META-ANALYSIS www.jasn.org

Extracorporeal Treatment for , Hydroxychloroquine, and : Systematic Review and Recommendations from the EXTRIP Workgroup

Ingrid Berling ,1,2,3 Joshua D. King,4,5 Greene Shepherd,6 Robert S. Hoffman ,7 Badria Alhatali ,8 Valery Lavergne,9 Darren M. Roberts ,10,11,12 Sophie Gosselin,13,14,15 Gabrielle Wilson,16 Thomas D. Nolin ,17,18 and Marc Ghannoum,16 for the EXTRIP workgroup*

Due to the number of contributing authors, the affiliations are listed at the end of this article.

ABSTRACT Background Although chloroquine, hydroxychloroquine, and quinine are used for a range of medical conditions, recent research suggested a potential role in treating COVID-19. The resultant increase in prescribing was accompanied by an increase in adverse events, including severe and death. The Extracorporeal Treatments in Poisoning (EXTRIP) workgroup sought to determine the effect of and indi- cations for extracorporeal treatments in cases of poisoning with these drugs. Methods We conducted systematic reviews of the literature, screened studies, extracted data, and sum- marized findings following published EXTRIP methods. Results A total of 44 studies (three in vitro studies, two animal studies, 28 patient reports or patient series, and 11 pharmacokinetic studies) met inclusion criteria regarding the effect of extracorporeal treatments. Toxicokinetic or pharmacokinetic analysis was available for 61 patients (13 chloroquine, three hydroxy- chloroquine, and 45 quinine). Clinical data were available for analysis from 38 patients, including 12 with chloroquine toxicity, one with hydroxychloroquine toxicity, and 25 with quinine toxicity. All three drugs were classified as non-dialyzable (not amenable to clinically significant removal by extracorporeal treat- ments). The available data do not support using extracorporeal treatments in addition to standard care for patients severely poisoned with either chloroquine or quinine (strong recommendation, very low quality of evidence). Although hydroxychloroquine was assessed as being non-dialyzable, the clinical evidence was not sufficient to support a formal recommendation regarding the use of extracorporeal treatments for this drug. Conclusions On the basis of our systematic review and analysis, the EXTRIP workgroup recommends against using extracorporeal methods to enhance elimination of these drugs in patients with severe chlo- roquine or quinine poisoning.

JASN 31: 2475–2489, 2020. doi: https://doi.org/10.1681/ASN.2020050564 META-ANALYSIS

Chloroquine, hydroxychloroquine, and quinine are hydroxychloroquine for COVID-19 and use used for a wide array of medical conditions, includ- of nonpharmaceutical chloroquine by the public ing and connective tissue diseases, and resulted in severe toxicity and death.3–5 Despite more recently, preliminary studies have focused appropriate supportive care and the advent of ex- on their potential role for the treatment of the tracorporeal membrane oxygenation, mortality from novel coronavirus disease 2019 (COVID-19).1,2 chloroquine toxicity remains high.6 Some reviews The expanded prescribing of chloroquine and and editorials have suggested that extracorporeal

JASN 31: 2475–2489, 2020 ISSN : 1046-6673/3110-2475 2475 META-ANALYSIS www.jasn.org treatments (ECTRs) can enhance elimination of these drugs in Significance Statement poisoning.7,8 The Extracorporeal Treatments in Poisoning (EXTRIP) Although poisoning by chloroquine, hydroxychloroquine, or qui- workgroup is composed of international experts representing nine is relatively uncommon, recent use of chloroquine and hy- diverse specialties and professional societies (Supplemental droxychloroquine for COVID-19 has elevated concerns regarding management of such . To investigate the effect of and Table 1). Its mission is to provide recommendations on the indications for extracorporeal treatments in cases of poisoning with use of ECTRs in poisoning (http://www.extrip-workgroup. these drugs, the Extracorporeal Treatments in Poisoning work- org).9,10 The objective of this article is to present EXTRIP’s group conducted systematic reviews of the relevant literature, systematic review of the literature and recommendations for screened studies, extracted data, and summarized findings. The the use of ECTR in patients poisoned from chloroquine, hy- group concluded that chloroquine, hydroxychloroquine, and qui- nine are not dialyzable (not amenable to clinically significant droxychloroquine, or quinine. removal by extracorporeal treatments) and the current clinical evi- dence does not support the use of such treatments for chloroquine and quinine poisonings. Considering that data on extracorporeal treatments for hydroxychloroquine toxicity are sparse, the group BACKGROUND proposed pharmacokinetic studies to confirm or refute the current impression that the drug is non-dialyzable. Clinical Pharmacology and Pharmacokinetics Bark from the Cinchona tree native to the Andean regions of South America was recognized as an effective treatment for available in some countries. Their physicochemical and malaria in the late 1600s.11,12 By the 1800s, extraction process- pharmacokinetic properties are summarized in Table 1. es were developed, and quinine sulfate became widely avail- able in tonic waters. Quinineremainedthemainstayof Chloroquine malaria treatment until the 1920s when more effective syn- Chloroquine has a molecular mass of 320 Da and is rapidly thetic antimalarials, such as chloroquine and its derivative absorbed after enteral administration with almost complete hydroxychloroquine, were approved by the US Food and oral bioavailability. It is only moderately bound to plasma Drug Administration (FDA) in 1949 and 1955, respectively. proteins, so physiologic changes such as hypoalbuminemia, These drugs exhibit a remarkable breadth of pharmacologic binding interactions, and supratherapeutic concentrations effects, including anti-inflammatory, anti-infective, immuno- that alter the extent of protein binding are not reported to modulatory, and antineoplastic activity. Chloroquine and have toxicologic implications.17,18 Chloroquine is extensively quinine are still popular therapeutics to prevent and treat distributed throughout the body with a massive apparent vol- . uncomplicated malaria, whereas hydroxychloroquine is used ume of distribution of 100 L/kg. Approximately half of in- primarily to treat connective tissue diseases, such as SLE, rheu- gested chloroquine is excreted unchanged in urine, but the matoid arthritis, and Sjogren syndrome.13 Despite a 2006 remainder is metabolized by cytochrome P450 (CYP) en- warning from the FDA regarding safety concerns, the use of zymes 2C8 and 3A4 to the primary metabolite desethylchlor- 17,19 quinine remains common for the treatment of leg .14 oquine. The total endogenous clearance of chloroquine t Recently, because of their recognized antiviral activity, these is high, and its terminal elimination half-life ( 1/2)isnormally drugs received enormous attention in both the lay press and in excess of 10 days (Table 1). Given its considerable renal t medical journals as potential treatments of COVID-19,15 clearance, the 1/2 is prolonged in patients with impaired 17 prompting the FDA and other governing agencies to issue an kidney function. emergency use authorization for this purpose.16 Chloroquine, hydroxychloroquine, and quinine are pri- Hydroxychloroquine marily available as tablets, although injectable forms are The molecular mass of hydroxychloroquine is 336 Da. It is rapidly absorbed after oral dosing, with time to peak plasma concentration of 2–6 hours.20,21 Hydroxychloroquine is mod- Received May 3, 2020. Accepted July 16, 2020. erately bound to plasma proteins and is extensively distributed *The EXTRIP workgroup also includes Kurt Anseeuw, Steven Bird, Timothy throughout the body with an exceedingly large apparent vol- Bunchman, Josée Bouchard, Diane Calello, Paul Chin, Kent Doi, Tais Galvao, ume of distribution.22 The drug is predominantly metabolized David Goldfarb, Hossein Hassanian, Lotte Hoegberg, Siba Kallab, SofiaKe- bede, Jan Kielstein, Andrew Lewington, Yi Li, Etienne Macedo, Rob MacLaren, by CYP3A4 and to a lesser extent, by CYP2C8 to desethylhy- Bruno Megarbane, Jim Mowry, Marlies Osterman, Ai Peng, Jean-Philippe Roy, droxychloroquine, with only about 20% of hydroxychloroquine Anitha Vijayan, Steven Walsh, Anselm Wong, David Wood, and Christopher excreted unchanged in urine.19,22 Similar to chloroquine, hy- Yates. droxychloroquine has a high endogenous clearance and a long Published online ahead of print. Publication date available at www.jasn.org. 20,22 terminal t1/2 (Table 1). Correspondence: Dr. Marc Ghannoum, Verdun Hospital, 4000 Lasalle Bou- levard, Verdun, Montreal, QC H4G2A3, Canada. Email: marcghannoum@ Quinine gmail.com Quinine has a molecular mass of 324 Da. After oral adminis- Copyright © 2020 by the American Society of Nephrology tration, quinine is rapidly absorbed with a time to peak plasma

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Table 1. Physicochemical and pharmacokinetic properties of chloroquine, addition to the negative inotropy hydroxychloroquine, and quinine17,18,20–22,24,93–97 and chronotropy, ventricular dys- Properties Chloroquine Hydroxychloroquine Quinine rhythmias (monomorphic and poly- Molecular mass, Da 320 336 324 morphic ventricular tachycardia, pKa 10.1 9.67 9.05 ventricular fibrillation) are common Bioavailability, % 80–100 67–74 76–88 in severe poisoning.33,39,42 Volume of distribution, L/kg 120–150 (p, b) .50 (p, b) 1.5–3.0 (p) The risk of toxicity correlates Protein binding, % 50–75 40–70 80–95 with the ingested dose, albeit with – – – Elimination t1/2, h 200 400 (p), 200 800 (p), 8 14 h (p) considerable interindividual variabil- 40–100 (b) 1000–1400 (b) ity. For all three drugs, acute ingestions – – – Total endogenous CL, ml/min 600 1000 (p), 140 (b) 200 600 (p), 100 (b) 120 150 (p) of ,2 g in the average adults are usu- – – Renal CL, % 40 50 15 20 20 ally benign.32,34,39,43–46 Cardiovascu- Therapeutic concentration, mg/L 0.3–1.0 (b) 0.3–1.0 (b) 5–10 (p) lar and neurologic impairments are p, plasma; b, blood; t , half-life; CL, clearance. 1/2 expected following acute ingestions .2g.32,34,39,43–47 Life-threatening toxicity and mortality are reported in concentration of 1.5–2.8 hours.17 It exhibits extensive protein untreated adult patients with acute ingestions .5g.34,39,40,42–45,48,49 binding and an apparent volume of distribution of 1–2.5 L/kg; However, there are also reports of survival after massive acute inflammation, active malaria, and kidney impairment increase ingestions, including 12 g of chloroquine,32 36 g of hydroxy- protein binding and decrease its volume of distribution.17,23,24 chloroquine,50 and 31 g of quinine.51 Quinine is predominantly (80%) metabolized by CYP3A4 in Although elevated concentrations of these drugs predict the liver to form the major metabolite 3-hydroxyquinine,25 toxicity, results are rarely available in a turnaround time whereas the remainder is excreted unchanged in urine.17,19 that is rapid enough to influence clinical decision making. The total endogenous clearance of quinine ranges from 120 A blood chloroquine concentration below 2.5 mg/L does not to 150 ml/min17 and is decreased by approximately 50% in appear to cause toxicity,43 whereas concentrations between patients with (Table 1).26,27 2.5 and 5 mg/L are associated with mild neurologic impair- ment and dysrhythmias.43 Blood chloroquine concentra- Overview of Toxicity tions above 5 mg/L are associated with severe cardiovascular Quinine toxicity, classically referred to as cinchonism (from poisoning, and life-threatening dysrhythmias.43 With the Cinchona tree), consists of , deafness, , prompt access to care, death is unlikely with blood chloro- , and visual disturbances. Visual symptoms range quine concentrations ,10 mg/L.6,32 The likelihood of from diplopia to blindness and reportedly occur in up to mortality increases steeply over 10 mg/L, although there 20%–40% of poisoned patients.28–31 Chloroquine and hy- are several cases of survival in excess of 30 mg/L.6,42 There droxychloroquine present similar toxic effects with notable are few toxicologic data on a concentration-response relation- differences; visual and auditory impairments are rarer with ship for hydroxychloroquine, but blood hydroxychloroquine these , whereas altered mental status is more promi- concentrations .2 mg/L are considered supratherapeutic,52 nent and includes agitated delirium, altered consciousness, and life-threatening poisoning is described after overdose at seizures, and coma.6,32–34 Rapid and profound hypokalemia blood and plasma concentrations over 20 mg/L.49,50,53 For occurs from intracellular potassium shifts.35–38 At high con- quinine, a plasma concentration ,10 mg/L is well tolerated centrations, all three drugs cause life-threatening cardiovas- and usually only causes minimal symptoms, such as tinni- cular toxicity as a result of their direct effects on the cardiac tus.30 With plasma concentrations between 10 and 15 mg/L, sodium and potassium channels. This cardiac channel block- visual symptoms are usually present,28,30 and over 15 mg/L, ade leads to prolongation of both the QRS complex and QT cardiac dysrhythmias are reported.28,30 Quinine’sprotein intervals on the electrocardiogram and .34,39,40 binding increases in active malaria, which lowers its free frac- QT interval prolongation is reported in patients prescribed tion, so patients with elevated parasitemia reportedly show chloroquine and hydroxychloroquine for COVID-19. A recent no symptoms with plasma quinine concentrations up to randomized, controlled trial of chloroquine for COVID-19 20 mg/L.17 was terminated early due to a new QTc .500 ms in 25% of Antimalarial poisonings occur more commonly in sub- patients prescribed 12 g over 10 days and in 11% of those pre- Saharan Africa and Europe (particularly in France, where scribed 2.7 g over 5 days, accompanied by ventricular dysrhyth- chloroquine ingestion was popularized as a means of suicide mias and a trend to higher mortality.3 Similarly, a QTc.500 ms in the 1980s).54–56 Although there are fewer reported cases of was reported in .10% of patients prescribed hydroxychloro- hydroxychloroquine overdose, several fatalities are de- quine and azithromycin for COVID-19.5 scribed.36,48,57 In the United States, data from the American The delay from ingestion of an acute overdose to cardio- Association of Control Centers in 2018 reported vascular collapse is typically short (,3 hours).34,39,41 In 826 human exposures to antimalarial drugs that resulted in

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185 patients treated in health care facilities and three deaths.58 Material. For reference (Supplemental Material), the term “di- Mortality and morbidity remain high today with overdose of alyzability” is used, as in aprioriaccepted methods and man- these drugs; for chloroquine, the overall mortality is approx- uscripts, to reflect the ability of an ECTR to remove a clinically imately 5%–8%32,40,56 but can exceed 10% following large significant percentage of the total body burden of a poison. ingestions, even with modern standard care.6,32,42,44 Older Clearance refers to the volume of blood (or solvent) cleared cohorts reported higher mortality of .30%, likely repre- of poison per unit time. Importantly, CLEC represents sol- senting differences in critical care management.34,39,59 ute clearance due exclusively to ECTR and is independent Mortality in hydroxychloroquine overdose appears consid- of endogenous systemic clearance (CLSYS;thesumofun- 48,60–62 erably lower than for chloroquine. Reported cohorts derlying renal and nonrenal clearances). CLTOT refers to for quinine poisoning are .20 years old, and they show a total clearance and is the sum of CLEC and CLSYS.Thepanel mortality rate near or under 5%28–31 and irreversible visual hadproposedthatfourdistinctcalculationswereaccept- damage in 20%–50% of patients who had initial visual able to estimate dialyzability with regards to poison elim- symptoms.28–31 ination (Supplemental Table 3). Aside from the ingested dose, clinical predictors of chloro- quine mortality include a QRS complex duration .120 ms, systolic pressure ,80 mm Hg,42 and the severity of hypoka- RESULTS lemia.35,38,39 In another cohort of 69 patients poisoned with hydroxychloroquine who received an electrocardiogram, no The results of the search and article selection are presented in patients with a QRS duration ,120 ms died.61 In a series of six Figure 1. A total of 44 articles were retained for final analysis, hydroxychloroquine ingestions, two presented with a QRS including three in vitro experiments,66–68 two animal experi- complex duration .150 ms, both had severe symptoms, and ments,69,70 11 pharmacokinetic studies,24,71–80 and 28 patient one patient died.48 The presence and severity of hypokalemia reports and patient series.30,81–107 No comparative observa- also predicts mortality for hydroxychloroquine.36,37,49,50 tional studies and no randomized trials were identified. Overdose from any of these drugs is a medical emergency. Standard care for quinine, chloroquine, and hydroxychloro- Toxicokinetic (Dialyzability) quine poisoning includes early endotracheal intubation for Chloroquine, hydroxychloroquine, and quinine have molec- exposures that are likely to be life threatening and those ular masses of ,350 Da, so they will readily cross ECTR with hemodynamic instability, correction of hypokalemia, membranes. However, their pharmacokinetic characteristics and institution of cardiac monitoring with close attention to (Table 1) are anticipated to limit the effect of ECTR according the duration of the QRS complex and QT interval. Sodium to previously described predictors of low dialyzability, notably bicarbonate boluses are often recommended for patients with volumes of distribution .1–2 L/kg and endogenous clear- QRS interval duration .120 ms for the treatment of sodium ances .4ml/min.66 The extensive protein binding of quinine channel blockade; however, in the context of chloroquine and is also expected to limit further the efficacy of diffusion- or hydroxychloroquine, careful monitoring of the electrolyte sta- convection-based techniques.66 tus, particularly potassium, is necessary as alkalization can Toxicokinetic or pharmacokinetic data were available on 61 exacerbate hypokalemia and prolong the QT interval.49,63,64 patients (13 chloroquine, three hydroxychloroquine, 45 qui- Hypotension is treated with epinephrine (adrenaline) infu- nine) and are summarized in Table 2. Although the concen- sions, and seizures are treated with benzodiazepines. The trations of chloroquine and quinine decrease during ECTR role of high-dose diazepam for treatment of cardiotoxicity (as expected from normal endogenous metabolism), neither remains poorly defined.6,40,42 The use of diazepam and epi- appear to be removed to any significant amount by ECTRs: nephrine was shown to statistically reduce mortality in pa- chloroquine clearance obtained during hemodialysis tients ingesting over 5 g of chloroquine,42 although a diazepam (50–75 ml/min) represented only 15% of total body clear- dose of 1.5 mg/kg over 24 hours did not reduce cardiotoxicity ance.67 During chloroquine poisonings, hemoperfusion in patients ingesting 2–4 g of chloroquine.40 Activated char- (HP) alone or in combination with hemodialysis (HD) re- coal is frequently administered to patients at high risk of tox- moved negligible quantities: in the most favorable cases, icity, depending on the history of the ingestion and clinical 1.1 g were eliminated in 46 hours by HP-HD (11% of the status. In the last two decades, reports of extracorporeal mem- ingested dose),68 and 0.47 g were eliminated in 6.5 hours by brane oxygenation use for severe chloroquine and hydroxy- HP (4.7% of the ingested dose, likely an overestimate given chloroquine poisoning have increased, with mixed results.65 the calculations provided).69 Rebound of chloroquine concen- trations post-ECTR was noted in many publications.68–72 Methods Neither HD nor HP removed .150 mg of quinine.30,73,74 The workgroup developed recommendations on the use of Hemodialysis clearances of quinine did not surpass ECTR following the EXTRIP methodology previously pub- 15 ml/min,24,73,74 and sieving coefficients during convective lished9 with modifications, updates, and clarifications. The techniques remained below 20%.75–77 Interestingly, therapeu- methods and glossary are presented in full in Supplemental tic plasma exchange (TPE), which seems best suited to remove

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1812 records identified 471 records identified 16 records identified 2 record identified through EAPCCT 47 records identified through EMBASE through Pubmed through Cochrane Library and NACCT conference abstracts through manual searches

1901 records identified after duplicates removed

1901 citations screened 1672 citations excluded

185 full-text articles excluded 87 unrelated 229 full-text articles 47 review/commentary/editorial assessed for eligibility 9 duplicated data 5 poor data 37 ECTR done for reasons other than poison removal

44 studies included in qualitative synthesis

Type: Case reports/series=28, PK studies=11, Animal studies=2, In-vitro studies=3 Languages: English=34, French=3, Danish=1, German=5, Russian=1 Inclusion Eligibility Screening Identification

Figure 1. The litterature search last performed on January 15th, 2020, after removal of duplicates and non-pertinent records, yielded 44 studies for analysis. No comparative observational studies or randomized trials were identified. EAPCCT, European Association of Poisons Centres and Clinical Toxicologists; NACCT, North American Congress of Clinical ; PK, pharmacokinetic. protein-bound drugs, removed only 8.5 mg of quinine in removal of either chloroquine or quinine.74,78–81 Dialyzability 3 hours (clearance was 12 ml/min).74 As expected, lower- data for hydroxychloroquine were limited to three patients efficiency techniques like peritoneal dialysis (PD) and ex- receiving routine hemodialysis, and extracorporeal drug re- change transfusion (ET) had an inconsequential effect on moval was not observed.82

Table 2. The pharmacokinetics of chloroquine, hydroxychloroquine, and quinine during ECTR (data shown combine both pharmacokinetic and toxicokinetic data)

t1/2 during Endogenous ECTR Clearance Endogenous Clearance, Level of ECTR ECTR Dialyzability t1/2,h ml/min Evidence h n ml/min n Chloroquine HD .200 9–77 4 400–800 ND C HP-HD 11.9 1 0–54 2 ND C PD 1.1–1.5 2 ND C HP 2.0–6.7 3 61–135 3 ND C Hydroxychloroquine HD .20 3 .200 a 3 100–300 ND D Quinine HD 21.2 1 8–14 0.2–13.8 17 100–150 ND B CRRT 0.3–3.7 3 ND C HD-HP 5.7 1 ND D ET 1.4–5.1 3 ,4.6 2 ND C PD 12.5–27.3 3 0.6–11.1b 8NDB TPE 11.8 1 ND D HP 2.5–21.7 2 16.7–115 3 ND D Data shown combine both pharmacokinetic and toxicokinetic data. HD, hemodialysis; ND, not dialyzable; HP-HD, hemoperfusion and hemodialysis in series; PD, peritoneal dialysis; HP, hemoperfusion; CRRT, continuous renal replacement therapy; HD-HP, hemodialysis and hemoperfusion in series; ET, exchange transfusion; TPE, therapeutic plasma exchange. aExtracorporeal clearance could not be calculated due to hydroxychloroquine being undetectable in the dialysis effluent, but this indicates that ECTR clearance is below 44 ml/min, assuming dialysate flow of 500 ml/min. bOne value was excluded103 because it was assessed as likely an error.

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Table 3. Clinical description of included patients with poisoning Parameters Chloroquine, 12 patients Hydroxychloroquine, 1 patient Quinine, 25 patients Patient characteristics Median age, yr 25.5 33 23 Men, % 33.3 0 44 Poisoning information Median dose, g 8.4 30 6.0 Median time from ingestion to admission, h 1.5 3.0 3.5 Median plasma concentration, mg/L 4.7 (p), 19 (b)a uncertainb 15.1 Signs/symptoms/laboratory Coma, % 60 100 42 Visual impairment, % 28 0 87 Hypotension, % 83 100 28 Respiratory depression, % 82 100 21 Severe dysrhythmia/cardiac arrest, % 64 100 21 Auditory impairment, % 0 0 88 AKI, % 20 100 29 Median potassium, mmol/L 2.6 3.0 4.0 Prolonged QRS complex duration, % 80 100 7 Median QRS complex duration, ms 140 140 110 Prolonged QT interval, % 83 100 23 Median QT interval, ms 490 576 420 Other treatments, % Gastric lavage 70 100 69 Activated charcoal 78 100 6 Benzodiazepines 71 100 0.6 Bilateral stellate ganglion block 0 0 33 Cardiac pacing 10 100 6 Mechanical ventilation 75 100 25 Vasopressors 86 100 31 ECTR, n Hemodialysis 0 100 7 Hemoperfusion 8 5 Exchange transfusion 0 5 Hemoperfusion and hemodialysis in series 2 1 Peritoneal dialysis 2 5 .1 ECTR used 0 2 Outcome Visual sequelae, % 0 0 26 Median LOS, d 11 6 (ICU) 13 Death, % 42 0 12 Percentages are on the basis of available data (if the data are not shown, they are removed). p, plasma; b, blood; LOS, length of stay ICU, intensive care unit. aBlood concentration can estimated to be approximately four times as high as the plasma concentration.6,69 bPlasma concentration stated in the article was 6425 mol/L, likely an error.

On the basis of previously defined criteria (Supplemental transiently decreased its plasma concentration. The trivial ef- Material),9 chloroquine, hydroxychloroquine, and quinine fect of hemodialysis on hydroxychloroquine removal is illus- were categorized as non-dialyzable with a level of evidence trated in the following simulated patient. Assuming a patient presented in Table 2. Although much of the data are on the weighing 50 kg ingests 10 g of hydroxychloroquine (volume basis of ECTR technology prior to the year 2000, an increase in of distribution 550 L/kg) and oral absorption is 100%, then drug clearance with current ECTR technology is anticipated the predicted plasma concentration of hydroxychloroquine to be insufficient for the drugs to be reclassified as potentially would be 4 mg/L. Assuming an ideal hemodialysis treatment dialyzable due to their intrinsic pharmacokinetic properties (hemodialysis plasma flow 5240 ml/min [14.4 L/h] and (Table 1). Although pharmacokinetic data for hydroxychlor- 100% extraction through the dialyzer) and an absence of oquine were limited to three patients,82 empirically it is likely drug distribution or endogenous clearance during hemodi- that hydroxychloroquine is non-dialyzable due to its enor- alysis, a 4-hour hemodialysis treatment would remove only mous volume of distribution, which would also cause a sub- 230.4 mg, or approximately 2.3% of the ingested dose, cal- stantial rebound in plasma concentration even if an ECTR culated as follows:

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31: Table 4. Evidence profile table: ECTR plus standard care compared with standard care in patients severely poisoned with chloroquine or quinine 2475 Quality Assessment Summary of Findings – 49 00Clrqie yrxclrqie rQiiePoisoning Quinine or Hydroxychloroquine, Chloroquine, 2020 2489, ECTR 1 Study Risk of Other Importance N studies Inconsistency Indirectness Imprecision Standard Standard Care Effect Quality Design Bias Considerations Care

Mortality Chloroquine55a Observational Very Not serious Seriousc Seriousd Publication bias All reported Cohorts of Groups not Very low Critical studies seriousb strongly suspectede patients hospitalized comparable receiving patients receiving ECTR with standard care alone standard care (large (median ingestions):19/91 ingestion of (.4g),32 1/9 (.5 8.4 g, median g),42 7/44 (median concentration 4.6 g),6 3/25 9.7 mg/L): 5/ (median 3.9 g)44 5 12 541.7% 8.4%–15.9%. Cohorts of hospitalized patients receiving standard care alone: (median blood chloroquine concentration .8.1 mg/L):13/ 6132 521.3% Quinine53f Observational Very Not serious Seriousc Seriousd Publication bias All reported Cohorts of Groups not Very low Critical studies seriousb strongly suspectede patients hospitalized comparable receiving patients receiving ECTR with standard care standard care: alone: 0/48,28 5/ 5 29 5

3/25 12.0% 165 0%-3% www.jasn.org Permanent visual deficit Quinine54g Observational Very Not serious Seriousc Seriousd Publication bias All reported Cohorts of Groups not Very low Critical studies seriousb,h strongly suspectede patients hospitalized comparable receiving patients receiving ECTR with standard care standard care: alone: 3/48,28 6/ META-ANALYSIS 6/23 526.1% 30,31 19/16529 56.3%-20.0% 2481 2482 META-ANALYSIS Table 4. Continued

Quality Assessment Summary of Findings

JASN ECTR 1 Study Risk of Other Importance N studies Inconsistency Indirectness Imprecision Standard Standard Care Effect Quality Design Bias Considerations Care

Length of hospitalization www.jasn.org Chloroquine52 (no data Observational Very Not serious Seriousc Seriousd Publication bias All reported Cohort of hospitalized Groups not Very low Important for quinine)i studies seriousb strongly suspectede patients patients receiving comparable receiving standard care ECTR with alone: median ICU standard care: stay in survivors median 11.0 d 4.567d(range: 9 h (n55) to 60 d) in 153 patients32 Serious complications of catheter insertionj 5k Observational Not Not seriousl Not seriousm Not seriousn Strong associationo Rate of serious Approximately 0 Absolute effect is Moderate Critical studies serious complications estimated to be of catheter varying from 1 insertion varies to 21 more from 0.1% to serious 2.1% complications per 1000 patients in the ECTR group Serious complications of ECTRp 6q Observational Not Not serious Not serious Not serious Strong associationr Rate of serious Approximately 0 Absolute effect is Moderate Critical studies serious complications estimated to be of ECTR varies varying from .0 according to to 19 more the type of serious ECTR complications performed per 1000 from 0.005% patients in the (HD and CRRT) ECTR group JASN to 0.6% (TPE) depending of and up to 1.9% the type of 31: (HP) ECTR 2475 performed

– “ ” “ fi ” 49 2020 2489, Bold text represents the likelihood of the measured outcome. Requirement for extracorporeal membrane oxygenation/ECLS and permanent auditory de cit were outcomes ranked critical, although no data were reported in the control group. ICU, intensive care unit; HD, hemodialysis; CRRT, continuous renal replacement therapy; TPE, therapeutic plasma exchange; HP, hemoperfusion. aIncludes our systematic review of the literature on ECTR (12 patient reports) and four patient series on standard care alone. JASN bPatient reports published on effect of ECTR. Uncontrolled and unadjusted for confounders, such as severity of poisoning, coingestions, supportive and standard care, and cointerventions. Confounding by indication is inevitable because ECTR is usually attempted in the sickest patients. 31: cECTR and standard care performed may not be generalizable to current practice (literature predating 2000). d 2475 Few events in small sample size: optimal information size criteria not met. ePublication bias is strongly suspected due to the study design (patient reports published in toxicology report very severe poisoning either with or without impressive recovery with treatments attempted).

– f

49 00Clrqie yrxclrqie rQiiePoisoning Quinine or Hydroxychloroquine, Chloroquine, 2020 2489, Includes our systematic review of the literature on ECTR (25 patient reports) and two patient series on standard care alone. gIncludes our systematic review of the literature on ECTR (23 patient reports) and three patient series on standard of care alone. hPermanent visual deficits varied from field constriction to complete blindness. This outcome was not systematically measured nor reported. iIncludes our systematic review of the literature on ECTR (five patient reports) and one patient series on standard care alone. jFor venous catheter insertion, serious complications include hemothorax, pneumothorax, hemomediastinum, hydromediastinum, hydrothorax, subcutaneous emphysema retroperitoneal hemorrhage, embolism, nerve injury, arteriovenous fistula, tamponade, and death. Hematoma and arterial puncture were judged not serious and thus, excluded from this composite outcome. Deep vein thrombosis and infection complications were not included considering the short duration of catheter use. kOn the basis of five single-arm observational studies: two meta-analyses comparing serious mechanical complications associated with catheterization using or not using an ultrasound, which included six RCTs in subclavian veins104 and 11 in internal jugular veins105 ; two RCTs comparing major mechanical complications of different sites of catheterization106,107 ; and one large multicenter cohort study reporting all me- chanical complications associated with catheterization.108 Rare events were reported from patient series and patient reports. lNot rated down for inconsistency because heterogeneity was mainly explained by variation in site of insertion, use of ultrasound, experience of the operator, populations (adults and pediatric), urgency of catheter insertion, practice patterns, and methodologic quality of studies. mNot rated down for indirectness because cannulation and catheter insertion were judged similar to the procedure for other indications. nNot rated down for imprecision because the wide range reported was explained by inconsistency. oThe events in the control group are assumed to be zero (because no catheter is installed for ECTR); therefore, the magnitude of effect is at least expected to be large, which increases the confidence in the estimate of effect. Furthermore, none of the studies reported 95% confidence intervals that included the null value, and all observed complications occurred in a very short time frame (i.e., few hours). pFor HD and CRRT, serious complications (air emboli, shock, and death) are exceedingly rare, especially if no net ultrafiltration. Minor bleeding from heparin, transient hypotension, and electrolytes imbalance were judged not serious. For HP, serious complications include severe thrombocytopenia, major bleeding, and . Transient hypotension, , hypocalcemia, and thrombocytopenia were judged not serious. For TPE, serious complications include citrate toxicity, severe allergic reaction, , and vasovagal reaction. Hypotension, hypocalcemia, and urticaria were judged as not serious. All nonserious complications were excluded from this composite outcome. qIHD/CRRT: on the basis of two single-arm studies describing severe adverse events per 1000 treatments in large cohorts of patients.109,110 TPE: on the basis of the two most recent one-arm studies reporting potential life-threatening adverse events.111,112 HP: on the basis of two small single-arm studies in poisoned patients.113,114 Rare events were reported in patient series and patient reports. rAssuming that patients in the control group would not receive any form of ECTR, the events in the control group would be zero; therefore, the magnitude of effect is at least expected to be large, which increases the confidence in the estimate of effect. Furthermore, none of the studies reported 95% confidence intervals that included the null value, and all observed complications occurred in a very short time frame (i.e., few hours). www.jasn.org META-ANALYSIS 2483 META-ANALYSIS www.jasn.org

5 3 3 ½ Removal Plasma flow TimeHD Hydroxychloroquine initial 5 ðÞ14:4L=h 3 ðÞ4 hour HD 3 ðÞ4mg=L 5 230:4mg: Then; 230:4mg=10; 000 mg ingested 5 2:3% of ingested dose:

Quinine Moreover, the calculation illustrates the dialytic removal as- There were 25 patients described from 17 articles (Table 3). All suming a near “best-case scenario” associated with each of were dated, with the most recent one published in 1993. The the important determinants of hydroxychloroquine dialyz- overall quality of patient reports was of low methodologic ability. Practically, the calculated concentration will be quality and generally lacked reporting of critical information. lower because the maximal oral bioavailability is about Low-efficiency techniques (PD, ET) were used in 40% of pa- 74% and the Vd typically exceeds 50 L/kg, the extraction tients. Several reports claimed some degree of improvement ratio is likely lower than 100% (i.e., the extracorporeal (resolution of hemodynamic instability, visual recovery); in clearance would be ,240 ml/min). Together, these would rare cases, dramatic improvements were noted with high- result in a lower removal of hydroxychloroquine than efficiency techniques,73,74,86 but in most, this occurred several calculated. hours following termination of the procedure, suggesting that this was coincidental and unrelated to the ECTR. There were three fatalities.30,87,88 Complications from ECTR included hy- Preclinical Data potension during hemodialysis89 and four cases of decreased In one animal experiment of chloroquine poisoning, nine platelet counts during hemoperfusion.87,90,91 Compared with dogs treated with HD were compared with nine controls. All historical cohorts (Table 4), mortality in patients receiving dogs survived a dose of 5 mg/kg, whereas none did after ECTR was higher (12% versus ,5%), as was the incidence 8 mg/kg.83 HD therefore failed to provide a survival advantage of permanent visual impairment (26% versus ,5%), but as to chloroquine-poisoned dogs. the ECTR group had more features of severity, a reliable as- sessment of clinical benefit from ECTR was not feasible. Clinical Data Chloroquine Compared with standard care alone, there was no direct or fi Among human reports, there were 12 patients (five fatalities) indirect evidence of added bene t from ECTR, but there was evidence of added harms and costs related to the insertion of a described from ten articles (Table 3). This cohort was some- double-lumen catheter and the procedure itself, the magni- what dated, with the most recent case published in the year tude of which varied according to local practices, methods of 2000. These patient reports were of low methodologic quality catheterization, and type of ECTR used.92 and lacked reporting of critical information.10 In only two patients was there an apparent temporal improvement with ECTR.70,84 Complications included hypothermia during PD80 and simultaneous declines of both hemoglobin and platelets during HP.70,84 As shown in the evidence table (Table 4), the DISCUSSION cohort of 12 patients receiving ECTR was sicker (median dose 8.4 g, median plasma chloroquine concentration Recommendation 1 4.7 mg/L, or blood chloroquine concentration 20.7 mg/L6) In patients severely poisoned with chloroquine, we recom- than other described cohorts. Despite the clinical severity, mend against using ECTR in addition to standard care (strong non-ECTR treatments were varied and heterogeneous (only recommendation, very low quality of evidence [1D]). 71% received benzodiazepines, none received ECLS). Mor- tality in the ECTR cohort was twice as high as the sickest Rationale for Recommendation cohort previously described.32 Considering the different de- The workgroup agreed almost unanimously that the risks and gree of poisoning severity and wide range of provided treat- costs associated with ECTR surpass any potential benefitin ments, the workgroup judged that no formal comparison chloroquine poisoning (results of votes: median 51, upper between the ECTR cohort and historical controls was quartile 51, disagreement index 50).Thisisonthebasisof possible. both the very poor dialyzability of chloroquine as well as the absence of direct or indirect clinical benefit from published Hydroxychloroquine reports. Even if the patient reports are dated and do not reflect There was a single patient report of ECTR used for hydroxy- current management, the workgroup evaluated that the results chloroquine poisoning in which treatment was also con- would not show differences in outcomes had they been per- founded by the use of intravenous lipid emulsion.85 formed with present-day standard care. The workgroup could

2484 JASN JASN 31: 2475–2489, 2020 www.jasn.org META-ANALYSIS not propose a hypothetical scenario in which ECTR would be In conclusion, chloroquine, hydroxychloroquine, and qui- beneficial for poison removal. nine have low therapeutic indices and can cause major toxicity and death in poisoning even with modern standard care. Research Gaps The EXTRIP workgroup assessed the three drugs to be non- There are no research gaps. dialyzable. Data regarding the clinical efficacy of ECTRs were dated and of poor quality overall. The workgroup recom- Recommendation 2 mended against extracorporeal removal of chloroquine and Similar to chloroquine, hydroxychloroquine was assessed as quinine in addition to standard care. non-dialyzable. Because of limited clinical data and despite the lack of biologic plausibility, no recommendation was devel- oped, as per aprioriagreed methods (minimal requirement of DISCLOSURES three reported patients describing clinical outcomes). Thomas D. Nolin reports personal fees from MediBeacon, personal fees Research Gaps from CytoSorbents, and other from McGraw-Hill Education outside the sub- Because of the minimal data on dialyzability of hydroxychlor- mitted work. Marc Ghannoum is a scholar of the Fonds de Recherche du ’ oquine, the workgroup proposed that pharmacokinetic stud- Québec - Santé. Darren Roberts acknowledges support of St. Vincent sCentre fi for Applied Medical Research Clinician “Buy-Out” Program. All remaining ies be performed to con rm or refute the current impression authors have nothing to disclose. that hydroxychloroquine is non-dialyzable.

Recommendation 3 FUNDING In patients severely poisoned with quinine, we recommend against using ECTR in addition to standard care (strong rec- EXTRIP received support consisting of an unrestricted grant of $60,633 ommendation, very low quality of evidence [1D]). Canadian from the Verdun Research Fund (the institution of Marc Ghan- noum) solely for the reimbursement of travel expenses for the in-person Rationale for Recommendations guideline meeting and payment to dedicated translators for retrieval and As opposed to chloroquine, quinine’s volume of distribution is translation of foreign language articles. smaller, although still large (1.5–3.0 L/kg). This, added to its extensive protein binding, limits its removal by diffusive and convective techniques, as confirmed from data presented ACKNOWLEDGMENTS above. Further, despite the dated and poor quality of the clin- ical evidence, when added to standard care ECTR did not pro- We would like to acknowledge the valuable help of our dedicated transla- fi vide any apparent benefit, but it did increase risks and costs. tors, librarian, and meeting secretary. Of cial translators were Alexandra Angulo, Alla Abbott, Anant Vipat, Andreas Betz, Angelina Kovaleva, Denise For these reasons, the workgroup strongly recommended Gemmellaro, Ewa Brodziuk, Helen Johnson, Junzheng Peng, Marcela Covic, against the use of ECTR (results of votes: median 51, upper Nathalie Eeckhout, Rosie Finnegan, Salih Topal, and Vilma Etchard. The quartile 51, disagreement index 50). Six of 37 participants librarian was Elena Guadagno. The meeting secretary was Brenda Gallant. would consider using ECTR in very limited settings, such as Marc Ghannoum, Sophie Gosselin, Robert S. Hoffman, Valery Lavergne, poisoning in a patient with a preexisting vascular access and Thomas D. Nolin, and Darren M. Roberts designed the study; Ingrid Berling, Marc Ghannoum, Joshua D. King, Greene Shepherd, and Gabrielle Wilson an available charcoal cartridge or high-cutoff dialyzer. Thera- carried out extractions; Ingrid Berling, Marc Ghannoum, Joshua D. King, peutic plasma exchange was not considered to be sufficiently Darren M. Roberts, and Greene Shepherd analyzed the data; Ingrid Berling, efficient in increasing total clearance of quinine to justify its Marc Ghannoum, and Valery Lavergne made the tables and figures; all authors risks in any hypothetical scenario of quinine poisoning. drafted and revised the paper; and all authors approved the final version of the manuscript. Research Gaps Because of the questions and the remaining uncertainties re- lated to quinine’s volume of distribution and in circumstances SUPPLEMENTAL MATERIAL in which protein binding might be lower (potentially over- dose), some members considered that there was some ratio- This article contains the following supplemental material online at http:// jasn.asnjournals.org/lookup/suppl/doi:10.1681/ASN.2020050564/-/ nale in further testing the capacity of high-cutoff hemodialysis DCSupplemental. or hemoperfusion to remove quinine using current standards Supplemental Figure 1. Approach to and implications of rating the quality for assessing dialyzability.10 It is conceivable that with modern of the evidence and strength of recommendations using the GRADE catheters, modern devices, and early use of these techniques methodology. after ingestion, a clinically relevant amount of quinine could Supplemental Figure 2. Voting process for recommendations. Supplemental Material. Supplemental material includes methods; EXTRIP be removed. The risk of the procedure would also be lowered clinical practice guidelines; disclosure and management of potential COI; assuming that a functional dialysis access is already available in clinical question; search strategy, screening, and study selection; evidence re- study participants. view: dialyzability; assessment of toxicokinetic data; evidence review: clinical

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outcomes; development of clinical recommendations; updating process; glos- 2019 coronavirus disease, 2020. Available at: https://www.fda.gov/ sary; and references. media/136534/download. Accessed April 20, 2020 Supplemental Table 1. Represented societies. 17. Krishna S, White NJ: Pharmacokinetics of quinine, chloroquine and Supplemental Table 2. EXTRIP criteria for assessing dialyzability. amodiaquine. Clinical implications. Clin Pharmacokinet 30: 263– 299, Supplemental Table 3. Quality of individual studies for toxicokinetic 1996 outcomes. 18. Ofori-Adjei D, Ericsson O, Lindström B, Sjöqvist F: Protein binding of Supplemental Table 4. Quality of evidence for toxicokinetic outcomes. chloroquine enantiomers and desethylchloroquine. Br J Clin Phar- macol 22: 356–358, 1986 19. Plantone D, Koudriavtseva T: Current and future use of chloroquine and hydroxychloroquine in infectious, immune, neoplastic, and neu- rological diseases: A mini-review. 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88. Hillman E, Harpur ER: Hazards to health. Quinine poisoning. NEngl 102. Sukontason K, Karbwang J, Rimchala W, Tin T, Na-Bangchang K, JMed264: 138–139, 1961 Banmairuroi V, et al: Plasma quinine concentrations in falciparum 89. Shimanko II, Yaroslavsky AA: Early hemodialysis in severe poisoning malaria with acute renal failure. Trop Med Int Health 1: 236–242, 1996 with ethylene glycol, quinine and pachycarpine[Russian]. Sov Med 37: 103. Markham TN, Dodson VN, Eckberg DL: Peritoneal dialysis in quinine 92–96, 1974 sulfate intoxication. JAMA 202: 1102–1103, 1967 90. Bodenhamer JE, Smilkstein MJ: Delayed cardiotoxicity follow- 104. Brass P, Hellmich M, Kolodziej L, Schick G, Smith AF: Ultrasound ing quinine overdose: A case report. JEmergMed11: 279–285, guidance versus anatomical landmarks for subclavian or femoral vein 1993 catheterization. Cochrane Database Syst Rev 1: CD011447, 2015 91. Morgan MD, Rainford DJ, Pusey CD, Robins-Cherry AM, Henry JG: 105. Brass P, Hellmich M, Kolodziej L, Schick G, Smith AF: Ultrasound The treatment of quinine poisoning with charcoal haemoperfusion. guidance versus anatomical landmarks for internal jugular vein cath- Postgrad Med J 59: 365–367, 1983 eterization. Cochrane Database Syst Rev 1: CD006962, 2015 92. Bouchard J, Lavergne V, Roberts DM, Cormier M, Morissette G, 106. Parienti JJ, Mongardon N, Mégarbane B, Mira JP, Kalfon P, Gros A, Ghannoum M: Availability and cost of extracorporeal treatments for et al; 3SITES Study Group: Intravascular complications of central ve- poisonings and other emergency indications: A worldwide survey. nous catheterization by insertion site. NEnglJMed373: 1220–1229, Nephrol Dial Transplant 32: 699–706, 2017 2015 93. Paintaud G, Alván G, Ericsson O: The reproducibility of quinine bio- 107. Shin HJ, Na HS, Koh WU, Ro YJ, Lee JM, Choi YJ, et al: Complications availability. Br J Clin Pharmacol 35: 305–307, 1993 in internal jugular vs subclavian ultrasound-guided central venous 94. Tett SE: Clinical pharmacokinetics of slow-acting antirheumatic drugs. catheterization: A comparative randomized trial. Intensive Care Med Clin Pharmacokinet 25: 392–407, 1993 45: 968–976, 2019 95. Gustafsson LL, Walker O, Alván G, Beermann B, Estevez F, Gleisner L, 108. Björkander M, Bentzer P, Schött U, Broman ME, Kander T: Mechanical et al: Disposition of chloroquine in man after single intravenous and complications of central venous catheter insertions: A retrospective oral doses. Br J Clin Pharmacol 15: 471–479, 1983 multicenter study of incidence and risks. Acta Anaesthesiol Scand 63: 96. Laurin LP, Lévesque R, Roy L: Hemodiafiltration does not improve 61–68, 2019 drug protein binding compared to conventional hemodialysis: An 109. Wong B, Zimmerman D, Reintjes F, Courtney M, Klarenbach S, in vitro study. Blood Purif 33: 307–308, 2012 Dowling G, et al: Procedure-related serious adverse events among 97. Walker O, Birkett DJ, Alván G, Gustafsson LL, Sjöqvist F: Character- home hemodialysis patients: A quality assurance perspective. Am ization of chloroquine plasma protein binding in man. Br J Clin Phar- J Kidney Dis 63: 251–258, 2014 macol 15: 375–377, 1983 110. Tennankore KK, d’GamaC,FaratroR,FungS,WongE,ChanCT: 98. Donadio JV Jr., Whelton A, Kazyak L: Quinine therapy and peritoneal Adverse technical events in home hemodialysis. AmJKidneyDis65: dialysis in acute renal failure complicating malarial haemoglobinuria. 116–121, 2015 Lancet 1: 375–379, 1968 111. Mokrzycki MH, Kaplan AA: Therapeutic plasma exchange: Compli- 99. Franke U, Proksch B, Müller M, Risler T, Ehninger G: Drug monitoring cations and management. Am J Kidney Dis 23: 817–827, 1994 of quinine by HPLC in cerebral malaria with acute renal failure treated 112. Sutton DM, Nair RC, Rock G: Complications of plasma exchange. by haemofiltration. Eur J Clin Pharmacol 33: 293–296, 1987 Transfusion 29: 124–127, 1989 100. Hall A, Yardumian A, Marsh A: Exchange transfusion and quinine 113. Yang X, Xin S, Zhang Y, Li T: Early hemoperfusion for emergency concentrations in falciparum malaria. Br Med J (Clin Res Ed) 291: treatment of carbamazepine poisoning. Am J Emerg Med 36: 1169–1170, 1985 926–930, 2018 101. Sharma AM, Keller F, Boeckh M, Heitz J, Borner K: Quinine dosage in 114. Shannon MW: Comparative efficacy of hemodialysis and hemo- severe malaria with renal failure necessitating haemodialysis. Eur perfusion in severe theophylline intoxication. Acad Emerg Med 4: J Clin Pharmacol 36: 535–536, 1989 674–678, 1997

AFFILIATIONS

1Department of Emergency Medicine, Calvary Mater Newcastle, Waratah, New South Wales, Australia 2Department of Clinical Toxicology and Pharmacology, Calvary Mater Newcastle, Waratah, New South Wales, Australia 3School of Medicine and Public Health, University of Newcastle Newcastle, New South Wales, Australia 4Department of Medicine, School of Medicine and School of Pharmacy, University of Maryland, Baltimore, Maryland 5Maryland Poison Center, Baltimore, Maryland 6Division of Practice Advancement and Clinical Education, University of North Carolina Eshelman School of Pharmacy, Chapel Hill, North Carolina 7Division of Medical Toxicology, Ronald O. Perelman Department of Emergency Medicine, New York University Grossman School of Medicine, New York City, New York 8Poison Control Section, Department of Environmental and Occupational Health, Ministry of Health, Muscat, Oman 9Research Center, Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l’île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada 10Department of Renal Medicine and Transplantation, St. Vincent’s Hospital, Sydney, New South Wales, Australia 11Department of Clinical Pharmacology and Toxicology, St. Vincent’s Hospital, Sydney, New South Wales, Australia 12St. Vincent’s Clinical School, University of New South Wales, Sydney, New South Wales, Australia 13Centre Intégré de Santé et de Services Sociaux Montérégie-Centre Emergency Department, Hôpital Charles-Lemoyne, Greenfield Park, Quebec, Canada 14Department of Emergency Medicine, McGill University, Montreal, Quebec, Canada

2488 JASN JASN 31: 2475–2489, 2020 www.jasn.org META-ANALYSIS

15Centre Antipoison du Québec, Quebec City, Quebec, Canada 16Research Center, Centre Intégré Universitaire de Santé et de Services Sociaux du Nord-de-l’île-de-Montréal, Hôpital du Sacré-Coeur de Montréal, University of Montreal, Montreal, Quebec, Canada 17Department of Pharmacy and Therapeutics, University of Pittsburgh School of Pharmacy, Pittsburgh, Pennsylvania 18Department of Medicine Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania

JASN 31: 2475–2489, 2020 Chloroquine, Hydroxychloroquine, or Quinine Poisoning 2489 Supplemental Material

A) METHODS

EXTRIP clinical practice guidelines As defined by the Institute of Medicine in 20111, clinical practice guidelines are statements that include recommendations intended to optimize patient care by assisting practitioners and patients in making decisions about appropriate health care for specific clinical circumstances. They are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options. Attributes of good guidelines include validity, reliability, reproducibility, clinical applicability, clinical flexibility, clarity, multidisciplinary process, review of evidence and documentation.

The EXTRIP-2 workgroup pursued a second phase of the international multidisciplinary effort started in 2010. Using established methodology, the EXTRIP workgroup reviewed the literature and developed recommendations on the use of ECTR in the context of poisoning for a new set of 10 poisons. More specifically, the effect of ECTR was measured against standard care and alternative treatments. Potential benefits of ECTR were balanced with potential harms from the procedure. Outcomes measured included mortality, relevant clinical and physiological endpoints, complications associated with ECTR procedure, as well as the extent of extracorporeal removal of the drug (i.e. dialyzability).

When applicable, different populations (including end-stage kidney disease and pediatric patients), types of poisoning (acute, acute-on-chronic and chronic), and types of ECTR were evaluated. When developing recommendations, variation in clinical practice in different settings across the globe was considered especially regarding resource use, costs and availability of ECTR2. Implementation issues were addressed when appropriate.

Workgroup composition The EXTRIP workgroup is an international collaborative comprising recognized experts from various clinical specialties (medical toxicology, emergency medicine, nephrology, critical care, pediatrics, and pharmacology). EXTRIP-2 workgroup renewed the participation of 15 members and invited 22 new experts to join the workgroup and increase representativeness across the world (See Table 1). Six co-chairs (M.G., V.L., B.H., D.R, S.G. and T.N), of which one is a non-voting guideline methodologist (V.L.), led and supervised the different aspects of the guideline development.

1 Table 1. Represented societies African Federation of Emergency Medicine Chinese College of Emergency Physicians Acute Dialysis Quality initiative Chinese Medical Association American College of Clinical Pharmacology European Association of Poison Centres and Clinical Toxicologists American Academy of Clinical Toxicology European Renal Association-European Dialysis and Transplant Association American College of Emergency Physicians European Society for Emergency Medicine American College of Medical Toxicology European Society of Intensive Care Medicine American Society of Nephrology Faculty of Intensive Care Medicine American Society of Pediatric Nephrology International Pediatric Nephrology Association Asia Pacific Association of Medical Toxicology* International Society of Nephrology Asian Pacific Nephrology Association Middle East and North Africa Clinical Toxicology Association Australian and New Zealand Intensive Care Society* National Kidney Foundation Australian and New Zealand Society of Nephrology* Pediatric Continuous Renal Replacement Therapy Brazilian Association of Information Centres and Pediatric Critical Care Medicine Toxicologic Assistance* Society of Academic Emergency Medicine Brazilian Society of Toxicology Society of Critical Care Medicine Canadian Association of Emergency Physicians The Renal Association *This representation does not signify endorsement. Recommendations will be submitted to societies for review and potential endorsement.

Disclosure and management of potential COI All prospective members were required to disclose any actual, potential, or perceived COI prior to inclusion in the workgroup. The disclosures were used to categorize the members as cleared for full participation, allowed to participate with recusal from certain aspects of guideline development, or disqualified from participation. The co-chairs remained free of any financial COI during the entire guideline development process, meaning avoidance of interests and relationships with pharmaceutical or device companies pertaining to the topic of poisoning. Members were required to disclose to the co-chairs any new activities that had the potential to be viewed as a COI prior to engaging in the activity, at the beginning of face-to-face meeting, and before submission of the manuscript. Co-chairs determined if specific activities were allowed under the COI rules. All COIs deemed as potential appearance of a conflict of interest were required to be included in the manuscript.

Clinical question An initial list of relevant clinical questions was developed by the co-chairs and then approved by the entire workgroup prior to the first iteration of EXTRIP-2. Clinical questions were formulated following the standard PICO format. Comparator(s) of interest were more explicitly stated and defined (e.g. standard care with/without antidotes). For a clinical question to be formally developed into a recommendation, the workgroup agreed a priori that a minimum of 3 reported cases describing clinical outcomes for a specific poison was required.

Search strategy, screening, and study selection One health sciences librarian in collaboration with one co-chair and the methodologist designed literature searches to address clinical questions. For the search strategy regarding the use of ECTR, the following electronic databases were searched: PubMed/Medline, EMBASE and Cochrane Database for systematic Reviews. Searches were not limited to English language or year of publication. To supplement the electronic searches, workgroup members had the option of contacting experts and manually searching journals, conference proceedings, reference lists, and regulatory agency websites for relevant articles.

2 The following search strategy was created: (dialysis or hemodialysis or haemodialysis or hemoperfusion or haemoperfusion or plasmapheresis or plasmaphaeresis or hemofiltration or haemofiltration or hemodiafiltration or haemodiafiltration or plasma exchange or CRRT or CVV* or exchange transfusion) and ((quinine) OR (chloroquine) OR (hydroxychloroquine)).

If the initial search of the literature did not identify comparative studies where ECTR is measured against standard care alone (with or without an antidote, if applicable), complementary searches on the comparator of interest and on prognostic factors were developed. Potential complications of ECTR (associated with catheterization as well as related to the procedure itself) were comprehensively searched in PubMed/Medline for the best available evidence. A web-based international survey performed in 2014-2015 by the EXTRIP workgroup provided the main source of evidence to address other important considerations such as resource use, costs and availability of ECTR worldwide.2 This survey also informed potential implementation issues. Titles were screened for appropriateness by two workgroup members independently and full text papers were obtained and abstracted by the same two members into a standardized data extraction tool.

Evidence review: dialyzability Dialyzability was defined a priori as the ability of any ECTR to remove a clinically significant percentage of the total body burden of the poison3. Different criteria were used to semi-quantitively categorize the dialyzability of the poison for each ECTR (Table 2)

Table 2. EXTRIP criteria for assessing dialyzability Dialyzability& Primary Alternative Alternative Alternative criteria criteria 1 criteria 2 criteria 3 $ & # % Removed* CLECTR / CLTOT (%) T1/2 ECTR / T1/2 (%) REECTR / RETOT (%) D, Dialyzable >30% >75% <25% >75% M, Moderately dialyzable >10-30% >50-75% >25-50% >50-75% S, Slightly dialyzable ≥3-10% ≥25-50% ≥50-75% ≥25-50% N, Not dialyzable <3% <25% <75% <25% & Applicable to all modalities of ECTR, including hemodialysis, hemoperfusion, hemofiltration. * Corresponds to % removal of ingested dose (adjusted for bioavailability) or total body burden, adjusted for a 6-hour ECTR period. $ Corresponds to the clearance by ECTR (CLECTR) compared to the total clearance (CLTOT i.e. endogenous + ECTR clearance) & Corresponds to the apparent half-life during ECTR (T1/2 ECTR) compared to the apparent half-life off ECTR (T1/2) # Corresponds to the amount removed by ECTR (REECTR) compared to the amount eliminated from the body (RETOT) measured during the same period. These criteria should only be applied if measured or calculated (not reported) endogenous T1/2 is > 4h (otherwise, the benefit of ECTR is not likely to be considered clinically relevant). Furthermore, the primary criteria is preferred for poisons having a large VD (>1-2L/Kg)

Assessment of toxicokinetic data The quality of individual studies reporting on toxicokinetic outcomes was assessed according to a pre-defined set of criteria (see Table 3) and then summarized into a quality of the overall evidence (Table 4). If the latter was judged low or very low, literature from non-poisoning contexts was also considered, such as CKD pharmacokinetics, animal, and in-vitro studies.

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Table 3: Quality of individual studies for toxicokinetic outcomes Quality of Interpretation and application to individual studies individual studies

High Sufficient TK/PK data present; % removed is reported or can be calculated; reported calculations are appropriate.

Moderate Sufficient TK/PK data present, but % removed is NOT reported or CANNOT be calculated; reported calculations (e.g., CLEC/CLTOT) are appropriate.

Low Sufficient PK parameters may be reported, but supporting data absent or suspect, reported calculations inappropriate, or other serious limitations exist.

Very Low Sufficient PK parameters and supporting data not adequately reported, questionable or no calculations reported. However, based on theoretical knowledge of VD, protein binding, CLSYS, molecular weight, etc., some assumptions can be made about dialyzability.

Reject Questionable parameters reported with no supporting data, fatal flaw in study design.

Table 4. Quality of evidence for toxicokinetic outcomes Quality of Reporting Interpretation evidence High A We are confident that the true effect lies close to our estimate of the effect. Moderate B The true effect is likely to be close to our estimate of the effect, but there is a possibility that it is substantially different. Low* C The true effect may be substantially different from our estimate of the effect. Very Low* D Our estimate of the effect is just a guess, and it is very likely that the true effect is substantially different from our estimate of the effect*. *If the quality of the evidence is low or very low, literature from non-poisoning contexts may be used, such as pharmacokinetic studies in ESKD populations, animal, and in-vitro studies.

Evidence review: clinical outcomes All outcomes of interest were identified a priori and the guideline workgroup explicitly rated their relative importance for decision making. Evidence summaries for each question were prepared by the members assigned to a specific drug or poison in collaboration with the methodologist. The risk of bias was assessed using the Cochrane risk of bias tool for randomized controlled trials, and modified domains to assess confounding bias, selection bias, and bias due to misclassification for non-randomized studies. The quality in the evidence (Figure 1) was initially assessed for each critical and important outcome, and then for each recommendation using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach4, 5. GRADE evidence profile tables were developed in GRADEpro Guideline Development Tool (Evidence Prime CITE software) (GRADEpro GDT: GRADEpro Guideline Development Tool [Software]. McMaster University, 2015 (developed by Evidence Prime, Inc.). Available from gradepro.org.https://gradepro.org/cite/).The summaries of evidence were reviewed by all workgroup members for drafting of recommendations.

4 Figure 1: Approach to and implications of rating the quality of the evidence and strength of recommendations using the GRADE methodology

*unrestricted use of the figure granted by the GRADE working group

Development of clinical recommendations The workgroup considered core elements of the GRADE evidence in the decision process, including the quality of evidence and balance between desirable and undesirable effects. Additional domains were acknowledged where applicable (feasibility, resource use, acceptability). For all recommendations, the workgroup members voted to reach agreement for final recommendations. The voting process followed the same set of rules as for EXTRIP-1 (i.e. anonymous online voting consisting of two-round modified Delphi with each statement voted on a 9-point Likert scale and final results interpreted according to EXTRIP voting rules based on median, lower or upper quartile (LQ or UQ) as appropriate, and disagreement index (DI) as calculated using RAND/UCLA Appropriateness Method (see Figure 2)), and was performed using SimpleSurvey software.

5 Figure 2: Voting process for recommendations

* These recommendations can be formulated for or against a course of action (the figure only shows voting results FOR a course of action)

All recommendations were labeled as either “strong” or “weak/ conditional” according to the GRADE approach. The words “we recommend” indicate strong recommendations and “we suggest” indicate weak recommendations. Figure A provides the suggested interpretation of strong and weak recommendations for patients, clinicians, and healthcare policy makers. High-quality evidence was expected to be lacking for the great majority of recommendations. According to GRADE guidance, strong recommendations in the setting of lower-quality evidence were only assigned when the workgroup members believed they conformed to one or several paradigmatic conditions. As per GRADE guidance on discordant recommendations6, two paradigmatic situations presented in the development of EXTRIP-2 guideline: 1) low-quality evidence suggested benefit in a life- threatening situation (with evidence regarding harms being low or high), and 2) when low- quality evidence suggested benefit and high-quality evidence suggested harm.

If the workgroup could not make a recommendation for or against a particular management strategy due to either 1) a close balance between the benefits and harms (no recommendation), or 2) insufficient evidence making a recommendation too speculative (research gap), either a “no recommendation” or “research gap” recommendation was formulated (a “neutral recommendation” interpreted as a

6 “reasonable course of action” was no longer accepted). Although there is arguably ongoing need for research on virtually all of the topics considered in this guideline, “Research Needs” were noted for recommendations in which the need was believed by the workgroup to be particularly relevant.

The entire workgroup gathered in Montreal, Canada in November 2019 for the presentation of evidence summaries and the development of the recommendations for the ten new poisons. The subgroup assigned to a specific poison participated in the preparation of the draft guideline in collaboration with co-chairs.

Updating process Ongoing screening of the literature will take place to determine the need for revisions based on the likelihood that any new data will have an impact on the recommendations. If necessary, the entire workgroup will reconvene to discuss potential changes.

B) GLOSSARY -Poison: A xenobiotic (exogenous chemical, including and drugs) or an endogenously found chemical (e.g., iron, copper, vitamins) resulting from exogenous exposure with the potential to cause toxicity. -Poisoning: Exposure to a poison causing or capable of causing toxicity, regardless of intent. It includes intoxication, toxicity, and overdose. -Severe Poisoning: Exposure to a poison causing or capable of causing, if left untreated, end-organ damage. -Extracorporeal treatment (ECTR): A treatment, occurring outside the body, which promotes poison removal by mechanisms different from endogenous pathways. ECTR includes HD, continuous renal replacement therapy, extended dialysis, peritoneal dialysis (although technically occurring in the body), hemofiltration, hemodiafiltration, hemoperfusion, therapeutic plasma exchange and albumin/ “liver” dialysis. -Dialyzability: This term reflects the ability of ECTR to remove a clinically significant percentage of the total body burden of the poison -Clearance : The volume of blood (or solvent) cleared of poison per unit time, typically reported in units of mL/min. Importantly, CLECTR represents solute clearance due exclusively to ECTR and is independent of endogenous clearance (CLENDO; the sum of underlying renal and non-renal clearances). CLTOT refers to total clearance and is the sum of CLECTR and CLENDO. -Shock or end-organ compromise: Hypotension (systolic < 90 mmHg or mean blood pressure < 65 mmHg) with the presence of cellular ischemia as evidenced by increased lactate concentration, acute kidney injury (AKI) as defined by the Kidney Disease Improving Global Outcomes (KDIGO) guideline, increased troponin, altered mental status, or decreased capillary refill. -Refractory hypotension: per age-related defined standards, after adequate fluid challenge and vasopressor/inotropic support -Refractory bradycardia: per age-related defined standards, after vasopressor/inotropic support -Altered mental status: poison-induced impairment in at least one brain function (cognition, alertness, or orientation), in the absence of another cause -Coma: a deep state of unconsciousness as defined per the American Academy of Neurology

7 -Acute liver failure : (a) the presence of hepatic encephalopathy of any degree; (b) evidence of moderately severe coagulopathy [i.e., international normalized ratio (INR) ≥1.5]; (c) presumed onset of acute illness of <26 weeks; and (d) the absence of cirrhosis. -Acute liver injury: (a) evidence of moderately severe coagulopathy (INR ≥2.0); (b) presumed onset of acute illness <26 weeks; and (c) the absence of cirrhosis -Kidney impairment: CKD as stage 3B, 4, or 5 CKD (i.e., eGFR < 45 mL/min/1.73m2) or AKI as KDIGO stage 2 or 3 AKI. In the absence of a baseline creatinine, a GFR < 45 mL/min in adults; in children with no baseline creatinine, the use of KDIGO criteria of AKI stage 2 and 3 after imputing a baseline serum creatinine using the Schwartz 2009 formula assuming 120 mL/min of "normal" eGFR. The presence of oligo/anuria unresponsive to fluid resuscitation should be considered as impaired kidney function, regardless of serum creatinine concentration.

C) REFERENCES

1. Institute of Medicine Committee on Standards for Developing Trustworthy Clinical Practice, G: In: Clinical Practice Guidelines We Can Trust. edited by GRAHAM, R., MANCHER, M., MILLER WOLMAN, D., GREENFIELD, S., STEINBERG, E., Washington (DC), National Academies Press (US), 2011. 2. Bouchard, J, Lavergne, V, Roberts, DM, Cormier, M, Morissette, G, Ghannoum, M: Availability and cost of extracorporeal treatments for poisonings and other emergency indications: a worldwide survey. Nephrol Dial Transplant, 32: 699-706, 2017. 3. Lavergne, V, Nolin, TD, Hoffman, RS, Robert, D, Gosselin, S, Goldfarb, DS, Kielstein, JT, Mactier, R, MacLaren, R, Mowry, JB, Bunchman, TE, Juurlink, D, Megarbane, B, Anseeuw, K, Winchester, JF, Dargan, PI, Liu, KD, Hoegberg, LC, Li, Y, Calello, D, Burdmann, EA, Yates, C, Laliberte, M, Decker, BS, Mello-Da-Silva, CA, Lavonas, E, Ghannoum, M: The EXTRIP (Extracorporeal Treatments In Poisoning) workgroup: Guideline methodology. Clin Toxicol, 50: 403-413, 2012. 4. Guyatt, GH, Oxman, AD, Vist, GE, Kunz, R, Falck-Ytter, Y, Alonso-Coello, P, Schunemann, HJ, Group, GW: GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ, 336: 924-926, 2008. 5. Schunemann, HJ, Oxman, AG: Handbook for grading the quality of evidence and the strength of recommendations using the GRADE approach. Hamilton, ONT, 2020. 6. Andrews, JC, Schunemann, HJ, Oxman, AD, Pottie, K, Meerpohl, JJ, Coello, PA, Rind, D, Montori, VM, Brito, JP, Norris, S, Elbarbary, M, Post, P, Nasser, M, Shukla, V, Jaeschke, R, Brozek, J, Djulbegovic, B, Guyatt, G: GRADE guidelines: 15. Going from evidence to recommendation-determinants of a recommendation's direction and strength. J Clin Epidemiol, 66: 726-735, 2013.

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