Demographics characteristics of study population.
Abstract
We investigated the association between serum valproic acid (VPA) levels and clinical conditions in patients after acute intoxication with this drug. We performed a retrospective study of cases of VPA intoxications hospitalized in Toxicology Unit in Cracow in 2 years of observation. The study included 26 patients (age: 35.69 ± 12.93 years). In all patients, the VPA plasma level was higher than the therapeutic range, mean ± SD: 275.32 ± 135.97 μg/ml. About half of poisoned patients described in this report were treated with VPA prior to the poisoning. We noted four cases of mixed VPA intoxications with ethanol. Acute pulmonary failure was observed in two persons. The mean hospital stay for all patients was 4.69 days. This analysis demonstrates that increased serum VPA levels, in acute intoxication with this drug, were associated with the severity of poisoning — in PSS (P = 0.019) and in Matthews coma scale (P = 0.022), diastolic pressure (P = 0.022) and length of stay in hospital (P = 0.001). No correlation was detected between the serum VPA concentration and the heart rate and systolic blood pressure. In persons treated with VPA earlier, the course of poisoning was less severe, although these results were not statistically significant.
Keywords
- valproic acid
- acute intoxication
- clinical manifestations
- drug serum level
- toxicity
1. Introduction
Valproic acid (VPA) (and its derivatives) is a commonly used conventional antiepileptic drugs (AED) for pharmacotherapy in epileptic patients. VPA was introduced in 1978 as AED [1]. Valproic acid is characterized by multidirectional action that involves increased gamma-aminobutyric acid (GABA)-ergic transmission, reduced release and/or effects of excitatory amino acids, blockage of voltage gated sodium channels and modulation of dopaminergic and serotonergic transmission [2]. This drug is effective in patients with all types of seizures, and especially in those with idiopathic generalized epilepsy [3, 4]. It is also prescribed to treat bipolar and schizoaffective disorders, social phobias and neuropathic pain, as well as for prophylaxis and treatment of migraine headache [5–9]. Valproic acid is a fatty acid which is about 90% bound to plasma proteins and the main metabolic transformations of valproic acid take place in liver, including that of the cytochrome P-450. Valproic acid follows a non-linear pharmacokinetic profile in terms of protein-binding saturation [10]. Acute VPA intoxication also occurs as a consequence of suicidal or accidental overdose. VPA intoxication incidence is increasing [11–14], probably because of its use in psychiatric disorders. It usually results in mild and self-limited central nervous system depression. However, serious toxicity and even deaths have been reported [15, 16]. The therapeutic serum concentrations for VPA are 50–100 μg/ml [17, 18]. Monitoring VPA serum levels helps to evaluate therapeutic response, compliance and possible toxicity.
2. Aim
The aim of study was to evaluate plasma concentrations of VPA and the clinical symptoms of acute intoxication.
3. Materials and methods
We performed a retrospective study of all cases of VPA intoxications (
The level of consciousness was graded on a scale of 0–IV according to Matthew and Lawson coma scale. Matthew-Lawson coma scale of determining severity of coma: grade 0—fully conscious, alert; grade I—drowsy but responds to verbal command; grade II—unconscious patient but responds to minimal painful stimuli, reflexes intact; grade III—unconscious patient but responds to maximal painful stimuli, absence of superficial reflexes and sluggish deep reflexes; grade IV—unconscious patient with no response to painful stimuli, loss of all reflexes including corneal, laryngeal, pharyngeal. Grades III and IV are considered as severe grades of poisoning [19].
Severity of intoxication was classified according to Poisoning Severity Score (PSS). The PSS is a classification scheme for cases of poisoning in adults and children. The PSS grades severity as (0) none—no symptoms or signs related to poisoning, (1) minor—mild, transient and spontaneously resolving symptoms, (2) moderate—pronounced or prolonged symptoms, (3) severe—severe or life-threatening symptoms, and (4) fatal poisoning—death [20].
3.1. Statistical analysis
The data were collected in a Microsoft Excel database. Data are presented as mean and standard deviations. Statistical analysis of all data was performed by Statistica version 12 using the Pearson’s
4. Results
We studied episodes of hospitalization for VPA intoxication in 26 patients, of whom 9 were men (34.61%). The mean age was 35.69 ± 12.93 years (range: 18–73 years) (Table 1).
Characteristics |
|
---|---|
Gender | |
Female | 17 (65.39%) |
Male | 9 (34.61%) |
Total | 26 (100%) |
Age, years Range: 18–73 Mean ± SD: 35.69 ± 12.93 |
Half of the poisoned patients (50%) described in this report were treated with valproic acid due to epilepsy or psychotic disorders prior to the poisoning. These patients had a less severe clinical course of poison, although these results were not statistically significant (
The following intensity of quantitative consciousness disturbances according to Matthew’s scale was observed: grade 0—26.92%, I—26.92%, II—30.77%, and III—15.39%.
Parameters | ||
---|---|---|
Systolic blood pressure (SBP), mmHg | ||
Range | 100–160 | |
Mean ± SD | 127.15 ± 16.55 | |
Diastolic blood pressure (DBP), mmHg | ||
Range | 50–100 | |
Mean ± SD | 79.23 ± 12.25 | |
Heart rate (HR), beats/min | ||
Range | 58–122 | |
Mean ± SD | 88.46 ± 17.58 | |
Breath | ||
Competence of a respiration | 24 (92.31%) | |
Intubation | 2 (7.69%) | |
Matthew coma scale (MCS) | ||
Grade 0 | 7 (26.92%) | |
Grade 1 | 7 (26.92%) | |
Grade 2 | 8 (30.77%) | |
Grade 3 | 4 (15.39%) | |
Grade 4 | 0 (0%) | |
Poisoning severity score (PSS) | ||
Minor | 14 (53.85%) | |
Moderate | 7 (26.92%) | |
Severe | 5 (19.23%) | |
Ethanol, ‰ | ||
Range | 0–2.92 | |
Mean ± SD | 0.305 ± 0.77 | |
Yes | 4 (15.38%) | |
No | 22 (84.62%) | |
Co-morbidity | ||
Depression | 7 (26.92%) | |
Alcohol dependence syndrome | 4 (15.38%) | |
Personality disorder | 5 (19.23%) | |
Somatic disease | 3 (11.54%) | |
Bipolar disorder | 2 (7.69%) | |
Schizophrenia | 4 (15.38%) | |
Other mental disorder | 5 (19.23%) | |
Epilepsy | 9 (34.62%) | |
Length of stay in hospital, days | ||
Range | 2–13 | |
Mean ± SD | 4.69 ± 2.57 | |
Treatment effect | ||
Discharged from hospital in good condition | 17 (65.39%) | |
Discharged from hospital on a voluntary distractions | 7 (26.92%) | |
Referral to mental hospital/ward | 2 (7.69%) | |
Toxic valproic acid level, μg/ml | ||
Range | 110–660 | |
Mean ± SD | 275.32 ± 135.97 |
The serum VPA concentration showed moderate positive correlations with Matthew’s scale (
The minimal and maximal values of blood pressure were: 100–160 and 50–100 mmHg, respectively, for systolic and diastolic blood pressure; heart rate: 58–122 beats/min; breathing rate in non-intubated patients: 13–20 breaths/min.
Correlational analysis (Pearson’s
In the study population, no statistical correlation was found between the serum VPA concentration and the heart rate (
Severity of intoxication was classified according to poisoning severity score (PSS). The PSS was minor in 14 patients, moderate in 7 patients and severe in 5 patients.
A positive relationship between the decrease in number of PSS and the increasing VPA serum level was demonstrated (
A significant proportion of patients had comorbid mental health disorders (e.g. depression, personality disorders, schizophrenia, and bipolar disorder).
Only two patients were inefficient to breathe and they required intubation. No patients had arrhythmias and seizures.
Alcohol was co-ingested by four patients. The mean ethanol concentration was 0.305‰.
The mean length of hospital stay was 4.69 days. We observed strong correlation between the serum level of VPA and the number of days of stay in hospital (
Seventeen of these 26 patients were discharged to home in good condition and two to a psychiatric ward. There were no reported mortalities among the cases of VPA intoxications.
The mean of serum level of valproic acid was 275.32 ± 135.97 μg/ml.
The characteristics of clinical parameters are shown in Table 2.
5. Discussion
Despite the fact that valproic acid is an old generation antiepileptic drug, in the literature, there is little information about the case series of VPA overdose. However, there is a description of case reports of VPA intoxication [21–24].
In our study, a positive relationship between the decrease in number of PSS and the increasing VPA serum level was demonstrated (
Symptoms of VPA intoxication are diverse. The most common manifestation of overdose is central nervous system (CNS) depression [25, 26]. Other studies show that some patients have mild to moderate lethargy [13, 27]. It was noted that patients who ingest more than 200 mg/kg VPA and/or have plasma concentrations greater than 180 μg/ml usually develop severe CNS depression [28]. Taking VPA at higher doses (>400 mg/kg) is associated with serious consequences such as coma, cerebral oedema [29], metabolic acidosis, hyperammonemia, thrombocytopenia and leukopenia, and circulatory collapse [11, 30, 31]. The study by Spiller et al. [11] show that the concentration of VPA > 850 μg/ml was more likely to be associated with coma (
Other possible adverse effects of valproic acid on the nervous system include agitation, hallucinations, tremors, myoclonus and seizures [28].
In addition to generally known symptoms, valproic acid intoxication may also be associated with hypotension [32]. In this study, correlational analysis (
Other clinical findings include respiratory depression and acute respiratory distress syndrome [33, 34]. In the study by Tank et al. [35], all patients with serum levels higher than 850 μg/ml were comatose, and 63% of these patients needed intubation.
In our study, out of 26 patients, only two experienced respiratory depression and required intubations. The first patient was a 49-year-old man, reportedly poisoned intentionally, admitted to Toxicology Department. His valproate sodium serum concentration was 224.8 μg/ml. The serum level of other drugs and ethanol were all negative. He had a history of psychiatric illness, including personality disorder and alcohol dependence syndrome. His vital signs were as follows: pulse rate 115 beats/min, blood pressure 155/100 mmHg, temperature 36.6°C and respiratory insufficiency. On the day of admission, the patient was unconscious, in the third stage coma by Matthew’s scale, with features of overt respiratory failure. The patient was immediately intubated and connected to a respirator. After the first day the patient was extubated, had efficient breathing, but with persistent disturbances of consciousness, periodically extremely agitated and psychotic. Gradually, the patient's condition experienced an improvement. From the fifth day there was a logical, calm. When the serum levels returned to normal, the patient made a complete recovery. On the seventh day of treatment, after psychiatric review, the patient was discharged home in good condition. The second patient was a 24-year-old woman admitted to the Toxicology Department after attempting suicide by ingesting tablets of valproic acid. Her valproate sodium serum concentration was high and peaked at 315 μg/ml. The serum level of other drugs and ethanol were all negative. She had a history of psychiatric illness, including paranoid schizophrenia. The patient was confused, hallucinated and developed deep coma. In addition, the physical examination revealed tachycardia 120 beats/min and normal blood pressure (110/70 mmHg). Her core body temperature was 36.8°C. In the early hours of observation, there were repeated spasms and respiratory insufficiency—the patient was intubated and connected to a respirator. Gradually, the patient's condition improved, and after 4 days of mechanical ventilation, the patient was extubated. In the fourth day the patient was in contact and began to walk in the fifth. Because of the high risk of recurrence of attempted suicide, the patient was urgently addressed without consent to the psychiatric ward for further treatment. At the time of discharge, the patient did not require hospitalization for toxicological reasons.
Haematological disturbances are rare, but there are potentially serious complication of chronic valproate therapy and overdose [11, 13]. Spiller et al. [11] demonstrated that thrombocytopaenia (<150 tys/μl), occurred with valproate concentrations >450 μg/ml, but did not correlate it with dose ingested, whereas fatal leukopenia (WBC < 1200 tys/μl) was observed in patients with VPA concentrations >1200 μg/ml. Hypernatremia (Na+ > 145 mmol/l) and hypocalcaemia were observed in patients with peak VPA concentrations >450 μg/ml [13].
In our study, there were no reported haematological disturbances among the cases of VPA intoxications.
In our study, mean length of hospital stay for all patients was 4.69 days; in the study by Spiller et al. [11], it was 42 ± 33.1 hours. In this study, statistical analysis found the relationship between the serum concentration of VPA and the duration of stay in hospital (
In the case series by Spiller et al. [11], patients with peak valproic acid concentrations above 450 μg/ml were more likely to develop significant clinical effects and have longer hospital stays (
Few fatalities of valproic acid overdose are reported in the literature [11, 27, 35–41]. Deaths were associated with plasma concentrations ranging from 305.4 μg/ml [37] to 1970 μg/ml [27]. In our study, the highest related VPA level was 660 μg/ml; however, the intoxication in this case was non-lethal.
6. Conclusions
Positive correlation of the serum VPA concentrations with diastolic blood pressure, poisoning severity score, Matthew’s coma scale and length of stay in hospital has been found.
We failed to find any significant correlation between the VPA plasma level and the remaining parameters.
Acknowledgments
We thank staff of University Hospital and Specialist Hospital Louis Rydgier’s in Cracow, Poland, for the availability of medical histories.
References
- 1.
Lisa KH, Philip AM. Valproic acid overdose and hemodialysis. Nephrol Transplant. 2001; 16 :1483–1486. DOI: 10.1093/ndt/16.7.1483 - 2.
Perruca E. Pharmacological and therapeutic properties of valproate: a summary after 35 years of clinical experience. CNS Drugs. 2002; 16 (10):695–714. - 3.
Kyngas H. Compliance with health regimens of adolescents with epilepsy. Seizure. 2000; 9 :598–604. DOI: 10.1053/seiz.2000.0470 - 4.
Kubotsu K, Goto S, Fujita M, et al. Automated homogeneous liposome immunoassay systems for anticonvulsant drugs. Clin Chem. 1992; 38 (6):808–812. - 5.
Davis LL, Ryan W, Adinoff B, et al. Comprehensive review of the psychiatric use of valproate. J Clin Psychopharmacol. 2000; 20 (suppl. 1):1S–17S. - 6.
Goldberg JF. Treatment guidelines: current and future management of bipolar disorder. J Clin Psychiatry. 2000;61(suppl. 13):12–18. DOI: 10.1017/S1461145708009231 - 7.
Norton J. Use of intravenous valproate sodium in status migraine. Headache. 2000; 40 :755–757. DOI: 10.1046/j.1526-4610.2000.00133.x - 8.
Hardy JR, Rees EAJ, Gwillian B, et al. A phase II study to establish the efficacy and toxicity of sodium valproate in patients with cancer-related neuropathic pain. J Pain Symptom Manage. 2001; 21 (3):204–209. DOI: 10.1016/S0885-3924(00)00266-9 - 9.
Johannessen CU, Johannessen SI. Valproate: past, present, and future. CNS Drug Rev. 2003; 9 :199–216. DOI: 10.1111/j.1527-3458.2003.tb00249.x - 10.
Hoofnagle JH. Drug-induced liver injury network (DILIN). Hepatology. 2004; 40 :773. DOI: 10.1002/hep.1840400403 - 11.
Spiller HA, Krenzelok EP, Klein-Schwartz W, et al. Multicenter case series of valproic acid ingestion: serum concentrations and toxicity. J Toxicol Clin Toxicol. 2000; 38 :755–760. DOI: 10.1081/CLT-100102388 - 12.
Watson WA, Litovitz TL, Klein-Schwartz W, et al. 2003 annual report of the American Association of Poison Control Centers Toxic Exposure Surveillance System. Am J Emerg Med.2004; 22 :335–404. DOI: 10.1016/j.ajem.2004.06.001 - 13.
Sztajnkrycer MD. Valproic acid toxicity: overview and management. J Toxicol Clin Toxicol. 2002; 40 :789–801. DOI: 10.1081/CLT-120014645 - 14.
Bedry R, Parrot F. Severe valproate poisoning [in French]. Réanimation. 2004; 13 :324–333. DOI: 10.1016/j.reaurg.2004.03.014 - 15.
Ellenhorn M. Diagnosis and treatment of human poisoning. In: Ellenhorn M, editor. Medical Toxicology. Baltimore: Williams and Wilkins; 1997:pp. 609–610. - 16.
Leikin JPF. Poisoning and Toxicology Handbook. 3rd ed. Hudson: Lexi-Comp; 2002. - 17.
Chadwick DW. Concentration-effect relationship of valproic acid. Clin Pharmacokinet. 1985; 10 :155–165. - 18.
Shakya G, Malla S, Shakya KN, et al. Therapeutic drug monitoring of antiepileptic drugs. J Nepal Med Assoc. 2008; 47 (171):94–97. - 19.
Matthew H, Lawson AAH. Treatment of Common Acute Poisonings. Edinburgh, London, New York: Churchill Livingstone; 1975. - 20.
Persson H, Sjöberg G, Haines J, Pronczuk de Garbino J. Poisoning Severity Score: Grading of acute poisoning. J Toxicol Clinical Toxicol. 1998; 36 :205–213. DOI: 10.3109/15563659809028940 - 21.
Berthelot-Moritz F, Chadda K, Chanavaz I, et al. Fatal sodium valproate poisoning. Intensive Care Med. 1997; 23 :599. - 22.
Brubacher JR, Dahghani P, McKnight D. Delayed toxicity following ingestion of enteric-coated divalproex sodium (Epival). J Emerg Med. 1999; 17 :463–467. DOI: 10.1016/S0736-4679(99)00008-6 - 23.
Van Keulen JG, Van der Deure J, Gemke RJBJ, et al. Treatment of valproic acid overdose with continuous arteriovenous hemofiltration. J Toxicol Clin Toxicol. 2000; 38 :219. - 24.
Ishikura H, Matsuo N, Matsubara M, et al. Valproic acid overdose and L-carnitine therapy. J Anal Toxicol. 1996; 20 :55–58. DOI: 10.1093/jat/20.1.55 - 25.
Khoo SH, Leyland MJ. Cerebral edema following acute sodium valproate overdose. J Toxicol Clin Toxicol. 1992; 30 :209–214. DOI: 10.3109/15563659209038632 - 26.
Andersen GO, Ritland S. Life threatening intoxication with sodium valproate. J Toxicol Clin Toxicol. 1995; 33 :279–284. DOI: 10.3109/15563659509018000 - 27.
Garnier R, Boudignat O, Fournier PE. Valproate poisoning. Lancet. 1982; 2 :97. DOI: 10.1016/S0140-6736(82)91713-5 - 28.
Lheureux PER, Penaloza A, Zahir S, et al. Science review: carnitine in the treatment of valproic acid-induced toxicity—what is the evidence? Crit Care. 2005; 9 (5):431–440. DOI: 10.1186/cc3742 - 29.
Dupuis RE, Lichtman SN, Pollack GM. Acute valproic acid overdose. Clinical course and pharmacokinetic disposition of valproic acid and metabolites. Drug Saf. 1990; 5 :65-71. - 30.
Garnier R, Fournier E. Intoxication associated with sodium valproate. Nouv Presse Med., 1982: 11 : 678. - 31.
Jones AL, Proudfoot AT. Features and management of poisoning with modern drugs used to treat epilepsy. Q J Med. 1998; 91 :325–332. DOI: 10.1093/qjmed/91.5.325 - 32.
Ota KS. Probable valproate sodium-associated hypotension, Am J Geriatr Pharmacol. 2010; 8 (3 ):281–284. DOI: 10.1016/j.amjopharm.2010.04.005 - 33.
Graudins A, Aaron CK. Delayed peak serum valproic acid in massive divalproex overdose—treatment with charcoal hemoperfusion. J Toxicol Clin Toxicol. 1996; 34 :335–341. DOI: 10.1046/j.1365-2125.2003.01772.x - 34.
Snodgrass WR. Critical Care Toxicology. In: Brent J, Phillips SD, Wallace KL, Donovan JW, Burkhart KK, editors. Diagnosis and Management of the Critically Poisoned Patient. Philadelphia: Elsevier Mosby; 2005. pp. 565–570. - 35.
Tank JE, Palmer BF. Simultaneous "in series" hemodialysis and hemoperfusion in the management of valproic acid overdose. Am J Kidney Dis. 1993; 22 (2):341–344. DOI: 10.1016/S0272-6386(12)70329-3 - 36.
Chadwick DW, Cumming WJK, Livingstone I, et al. Acute intoxication with sodium valproate. Ann Neurol. 1978; 6 :552–553. DOI: 10.1002/ana.410060616 - 37.
Oamilleri C, Albertson T, Offerman S. Fatal cerebral edema after moderate valproic acid overdose. Ann Emerg Med. 2005; 45 (3):337–338. - 38.
Schnabel R, Rambeck B, Janssen F. Fatal intoxication with sodium valproate. Lancet. 1984; 1 :221–222. DOI: 10.1016/S0140-6736(84)92140-8. - 39.
Connacher AA, Macnab MS, Moody JP, et al. Fatality due to massive overdose of sodium valproate. Scott Med. J. 1987; 32 :85–86. DOI: 10.1177/003693308703200312 - 40.
Lokan RJ, Dinan AC. An apparent fatal valproic acid poisoning. J. Anal. Toxicol. 1988; 12 :35–37. DOI: 10.1093/jat/12.1.35 - 41.
Ryall JE. Fatal overdose sodium valproate. Bull. Int. Assoc. Forensic Toxicol. 1992; 22 :23–26.