Emergency department management of acute agitation in the reproductive age female and pregnancy

Ariella Gartenberg, Kayla Levine, Alexander Petrie

Table 1. Five major drug classes utilized in the treatment of acute agitation, with a focus on the mechanism of action, adverse effect profiles, general recommendations for use, and use during pregnancy

Drug class Mechanism of action Adverse effects General recommendations for use in agitation Use in pregnancy Typical psychotropics (haloperidol, droperidol) Dopamine D2 receptor antagonism ● QTc prolongation ● Extrapyramidal symptoms (EPS) ● Agitation secondary to a primary psychiatric condition (WFSBP) ● Agitation secondary to alcohol intoxication (WFSBP) ● Agitation secondary to delirium (haloperidol) ● High potency agents (haloperidol): first-line in pregnancy. No reported effects in 2nd to 3rd trimester use. Limited case reports regarding 1st trimester use ● Low potency agents (chlorpromazine, perphenazine): sedative and hypotensive effects; higher risk of congenital malformations after 1st trimester use (cleft palate, micromelia, CNS and skeletal malformations, embryonic death, decreased fetal growth, alterations in offspring behavior)[19] Atypical psychotropics (clozapine, olanzapine, quetiapine, lurasidone, ziprasidone) Antagonism of serotonin 5-HT2 receptors, lower affinity for D2 receptors ● Lower EPS risk ● Higher metabolic adverse effects ● Ziprasidone: high risk of QT prolongation ● Agitation secondary to a primary psychiatric condition (WFSBP) ● Agitation secondary to alcohol intoxication (WFSBP) ● Agitation secondary to frustration or communication difficulties including autism spectrum disorder (risperidone and aripiprazole) ● Clozapine/risperidone: NO evidence of impaired fertility or congenital malformations in human and animal models.[26⇓-28] Potential oral agent for agitation in pregnancy ● Other agents: increased risk of gestational metabolic complications and neonates large for gestational age[23] ● Quetiapine: soft tissue anomalies and delays in skeletal ossification[22] ● Olanzapine: higher rates of placental passage, early resorptions and fetal nonviability[22,25] Benzodiazepines (midazolam, lorazepam) Increase affinity of GABA to GABA-A receptors Dose dependent CNS depression ● CNS depression ● Respiratory depression ● Sensory and motor impairments ● Anterograde amnesia ● Agitation secondary to alcohol withdrawal ● Agitation secondary to benzodiazepine withdrawal ● Agitation from stimulant toxicity ● Avoid if possible in pregnancy ● Animal models with mal-rotated limbs, malformed skulls, microphthalmia, gastroschisis, reduction of tibial, tarsal, metatarsal bones[31] ● Absolute risk difference: 13.9 per 1,000 pregnancies for overall malformations and 11.5 per 1,000 pregnancies for heart defects in infants of mothers exposed to benzodiazepines in the 1st trimester [31] ● Benzodiazepine withdrawal during post-natal period [32,33] Ketamine Noncompetitive NMDA and glutamate receptor antagonist Partial agonist on opiate receptors ● Can worsen tachycardia and hypertension ● Dysphoric emergence phenomena[14] ● Hypersalivation, vomiting, laryngospasm, increased rate of intubation, transient hypoxia[14] ● Potential increase in schizophrenic symptoms[16] ● Rapid control of severe and combative agitation ● Impaired learning abilities, spatial and conditioned memory in rat offspring [36] ● Neuronal loss, pyramidal neuronal abnormalities, and reduced hippocampal cell proliferation in rat offspring [35,37] ● Impairment of neuronal development in prefrontal cortex. Indirectly associated with abnormal offspring behaviors (depression, anxiety, memory impairment)[38] ● Neurodegeneration in developing rhesus macaque brains[39] Diphenhydramine Competes with histamine for H1-receptor sites on effector cells in GI tract, blood vessels, and respiratory tract; anticholinergic and sedative effects ● Anticholinergic symptoms (blurred vision; urinary retention; tachycardia; nausea, constipation) ● CNS depression or paradoxical agitation /insomnia ● Mild to moderate agitation ● FDA approved in pregnancy ● No major malformations reported with 1st trimester exposure ● Individual case reports of cleft palates and neonatal withdrawal [29,30]