key: cord-0996401-cv3mzfw5
authors: Mahan, Keenan M.; Hayes, Bryan D.; North, Crystal M.; Becker, Justin S.; Fenves, Andrew Z.; Hyppolite, Guibenson; Khosrowjerdi, Sara; Sinden, Daniel; Stearns, Dana A.
title: Utility of hypertonic saline and diazepam in COVID-19-related hydroxychloroquine toxicity
date: 2020-10-29
journal: J Emerg Med
DOI: 10.1016/j.jemermed.2020.10.048
sha: 15597a9ab4c79af6174c693bb294780031eddd1f
doc_id: 996401
cord_uid: cv3mzfw5

Background Hydroxychloroquine (HCQ) poisoning is a life-threatening but treatable toxic ingestion. The scale of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (COVID-19) and the controversial suggestion that HCQ is a treatment option have led to a significant increase in HCQ use.1 Hence, HCQ poisoning should be at the top-of-mind for emergency providers in cases of toxic ingestion. Treatment for HCQ poisoning includes sodium bicarbonate, epinephrine, and aggressive electrolyte repletion.2–5 Here, we highlight the use of hypertonic saline and diazepam. Case Report We describe the case of a 37-year-old man who presented to the emergency department (ED) after the ingestion of approximately 16 grams of HCQ tablets (initial serum concentration 4,270 ng/mL). He was treated with an epinephrine infusion, hypertonic sodium chloride, high-dose diazepam, sodium bicarbonate, and aggressive potassium repletion. Persistent altered mental status necessitated intubation, and he was managed in the medical intensive care unit until his QRS widening and QTc prolongation resolved. After his mental status improved and it was confirmed that his ingestion was not with the intent to self-harm, he was discharged home with outpatient follow-up. Why should an emergency physician be aware of this? For patients presenting with HCQ overdose and an unknown initial serum potassium level, high-dose diazepam and hypertonic sodium chloride should be started immediately for the patient with widened QRS. The choice of hypertonic sodium chloride instead of sodium bicarbonate is to avoid exacerbating underlying hypokalemia which may in turn potentiate unstable dysrhythmia. In addition, early intubation should be a priority in vomiting patients as both HCQ toxicity and high-dose diazepam cause profound sedation.

level, high-dose diazepam and hypertonic sodium chloride should be started immediately for the 25 patient with widened QRS. The choice of hypertonic sodium chloride instead of sodium 26 bicarbonate is to avoid exacerbating underlying hypokalemia which may in turn potentiate 27 unstable dysrhythmia. In addition, early intubation should be a priority in vomiting patients as 28

both HCQ toxicity and high-dose diazepam cause profound sedation. 29 30 Keywords: hydroxychloroquine; plaquenil; chloroquine; overdose; SARS-CoV-2; COVID-19; 31 toxicology; hypertonic saline; hypertonic sodium chloride; sodium bicarbonate; diazepam; 32 epinephrine; dysrhythmia; arrhythmia; ECG 33 INTRODUCTION episodes of nonbloody, nonbilious emesis without tablets or fragments. His temporal 58 temperature was 30°C (86°F), he was bradycardic to 56 beats per minute (BPM), and his initial 59 blood pressure (BP) could not be obtained with an automatic BP cuff; manual BP measurement 60 was deferred to facilitate the placement of large bore intravenous (IV) access as the patient 61 maintained his mental status and had palpable femoral pulses without distal cyanosis or 62 duskiness of the extremities. The remainder of his physical exam was remarkable for shivering, 63 cool and clammy skin, and irregular bradycardia. Initial ECG in the ED revealed complete heart 64 block, QRS interval of 124 ms, and QTc of 548 ms ( Figure 1 ). Fifteen minutes after arrival, an 65 epinephrine infusion was initiated at 10 micrograms per minute (mcg/min) with improvement in 66 his heart rate to 72 BPM and BP to 90/48 millimeters of mercury (mmHg). Central IV access 67 was obtained and the patient was placed on an involuntary psychiatric hold out of concern for 68 possible self-harm. 69 HCQ poisoning causes significant hypokalemia. 15 IV potassium repletion at 20 mEq/hour to achieve a potassium level of at least 4.0 mEq/L; he 77 received a total of 130 mEq IV potassium chloride in the ED. Following potassium repletion, 78 and his QRS and QTc narrowed to 118 ms and 383 ms, respectively. His epinephrine infusion 81 was increased to a rate of 15 mcg/min for intermittent hypotension with mean arterial pressure 82 (MAP) of 55 mmHg with subsequent improvement to 67 mmHg prior to transfer to the medical 83 intensive care unit (MICU) five hours after arrival to the ED. At that time his heart rate was 84 noted to be 107 BPM. 85

He was admitted to the MICU where he was intubated for airway protection in the setting 86 of altered mental status. Epinephrine infusion was titrated to maintain MAP > 65 mmHg and 87 heart rate > 100 BPM, the latter to reduce the risk of torsades de pointes (TdP). ECG shortly 88 after arrival to the MICU showed a QRS of 114 ms, TU-fusion waves, and QTc of 666 ms 89 ( Figure 2 ). In the setting of a widened QRS and prolonged QTc, he was given an additional 90 bolus of 100 mL IV 3% sodium chloride; he also received 2 g IV magnesium sulfate and 2 g IV 91 calcium gluconate to promote cardiac myocyte stability. ECGs were obtained every two hours 92 and we planned to give additional boluses of 100 mL IV 3% sodium chloride as needed for 93 widened QRS or prolonged QTc. The patient's hypokalemia persisted while in the MICU and an 94 additional 80 mEq IV potassium chloride was administered for an initial serum potassium of 2.3 95 mEq/L. Repeat labs were drawn every 2 hours and IV potassium chloride was given as needed 96 to achieve normokalemia. Diazepam 6 mg IV was administered every two hours for 24 hours 97 after the initial 50 mg IV bolus to antagonize cardiac myocyte toxicity and for seizure 98 prophylaxis. We chose intermittent diazepam dosing over an infusion based on clinical 99 pharmacist and poison control recommendations. 100

Over the next 24 hours, the patient received one additional bolus of 100 mL IV 3% 101 sodium chloride for a prolonged QTc of 534 ms. Serial ECGs showed narrowing of the QRS and QTc remained within normal limits without additional 3% sodium chloride boluses at 104 approximately the 24-hour mark, epinephrine was weaned off over 12 hours while monitoring 105 closely for rebound hyperkalemia (none observed). We discontinued diazepam after 24 hours 106 both because this was the expected window of toxicity and to avoid propylene glycol toxicity 107 from prolonged diazepam administration. 18,19 An ECG 37 hours after presentation showed 108 resolution of U-waves, a normal QTc (434 ms), and diffuse J-point elevations (Figure 4) At normal serum potassium concentrations, the sodium-containing fluid of choice for 146 HCQ toxicity is sodium bicarbonate, administered in boluses of 50 to 150 mEq followed by an 147 isotonic sodium bicarbonate infusion at 10 to 20 mEq/hour. The infusion is continued until the 148

Once the above treatments have been initiated, clinicians should monitor QRS and QTc intervals 150 with frequent ECGs and follow serum potassium levels every one to two hours, targeting a value 151 of ≥ 4.0 mEq/L. We recommend close ECG and serum potassium monitoring for 36 hours to 152 include the expected window of HCQ toxicity (24 hours) and assess for rebound hyperkalemia 153 after toxicity resolves. 19 its inotropic effects secondary to beta agonism; norepinephrine is a second choice agent. 31,32 159 Experts generally recommend titrating the beta-agonist to a target heart rate of at least 90 BPM 160 while the QTc is prolonged to avoid R-on-T phenomenon from an ectopic beat on a preceding T 161 wave, which may precipitate malignant dysrhythmias. 33 162

Diazepam administration is the mainstay of seizure prophylaxis in HCQ overdose, and 163 was associated with reduced mortality when used in combination with epinephrine in a 164 retrospective analysis, potentially related to effects on cardiac ion channels. 4,34 Generally, a 1-2 165 mg/kg bolus of IV diazepam is administered followed by either a continuous infusion or frequent When hypokalemia has been addressed, sodium bicarbonate should be administered to address 182 cardiac myocyte channel toxicity. We also encourage early intubation to address the sedating 183 effects of HCQ and high-dose diazepam. 184 J o u r n a l P r e -p r o o f 

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