This is Janice Zimmerman, and in this presentation, I'll be reviewing specific toxic agents and interventions to either prevent or minimize those toxic effects. I have no conflict of interest in relation to this presentation, however, I may mention several off-label uses of drugs that are used for treatment interventions. Let's start with acetaminophen poisoning. In general, the pediatric population does much better than the adult population with this type of overdose. However, toxicity may develop due to dosing errors in the very young, and that can happen with either PO medications or IV acetaminophen. Acetaminophen is effective in absorbing acetaminophen for oral ingestions if it's given early, usually within that one- to two-hour time frame. Treatment will be based on your assessment of acetaminophen level at least four hours after ingestion. And here, you're going to use the RUMAC Matthew Nomogram to evaluate for toxicity, but it's only valid for single acute ingestions that present within 24 hours. There's actually no line between zero and four hours. You also know the antidote, which is either the oral 72-hour course of treatment of N-acetylcysteine or the 21-hour IV course of N-acetylcysteine. I think most people are using IV N-acetylcysteine, but particularly in the pediatric population, you have to be cautious about dosing errors with the IV formulation. The most important thing about treatment is to administer the N-acetylcysteine within eight hours of ingestion to avoid hepatotoxicity. So even if you don't have your level back and you're approaching that eight-hour time frame, then go ahead and start treatment, which can always be stopped if the level is non-toxic. Now, in general, we don't repeat tests, but you might consider repeating an acetaminophen level as well as your transaminases before completing the IV course of N-acetylcysteine. And this is particularly true in massive overdoses, which is defined as a level greater than 300 micrograms per ml, or where there might be slowed GI motility due to multiple ingestants being involved. In these cases, a course of treatment longer than 21 hours might be needed. In these cases, you probably should also consult with your poison control center. Now, what about ingestions that don't fit the rheumatic mathenomegram? People who chronically ingest acetaminophen, or they've taken multiple ingestions over time, or they present after the 24-hour period. Here you want to administer N-acetylcysteine if you have transaminases that are greater than 50 international units per liter, an acetaminophen level greater than 10 micrograms per ml, or in a setting of hepatic failure, you're going to give a complete course. Massive overdoses of acetaminophen can be associated with a metabolic acidosis, so I've added it to this list of other agents that may cause a metabolic acidosis and overdose. In general, metabolic acidosis is not a good finding in your patient, so keep in mind these agents when you have an overdose patient and you see that metabolic acidosis, particularly the anti-GAP. But we'll start off in talking about a few of these by talking about the toxic alcohols. Let's start with our first question. A six-year-old was suspected to have accidentally ingested antifreeze. That's revealed acute kidney injury, an anti-GAP of 24 millimoles per liter, and osmolar GAP of 7 milliosmoles per kilo. The intensivist requests fomepisol stat. Which of the following is the likely response by the pharmacist? A, there's no benefit of using fomepisol, B, fomepisol will be dispensed, C, let's wait for an ethylene glycol level, or D, I have to get approval from my supervisor. Now your response may depend on the situation in your particular institution, but I want to use this question to get at the metabolism of alcohol. So the correct answer is actually there is no benefit of using fomepisol in this scenario. And the key finding here is that the osmolar GAP is normal, it's less than 10. Ethylene glycol and methanol have similar clinical findings in the patients. They get CNS depression, GI upset, and they can have cardiopulmonary symptoms. Now the classic metabolic findings in the textbook at least are anti-GAP metabolic acidosis and osmolar GAP. However, our patients don't often present exactly in that manner. You may also see an increased lactate due to interference with the laboratory assay. Now if you see oxalate crystals in the urine, that should make you think about ethylene glycol. And the presence of either of optic neuropathy or the presence of intracranial bleed or infarct should make you think more of methanol ingestion. Let's review the metabolism of alcohols because it will help you understand the clinical presentation of your patient and also the interventions used in treatment. So all alcohols will give you an osmolar GAP. All alcohols are also metabolized by alcohol dehydrogenase, but this enzyme preferentially prefers ethanol. You can see that ethylene glycol and methanol are metabolized to acids, whereas ethanol is metabolized to acetyl-CoA. This graph shows how the metabolic findings can vary with the time of presentation. The osmolar GAP in blue decreases over time due to metabolism of the alcohol to acids. The red line indicates the increase in anion GAP as acid metabolites appear. You can also see that as the osmolar GAP decreases, if it's a late presentation, with all of the alcohol gone, you may have a normal osmolar GAP. Similarly, with an early presentation, you may not have an anion GAP because the alcohols have not yet been metabolized to acid. So the treatment of ethylene glycol and methanol poisoning rests on inhibition of alcohol metabolism and then removal of either the alcohol or alcohol and metabolites. So traditionally, ethanol was used to inhibit that alcohol dehydrogenase, but today, fomefazol is more commonly used because of its ease of administration. It's given as a Q12-hour bolus, and it's a competitive inhibitor of alcohol dehydrogenase. Now, in most cases, you still need hemodialysis to remove residual alcohol, but primarily the acid metabolites. Now, the indications are a level greater than 25 milligrams per deciliter, but most laboratories cannot provide this type of information in a short period of time, so you're really left using your clinical situation and the presence of a metabolic acidosis. An osmolar gap greater than 25 milliosmoles per kilo might also be another indication and renal failure and visual symptoms, but these are usually late findings. Folinic acid is appropriate to administer in the setting of methanol poisoning because it does increase formic acid elimination. Your patient may also be exposed to other alcohols. Ethanol, of course, will give you sedative-hypnotic effects, and you may possibly see hypoglycemia, but it's actually probably rarer. Isopropyl alcohol, or rubbing alcohol, is metabolized to acetone, so you won't see acids, and primarily, it's just supportive care for symptoms, and unfortunately, it may require intubation and a significant exposure. Benzodiazepines are agents of both abuse as well as intentional suicide attempts. The most common benzodiazepines in overdose is alprazolam, but you may also see clonazepam or lorazepam. Now, unfortunately, there's now a new generation of designer benzodiazepines. You'll see names such as flubromazolam or clonazolam, and a few others out there, but clonazolam and a few others out there, and these new designer agents are more potent and longer-acting. Now, they look just like any other illicit drug. It's a white powder, so you can't really distinguish them on a drug screen from other agents. Now, there is a reversal agent for benzodiazepines, which is flumazenil, but it has a very short half-life. It can be active in reversing zolpidem effects, but the use of flumazenil in overdose is not routinely recommended, and that's due to the contraindications and adverse effects. Flumazenil is contraindicated in patients who take cyclic antidepressants and those who chronically use benzodiazepines. In general, if someone has overdosed on a benzodiazepine, the chances are they've been taking it for some time, so they do have chronic use. Now, a recent meta-analysis found that the significant adverse effects associated with flumazenil were seizures and arrhythmias, particularly supraventricular arrhythmias. Let's ask a second question here. You have a 10-year-old girl who presented after ingesting unknown pills at her grandparent's house. She is lethargic with a pulse of 52 and a blood pressure of 72 over 40. Which of the following is the best initial intervention? Transthoracic pacing, lipid emulsion, glucagon and calcium, or dopamine? Well, hopefully you chose glucagon and calcium, and here you have a patient who has bradycardia and hypotension, so you should be thinking about some type of cardiovascular drug such as a beta blocker or calcium channel blocker. Let's go on. There is no hemodynamic improvement after two doses of glucagon and high doses of calcium. Which of the following is the appropriate intervention at this time? Transthoracic pacing, lipid emulsion, ECMO, or high-dose insulin infusion? Well, the correct answer here is high-dose insulin infusion. Beta blockers and calcium channel blockers are probably the most common drugs you'll see causing bradycardia in an overdose. This list gives you other drugs that you might associate with bradycardia, but they're much less common. We don't see much digoxin out in the community anymore and not as much clonidine. The typical clinical manifestations suggesting beta blocker or calcium channel blocker overdose are hypotension and bradycardia. Altered mental status may be a clue to a beta blocker overdose as more of these agents cross the blood-brain barrier. Hyperglycemia is a hallmark of calcium channel blocker toxicity. When approaching the management of these patients, take into consideration the specific agent, if you know it, whether there's myocardial dysfunction, usually manifested as hypotension, bradycardia or AV block, and then also how have they responded to your previous interventions? This is an algorithm that you can follow in managing these patients. If you know the agent that was ingested, then you would choose glucagon, if it's a beta blocker overdose, or calcium chloride, if it's a calcium channel blocker overdose. If you don't know which drug it is, then you can give both of these agents as the initial intervention. Remember that the hypotension in these overdoses is more frequently due to the negative inotropic effects. So in this case, glucagon is an inotropic agent that doesn't require the beta receptor. If you have persistent hypotension, then you can try norepinephrine or epinephrine, but keep in mind that beta receptors are blocked in the setting of a beta blocker overdose. Now, if these interventions are ineffective, then you should try high-dose insulin. And please note the dose here. It's one unit per kilogram, bolus, and then one unit per kilogram per hour. This is 10 times the doses used for DKA. We have more experience with this intervention in calcium channel blocker overdoses than beta blockers, but it has been used successfully in both. Now, you can give atropine, but it really doesn't work. Now, what happens if your patient doesn't respond to these interventions? Well, you can go even higher with reports of up to 10 units per kilogram per hour of insulin. Now, of course, if you're giving an insulin infusion, you're going to be giving concentrated glucose. You can try pacing, but just increasing the heart rate may not improve hypotension. And this is an intervention where lipid emulsion should be considered if your other standard interventions have failed. Of course, there's complications associated with high-dose insulin use. 30% will develop hypokalemia, and 30% will develop hypoglycemia. There are various rescue therapies that have been reported, including balloon pump and ECMO. And this is one situation in a cardiac arrest due to these agents where you should give calcium, and you may consider giving lipid emulsion. I want to briefly mention lipid emulsion as a potential antidote in overdoses. Lipid emulsion is the indicated antidote for poisoning due to a topical anesthetic. However, its use in other overdoses lacks significant evidence. It has been proposed that it may be helpful for lipophilic cardiotoxins, but the case reports have reported success with a variety of different drugs used in overdose. It is administered as a lipid bolus and then an infusion. As we've had more reports of its use, we've also seen more reports of adverse effects, including pancreatitis, acute lung injury. The hyperlipidemia can interfere with your lab assays. It can also obstruct dialysis filters. And fat embolism and even cardiac arrest have been reported. The lipid emulsion is never the first antidote to be tried, but can be considered when you have a patient refractory to other interventions and who has a toxin on board that might benefit from lipid emulsion. Carbon monoxide poisoning is often seen in younger children. And when you are faced with this type of patient, you wanna make sure that you assess the carboxyhemoglobin level along with symptoms, particularly CNS symptoms and cardiovascular symptoms, and also assess the presence of metabolic acidosis. The acidosis is usually lactate and that lactate level predicts the severity of exposure even better than the carboxyhemoglobin level. A oxyhemoglobin saturation gap between a measured and a calculated saturation is another clue to the presence of carboxyhemoglobin. Of course, you know the treatment is 100% oxygen and intubation may be needed to administer the oxygen. The indications for hyperbaric oxygen use are continually debated. And unfortunately, the few clinical trials have not enrolled children. So the benefits of hyperbaric oxygen in children is really unclear. I want to call your attention to a cause of carbon monoxide poisoning that you might not be aware of, which is water pipe or hookah smoking, which is popular with adolescents. In this case, carbon monoxide results from the combination of carbon dioxide and the heated charcoal. Individuals who smoke the hookahs and also those who are just present in a hookah lounge can have carboxyhemoglobin levels as high as 20 to 35%. And the reports show the similar manifestations that you would expect of syncope, headache, dizziness, nausea, and weakness. And of course, the management is oxygen. Let's go over this question. A 16-year-old is admitted to the ICU for seizures, hyperthermia, tachycardia, and agitation. Drug use is suspected, but the urine toxicology is negative for phencyclidine, cocaine, and amphetamines. Which of the following is the most likely toxin? Ketamine, LSD, synthetic marijuana, or gamma-hydroxybutyrate? The correct answer is synthetic marijuana. Ketamine is a dissociative anesthetic and would usually give you more bradycardia. LSD certainly can give agitation, but usually not hyperthermia. And gamma-hydroxybutyrate is a sedative hypnotic, so it would really give you opposite types of findings. Now, I'd like to kind of talk about the sympathomimetic toxins as a group. And here's a list of the ones that your patients may be exposed to. There are the ones you might expect, cocaine, amphetamines, and methamphetamines, bath salts, which we'll talk about, synthetic cannabinoids, phenylethylamines, and then methylphenidate. And these drugs look about the same. They're all white powders, crystals, and you can't tell them apart. And they're abused by a variety of routes. The toxicities affect all organ systems. The cardiovascular system, you can see arrhythmias or acute ischemia. You can have seizures, intracranial bleeds, and stroke in the central nervous system. Pulmonary complications are not as common, but you can see pulmonary edema and hemorrhage. Rhabdomyolysis is very common, as is self-induced or accidental trauma, acute kidney injury, and also ischemia in the GI tract with infarction even occurring, and hyperthermia. And then, of course, there's always the effects of potential contaminants in these drugs. Just a few extra words about amphetamines and methamphetamines. These drugs are primarily produced in Mexican super laboratories, and they're associated with raves and the nightlife in adolescents and young adults. And they're usually in the form of a variety of pills, which are very easy to bring into a nightclub or a dance venue. In addition to the typical sympathomimetic toxicities, you may also see acute and chronic cardiomyopathy with these drugs, as well as pulmonary hypertension. And of course, there may be cognitive and behavioral changes as well. Treatment of most sympathomimetic toxicity is the same. Gastric decontamination is not helpful because the drugs are usually already absorbed. So you're left with really controlling the agitation, which is primarily done with either IV or intramuscular benzodiazepines. CDX-metatomidine use has also been reported, but in general, you wanna avoid haloperidol if at all possible, because haloperidol will lower the seizure threshold as many of these drugs do as well. Often IV fluids should be started initially with any agitated patient to start to treat the possibility of rhabdomyolysis. And then you're left with really anticipating and treating all of the other potential complications. Bath salts are a group of products that are very popular with young adults and adolescents. And they contain a variety of compounds such as methadrone, pyrovalerone. And these are synthetic cathinones derived from the cat. That's the K-H-A-T plant from Eastern Africa. The new one on the market is called flakka or gravel, and that's because it looks like white pieces of gravel. These drugs have stimulant and hallucinogenic properties. The appealing part of these drugs is that they are not detected on a routine drug screen. In addition to the sympathomimetic effects, they're associated with significant paranoia and aggressive behavior. And in general, these patients require sedation with higher doses of benzodiazepines compared to cocaine abuse. There are reports of prolonged delirium and psychosis in some of these patients, and the use of haloperidol or risperidone has been reported to be successful. Synthetic marijuanas or cannabinoids are also popular with the adolescents. And these compounds bind to cannabinoid receptors in the brain and spinal cord. Now, these products were initially sold as K2 and Spice coming from Europe. And there are now even, unfortunately, liquid forms for vaping. But most are sold in a variety of packages that you can see appeal to adolescents. There's potpourri, but there's Scooby Snacks and the Green Monster. It's been estimated that about 11% of high school seniors smoke these products, and it's predominantly males. This group of compounds is also not detected in urine drug screen. These synthetic marijuanas produce sympathomimetic effects plus very aggressive behavior, including self-harm such as jumping off of buildings along with paranoia. Acute kidney injury is more common with these compounds, and you may also see long-lasting psychosis. Management is similar to bath salts using higher dose benzodiazepines in supportive care. There's been recent reports of memory deficits and decreased cognitive function in chronic users of these compounds. For this question, we have a 15-year-old with history of depression who presents with altered mental status in the EKG that you see here. Which one of the following interventions is indicated for the arrhythmia? Amiodarone, cardioversion, magnesium sulfate, or sodium bicarbonate? Hopefully you chose sodium bicarbonate as the correct answer. So the key here is history of depression and a wide complex tachycardia. That should make you think of an antidepressant. When we talk about antidepressants, I think it's important to realize that SSRIs and bupropion are much more common in teens than tricyclic agents in overdose. However, all antidepressants may have similar toxicity. That includes arrhythmias, depressed level of consciousness, which is most common for your tricyclic agents, seizures, which are more common with bupropion, and hypotension. In patients who present with an antidepressant overdose, you can use charcoal if they present early. This is an ingestion where you may consider lavage if it's a significant toxic ingestion, but you don't have to do gastric lavage. In the setting of evidence of cardiovascular toxicity, and that usually means a widened QRS, then blood alkalinization or sodium loading is indicated. Blood alkalinization with sodium bicarb was thought to change the binding of drug and altering the free drug and bound drug ratios. However, these drugs also bind to the sodium potassium ATPase receptors in the myocardium. So sodium loading may actually be the mechanism. So sodium helps to displace these drugs from the myocardial receptors. In refractory cases, you can try hypertonic saline or lipid emulsion. Other antiarrhythmic drugs that you may consider primarily are magnesium, which has been used successfully after sodium bicarbonate. If you have persistent hypotension that does not respond to fluids, then you want a vasopressor with direct alpha agonist activity. And of course, for any drug-induced seizures, benzodiazepines are the agent of choice. Selective serotonin reuptake inhibitors can exhibit toxicity similar to other antidepressants, but a unique type of toxicity associated with these drugs is the serotonin syndrome, which is manifested as altered mental status, autonomic dysfunction, and neuromuscular abnormalities. I'm often asked what the difference between serotonin syndrome is compared to neuroleptic malignant syndrome, and it really is the neuromuscular abnormalities. In serotonin syndrome, the neuromuscular abnormalities are usually tremor or clonus, not rigidity that you would see with neuroleptic malignant syndrome. In ICU patients, primarily adults, this has been seen where an SSRI is combined with an opiate or antiemetic. But don't forget that this syndrome can develop in the combination with lenazolid, tramadol, or dextromethorphan. If you're dealing with serotonin syndrome, then the easiest thing is just to stop the precipitating agent and provide supportive care. This might include cooling or sedation, and you can choose the sedative that you normally would use, and rarely would neuromuscular blockade be indicated. This syndrome usually resolves in 24 to 72 hours. You may have seen reports of using cyproheptadine as a serotonin antagonist, but this is limited evidence and it is not routinely recommended that you use these agents for this syndrome. Due to the prevalence of diabetes in this country, it means that you may see patients with toxicity due to these hypoglycemic agents. If someone has overused insulins, then they usually develop hypoglycemia that we treat with concentrated glucose that can be administered either intravenously or orally. Glucagon may be an option, usually when you don't have IV access and you can administer this subcutaneously. Sulfonylureas are more likely to give prolonged hypoglycemia, and in this case, what you want to use is octreotide. It's the only agent that will actually inhibit insulin release and shorten the hypoglycemic period. Remember that concentrated glucose actually increases insulin release. So in situations with sulfonylurea poisoning, you would like to try to avoid concentrated glucose if at all possible. Now, metformin usually has minimal effects as far as toxicity, but in certain circumstances, you may see a metabolic acidosis, which is called MALA, metformin-associated lactic acidosis. And in some cases, this can proceed to hypotension, altered mental status, and in very severe cases may require hemodialysis. Hydrocarbon toxicity is more likely to be seen in the toddler population who come in contact with household products. The primary toxicity is pulmonary with the onset of pneumonitis. Usually gastric emptying is not recommended because of the potential for aspiration and charcoal is not effective. So the mainstay of treatment is respiratory support. Now, inhaled hydrocarbons are typically abused by adolescents. And this comes from a variety of agents, such as Freon, which is not as common today because it is not as readily available, but more likely you'll see exposures due to the aromatic hydrocarbons, primarily toluene, and carburetor cleaner is a popular product. But you may also see exposure to butane and gasoline. And these are abused in a variety of manners, sniffing directly from containers, or what's called bagging, pouring into a bag and then inhaling. The effects can be multiple, CNS depression, acidosis, arrhythmias, and pneumonitis. And here the care is primarily supportive. Iron poisoning is much more common in pediatrics than in adult toxicology, but the incidence of iron poisoning has decreased significantly along with a decrease in mortality. Poisoning was often due to the fact that many of the iron supplement pills looked like candy, but today there's such a variety out there that it's no longer just looking like candy. Now, toxic dose is based on elemental iron. So I've put here some of the content of iron supplements in adults, which is 45 to 65 milligrams of elemental iron per pill. And in prenatal vitamins, it's 27 to 35 milligrams per pill. A toxic dose of about 20 milligrams per kilogram may cause symptoms and you'll start to see severe toxicity when the elemental iron exposure is greater than 60 milligrams per kilogram. Now the clinical manifestations are staged. Early you're going to see vomiting and diarrhea and abdominal pain and then there's a latency period which can be 6 to 24 hours before they go in to what I would call the critical care period where you're going to see hypovolemia, hemodynamic instability and acidosis and then hepatic failure usually follows. If they survive the poisoning then they may be at risk for gastric outlet obstruction weeks later. When you're evaluating a patient with a potential iron ingestion you want to get an abdominal radiograph because many of these will be visible on radiograph. You're going to need serial electrolytes looking at acid-base status and LFTs. You want to get a serum iron level after ingestion usually the first one around 3 to 5 hours after ingestion and then a second level at 6 to 8 hours after ingestion and you're going to base your management on the higher levels of these that you obtain. In the past total iron binding capacity has been used but this is really of little value and shouldn't routinely be obtained. When you're treating these patients you may consider whole bout irrigation but again the evidence is not clear that it's going to eliminate the products. The treatment is daphoroxamine which is administered intravenously which helps to chelate the iron and then renally excrete the drug. When do you give daphoroxamine? Well if they look toxic or they have an iron level greater than 500 micrograms per deciliter. Before administering daphoroxamine you want to get a baseline urine for color and then you administer the daphoroxamine and you'll start to get the red and then pink urine so you want titrate to affect with the goal of having a clear urine at the end of treatment and you want to discontinue when the patient's improved symptomatically the acidosis is resolved and you don't have any further color change in the urine. Lithium toxicity may be seen as an accidental ingestion or as a deliberate ingestion particularly adolescents who may be taking lithium. The primary toxicity is central nervous system. They can develop tremor, agitation, all the way to being comatose and levels do correlate with toxicity but it depends if they're a chronic or an acute ingester. Chronic ingesters develop symptoms at a lower level. Acute single ingestions may have levels even as high as 6 millimoles per liter and be asymptomatic. This is another ingestion where you may consider whole bowel irrigation. Lithium causes a diuresis so in these patients you want to make sure you administer fluids to optimize intravascular volume. You want to get an immediate lithium level and then repeat it two hours later. Keep in mind that most of these preparations are sustained release so in general you want to make sure that the lithium levels are not continuing to go up. The treatment of choice for significant toxicity is hemodialysis or the use of continuous renal replacement therapy. Well let's talk about opioids in children. In general the pattern of opioid exposures in children parallels the experience in adults so this will give you an idea of the history and the timeline of what has happened in adults. In a one-year period between 2020 and 2021 there were over 100,000 deaths from overdose and almost two-thirds of those deaths involved opioids other than methadone. This epidemic started with the use of natural and semi synthetic opioids which is that dark green line that you see. However as restrictions were put in place supplies were limited to individuals and you saw the rise of heroin because it became more accessible. But what we have today is now the synthetic opioids. This is the fentanyls and this is the growing epidemic which is particularly toxic. This is data from on opioid deaths in the pediatric population that came from CDC and you'll see that this varies over time but predominantly deaths occur in the adolescents, males, they're white and the majority of these overdoses are unintentional. Mortality increased the highest in that 15 to 19 age group but also in that toddler age group because they accidentally were exposed to these drugs. Prescription opioids were implicated in the majority of deaths but we've also seen that increase in deaths from heroin and if we had more recent data I'm sure there would be even more deaths from the fentanyls. Well that epidemic started with prescription opioids and these were abused by either ingesting them, snorting them, they smoke them and they even injected them. And the problem here is that there's often prolonged effects because of sustained release forms of these products being available and many of these agents are long-acting. Oxycodone and hydrocodone are still popular but what we're seeing today is an increase in buprenorphine use which is a partial opioid agonist and the reason for this is that buprenorphine is being used to treat opioid addiction so these pills are present in the homes and more prescriptions are available. We also see the rise of synthetic opioids and these are the non fentanyls they're often a you number and these are the what you'll find on the dark web. But as people have tried to go away from prescribing opioids you'll also see more tramadol and tepentadol prescriptions which has led to more overdoses with these drugs. Well following prescription opioids as the restrictions went into place they became less accessible so heroin saw a rise and this primarily comes from Mexico and Colombia. We saw mortality go up in the early 2000s all the way to 2014 and in these are patients who usually started their addiction with prescription drugs and then moved to heroin when it became more accessible than the pills and unfortunately heroin that was being produced now is much more potent and they had no history of exposure so it often resulted in overdose. If you're in California you're probably aware of the use of black tar heroin and I put some cost here I don't this is the most recent I could find and it this helps to explain some of the epidemiology that we've seen. So heroin which is labor-intensive because it's requires a lot of human effort cost about $6,000 per kilogram in 2017. The latest phase in the epidemiology of opioid abuse is the rise of fentanyl and IMS and that stands for illicitly manufactured fentanyls and these drugs are usually available as a powder for IV use or pills and they predominantly come from Mexico and China. As you know these drugs have very high potency and rapid onset of toxicity so patients may be found with the dead with the needle still in their arm. These drugs are often combined with other drugs including benzodiazepines and cocaine. There are a multitude of analogs out there acetyl fentanyl, carfentanil, furanyl fentanyl and again these are often more potent carfentanil is used to sedate elephants. Fentanyls are not detected on drug screens. The cost in the US is about $4,000 per kilogram so the cost is lower due to the fact that these can be manufactured and don't require as much human labor. So that explains a lot of their popularity on the market today. Tramadol to pentadol prescriptions have increased and also the exposures and overdoses and there's some interesting manifestations you might not be aware of. Of course you're familiar with lethargy and coma and respiratory depression but some of these patients actually present with agitation. Seizures can be seen particularly with tramadol and also the serotonin syndrome but both drugs may be associated with hypertension, tachycardia and even cardiogenic shock. Naloxone will reverse the opioid effects but not all of the effects. One clue to the presence of tramadol is that it gives a false positive on the urine tox screen for phencyclidine. You know the antidote for opioids which is naloxone and it can be administered in a variety of routes if you don't have intravenous access. What's grown in popularity has been the intranasal naloxone which is available for home use as well as public use and it was initially available only in two-milligram form but now due to the potency of these fentanyls and other drugs it's now available in four and eight milligram doses as well. For your pediatric patients the initial doses are here. I will tell you that in many cases higher doses are being used even for the initial dose and then you need higher doses and more frequent dosing for these synthetic agents. If you get to the patient in time a continuous infusion of naloxone can avoid intubation. I do want to mention some recent trends to be aware of and that's the abuse of loperamide which has been called the poor man's methadone and often this drug is obtained which is over-the-counter when someone who is addicted can't get access to their other drugs. Unfortunately loperamide increases the QTC interval and is associated with arrhythmias. Gabapentin is also often being combined with opioids which leads to increased sedation and baclofen also we're seeing more hospitalizations and ICU admissions. A new one to keep a lookout for is xylosine. Of course this isn't picked up on a drug screen but this is a non-opioid veterinary sedative and it's now been seen combined with heroin and fentanyls and of course results in even greater sedation. This is our last question. An intubated patient is admitted following exposure to an unknown gas. Findings include hypoxemia, copious respiratory secretions, small pupils, bradycardia, and diarrhea. Appears to have significant diffuse weakness. Which of the following interventions should be instituted? Pyridostigmine, atropine, sodium nitrite, and sodium thiosulfate, hyperbaric oxygen, or halidoxine. Well the correct answer here is atropine and this is a classic cholinergic poisoning that hyper secretory toxidrome if you will. Now cholinergic poisoning is classically associated with organophosphate or pesticide poisoning but we don't have much use of organophosphates in the United States but you can see this syndrome with carbamate which is also used in pesticides. Keep in mind that nerve gases such as sarin also produce cholinergic syndromes and as I mentioned this is the hyper secretory syndrome, salivation, lacrimation, urination, defecation, GI upset, and emesis. Along with either bradycardia or tachycardia and the weakness. So the treatment here is atropine for control of secretions and you may need very high doses, repeated boluses, or a continuous infusion. Atropine supply is limited which it would be in a mass exposure then glycopyrrolate can be used to help control secretions and since atropine does not reverse the nicotinic effects then pralidoxine is needed for weakness but you have time to administer this drug. It's not as immediate as the need for atropine. Keep in mind that in these patients you do want to avoid succinylcholine for intubation as that will just prolong the period of weakness in these individuals. I want to briefly review a few hospital acquired intoxications that you may come across. In pediatrics of course dosing errors with heparin can lead to toxicity. Unfortunately opioid overdoses can still occur in the hospital setting because of our need to control pain and we seek those smiley faces. Keep in mind that hand sanitizers which are everywhere in the hospital setting contain 70% ethanol or isopropyl alcohol. Topical anesthetics can lead to methemoglobinemia that's particularly true in the setting of transesophageal echoes and other endoscopies and of course the treatment here the antidote is methylene blue. High-dose lorazepam which is has a diluent of propylene glycol can result in intoxication but we seldom use high doses of lorazepam anymore. Lastly let's just talk briefly about propofol infusion syndrome. Propofol infusion syndrome was first described in the pediatric population. The patients who are at high risk include almost all of our critically ill patients but toxicity is more likely with higher doses that are administered over a longer period of time. There are a wide variety of clinical manifestations but there are several I think you need to look out for. First if you see a new or worsening metabolic acidosis think about this syndrome. The presence of rhabdomyolysis is evidenced by an increased CK. The other clue is often worsening hypotension or a new onset of hypotension and in some cases this may be evident by the need to increase your dose of vasopressor. Management of course includes the discontinuation of propofol and use of another sedative agent. More aggressive interventions have been described for severe cases including plasma exchange, ECMO, and partial exchange transfusion. I'd like to thank you very much for your attention.

toxic agents

interventions

acetaminophen poisoning

benzodiazepine overdose

carbon monoxide poisoning

serotonin syndrome

antidotes

poisonings