Valproic acid poisoning: An evidence-based consensus guideline for out-of-hospital management

Figures & data

Table 1. Oral dosage forms of valproic acid marketed in the US (2,83)

Generic name	Trade name	Dosage forms
Valproic acid	Depakene	250 mg capsule
Valproic acid		250 mg capsule
		250 mg extended-release capsule
Valproic acid (as the sodium salt)	Depakene	250 mg/5 mL syrup
Valproic acid (as the sodium salt)		250 mg/5 mL syrup
Divalproex sodium	Depakote	125, 250, 500 mg (valproic acid equivalent) delayed-release tablets
		125 mg (valproic acid equivalent) sprinkle delayed-release capsule
Divalproex sodium	Depakote ER	250 mg (valproic acid equivalent) extended-release tablet
		500 mg (valproic acid equivalent) extended-release tablet

Table 2. Published valproic acid poisoning cases in patients less than 6 years of age

Age	Estimated dose	Reported effects	Onset*	Ref.
3 yr	38.5 mg/kg valproic acid	Ataxia, coma, miosis, respiratory depression. Responded to naloxone (mental status improved).; recovered	NR	8
19 mo	205 mg/kg valproic acid	Lethargy, irritability, coma, miosis; became alert after naloxone; Recovered	< 45 min	40
26 mo	375 mg/kg divalproex	Obtunded, limp, cyanosis, apnea, tachycardia, hypotension, tachypnea, acidosis; no response to naloxone; recovered	4 hr	9
15 mo	400 mg/kg valproic acid	Coma; recovered	< 2 hr	20
16 mo	412 mg/kg valproic acid	Abnormal breathing, coma, hypertension, tachycardia, shallow respirations, hyperglycemia, acidosis, increased CK; recovered	2 hr	37
20 mo	937.5 mg/kg sodium valproate	Coma, areflexia, miosis, respiratory depression, cyanosis; died	45–75 min	38
20 mo	938 mg/kg sodium valproate	Coma, respiratory depression, areflexia, acidosis, hypernatremia, hyperosmolarity, hypocalcemia, leucopenia, bacterial pneumonia; died 46 hours after ingestion	NR	84
23 mo	513 mg/kg sodium valproate	Drowsy; recovered	Several hr	39
18 mo	20–60 tablets of valproic acid, unreported strength	Lethargy, tachycardia, hypotension, acidosis, hypocalcemia, hypoglycemia, increased ammonia, cerebral edema, increased liver function tests, bone marrow suppression; recovered	< 2 hr	35
3 yr	Unknown amount of divalproex	Unresponsive, grunting respirations, seizures, tachycardia, mydriasis, dusky and cool extremities, methemoglobinemia (39%), increased amylase; recovered	< 6 hr	14
4 yr	Unknown amount of valproic acid	Coma, hypotension, bruising, increased ammonia, increased transaminases and CK, bone marrow suppression; recovered	< 22 hr	85
5 yr	Unknown amount of sodium valproate	Lethargy, seizures, hypernatremia, acidosis; recovered	NR	11

*NR = not reported.

Table 3. Published acute valproic acid poisoning cases with dose information in patients 6 years of age and older

Age (yr)	Estimated dose	Reported effects	Onset*	Ref.
19	1200 mg sodium valproate and 1500 mg aspirin	Coma, tachypnea, stridor, hypothermia, hyporeflexia, increased BUN, creatinine, AST, LDH andPT/PTT ratio, acidemia, cerebral edema	NR	55
22	5 g valproic acid	Somnolent, respiratory depression, pinpoint pupils; responded to naloxone	< 6 hr	7
22	8 g sodium valproate enteric-coated	Coma, apnea, bradycardia, hypotension, hypoglycemia, hypothermia, acidosis, elevated CK, atrial fibrillation	< 15 hr	68
19	18 g (409 mg/kg) valproic acid	Coma, leukocytosis, hypertension, hyperammonemia, hypoglycemia, acidosis	< 6 hr	61
NR	18 g sodium valproate	Coma, hyperammonemia, increased lipase	NR	23
29	18 g valpromide*	Coma, respiratory depression	NR	66
43	19 g divalproex delayed-release	Coma, hypotension, hypothermia, thrombocytopenia, acidosis, hyperlactatemia, aspiration pneumonia	NR	52
15	20 g (330 mg/kg) valproic acid	Coma, areflexia, repiratory depression, tachycardia, hypotension, acisosis, hyperglycemia, hypernatremia, leucopenia, cerebral edema, death	< 5 hr	69
19	20 g valproic acid extended-release	Lethargy, tachycardia, hypertension, hyperammonemia, dilated pupils, cerebral edema, brain herniation, death	< 90 min	47
21	22.5 g sodium valproate	Coma, cardiovascular depression	NR	34
NR	24 g sodium valproate	Coma, respiratory depression, hyperammonemia	NR	23
48	25 g sodium valporate enteric-coated	Coma, elevated AST, hypophosphatemia	< 4 hr	58
21	25 g valproic acid	Tachycardia, acidosis, coma, dry hot skin, respiratory depression	< 3 hr	65
60	30 g (430 mg/kg) valproic acid	Coma, mydriasis, hypotension, acidosis, hyperlactatemia	< 4 hr	46
32	30 g divalproex delayed-release	Elevated bilirubin and AST, coma, thrombocytopenia	4½–8 hr	50
NR	30 g sodium valproate	Hyperammonemia, increased lipase	NR	23
35	30 g valproic acid	Lethargy, coma, respiratory failure, hemodynamic instability; treated with dialysis	< 3 hr	43
15	30 g valproic acid	Drowsiness, trismus	NR	45
16	30 g valproic acid	Soporous, frequent ectopic beats on EKG	< 6 hr	53
26	30 g valproic acid	Coma, acute-on-chronic renal failure, hyperammonemia, aspiration pneumonia, thrombocytopenia	< 8 hr	56
15	30 g valproic acid “slow release”	“abnormal neurologic and liver function”	NR	70
29	36 g valpromide^†	Coma, hyperammonemia, thrombocytopenia, elevated ALT and CK, respiratory depression	< 44 hr	66
38	45 g divalproex	Confused, restless, lethargic, acidosis, respiratory depression	> 1 hr	57
18	45 g sodium valproate	Drowsy, lethargic, irritable, hypernatremai, elevated transaminases, CPK, ammonia. Leucopenia, acidosis	< 5 hr	59
48	48 g sodium valproate	Coma, hypotension, acidosis, thrombocytopenia	< 5½ hr	54
41	50 g divalproex extended release	Lethargy, hypertension	2 hr	51
NR	50 g sodium valproate	Coma, hyperammonemia	NR	23
28	51.5 g valproic acid	Found dead	Unk	67
19	52 g valproic acid	Coma, respiratory failure, EEG abnormalities, aspiration pneumonia, elevated creatinine and transaminases, anemia, thrombocytopenia, cerebral edema	NR	44
15	60 g (1016 mg/kg) valproic acid	Coma, areflexia, hypotension, hypothermia, atrial tachycardia, respiratory alkalosis, metabolic acidosis, hypernatremia, hypochloremia, hyperammonemia, elevated CK, thrombocytopenia	< 20 hr	62
NR	60 g sodium valproate	Drowsy, coma, respiratory arrest, hyperammonemia, pancreatitis, circulatory failure, cerebral edema, cardiac arrest, death	< 6 hr	23
36	60 g valproic acid sustained release	Somnolence, depressed respirations, hypoxia, seizures, cerebral edema	NR	64
34	65 g valproic acid enteric-coated	Found dead at home	Unk	60
17	75 g sodium valproate	Seizure, EEG abnormalities, thrombocytopenia, increased amylase and LDH; hemodialysis	NR	49
20	75 g valproic acid enteric-coated	Coma, respiratory depression, EEG abnormalities, cerebral edema, pancreatitis, hyperammonemia	<4 hr	19
31	105 g (1180 mg/kg) divalproex delayed-release	Coma, poor ventilation, pinpoint pupils, anion gap acidosis, hypotension, bradycardia, thrombocytopenia, aspiration pneumonia; hemodialysis	NR	48
29	160 g valproic acid	Coma, respiratory depression, hypotension, acidosis, elevated transaminases, elevated PT, hypernatremia, hypocalcemia, thrombocytopenia and leucopenia	NR	63
15	38 tablets of divalproex sodium delayed-release	Acting strange, abdominal pain, dizziness, weakness,chest pain, ataxia, nystagmus, hypertension, hyperammonemia	<4 hr	71

*N = not reported.

^†Valpromide is a valproic acid prodrug not available in the US.

Table

Grade of Recommendation	Level of Evidence	Description of Study Design
A	1a	Systematic review (with homogeneity) of randomized clinical trials
	1b	Individual randomized clinical trials (with narrow confidence interval)
	1c	All or none (all patients died before the drug became available, but some now survive on it; or when some patients died before the drug became available, but none now die on it.)
B	2a	Systematic review (with homogeneity) of cohort studies
	2b	Individual cohort study (including low quality randomized clinical trial)
	2c	“Outcomes” research
	3a	Systemic review (with homogeneity) of case-control studies
	3b	Individual case-control study
C	4	Case series, single case reports (and poor quality cohort and case control studies)
D	5	Expert opinion without explicit critical appraisal or based on physiology or bench research
Z	6	Abstracts

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