SCCM Resource Library-Emerging Issues in Toxicology

Video Transcription

Welcome, SECM members are especially aware that poisoning is a significant problem in the United States, and it is a leading cause of unintentional injury death.  My name is Jamie Rossini. I've been a pharmacist in the emergency department for over 13 years at Christiana Care in New  York, Delaware, and I work closely with the Poison Control Center at the Children's Hospital of Philadelphia.  I'm really excited to be moderating this session on emerging issues in toxicology. I want to thank SECM for the programming of this session and the opportunity to moderate.  Over a year ago, we were hit with a mysterious lung disease associated with e-cigarettes and vaping devices.  Then a few months later, a new viral lung disease took over public consciousness and our race to find a cure led to new toxic problems.  Meanwhile, we still continue to try to find new ways to alleviate pain among the ongoing opioid epidemic.  We have a great panel of speakers to address the toxic implications of those issues today. Without any further delay, I'll send the mic over to our first speaker.  Hello, my name is Caitlin Brown. I'm an emergency medicine and neurocritical care pharmacist at Mayo Clinic in Rochester, Minnesota.  Amid the COVID-19 pandemic, it has been easy to overlook the ongoing battle with the opioid epidemic.  However, the opioid epidemic has had an alarming increase in drug overdoses and drug overdose related deaths, likely secondary to social isolation, closing of treatment centers, and  lack of resources. It's imperative that we look to alternative analgesics for pain management. However, these alternatives come with related toxicities.  Today, I'll be discussing good intentions but risky propositions, toxicities associated with alternative analgesics. I have no financial disclosures or conflicts of interest.  The objective of my presentation today will be to discuss toxicities of analgesics that are being more commonly used as alternatives to our traditional opioids.  Let's first take a step back and see how we got where we are today. In 2012, we had a peak in the U.S. of opioid prescriptions being written.  The opioid epidemic continued, and in 2017, there were 58 opioid prescriptions written for every 100 Americans.  More than 17% of Americans had at least one opioid prescription still. Continuing into 2018, 41 people died every day from an overdose involving prescription opioids.  As the number of opioid prescriptions written decreased, the amount of heroin use increased,  and heroin-involved overdose deaths were more than seven times higher in 2018 compared to 1999.  Looking at the past year, 2020, there was a 10% increase in overdose deaths from March 2019 to March 2020.  In 2019, we had seen a decline in these deaths, but now in 2020, we are seeing an increase.  There were 19,416 individuals dying of a drug overdose in the U.S. in just the first three months of 2020.  Because of these alarming numbers, we need to look to alternative analgesics for pain management.  In my discussion today, I'll be focusing on oral analgesics, mostly tramadol and gabapentin, as we're seeing increased use and misuse of these agents.  I'll close my presentation by briefly discussing some other emerging toxicities with alternative analgesics.  Tramadol was created in 1977 by Kirk Flick, a chemist in Germany, and his goal was to create an opioid that had less side effects compared to its counterpart.  It was approved for use in the United States in 1995, and it wasn't until recent years that tramadol gained popularity.  As we battle the opioid epidemic, there is a perception that tramadol was a safer alternative to our traditional opioids, and prescribing of tramadol increased.  From 2008 to 2013, tramadol prescriptions doubled from 23 million to 44 million.  In a study by Fields and colleagues, they looked at post-operative patients who received opioids and found that patients who received tramadol alone compared to other short-acting  opioids actually had a 6% increase of becoming prolonged opioid users. This isn't isolated to the United States, as global tramadol consumption has increased 186% from 2000 to 2012.  This is likely due to it not being a controlled substance and being easily sold and bought across the world.  In addition to an increase in tramadol prescriptions, we've also seen an increase in tramadol-related ED visits.  A study looked at tramadol-related visits from 2005 to 2011, and we can see more than a threefold increase.  In 2005, there were approximately 6,000 ED visits for tramadol-related events, and in 2011, this number increased to approximately 21,500.  To better understand the toxicities of tramadol, we need to first understand its pharmacology. Tramadol has two enantiomers, and what this means is that it has two parts of the drug  that work on different mechanisms. The first enantiomer is responsible for mu-receptor analgesia, so this is working on our opioid receptors.  Of note, tramadol has approximately 4,000 less folds, infinity to binding to the mu-receptor compared to morphine.  This enantiomer is also responsible for the inhibition of serotonin reuptake. And lastly, it's important to note that this enantiomer has an active metabolite, O-methyltramadol,  which also has mu-receptor activity, so it's also working on our opioid receptors. This metabolite is actually upwards of six times higher affinity to binding to the opioid  receptor compared to tramadol enantiomer itself, so this metabolite is having a large role in the opioid activity we see from tramadol.  The second enantiomer is responsible for inhibition of norepinephrine reuptake. So to summarize, tramadol is an opioid agonist, and its metabolite works on the mu-opioid  receptor in the CNS, causing inhibition of our pain pathways. This alters the perception of pain, and then we also have tramadol working as a serotonin  norepinephrine reuptake inhibitor, working on our descending pain pathways, which is responsible for pain relief.  This dual mechanism, along with some pharmacokinetic factors of tramadol, leads to many of its toxicities.  I often refer to tramadol as a dirty drug, and that's because its metabolism is not very clean. Tramadol is metabolized by CYP2D6 to that active metabolite, which I'll refer to as  the M1 metabolite. Based on pharmacogenomic factors of patients, they could be ultrametabolizers or slow metabolizers.  So for example, if someone was an ultrametabolizer, they would metabolize tramadol to its active M1 metabolite and have more activity on the opioid receptors.  However, if they were a slow metabolizer, they would slowly metabolize tramadol to the active metabolite and have less activity on its mu-opioid receptors.  CYP2D6 is also responsible for many drug interactions, both inhibiting and inducing the metabolism of tramadol.  And lastly, to complicate and make things even worse, tramadol is 90% renally eliminated. Both tramadol and its active metabolite go through renal elimination.  So if anyone has acute kidney injury or chronic kidney disease, they're going to accumulate tramadol in the active metabolite, leading to more affinity and more action on the opioid  receptors.  So for example, if we gave patient A 50 mg of tramadol and we gave patient B 50 mg of tramadol, the effects they have could be very different based on their pharmacogenomic profile,  their drug interactions, and their renal elimination.  These factors lead to many severe toxicities dealing with tramadol, the first of these being respiratory depression.  Since tramadol has opioid receptor activity, it will present as an opioid toxidrome, and you will see respiratory depression, CNS depression, and sedation.  Secondarily, tramadol ingestions can lead to seizures. The mechanism of tramadol is not fully elucidated, but it is thought that higher doses of tramadol inhibit GABA receptors.  And lastly, serotonin syndrome is another toxicity that can be seen with tramadol ingestion. This is most likely seen with ingestion of other serotonergic agents, but it can be seen  in isolated events. A retrospective study of cases reported to an Australian poison center found no cases  of serotonin syndrome, but in the literature, there are reports of serotonin syndrome happening  with other serotonergic agents and a few case reports of serotonin syndrome happening with tramadol alone.  Because of the increase in prescribing of tramadol and ingestions of tramadol, there have been a number of reports recently in the literature looking at tramadol's toxic effects.  Retrospective review of case reports to poison centers in the U.S., Iran, and Australia have been published.  These reports looked at demographics and symptoms from cases reported to their poison centers from tramadol ingestion.  Doses from these reports range from a taste amount to just a child putting a tramadol tablet in its mouth and spitting it out, all the way up to 20,000 milligrams.  Additionally, there have been prospective evaluations. One study looked at patients with a history of tramadol abuse and misuse and were followed  for three years to monitor their incidence of seizure. Another prospective evaluation was done at seven poison centers, and they prospectively  collected data when they had tramadol exposures.  I've collated the toxicities reported in the literature on this slide here. The incidence of seizures in tramadol ingestions ranged from 14 to 55 percent.  However, most cases were in the 30 to 50 percent incidence range. Seizures happened with tramadol at a variety of doses, but the lowest dose causing seizures was 200 milligrams.  Seizures occurred after ingestion mostly in the first six hours, and most of those in the first six hours occurred in the first two hours of ingestion.  So if you're going to see seizures, it is likely to happen during the beginning phases right after the patient ingests tramadol. The next toxicity is respiratory depression.  This is from the opioid receptor activity, and this also ranged from 0.5 to 20 percent incidence in tramadol ingestions.  One study found that 3 percent of patients with tramadol ingestion required respiratory support.  There has been a dose response found for respiratory depression after tramadol ingestion. One study found that doses greater than or equal to 21,000 milligrams were correlated  with respiratory depression, and another study found doses greater than or equal to 25,000 correlated with respiratory depression.  However, doses as low as 800 milligrams have been found to associate with respiratory depression. A third toxicity commonly reported was nausea and vomiting.  This incidence was 22 to 76 percent. For nausea and vomiting, we can consider an anti-emetic.  The reports of serotonin syndrome were minimal in these studies, and another toxicity to be notable with tramadol is dysglycemia.  So there have been notes of hypo- or hyperglycemia seen with tramadol ingestions, and it's important to monitor glucose in these patients.  So let's discuss how we treat these toxicities, first being respiratory depression. Because it has opioid receptor activity, a naloxone should be considered, and as well  as intubation if they cannot protect their airway. In one study, patients given naloxone for tramadol ingestions had a 64 percent efficacy rate.  There have been reports that naloxone can induce seizures in tramadol overdoses, but more recent and larger studies have shown that is not the case.  And in one study, naloxone actually decreased the incidence of seizures from 14 to 5 percent. For the treatment of seizures, we should use benzodiazepines.  Patients who have seizures from tramadol likely won't go on to need antiepileptic drugs, since the drug tramadol will be cleared.  And lastly, serotonin syndrome should be treated with benzodiazepines. In severe cases, ciproheptidine may be considered, but that is out of the scope of this presentation today.  The last one to consider is decontamination and if there is a role for activated charcoal in tramadol ingestions. Really, this should be a discussion with the healthcare team.  The risk of activated charcoal with tramadol toxicity include vomiting and aspiration, and I would recommend avoiding this in patients with altered mental status.  There may be a benefit of activated charcoal if the tramadol ingestion happens within one hour. Some conclusions about tramadol.  Tramadol prescribing abuse and misuse are increasing. Seizures occurred in 15 to 50% of patients with tramadol ingestion and have been reported  with doses as little as 200 milligrams. Respiratory depression has been found with a dose response of ingestions greater than  approximately 2,100 milligrams, but seen with doses as little as 800 milligrams. And supportive care and benzodiazepines should be used for tramadol toxicity management.  Now moving on to gabapentin. Gabapentin is most commonly prescribed for neuropathic pain, and again, to combat the  opioid epidemic, we have been seeing an increase in gabapentin prescribing. In 2016, gabapentin was actually the 10th most commonly prescribed prescription in the United States.  A study looked at private insurance claims and found that from 2009 to 2016, gabapentin  prescriptions more than doubled, from 13.3 to 27.1 prescriptions per 1,000 beneficiaries. An ambulatory care study looked at patients they saw in their visits who were on gabapentin  and the number of patients on gabapentin quadrupled from 2003 to 2016. It's also important to note that about 33% of these patients were also taking concomitant  opioid prescriptions, and over 90% of patients on gabapentin were on it for off-label use.  Similar to tramadol, since gabapentin prescribing has increased, the reports to Poison Center for gabapentin exposures has also increased.  A study looked at the number of exposures reported to poison centers on a national database from 2013 to 2017, and there was a 72.3% increase in exposures.  To help understand the toxicities of gabapentin, we'll briefly discuss the pharmacology. Much of the pharmacology of gabapentin is not fully understood, but what we do know  is that it binds to voltage-dependent calcium ion channels. This blocks the development of hyperalgesia and inhibits excitatory neurotransmitters.  Similar to tramadol, gabapentin also does have renal clearance, so patients with renal dysfunction will accumulate gabapentin and be at risk of increased toxicities.  The toxicities seen with gabapentin are sedation, dizziness, and ataxia. The usual dose of gabapentin ranges from about 100 to 900 mg, and in isolated gabapentin  ingestions, symptoms were seen from doses ranging from 12,000 mg to 35,000 mg. Of gabapentin ingestions and overdoses, about 16% need to be admitted to the hospital, and  of those, 50% are admitted to the intensive care unit, so these toxicities can be severe.  The most troublesome thing with gabapentin overdoses and ingestions is co-ingestions. Approximately 60% of patients ingesting gabapentin are also ingesting other co-ingestions.  This can be opioids and benzodiazepines, which worsen the effects of sedation, respiratory depression, and CNS depression.  So what's the big deal with these co-ingestions, really? The CDC reported that gabapentin was detected in 20% of opioid-related deaths, and a study  in Canada found that co-prescriptions of gabapentin in opioids resulted in increased risk of opioid-related deaths, with an odds ratio of 1.99.  So patients taking opioids are also taking gabapentin and at increased risk of opioid-related deaths.  A study looking at toxicological gabapentin-positive blood samples found that opioids were also  detected in 43% of cases, and only 7% of cases were solely gabapentin, again emphasizing that gabapentin is being ingested with other agents.  There was a study done that surveyed patients in Kentucky who were diverting and using opioids  for non-medical purposes, and 15% of them reported to using gabapentin specifically to get high. This was an alarming 165% increase just in one year.  So gabapentin is being used with these other agents of abuse to help get high and leading to worse toxicities.  The treatment of gabapentin overdose will really depend on what they co-ingested. They'll likely result in sedation and drowsiness, and supportive care and airway management  is the treatment.  So in conclusion, there's been an increase in prescribing and misuse of gabapentin, similar to that of tramadol.  Gabapentin ingestions are most commonly co-ingestions, and there's an increased risk of opioid-related  death in patients prescribed both gabapentin and opioids, and management of gabapentin toxicity is mostly supportive care.  Lastly, I'll close by briefly discussing some other emerging toxicities, the first of that being antidepressants.  Antidepressants are being used for pain management, particularly in neuropathic pain, but they've also been seen with increased ingestions and toxicities.  In 2018, antidepressants were responsible for 5,064 drug overdose deaths.  In 2018, a study was done to look at drug classes that had the highest rates of fatalities  and the highest increases in exposure, so this being calls to poison centers for ingestions  or overdoses, and antidepressants were actually the drug class with the highest rate of toxicological exposures.  A pro in treating antidepressant toxicities is alkalization may be needed for TCA overdoses.  The next drug class is antiepileptics, so that same study that was done in 2018 found  that antiepileptics were the fourth most common drug class with increased toxicological exposures, again, calls to poison centers or overdoses described.  And carbamazepine is being used for neuropathic pain.  And lastly, acetaminophen and NSAIDs, the backbone of our multimodal pain management, have toxicities associated.  These occur when they're used beyond the recommended dosing recommendations, and in 2018, acetaminophen was the second highest for non-illicit drug-related fatalities.  Insulicilates and other NSAIDs accounted for 6.9% of suicide acts. We should continue to use these agents when appropriate for pain management, but be conscious  considerate of the toxicities associated with them.  So, in conclusion, prescriptions from Pramodol have been increasing, and dangerous toxicities to monitor for include respiratory depression and seizures.  Javapentin prescriptions have also been increasing and are involved in many co-ingestions, leading to worsening central nervous system depression.  And lastly, additional emerging alternatives are being utilized, and risk versus benefit should be considered in patients prescribing, when prescribed these agents.  And in conclusion, you can reach out to me at my email, brown.caitlyn1 at Mayo.edu for questions, or you can find me on Twitter. Thank you.  Thank you. I'm very excited to be here today, speaking to you from my office on the collateral damage of COVID-19.  We'll be speaking about emerging toxicities associated with the pharmacotherapies for treatment of COVID-19.  I have no actual or potential conflicts of interest to disclose pertaining to this presentation.  The learning objective is to discuss potential toxicologic adverse effects from pharmacotherapies for the treatment of COVID-19.  So, it's hard to believe that a little over a year has transpired since the start of the pandemic.  In December 2019, the first case of the SARS-CoV-2 virus causing COVID-19 pneumonia was detected in China, and then shortly thereafter, the first case was in the United States.  In February, the Secretary of Health and Human Services initiated a public health emergency.  And then in March, an emergency use authorization declaration was made, which allowed emergency  use authorization, or EUAs, for pharmacotherapies and other treatment modalities for COVID-19.  The first of which was hydroxychloroquine, and this EUA was issued in March and subsequently revoked in June due to lack of efficacy in treatment and serious cardiotoxicities.  The next EUA that was issued was for remdesivir, and this came in May, and then it was subsequently FDA approved in October.  This was followed by convalescent plasma in August, and then we got three new therapies under EUAs in November, including bamlamivinib, baricitinib, and then the combination product  casorivimab, imdevimab.  So, and then recently, most recently, we saw the EUA issued for two different COVID-19 vaccines.  These are mRNA vaccines, and this was in December.  So, an overview for today, we'll be discussing the toxicologic adverse effects associated  with three classes of medications, including remdesivir, baricitinib, and then the monoclonal antibodies.  So, the first agent that I'd like to discuss is remdesivir, and again, this is the only agent that is FDA approved.  It's been in use since 2016 for the treatment of Ebola, and this is an IV infusion that is given for five to 10 days. So, how does it work?  Well, we have our human cell here, and on the surface of that cell, the ACE2 receptors, the SARS-CoV-2 virus, which causes COVID-19, binds to that ACE2 receptor at the receptor  binding domain of the spike protein, and then it is internalized into the cell where viral  RNA is unpacked, and then it is replicated via the RDRP or the RNA-dependent RNA polymerase.  Subsequently, this RNA is transcribed and translated into proteins that are then packed  back into the virus in the endoplasmic reticulum and then leave the cell as new virus.  So, remdesivir works at the RNA-dependent RNA polymerase. It inhibits that process, thus halting viral replication.  So, as the purpose of this talk is to discuss the toxicities associated with all of these therapies, we'll mostly be focusing on the adverse effects that have been observed and less  focusing on the outcomes associated with these agents.  So, remdesivir adverse effects most commonly observed in clinical trials include gastrointestinal  effects, such as nausea, vomiting, diarrhea, and then constipation and gastroparesis have also been observed.  The next adverse effect I'd like to discuss is hepatic injury.  In animal studies, no liver changes were observed. However, there have been three case reports so far of liver injury induced by remdesivir,  the first of which is in a 68-year-old female who was admitted to the hospital with COVID-19 pneumonia, received remdesivir on day 8, followed by amiodarone initiation on day 9.  Subsequently, around day 10, ALT spiked at over 5,000.  Both the remdesivir and amiodarone were stopped and the N-acetylcysteine was initiated.  This patient had resolution of their liver injury and was discharged.  The second case in this case series was an 80-year-old female who received remdesivir from day 5 to day 9, and subsequently ALT peaked around 1,500, and N-acetylcysteine  was also initiated in this case.  In a separate case report of liver injury, this patient was a 64-year-old male who was admitted and started on chloroquine on day 1 of admission and received that for 7 days.  Subsequently, on day 16, remdesivir was started. The next day, the patient went into atrial fibrillation and received 700 mg total of  amiodarone, and then 3 days later, the ALT peaked at around 1,500, and the remdesivir was discontinued.  This patient did not receive N-acetylcysteine and subsequently recovered the liver transaminases and was discharged from the ICU.  So why does this occur? Well, one potential mechanism is that as remdesivir is circulating in the blood, it transfers  over into the hepatocyte and it is metabolized there into active metabolites, some of which are transported via P-glycoprotein into the bile and then excreted in the intestines.  When P-glycoprotein is inhibited, there are more active metabolites, which can be directly hepatotoxic.  Some common P-glycoprotein inhibitors include chloroquine and amiodarone, which our third case received both of those, and then another inhibitor is cyclosporine that is commonly  used.  The next adverse effect I'd like to mention for remdesivir is nephrotoxicity, and this is really due to the cyclodextrin diluent, the solubility agent that is included that  increases solubility of the product and also increases bioavailability. So we see here on this chart, the Y-axis is plasma clearance of cyclodextrin and the  X-axis is keratinine clearance. So as we have increases in keratinine clearance, we have this linear increase in plasma clearance  of cyclodextrin, but we see here that 40 and under for our keratinine clearance, we're really not clearing the cyclodextrin.  So because of this, we should avoid in keratinine clearance less than around 30 mLs per minute.  In hemodialysis, this study is comparing patients on the top line there, our patients on hemodialysis  compared to healthy controls on the bottom, and what we see is that hemodialysis does remove the cyclodextrin, but we do have some accumulation over time.  In CVVH, this was a pharmacokinetic study in patients receiving IV voriconazole, which also contains cyclodextrin. We do have adequate clearance of cyclodextrin by CVVH.  The last adverse effect I just want to mention with remdesivir is hypersensitivity because reports of hypersensitivity, including anaphylaxis, have been reported in the literature.  Moving over to the ACT-1 study, this was the large randomized control trial that was in over 50 sites in the U.S. and Europe, and this is how remdesivir was approved and brought  to market, found that faster time to recovery in the remdesivir group compared to placebo by about five days.  In terms of adverse effects in this study, they collected adverse effects in a systematic fashion, so grades 1 through 4, where 1 is mild, 4 is life-threatening, and for this  study, they collected grade 2 if it pertained to hypersensitivity, and then all grade 3, which is severe, and grade 4, which is life-threatening.  Serious adverse effects were also determined, and these were evaluated for death, life threat, inpatient hospitalization or prolongation of hospitalization, and then interruption  of activities of daily living. So, for this study, in terms of safety outcomes, over 50 percent of patients had a grade 3 or 4 adverse effect, so a majority of the study.  Note that this was actually numerically higher in the placebo group, and many of these potential  adverse effects were likely due to the underlying disease state itself rather than the intervention that was given.  For serious adverse effects, there was actually statistically higher serious adverse effects  in the placebo group compared to the remdesivir group, and a minority of these were deemed to be due to the treatment itself.  So, categorizing adverse effects according to the serious adverse effect category, I want to highlight two things here. First, note that  cardiac adverse effects were the only thing that occurred more frequently in the remdesivir group and that respiratory adverse effects, namely acute respiratory failure,  was the most common effect that occurred. Again, this is probably due to the underlying COVID pneumonia and not due to the treatment or the placebo that were given.  And then, lastly, I want to highlight a study that randomized patients to receive either five or ten days of remdesivir and  found that serious adverse effects were increased with the longer treatment course, though the most common type of adverse effects were respiratory failure in this study,  so that's likely due to the underlying disease state.  So, in summary, remdesivir is a nucleoside analog. It's the only FDA-approved pharmacotherapy for treatment of COVID-19.  The most common adverse effects are gastrointestinal and hepatic. It may cause liver injury and consider acetylcysteine in these patients.  And then, P-glycoprotein inhibition may be a factor and we should screen for interacting medications, including chloroquine, amiodarone, and  cyclosporine, and consider  monitoring for these patients.  Cyclodextrin vehicle should be avoided and create a clearance less than 30 mLs per minute  as it has the potential to accumulate.  However, in patients on dialysis or CBVH, it appears to be eliminated. And then, I would recommend avoiding with concomitant voriconazole as you can expect  more accumulation. And finally, a longer course of remdesivir may be associated with  increased adverse effects. So, the next agent I would like to discuss is called baricitinib, and this is a  Janus kinase inhibitor that inhibits the JAK stat pathway, and it's approved since  2018 for treatment of rheumatoid arthritis.  And this was issued an emergency use authorization for hospitalized patients with COVID-19. So, how does this agent work?  Well, when a cytokine binds to the JAK receptor, it is autophosphorylated and then the stat  molecules are phosphorylated and  relocate to the nucleus of the cell, which signals a cascade of events that results in cytokine production and hyper  inflammation. So, with the addition of baricitinib,  that pathway is blocked, resulting in overall an increase in lymphocytes, increase in immune globulins, and a decrease in the  pro-inflammatory cytokines, so a lower inflammatory state.  As baricitinib is immune modulating, the most common adverse effect are secondary infections,  including upper respiratory infection and nasopharyngitis.  It should be avoided in patients with active tuberculosis, and in the RA studies,  reactivation of herpes simplex virus has been observed.  The next adverse effect that occurs with some frequency is thrombosis.  The mechanism for thrombotic events is not currently known,  but it is potentially due to the rapid increase in platelet count that is observed within the first two weeks of therapy here.  Because of thrombotic events and other side effects, it took an additional year of  studies to obtain FDA approval of this agent for treatment of  rheumatoid arthritis, and the FDA  initially, the drug company was going for 4 mg for a dose for RA and they only approved a 2 mg dose  due to side effects, so we do have to monitor for thrombosis and this is concerning given that  thrombosis is associated with COVID-19 as well.  Finally, there are several laboratory abnormalities that have been observed with baricitinib, including the increase in platelets, increased triglycerides, liver transaminases, and  creatinine phosphokinase, and while most of these have been observed with long-term use in the RA population,  there's one case so far of baricitinib-induced,  potentially induced pancreatitis. This CT shows the diffuse pancreatic enlargement with edema and this ultimately led to the demise of this patient.  So, the ACT-2 study was the next arm of the ACT-1 study. Once a benefit was observed with remdesivir,  all patients received remdesivir and  randomization occurred, then pivoted to baricitinib or placebo. An enhanced time to recovery was also observed with this intervention.  Adverse effects were collected in a similar manner to the ACT-1 study. Grade 3 or 4 adverse effects occurred in over 40% of both treatment groups.  Serious adverse effects occurred in a minority of patients, 16% of the baricitinib group, compared to 21% with placebo.  Around 5% in both treatment groups were deemed to be due to the study treatment, and then I do want to highlight that venous thromboembolism was rare,  occurring in around 4% of the baricitinib patients compared to 3% in placebo.  Breaking out serious adverse effect categories, similar to the ACT-1 study,  note that all of these occurred more frequently in the placebo group.  So, in summary, baricitinib is a Janus kinase inhibitor.  It received EUA designation in November for adults and children greater than 2 that are hospitalized with COVID-19. The most common adverse effects are secondary infection,  so consider avoiding with active secondary infection,  thrombosis, so VTE prophylaxis should be initiated in all of these patients, and I would recommend avoiding with an active  venous thromboembolic event, and then laboratory abnormalities,  including elevated liver enzymes,  elevated platelets, creatinine phosphokinase, and  these should be monitored.  So, the last class  of agents I'd like to briefly discuss today are the anti-SARS-CoV-2 monoclonal antibodies.  Bear with me, these are the the hardest agents to pronounce. So, that includes bamlanivimab, which is a fully human monoclonal antibody, and then the antibody cocktail  combination, casorivimab, emdevimab.  This is the Regeneron product that President Trump received prior to the issuance of the EUA, and this is a combination product that is  both chimeric and derived from B-cells of convalescent plasma, and both of those are given together.  So, how do these agents work? Well, we have our cell surface again with our ACE2 receptor,  the SARS-CoV-2 virus approaches and normally would bind the spike protein at the  receptor binding domain. The monoclonal antibodies target this binding domain and prevent it from attaching and going into the cell.  So, adverse effects, we have limited data in terms of adverse effects here, but as this is a monoclonal antibody,  we would expect that infusion reactions, including anaphylaxis, may occur. In clinical studies,  gastrointestinal adverse effects, including nausea, vomiting, were most common, and then I do want to mention vaccine efficacy. It's not technically an adverse effect,  but really something that we would want to consider in all of these patients. So, because these monoclonal antibodies are directed at the spike protein  on the surface of the cell and the mRNA vaccines produce that spike protein, we wouldn't want to give these  monoclonal antibodies within the same time frame of the vaccine.  We would want to wait to administer the vaccine at least 90 days after receipt of these monoclonal antibody agents. This is a reasonable time frame  anyway, because patients with COVID-19 should have residual immunity for that time, but we should be counseling any patient that receives these agents to avoid the COVID vaccine  for 90 days after receipt of these therapies.  So, this has been studied in hospitalized patients. This is the Bamla-Nivimab  intervention in hospitalized patients. Also looked at time to recovery and there was no difference between these groups, so this study was stopped early due to futility.  However, in non-hospitalized patients, including those patients presenting to the emergency department,  it has been associated with a decrease in viral load.  This is the Blaze-1 study, which is the Bamla-Nivimab group.  And then this is the antibody cocktail study.  One interesting thing that they did here is that they  separated patients according to whether they were serum antibody negative or serum antibody positive. And in the negative patients,  there was a difference between placebo and the antibody cocktail, whereas in the positive patients, there was no difference.  So, this tells us that these agents should be administered early in the disease course to prevent progression  for severe disease. The thing that has everyone excited about these interventions  is the outcome of a decrease in medical visits. Both of these studies showed a significant decrease in medical visits, including emergency department visits and hospitalizations.  So, this should be given in mild to moderate  COVID-19 in patients that are at high risk of progression to severe disease. In terms of the adverse effects, there was  a very low percentage of serious adverse effects. None observed in the initial Bamla-Nivimab study compared to  1-2% in the antibody cocktail study.  So, in summary, the FDA issued an EUA for these monoclonal antibodies in November for treatment of mild to moderate  COVID-19 in adults and pediatric patients who are at high risk for progression to severe disease. So, we may be seeing these in some emergency departments in the U.S.  These agents overall are well tolerated with the most common adverse effects being infusion reactions and gastrointestinal effects.  And then we should be delaying the mRNA vaccines 90 days after receipt of these agents.  So, overall, we have discussed  several new COVID-19 pharmacotherapies, each with unique toxicities. For remdesivir,  we have to worry about gastrointestinal, hepatic, and renal adverse effects. For baricitinib, secondary infection,  thrombosis, and laboratory abnormalities leading to things like pancreatitis may occur.  And then for the anti-SARS-CoV-2 monoclonal antibodies,  infusion reactions, and gastrointestinal effects.  That concludes my presentation. I thank you for your attention.  Good morning, everybody. My name is Steven Greenberg, and I'm the Vice Chair of Education in the Department of Anesthesiology,  Director of Critical Care at Evanston Hospital,  North Shore University Health Systems, and Clinical Professor at the University of Chicago Pritzker School of Medicine.  And the title of my talk today is Vaping-Associated Lung Injury, Lessons Learned, and Future Implications.  I'm delighted to take part in the 50th anniversary of the Annual Critical Care Congress.  My disclosures are that I'm Editor-in-Chief of the Anesthesia Patient Safety Foundation Newsletter and Secretary  of the Anesthesia Patient Safety Foundation, none of which have anything to do with the conversation and lecture today.  So I first would like to provide you an overview of eSegred, Vaping-Associated Lung Injury. The use of e-cigarettes has doubled between the years of 2017 and 2019.  In fact, over 40 million Americans today  use Vaping-Associated products.  As of February 2020,  2,807 cases were diagnosed in the United States,  and there have been 68 deaths in the United States so far.  78% of the cases have been in patients less than 35 years old. The most common symptoms include 95% respiratory, which is your shortest breath, cough, dyspnea and exertion,  85% constitutional, like night sweats,  chills, fever, and 77% gastrointestinal,  such as nausea, vomiting, and diarrhea.  Over 80% of cases reported using THC products, of which about 78% are illicit use.  47% of the cases have required ICU care for treatment of respiratory failure. And vitamin E acetate seems to be the most commonly implicated  etiologic agent. In fact, one New England Journal of Medicine article this year showed that when they compared 51 patients with Evali with 99 healthy controls,  they found that 94% of the Evali group BAL samples were positive for vitamin E, while none of the healthy controls were positive for vitamin E.  Another study by Werner in New England Journal of Medicine in 2020  compared patients who had non-fatal cases of Evali with those who ended up dying of Evali.  And they found that there was a significantly significant association in terms of risk factors in those patients who died who also had asthma,  cardiac disease, and mental health conditions. This might provide us some information on really severe cases of Evali.  Now, this is a map of Evali-related U.S. hospitalizations and death in  2020 and 2019. And you can see my own state of Illinois was hard hit back in 2019 with about 200 to 250 cases.  Other states such as California and Texas were also hit by this epidemic of Evali.  The suggested diagnostic criteria include the use of e-cigarettes. We don't know much about secondhand  smoke or vaping smoke and its cause or effect on other patients.  But you also have to have pulmonary infiltrates on chest x-ray or ground glass opacities on CT, an elevated white cell count, and inflammatory markers that are elevated.  But really the most important thing is the absence of pulmonary infection, particularly as we all go through the COVID-19 pandemic.  You have to have negative respiratory virus panels,  negative for influenza or HIV.  And it may help to diagnose Evali with positive vitamin E acetate on the BAL samples. There should be no evidence of alternative medical causes such as heart failure,  rheumatologic diseases, and of course cancer.  Now, there are a variety of delivery systems and liquids out there.  And on one side of your screen here, you see the first generation or e-cigarette disposable  types, the second generation or cartridge pre-filled or refillable types, the third generation, which you can modify and allow  for a variable amount of voltage and wattage, which can heat up the substances to different temperature and generate different sorts  of reactive oxygen substances, and then the fourth generation, which is a pod mod.  On the other side of the screen, you can see there's a variety of e-liquids,  such as THC, cannabis, propylene glycol, vegetable glycerin, diacetyl.  The reason why I point this out is that  this is why Evali presents itself in so many different ways.  Because when you heat these variety of substances up, they actually generate different reactive oxygen species, which then cause different harm to our own lungs.  And some of the proposed mechanisms of injury of e-cigarettes include, when we look at cigarette vapor, asthma, cough, histologic damage, DNA damage,  inflammatory changes, or oxidative changes.  Vitamin E acetate has been associated with cervactin dysfunction and ketene production, which can cause direct lung injury or in irritant.  Heating the coil causes heavy metal toxicity. The wicking material can cause silicosis,  Flavoring, particularly the diacetyl, can cause bronchiolitis obliterans and propylene glycol and vegetable glycerin can cause airway epithelia injury and thermal degradation, formation of formaldehyde and acetyl aldehyde,  all of which can cause harm to our lungs.  Now, managing Evali is really supportive. We need early consultation with pulmonary and toxicology and screen for urine THC.  You need to perform a lung protective strategy and use just judicious levels of PEEP.  Empiric antibiotics should continue for 48 hours,  if the etiology is, of course, unclear,  and systemic corticosteroids if there's no improvement with the antibiotics or respiratory support.  But the dosing and duration should be considered on a case-by-case basis and the length of steroid taper is made also based on the clinical course and close follow-up.  There are three types of pneumonias or pneumonitis that actually seem to  be positively affected by the use of corticosteroids. They are lipid pneumonia,  eosinophilic pneumonia, and hypersensitivity pneumonitis.  We should arrange for outpatient follow-up, collect the vaping cartridges for state public health lab testing,  and consider ECMO for refractory cases.  Now, this was a case series of 13 teenagers who presented with EVALI, and what they did is they gave these teenagers glucocorticoids, and here you can see  their pulmonary function tests, the FEV1-FECP4 glucocorticoids,  and you can see afterwards, and there was a statistically significant benefit in those studies when given glucocorticoids.  So the authors provided treatment considerations that I'm about to go through.  Use of high dose, or one gram IV daily for three doses, was with moderate to severe disease on CT scan, patients in the ICU, and a lack of improvement with lower doses.  Moderate dose, or 500 milligrams IV daily for three doses, with moderate disease on CT scan, mild hypoxemia not improving,  mild PFT abnormalities, and lack of improvement with low dose.  Low dose, 60 to 300 milligrams per day,  for three to five days, with mild disease on CT scan, mild or no hypoxemia, normal PFTs.  And then, of course, oral dose, 30 to 40 milligrams twice a day for five days, with mild disease on CT, no hypoxemia, normal PFT results.  So glucocorticoid treatment led to an improvement in these patients' symptoms and lung function.  Kalinsky and colleagues performed and created a diagnostic and therapeutic guidance, and this algorithm is extremely helpful when approaching patients with EVALI.  What I really want you to focus on here is that it's really important, again, to rule out infectious etiologies,  and if you perform bronchoscopy, you should definitely stain those samples with oil red,  and look again for vitamin E acetate.  Now, I'd be remiss without talking and differentiating EVALI versus COVID-19.  And the short answer is they actually present extremely similarly.  In fact, to differentiate the two, EVALI patients have to have, obviously, a history of vaping and e-cigarette use.  Unfortunately, a recent study showed that patients who vape have a five-time increased risk of developing COVID-19.  And in fact, there are case reports already in the literature  that demonstrate patients that have simultaneous cases of both EVALI and COVID-19.  Of course, with COVID-19, you want a positive PCR test,  the loss of taste and smell, but I want you to focus here on the differences in radiologic findings.  This doesn't hold true for every case, but in the EVALI cases, there's distinct areas of subplural sparing,  and in the COVID-19 cases, the opacities are plural-based with immediate involvement of subplural spaces. So you can see the difference of these two CT scans.  You see this. This may draw you to one or the other.  Now, the CDC has proposed EVALI management and follow-up,  and this really decides whether a patient should be evaluated on an outpatient or inpatient basis.  It comes down to patients with O2 saturations greater than or equal to 95% while breathing room air,  no respiratory distress, or no comorbidities that can cause cardiopulmonary compromise. Those can be managed on an outpatient basis.  But we have to make sure that these patients are plugged in and that they get their vaccinations  and that we ensure follow-up within 24 to 48 hours. Reason being is that a study showed that about 25% of  re-hospitalizations and deaths in these patients actually occurred within two days post-discharge.  So we also have to ensure that these patients are stable within 24, 48 hours before we discharge them as well.  Inpatient clinical evaluation includes saturations less than 95% on room air, respiratory distress, and comorbidities including cardiopulmonary reserve, and again,  psychiatry consult for inpatient evaluation, vaccinations, and again, close follow-up with pulmonology within two to four weeks.  And the preventative strategies really focus on refraining and not using e-cigarette or vaping products at all that contain THC or really any vaping products for that matter at all.  I'd like to briefly talk about the case study that I took care of last year. It's a 29-year-old man with daytime sweats and progressive shortness of breath,  multiple sclerosis and remission, the seven to 10-day history of nasal congestion, daytime chills.  But in the past 24 hours after being given azithromycin, his wife noted that his respiratory rate was going up and he was more short of breath.  So she brought him to the emergency room and he had reported to the emergency room doctor that he  vaped for over five years now and constantly vaped. His urine concentration of THC was over 500 nanograms per cc, where 15 nanograms per cc or less is negative.  He stated that he both vaped nicotine and THC with a mango-flavored fluid, diacetyl, and he smoked cigarettes significantly five years before that.  These are his admission physical exam laboratory findings and diagnostic testing.  I really want you to focus on that he had a very high respiratory rate, his saturations were low despite a very high  FiO2 concentration, he had a leukocytosis with a neutrophil predominance, and of course his urine tox screen was positive for cannabis.  His initial x-ray showed that there were bilateral opacities right greater than left and the intensivist then put him on BiPAP  with a low threshold for intubation and started broad-spectrum antibiotics.  The critical care physician also sent a respiratory viral panel, which was negative, and then a BAL that would show only mild inflammation, it was negative for bacterial fungal infections.  He was started on methamphetamines alone 40 milligrams twice daily.  Well, this was his first hospital day x-ray, there had been progression in the bilateral infiltrates, but no pneumothorax or effusion.  In hospital day four, he remained on and off BiPAP and high flow nasal cannula with reducing the  FiO2 concentrations. However, that afternoon he developed acute desaturation hypotension with no left chest breath sounds and had this chest x-ray,  which obviously is a persistent large left tension pneumothorax, which was treated with a chest tube with symptomatic improvement.  He also had a second chest tube placed and was intubated for three days and then extubated, but remained on high flow nasal cannula and BiPAP.  Six days after the tension pneumothorax, the patient underwent a VATS,  pleurodesis, and blood resection and got a CT scan just prior to surgery showing that large left pneumothorax and a right up apical blood.  Now the plan for surgery was  performing a general anesthesia with a double lumen tube and proceeding with IV access and a radial arterial line.  Here's the anesthesia record. I just want you to really focus on the fact that we adequately  pre-oxygenated the patient and immediately after general anesthesia induction, the patient's SATS dropped to 51%.  And interestingly enough, we were extremely difficult time ventilating and oxygenating in the patient until we resumed two lung ventilation. So what about ECMO for EVALI?  Well, there have been emerging case reports in the literature in the last six to seven months showing some success with particularly a younger age population  and a duration of ECMO between one and three weeks. These are three of such case reports. All these patients survived.  There also is another case report indicating a patient who required ECMO and then subsequent lung transplant. So ECMO can be used in EVALI's cases,  but further evidence is required to figure out what patients benefit most from this refractory therapy.  The post-operative course was consistent with post-operative day one getting extubated. His left upper lobe  was significant for diffuse alveolar damage on histology and reactive pneumocyte hyperplasia.  Unfortunately, on post-operative day three, he suddenly developed acute shortness of breath, desaturation, low blood pressure, and again,  he had another right tension pneumothorax, which was again treated with a chest tube.  The surgeon again was consulted and he performed a VATS on the right side now,  and we also had similar hypercarbion hypoxemia, but less so because the left lung was doing better at this point.  The histology and pathology findings were very similar to the previous lung.  Fortunately for this patient, after 22 days in the ICU, he was sent to rehabilitation and his total hospital length of stay was 34 days.  Now, this is very interesting. We actually followed this patient up and recently saw him in a clinic about a few months ago.  His three-month follow-up was consistent with chronic fatigue with exercise and his PFTs were normal,  but his DLCO was 61% predicted. On the left side of the screen, you can see that he has mild to moderate emphysematic changes within the lung and parenchymal scarring,  and we don't know what his lungs look like before the EVALI case.  The 12-month follow-up was consistent with that he had continuous exercise capacity limitation and he had four respiratory infections throughout the year.  So we plan on continuing aerobic exercise and he remains abstinent today from all vaping products.  These are two case series of patients with follow-up from EVALI. The one on the left is from JAMA, recently reported 31 patients with a medium-time follow-up of only 16 days.  All patients had near complete radiographic resolution  and normal spirometric measurements except for reduced DLCO.  In the other case report of two patients, there was a longer follow-up, two months,  had radiographic resolution and normal spirometric measurements, but also a reduced DLCO, which can be a predictor of mortality.  So we really need more long-term follow-up of these patients to see how they actually do  years and years to come.  So the take-home points today are that vaping-induced lung injury mimics many other causes of acute respiratory distress syndrome, particularly COVID-19.  This specific type of vaping-induced lung injury seems to have a propensity for a formation of blebs and tension pneumothoraces.  The perioperative management of these patients can be challenging and might include low tidal volume ventilation,  control of positive anti-expiratory pressure, and possibly instituting extracorporeal membrane oxygenation.  Further studies are really needed to provide clarity on the role of ECMO in vaping-induced lung injury.  Further studies are really needed to provide clarity on the role of ECMO in EVALI and the dosing type and duration of steroid therapy.  And I'll end with the fact that this was in large part a success of a public health action.  A lot of the vitamin E was removed from diluents and the DEA reduced the illicit THC supply that all curbed this epidemic and got it under control  very quickly. And so today we see far less cases of EVALI than we did in September of 2019.  Thank you very much and have a wonderful day.

Video Summary

The video transcript discusses the emerging issue of toxicities associated with alternative analgesics, specifically tramadol and gabapentin. These alternative analgesics have been increasingly used as alternatives to traditional opioids in the ongoing opioid epidemic. The transcript highlights the increase in prescriptions for tramadol and gabapentin and the corresponding increase in toxicity associated with their use. Tramadol, a synthetic opioid, has been touted as a safer alternative to traditional opioids, but it is shown to have significant toxicities including respiratory depression, seizures, and serotonin syndrome. Gabapentin, an antiepileptic drug, is also being used as an alternative analgesic and is associated with sedation, dizziness, and an increased risk of opioid-related deaths when co-prescribed with opioids. The transcript also briefly mentions other emerging toxicities associated with alternative analgesics, including those associated with antidepressants and NSAIDs. Overall, the transcript emphasizes the need for careful consideration of the risks and benefits of alternative analgesics and the importance of monitoring and managing the toxicities associated with their use.

Asset Subtitle

Pharmacology, Crisis Management, 2021

Asset Caption

The Society of Critical Care Medicine's Critical Care Congress features internationally renowned faculty and content sessions highlighting the most up-to-date, evidence-based developments in critical care medicine. This is a presentation from the 2021 Critical Care Congress held virtually from January 31-February 12, 2021.

Learning Objectives

Identify causative agents and underlying pathophysiology and discuss the importance of coordinated public health response in toxic surveillance
Discuss toxicities of analgesics that are being more commonly used as alternatives to traditional opioids
Discuss potential toxicologic adverse effects of therapies associated with COVID-19

Good Intentions but Risky Propositions: Toxicities Associated with Alternative Analgesics
Caitlin Brown

The Collateral Damage of COVID-19: Emerging Toxicities
Megan A Rech

Vaping-Associated Lung Injury: Lessons Learned and Future Implications
Steven Greenberg

Meta Tag

Content Type Presentation

Knowledge Area Pharmacology

Knowledge Area Crisis Management

Knowledge Level Intermediate

Knowledge Level Advanced

Membership Level Select

Tag Toxicology

Tag Analgesia and Sedation

Tag COVID-19

Year 2021

Keywords

toxicities

alternative analgesics

tramadol

gabapentin

traditional opioids

opioid epidemic

respiratory depression

seizures

antiepileptic drug

opioid-related deaths

	Society of Critical Care Medicine 500 Midway Drive Mount Prospect, IL 60056 USA Phone: +1 847 827-6888 Fax: +1 847 439-7226 Email: support@sccm.org	Contact Us About SCCM Newsroom Advertising & Sponsorship DONATE	MySCCM LearnICU Patients & Families Surviving Sepsis Campaign Critical Care Societies Collaborative	GET OUR NEWSLETTER
© Society of Critical Care Medicine. All rights reserved. \| Privacy Statement \| Terms & Conditions The Society of Critical Care Medicine, SCCM, and Critical Care Congress are registered trademarks of the Society of Critical Care Medicine.