By Brian R. Schuler, PharmD, senior pharmacist; Kaylee K. Marino, PharmD, BCCCP, BCPS, clinical pharmacy specialist; and Michael Reznik, MD
As pharmacists and clinicians working in the neurosciences intensive care unit (ICU), we understand the importance of agitation and delirium management and acknowledge the lack of evidence related specifically to the neurocritical care population. Although we do use propofol and antipsychotic medications in many cases, and prefer quetiapine or olanzapine because of less potent antidopaminergic effects, we have aimed to highlight alternative strategies used at our institution while welcoming additional insights into management strategies of other institutions.
We will describe several adjunctive pharmacologic options used in our ICU, including dexmedetomidine, ketamine and phenobarbital. We will also review the mood-stabilizing properties of antiepileptics and those that can hypothetically contribute to agitation. Ultimately, our goal is to develop an agitation and delirium management protocol utilizing the available literature within our neurosciences ICU.
According to the Diagnostic and Statistical Manual of Mental Disorders (5th Edition), delirium is an acute disorder of cognition and consciousness that leads to disturbances in attention, awareness and other cognitive domains.1 The incidence of delirium varies depending on patient population, with studies suggesting as few as 25% or as many as 80% of critically ill patients may develop delirium depending on illness severity and other characteristics.2-4
Delirium has been associated with increased mortality, length of intensive care unit (ICU) and hospital stay, overall healthcare costs and long-term cognitive dysfunction.5-9 Risk factors for delirium in the ICU include increased age and history of dementia or poor cognitive baseline, and may also potentially include poorly controlled pain, benzodiazepine use, emergency surgery or trauma and a higher severity of critical illness.10 As there is evidence to suggest that steroids, especially at high doses, may be associated with an increased risk of delirium in non-neuroscience patients, there may be similar concern for steroid use as a delirium risk factor in some neurocritical care patients.11
Non-pharmacologic treatments for agitation, such as redirection and one-to-one observation, are generally preferable whenever possible, but these are often insufficient in urgent and high-risk scenarios. Antipsychotics have traditionally been a staple of pharmacologic management of agitation, but there is data to support the use of several alternative pharmacologic agents in the general critical care population. These data and the use of these medications have also been extrapolated to the neurocritical care population, but there is currently no high-quality evidence to guide the management of neurocritically ill patients with agitation and delirium, as such patients have traditionally been excluded from large clinical trials.
Dexmedetomidine is a highly-selective alpha-2 adrenergic agonist used as a light sedative and anxiolytic in the ICU.12 One of its major advantages is providing sedation and modest analgesia with minimal depression of respiratory function, allowing it to be utilized in both intubated and non-intubated patients.13 The Society of Critical Care Medicine (SCCM) Guidelines for the Prevention and Management of Pain, Agitation/Sedation, Delirium, Immobility, and Sleep Disruption (PADIS) conditionally recommend the use of dexmedetomidine as a first-line sedative over benzodiazepines.10
Use of dexmedetomidine has been associated with decreased length of mechanical ventilation but has not yet been shown to have a consistent impact on delirium rates.14-17 Its relatively light level of sedation can allow easier detection of neurologic deterioration, which is an additional advantage in neurocritical care patients. However, its use in some patients is limited by hypotension and bradycardia,18,19 especially those with higher degrees of critical illness and a history of heart disease.20 Further, some patients may have re-emergence of agitation after dexmedetomidine is weaned. In such cases, some evidence suggests there may be a benefit in transitioning to oral clonidine, another alpha-2 agonist.21 Data for dexmedetomidine use in neurocritical care patients is of low quality, but it is being increasingly used in the neuro-ICU and is currently believed to be safe.22
Ketamine is an anesthetic with dissociative effects through its inhibition of N-methyl-D-aspartate receptors and analgesic effects through its agonism of mu, delta and kappa opioid receptors.23,24 As a result of its mechanisms of action, ketamine has been associated with a positive hemodynamic response and minimal respiratory depression.
Although historically there had been hesitation in the use of ketamine in brain-injured patients due to early studies describing an increase in ICP, modern studies have not shown any impact on ICP or clinical outcomes.25-27 The 2018 SCCM PADIS guidelines conditionally recommend the use of low-dose ketamine as an opioid-sparing analgesic in post-surgical patients.10 Ketamine may also be effective in the management of refractory status epilepticus (SE)28-30 and is included in the Neurocritical Care Society’s (NCS) guidelines as an alternative therapy for refractory SE.
However, ketamine comes with potential behavioral effects, as its use has been associated with psychosis, especially as an emergence phenomenon — an especially undesirable effect in patients at risk of delirium. However, synergy with GABA agonists has been described,31 which may also reduce the incidence of emergence psychosis. Although ketamine causes minimal respiratory depression, its use in non-intubated patients may be limited by prominent sialorrhea, and caution should be exercised in patients unable to clear their secretions due to poor arousal or an impaired cough reflex.
Phenobarbital is a sedative-hypnotic that exerts its effects through the prolongation and potentiation of GABA on GABAA receptors.32 While still widely used as an anti-epileptic in developing countries, barbiturates continue to see a decreased use in developed countries due to a concern for adverse effects, including sedation and impaired cognition.33 However, interest in phenobarbital has been renewed in the management of alcohol withdrawal, for which its prolonged half-life may reduce benzodiazepine requirements and the need for high-dose continuous anesthetic infusions.
Some small studies have also considered phenobarbital (via both enteral and intravenous routes) as an anesthetic-sparing agent in other critically ill patients.34-36 Recently, phenobarbital use has also increased for general sedation purposes due to shortages of other medications during the COVID pandemic, and our institution has used it as an alternative to propofol when limited by propofol-related adverse effects. However, because of its prolonged half-life and similar mechanism of action as benzodiazepines, which are known to be deliriogenic, phenobarbital may also potentially be a risk factor for delirium. Further studies are needed to assess its safety and efficacy in neurocritical care patients.
Antiepileptics are often used prophylactically in some neurocritical care patients, such as those with traumatic brain injury and those undergoing craniotomy procedures. They are also used in the longer-term management of patients with diagnosed seizure disorders. Some antiepileptics have been shown to have mood-stabilizing effects, while others may potentially contribute to agitation, delirium and psychosis.
In patients with brain injury, small case studies have shown an improvement in agitation with both carbamazepine and valproate.37-40 Carbamazepine is only available enterally, which may limit its utility in the ICU, and is associated with side effects including hyponatremia, the syndrome of inappropriate antidiuretic hormone secretion, bone marrow suppression and Stevens-Johnson syndrome.41
Valproate is available as an intravenous or enteral formulation but is associated with hepatotoxic effects including hyperammonemia encephalopathy.42 Other antiepileptics, including levetiracetam and perampanel, may increase the risk of psychosis and aggressive behavior in some patients.43-45 It may, therefore, be reasonable to consider transitioning some patients from levetiracetam to valproate if they develop severe agitation or other adverse behavioral symptoms, but further studies are needed to determine the efficacy of this strategy.
Management of agitation and delirium should first ensure appropriate pain control, reduction of external stimuli and other non-pharmacological approaches, whenever possible. In cases where agitation and delirium persist despite optimization of these therapies, alternative agents can be considered.
Neurocritical care patients present unique concerns relative to non-neurologic critically ill patients, with potential concerns related to neurotoxic effects of sedatives that may inhibit recovery after severe neurologic injury. Other factors, such as antiepileptic medications, may also play a contributory role. Further studies of agitation and delirium treatment in patients with severe neurologic injury are critically necessary, and future guidelines should consider the risks and benefits of a wide variety of potential treatments. We also recognize that there is likely to be substantial variability in institutional practices, and we welcome discussion and comments on others’ experiences in using various agitation treatment strategies.
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- Cavallazzi R, Saad M, Marik PE. Delirium in the ICU: an overview. Ann Intensive Care. 2012;2:49.
- Ely EW, Inouye SK, Bernard GR, et al. Delirium in mechanically ventilated patients: validity and reliability of the confusion assessment method for the intensive care unit (CAM-ICU). JAMA. 2001;286(21):2703-10.
- Sharma A, Malhotra S, Grover S, et al. Incidence, prevalence, risk factor and outcome of delirium in intensive care unit: a study from India. General Hospital Psychiatry. 2012;34(6):639-46.
- Vasilevskis EE, Chandrasekhar R, Holtze CH, et al. The Cost of ICU Delirium and Coma in the Intensive Care Unit Patient. Med Care. 2018;56(10):890-7.
- Pisani MA, Kong SY, Kasl SV. Days of delirium are associated with 1-year mortality in an older intensive care unit population. Am J Respir Crit Care Med. 2009;180(11):1092-7.
- Ely EW, Shintani A, Truman B, et al. Delirium as a predictor of mortality in mechanically ventilated patients in the intensive care unit. JAMA. 2004;291(14):1753-62.
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