Extracorporeal treatment for ethylene glycol poisoning: systematic review and recommendations from the EXTRIP workgroup

Ghannoum, Marc; Gosselin, Sophie; Hoffman, Robert S.; Lavergne, Valery; Mégarbane, Bruno; Hassanian-Moghaddam, Hossein; Rif, Maria; Kallab, Siba; Bird, Steven; Wood, David M.; Roberts, Darren M.

doi:10.1186/s13054-022-04227-2

Table 7 Evidence profile table: ECTR + standard care compared to standard care in patients with “early” ethylene glycol poisoning^#

From: Extracorporeal treatment for ethylene glycol poisoning: systematic review and recommendations from the EXTRIP workgroup

Certainty assessment							Summary of findings				Importance
№ of studies	Study design	Risk of bias	Inconsistency	Indirectness	Imprecision	Other considerations	ECTR + standard care*	Standard care (controls)	Impact	Certainty
Inpatient mortality
Early EG poisoning n = 2 ^a	Observational studies	Very serious^b	Not serious	Serious^c	Serious^d	Publication bias strongly suspected^e	This systematic review: 3.6%	Fomepizole: 0.0% [358]	No reduction with ECTR	VERY LOW	CRITICAL
								Ethanol: 0.0% [358]	No reduction with ECTR
								No antidote: Expected high	Very probable reduction with ECTR
Dialysis dependence at 3 months
Early EG poisoning n = 2 ^a	Observational studies	Very serious ^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	This systematic review: 1.2%	Fomepizole: 0% [358]	No reduction with ECTR	VERY LOW	CRITICAL
								Ethanol: 0% [358]	No reduction with ECTR
								No antidote: Expected high	Probable reduction with ECTR
Irreversible neurological damage
Early EG poisoning n = 2 ^a	Observational studies	Very serious ^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	This systematic review: 0%	Fomepizole: 0% [358]	No reduction with ECTR	VERY LOW	CRITICAL
								Ethanol: 0% [358]	No reduction with ECTR
								No antidote: Expected high	Probable reduction with ECTR
AKI requiring short-term dialysis
Early EG poisoning n = 2 ^a	Observational studies	Very serious ^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	This systematic review: 15.5%	Fomepizole: 0.0% [358]	No reduction with ECTR	VERY LOW	CRITICAL
								Ethanol alone: 3.8% [358]	No reduction with ECTR
								No antidote: Expected high	Probable reduction with ECTR
Length of ICU stay
Early EG poisoning n = 1 ^f	Observational studies	Very serious ^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	This systematic review: Median 5 days [2, 8]	Fomepizole: Theoretically, ICU admission not needed	No reduction with ECTR	VERY LOW	IMPORTANT
								Ethanol: requires ICU admission and this would be prolonged	Data incomplete
								No antidote: Expected high	Probable reduction with ECTR
Length of hospital stay
Early EG poisoning n = 2 ^a	Observational studies	Very serious^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	This systematic review: Median 8 days [2, 15]	Fomepizole: Median 4 days [3, 5] [358]	No reduction with ECTR	VERY LOW	IMPORTANT
								Ethanol: Median 3 days [2,4] [358]	No reduction with ECTR
								No antidote: Expected high	Probable reduction with ECTR
Cost
Early EG poisoning n = 8^g	Observational studies	Very serious^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	Fomepizole: varies (See Table 6) [107,108,109,110,111, 227, 355, 427]	Fomepizole: varies (See Table 6) [107,108,109,110,111, 227, 355, 427]	Analyses and/or reporting incomplete. Cost of ECTR and fomepizole vary across countries and across institutions. HD appears cost-effective in smaller patients and high EG concentration	VERY LOW	IMPORTANT
							Ethanol: data incomplete (see Table 6) [227, 355]	Ethanol: No data	Data incomplete
							No antidote: No data	No antidote: No data	No data
Serious complications of catheter insertion ^h
n = 5 ⁱ	Observational studies	Not serious	Not serious ^j	Not serious ^k	Not serious ^l	Strong association ^m	Rate of serious complications of catheter insertion varies from 0.1% to 2.1%	≈ 0	Absolute effect is estimated to be varying from 1 to 21 more serious complications per 1000 patients in the ECTR group	MODERATE	CRITICAL
Serious complications of ECTR ⁿ
n = 6 ^o	Observational studies	Not serious	Not serious	Not serious	Not serious	Strong association ^p	Rate of serious complications of ECTR varies according to the type of ECTR performed from 0.005% (HD and CKRT), to 1.9% (HP)	≈ 0	Absolute effect is estimated to be varying from > 0 to 19 more serious complications per 1000 patients in the ECTR group depending on the type of ECTR performed	MODERATE	CRITICAL
Complications related to antidote
n = 7 ^q	Observational studies	Very serious^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	Fomepizole: Rare cases of anaphylaxis, bradycardia, hypotension [68, 428,429,430,431,432]		Smaller incidence with ECTR but minimal impact	VERY LOW	IMPORTANT
n = 7 ^q	Observational studies	Very serious^b	Not serious	Serious ^c	Serious ^d	Publication bias strongly suspected ^e	Ethanol: Altered consciousness in 5–15%, occasionally requiring mechanical ventilation [68, 431, 432], hypoglycemia in 16% of children [433], bradycardia in 10–12% [431, 432]		Smaller incidence with ECTR because of shorter duration of ethanol and lower risk of hypoglycemia because of dextrose in dialysate bath	VERY LOW	IMPORTANT

Bold text was inserted to highlight the result
ECTR Extracorporeal treatments, HD Hemodialysis, CKRT Continuous kidney replacement therapy, HP Hemoperfusion, US Ultrasound, ICU Intensive care unit
^#Refers to patients with a glycolate concentration ≤ 12 mmol/L or an anion gap with potassium ≤ 28 mmol/L. As mentioned, an evidence profile table could not be constructed for patients with “late” ethylene glycol poisoning, i.e., those with a serum glycolate over 12 mmol/L, or an anion gap over 28 mmol/L, although ECTR would be considered lifesaving in this context
^* Cases of ECTR were regrouped regardless of antidote used
a. Includes our systematic review of the literature on ECTR (181 case reports and 446 patients, 84 of which had “Early EG poisoning”) and 1 systematic review on standard care alone
b. Case reports published on effect of ECTR. Uncontrolled and unadjusted for confounders such as severity of poisoning, co-ingestions, supportive and standard care, and co-interventions. Confounding-by-indication is inevitable since ECTR was usually attempted when other therapies have failed
c. ECTR and standard care performed may not be generalizable to current practice (literature pre-dating 2000)
d. Few events in small sample size, optimal information size criteria not met
e. Publication bias is strongly suspected due to the study design (case reports published in toxicology)
f. Includes our systematic review of the literature on ECTR 181 case reports (446 patients, 84 of which had “Early EG poisoning”)
g. Includes 8 articles
h. For 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. DVT and infection complications were not included considering the short duration of catheter use
i. Based on 5 single-arm observational studies: 2 meta-analyses comparing serious mechanical complications associated with catheterization using or not an ultrasound, which included 6 RCTs in subclavian veins [434] and 11 in internal jugular veins [435]; 2 RCTs comparing major mechanical complications of different sites of catheterization [436, 437]; and one large multicenter cohort study reporting all mechanical complications associated with catheterization [438]. Rare events were reported from case series and case reports
j. Not rated down for inconsistency since 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 methodological quality of studies
k. Not rated down for indirectness since cannulation and catheter insertion was judged similar to the procedure for other indications
l. Not rated down for imprecision since wide range reported explained by inconsistency
m. The events in the control group are assumed to be zero (since 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%CI which included the null value and all observed complications occurred in a very short time frame (i.e., few hours)
n. For HD and CKRT: 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 hemolysis. Transient hypotension, hypoglycemia, hypocalcemia, and thrombocytopenia were judged not serious
o. HD/CKRT: Based on 2 single-arm studies describing severe adverse events per 1000 treatments in large cohorts of patients [439, 440]. HP: Based on 2 small single-arm studies in poisoned patients [441, 442]. Rare events were reported in case series and case reports
p. Assuming 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%CI which included the null value and all observed complications occurred in a very short time frame (i.e., few hours)
q. Includes seven observational cohorts of patients receiving ethanol or fomepizole

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