Four Steps to Diagnosing Bedside basics can help you determine what was ingested in order to quickly stabilize the patient.

By Scott Goldstein, DO

he morning starts as usual, with three testing that should be undertaken to narrow down patients to see: a 46-year-old with chest the possible and ensure that a life-threatening pain, a 25-year-old with back pain, and overdose is not about to go untreated. Those phases a 27-year-old schizophrenic brought in are the subject of this article. Tby friends who believe he may have overdosed but aren’t sure what drug he might have taken. FIRST: TEST BLOOD GLUCOSE One of the many challenges faced by today’s emer- If there is any change in mental status, the first test gency departments is a rising incidence of overdoses, should be a blood glucose level. This is one of the few both intentional and accidental, in the population times in current medicine when you can treat someone as a whole but especially in schizophrenic patients.1 and see a therapeutic change within seconds—possibly Fortunately, there is a way to pursue the suspicion of avoiding intubation, unnecessary imaging, and days in overdose that’s thorough enough to pick up any life- the ICU. If a patient is obtunded, and the glucose is threatening ingestions but efficient enough to save low, an ampule of dextrose should fix the problem. both practitioner and patient time in the emergency Many drugs and substances can lower blood glu- department. The predictable actions of drugs on the cose—most obviously, the antidiabetic medications, body fall into six broad classifications—anticholin- such as biguanides and sulfonylureas, which have be- ergic, , hallucinogenic, opiate/narcotic, come ubiquitous as more and more people develop /hypnotic, and sympathomimetic—called diabetes and live longer with the condition. Not only toxidromes (Table).2 Temperature, , re- can patients overdose on their spiratory rate, pulse oximetry, and own diabetic medications, but >>FAST TRACK<< are all clues to a specific toxidrome. Most their family members may Almost all toxidromes from overdosing either an illicit or a prescribed drug also be at risk. use the vital signs in can be treated symptomatically under the general Alcohol, so often used and evaluating what the guidance of the toxidromes. The caveat is that the abused as self-medication by patient may have picture may be clouded by multiple offending agents individuals with psychiatric ingested. that bring different toxidromes into play if the pa- diagnoses, causes hypoglyce- tient has taken drugs from more than one class. mia by dysregulating pancreatic control of insulin The physician’s first task, of course, is to ana- release and decreasing glucose production by lyze the patient’s vital signs for insight into how the the liver. body is reacting to whatever pathological process is Hypoglycemia has been associated with acetamin- happening. Almost all toxidromes use the vital signs ophen overdose in a few cases, possibly secondary to in evaluating what the patient may have ingested. liver failure.3 Once that has been done, there are four phases of SECOND: GET AN ECG Dr. Goldstein is an assistant professor of emergency medicine at Penn State Hershey Medical Center in Like the blood glucose level, the ECG is easily ob- Hershey, Pennsylvania. tainable, readily available, and full of valuable infor- www.emedmag.com APRIL 2009 | EMERGENCY MEDICINE 17 DRUG OVERDOSE

TABLE. Toxidromes as a Diagnostic Guide in Suspected Overdose

Toxidrome Vital sign Classic agents

, flushed , dilated , urinary retention, decreased bowel sounds, memory loss, tricyclic

(mnemonic: “hot as a hare, dry as a bone, red as a beet, blind as a bat, mad as a hatter”)

cholinergic , weakness, bradycardia salivation, lacrimation, carbamates urination, defecation, gastrointestinal motility, emesis, diaphoresis, muscle , , seizures, “Killer Bs”: bradycardia, bronchorrhea, bronchospasm

hallucinogenic disorientation, tachycardia , visual tachypnea lysergic acid illusions, panic reaction, hypertension diethylamide moist skin, hyperactive cannabis bowel sounds, seizures

opiate/narcotic altered mental status, bradypnea dextromethorphan unresponsiveness, bradycardia opiates: miosis, , hypothermia morphine decreased respiration propoxyphene

sedative/hypnotic , stupor, confusion, ethanol sedation, CNS dsyfunction

sympathomimetic , , tachycardia diaphoresis, piloerection, hypertension , hyperreflexia, hyperthermia seizures,

Source: Florida Information Center, Jacksonville.2

mation for the treating physician about what drug One of the main things to watch for is possible or drugs may have been taken. Keep in mind the overdose with a tricyclic (TCA).

normal heart rate (60 to 100 bpm), the normal QTc These drugs have a notoriously narrow therapeu- (less than 0.45 s for men or 0.42 s for women) and tic window and a dangerous potential for severe the normal QRS (less than 0.12 s). neurologic and cardiovascular , including

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life-threatening arrhythmias.4 The ECG can help do not cause hypoglycemia. In contrast, bradycar- with ruling TCA toxicity in or out and formulating dia with hyperglycemia may signal an overdose of a treatment plan. the calcium blocker nifedipine. All the information The most common ECG finding in a TCA gathered needs to be used together to formulate a overdose is sinus tachycardia. If you see evidence of safe and effective plan. tachycardia and the suspicion for TCA overdose is high, look for additional ECG clues to the use of a THIRD: CHECK THE ACETAMINOPHEN LEVEL TCA, such as a strong rightward axis or terminal R The acetaminophen level is not as easy to obtain as wave in aVR. The latter finding is very sensitive for the bedside glucose or ECG, but it’s very important TCA overdose and signals an urgent need for treat- because acetaminophen can be a silent killer—there ment, because it means that the drug has already is no toxidrome with acute ingestion. It is ubiqui- affected the cardiac electrical system. Recent studies tous in today’s society and should be considered in show that if the terminal R wave is greater than 3 all intentional overdoses; liberal testing for it will mm, there is a higher risk of seizures.4,5 help save many lives at modest cost.8 When it is not The QRS is another important place to look for picked up and treated early, acetaminophen toxicity electrocardiographic clues to a TCA overdose. Nor- takes a protracted, painful, and deadly course. mal QRS is defined for general purposes as less than Even though there are no telltale signs, there 0.12 s, but if TCA overdose is a concern, the thresh- are “phases” in acetaminophen overdose. The first old drops to 0.10 s. Numerous studies have shown phase consists of gastrointestinal upset with that the risks of arrhythmia and increase as the and , usually in the first 24 hours. This is QRS increases, and markedly so once it exceeds 0.16 the most important phase to consider, since most s, which occurs in about 50% of patients who have a overdoses and medical clearance cases come to the wide QRS associated with TCA overdose.6,7 ED within this time frame.9 The subsequent phases Any of the above abnormalities in a patient sus- correlate with liver injury, spanning from right up- pected of TCA overdose warrants treatment with per quadrant pain to jaundice, vomiting, and frank sodium bicarbonate and admission to the ICU. liver failure. Clues to the presence of many potentially deadly Always keep the time frame in mind. Acetamino- cardiac medications can be picked up on the ECG, phen has a half-life of four hours; after a toxic in- mostly by looking at the rate. The two most common gestion the level usually peaks at four hours.3 When are beta-blockers and calcium channel blockers—it’s there is concern for acute acetaminophen toxicity, hard to go through a shift without seeing a patient the level does not need to be tested until four hours on either of these medications. Both slow the heart have passed since ingestion, but treatment can begin rate, leading to bradycardia, first-degree heart block immediately. If you suspect a chronic overdose span- and prolonged QT interval. These similarities make ning days to weeks, check it difficult to discern which type of drug is causing the the acetaminophen level >>FAST TRACK<< changes, but the combination of hypotension with and liver functions and in- Normal QRS is defined bradycardia and conduction abnormalities should stitute treatment, if neces- for general purposes as always raise suspicion for cardiotropic drug over- sary, as soon as possible. If less than 0.12 s, but if TCA dose. The patient likely needs emergent treatment you are certain the inges- overdose is a concern, with either calcium (for hyperkalemia or calcium- tion is acute, you can plot the threshold drops channel overdose) or glucagon (for beta-blocker the level against the Ru- to 0.10 s. overdose). However, if the agent is unknown, it is mack-Matthew nomogram always safe to treat symptomatically with atropine to see if it is in the toxic range, which mandates and cardiopulmonary support. emergent treatment with acetylcysteine (Mucomyst) The ECG is just one of many screening tools for and admission.10 possible overdose and needs to be used in conjunc- tion with all other tests. For example, a patient with FOURTH: LOOK FOR AN ANION GAP bradycardia and hypoglycemia may have overdosed A basic metabolic panel (BMP) can provide valuable on a beta-blocker, since calcium channel blockers clues to the presence and effects of many medications www.emedmag.com APRIL 2009 | EMERGENCY MEDICINE 19 DRUG OVERDOSE

if you look at the totality of it, even though a single Uremia. The definition of uremia seems to be electrolyte or other value may not tell you much by changing on a regular basis due to advancements itself. That makes the BMP one of the most effective in medicine, but it can be basically described as ill- assessment tools when overdose is suspected. If used ness accompanying kidney failure that cannot be well, it can make hours’ worth of additional labora- explained by derangements in extracellular volume, tory studies unnecessary. inorganic ion concentrations, or lack of known re- The first and probably most important function nal synthetic products. Initially, acidosis develops in of the BMP in these patients is to reveal an anion uremia as a consequence of the kidney’s inability to gap. If there is an anion gap, there is an acidosis, excrete ammonium and the accumulation of various and if there is an acidosis, the number of possible organic acids. Most commonly, uremia is found in causes is limited. The most commonly used formula the patient with chronic renal failure and diabetes

is sodium – (chloride + bicarbonate [total CO2 ]). If the mellitus. The uremic patient is usually sallow and result is greater than 12 to 15 mEq/L, there is an thin, and presents with nausea and vomiting. One anion gap.11 more clue, besides the anion gap, is that uremia is A mnemonic often used in this context is MUD- often accompanied by hypocalcemia, due to lower PILES—methanol, uremia, diabetic ketoacidosis, vitamin D levels and high phosphate levels. paraldehyde (or propylene glycol or phenformin), Diabetic ketoacidosis (DKA). A clinical picture iron and/or isoniazid, lactic acid, ethanol, and salicy- featuring somnolence, vomiting, and abdominal pain lates—which covers the most likely perpetrators of may mean DKA rather than overdose. If it’s DKA, an anion gap, but is by no means all-encompassing.12 the patient will have an anion gap and high glucose A positive anion gap can be seen with many drugs, in- on BMP, usually over 200 mg/dL. Maintain a high cluding bromide, iodide, and lithium.13 Other com- level of suspicion for DKA, in which mortality is close pounds, such as carbonic anhydrase, lysine, NADP+, to 100% without treatment. The combination of hy- or spirolactone, produce a hyperchloremic acidosis perglycemia, glycosuria, ketonuria, and a metabolic with minimal to no gap when overdosed. That is acidosis should be managed as diabetic ketoacidosis why determining the anion gap is useful in the until proven otherwise. asymptomatic patient but is not the definitive study Paraldehyde. Used regularly in the 1960s to treat of choice in the known overdose. seizures and agitation, paraldehyde has fallen out of Methanol. This toxic alcohol is converted into favor as a drug but is still used in resin manufacturing. formic acid in the body via the alcohol dehydro- It is excreted mostly by the lungs, which imparts a genase pathway, which leads to a buildup of un- characteristic offensive odor to the breath of patients measured anions. If a patient presents early or has with paraldehyde poisoning. Other symptoms and ingested only a small amount, there will be no anion signs are mild to moderate dehydration, hypoten- gap, which means the diagnosis is based more on sion, Kussmaul respirations, mental-status changes, history and physical. Most of the physical examina- heme-positive gastrointestinal contents, and pulmo- tion findings are localized to the visual system, rang- nary edema. The elevated anion gap is caused by pro- ing from dilated pupils to duction of acetic acid and chloracetic acid. Be aware >>FAST TRACK<< “snowstorm blindness.” that when the nitroprusside reaction test is used, A clinical picture If there is high concern paraldehyde may cause a false-positive reaction for featuring somnolence, for methanol ingestion, ketones, leading to a misdiagnosis of another cause vomiting, and abdominal you’ll want to know the os- of mental status change. pain may mean DKA rather molar gap—(the difference Isoniazid (INH). One of the many drugs used than overdose. between estimated serum to treat tuberculosis, INH can be a cause of acido- osmolarity using the for- sis. Suspect INH overdose when a patient presents mula 2(Na) + glucose/18 + BUN/2.8 + ethanol/4.6 and in status epilepticus with metabolic acidosis that the patient’s actual, lab-measured serum osmolarity. A appears unresponsive to conventional antiseizure gap between these two values of more than 10 to 20 is medication—although that can be a tricky call, due considered abnormal.14 Anything that increases serum to the acidosis caused by the seizures themselves. A osmolarity (usually alcohol) is concerning in overdose. detailed drug history from the family (don’t forget

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to ask about medications for other family members, advertised as such, so accidental overdoses are quite too) and paramedics is often very helpful. The treat- common. The toxic effect of salicylate is multifac- ment is supportive in most cases, but up to 5 g of torial, involving various metabolic systems. Direct vitamin B6 (pyridoxine) can be administered to stop stimulation of the respiratory center increases re- refractory seizures.15 spiratory rate and carbon dioxide excretion, causing Iron. Toxicity from iron is extremely detrimental respiratory alkalosis. Salicylates also inhibit the citric and more common in children, thanks to the enticing acid cycle and interfere with oxidative phosphoryla- candy-like appearance of some iron pills. It is cor- tion, leading to hyperpyrexia, increased oxygen con- rosive to the , leading to symp- sumption and depletion of hepatic glycogen stores. toms such as nausea and vomiting (with or without Following the respiratory alkalosis, usually seen early blood). On the cellular level, iron overdose impairs and with mild salicylism, the body goes into meta- oxidative phosphorylation. After an asymptomatic bolic acidosis, due to the dysregulated citric acid period lasting up to 24 hours, due to the time it cycle and increased oxygen consumption. takes for the iron to be absorbed and transported to The toxic dose of salicylate depends on the timing the body tissue, metabolic acidosis and cellular tox- and duration of ingestion (chronic versus acute). A icity develop.16 These patients are usually hypoten- chronic history is more common in elderly patients, sive and require aggressive intravenous fluids, critical who may take aspirin regularly for coronary artery monitoring and, in some cases, possibly chelation disease or joint pain. It’s important to bear in mind therapy with deferoxamine. that the signs and symptoms of chronic toxicity, such Lactic acid. Type A lactic acidosis, caused by hypo- as change in mental status, low-grade , dehydra- perfusion, cell anoxia and anaerobic metabolism, is seen tion, and renal dysfunction, can occur with even a in many types of overdoses involving drugs of abuse or mild increase in dosage, are usually subtle, and can suicidal intent. Treatment is supportive (intravenous be confused with those of various other processes, fluids, oxygen) while you identify the offending sub- such as sepsis or pneumonia.17 stance. The suspect list includes biguanides, cocaine, Acute ingestion is defined as a single ingestion of cyanide, niacin, nitroprusside, lactulose, ether, sorbi- non-enteric-coated acetaminophen within a 24-hour tol, streptozosyn, theophylline and, of course, alcohol, period. The toxic dose is anything over about 140 which drives a large share of emergency department mg/kg in adults and children; this level is halved (70 visits due to consequences ranging from motor vehicle mg/kg) in people with chronic disease. The blood accidents to violence to liver failure. salicylate level is available When a patient seems to be intoxicated, a good in most, if not all, hospital >>FAST TRACK<< neurologic examination (with or without a CT scan) laboratories. The older fer- When a patient seems to and observation are all that is needed. Debates ric chloride urine test (Fig- be intoxicated, a good abound over alcohol levels and their utility. The real- ure) reliably demonstrates neurologic exam (with or ity is that each person metabolizes alcohol differently recent salicylate ingestion, without a CT scan) and and a level is just a number, not a sign of intoxication. but gives no clue to the observation are all that is needed. If someone who is not a baseline alcoholic goes on amount taken. a drinking binge and presents with an alcohol level Both acute and chronic salicylate overdose are of 150 mg/dL, he may be inebriated and need in- treated with supportive care and fluids to maintain tubation for airway control. But a chronic alcoholic urinary alkalinization. Be careful, however, not to al- with the same blood-alcohol level will be in complete kalinize the serum, which can worsen CNS toxicity. withdrawal, requiring benzodiazepines. Most binge drinkers don’t take in enough car- ADDITIONAL CONSIDERATIONS bohydrates, leading to ketogenesis for energy. The In addition to the above workup, a human chorionic anion gap seen in alcohol intoxication reflects a com- gonadotropin (hCG) test is mandatory for female bination of lactic acidosis and ketosis (predominantly patients. Any woman of childbearing age should beta-hydroxybutyrate). have her pregnancy status checked regardless of her Salicylates. Many prescription and nonprescrip- last menstrual period and sexual activity. For some tion medications contain salicylates but may not be women, the news of a pregnancy may trigger fear, www.emedmag.com APRIL 2009 | EMERGENCY MEDICINE 21 DRUG OVERDOSE

will have no signs or symptoms of acute ingestion, because there is no acute ingestion. And agitation from phencyclidine (PCP) and sympathomimetics will be treated with sedation and cooling methods regardless of the agent involved. Due to the many agents that can cause false posi- tive and negatives, the UDS is a poor test, at best, that can lead to the wrong diagnosis or sway a pro- vider into treating a result and not the patient.18 Q

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