Treating ethylene glycol poisoning with alcohol dehydrogenase inhibition, but without extracorporeal treatments: a systematic review

Figures & data

Figure 1. Flow diagram (February 24^th, 2021). ECTR: extracorporeal treatment; ADH: Alcohol dehydrogenase; EG: ethylene glycol.

Table 1. Characteristics of included cases with case-level data.

	Cases identified
	Either antidote		Ethanol alone		Fomepizole alone
	All cases (n = 411)	Only 1 case per patient (n = 333)	All cases (n = 180)	Only 1 case per patient (n = 165)	All cases (n = 231)	Only 1 case per patient (n = 168)
Age (years)
Median	30 [27,45]	37 [23, 48]	32 [23,47]	35 [22, 48]	29 [29, 43]	37 [25, 48]
Range	0.5 to 95	0.5 to 95	1 to 95	1 to 95	0.5 to 86	0.5 to 86
Sex (Male)	52%	67%	73%	80%	35%	52%
EG dose (mL, equivalent of 100% EG solution)
Median	80 [30, 350]	73 [30, 205]	50 [30, 100]	50 [30, 100]	490 [139, 1000]	350 [100, 500]
Range	10 to 3800	10 to 3800	10 to 2250	10 to 2250	17 to 3800	17 to 3800
Time from exposure to health care facility arrival (hours)
Median	3 [1, 7.5]	3 [1, 8]	2 [1, 6]	2 [1,6]	5 [3, 9]	5 [2.5, 10]
Range	0.3 to 120	0.3 to 120	0.3 to 60	0.3 to 60	0.5 to 120	0.5 to 120
Ethanol co-ingestion? (Yes)	32%	35%	35%	39%	30%	34%
Time from arrival to health care facility to antidote administration (hours)
Median	2 [1, 4]	2 [1, 4]	2 [1, 4]	2 [1, 4]	2 [2, 4]	2 [2, 4]
Range	0 to 48	0 to 48	0 to 24	0 to 24	0 to 48	0 to 48
Initial EG concentration (mmol/L) $
Median	13.9 [3.1, 42]	9.4 [2.3, 24]	4.7 [1.5, 13]	3.9 [1.5, 10]	22 [8.5, 56]	15 [5.7, 34]
Range	0.2 to 258	0.2 to 258	0.2 to 135	0.2 to 135	0.2 to 258	0.2 to 258
Blood pH*
Median	7.34 [7.24,7.39]	7.35 [7.27, 7.40]	7.35 [7.24, 7.40]	7.35 [7.23, 7.40]	7.33 [7.26, 7.38]	7.35 [6.77, 7.47]
Range	6.60 to 7.54	6.60 to 7.54	6.60 to 7.54	6.60 to 7.54	6.77 to 7.49	6.77 to 7.47
Anion gap (mmol/L)*
Median	21 [15, 28]	19 [15, 25]	22 [15, 31]	20 [14, 31]	21 [16, 27]	19 [15, 24]
Range	4 to 49	4 to 46	6 to 46	6 to 46	4 to 49	4 to 45
Serum HCO3^- concentration (mmol/L)*
Median	18 [10, 23]	20 [10, 24]	20 [10, 24]	21 [11, 24]	16 [10, 22]	18 [10, 23]
Range	1 to 35	1 to 35	2 to 35	2 to 35	1 to 31	1 to 31
Base excess (mmol/L)*
Median	−14 [−7, −21]	−23 [−14, −29]	−18 [−7, −29]	−25 [−13, −30]	−11 [−7, −17]	−21 [−14, −26]
Range	0.9 to −39	0.9 to −39	0.9 to −39	0.9 to −39	0.8 to −28	−1 to −26
Serum creatinine concentration (µmol/L)*&
Median	78 [65, 97]	80 [69, 97]	80 [70, 96]	80 [70, 97]	71 [62, 97]	79 [62, 97]
Range	18 to 298	18 to 298	24 to 298	24 to 298	18 to 235	18 to 235
Length of stay (days)
Median	3 [2, 5]	4 [3, 6]	4 [2, 6]	4 [3, 10]	3 [2, 5]	4 [3, 6]
Range	1 to 28	1 to 28	1 to 28	1 to 28	1 to 18	1 to 18
Acute kidney injury (Yes)**	9.2%	11.4%	14.0%	15.3%	5.1%	7.2%
Received extracorporeal treatments as rescue therapy (Yes)	7.3%	9.2%	9.4%	10.6%	5.2%	7.8%
Neurological worsening (Yes)	6.2%	8.4%	15.8%	17.7%	2.8%	3.9%
Death (Yes)	4.9%	6.0%	9.4%	10.3%	1.3%	1.8%
Treatment failure (Yes)	12.2%	15.3%	16.7%	18.8%	8.7%	11.9%

*Value preceding the initiation of ADH inhibition.

**Defined as KDIGO stage 2 or 3 acute kidney injury (increase in serum creatinine concentration >2.0 times, urine output <0.5 mL/kg/h for ≥12 h).

$To convert ethylene glycol concentration from mmol/L to mg/dL, multiply by 6.2.

& To convert serum creatinine from µmol/L to mg/dL, divide by 88.4.

Medians are presented with first and third quartiles; EG: ethylene glycol.

When values were reported as “normal” they were interpreted as pH = 7.40, HCO₃⁻ concentration = 25 mmol/L, anion gap =14 mmol/L, age-expected creatinine concentration.

Table 2A. Comparison of characteristics with or without ADH inhibitor treatment failure (all included cases).

	Ethanol					Fomepizole
	Treatment failure (n = 30)		No treatment failure (n = 150)		P-value	Treatment failure (n = 20)		No treatment failure (n = 211)		P-value
	N	Median, IQR	n	Median, IQR		n	Median, IQR	N	Median, IQR
Age (Years)	27	45 [29, 57]	136	31 [20, 44]	0.003	20	35 [16, 45]	205	29 [29, 43]	NS (1.0)
Gender (Male)	27	70%	135	73%	NS (0.8)	20	65%	203	32%	0.001
EG dose (mL equivalent of 100% EG solution)	11	207 [125, 425]	96	30 [30, 100]	0.0002	6	150 [94, 2288]	36	500 [184, 1000]	NS (0.6)
Time from EG exposure to presentation to health care facility (h)	19	6 [3.8, 8.5]	117	1.5 [1, 4.5]	0.0002	8	3 [3, 13]	88	5 [3, 9]	NS (0.7)
Ethanol co-ingestion? (Yes)	16	50%	64	31%	NS (0.1)	19	16%	156	32%	NS (0.2)
Time from presentation to antidote (h)	5	10 [6, 18]	12	1 [0.5, 2]	0.02	8	3.5 [1.7, 4.5]	31	2 [2, 4]	NS (0.6)
Initial EG concentration (mmol/L)$	16	9.5 [5.5, 22.3]	108	4.1 [1.4, 12.5]	0.04	19	12.4 [4.3, 37]	204	24.6 [9.3, 56]	NS (0.3)
Blood pH*	29	6.96 [6.73, 7.19]	134	7.37 [7.31, 7.40]	<0.00001	19	7.20 [7.01, 7.33]	159	7.34 [7.27, 7.38]	0.0008
Anion gap (mmol/L)*	11	34 [33, 37]	45	20 [13, 25]	0.0002	16	34 [22, 39]	152	20 [15, 25]	0.001
HCO3^−, concentration (mmol/L)*	24	6 [3, 10]	102	22 [17, 24]	<0.00001	13	8 [4, 11]	116	17 [11, 22]	0.0004
Base excess (mmol/L)*	13	−32 [−25, −36]	29	−14 [−6, −21]	0.0006	7	−21 [−15, −25]	63	−11 [−7, −16]	0.004
Creatinine concentration (µmol/L)*&	18	130 [77, 180]	109	80 [69, 96]	0.0005	16	101 [77, 126]	154	71 [62, 90]	0.007

Table 2B. Comparison of characteristics with or without ADH inhibitor treatment failure (1 case per patient).

	Ethanol					Fomepizole
	Treatment failure (n = 30)		No treatment failure (n = 135)		P-value	Treatment failure (n = 20)		No treatment failure (n = 148)		P-value
	n	Median, IQR	N	Median, IQR		n	Median, IQR	N	Median, IQR
Age (Years)	27	45 [29, 57]	121	34 [17, 47]	0.005	20	35 [16, 45]	142	38 [26, 48]	NS (0.9)
Gender (Male)	27	70%	120	83%	NS (0.2)	20	65%	140	56%	NS (0.5)
EG dose (mL equivalent of 100% EG solution)	11	207 [125, 425]	88	30 [30, 100]	0.0001	6	150 [94, 2288]	29	400 [100, 500]	NS (0.8)
Time from EG exposure to presentation to health care facility (h)	19	6 [3.8, 8.5]	111	1.5 [1, 4.3]	0.0002	8	3 [3, 13]	73	5 [2.5, 10]	NS (0.7)
Ethanol co-ingestion? (Yes)	16	50%	56	34%	NS (0.3)	19	16%	140	36%	NS (0.1)
Time from presentation to antidote (h)	5	10 [6, 18]	12	1 [0.5, 2]	0.02	8	3.5 [1.7, 4.5]	31	2 [2, 4]	NS (0.6)
Initial EG concentration (mmol/L)	16	9.5 [5.5, 22.3]	95	2.7 [1.2, 8.3]	0.007	19	12.4 [4.3, 37]	145	16 [5.8, 34]	NS (0.9)
Blood pH*	29	6.96 [6.73, 7.19]	120	7.37 [7.32, 7.40]	<0.00001	19	7.20 [7.01, 7.33]	102	7.36 [7.31, 7.40]	0.0001
Anion gap (mmol/L)*	11	34 [33, 37]	36	17 [13, 22]	0.00008	16	34 [22, 39]	123	19 [15, 23]	0.0009
HCO3^−, concentration (mmol/L)*	24	6 [3, 10]	89	23 [19, 25]	<0.00001	13	8 [4, 11]	56	20 [11, 25]	0.0002
Base excess (mmol/L)*	13	−32 [−25, −36]	15	−19 [−7, −29]	0.009	7	−21 [−15, −25]	4	−13 [−2, −24]	NA**
Creatinine concentration (µmol/L)*	18	130 [77, 180]	93	80 [70, 96]	0.0006	16	101 [77, 126]	107	75 [62, 97]	0.02

Medians are presented with first and third quartiles, EG, ethylene glycol.

*Prior to ADH inhibition.

$To convert ethylene glycol concentration from mmol/L to mg/dL, multiply by 6.2.

& To convert serum creatinine from µmol/L to mg/dL, divide by 88.4.

NA** Mann U-test not calculable since less than 5 observations in one group.

Table 3. Cohorts of patients receiving fomepizole or ethanol.

Cohort	Full cohort (n)	EG patients treated with ethanol or fomepizole as monotherapy (n)	Co-exposure of ethanol	Antidote given	EG concentration (mmol/L)$	Acid-base status	Kidney function	Notes
[134]	14	3	NR	Ethanol	NR	NR	NR	1 died before receiving ECTR. 2 survived. No other details.
[135]	15	3	NR	Ethanol	NR	No acidemia	No AKI	Ingested ≤ 100 mL EG, symptoms were slight. No deaths
[136]	170 (only those ingesting concentrated EG)	58	NR	Ethanol	NR	NR	50% AKI	54/58 survived. 4 died while being prepared for ECTR. No data on these.
[137,167]	36	7	NR	Ethanol	19, 19, and 10 in 3 patients	NR	NR	2/7 patients died: 1 had poor clinical status that prevented hemodialysis and died within 24 h, the other within 48 h from therapy-resistant hypotension.
[138]	20 (symptomatic patients only)	20	NR	Ethanol	NR	NR	NR	No deaths
[139]	75	19	NR	Ethanol	<8.1	pH > 7.0	No AKI	All survived. All presented early and/or had small ingestions,
[140]	34	2	NR	Ethanol	NR	No acidemia	NR	Both survived
[141]	24 toxic alcohols (18 EG)	≥10	NR	Fomepizole	2.6 [1.0;11.3] Max 53.5	NR	NR	Results mixed with methanol cohort. Outcomes unclear. 1 patient died out of 24. Length of stay 2 [1–3] days in those with EG poisoning receiving oral fomepizole
[142]*	24	24	29%	88% fomepizole, 10% fomepizole + ethanol, 2% fomepizole and isopropanol	All over 8.1 Mean 22.2 ± 15.7 (range 8.4–69.1)	Mean pH 7.32 Mean HCO3^− 22 mmol/L	Mean peak creatinine concentration = 123 µmol/L&	Good evolution in all patients, no progression of acidemia, no death
[143]	68	NR	NR	Fomepizole (all misdosed)	NR	NR	NR	No progression of acidemia in all
[144]*	14 (unintentional)	13	NR	46% fomepizole, 23% ethanol, 8% both	All <4.8	NR	NR	Good outcome
[145]*	29 toxic alcohols (mixed) all < 18 y	18	0%	Fomepizole	<6.0	3 in whole cohort had pH = 7.30–7.34. 3 in whole cohort had AG = 20–23 mmol/L. Others normal	Normal in all	Favorable outcome in all
[146]	32	≤4	NR	Ethanol	NR	NR	NR	No deaths. Baseline characteristics of EG and methanol cases mixed together.
[147]	174	78	NR	Ethanol or fomepizole	NR	NR	NR	21 died. No other data on those 78 patients and why they were not dialyzed.
[114]	38 children (methanol and EG)	27	NR	Fomepizole	NR	NR	NR	No patient received ECTR. Outcome was favorable in all. No sequelae.
[148]	2	1	NR	Ethanol	NR	NR	NR	Discharged within 24 h. Good outcome. LOS = 1 day
[149]*	113 (all unintentional)	104	NR	67% fomepizole, 4% ethanol	All ≤6.8	NR	NR	No deaths, 12 moderate effect, 3 major effect
[150]*	56	28	NR	Unclear	NR	HCO3^− <22 mmol/L	Creatinine concentration  > 88 µmol/L&	8/28 died. No data presented. Unclear if patients were meant to be dialyzed. Death more likely if pH < 7.05, coma or AKI. No CKD in survivors
[151]	59	34	NR	All cohort: 90% fomepizole, 5% ethanol	Mean: 20.3, range 0.8–134.5	Mean 7.28 Range 6.60–7.52	Mean creatinine concentration: 109 µmol/L, range 26–431&	1 death. EG concentration = 42.9 mmol/L, unclear if received ECTR

*Conference abstract.

$To convert ethylene glycol concentration from mmol/L to mg/dL, multiply by 6.2.

& To convert serum creatinine from µmol/L to mg/dL, divide by 88.4.

AKI: Acute kidney injury; EG: Ethylene glycol; ECTR: Extracorporeal treatment; AG: Anion gap; LOS: Length of stay; NR: Not reported.

Table 4. Baseline features, treatment and outcomes relative to the admission anion gap.

	All		Anion gap < 24 mmol/L		Anion gap 24–28 mmol/L		Anion gap > 28 mmol/L
	All cases (n = 207)	1 case/patient (n = 171)	All cases (n = 132)	1 case/patient (n = 119)	All cases (n = 24)	1 case/patient (n = 16)	All cases (n = 51)	1 case/patient (n = 36)
Age (years)	31 [27, 45]	35 [23, 48]	34 [27, 45]	37 [27, 46]	29 [26, 41]	28 [17, 52]	29 [28, 44]	35 [17, 51]
Sex (male)	44%	55%	50%	56%	18%	29%	43%	63%
EG dose (mL equivalent of 100% EG solution)	300 [100, 838]	207 [100, 500]	300 [100, 613]	300 [100, 613]	138 [69, 238]	138 [69, 238]	500 [200, 1125]	200 [175, 354]
Time from exposure to presentation (h)	4 [2, 7]	4 [2, 7]	3.5 [2, 6]	3.5 [1.5, 6.5]	4 [2.5, 6]	4 [2.3, 8]	6 [3.5, 10]	6 [3.3, 13]
Ethanol co-ingestion? (Yes)	32%	35%	39%	40%	12%	17%	20%	26%
Time from presentation to antidote (h)	2 [1, 4]	2 [1, 4]	2 [0.5, 3]	2 [0.5, 3]	3 [2, 4]	3 [2, 4]	4 [2, 8]	4 [2, 8]
Initial EG concentration (mmol/L)*$	19 [6.7, 56]	16 [4.8, 37]	17 [5.9, 45]	16 [4.4, 33]	33 [16, 56]	22 [12, 34]	25 [8.2, 59]	13 [3.1, 53]
Anion gap (mmol/L)*	21 [15, 28]	19 [15, 25]	18 [14, 20]	17 [14, 20]	26 [25, 27]	25 [24, 27]	33 [31, 39]	34 [31, 40]
Creatinine concentration (µmol/L)*&	79 [66, 97]	80 [68, 97]	74 [63, 90]	79 [65, 95]	74 [66, 84]	80 [70, 95]	91 [70, 114]	99 [72, 124]
Treated with ethanol alone (Yes)	22%	22%	20%	19%	25%	31%	25%	25%
Treated with fomepizole alone (Yes)	78%	78%	80%	81%	75%	69%	75%	75%
Death (Yes)	1.9%	2.3%	0.0%	0.0%	0.0%	0.0%	7.8%	11.1%
Stage 2 or 3 AKI (Yes)	7.2%	8.9%	1.6%	1.8%	4.2%	6.3%	23.4%	34.4%
Needed extracorporeal treatments as rescue therapy (Yes)	8.5%	10.9%	0.0%	0.0%	5.6%	10%	27.7%	40.6%

*Value preceding the initiation of ADH inhibition.

$To convert ethylene glycol concentration from mmol/L to mg/dL, multiply by 6.2.

& To convert serum creatinine from µmol/L to mg/dL, divide by 88.4.

AKI is defined as KDIGO stage 2 or 3 acute kidney injury (increase in serum creatinine concentration >2.0 times, urine output <0.5 ml/kg/h for ≥12 h).

Data are presented as medians with first and third quartiles.

N: number of cases; AKI: acute kidney injury; EG: ethylene glycol.

Figure 2. Relationship between anion gap and the risk of acute kidney injury or death in patients treated with ADH blockade but without extracorporeal treatments.

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