Poison Control: Management of Hydroxychloroquine & Chloroquine Toxicity

Management of Hydroxychloroquine & Chloroquine Toxicity

Joshua Newell, PharmD, PGY-2

UF Jacksonville Emergency Medicine

Anthony DeGelorm, Pharm.D.

Clinical Toxicology/EM Fellow at Florida/USVI Poison Information Center-Jacksonville

What is hydroxychloroquine?

Hydroxychloroquine (HCQ) is a part of the 4-aminoquinolones family. The drug is structurally related to chloroquine (CQ), which has historically been utilized for malaria prophylaxis. HCQ is similar to CQ in therapeutic, pharmacokinetic, and toxicologic properties. The side effect profiles of the two are slightly different, favoring CQ use for malarial prophylaxis and HCQ use as an anti-inflammatory. 1-2 HCQ is used in the treatment of rheumatic diseases such as rheumatoid arthritis and lupus erythematosus. 3 HCQ, like CQ, is a weak base and may exert its effect by concentrating in the acid vesicles of the parasite and by inhibiting polymerization of heme. It can also inhibit certain enzymes by its interaction with DNA. The mechanisms underlying the anti-inflammatory and immunomodulatory effects of HCQ for rheumatoid arthritis and systemic lupus erythematosus are unknown. 4-5

Why was it recommended for use in COVID-19?

CQ and HCQ appear to have invitro inhibition of the SARS-CoV-2 (COVID-19) virus, which has led many to explore these agents as potential treatment options. These drugs are hypothesized to block viral entry into the cell by inhibiting glycosylation of host receptors, proteolytic processing, and endosomal acidification. 6 Subsequently, its use was propagated by the media and early studies demonstrating possible utility during the COVID-19 pandemic.

Toxicity of the drug?

CQ and HCQ both have narrow therapeutic windows. Symptoms may become evident as early as 30 minutes after ingestion and death has been reported in as early as 1-3 hours post ingestion. Patients may present with neurologic, cardiovascular, ophthalmic, and various other systemic manifestations such as: nausea, vomiting, diarrhea, abdominal pain, convulsions, visual and auditory disturbances, hypotension, hypoglycemia, respiratory depression, apnea, QTc prolongation, QRS prolongation, hypokalemia, and subsequent cardiac dysrhythmias. 7-8 The mechanism of cardiovascular toxicity is related to sodium and potassium channel blockade leading to hypokalemia with cardiovascular collapse.

Case reports of toxicity

Unfortunately, a tweet by a government official on March 21, 2020 claimed that the combination of HCQ and azithromycin “has a real chance to be one of the biggest game changers in the history of medicine.” This accelerated a worldwide demand on the medications, with pharmacies reporting shortages within 24 hours. The U.S. Food and Drug Administration released a letter to the stakeholders regarding chloroquine phosphate after a case report of a husband and wife ingested an aquarium product containing chloroquine phosphate in order to prevent viral illness, which ultimately led to death.

Management of the toxidrome Aggressive supportive care, oxygen, cardiac and hemodynamic monitoring, large-bore IV access, and serial blood glucose concentrations should be performed. Gastric decontamination techniques, such as activated charcoal, are recommended for patients presenting early as activated charcoal adsorbs chloroquine well, binding 95% to 99% when administered within 5 minutes of ingestion. 9 If hypotension is present, then fluid resuscitation, followed by vasopressors, should be considered with a focus on epinephrine per previous studies. 10-11 High dose diazepam has been shown to demonstrate efficacy in CQ toxicity to augment the

treatment of dysrhythmias and hypotension while also treating convulsions. 12-13 Previously studied doses included diazepam 2 mg/kg IV over 30 minutes followed by 1–2 mg/kg/day for 2–4 days). The postulated mechanism of action for diazepam during CQ overdose includes: (1) a central antagonistic effect, (2) an anticonvulsant effect, (3) an antidysrhythmic effect by an electrophysiologic action inverse to chloroquine, (4) a pharmacokinetic interaction between

REFERENCES

1. Luzzi GA, Peto TE. Adverse effects of antimalarials. An update. Drug Saf. 1993;8:295–311 2. Vinetz J, et al. Chemotherapy of malaria. In: Brunton L, et al., eds. Goodman & Gilman’s The

Pharmacological Basis of Therapeutics. 12th ed. New York: McGraw-Hill

Companies; 2011. 3. Jordan P, et al. Hydroxychloroquine overdose: toxicokinetics and management. J Toxicol. 1999;37:861–864. 4. Product Information: PLAQUENIL(R) oral tablets, hydroxychloroquine sulfate oral tablets. Concordia

Pharmaceuticals Incw (per DailyMed),

Kansas City, MO, 2019 5. Titus EO: Recent developments in the understanding of the pharmacokinetics and mechanism

diazepam and chloroquine, and (5) a decrease in chloroquine-induced vasodilation. 10,11,13,14 The utilization of sodium bicarbonate for correction of QRS prolongation is controversial as it may worsen hypokalemia. No clinical trials regarding sodium bicarbonate have been conducted evaluating safety and efficacy in CQ overdose; however it may be necessary to prevent dysrhythmias from occurring. Correction of hypokalemia should be done so cautiously as hyperkalemia

of action of chloroquine.. Ther Drug

Monit 1989; 11(4):369-79. 6. Awadhesh K, et al. Diabetes Metab

Syndr. May-Jun 2020;14(3):241-246. doi: 10.1016/j.dsx.2020.03.011. Epub 2020 Mar 26 7. Guly U, Driscoll P. The management of quinine-induced blindness. Arch

Emerg Med. 1992;9:317–322. 8. Jaeger A, et al. Clinical features and management of poisoning due to antimalarial drugs. Med Toxicol

Adverse Drug Exp. 1987;2:242–273 9. Kivisto KT, Neuvonen PJ. Activated charcoal for chloroquine poisoning.

BMJ. 1993;307:1068. 10. Riou B, et al. Treatment of severe chloroquine poisoning. N Engl J Med. 1988;318:1–6.

FPICN toxicologists are available 24 hours a day, free of charge, at 1-800-222-1222 for consultation regarding monitoring, management and disposition.

can occur while toxicity resolves with subsequent redistribution of drug from the intracellular space. ■

Image Credit: Adobe Stock

11. Riou B, et al. Protective cardiovascular effects of diazepam in experimental acute chloroquine poisoning. Intensive Care Med. 1988;14:610–616 12. Clemessy JL, et al. Treatment of acute chloroquine poisoning: a 5-year experience. Crit Care Med. 1996;24:1189–1195. 13. Marquardt K, Albertson TE.

Treatment of hydroxychloroquine overdose. Am J Emerg Med. 2001;19:420–424. 14. Reddy VG, Sinna S. Chloroquine poisoning: report of two cases. Acta

Anaesthesiol Scand. 2000;44:1017–1020.

Lung Ultrasound in the COVID-19 Pandemic

By Dennis D’Urso, MD, PGY-3

Jackson Memorial Hospital pneumonia can approach or even lung ultrasound (POC-LUS) has been information such as left ventricular of a nasopharyngeal specimen is has been successfully utilized to Noncontrast chest CT is highly sensitive (approximately 97%) for detecting the usual lung changes seen in COVID-19; however, it has several limitations preventing its widespread use, including availability, cost, radiation exposure, requirement for the patient to leave the evaluation area, and necessary cleaning between patients. Portable chest X-ray is often more rapidly available; however, it has poor sensitivity (approximately 65%), limiting its reliability as a screening or stratifying tool. excellent imaging modality for COVID-19. First, the disease tends to follow a peripheral to central

Edited by Leila Posaw, MD, MPH

Emergency Ultrasound Director,

Have you ever asked yourself how your ultrasound probe can be used to fight the COVID-19 pandemic? Well, read on.

In my experience, point-of-care invaluable in the bedside assessment of patients with respiratory complaints, helping to differentiate among the most common diagnoses, including congestive heart failure, pneumonia, pneumothorax or COPD. Now, I can add COVID-19 to my list!

In the setting of a pandemic, rapid case identification and severity stratification are crucial. RT-PCR the current standard for diagnosis, with rapid testing turnaround time approaching 1 hour or less. Meanwhile, patient disposition is determined — and often delayed — by a combination of clinical and radiographic assessment.

POC-LUS has proven to be an progression, making it amenable to surface imaging even in its earliest stages. In fact, the sensitivity of POC-LUS for detecting COVID-19 exceed that of chest CT.

Furthermore, POCUS has utility beyond lung imaging alone. A more extensive evaluation of dyspnea can be performed in the same bedside assessment by evaluating the heart and IVC in addition to the lungs. This “triple scan” can provide important function, presence of right ventricular strain, and volume status to further guide patient care.

Additionally, POCUS is portable, inexpensive, rapid, and therefore easily repeatable, making it an effective tool for monitoring the progression of disease and recovery without exposure to ionizing radiation. POC-LUS Jackson Memorial determine responsiveness to alveolar recruitment maneuvers such as proning and mechanical ventilation, as well as to guide mechanical ventilation weaning and extubation.

TECHNIQUE

Probe: High-frequency linear or curvilinear probe Settings: Select the lung preset (or manually disable filters and tissue harmonics; lung ultrasound is based on artifacts!). Use adequate depth to visualize the pleura and peripheral parenchyma, less than 5 cm to evaluate the pleural line, and more than 15 cm to evaluate B-lines. Position: Seated positioning is preferred. Lateral decubitus positioning may be required to access all lung fields (e.g. in patients lying supine or prone). Technique: Orient the probe marker cephalad. Systematically scan the lungs in “lawn mower”

Fig. 1: Lung scanning in 12 zones (R1-6 and L1-6). The anterior axillary line and posterior axillary line divide the hemithorax into anterior, lateral, and posterior segments. An imaginary horizontal line further divides into upper and lower segments. Scan each zone in a systematic horizontal “lawnmower” fashion. Repeat on the contralateral side. Image Credit: Marini TJ, Castaneda B, Baran T, et al. Lung Ultrasound

Fig. 2: Ultrasonographic findings in COVID-19 correspond to clinical severity. A) A-lines represent well aerated normal lungs. B) Irregular pleural line and few scattered B-lines are seen in mild disease. C) Coalescent B-lines, small subpleural consolidation, and more diffuse involvement is characteristic of more severe disease. D) Consolidations with air bronchograms suggest severe disease in a critical patient. Small pleural effusions can occur.

Image Credit: Smith, et al. 4

fashion in 12 zones (upper and lower portions of the anterior, lateral, and posterior segments of each lung) as demonstrated in Figure 1.

FINDINGS

The typical CT pattern of COVID-19 is a diffuse bilateral interstitial pneumonia, with “ground glass” infiltrates primarily affecting the bases. Investigators in China and Italy have demonstrated that these pleural effusions are sometimes present, however large effusions are suggestive of alternative pathologies. Figure 3 demonstrates ultrasonographic images of these changes. While no imaging findings are specific for COVID-19, the constellation of these POCUS-LUS findings in the setting of a clinical

infiltrates can be identified on ultrasound as B-lines; the density and scope of these B-lines were found to correspond with both CT findings and the clinical condition of the patients. Additional lung ultrasound findings are summarized in Figure 2 and include 1) a thickened pleural line, 2) multifocal B lines ranging from discrete to confluent, 3) small subpleural consolidations, with air bronchograms. Small

and 4) large consolidations picture with high pretest probability is strongly suggestive of COVID-19. Next time you evaluate a patient presenting with dyspnea, make sure to bring your ultrasound for a quick visual assessment that may support a rapid diagnosis and disposition!

LIMITATIONS

For those without any prior

CONTINUE ON PAGE 38 �

Pneumoperitoneum.To.Go.

Stick in your wallet. Reference on-the-go. Courtesy of authors Leila Posaw, MD, MPH and Dennis D’Urso, MD

ultrasonography experience, a short training session in knobology will be useful; otherwise, the technique of lung scanning is simple and the interpretation is fairly straightforward.

A recognized limitation of lung ultrasonography is that it cannot detect lesions that are deep within the lung, as aerated lung blocks transmission of ultrasound waves. Chest CT is required to detect pneumonia that does not extend to the pleural surface.

Finally, adequate safety measures are required to prevent disease transmission. At minimum, the ultrasound probe and the machine in its entirety should be cleaned with an appropriate cleaning solution after each use. During this pandemic, additional measures such as covering the probe and machine in a protective barrier is recommended — especially during any aerosolizing procedures. ■

Figure 3. Ultrasonographic images of COVID-19 Pneumonia. A) A-lines in a well aerated normal lung. B) Pleural thickening. C) Multiple B-lines and a small subpleural consolidation. D) Consolidation with air bronchograms. Image credit: Eric Abrams, MD and Nicholas Hoda, MD

REFERENCES

Nazerian P, Volpicelli G, Vanni S, et al. Accuracy of lung ultrasound for the diagnosis of consolidations when compared to chest computed tomography. Am J Emerg Med. 2015;33(5):620–625 Wu J, Wu X, Zeng W, et al. Chest CT findings in patients with coronavirus disease 2019 and its relationship with clinical features. Invest Radiol. 2020 Peng Q, Wang X, Zhang L. Findings of lung ultrasonography of novel corona virus pneumonia during the 2019–2020 epidemic. Intensive Care Med. 2020 Smith, et al. Point‐of‐care lung ultrasound in patients with COVID‐19 – a narrative review. Anaesthesia. 2020 5.

6.

7.

8. Is Superior to Plain Radiography in the Diagnosis of Pneumoperitoneum.” British Journal of Surgery, vol. 89, no. 3, 2002, pp. 351–354., doi:10.1046/j.0007- 1323.2001.02013.x. Grassi, Roberto, et al. “GastroDuodenal Perforations: Conventional Plain Film, US and CT Findings in 166 Consecutive Patients.” European Journal of Radiology, vol. 50, no. 1, 2004, pp. 30–36., doi:10.1016/j. ejrad.2003.11.012. Hefny, Ashraf, and Fikri AbuZidan. “Sonographic diagnosis of intraperitoneal free air.” Journal of Emergencies, Trauma, and Shock, vol. 4, no. 4, 2011, p. 511. Karahan, Okkes Ibrahim, et al. “New Method for the Detection of Intraperitoneal Free Air by

Sonography: Scissors Maneuver.”

Journal of Clinical Ultrasound, vol. 32, no. 8, 2004, pp. 381–385., doi:10.1002/ jcu.20055. 9. 1Asrani, Ashwin. “Sonographic

Diagnosis of Pneumoperitoneum Using the ‘Enhancement of the Peritoneal

Stripe Sign.’ A Prospective Study.”

Emergency Radiology, vol. 14, no. 1, 2007, pp. 29–39., doi:10.1007/s10140- 007-0583-3. 10. Indiran, Venkatraman, et al. “Enhanced

Peritoneal Stripe Sign.” Abdominal

Radiology, vol. 43, no. 12, 2018, pp. 3518–3519., doi:10.1007/s00261-018- 1628-7.