Old standby valproic acid appears effective against hyperactive delirium

NEW YORK – Valproic acid might be effective for treating hyperactive delirium, results of a small, retrospective study suggest.

Among 16 patients with hyperactive delirium, 13 had complete resolution of delirium according to the DSM-IV-TR criteria, reported Dr. Yelizaveta I. Sher, an instructor in psychiatry and behavioral science at Stanford (Calif.) University.

"You should definitely consider this medication where antipsychotics are ineffective or there are concerns about side effects from antipsychotics, and you need rapid control of agitation," Dr. Sher said at the annual meeting of the American Psychiatric Association.

Delirium is the most frequent psychiatric diagnosis in general hospital settings and has been reported to occur in up to 85% of patients in intensive care units (ICUs), she noted.

"It prolongs hospital stays and significantly increases morbidity and mortality of these patients," Dr. Sher said.

Antipsychotic agents are usually first-line pharmacological therapies for delirium, but these agents are sometimes ineffective in this setting, and are associated with adverse events such as prolongation of the QT interval, and with extrapyramidal side effects such as akathisia, tremors, and, less frequently, the neuroleptic malignant syndrome, Dr. Sher said.

Antispychotics also are less-than-ideal agents for treatment of agitation associated with acute delirium after traumatic brain injury or from alcohol withdrawal, she added.

Valproic acid is the most widely used agent for the treatment of seizures worldwide, and is approved in the United States for seizures, migraine prophylaxis, and acute manic or mixed bipolar episodes. It often is used off-label for treatment of agitation, neuropathic pain, and personality disorder, according to Dr. Sher.

In addition, its use has been explored in agitated patients with dementia, agitation in traumatic brain injury, and corticosteroid-induced mania.

The use of valproic acid has been associated with neural tube defects in fetuses and must be avoided in women who are pregnant. It also has been associated with mild blood dyscrasias, abnormal liver function tests, and, in patients with urea-cycle enzyme deficiencies, symptomatic hyperammonemia, Dr. Sher cautioned.

Medication interactions with valproic acid include a decrease in blood levels of up to 80% when it is used with meropenem, and an increase in warfarin levels when valproic acid is used with the anticoagulant. Valproic acid also can decrease clearance of carbamazepine, lamotrigine, nortriptyline, and amitriptyline.

Dr. Sher and her colleagues conducted a retrospective study of charts for patients with episodes of hyperactive delirium who were treated with adjunct valproic acid by a consulting or liaison psychiatrist on the psychosomatic medicine service at their center from Aug. 1, 2011, through Aug. 31, 2012. All the patients had hyperactive or mixed delirium as defined by Dr. Benjamin Liptzin’s criteria (Am. J. Psychiatry 1991;148:454-7).

For their investigation, Dr. Sher and her associates reviewed daily notes from the primary ICU team and nurse; daily mental status examination results; daily medication use and doses of psychotropic medications, sedatives, and related medications; daily lab data; descriptions of agitation; and important clinical events such as the use of restraints, extubation, and death.

They identified 16 patients (14 men and 2 women) treated for hyperactive delirium, all but 3 of whom were treated in the ICU. Of this group, 15 patients had received multiple drug treatments for delirium and/or agitation prior to valproic acid use.

The average dose of valproic acid used on days 2-5 was 1,133-1,258 mg per 24 hours in divided daily doses.

As noted before, 13 patients had complete resolution of delirium, at an average of 7.2 days from the start of valproic acid. Two patients had resolution of delirium within 2 days, 4 within 3 days, 2 within 4 days, 1 within 5 days, and the remaining 4 patients at 10, 12 (2 patients), and 31 days.

In all patients, agitation was markedly decreased as rated by mental status examination, agitation scale ratings, and reduced need for sedatives.

In three patients, meropenem might have affected valproic acid levels; two of the patients developed thrombocytopenias.

A randomized controlled trial of valproic acid for the treatment of hyperactive delirium in the ICU is underway, Dr. Sher noted.

The study was internally funded. Dr. Sher reported having no financial disclosures.

NEW YORK – Valproic acid might be effective for treating hyperactive delirium, results of a small, retrospective study suggest.

Among 16 patients with hyperactive delirium, 13 had complete resolution of delirium according to the DSM-IV-TR criteria, reported Dr. Yelizaveta I. Sher, an instructor in psychiatry and behavioral science at Stanford (Calif.) University.

"You should definitely consider this medication where antipsychotics are ineffective or there are concerns about side effects from antipsychotics, and you need rapid control of agitation," Dr. Sher said at the annual meeting of the American Psychiatric Association.

Delirium is the most frequent psychiatric diagnosis in general hospital settings and has been reported to occur in up to 85% of patients in intensive care units (ICUs), she noted.

"It prolongs hospital stays and significantly increases morbidity and mortality of these patients," Dr. Sher said.

Antipsychotic agents are usually first-line pharmacological therapies for delirium, but these agents are sometimes ineffective in this setting, and are associated with adverse events such as prolongation of the QT interval, and with extrapyramidal side effects such as akathisia, tremors, and, less frequently, the neuroleptic malignant syndrome, Dr. Sher said.

Antispychotics also are less-than-ideal agents for treatment of agitation associated with acute delirium after traumatic brain injury or from alcohol withdrawal, she added.

Valproic acid is the most widely used agent for the treatment of seizures worldwide, and is approved in the United States for seizures, migraine prophylaxis, and acute manic or mixed bipolar episodes. It often is used off-label for treatment of agitation, neuropathic pain, and personality disorder, according to Dr. Sher.

In addition, its use has been explored in agitated patients with dementia, agitation in traumatic brain injury, and corticosteroid-induced mania.

The use of valproic acid has been associated with neural tube defects in fetuses and must be avoided in women who are pregnant. It also has been associated with mild blood dyscrasias, abnormal liver function tests, and, in patients with urea-cycle enzyme deficiencies, symptomatic hyperammonemia, Dr. Sher cautioned.

Medication interactions with valproic acid include a decrease in blood levels of up to 80% when it is used with meropenem, and an increase in warfarin levels when valproic acid is used with the anticoagulant. Valproic acid also can decrease clearance of carbamazepine, lamotrigine, nortriptyline, and amitriptyline.

Dr. Sher and her colleagues conducted a retrospective study of charts for patients with episodes of hyperactive delirium who were treated with adjunct valproic acid by a consulting or liaison psychiatrist on the psychosomatic medicine service at their center from Aug. 1, 2011, through Aug. 31, 2012. All the patients had hyperactive or mixed delirium as defined by Dr. Benjamin Liptzin’s criteria (Am. J. Psychiatry 1991;148:454-7).

For their investigation, Dr. Sher and her associates reviewed daily notes from the primary ICU team and nurse; daily mental status examination results; daily medication use and doses of psychotropic medications, sedatives, and related medications; daily lab data; descriptions of agitation; and important clinical events such as the use of restraints, extubation, and death.

They identified 16 patients (14 men and 2 women) treated for hyperactive delirium, all but 3 of whom were treated in the ICU. Of this group, 15 patients had received multiple drug treatments for delirium and/or agitation prior to valproic acid use.

The average dose of valproic acid used on days 2-5 was 1,133-1,258 mg per 24 hours in divided daily doses.

As noted before, 13 patients had complete resolution of delirium, at an average of 7.2 days from the start of valproic acid. Two patients had resolution of delirium within 2 days, 4 within 3 days, 2 within 4 days, 1 within 5 days, and the remaining 4 patients at 10, 12 (2 patients), and 31 days.

In all patients, agitation was markedly decreased as rated by mental status examination, agitation scale ratings, and reduced need for sedatives.

In three patients, meropenem might have affected valproic acid levels; two of the patients developed thrombocytopenias.

A randomized controlled trial of valproic acid for the treatment of hyperactive delirium in the ICU is underway, Dr. Sher noted.

The study was internally funded. Dr. Sher reported having no financial disclosures.

NEW YORK – Valproic acid might be effective for treating hyperactive delirium, results of a small, retrospective study suggest.

Among 16 patients with hyperactive delirium, 13 had complete resolution of delirium according to the DSM-IV-TR criteria, reported Dr. Yelizaveta I. Sher, an instructor in psychiatry and behavioral science at Stanford (Calif.) University.

"You should definitely consider this medication where antipsychotics are ineffective or there are concerns about side effects from antipsychotics, and you need rapid control of agitation," Dr. Sher said at the annual meeting of the American Psychiatric Association.

Delirium is the most frequent psychiatric diagnosis in general hospital settings and has been reported to occur in up to 85% of patients in intensive care units (ICUs), she noted.

"It prolongs hospital stays and significantly increases morbidity and mortality of these patients," Dr. Sher said.

Antipsychotic agents are usually first-line pharmacological therapies for delirium, but these agents are sometimes ineffective in this setting, and are associated with adverse events such as prolongation of the QT interval, and with extrapyramidal side effects such as akathisia, tremors, and, less frequently, the neuroleptic malignant syndrome, Dr. Sher said.

Antispychotics also are less-than-ideal agents for treatment of agitation associated with acute delirium after traumatic brain injury or from alcohol withdrawal, she added.

Valproic acid is the most widely used agent for the treatment of seizures worldwide, and is approved in the United States for seizures, migraine prophylaxis, and acute manic or mixed bipolar episodes. It often is used off-label for treatment of agitation, neuropathic pain, and personality disorder, according to Dr. Sher.

In addition, its use has been explored in agitated patients with dementia, agitation in traumatic brain injury, and corticosteroid-induced mania.

The use of valproic acid has been associated with neural tube defects in fetuses and must be avoided in women who are pregnant. It also has been associated with mild blood dyscrasias, abnormal liver function tests, and, in patients with urea-cycle enzyme deficiencies, symptomatic hyperammonemia, Dr. Sher cautioned.

Medication interactions with valproic acid include a decrease in blood levels of up to 80% when it is used with meropenem, and an increase in warfarin levels when valproic acid is used with the anticoagulant. Valproic acid also can decrease clearance of carbamazepine, lamotrigine, nortriptyline, and amitriptyline.

Dr. Sher and her colleagues conducted a retrospective study of charts for patients with episodes of hyperactive delirium who were treated with adjunct valproic acid by a consulting or liaison psychiatrist on the psychosomatic medicine service at their center from Aug. 1, 2011, through Aug. 31, 2012. All the patients had hyperactive or mixed delirium as defined by Dr. Benjamin Liptzin’s criteria (Am. J. Psychiatry 1991;148:454-7).

For their investigation, Dr. Sher and her associates reviewed daily notes from the primary ICU team and nurse; daily mental status examination results; daily medication use and doses of psychotropic medications, sedatives, and related medications; daily lab data; descriptions of agitation; and important clinical events such as the use of restraints, extubation, and death.

They identified 16 patients (14 men and 2 women) treated for hyperactive delirium, all but 3 of whom were treated in the ICU. Of this group, 15 patients had received multiple drug treatments for delirium and/or agitation prior to valproic acid use.

The average dose of valproic acid used on days 2-5 was 1,133-1,258 mg per 24 hours in divided daily doses.

As noted before, 13 patients had complete resolution of delirium, at an average of 7.2 days from the start of valproic acid. Two patients had resolution of delirium within 2 days, 4 within 3 days, 2 within 4 days, 1 within 5 days, and the remaining 4 patients at 10, 12 (2 patients), and 31 days.

In all patients, agitation was markedly decreased as rated by mental status examination, agitation scale ratings, and reduced need for sedatives.

In three patients, meropenem might have affected valproic acid levels; two of the patients developed thrombocytopenias.

A randomized controlled trial of valproic acid for the treatment of hyperactive delirium in the ICU is underway, Dr. Sher noted.

The study was internally funded. Dr. Sher reported having no financial disclosures.