. 122 , 123 Animal models have demonstrated benefi t in the management of bupi-vacaine, 124 clomipramine, 125 verapamil, 126 , 127 and pos-sibly propranolol. 128 There is also a case of prolonged cardiac arrest due to lamotrigine and bupropion whose successful resuscitation involved ILE. 113

The exact mechanism of ILE is unknown, but likely involves decreasing the toxin’s Vd by shifting lipo-philic drugs into the vascular compartment and lim-iting target tissue concentration. Other theories include inhibition of mitochondrial metabolism of lipids, impairment of fatty acid delivery to mitochon-dria, and activation of potassium and calcium chan-nels involved with local anesthetic toxicity. 129

Use of ILE should be considered for patients with severe toxicity due to a lipophilic drug who do not respond to standard measures. ILE is available in 10%, 20%, and 30% solutions, and several dosing regi-ments have been suggested. No prospective human studies have been performed. Based on human expe-rience and animal research, one regimen involves administering 1.5 mL/kg of a 20% ILE over 1 min, followed by a continuous infusion of 0.25 mL/kg/min for 60 min. 130 If there is no response to the initial bolus, it can be repeated twice in 5-min increments. If hypotension persists, the maintenance infusion can be increased to 0.5 mL/kg/min. 129 Pyrogenic reac-tions, hyperlipidemia, pulmonary injury, hepatos-plenomegaly, thrombocytopenia, and fat embolism are theoretic concerns. 131 When administered as a resuscitative drug, however, few adverse events have been described. Because of the lipemia, laboratory studies may be diffi cult to analyze transiently or may produce spurious results. 132 It is important to recog-nize that propofol is not a substitute for ILE, because of myocardial depressant effects and different lipid content. 133

Hydroxocobalamin

Traditional therapy for cyanide toxicity involves the administration of nitrites (to produce methemoglobi-nemia) and sodium thiosulfate (to convert cyanide into thiocyanate). 134 These therapies may not be ideal for patients who have high carboxyhemoglobin levels. 135 Hydroxocobalamin (Cyanokit) is an alternative cya-nide antidote now approved by the US Food and Drug Administration. Hydroxocobalamin is vitamin B 12a , the precursor for cyanocobalamin (vitamin B 12 ). It combines with cyanide to form cyanocobalamin, which is then excreted renally. 136 The typical treatment dose is 5 g IV, which can be repeated once if needed. In a swine model, the administration of hydroxocobala-min and sodium thiosulfate appeared to be as effec-tive as sodium nitrite and sodium thiosulfate in the treatment of cyanide toxicity. 134 When using both antidotes, they cannot be administered in the same IV because of incompatability. 137 Hydroxocobala-min has some side effects. Although not necessarily undesired, it can augment mean arterial pressure because of the nitric oxide scavenging effects of cobalamin. 134 , 138 Use of hydroxocobalamin transiently produces a pink discoloration of tissue and blood, abnormal cooximetry measurements, and altered serum values for aspartate aminotransferase, bilirubin, creatinine, magnesium, and iron. 139 - 141 Because of the blood discoloration, HD machines may interpret a “blood leak” incorrectly and delay or prevent the use of HD. 142 An acneiform rash and erythema are com-monly encountered.




Conclusions

Severe clinical illness can occur following overdose or exposure to certain chemicals and illicit substances. Many agents produce toxidromes, which allows the physician to identify a probable poisoning syndrome and empirically determine the most appropriate management. Knowledge of the various routes of decontamination, emerging antidotal therapies, and opportunities for enhanced elimination allow for pro-vision of optimal care in the critical care setting. Many cases of poisoning present diagnostic and therapeutic challenges. It is recommended that physicians con-sult a medical toxicologist or regional poison control center (800-222-1222) to discuss individual cases to assist in the management of each patient.

Acknowledgments Financial/nonfi nancial disclosures: The authors have reported to CHEST that no potential confl icts of interest exist with any companies/organizations whose products or services may be dis-cussed in this article .

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DOI 10.1378/chest.10-2548 2011;140; 795-806Chest

Boyer and Anne-Michelle RuhaMichael Levine, Daniel E. Brooks, Carrie A. Truitt, Brian J. Wolk, Edward W.

TreatmentToxicology in the ICU : Part 1: General Overview and Approach to

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Toxicology in the ICU - Part1

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