Ken Miller MD, PhD

Objectives

· Define delayed onset toxicity.

· Identify some mechanisms of delayed onset toxicity

· Identify drug dosage forms which contribute to delayed onset toxicity in overdose

· Identify specific drugs with characteristic delayed onset toxicity in overdose

· Identify specific hazardous chemicals that can cause delayed onset toxicity

Delayed Onset Poisoning

Poisoning and overdose can take on many forms. In some cases the toxic material or overdosed drug causes immediate symptoms. In other cases exposure to a substance can cause no immediate symptoms but may lead to an increase in lifetime risk of cancer, blood, liver, or lung disease. Yet another possibility is that the drug or chemical may produce mild or no immediate symptoms but within hours or a few days cause harm if not treated. This is where we’ll focus. In poisoning cases with immediate symptom onset, the need for intervention is usually clear. But in delayed, or subacute, poisoning cases the major contribution of Fire EMS will be recognizing the potential for delayed toxicity. Some of these delayed poisoning cases are readily treatable if recognized. Another possibility is that EMS is called sometime after the ingestion or exposure and a victim is now presenting with symptoms after previously appearing well. These cases can be challenging since the risk to the patient is not immediate but delay in treatment can result in injury. Another confounding factor in prehospital care of poisoning or overdose cases is the potential unreliability of the patient’s history. Knowing which toxicants have potential for delayed toxicity may help during scene survey for evidence of materials involved. Field treatment in the otherwise asymptomatic patient may be minimal. The challenge is recognizing the problem.

We can look at this problem several ways. General principles of delayed toxicity, pharmaceutical dosage forms leading to delayed toxicity, specific pharmaceuticals known for delayed toxicity and chemicals with delayed toxicity.

General Mechanisms and Pharmaceutical Dosage Forms Leading to Delayed Onset Toxicity

Some drugs and chemicals are known to cause delayed onset toxicity. These are surprisingly common and we’ll get to them later. But some common mechanisms can lead to delayed onset of symptoms from other drugs and chemicals as well. Absorption of most drugs occurs across the lining of the small intestine. In order for drugs or chemicals to be absorbed they must first be dissolved. So the onset of effects of a solid dosage form will be slower than a liquid dosage form.

Ingestion of very large amounts of solid tablets or capsules containing solid granules can cause aggregates to form into large masses in the stomach called concretions or bezoars. Because only the surface of this mass is available to dissolve, the effects may be delayed in onset and may last longer than expected. A similar effect occurs when illegal drug packets transported in body cavities leak. The practice of transporting well wrapped packets of heroin, cocaine or other drugs by ingestion or rectal or vaginal insertion is called body packing and can cause lethal overdose if the packets leak or rupture. An attempt to evade arrest by swallowing poorly secured aluminum foil, plastic baggies, balloons or vials of drugs can also lead to delayed onset symptoms. There are several implications for field management. Leaking or ruptured heroin packets may cause deep coma unresponsive to usual doses of naloxone (Narcan). Prolonged airway management, high doses of naloxone and ultimately a continuous naloxone infusion may be necessary. Absorption of large amounts of cocaine can cause initial agitation and psychosis, hyperthermia, seizures, dysrhythmias, and profound hypertension followed by hypotension.

Serious cocaine toxicity can be challenging to manage. The first goal is to manage agitation. Controlling agitation can control hyperthermia, tachycardia and hypertension all without adding other therapeutic drugs. Midazolam (Versed) 5mg IV (or even IM for initial management of severe agitation before an IV can safely be established) is the best place to start. In most cases of recreational cocaine use this will be the only drug needed to control symptoms. Once agitation is controlled the heart rate and blood pressure follow. In larger overdoses that might follow body packing the central nervous system and cardiovascular symptoms might be more profound. Even here if the patient is agitated, psychotic or seizing midazolam is the place to start along with supplemental oxygen and cooling measures. Sedation alone might control other symptoms. If the patient is already unconscious or if sedation fails to control tachycardia or blood pressure then another approach is needed. A narrow complex tachycardia won’t respond to adenosine because the problem is excessive myocardial stimulation (increased automaticity) not reentry. For the same reason synchronized cardioversion won’t convert a narrow complex tachycardia caused by cocaine. If sedation and control of hyperthermia don’t work to control tachycardia then further drug therapy or overdrive pacing may be needed in the emergency department. If this narrow complex tachycardia is accompanied by hypotension then IV saline boluses can be tried as long as there is no significant pulmonary edema.

Wide complex tachycardia is another problem. Monomorphic ventricular tachycardia (the usual V Tach we see), polymorphic VTach (Torsade de Pointes) or V Fib can all result from cocaine toxicity. When VTach is accompanied by hypotension then cardioversion (with sedation if needed) can be tried. VFib can be defibrillated like usual. What’s different is drug therapy for cocaine induced VTach. Lidocaine can be tried but lidocaine has certain similar effects on the myocardial cell membrane as cocaine. Both reduce sodium ion movement across the myocardial cell membrane. There isn’t a lot of science to guide us here but there is a theoretical advantage of using sodium bicarbonate to treat VTach due to cocaine toxicity rather than lidocaine. This is similar to the strategy of using sodium bicarb in tricyclic antidepressant overdoses. It’s the sodium ion that is therapeutic. The dose is the same as usual, 1 mEq/kg. In the nightmare scenario of seizing or psychotic, hyperthermic cocaine toxicity with ventricular tachycardia, the treatment strategy would be airway management, suctioning, and supplemental oxygen, cooling measures (expose head, neck and chest then wet down and fan) and IV midazolam. Then try IV sodium bicarbonate, cardioversion if sodium bicarb alone doesn’t convert the VTach, and then maybe lidocaine.

In less severe cocaine toxicity the patient may experience chest pain. This is significant because cocaine can cause coronary artery vasospasm and myocardial ischemia just like a cholesterol plaque or a thrombus. Supplemental oxygen and sublingual nitroglycerin is the treatment just like any other suspected myocardial ischemia.

Another cause of delayed poisoning syndromes is the nature of the pharmaceutical dosage form, enteric coated and sustained release products. These are both quite common dosage formulations for both prescription and over-the-counter medications and are engineered to improve product safety or make dosage administration more convenient. Enteric coated tablets are designed to dissolve only in the more alkaline small intestine and not in the acidic stomach. Aspirin and iron tablets are common enteric coated tablets since both can be irritating to the stomach lining. Enteric coating prevents release of the drug in the stomach where side effects can occur and allows dissolution in the small intestine where absorption occurs. So in overdose absorption of these or other enteric coated tablets will be delayed until they pass into the small intestine. Symptoms can therefore also be delayed.

Sustained release products allow for slower absorption of the drug over time and therefore increase the dosing interval. Longer dosing intervals make taking medication more convenient for patients. Because the drug is released slowly peak drug concentrations in blood and target organs will occur later than in immediate release formulations and symptom onset may be delayed. Some common sustained release drugs are lithium (for psychiatric disorders), theophylline (for emphysema or asthma, like TheoDur or Slo-BID), calcium channel blockers (for hypertension, like Procardia SL or Cardizem CD) and acetaminophen. Each of these can be quite toxic in overdose. Sometimes the proprietary (trade) name of the drug will be followed by –SR (for sustained release), -XR (extended release) or –CD. Sustained release products may also predispose an overdose patient to delayed deterioration. The principle is the same as delayed onset toxicity. The difference is that a patient may be mildly symptomatic but quite stable now only to suddenly deteriorate later as absorption of the drug continues. This can occur with the tricyclic antidepressants in general, but also with the sustained release forms of the calcium channel blocker antihypertensives (verapamil, which is Isoptin-SR and Calan-SR, in particular). In cases of sustained release product overdose delayed onset toxicity may occur in the 4-6 hour range and up to 24 hours or more post-ingestion depending on the drug.

Specific Pharmaceuticals with Delayed Onset Toxicity

Acetaminophen (Tylenol, Tempra, Panadol, many others)

There are two reasons for the delay in onset of acetaminophen toxicity. The most important one is the drug undergoes metabolism to a toxic product that causes injury once a sufficient amount has been formed. The second is that it is now available over the counter in an extended release form. Acetaminophen is readily available over the counter in many single and combination products.

Acetaminophen causes no immediate symptoms following overdose. Co-ingestants like alcohol or other drugs may produce symptoms independent of acetaminophen. If untreated, an acetaminophen overdose will cause vague symptoms like nausea, vomiting, anorexia and abdominal pain after about 24 to 48 hours. These symptoms will improve or resolve until about 72 to 96 hours post-ingestion when signs of liver failure begin to show up. These symptoms are return of nausea, vomiting and abdominal pain, jaundice, right upper quadrant abdominal pain and tenderness and fatigue. Unlike infectious causes of acute hepatitis, like hepatitis A, there is no fever. Once the chemical hepatitis symptoms develop, reversal of the course of liver toxicity is less successful. The liver damage can result in chronic liver failure, may require liver transplantation or can lead to death. So the key to acetaminophen toxicity treatment is early recognition, either by history or physical evidence at the scene or blood concentration measurement in the emergency department.

If the product containing acetaminophen is not one of the sustained release forms, then the dose sufficient to cause liver injury can be estimated. In general a single dose of greater than 140mg/kg of acetaminophen can be hepatotoxic. This is about 9-10 grams in an average size adult. After a single overdose the blood concentration of acetaminophen peaks within 4 hours. So 4 hours after the overdose the blood level can be used to estimate the risk of hepatotoxicity and guide further treatment. The treatment for acetaminophen overdose is to supply the body with a sulfur-containing chemical called N-acetylcystine. This chemical combines with the toxic metabolite of acetaminophen to prevent it from interacting with liver cells and causing liver damage. But it has to be given before the liver damage phase occurs. It is less effective once liver damage begins. Induction of vomiting and gastric lavage is relatively ineffective if initiated later than one-half hour to one hour after ingestion. There is also the risk of pulmonary aspiration. Orally administered activated charcoal is a safer alternative to vomiting or lavage and will bind the ingested drug in the stomach and small intestine to prevent absorption. So from an EMS perspective, recognizing the potential of an acetaminophen overdose and the approximate dose will be useful historical information.

Hypoglycemic Agents (Diabinese [chlorpropamide], Tolinase [tolazamide], Orinase [tolbutamide], Amaryl [glimepiride], Glucotrol [glipizide], DiaBeta or Micronase [glyburide])

We are quite used to the occasional diabetic patient who uses their usual dose of insulin and than forgets to eat an adequate amount of food to balance the body’s utilization of glucose. Their blood glucose drops, they become symptomatic with altered level of consciousness, and require oral or IV glucose to correct the problem. After successful treatment, frequently these patients prefer not to be transported. In this setting with a clear history and an otherwise competent and well informed patient they can safely be left at home. However, when the use or abuse of the oral hypoglycemic drugs causes hypoglycemia, then there is the added risk of recurrent profound hypoglycemia. There are several new oral hypoglycemic drugs on the market. These along with the older drugs can cause delayed onset hypoglycemia after ingestion as well as recurrent hypoglycemia after treatment. This is also true for single tablet ingestion in children. Because of the delay in onset of the hypoglycemia and the recurrence of hypoglycemia after treatment these patient should be transported to the emergency department where they should then be observed for up to 24 hours. The delay in onset of symptoms following oral hypoglycemic drug overdose varies widely. One review reported a delay ranging from 30 minutes to 16 hours with a mean of a little over 4 hours.

Treatment of hypoglycemia from oral hypoglycemic drug overdose is the same as for any other cause; D50W, 25 grams IV or oral glucose if the patient is awake enough to protect his/her airway and tolerate oral liquids. One easy way to judge whether a patient is capable of taking oral liquids is to have the patient sit upright unsupported and drink unassisted. If they can go through these motor skills without help they can probably protect their airway. The IV dose of 25 grams (50 ml) of D50W is the adult dose. In children older than 2 years the dose is 1 ml/kg of D50W up to 50ml. For the accidental overdose of oral hypoglycemic drugs, or other causes of hypoglycemia, in children younger than 2 years the dose has to modified. D50W is a hyperosmolal solution. Its osmotic pressure is much greater than body fluids. This osmotic pressure draws water across cell membranes into the blood following intravenous administration of D50W. The problem in very young children, mostly neonates, is this change in blood osmotic pressure can cause intracranial bleeding. Because of this the concentration of glucose has to be reduced. So for children under 2 years the D50W is first diluted in half with saline to make D25W. The dose of the D25W is 2 ml/kg. So we are giving the same amount of glucose just in a more dilute form.

Iron

Similar to acetaminophen, iron toxicity has a multiphasic syndrome. There are mild early symptoms, a largely asymptomatic period then the manifestation of multiorgan toxicity. These phases tend not to be very distinct. The tricky thing about iron ingestion, particularly in children, is the apparently nonthreatening dosage forms in which iron can appear. Prenatal vitamins are a good example of a widely used supplement during pregnancy. Multivitamins with iron are another widely available supplement that can cause iron overdosage in children. Prescription forms of iron include Fergon (ferrous gluconate), Feosol and other brand names (ferrous sulfate). The toxicity of these iron supplements depends upon their elemental iron content. The elemental iron content varies from one dosage form to another. So from a practical perspective, identifying the exact dosage form of iron involved will allow the emergency department to calculate the dose of elemental iron ingested and predict to some extent the potential severity of the ingestion. In general, suspected iron ingestions especially in children should be transported and carefully evaluated for early signs of shock.

An untreated iron overdose can be quite toxic, especially in children. Within about 6 hours of ingestion symptoms of nausea, vomiting, diarrhea, hematemesis (vomiting blood) and melena (black stool) develop. Iron is particularly irritating to the gastrointestinal tract so if there are no early GI symptoms after presumed iron ingestion the dose was probably low enough to avoid serious toxicity later. These early GI symptoms may appear to resolve after 6 to 24 hours. However the next phase of untreated iron toxicity is metabolic acidosis, liver failure and coma. If the patient survives this, a final outcome of untreated iron toxicity is scarring of the damaged stomach lining with pyloric obstruction. These symptom phases are not necessarily distinct and may overlap.

We can’t measure metabolic acidosis in the field (at least not yet) but one important observation that will suggest the presence of acidosis is rapid, deep breathing (tachypnea and hyperpnea). Signs of shock in children may be subtle at first. Less vigorous behavior, tachycardia, tachypnea, delayed capillary refill, and dry mucosa are fairly reliable signs of compromised perfusion. Changes in expected behavior for the child’s age is the most sensitive sign of early shock. Supplemental oxygen and IV saline boluses of 20 ml/kg are the primary treatment. Although sodium bicarbonate is useful in metabolic acidosis, there is as yet no practical way to know the presence or extent of acidosis in the field. A calculated bicarb dose can be given once blood pH is measured in the emergency department. So iron overdose (or toxic ingestion in general) is one more possibility as a cause of shock in children along with dehydration, sepsis, and occult trauma (like child abuse).

Monoamine Oxidase Inhibitors, Tricyclic Antidepressants, and Thyroid Hormone

Antidepressants like the monoamine oxidase inhibitors (Nardil, Parnate) and tricyclics (Norpramin, Pamelor, Aventyl, Vivactil) are notorious for delayed onset and delayed deterioration in overdose. The monoamine oxidase inhibitors (MAOI) are a particularly temperamental group of drugs. They have many drug-drug interactions and in overdose cause a hyperadrenergic state of hyperthermia, agitation, tachycardia, hypertension, dysrhythmias and seizures very similar to cocaine or methamphetamine overdose. Primary treatment is control of agitation or seizures with midazolam, IV fluid hydration and cooling measures.

Tricyclic antidepressants (TCA) cause anticholinergic effects. The distinction between anticholinergic effects and hyperadrenergic effects in an acutely ill patient can be difficult. Both cause mental status changes but anticholinergic effects cause delirium (confusion, hallucinations) while hyperadrenergic effects can cause violent agitation. Both cause pupillary dilation (mydriasis), tachycardia, hypertension followed by hypotension and seizures. One difference may be skin moisture. Hyperadrenergic effects can cause marked diaphoresis. Anticholinergic effects cause dry, red skin. Initial management includes airway management, cooling measures, IV fluid hydration (in the absence of pulmonary edema) and seizure or agitation control with midazolam. Tachycardia may be the first evidence of toxicity in TCA overdose. The tachycardia may begin as narrow complex and then start to widen. The initial management of tachycardia, especially with a widened QRS, after TCA overdose is hyperventilation and/or sodium bicarbonate. One reason this is thought to work is that alkalinization of the blood helps clear the TCA from the blood by reducing its binding to plasma proteins. The sodium ion specifically helps to reverse the sodium channel blocking effects of TCAs on myocardial cells. As with cocaine dysrhythmias, the dose is the usual 1 mEq/kg.

Thyroid hormone overdose is kind of unusual, but it too tends to have delayed onset. Symptoms can be delayed hours or even days after ingestion. Symptoms include fever, tachycardia, vomiting, tremor, anxiety and diaphoresis.

Hazardous Materials with Delayed Onset Toxicity

Hydrofluoric Acid

Hydrofluoric acid is unique among acids for its clinical effects. Unlike bases, acids generally cause a proteinaceous coagulum in skin which limits further penetration unless concentrations are high or contact times are prolonged. Bases liquefy tissue by hydrolyzing the fats in adipose tissue and cell membranes and tend to produce deeper burns for a shorter period of contact. Hydrofluoric acid is unique because of the fluoride ion. There is less coagulation necrosis of skin and deeper penetration occurs than with other acids. Also, the fluoride ion associates with calcium ions that can cause bone demineralization at the burn site or can deplete calcium from blood and cause cardiac dysrhythmias. Hydrofluoric acid toxicity could occur from inhalation of or skin exposure to hydrogen fluoride gas, skin or eye contact with the aqueous acid solution or potentially from intentional or accidental ingestion of the acid.

The physical evidence of acid exposure to the skin depends on the concentration. Concentrations greater than 50% cause immediate pain and victims will know to seek help. Concentrations below 50% may not cause immediate symptoms, especially concentrations in the range of 20-25%. These lower concentrations can cause skin burns and even systemic toxicity but may not produce symptoms for several hours after exposure. Early intervention may reduce the need for difficult medical therapies later. Water decontamination is the first priority. After a thorough water wash, applying a calcium salt in solution or dissolved in a water soluble gel can help to prevent further absorption of the fluoride ion which can go on to cause systemic toxicity. The calcium salt used has been calcium gluconate mixed with surgical lubricant. The sooner this can be done the more likely it will bind up the fluoride ion. The deeper the fluoride ion penetrates the skin the less effective topical calcium will be. There have been reports that applying a solution of magnesium sulfate (Epsom salt) will bind the fluoride too, but calcium has remained the standard. The significance of recognizing the hazard of delayed onset toxicity from hydrofluoric acid and implementation of early skin decontamination is that it may reduce the need for other more complicated treatments later. Once the fluoride ion has penetrated the skin, calcium gluconate may need to be injected in and around the skin site to prevent further tissue destruction or systemic toxicity. On hand burns, an intra-arterial infusion of calcium may be needed to treat extensive burns. Cardiac dysrhythmias from systemic fluoride toxicity may need treatment with intravenous calcium chloride.

Acetonitrile and Methanol

Industrial chemicals and chemicals used in household products may also present with delayed onset toxicity. Acetonitrile is used in acrylic nail remover and industrial applications. When ingested or inhaled, one product of acetonitrile metabolism is cyanide. The onset of cyanide toxicity takes several hours following an acute exposure to the liquid or vapor. Clinically, cyanide toxicity will present as metabolic acidosis without hypoxia by pulse oximetry. Early symptoms will reflect tissue hypoxia due to the inability of organs to extract oxygen from the blood. Initially there may be dyspnea, chest pain, headache or altered mental status. Later there can be coma, hypotension and dysrhythmias. Evidence at the scene that acetonitrile is the toxicant will guide treatment for cyanide toxicity which may not be detected without suspecting it among the many causes of metabolic acidosis and specific laboratory tests.

The delayed onset of methanol toxicity also results from metabolic products. Ethanol and methanol are first metabolized to aldehydes then to organic acids in the liver. So, they are another cause of metabolic acidosis. Unlike acetonitrile, methanol causes inebriation just like ethanol. Other than accidental ingestion, it is the intoxicating effects that may be sought which lead to toxicity later. The end product of methanol metabolism is formic acid. This is responsible for the metabolic acidosis as well as damage to the optic nerves (which can lead to blindness) and altered mental status. This will follow the period of inebriation.