Introduction

Antipsychotics are a treatment option for delirium in the intensive care unit. Atypical antipsychotics are preferred over first-generation antipsychotics because of their lower incidence of extrapyramidal adverse effects. The most common such effect is akathisia or restlessness. This report describes a case of atypical antipsychotic–induced akathisia and addresses the clinical distinction between extrapyramidal movements and movements due to intensive care unit delirium.

Clinical Findings

A 56-year-old man who had a prolonged hospital stay after orthotopic liver transplant complicated by multisystem organ failure, primary graft failure requiring a second transplant, and enterocutaneous fistula developed agitated delirium on hospital day 28. Initial treatment included intravenous haloperidol and scheduled sublingual olanzapine (5 mg daily). His delirium and insomnia persisted, requiring dexmedetomidine infusion. Olanzapine dosing was increased to 10 mg daily on hospital day 34 and 15 mg daily on hospital day 45. The following day, his mentation improved; however, he exhibited asynchronous, nonrhythmic, involuntary rolling motions of his hands and choreiform gait.

Diagnosis and Outcomes

Antipsychotics were immediately discontinued owing to acute akathisia. All symptoms resolved within 2 days, and the patient was transferred out of the intensive care unit on hospital day 52.

Conclusion

Although extrapyramidal adverse effects are less common with olanzapine than with typical antipsychotics, they sometimes occur and can mimic manifestations of delirium. Restlessness should alert the nurse to assess for possible extrapyramidal adverse effects. If they are suspected, antipsychotic medications should be reduced or discontinued to prevent progression to functional disability.

This article has been designated for CE contact hour(s). The evaluation tests your knowledge of the following objectives:

  1. Discuss the difference between movement-based symptoms of delirium and extrapyramidal side effects.

  2. Identify screening tools used assess intensive care unit patients for signs of delirium.

  3. Describe nonmodifiable risk factors for delirium.

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Delirium is a common complication in critically ill patients, occurring in up to 80% of those undergoing mechanical ventilation.1  Because delirium is associated with higher 1-year mortality and is an independent predictor of long-term cognitive impairment, early identification and treatment are imperative.2 

Although they are not recommended in clinical practice guidelines for routine treatment of delirium, antipsychotics are used in patients who have associated anxiety or hallucinations or are a danger to themselves or others.3  Atypical antipsychotics are preferred over first-generation antipsychotics because of their lower incidence of extrapyramidal adverse effects.3,4  The most common extrapyramidal sign associated with second-generation antipsychotics is akathisia, which manifests as restlessness, the inability to sit still, and a constant subjective urge to move.5  We describe a case of delirium with subsequent atypical antipsychotic–induced akathisia and discuss the critical care nurse’s role in prevention, identification, and management of delirium and extrapyramidal symptoms.

Case Report

Patient Information

A 56-year-old man with end-stage liver disease secondary to alcoholic cirrhosis and nonalcoholic steatohepatitis was admitted to the hospital in anticipation of transplant. His preoperative disease process was complicated by hepatic encephalopathy, refractory ascites, moderate malnutrition, and grade 2 esophageal varices after variceal banding and transjugular intrahepatic portosystemic shunt. He underwent an orthotopic liver transplant from a donor with cardiac death on hospital day 2. Postoperatively, his course was complicated by multisystem organ failure, including acute renal failure requiring continuous renal replacement therapy, hypoxic respiratory failure secondary to Stenotrophomonas and methicillin-resistant Staphylococcus epidermis pneumonia requiring mechanical ventilation with subsequent tracheotomy on hospital day 20, and primary graft failure requiring molecular adsorbent recirculating system therapy and subsequent secondary transplant on hospital day 11. His course was further complicated by duodenal perforation, enterocutaneous fistula requiring total parenteral nutrition, polymicrobial peritonitis, subdural hemorrhage secondary to coagulopathy, and critical illness myopathy. He exhibited hyperactive agitated delirium on hospital day 28.

Clinical Findings

At initial onset of delirium, physical examination revealed a Glasgow Coma Scale (GCS) score of 11 (eyeopening response, 4 [opens eyes spontaneously]; verbal response, 1 [nonverbal due to tracheostomy]; motor response, 6 [follows all commands]), and the patient was alert and oriented to person, place, and time, with no focal neurological deficits noted. His score on the Richmond Agitation-Sedation Scale (RASS) was +1 (restless). The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) score indicated inattention and disorganized thinking. He was also noted to have persistent insomnia. The patient denied pain on a numeric pain scale of 0 to 10.

Although not recommended for routine treatment of delirium, antipsychotics are used in patients who have associated anxiety or hallucinations or are a danger to themselves or others.

On hospital day 46, clinical examination revealed improved mentation; however, the patient had asynchronous, nonrhythmic, involuntary rolling motions of both hands, as well as choreiform gait, suggestive of acute akathisia (see Figure).

Figure

Timeline of events in the intensive care unit.

Figure

Timeline of events in the intensive care unit.

Diagnostic Assessment

Upon onset of delirium, pertinent laboratory values (reference ranges) were as follows: sodium, 134 mmol/L (135-145 mmol/L); potassium, 3.6 mmol/L (3.6-5.2 mmol/L); creatinine, 0.8 mg/dL (0.74-1.35 mg/dL); serum urea nitrogen, 38 mg/dL (8-24 mg/dL); glucose, 194 mg/dL (70-140 mg/dL); and tacrolimus level, 6.9 ng/mL (5-15 ng/mL). Results of liver function tests and ammonia level were within reference ranges. Bronchoscopy with bronchial alveolar lavage revealed Stenotrophomonas maltophilia pneumonia.

Differential diagnoses included acute delirium secondary to infection and/or insomnia, toxic metabolic encephalopathy secondary to uremia and/or hepatic failure, and stroke. Diagnostic brain imaging was deferred, as no focal deficits were present and there were alternative explanations for altered mental status.

Therapeutic Intervention

The Society of Critical Care Medicine recommendations for the evaluation of pain, agitation, and delirium were routinely and consistently used by critical care nurses and other health care providers. Components of the ABCDE bundle (awakening and breathing, coordination of daily sedation and ventilator removal trials, delirium monitoring and management, and early mobility and exercise) were also implemented as appropriate.3  The patient received pulmonary support from respiratory therapists and nurses who assisted with “pulmonary toileting” exercises, which were important because of the new diagnosis of Stenotrophomonas maltophilia pneumonia and the need to treat precipitating factors in delirium such as infection.4  The CAM-ICU and RASS were used for ongoing evaluation of cognition. The patient continued to participate in physical and occupational therapy as appropriate and was also allowed to visit the hospital’s patio when accompanied by a nurse. A sleep enhancement protocol was implemented including limiting disturbances from 11 pm to 5 am and promoting wakefulness during the day.

Initial pharmacological treatment of the patient’s agitation included intravenous (IV) haloperidol (5 mg) on hospital day 28. As he was unable to tolerate enteral medications because of enterocutaneous fistula management, sublingual olanzapine (5 mg daily) was initiated at bedtime for insomnia and delirium. Despite nonpharmacological and pharmacological therapies, the delirium and insomnia persisted, prompting nightly administration of a dexmedetomidine infusion (2 μg/kg/h) from 8 pm to 5 am from hospital day 34 through day 41. Olanzapine dosing was also increased to 10 mg daily on hospital day 34 and then to 15 mg on hospital day 45. Additionally, diphenhydramine, 50 mg IV, was tried on hospital day 43, which failed to result in restful sleep. Finally, the patient was sedated with propofol, with mechanical ventilation nightly on hospital days 44 and 45.

On hospital day 46, extrapyramidal symptoms appeared, prompting immediate discontinuation of all antipsychotics. That evening, only propofol was used for sleep. The following 2 nights, the patient slept without any pharmacological assistance, and all symptoms resolved within 2 days of antipsychotic cessation. The patient was transferred out of the intensive care unit (ICU) on hospital day 52.

Follow-up and Outcomes

Assessments of mental status including GCS, RASS, and CAM-ICU were performed by the nursing staff every 4 hours and by the provider team every shift and as needed. Although the patient’s GCS and RASS scores fluctuated with changes in treatment strategy, his CAM-ICU assessment remained positive for inattention and disorganized thinking until after discontinuation of antipsychotics. Once his mentation improved, follow-up diagnostic tests were not warranted. Nursing assessments of orientation and cognition continued throughout his hospitalization, although they were tapered off as his care was transitioned from critical care to hospital medicine.

The patient was transferred out of the ICU on hospital day 52. He remained on the medical unit for total parenteral nutrition weaning and subsequent intra-abdominal abscess identification requiring IV antibiotics and drain management until hospital day 63, when he was transferred to an inpatient rehabilitation center. He remained there for an additional 15 days before finally being discharged home.

Discussion

Delirium is an acute confusional state featuring attention deficits, disordered thinking, and fluctuating awareness. It can include psychotic symptoms and can be either hypoactive or hyperactive. Patients with hyperactive delirium can be restless and impulsive.6,7  Extrapyramidal symptoms include restlessness, the inability to sit still, and/or pacing (akathisia); abnormal postures and muscle spasms, especially of the head or neck (acute dystonia); tremor, skeletal muscle rigidity, and/or bradykinesia (parkinsonism); and ultimately involuntary, repetitive facial movements such as grimacing, tongue protruding, or lip puckering, as well as torso and limb movements (tardive dyskinesia). The latter can be irreversible.8 

Because of its numerous etiologies and mechanisms, the exact pathophysiology of delirium is poorly understood. Delirium has been associated with alteration in neurotransmitter synthesis, function, and availability as well as dysregulation of neuronal activity, which combine to create this neurobehavioral syndrome. A multitude of neurotransmitter systems have been implicated as increasing the risk of delirium, including deficits in acetylcholine and/or melatonin; excess dopamine, norepinephrine, and/or glutamate release; and alterations in serotonin, histamine, and/or γ-aminobutyric acid.6 

Delirium usually originates in the ICU, occurring in up to 80% of patients undergoing mechanical ventilation, and is the most common behavioral manifestation of acute brain dysfunction in the ICU.1,2,9  The true prevalence is unknown, as it is commonly erroneously documented as encephalopathy, ICU psychosis, altered mental status, or acute confusional state.10  Marcantonio11  reported study findings indicating poor recognition of delirium, with only 12% to 35% of delirium cases acknowledged as such. The consequences, however, are significant, including increased length of mechanical ventilation, increased length of ICU stay, increased cost, long-term cognitive impairment, and mortality.6  Identification of risk factors, prevention, and early recognition of symptoms are vital and begin with the critical care nurse.

Nonmodifiable risk factors associated with delirium include older age, dementia, prior coma, pre-ICU surgery or trauma, and increased Acute Physiology and Chronic Health Evaluation and American Society of Anesthesiologists Classification of Physical Health scores. Modifiable risk factors include benzodiazepine use and blood transfusions.3  According to the Society of Critical Care Medicine pain, agitation, and delirium guidelines, use of delirium screening tools such as the CAM-ICU or the Intensive Care Delirium Screening Checklist should be incorporated into daily nursing assessments for all ICU patients, particularly for high-risk patients (those with previously mentioned risk factors). The critical care nurse can also implement daily preventive measures for high-risk patients, including sleep enhancement, minimizing sedation and benzodiazepine use, managing pain, promoting early progressive mobility, and assisting with and promoting daily awakening trials and spontaneous breathing trials to aid in weaning from mechanical ventilation.3,7 

Nurses should assess and monitor for side effects of antipsychotics, including QT prolongation and extrapyramidal symptoms.

In addition to the above-mentioned preventive measures, nurses can help improve cognition through reorientation, use of clocks, and cognitive stimulation as well as engagement of the family and enabling the use of hearing aids and eyeglasses for all patients with positive CAM-ICU scores. Antipsychotics should be reserved for patients with delirium-associated anxiety or hallucinations or who may be physically harmful to themselves or others.3  Currently there are no medications approved by the US Food and Drug Administration for the treatment of delirium; however, second-generation antipsychotic agents such as olanzapine are commonly used despite conflicting results of systematic reviews regarding their potential benefits.4 

Antipsychotics antagonize dopamine D2 receptors. Second-generation antipsychotics, specifically, have additional antagonistic effects at serotonin, histamine, and α2 receptors. This multireceptor antagonism is what makes second-generation antipsychotics less likely to result in extrapyramidal symptoms.12  However, the risk of extrapyramidal symptoms is still present, and they can be easily confused with symptoms of worsening delirium, as evidenced in this case.

Conclusion

This case exemplified an instance of proper assessment and monitoring leading to early identification of extrapyramidal symptoms, cessation of antipsychotics, and resolution of both delirium and akathisia. As with any medication, nurses should assess and monitor for side effects of antipsychotics, including QT prolongation and extrapyramidal symptoms. Understanding the difference between symptoms of delirium and extrapyramidal symptoms is essential to ensure patient safety and good long-term outcomes.

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Footnotes

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Financial Disclosures

None reported.

 

See also

To learn more about delirium, read “Update on the Prevention and Treatment of Intensive Care Unit Delirium” by Marsh and Alexander in AACN Advanced Critical Care, 2021;32(1):5-10. Available at www.aacnacconline.org.