Controversial COVID-19 Cures: Hydroxychloroquine and Oleander Pediatric Ingestion Simulation Cases

Introduction: The use of hydroxychloroquine has dramatically increased since being touted as a potential therapeutic in combating coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus. This newfound popularity increases the risk of accidental pediatric ingestion, whereby just one or two tablets causes morbidity and mortality from seizures, cardiac dysrhythmias, and cardiogenic shock. The unique management of hydroxychloroquine overdose makes it imperative for emergency medicine physicians to have familiarity with treating this condition. Similarly, during the COVID-19 pandemic, there have been publicized cases touting extracts of oleander as being a potential therapeutic against the illness. Since it is commonly available and potentially lethal ingestion with a possible antidote, we developed a simulation case based on the available literature. The two cases were combined to create a pediatric toxicology curriculum for emergency medicine residents and medical students. Both of these treatments were selected as simulation cases since they were being touted by prominent national figures as potential cures for COVID-19. Methods: Two series of simulation cases were conducted in a high-fidelity simulation lab with emergency medicine residents and medical students. The hydroxychloroquine simulation case involved the management of a four-year-old male who presented to the emergency department with nausea, vomiting, and tachycardia after ingesting hydroxychloroquine tablets. As the case unfolded, the child became increasingly unstable, eventually experiencing QT prolongation, torsades de pointes, and ventricular fibrillation arrest requiring appropriate resuscitation to achieve a return of spontaneous circulation. The oleander simulation case involved the management of a three-year-old male who presented to the emergency department with nausea, vomiting, and tachycardia after ingesting parts of an unknown plant. As that case progresses, the child becomes increasingly unstable, eventually experiencing atrial fibrillation, bradycardia, and degenerating into pulseless electrical activity and cardiac arrest requiring appropriate resuscitation to achieve the return of spontaneous circulation. Both series of simulation cases were modifiable based on trainee level and had the ability to include ancillary emergency department staff. Results: Each simulation case was performed six times at our simulation center, with a total of 22 learners for the hydroxychloroquine case, and 14 for the oleander case. Through pre- and post-simulation confidence assessments, learners demonstrated increases in knowledge of toxidromes, evaluating pediatric overdoses, treating cardiac dysrhythmias, performing pediatric advanced life support, and managing post-arrest care. Learners also demonstrated improvements in recognizing the unique treatment of hydroxychloroquine and oleander toxicity, the toxic dose of both substances in a child, and the most common electrolyte anomaly seen in each toxicity. Discussion: Simulation training enables learners to manage rare and complex disease processes. These cases were designed to educate trainees in recognizing and treating rare overdoses of emerging “therapeutics” that were touted early in the COVID-19 pandemic.


Introduction
The first patients of the coronavirus disease 2019 (COVID-19) pandemic presented in the United States in early 2020. With few effective treatment options immediately available, many unproven substances began to be discussed as potential "cures" for COVID-19. Among the more promulgated theoretical therapies were hydroxychloroquine, an anti-malarial medication, and oleander, a subtropical plant, both of which were being highly touted by prominent national leaders with wide audiences over social and conventional media platforms. Concerns began to arise about potential toxic ingestions in patients taking these medications without instructions from their physicians, or the possibility of children accidentally ingesting their parents' 1 1 2, 3 1 1 Prior to 2020, there was a relatively low baseline prevalence of hydroxychloroquine utilization in American households; therefore, the risk of accidental pediatric ingestion was fairly low. Considered a potential therapy against COVID-19 during the early stages of the pandemic, the magnitude of prescriptions filled nationally for hydroxychloroquine increased substantially [5]. This widespread distribution markedly increased the risk of children's potential accidental ingestion of hydroxychloroquine.
Providing instruction in both the management of hydroxychloroquine toxicity and QT-prolonging medication exposure overall, this case is ideally led by emergency medicine and pediatrics residents and fellows, while also providing useful learning for medical students. There are no known published curricula related to hydroxychloroquine toxicity. In addition, the treatment approach to hydroxychloroquine toxicity is uncommon and is best reinforced via a simulation session in which participants can learn via trial and error.
Unlike hydroxychloroquine, Oleander (Nerium oleander) is not a commonly prescribed medicinal, but a common plant that is found worldwide in subtropical and temperate areas. In the United States, it is found in the southern and western regions and is commonly used in residential areas as a small shrub or tree. All parts of the plant contain cardiac glycosides that have significant cardiac effects [6]. This toxicity is magnified in pediatric patients due to their smaller mass. Symptoms of severe toxicity include altered mental status, mydriasis, peripheral neuritis, qt prolongation, hypotension, heart block, atrial fibrillation, and ventricular dysrhythmias [6].
The mechanism for the toxicity stems from the cardiac glycosides that bind and inhibit the sodium/potassium ATPase pump leading to increased myocyte calcium. This leads to increased inotropy and increased extracellular potassium. Increased cardiac irritability with several different dysrhythmias has been noted [6]. Because of the cardiac impacts of oleander, several case reports of fatalities have occurred [6][7][8].
The use of digoxin immune fab has been shown to be helpful clinically and in the lab [7,[9][10].
Oleander extract has been investigated as a remedy for cancer and as a cure for other conditions [11]. During the COVID-19 pandemic in 2020 oleander was touted as a possible treatment or preventative for COVID-19 infection by several high-profile figures in the United States [12,13]. Therefore oleander toxicity may become a concern if people attempt to utilize it as home therapy. Currently, there are no known published curricula related to oleander ingestion. The mechanism of oleander serves to discuss similar pathophysiology in digitalis overdoses. The case allows for discussion of cardiac glycosides and their mechanism and toxicity in clinical situations.

Curriculum development
Both cases were written by a panel of simulation fellowship-trained faculty, emergency medicine core faculty, and board-certified toxicologists. The facilitators consisted of the emergency medicine core faculty and members of the simulation center professional staff. The simulations occurred on separate days spaced months apart with residents and medical students. It was part of a pilot pediatric toxicology curriculum.
These cases were designed to guide learners through the management of severe, acute toxicity resulting from a hydroxychloroquine overdose and an oleander overdose, respectively. It was designed for resident and fellow physician learners who may encounter such a case in the emergency department, including pediatric emergency medicine fellows, pediatric residents, and emergency medicine residents.

Equipment/environment
The simulation cases were conducted in the simulation lab using a pediatric high-fidelity manikin. The learning management system was preloaded with the requisite vital signs, laboratory values, x-ray imaging, and electrocardiograms (EKG). Medical equipment available in the room included a crash cart, pediatric-size defibrillator pads, defibrillator, stethoscopes, medication vials, Broselow tape, intravenous (IV), interosseous (IO) supplies, endotracheal tubes, laryngoscopes, bag-valve masks, nasal-and oral-pharyngeal  In the hydroxychloroquine knowledge-based post-test, 100% of participants correctly identified diazepam as the antidote of choice for hydroxychloroquine toxicity; 95% correctly chose 10mg/kg as the recognized toxic dose of hydroxychloroquine in a child; 90% correctly chose 30 minutes as the time it takes for symptoms to develop after ingestion of a hydroxychloroquine overdose; 100% identified QT prolongation as the most common EKG abnormality of severe hydroxychloroquine overdose; and finally, 100% identified hypokalemia as the most common electrolyte disturbance found on initial lab work of patients experiencing hydroxychloroquine toxicity. Using the McNemar test for comparison of binomials, there was a statistically significant improvement in knowledge of the antidote to hydroxychloroquine, the toxic dose, and the most common electrolyte anomaly (p<0.01 for each), and time from ingestion to symptoms (p=0.016) (  Of the 12 critical actions on the critical action checklist for the hydroxychloroquine case listed in Table 3, all six groups (100%) obtained IV or IO access, utilized the PALS algorithm in resuscitating the patient, admitted the patient to the intensive care unit (ICU), and demonstrated clear communication with the patient and fellow team members. Five groups (83%) recognized the patient's decompensation to ventricular fibrillation arrest, defibrillated appropriately, and utilized appropriate weight-based dosing for medications, equipment, and interventions. Four groups (67%) performed an initial primary survey, obtained an accurate history of hydroxychloroquine ingestion, obtained an initial EKG and lab studies, placed the patient on a cardiac monitor, and contacted the poison control center for recommendations. Only three groups (50%) promptly recognized the torsades de pointes dysrhythmias and treated the torsades appropriately with magnesium sulfate.  The oleander simulation case was similarly performed at our simulation center six times, in groups of two to three learners per group -a total of 13 residents and 1 medical student. Each group was composed of emergency medicine residents at various stages of training and medical students. All 14 learners filled out both the pre-simulation and post-simulation assessments.
In the pre-oleander simulation assessments, the mean confidence level for evaluating accidental toxic plant ingestion in a pediatric patient and the knowledge and ability to manage a pediatric toxidrome were the lowest assessed. The antidote, timing of the toxicity, and the most common rhythm associated with toxidrome were the lowest areas for knowledge assessment. In the post-oleander toxicity simulation assessment, the mean comfort level for evaluating accidental plant ingestion in a pediatric patient was 3.5± 0.86; the mean level of confidence in managing a pediatric dysrhythmia was 3.79 ± 0.7; the mean level of confidence in managing a pediatric pulseless electrical activity was 3.93 ± 0.73; mean level of confidence stabilizing a pediatric patient after achieving the return of spontaneous circulation (ROSC) was 3.5 ± 0.76; and mean level of confidence and knowledge in their ability to manage pediatric toxidromes was 3.36 ± 0.84.
Comparing the pre-test and post-test results using the Wilcoxon signed ranks test, there was a statistically significant increased comfort level for all differences (p<0.01) ( Table 4).   Of the 12 critical actions on the critical action checklist for the oleander case in Table 6, six groups (100%) performed the initial primary assessment, obtained IV or IO access, obtained an accurate history of oleander ingestion, placed the patient on a cardiac monitor, recognized the patient's decompensation to pulseless electrical activity, utilized appropriate weight-based dosing for medications, and admitted the patient to the ICU. Five groups (83%) contacted the poison control center for recommendations and demonstrated closedloop communication with team members. Four groups (67%) obtained an initial EKG and lab studies.

Discussion
These cases were designed to teach emergency medicine residents and medical students how to resuscitate a pediatric patient after accidental ingestion of near-fatal doses of hydroxychloroquine or oleander. During the COVID-19 pandemic, hydroxychloroquine experienced a dramatic increase in availability in American households. Unfortunately, many parents and physicians were unaware of the medication's potentially deadly risk to children who accidentally ingest even a few tablets [1]. Few physicians in the United States have previously cared for patients experiencing hydroxychloroquine toxicity, however, case reports and therapeutic guidelines are fairly well-established in the toxicology literature [4]. Early intubation, cardiovascular support, diazepam administration, epinephrine drips, and careful electrolyte monitoring, have all been described as pivotal measures for physicians to employ early in the process of resuscitating a patient with severe hydroxychloroquine toxicity [2]. While some of these measures are already part of typical resuscitation protocols, others are less commonly considered -especially the administration of diazepam, even in patients who are not actively seizing. This unique therapeutic approach made the creation and execution of this simulation case both timely and important for the learners involved.
To ensure a seamless case flow without overly cumbersome complexity, certain features of hydroxychloroquine toxicity were left out or de-emphasized but discussed during the post-simulation debriefing. For example, the case takes place more than an hour after the child ingested hydroxychloroquine. This timing was chosen to avoid the debate among toxicologists regarding the utility of gastric lavage for patients who present to the emergency department less than one hour after ingestion. Case reports on the subject demonstrate equivocal advice regarding this decision [4]. The child did not experience a seizure even though nearly half of the case reports of severe hydroxychloroquine toxicity involve seizures as a presenting symptom [2]. This decision was made primarily out of time constraints and case-flow concerns, but also to highlight the use of diazepam, even for patients who are not actively seizing. Thirdly, hydroxychloroquine commonly presents with hypokalemia [4]. However, hydroxychloroquine-induced hypokalemia is a temporary condition, transpiring while potassium is driven intracellularly [15]. Theoretically, there is a risk that once the patient stabilizes, the potassium will shift back into the serum, and severe hyperkalemia may result if the potassium has been replaced too aggressively. Case reports are mixed on the subject, as are toxicologists' recommendations on repletion, so this aspect of the toxicity was avoided. Lastly, the case was intentionally designed to result in cardiac arrest. Even if teams performed optimal resuscitation during the early phase of the simulation, barriers were intentionally placed (such as delayed availability of medications) to ensure that the primary learning objective for the learners -assisting during a pediatric code -was a key component of the simulation.
Similarly, oleander ingestion was chosen as the second toxic substance because, at the time of the inception of this case during the COVID-19 pandemic, oleander and oleander extract had also been proposed as having possible curative or preventative properties to COVID-19 [12][13]. Unfortunately, many were unaware of the medication's potentially deadly risk to children who accidentally ingest the plant, extracts, or teas [6,8]. Few physicians in the United States have previously cared for patients experiencing oleander toxicity, however, case reports and therapeutic guidelines are in the toxicology literature [6][7][8]. Cardiovascular support, digoxin immune fab administration, and careful electrolyte monitoring have all been described as pivotal measures for physicians to employ early in the process of resuscitating a patient with severe oleander toxicity [6,8].
In each of these two disparate simulation cases, learners demonstrated improvements in their knowledge base regarding the specific details of the respective pediatric toxidrome management. Learners also demonstrated improved confidence scores in all categories -confidence in evaluating a pediatric drug overdose, managing a pediatric cardiac dysrhythmia, managing a pediatric code, stabilizing a pediatric patient after ROSC, and managing pediatric toxidromes overall. Some learners with the lowest initial presimulation confidence scores reported some of the largest increases in post-simulation confidence. This may be a result of more inexperienced learners, with a lack of initial exposure to pediatric resuscitations overall, or certainly lack of exposure to these rare toxidromes, suddenly receiving a surge of information and confidence on these relevant topics. On knowledge and confidence assessments some statistically significant increases were seen, most learners ended up with an average of "3," which equates to neutral on the scale. Since we attempted to balance teams by training level it is unclear why some performed more critical actions than others. We were unable to discern a pattern in why some groups performed better than others in the simulation.

Limitations
Perhaps ironically, the inspiration for these cases, the COVID-19 pandemic, was the biggest barrier to the implementation of the simulation. The pediatric emergency department made the decision to postpone insitu simulations because of concern for an excess number of people congregating at the same time in a confined area. As a result, the cases were executed in a simulation lab with emergency medicine residents and medical students.
In addition, as described in the discussion section, we did not study long-term knowledge retention as part of our study. It is possible that, while short-term knowledge gains were identified, over time, that knowledge base will wane. Ideally, even if learners do not recall specifics of the case management, they will retain basic tenets, such as obtaining as much collateral information from patients and their families as possible, calling poison control for help in managing potential intoxications, and being careful when determining ageappropriate dosages and equipment sizes during pediatric resuscitations.
Lastly, both cases were intentionally designed to result in pulseless arrest. Even if teams performed optimal resuscitation during the early phases of the simulations, barriers may be intentionally placed (such as delayed availability of medications) to ensure that one of the primary learning objectives, managing a pediatric code, was a key component of the simulations.

Conclusions
This simulation case series was developed to educate emergency physicians about the management of overdoses from popularized COVID-19 therapies. The oleander and hydroxychloroquine pediatric toxicity cases are easily performed using commonly available simulation materials. Simulation is the ideal methodology for increasing learner knowledge, skills, and attitudes about low-frequency high-risk cases such as pediatric overdoses.

Appendices PATIENT NAME: Alex PATIENT AGE: 4 years old PATIENT WEIGHT: 15 kg CHIEF COMPLAINT: "Nausea & Vomiting"
Brief narrative description Alex is a 4-year-old male with no past medical history who complained to his parents that he was feeling "yucky" before vomiting. When his mother went to the bathroom to grab a thermometer, she noticed her hydroxychloroquine tablets were spilled out on the counter, prompting her to bring Alex straight to the Emergency Department. (ED) Upon initial evaluation in the ED, Alex is mildly tachycardic, but Ideal Scenario Flow Ideally, the learners assign team roles outside the room and observe the patient walking in to the room. When the learners enter, they promptly obtain the patient's vital signs, which demonstrate tachycardia, but are otherwise normal. Team members obtain a history and physical exam while also initiating obtaining IV access and placing patient on cardiac, blood pressure, and pulse ox monitoring. Ideally, the team elicits the information about the found hydroxychloroquine tablets from the patient's mother. After IV access is secured, initial labs are obtained and IV fluids are ordered. Initial labs are within normal range for the patient's age. EKG is ordered and demonstrates QTc prolongation to 500ms. Ideally, the team recognizes the need to obtain an EKG, blood glucose, serum electrolytes, liver function tests, acetaminophen, salicylate, EtOH levels and a UDS to assess for the broad range of sequelae from a hydroxychloroquine overdose and to assess for other medications that may have been consumed in addition to the hydroxychloroquine. The team may wish to obtain additional imaging to rule out alternate causes of abdominal pain and vomiting, but will be re-directed by the embedded participant nurse. The team may also consider administering activated charcoal, but as the ingestion has occurred longer than 1 hour prior to presentation, the intervention will provide minimal effect, and the case will continue as planned. When the patient begins to vomit, the team may choose to intervene by administering anti-emetics. If the prolonged QTc is overlooked and a medication such as ondansetron is ordered, the patient's rhythm will immediately become torsades de pointes. The patient must be reassessed numerous times and the team will discover that the patient's clinical status has deteriorated to a torsades dysrhythmia with faint pulses and agonal breathing. The team will work to calmly keep the family informed of the patient's status while simultaneously working to address the airway, breathing, and circulation and resuscitate the patient appropriately. Ideally, a bag-valve mask will be utilized until a more advanced airway can be secured. The team will administer magnesium sulfate in an attempt to stop the torsades rhythm. The team will also anticipate the next steps, and will bring advanced airway equipment and the crash cart to the bedside, and will place pediatric pads on the patient. Despite the team's best efforts, the patient will decompensate further to a ventricular fibrillation arrest. Upon loss of pulses, the team will recognize further decompensation in the patient's status, and will correctly identify ventricular fibrillation as a shockable rhythm. Following the PALS algorithm, the team will defibrillate the patient with weight-corrected joules and will subsequently begin compressions.
They will conduct pulse checks every 2 minutes, administer weight-adjusted epinephrine every 3-5 minutes, and will administer at least one weight-adjusted dose of amiodarone. By the fourth pulse check, if the PALS algorithm is followed appropriately, ROSC will be established. Post-ROSC care will be initiated. If not already performed, the patient will be successfully intubated and connected to a ventilator. A chest x-ray will confirm proper tube placement. The patient's vitals will be reassessed, which will reveal that the patient is hypotensive. The team will ideally correct with an epinephrine drip.    "Caleb has been vomiting and having diarrhea for a few hours. He had been playing outside in our yard. He may have eaten some seeds from the bushes we have." When asked about events leading up to the event (SAMPLE): SAMPLE history: Signs/symptoms (sx)-"Caleb was acting normally 3 hours ago. He was outside playing and then came into the house. He started vomiting and then developed diarrhea. He also said he could not see right and that made me concerned. He has never complained of anything like that before. He does have a habit of putting everything in his mouth." Allergies-none Medications-none Past Medical History: "He has autism. He was born full term, no complications. His immunizations are up to date. He was hospitalized for endoscopy after swallowing a nickel. He has never had surgery. He has not had any sick contacts." Last meal: "He had grilled cheese at noon." Events preceding: "We have new plants that are producing seeds and he tried to put some in his mouth the other day, but I stopped him. He is very curious and is a gustatory learner. Our backyard is well fenced so I let him play out there after lunch unsupervised." If asked for review of systems: Positive for nausea, vomiting, abdominal pain, diarrhea and blurry vision. Parent denies fevers, headaches, eye redness or discharge, congestion, shortness of breath, chest pain, bloody stool, abnormal bleeding, bruising, musculoskeletal or skin abnormality. If asked about home environment/social history: He lives at home with his parents. He often plays in his fenced in yard. His mother is currently working from home, father is on a business trip and deny any drugs in the house,

Additional Information
Disclosures Human subjects: Consent was obtained or waived by all participants in this study. Florida Atlantic University issued approval 1630432-1. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.