valproic acid ( vpa ) is currently not only used in epilepsy treatment but also in the treatment of bipolar disorders and migraine prophylaxis . although some side effects of vpa are not dose - dependent , toxic effects are associated with daily doses above 1,800 mg and blood levels above 100 g / ml . prospective studies are lacking with regard to the management of poisoned patients , and the available data are mainly from case reports or small retrospective studies . we present a case of sodium valproate overdose where hemodialysis was used because of rapid clinical deterioration and a serum vpa level greater than 1,000 g / ml . a 21-year - old man with a history of bipolar disorder , who was on sodium valproate 400 mg twice a day since 3 years , had an alleged history of consumption of about 30 g sodium valproate ( 150 - 170 tablets , 200 mg each ) . he complained of headache 1 hour later and was shifted to a government hospital where gastric lavage with activated charcoal 50 g was done . he became agitated and drowsy 4 hours after the episode and was shifted to our hospital for further management . on examination , the patient was comatose and not responding to painful stimuli with glasgow coma scale ( gcs ) 6/15 ( e1v2m3 ) , pupils bilaterally constricted , 1 mm , sluggishly reacting to light with plantars flexor , respiratory rate was 10 - 12/min , spo2 92% on 10 l of oxygen with face mask , abg showing acute respiratory and metabolic acidosis and po2 52 mm hg [ table 1 ] . the patient was intubated with 8.0 mm portex endotracheal tube and put on volume - controlled ventilation with tidal volume 8 ml / kg , respiratory rate 18/min and fio2 0.5 . the spo2 level increased to 98% , with abg showing correction of respiratory acidosis and po2 98 mm hg [ table 1 ] . his heart rate was 118/min and blood pressure in the right forearm was 84/60 mm hg . he was given fluid bolus of 1 l normal saline , after which his blood pressure increased to 102/64 mm hg . the patient was injected naloxone 1.5 mg iv stat , and 0.5 mg repeated every 10 min for a total of 12 mg , but his comatose condition persisted . nine hours after ingestion , his valproate levels were 1,060 g / ml ( normal , 50 - 100 ) and serum ammonia 98 g / dl ( normal , 9 - 33 ) . he was started on l - carnitine with 5-g bolus iv followed by 750 mg four hourly for 24 hours . urgent high - flux hemodialysis ( hd ) with fx80 dialyzer ( helixone , 1.8 m , fresenius medical care ) , blood flow rate 350 ml / min and ultrafiltration rate 450 ml / hr for duration of 4 hours was performed , using right femoral venous access . post dialysis , he became more conscious and was extubated after about 24 h of admission to hospital . he was observed closely for any deterioration in consciousness along with valproate levels [ table 2 ] and serum ammonia levels [ table 3 ] . his oral feeding was started on the 3rd day and was discharged to high - dependency unit the next day . his psychiatric counselling was done on the same day and then discharged on day 5 with advice for regular follow - up to psychiatric out - patient department ( opd ) . vpa is an 8-carbon 2-chain fatty acid mainly used as primary and adjuvant drug in epilepsy treatment . recently , it has also been finding use in acute and maintenance therapy of bipolar disease , for migraine prophylaxis and as adjunctive therapy for treatment of alcohol and other sedative - hypnotic withdrawal syndromes . vpa increases the levels of gamma - amino butyric acid ( gaba ) and prolongs the recovery of inactivated sodium channels , thereby causing central nervous system ( cns ) depression . vpa may also cause impairments in fatty - acid metabolism and disrupt the urea cycle , leading to hyperammonemia . however , time to maximum concentration ( t 
 max and cmax ) , which represents the rate of absorption , depends on the preparation from vpa syrup ( 34.2 mg / l , 0.9 h ) and vpa capsule ( 31.4 mg / l , 2.2 h ) to enteric - coated delayed - release tablet ( 26.0 mg / l , 3.4 h ) and finally , extended - release tablet ( 11.8 mg / l , 19.7 h ) . in our case , the patient took enteric - coated delayed - release preparation , and thus he started deteriorating after 4 hours of ingestion , and serum levels taken 9 hours after ingestion were very high . vpa is a small molecule ( mw 144.2 ) and is highly protein bound ( 85 - 90% ) . it has a half - life of 10 - 20 hours ( mean , 15 h ) and has an apparent volume of distribution ( vd ) that is in the range of 0.1 - 0.4 l / kg , at therapeutic levels . after an overdose , at serum concentrations of more than 300 g / ml , protein - binding sites are saturated and only 35% binds to protein , increasing the free fraction of vpa and vd . low molecular weight and decreased protein binding during toxicity make valproate make it ideal for removal through extracorporeal circulation . hemodiafiltration ( hdf ) and high - flux hd are effective in reducing serum valproate levels during valproate toxicity . vpa overdose most commonly presents with nausea and vomiting closely followed by cns symptoms of headache , ataxia , decreased level of consciousness , confusion and coma . with serum levels more than 850 g / ml , hypotension , cardiac arrest , respiratory depression requiring intubation has been reported . the coma is multifactorial , with the contributory factors including hyperammonemia , high anion gap lactic acidosis , direct sedative effects , cerebral edema and mitochondrial dysfunction . pancreatitis , elevated hepatic transaminases and bone marrow suppression may complicate both overdose and therapeutic dosing . laboratory manifestations include hypernatraemia ( sodium salt of valproate ) , hypocalcaemia , hyper or hypophosphataemia , high anion and osmolar gap . cerebral edema is a delayed presentation and usually occurs 48 - 72 hours after ingestion , even as serum levels are decreasing . the disruption of the osmotic gradient , caused by elevated serum ammonia levels is thought to be the precipitating cause of the edema . our patient did not show secondary deterioration , may be due to early institution of hemodialysis , and hence correction of hyperammonemia . oral activated charcoal 1 mg / kg can be administered to reduce gastrointestinal adsorption , especially if presented within the first hour . in our patient , medical management for coma using naloxone and l - carnitine has been described in isolated case reports . l - carnitine supplementation is indicated in patients with concomitant hyperammonemia , encephalopathy , and/or hepatotoxicity . hemodialysis , haemoperfusion , and a combination of the two , all appear to effectively reduce the serum levels of valproate . vpa because of its low molecular weight ( 144.2 ) is highly dialysable , which is partially opposed by its high protein binding . in a meta - analysis , it was found that low - efficiency or low - flux hd removes only 20% of administered dose at therapeutic levels . however , in toxic levels due to saturation of plasma protein binding sites , clinically significant removal of valproate can be done with dialysis . high - flux hd and hdf are effective in reducing serum valproate levels both during toxic and therapeutic states . recommended indications for renal replacement therapy during sodium valproate intoxication are plasma levels above 700 g / ml , rapid clinical deterioration , evidence of hepatic dysfunction , and continued drug absorption . in our patient , we used high - flux hd without haemoperfusion and found significant drop in both serum valproate and serum ammonia levels . in conclusion , the use of renal replacement therapies seems the most effective treatment for valproate overdose and should be strongly considered besides other supportive therapies in a patient with refractory coma and serum valproate levels above 700 g / dl . vpa increases the levels of gamma - amino butyric acid ( gaba ) and prolongs the recovery of inactivated sodium channels , thereby causing central nervous system ( cns ) depression . vpa may also cause impairments in fatty - acid metabolism and disrupt the urea cycle , leading to hyperammonemia . however , time to maximum concentration ( t 
 max and cmax ) , which represents the rate of absorption , depends on the preparation from vpa syrup ( 34.2 mg / l , 0.9 h ) and vpa capsule ( 31.4 mg / l , 2.2 h ) to enteric - coated delayed - release tablet ( 26.0 mg / l , 3.4 h ) and finally , extended - release tablet ( 11.8 mg / l , 19.7 h ) . in our case , the patient took enteric - coated delayed - release preparation , and thus he started deteriorating after 4 hours of ingestion , and serum levels taken 9 hours after ingestion were very high . vpa is a small molecule ( mw 144.2 ) and is highly protein bound ( 85 - 90% ) . it has a half - life of 10 - 20 hours ( mean , 15 h ) and has an apparent volume of distribution ( vd ) that is in the range of 0.1 - 0.4 l / kg , at therapeutic levels . after an overdose , at serum concentrations of more than 300 g / ml , protein - binding sites are saturated and only 35% binds to protein , increasing the free fraction of vpa and vd . low molecular weight and decreased protein binding during toxicity make valproate make it ideal for removal through extracorporeal circulation . hemodiafiltration ( hdf ) and high - flux hd are effective in reducing serum valproate levels during valproate toxicity . vpa overdose most commonly presents with nausea and vomiting closely followed by cns symptoms of headache , ataxia , decreased level of consciousness , confusion and coma . with serum levels more than 850 g / ml , hypotension , cardiac arrest , respiratory depression requiring intubation has been reported . the coma is multifactorial , with the contributory factors including hyperammonemia , high anion gap lactic acidosis , direct sedative effects , cerebral edema and mitochondrial dysfunction . pancreatitis , elevated hepatic transaminases and bone marrow suppression may complicate both overdose and therapeutic dosing . laboratory manifestations include hypernatraemia ( sodium salt of valproate ) , hypocalcaemia , hyper or hypophosphataemia , high anion and osmolar gap . cerebral edema is a delayed presentation and usually occurs 48 - 72 hours after ingestion , even as serum levels are decreasing . the disruption of the osmotic gradient , caused by elevated serum ammonia levels is thought to be the precipitating cause of the edema . our patient did not show secondary deterioration , may be due to early institution of hemodialysis , and hence correction of hyperammonemia . oral activated charcoal 1 mg / kg can be administered to reduce gastrointestinal adsorption , especially if presented within the first hour . in our patient , medical management for coma using naloxone and l - carnitine has been described in isolated case reports . l - carnitine supplementation is indicated in patients with concomitant hyperammonemia , encephalopathy , and/or hepatotoxicity . hemodialysis , haemoperfusion , and a combination of the two , all appear to effectively reduce the serum levels of valproate . vpa because of its low molecular weight ( 144.2 ) is highly dialysable , which is partially opposed by its high protein binding . in a meta - analysis , it was found that low - efficiency or low - flux hd removes only 20% of administered dose at therapeutic levels . however , in toxic levels due to saturation of plasma protein binding sites , clinically significant removal of valproate can be done with dialysis . high - flux hd and hdf are effective in reducing serum valproate levels both during toxic and therapeutic states . recommended indications for renal replacement therapy during sodium valproate intoxication are plasma levels above 700 g / ml , rapid clinical deterioration , evidence of hepatic dysfunction , and continued drug absorption . in our patient , we used high - flux hd without haemoperfusion and found significant drop in both serum valproate and serum ammonia levels . in conclusion , the use of renal replacement therapies seems the most effective treatment for valproate overdose and should be strongly considered besides other supportive therapies in a patient with refractory coma and serum valproate levels above 700 g / dl . vpa increases the levels of gamma - amino butyric acid ( gaba ) and prolongs the recovery of inactivated sodium channels , thereby causing central nervous system ( cns ) depression . vpa may also cause impairments in fatty - acid metabolism and disrupt the urea cycle , leading to hyperammonemia . however , time to maximum concentration ( t 
 max and cmax ) , which represents the rate of absorption , depends on the preparation from vpa syrup ( 34.2 mg / l , 0.9 h ) and vpa capsule ( 31.4 mg / l , 2.2 h ) to enteric - coated delayed - release tablet ( 26.0 mg / l , 3.4 h ) and finally , extended - release tablet ( 11.8 mg / l , 19.7 h ) . in our case , the patient took enteric - coated delayed - release preparation , and thus he started deteriorating after 4 hours of ingestion , and serum levels taken 9 hours after ingestion were very high . vpa is a small molecule ( mw 144.2 ) and is highly protein bound ( 85 - 90% ) . it has a half - life of 10 - 20 hours ( mean , 15 h ) and has an apparent volume of distribution ( vd ) that is in the range of 0.1 - 0.4 l / kg , at therapeutic levels . after an overdose , at serum concentrations of more than 300 g / ml , protein - binding sites are saturated and only 35% binds to protein , increasing the free fraction of vpa and vd . low molecular weight and decreased protein binding during toxicity make valproate make it ideal for removal through extracorporeal circulation . hemodiafiltration ( hdf ) and high - flux hd are effective in reducing serum valproate levels during valproate toxicity . vpa overdose most commonly presents with nausea and vomiting closely followed by cns symptoms of headache , ataxia , decreased level of consciousness , confusion and coma . with serum levels more than 850 g / ml , hypotension , cardiac arrest , respiratory depression requiring intubation has been reported . the coma is multifactorial , with the contributory factors including hyperammonemia , high anion gap lactic acidosis , direct sedative effects , cerebral edema and mitochondrial dysfunction . pancreatitis , elevated hepatic transaminases and bone marrow suppression may complicate both overdose and therapeutic dosing . laboratory manifestations include hypernatraemia ( sodium salt of valproate ) , hypocalcaemia , hyper or hypophosphataemia , high anion and osmolar gap . cerebral edema is a delayed presentation and usually occurs 48 - 72 hours after ingestion , even as serum levels are decreasing . the disruption of the osmotic gradient , caused by elevated serum ammonia levels is thought to be the precipitating cause of the edema . our patient did not show secondary deterioration , may be due to early institution of hemodialysis , and hence correction of hyperammonemia . oral activated charcoal 1 mg / kg can be administered to reduce gastrointestinal adsorption , especially if presented within the first hour . in our patient , medical management for coma using naloxone and l - carnitine has been described in isolated case reports . l - carnitine supplementation is indicated in patients with concomitant hyperammonemia , encephalopathy , and/or hepatotoxicity . hemodialysis , haemoperfusion , and a combination of the two , all appear to effectively reduce the serum levels of valproate . vpa because of its low molecular weight ( 144.2 ) is highly dialysable , which is partially opposed by its high protein binding . in a meta - analysis , it was found that low - efficiency or low - flux hd removes only 20% of administered dose at therapeutic levels . however , in toxic levels due to saturation of plasma protein binding sites , clinically significant removal of valproate can be done with dialysis . high - flux hd and hdf are effective in reducing serum valproate levels both during toxic and therapeutic states . recommended indications for renal replacement therapy during sodium valproate intoxication are plasma levels above 700 g / ml , rapid clinical deterioration , evidence of hepatic dysfunction , and continued drug absorption . in our patient , we used high - flux hd without haemoperfusion and found significant drop in both serum valproate and serum ammonia levels . in conclusion , the use of renal replacement therapies seems the most effective treatment for valproate overdose and should be strongly considered besides other supportive therapies in a patient with refractory coma and serum valproate levels above 700 g / dl .
a case of severe sodium valproate overdose is presented in which medicinal management failed to reverse coma of the patient . 
 high - flux hemodialysis was then used to eliminate sodium valproate . 
 this case demonstrated the effectiveness of hemodialysis in not only decreasing valproate levels very rapidly but also as an effective anti - coma management .