key: cord-349561-4mkiwg9k authors: Porta, Alessandra Della; Bornstein, Kasha; Coye, Austin; Montrief, Tim; Long, Brit; Parris, Mehruba Anwar title: Acute chloroquine and hydroxychloroquine toxicity: A review for emergency clinicians date: 2020-07-19 journal: Am J Emerg Med DOI: 10.1016/j.ajem.2020.07.030 sha: doc_id: 349561 cord_uid: 4mkiwg9k BACKGROUND: Acute chloroquine and hydroxychloroquine toxicity is characterized by a combination of direct cardiovascular effects and electrolyte derangements with resultant dysrhythmias and is associated with significant morbidity and mortality. OBJECTIVE: This review describes acute chloroquine and hydroxychloroquine toxicity, outlines the complex pathophysiologic derangements, and addresses the emergency department (ED) management of this patient population. DISCUSSION: Chloroquine and hydroxychloroquine are aminoquinoline derivatives widely used in the treatment of rheumatologic diseases including systemic lupus erythematosus and rheumatoid arthritis as well as for malaria prophylaxis. In early 2020, anecdotal reports and preliminary data suggested utility of hydroxychloroquine in attenuating viral loads and symptoms in patients with SARS-CoV-2 infection. Aminoquinoline drugs pose unique and significant toxicological risks, both during their intended use as well as in unsupervised settings by laypersons. The therapeutic range for chloroquine is narrow. Acute severe toxicity is associated with 10–30% mortality owing to a combination of direct cardiovascular effects and electrolyte derangements with resultant dysrhythmias. Treatment in the ED is focused on decontamination, stabilization of cardiac dysrhythmias, hemodynamic support, electrolyte correction, and seizure prevention. CONCLUSIONS: An understanding of the pathophysiology of acute chloroquine and hydroxychloroquine toxicity and available emergency treatments can assist emergency clinicians in reducing the immediate morbidity and mortality associated with this disease. J o u r n a l P r e -p r o o f rheumatologic indications, raising concern for toxicological implications in susceptible patients. Following the United States Food and Drug Administration emergency use authorization for chloroquine and hydroxychloroquine in the treatment of SARS-CoV-2, many additional clinical trials with randomization, blinding, and larger sample sizes were initiated to determine the benefit and risks. The largest of these studies, enrolling over 96,000 patients, initially demonstrated increased in-hospital mortality rates in patients treated with chloroquine or hydroxychloroquine. 35 However, that study has since been retracted due to concerns regarding veracity of the data and analyses conducted and inability to conduct an independent and private peer review. 36 Additional studies have demonstrated similar findings of increased mortality or did not find any evidence of prevention of primary endpoints, such as need for mechanical ventilation or death in patients treated with aminoquinolines. [37] [38] [39] As of June 2020, there are over 40 ongoing clinical trials actively assessing the efficacy of chloroquine or hydroxychloroquine, demonstrating continued interest in its role as a therapeutic agent for COVID-19. Furthermore, additional trials targeting frontline healthcare workers are underway to assess for the possible preventative action of these agents. The use of chloroquine or hydroxychloroquine sulfate in combination with other novel antiviral agents has been discouraged by the United States Food and Drug Administration, as recent in-vitro data demonstrating increasing concentrations of chloroquine phosphate reduced formation of activated remdesivir triphosphate in human bronchial epithelial cells, raising concerns that it may reduce the antiviral activity of this medication. 40 Widespread non-prescription use of aminoquinolines for either prophylaxis or treatment by laypersons in response to fears of COVID-19 raises significant and continued concern for unintended toxicity from overdose and/or drug-drug interactions. Despite slight differences in chemical structure, chloroquine and hydroxychloroquine are similar in regard to both metabolism and toxicity. 41, 42 Both molecules are highly lipophilic, have a high volume of distribution, and have mild-to-moderate protein binding. 43, 44 Following ingestion, the drugs are rapidly absorbed from the upper gastrointestinal (GI) tract and slowly redistribute to other compartments, eventually accumulating in erythrocytes, liver, lung, kidney, heart, muscle, and retinal tissue. 43 The combination of rapid absorption, high oral bioavailability, and slow redistribution prompts early peak serum levels post-ingestion which correlate with symptom severity in overdose. 41 Recent trials for COVID-19 have used regimens starting with 1 g on day one followed by 500 mg once daily for 4-7 days. 6 Median lethal doses (LD50) for chloroquine and hydroxychloroquine in humans are unknown as most available mortality data derives from case reports and case series. As little as 2-3 g of chloroquine may be fatal in adult patients, though the most commonly reported lethal dose in adults is 3-4 g. 19 The minimum lethal dose of chloroquine is estimated at 30-50 mg/kg. 45 Whole blood concentrations of 2.5 µg/L and above are considered to be lethal. 46 Significant toxicity from hydroxychloroquine has been reported in patients with plasma levels ranging between 2.05-18. 16 enzymes. 47 Intrinsic liver disease, such as hepatitis, alcoholism, or those taking additional medications metabolized by the same P450 isozymes can also modify chloroquine and hydroxychloroquine metabolism. 48 Following hepatic metabolism, aminoquinolines are mainly excreted renally (Table 1) . A small percentage of the initial ingested quantity of chloroquine or hydroxychloroquine is excreted unchanged. 49 Plasma half-life is extended in patients with renal insufficiency. 50 Chloroquine and hydroxychloroquine are distinct in terms of serum concentration required to produce toxicity, as chloroquine produces lethal effects at approximately 25% of the serum concentration of hydroxychloroquine. 45 However, both drugs have similar mechanisms of action. Aminoquinolines are pharmacologically diverse with activity on many distinct organ systems, cellular receptor sites, and intracellular organelles. This versatility contributes to the myriad uses of aminoquinolines from antimalarial prophylaxis to immunomodulation. 51 Most acutely lethal in cases of toxicity is the ability of aminoquinolines to inhibit myocardial sodium and potassium channels. 52 They behave as class IA antiarrhythmics with "Quinidine-like" effects, decreasing inotropy and producing characteristic electrocardiographic (ECG) changes. 52 Aminoquinolines also cause α 1 -adrenergic receptor blockade with loss of vascular sympathetic tone and resultant J o u r n a l P r e -p r o o f hypotension. 52 Finally, aminoquinolines have the ability to bind to and inhibit ATP-dependent potassium channels on pancreatic β-cells leading to a similar mechanism of systemic release of insulin as is observed with sulfonylureas. 53 Acute aminoquinoline toxicity affects multiple organ systems. The following sections describe effects from acute and chronic toxicity. Many of the features of aminoquinoline toxicity are pertinent to ED care, particularly serum abnormalities and cardiac, respiratory, and neurologic phenomena. Others may occur following admission or discharge from the ED and become more relevant in the context of patient history, including otologic and ophthalmic sequelae. A summary of these findings is displayed in Table 2 . Patient outcomes in acute toxicity depend on the degree of observed cardiovascular dysfunction. 20, 54 Aminoquinolines produce multiple effects on cardiac electrical conduction via sodium and potassium channel inhibition and α 1 -adrenergic receptor antagonism as previously mentioned. 20 Similar to class I antiarrhythmics, aminoquinolines have a dose-dependent effect on the cardiac action potential; the drug binds more avidly to ion channels and exerts greater sodium channel blockade at faster heart rates. 52 The effect leads to the classic PR prolongation, QRS complex widening, and QT prolongation associated with toxicity. 55 Also similar to class IA antiarrhythmics is the dose-dependent ability of aminoquinolines to bind and inhibit the action of potassium channels. As potassium is responsible for myocyte repolarization, potassium channel blockade delays repolarization. Clinically, this produces additional QT prolongation and J o u r n a l P r e -p r o o f predisposes to torsades de pointes (TdP). 52 Delay of repolarization is greatest at slower heart rates. 52 Acute cardiac toxicity manifests as conduction blocks involving the atrioventricular junction and His-Purkinje system and ECG changes with prolongation in PR, QRS, and QT intervals. 11, 52 Following overdose, these abnormalities can be profound, with reports of corrected QT (QTc) intervals of 563 milliseconds (ms) and 600 ms in case reports detailing oral hydroxychloroquine overdoses of 36 g and 22 g, respectively. 42 Dysrhythmias are typically present in moderate to severe toxicity. 52, 56 Patients with underlying prolonged QTc from structural heart disease, congenital long-QT syndromes, electrolyte disturbances, renal failure, and/or use of additional QT prolonging medications are at heightened risk for development of dysrhythmias including TdP. 56, 57 Hydroxychloroquine induced conduction delay often presents as a progression from a singular fascicular block to bundle branch block, followed by third-degree AV block. 58 Secondary to α 1 -adrenergic blockade, acutely toxic patients present with hypotension, which in addition to dysrhythmias may cause presyncope or syncope. 59 While unlikely to occur in acute overdose, cardiomyopathy is described in case reports of patients presenting with chronic chloroquine and/or hydroxychloroquine toxicity. 60, 61 Aminoquinoline-induced cardiomyopathy is believed to result from lysosomal dysfunction and toxic phospholipid accumulation in cardiomyocytes. 61 Aminoquinoline-related cardiomyopathy has been reported with findings of biatrial and/or biventricular enlargement as well as concentric hypertrophy with restrictive features. 62 Chronic exposure to cumulative doses of 1277 g and 1843 g of chloroquine and hydroxychloroquine, respectively, over an average of 13 years has J o u r n a l P r e -p r o o f been demonstrated to produce this effect. 63 Risk of development is greater in patients with underlying heart failure or structural heart defects. Sequelae of drug-induced cardiomyopathy include acute and chronic heart failure, recurrent syncopal episodes, and newly developed conduction disorders. 52, 55 Serum Abnormalities Plasma potassium levels vary inversely with the degree of blood chloroquine concentrations. 11, 64, 65 Hypokalemia is invariably present in overdose, and the extent of hypokalemia is an indicator of the severity of overdose. 54, 64 Treatment-refractory hypokalemia is often one of the most challenging features following acute intoxication and is associated with cardiac manifestations including dysrhythmias. 64, 66 Case reports from acute overdose report serum potassium concentrations of 2.5-2.7 mEq/L despite management with up to 280 mEq of potassium chloride. 66 The mechanism underlying hypokalemia is believed to be due to an intracellular shift of potassium as opposed to total body depletion, as aminoquinolines cause blockade of potassium channels on the pancreatic β-cells. 42, 64, 67 Similar to the mechanism of action of sulfonylureas, hyperinsulinism can produce additional serum abnormalities of hypoglycemia, particularly in patients with underlying metabolic derangements. 68, 69 J o u r n a l P r e -p r o o f Ophthalmologic sequelae of acute aminoquinoline intoxication include diplopia, loss of visual acuity, tunnel vision, mydriasis, and scotomata. 81 Onset of ocular symptoms often follows other clinical presentations, such as arrhythmia or hypotension by several hours. Vision improvement may occur rapidly or have a protracted recovery course of months following exposure. 81 Retinal toxicity has been reported at higher cumulative aminoquinoline doses, most often seen with chronic use. Following cumulative doses of 1000 g, the prevalence of retinal toxicity increases to 1% and is associated with an irreversible loss of vision despite cessation of the drug. 82 In some cases, progression of vision loss is present for up to one year after discontinuation of the offending agent. Vision loss is often bilateral and is characterized as a "bull's-eye" maculopathy and depigmentation of the retinal pigment epithelium (RPE). 83 This begins in the central visual fields, but with continued exposure leads to atrophy of the RPE and visual acuity loss. The mechanism underlying toxicity to the cells of the retina is believed to be multifactorial, including direct photoreceptors damage via alterations in metabolism and secondary effects due to the binding of aminoquinolines to the melanin cells within the RPE. 83 As opposed to quinine, aminoquinoline toxicity is less commonly associated with acute onset of GI symptoms such as nausea, vomiting, and diarrhea. While these may occur in both acute toxicity and in chronic therapeutic use, there are no long-term GI sequelae. 51 Aminoquinolinerelated nausea and vomiting is mediated both by direct gastric irritant effects and activation of emetic centers in the brain. 84 Symptoms are usually transient following acute intoxication or therapeutic doses. 84 Fewer than 1% of patients display an increase in transaminases following J o u r n a l P r e -p r o o f initiation of aminoquinolines. 85 Case reports of drug induced liver injury (DILI) have reported AST and ALT elevations of 399 IU/L and 285 IU/L, respectively, within eight hours of initial dosing. 86, 87 However, in patients with underlying liver disease or porphyria cutanea tarda, DILI has been reported in up to 50% of cases, and observed transaminitis may be much more severe. 86, 87 In the majority of cases transaminases returned to baseline following drug discontinuation. 85, 86 Myotoxicity Similar to the mechanism underlying aminoquinoline-induced cardiomyopathy, lysosomal dysfunction with vacuolar accumulation of metabolic products is believed to play a role in skeletal muscle toxicity. 21 Clinically, myopathy tends to be mild when symptomatic and affects the proximal muscles to a greater degree than distal groups, presenting as weakness. 88 While the incidence of chronic aminoquinoline use-induced myopathy is reportedly as high as 12.6%, it is believed to be higher due to two factors. 86, 87 First, patient underreporting is likely, as elevations in creatine phosphokinase may be seen in patients even with normal strength testing. Second, myopathy may be difficult to distinguish from baseline, as myopathy-related pain and weakness are often associated with the rheumatologic diseases that these drugs are often prescribed to treat. 88 It is unknown if myopathy is dose-dependent, although myotoxicity progression has been observed with prolonged treatment ( Table 2) . 89 J o u r n a l P r e -p r o o f including jaundice, hemoglobinuria, and renal failure. 90, 91 In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemolysis can occur due to free radical accumulation in erythrocytes. 91, 92 Due to a lack of reduced glutathione, oxidative stress denatures heme, causing extravascular hemolysis. The extent of hemolysis depends on the drug, dose, and the degree of enzyme deficiency, leading to a range of asymptomatic to life-threatening hemolysis. 93 Primaquine is more closely associated with G6PD-mediated hemolysis. Although case report literature describes the finding in chloroquine and hydroxychloroquine use, the largest chart review to date examining these drugs in patients with G6PD noted no occurrence of hemolysis. 91, 92 Gold-standard evidence such as randomized controlled trials, systematic reviews, or metanalyses for management of aminoquinoline toxicity do not currently exist in the literature. The following recommendations are based on published expert opinion from poison control centers and medical toxicologists, as well as frequent findings described in case report literature. Consultation with a poison control center and/or medical toxicologist is recommended early in the management of these patients in the emergency department. Aminoquinoline overdose produces toxicity ranging from mild to severe. Unlike with chloroquine overdoses, there is no established lethal or toxic dose of hydroxychloroquine in adults, and management should be tailored to observed toxicity. 22 Mild chloroquine toxicity in adults is defined as symptomatology occurring with suspected ingested dose <2 g, normal systolic blood pressure, and normal QRS (≤120 ms). 19 Moderate chloroquine toxicity occurs with suspected ingested dose 2-4 g, normal systolic blood pressure, and normal QRS (≤120 ms). 19 Severe chloroquine toxicity occurs with suspected ingested dose >4 g, hypotension, and QRS prolongation (>120 ms). 54 Doses exceeding 5 g are highly associated with mortality due to arrhythmias and hypokalemia. 94 Treatment in the ED setting is focused on high-quality symptomatic and supportive measures, decontamination, stabilization of cardiac dysrhythmias if present, hemodynamic support, and electrolyte correction as necessary. 22 Indications for intensive care unit admission include persistent systemic hypotension, QRS elongation >120 ms, ventricular arrhythmias, seizures, coma, and persistent hypoglycemia. 95 Multiple reports cite early intubation and mechanical ventilation as critical for survival. The combination of altered mentation, apnea, and vomiting present in many aminoquinoline-intoxicated patients heightens the necessity for early and aggressive airway intervention to reduce aspiration risk. Given concerns for rapid potassium shifts in toxicity and repletion, an alternative to succinylcholine should be considered for rapid sequence induction and paralysis to avoid provoking rapid onset of hyperkalemia. Additionally, clinicians should avoid barbiturates for induction, as they may precipitate sudden cardiac arrest. 96 In the following sections, strategies for the emergency management of aminoquinoline intoxication will be addressed, including decontamination, pharmacotherapeutics, elimination J o u r n a l P r e -p r o o f methods, and emerging modalities (i.e. ECMO and ILE). Algorithmic application of these strategies to the categorization of mild, moderate, and severe toxicity is shown in Figure 1 . Overdose. Hydroxychloroquine and chloroquine have high volumes of distribution and significant protein binding, complicating modalities for augmenting elimination. 11 Although these drugs are ingested, patients should not receive emetics such as syrup of ipecac, as toxicity sequelae of seizures, altered mentation, dysrhythmias, and hypotension heighten risks of aspiration. 11 Similarly, orogastric lavage has fallen out of favor due to the risks of aspiration. In cases of life threatening ingestion, orogastric lavage can be considered in patients presenting early following ingestion, within one hour. 41, 66 Activated charcoal effectively absorbs aminoquinoline in the gastrointestinal tract with 95%-99% binding when administered in the first five minutes following ingestion. 97 As with other decontamination strategies, the use of activated charcoal will depend on patient presentation (i.e. those who are not nauseated or vomiting) and duration of intoxication. 11 While serum drug levels may be drawn, they are not readily available and therefore are not a practical measure to guide initial management of acute toxicity in the ED setting. 74 However, for inpatient treatment, early and serial measurements of blood chloroquine concentrations are more accurate compared to estimated oral ingestion for predicting cardiovascular severity of chloroquine poisonings. 98 Hypokalemia is a marker of severity of toxicity in acute poisoning and must be carefully monitored and managed as intracellular shifts can reverse as acute toxicity resolves, with rapid onset of hyperkalemia. 11 Potassium may be repleted cautiously in severe hypokalemia (<1.9 mEq/L), and monitoring of potassium levels should occur regularly. While older studies indicate that hypokalemia may prolong survival, contemporary data favor potassium repletion, generally to >4 mEq/L. 64 Dysrhythmias resulting from electrolyte derangements including potassium should be rapidly but carefully corrected. 11 Class IA, IC, and III antiarrhythmics should be avoided as they may worsen conduction delays. 11 Magnesium sulfate 2g IV over 10 minutes may be used for TdP treatment, but has an unclear role in prophylaxis for QT prolongation ≥500 ms. 100 Potassium repletion to achieve serum concentration between 4.7-5. to mechanical ventilation increased survival from 9% to 91%. 20 If epinephrine fails to adequately raise mean arterial pressure, a second pressor such as norepinephrine or phenylephrine can be titrated to effect, though alpha agonists increase the effective refractory period and may increase the occurrence of arrythmias. 103, 104 If hypotension is due to myocardial depression rather than arterial vasodilation, these vasoactive medications may worsen cardiac output. 104 Patients requiring additional vasopressor support beyond epinephrine and diazepam should receive close attention to hemodynamic parameters to ensure treatment efficacy. Diazepam is used in the management of both hypotension and dysrhythmias in dosages of 2 mg/kg IV over 30 minutes, followed by 1 to 2 mg/kg/d for 2-4 days in severe cases. 51 The mechanism of diazepam in attenuation cardiotoxicity is believed to have a central antagonistic effect, anticonvulsant effect, antidysrhythmic effect and interaction inverse to aminoquinolines, and decrease aminoquinoline induced-vasodilation. 22, 105, 106 Experimental use of diazepam in animal models of severe chloroquine overdose demonstrates improved systolic and diastolic arterial pressures, heart rate, urine volume, urinary excretion of chloroquine, and shortened QRS duration. 102, 107 No studies have compared efficacy between different benzodiazepines for treatment of acute aminoquinoline toxicity. With medication shortages or variation in ED pharmacy stock, another benzodiazepine may be substituted for treatment of seizures and for maintenance of sedation. Gastrointestinal symptoms, such as nausea, vomiting, and diarrhea, can be found in mildly intoxicated patients and more severe overdoses. Vomiting in early stages of intoxication may be due to direct irritant effects of aminoquinolines, and may be better managed with the decontamination strategies addressed above. Nausea and vomiting can be treated symptomatically while avoiding QTc prolonging agents such as serotonin antagonists (ondansetron) and phenothiazines (promethazine, prochlorperazine). 108 Antihistamine (meclizine) and dopamine receptor antagonist (metoclopramide) antiemetics may be safer options. There are currently no accepted treatments for quinine-induced ocular toxicity, but fundoscopic examination, visual field examination, and color testing are appropriate to assess injury ideally by an ophthalmologist. 19 Hyperbaric oxygen has been used successfully in vision recovery, but causality was not established. 109 To address sodium channel, blockade sodium loading with sodium bicarbonate (NaHCO 3 ), sodium acetate, or hypertonic saline (3% NaCl) may be used. 11 Consideration should be given to the degree of cardiac toxicity and severity of hypokalemia if present, favoring use of sodium acetate or hypertonic saline to avoid worsening hypokalemia. The pH can be used as an indirect indicator of sodium load. When using NaHCO 3 , a bolus of 1-2 mEq/kg is recommended, repeated as needed to terminate dysrhythmias or narrow QRS complex, then utilizing a NaHCO 3 infusion. 11 When using sodium acetate, 1 mEq/kg body weight may be infused over 15-20 min as a bolus. 110 Potassium should be closely monitored for intracellular shifting of potassium with J o u r n a l P r e -p r o o f development of clinically significant hypokalemia. Hypertonic saline contains the same quantity of sodium in 97 mEq as sodium bicarbonate in 50 mEq. When using 3% NaCl, a bolus of 2-4 mEq/kg may be considered, and sodium levels should be closely monitored. 111 Approximately 50% of chloroquine is excreted renally, and acute renal failure is possible following acute intoxication. 112 Providers should anticipate the possibility of extended toxicity course in patients with acute and/or chronic renal failure. Unfortunately, hemodialysis use has been reported as ineffective due to high protein binding and large volume of distribution intrinsic to the aminoquinolines. 112 Case report evidence suggests hemodialysis efficacy can be augmented by use of ILE. 22 There are multiple reports of veno-arterial ECMO to successfully treat aminoquinoline toxicity. 98, [113] [114] [115] [116] ECMO may be considered in severe toxicity refractory to standard supportive care and other therapies (i.e. escalation of epinephrine drip rate to > 3 mg/hr, persistent endorgan failure). One case report describes ECMO initiation on intensive care unit admission following a 9.5 g chloroquine ingestion (initial blood chloroquine concentration 6215 µg/L). The patient presented with altered mental status, left ventricular systolic dysfunction with a dyskinetic interventricular septum, and hypotension unresponsive to crystalloid fluid resuscitation as well as 3 mg/hour epinephrine infusion. The patient was weaned from vasopressors on day three, decannulated from ECMO on day four, extubated on day seven, and discharged on day ten with no neurological sequelae. 117 Another case detailing ECMO use in a patient experiencing ventricular fibrillation following 12 g hydroxychloroquine overdose noted J o u r n a l P r e -p r o o f "spectacular improvement of hemodynamic parameters and electrocardiographic normalization at day one." 114 Owing to the lipophilicity of aminoquinolines, there are several reports of successful outcomes following ILE use. 22, 46, 118, 119 Recommended ILE treatment is 1.5 mL/kg lean body mass (~100mL in adults) as bolus over two to three minutes followed by 200 mL over 10-15 minutes. 22 If benefit is seen in vital signs and/or ECG parameter normalization, slower continuous infusion of ~0.25 mL/kg/min can be administered until resolution of toxicity. 119 Combined ILE, NaHCO 3 , and vasopressor support has been reported in profound hydroxychloroquine overdose of 40 g presenting with hypokalemia and refractory ventricular fibrillation with positive outcome. 22 Protracted ILE has been associated with dysfunction of ECMO circuits, though this is unlikely in short-term ILE use (<24 hours continuous infusion), and case reports have described safe concomitant use of both modalities. 118 ,120 Serum triglyceride levels may be monitored to guide ILE extent of infusion, with ~1000 mg/dL as a lipid volume limit of efficacy. 121 Given the wide publicity in the lay media regarding the use of aminoquinolines for COVID-19 and trends in national poison control center data, a more current exploration of the acute management of aminoquinoline toxicity is necessary. This class of drugs has a narrow therapeutic range and a large variance in toxic dose from person to person. Severe symptoms can occur with doses as small as 1.5 g with onset one to three hours post-ingestion. Management of acute toxicity often occurs in the emergency department and should focus on hemodynamic J o u r n a l P r e -p r o o f stabilization with the use of early mechanical ventilation, diazepam, epinephrine, frequent ECGs, and repeated blood glucose monitoring, with early step-up to aggressive resuscitative measures including ECMO to support vital functions until the offending agent is metabolized and cleared. 25, 26 Coronavirus disease 2019 (COVID-19) , caused by SARS-CoV-2, is responsible for a major international pandemic with significant morbidity and mortality rates between 1.5-9% depending on the population investigated. 27, 28 The pathophysiology of SARS-CoV-2 includes but is not limited to cytokine dysregulation, direct cytopathic effects on respiratory tract epitheliocytes, and down-regulation of lung protective angiotensin converting enzyme resulting in diffuse alveolar damage and hypercoagulability. 29, 30 Viral entry is facilitated by cellular protease-primed spike protein binding to angiotensin-converting enzyme 2 (ACE2) receptors. 31 Efforts to repurpose or develop targeted therapeutics for SARS-CoV-2 infection have included assessment of antiinflammatory drugs such as corticosteroids and interleukin inhibitors, macrolide antibiotics such as azithromycin, and direct-acting antivirals such as protease inhibitors and adenosine analogs. 6 The utility of aminoquinolines in attenuating infection severity is hypothesized to derive from preventing SARS-CoV-2 binding to target receptors and inhibiting viral cell entry. 6 Chloroquine and hydroxychloroquine are concentrated within the endosome, where they are thought to modulate organelle pH, inhibiting autophagosome formation and impairing cleavage of the SARS-CoV-2 spike protein. 32 Additional hypothesized immunomodulatory effects in SARS- that play a role in organ injury and acute respiratory distress syndrome. 32 concern for unintended toxicity from overdose and/or drug-drug interactions. Despite slight differences in chemical structure, chloroquine and hydroxychloroquine are similar in regard to both metabolism and toxicity. 41, 42 Both molecules are highly lipophilic, have a high volume of distribution, and have mild-to-moderate protein binding. 43, 44 Following ingestion, the drugs are rapidly absorbed from the upper gastrointestinal (GI) tract and slowly redistribute to other compartments, eventually accumulating in erythrocytes, liver, lung, kidney, heart, muscle, and retinal tissue. 43 The combination of rapid absorption, high oral bioavailability, and slow redistribution prompts early peak serum levels post-ingestion which correlate with symptom severity in overdose. 41 Recent trials for COVID-19 have used regimens starting with 1 g on day one followed by 500 mg once daily for 4-7 days. 6 Median lethal doses (LD50) for chloroquine and hydroxychloroquine in humans are unknown as most available mortality data derives from case reports and case series. As little as 2-3 g of chloroquine may be fatal in adult patients, though the most commonly reported lethal dose in adults is 3-4 g. 19 The minimum lethal dose of chloroquine is estimated at 30-50 mg/kg. 45 Whole blood concentrations of 2.5 µg/L and above are considered to be lethal. 46 enzymes. 47 Intrinsic liver disease, such as hepatitis, alcoholism, or those taking additional medications metabolized by the same P450 isozymes can also modify chloroquine and hydroxychloroquine metabolism. 48 Following hepatic metabolism, aminoquinolines are mainly excreted renally (Table 1) . A small percentage of the initial ingested quantity of chloroquine or hydroxychloroquine is excreted unchanged. 49 Plasma half-life is extended in patients with renal insufficiency. 50 Chloroquine and hydroxychloroquine are distinct in terms of serum concentration required to produce toxicity, as chloroquine produces lethal effects at approximately 25% of the serum concentration of hydroxychloroquine. 45 However, both drugs have similar mechanisms of action. Aminoquinolines are pharmacologically diverse with activity on many distinct organ systems, cellular receptor sites, and intracellular organelles. This versatility contributes to the myriad uses of aminoquinolines from antimalarial prophylaxis to immunomodulation. 51 Most acutely lethal in cases of toxicity is the ability of aminoquinolines to inhibit myocardial sodium and potassium channels. 52 They behave as class IA antiarrhythmics with "Quinidine-like" effects, decreasing inotropy and producing characteristic electrocardiographic (ECG) changes. 52 Aminoquinolines also cause α 1 -adrenergic receptor blockade with loss of vascular sympathetic tone and resultant J o u r n a l P r e -p r o o f hypotension. 52 Finally, aminoquinolines have the ability to bind to and inhibit ATP-dependent potassium channels on pancreatic β-cells leading to a similar mechanism of systemic release of insulin as is observed with sulfonylureas. 53 Acute aminoquinoline toxicity affects multiple organ systems. The following sections describe effects from acute and chronic toxicity. Many of the features of aminoquinoline toxicity are pertinent to ED care, particularly serum abnormalities and cardiac, respiratory, and neurologic phenomena. Others may occur following admission or discharge from the ED and become more relevant in the context of patient history, including otologic and ophthalmic sequelae. A summary of these findings is displayed in Table 2 . Patient outcomes in acute toxicity depend on the degree of observed cardiovascular dysfunction. 20,54 Aminoquinolines produce multiple effects on cardiac electrical conduction via sodium and potassium channel inhibition and α 1 -adrenergic receptor antagonism as previously mentioned. 20 Similar to class I antiarrhythmics, aminoquinolines have a dose-dependent effect on the cardiac action potential; the drug binds more avidly to ion channels and exerts greater sodium channel blockade at faster heart rates. 52 The effect leads to the classic PR prolongation, QRS complex widening, and QT prolongation associated with toxicity. 55 Also similar to class IA antiarrhythmics is the dose-dependent ability of aminoquinolines to bind and inhibit the action of potassium channels. As potassium is responsible for myocyte repolarization, potassium channel blockade delays repolarization. Clinically, this produces additional QT prolongation and J o u r n a l P r e -p r o o f predisposes to torsades de pointes (TdP). 52 Delay of repolarization is greatest at slower heart rates. 52 Acute cardiac toxicity manifests as conduction blocks involving the atrioventricular junction and His-Purkinje system and ECG changes with prolongation in PR, QRS, and QT intervals. 11, 52 Following overdose, these abnormalities can be profound, with reports of corrected QT (QTc) intervals of 563 milliseconds (ms) and 600 ms in case reports detailing oral hydroxychloroquine overdoses of 36 g and 22 g, respectively. 42 Dysrhythmias are typically present in moderate to severe toxicity. 52, 56 Patients with underlying prolonged QTc from structural heart disease, congenital long-QT syndromes, electrolyte disturbances, renal failure, and/or use of additional QT prolonging medications are at heightened risk for development of dysrhythmias including TdP. 56, 57 Hydroxychloroquine induced conduction delay often presents as a progression from a singular fascicular block to bundle branch block, followed by third-degree AV block. 58 Secondary to α 1 -adrenergic blockade, acutely toxic patients present with hypotension, which in addition to dysrhythmias may cause presyncope or syncope. 59 While unlikely to occur in acute overdose, cardiomyopathy is described in case reports of patients presenting with chronic chloroquine and/or hydroxychloroquine toxicity. 60, 61 Aminoquinoline-induced cardiomyopathy is believed to result from lysosomal dysfunction and toxic phospholipid accumulation in cardiomyocytes. 61 Aminoquinoline-related cardiomyopathy has been reported with findings of biatrial and/or biventricular enlargement as well as concentric hypertrophy with restrictive features. 62 Chronic exposure to cumulative doses of 1277 g and 1843 g of chloroquine and hydroxychloroquine, respectively, over an average of 13 years has J o u r n a l P r e -p r o o f been demonstrated to produce this effect. 63 Risk of development is greater in patients with underlying heart failure or structural heart defects. Sequelae of drug-induced cardiomyopathy include acute and chronic heart failure, recurrent syncopal episodes, and newly developed conduction disorders. 52, 55 Serum Abnormalities Plasma potassium levels vary inversely with the degree of blood chloroquine concentrations. 11, 64, 65 Hypokalemia is invariably present in overdose, and the extent of hypokalemia is an indicator of the severity of overdose. 54, 64 Treatment-refractory hypokalemia is often one of the most challenging features following acute intoxication and is associated with cardiac manifestations including dysrhythmias. 64, 66 Case reports from acute overdose report serum potassium concentrations of 2.5-2.7 mEq/L despite management with up to 280 mEq of potassium chloride. 66 The mechanism underlying hypokalemia is believed to be due to an intracellular shift of potassium as opposed to total body depletion, as aminoquinolines cause blockade of potassium channels on the pancreatic β-cells. 42, 64, 67 Similar to the mechanism of action of sulfonylureas, hyperinsulinism can produce additional serum abnormalities of hypoglycemia, particularly in patients with underlying metabolic derangements. 68, 69 J o u r n a l P r e -p r o o f Ophthalmologic sequelae of acute aminoquinoline intoxication include diplopia, loss of visual acuity, tunnel vision, mydriasis, and scotomata. 81 Onset of ocular symptoms often follows other clinical presentations, such as arrhythmia or hypotension by several hours. Vision improvement may occur rapidly or have a protracted recovery course of months following exposure. 81 Retinal toxicity has been reported at higher cumulative aminoquinoline doses, most often seen with chronic use. Following cumulative doses of 1000 g, the prevalence of retinal toxicity increases to 1% and is associated with an irreversible loss of vision despite cessation of the drug. 82 In some cases, progression of vision loss is present for up to one year after discontinuation of the offending agent. Vision loss is often bilateral and is characterized as a "bull's-eye" maculopathy and depigmentation of the retinal pigment epithelium (RPE). 83 This begins in the central visual fields, but with continued exposure leads to atrophy of the RPE and visual acuity loss. The mechanism underlying toxicity to the cells of the retina is believed to be multifactorial, including direct photoreceptors damage via alterations in metabolism and secondary effects due to the binding of aminoquinolines to the melanin cells within the RPE. 83 As opposed to quinine, aminoquinoline toxicity is less commonly associated with acute onset of GI symptoms such as nausea, vomiting, and diarrhea. While these may occur in both acute toxicity and in chronic therapeutic use, there are no long-term GI sequelae. 51 Aminoquinolinerelated nausea and vomiting is mediated both by direct gastric irritant effects and activation of emetic centers in the brain. 84 Symptoms are usually transient following acute intoxication or therapeutic doses. 84 Fewer than 1% of patients display an increase in transaminases following J o u r n a l P r e -p r o o f initiation of aminoquinolines. 85 Case reports of drug induced liver injury (DILI) have reported AST and ALT elevations of 399 IU/L and 285 IU/L, respectively, within eight hours of initial dosing. 86, 87 However, in patients with underlying liver disease or porphyria cutanea tarda, DILI has been reported in up to 50% of cases, and observed transaminitis may be much more severe. 86, 87 In the majority of cases transaminases returned to baseline following drug discontinuation. 85, 86 Myotoxicity Similar to the mechanism underlying aminoquinoline-induced cardiomyopathy, lysosomal dysfunction with vacuolar accumulation of metabolic products is believed to play a role in skeletal muscle toxicity. 21 Clinically, myopathy tends to be mild when symptomatic and affects the proximal muscles to a greater degree than distal groups, presenting as weakness. 88 While the incidence of chronic aminoquinoline use-induced myopathy is reportedly as high as 12.6%, it is believed to be higher due to two factors. 86, 87 First, patient underreporting is likely, as elevations in creatine phosphokinase may be seen in patients even with normal strength testing. Second, myopathy may be difficult to distinguish from baseline, as myopathy-related pain and weakness are often associated with the rheumatologic diseases that these drugs are often prescribed to treat. 88 It is unknown if myopathy is dose-dependent, although myotoxicity progression has been observed with prolonged treatment ( Table 2 ). 89 Thrombocytopenia, agranulocytosis, and disseminated intravascular coagulation have been reported with aminoquinoline use. 90 Hemolytic anemia has also been reported with findings J o u r n a l P r e -p r o o f including jaundice, hemoglobinuria, and renal failure. 90, 91 In patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemolysis can occur due to free radical accumulation in erythrocytes. 91, 92 Due to a lack of reduced glutathione, oxidative stress denatures heme, causing extravascular hemolysis. The extent of hemolysis depends on the drug, dose, and the degree of enzyme deficiency, leading to a range of asymptomatic to life-threatening hemolysis. 93 Primaquine is more closely associated with G6PD-mediated hemolysis. Although case report literature describes the finding in chloroquine and hydroxychloroquine use, the largest chart review to date examining these drugs in patients with G6PD noted no occurrence of hemolysis. 91, 92 Gold-standard evidence such as randomized controlled trials, systematic reviews, or metanalyses for management of aminoquinoline toxicity do not currently exist in the literature. The following recommendations are based on published expert opinion from poison control centers and medical toxicologists, as well as frequent findings described in case report literature. Consultation with a poison control center and/or medical toxicologist is recommended early in the management of these patients in the emergency department. Aminoquinoline overdose produces toxicity ranging from mild to severe. Unlike with chloroquine overdoses, there is no established lethal or toxic dose of hydroxychloroquine in adults, and management should be tailored to observed toxicity. 22 Mild chloroquine toxicity in adults is defined as symptomatology occurring with suspected ingested dose <2 g, normal systolic blood pressure, and normal QRS (≤120 ms). 19 Moderate chloroquine toxicity occurs with suspected ingested dose 2-4 g, normal systolic blood pressure, and normal QRS (≤120 ms). 19 Severe chloroquine toxicity occurs with suspected ingested dose >4 g, hypotension, and QRS prolongation (>120 ms). 54 Doses exceeding 5 g are highly associated with mortality due to arrhythmias and hypokalemia. 94 In the following sections, strategies for the emergency management of aminoquinoline intoxication will be addressed, including decontamination, pharmacotherapeutics, elimination J o u r n a l P r e -p r o o f methods, and emerging modalities (i.e. ECMO and ILE). Algorithmic application of these strategies to the categorization of mild, moderate, and severe toxicity is shown in Figure 1 . Overdose. Hydroxychloroquine and chloroquine have high volumes of distribution and significant protein binding, complicating modalities for augmenting elimination. 11 Although these drugs are ingested, patients should not receive emetics such as syrup of ipecac, as toxicity sequelae of seizures, altered mentation, dysrhythmias, and hypotension heighten risks of aspiration. 11 Similarly, orogastric lavage has fallen out of favor due to the risks of aspiration. In cases of life threatening ingestion, orogastric lavage can be considered in patients presenting early following ingestion, within one hour. 41, 66 Activated charcoal effectively absorbs aminoquinoline in the gastrointestinal tract with 95%-99% binding when administered in the first five minutes following ingestion. 97 As with other decontamination strategies, the use of activated charcoal will depend on patient presentation (i.e. those who are not nauseated or vomiting) and duration of intoxication. 11 While serum drug levels may be drawn, they are not readily available and therefore are not a practical measure to guide initial management of acute toxicity in the ED setting. 74 However, for inpatient treatment, early and serial measurements of blood chloroquine concentrations are more accurate compared to estimated oral ingestion for predicting cardiovascular severity of chloroquine poisonings. 98 Hypokalemia is a marker of severity of toxicity in acute poisoning and must be carefully monitored and managed as intracellular shifts can reverse as acute toxicity resolves, with rapid onset of hyperkalemia. 11 Potassium may be repleted cautiously in severe hypokalemia (<1.9 mEq/L), and monitoring of potassium levels should occur regularly. While older studies indicate that hypokalemia may prolong survival, contemporary data favor potassium repletion, generally to >4 mEq/L. 64 Dysrhythmias resulting from electrolyte derangements including potassium should be rapidly but carefully corrected. 11 Class IA, IC, and III antiarrhythmics should be avoided as they may worsen conduction delays. 11 Magnesium sulfate 2g IV over 10 minutes may be used for TdP treatment, but has an unclear role in prophylaxis for QT prolongation ≥500 ms. 100 20 If epinephrine fails to adequately raise mean arterial pressure, a second pressor such as norepinephrine or phenylephrine can be titrated to effect, though alpha agonists increase the effective refractory period and may increase the occurrence of arrythmias. 103, 104 If hypotension is due to myocardial depression rather than arterial vasodilation, these vasoactive medications may worsen cardiac output. 104 Patients requiring additional vasopressor support beyond epinephrine and diazepam should receive close attention to hemodynamic parameters to ensure treatment efficacy. Diazepam is used in the management of both hypotension and dysrhythmias in dosages of 2 mg/kg IV over 30 minutes, followed by 1 to 2 mg/kg/d for 2-4 days in severe cases. 51 The mechanism of diazepam in attenuation cardiotoxicity is believed to have a central antagonistic effect, anticonvulsant effect, antidysrhythmic effect and interaction inverse to aminoquinolines, and decrease aminoquinoline induced-vasodilation. 22, 105, 106 Experimental use of diazepam in animal models of severe chloroquine overdose demonstrates improved systolic and diastolic arterial pressures, heart rate, urine volume, urinary excretion of chloroquine, and shortened QRS duration. 102, 107 No studies have compared efficacy between different benzodiazepines for treatment of acute aminoquinoline toxicity. With medication shortages or variation in ED pharmacy stock, another benzodiazepine may be substituted for treatment of seizures and for maintenance of sedation. Gastrointestinal symptoms, such as nausea, vomiting, and diarrhea, can be found in mildly intoxicated patients and more severe overdoses. Vomiting in early stages of intoxication may be due to direct irritant effects of aminoquinolines, and may be better managed with the decontamination strategies addressed above. Nausea and vomiting can be treated symptomatically while avoiding QTc prolonging agents such as serotonin antagonists (ondansetron) and phenothiazines (promethazine, prochlorperazine). 108 Antihistamine (meclizine) and dopamine receptor antagonist (metoclopramide) antiemetics may be safer options. There are currently no accepted treatments for quinine-induced ocular toxicity, but fundoscopic examination, visual field examination, and color testing are appropriate to assess injury ideally by an ophthalmologist. 19 Hyperbaric oxygen has been used successfully in vision recovery, but causality was not established. 109 To address sodium channel, blockade sodium loading with sodium bicarbonate (NaHCO 3 ), sodium acetate, or hypertonic saline (3% NaCl) may be used. 11 Consideration should be given to the degree of cardiac toxicity and severity of hypokalemia if present, favoring use of sodium acetate or hypertonic saline to avoid worsening hypokalemia. The pH can be used as an indirect indicator of sodium load. When using NaHCO 3 , a bolus of 1-2 mEq/kg is recommended, repeated as needed to terminate dysrhythmias or narrow QRS complex, then utilizing a NaHCO 3 infusion. 11 When using sodium acetate, 1 mEq/kg body weight may be infused over 15-20 min as a bolus. 110 Potassium should be closely monitored for intracellular shifting of potassium with J o u r n a l P r e -p r o o f development of clinically significant hypokalemia. Hypertonic saline contains the same quantity of sodium in 97 mEq as sodium bicarbonate in 50 mEq. When using 3% NaCl, a bolus of 2-4 mEq/kg may be considered, and sodium levels should be closely monitored. 111 Approximately 50% of chloroquine is excreted renally, and acute renal failure is possible following acute intoxication. 112 Providers should anticipate the possibility of extended toxicity course in patients with acute and/or chronic renal failure. Unfortunately, hemodialysis use has been reported as ineffective due to high protein binding and large volume of distribution intrinsic to the aminoquinolines. 112 Case report evidence suggests hemodialysis efficacy can be augmented by use of ILE. 22 There are multiple reports of veno-arterial ECMO to successfully treat aminoquinoline toxicity. 98, [113] [114] [115] [116] ECMO may be considered in severe toxicity refractory to standard supportive care and other therapies (i.e. escalation of epinephrine drip rate to > 3 mg/hr, persistent endorgan failure). One case report describes ECMO initiation on intensive care unit admission following a 9.5 g chloroquine ingestion (initial blood chloroquine concentration 6215 µg/L). The patient presented with altered mental status, left ventricular systolic dysfunction with a dyskinetic interventricular septum, and hypotension unresponsive to crystalloid fluid resuscitation as well as 3 mg/hour epinephrine infusion. The patient was weaned from vasopressors on day three, decannulated from ECMO on day four, extubated on day seven, and discharged on day ten with no neurological sequelae. 117 Another case detailing ECMO use in a patient experiencing ventricular fibrillation following 12 g hydroxychloroquine overdose noted J o u r n a l P r e -p r o o f "spectacular improvement of hemodynamic parameters and electrocardiographic normalization at day one." 114 Owing to the lipophilicity of aminoquinolines, there are several reports of successful outcomes following ILE use. 22, 46, 118, 119 Recommended ILE treatment is 1.5 mL/kg lean body mass (~100mL in adults) as bolus over two to three minutes followed by 200 mL over 10-15 minutes. 22 If benefit is seen in vital signs and/or ECG parameter normalization, slower continuous infusion of ~0.25 mL/kg/min can be administered until resolution of toxicity. 119 Combined ILE, NaHCO 3 , and vasopressor support has been reported in profound hydroxychloroquine overdose of 40 g presenting with hypokalemia and refractory ventricular fibrillation with positive outcome. 22 Protracted ILE has been associated with dysfunction of ECMO circuits, though this is unlikely in short-term ILE use (<24 hours continuous infusion), and case reports have described safe concomitant use of both modalities. 118 ,120 Serum triglyceride levels may be monitored to guide ILE extent of infusion, with ~1000 mg/dL as a lipid volume limit of efficacy. 121 Given the wide publicity in the lay media regarding the use of aminoquinolines for COVID-19 and trends in national poison control center data, a more current exploration of the acute management of aminoquinoline toxicity is necessary. This class of drugs has a narrow therapeutic range and a large variance in toxic dose from person to person. Severe symptoms can occur with doses as small as 1.5 g with onset one to three hours post-ingestion. 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