TABLE 57.1 Differential Diagnosis for Acute Undifferentiated Agitation
BACKGROUND
Emergency physicians are frequently called upon to provide care to agitated, violent, and combative patients. These patients pose a significant safety threat to themselves and to the providers who care for them; furthermore, their agitation can impede the diagnostic workup and delay potentially lifesaving care. Chemical sedation is often necessary in order to ensure patient and provider safety and to expedite the diagnostic workup.
Acute undifferentiated agitation can be classified broadly into medical, toxicologic, or psychiatric etiologies (Table 57.1). It may present with a wide spectrum of severity; patients may be agitated but cooperative or dangerously combative. Excited delirium syndrome (ExDS), also referred to as agitated delirium, is a recently-recognized syndrome that represents the most severe form of agitation. ExDS can be precipitated by almost any psychiatric or medical condition, drug, toxin, or biochemical or physiologic alteration.1 Patients with ExDS are typically young males; they present in a hyperadrenergic autonomic state characterized by hyperthermia, tachycardia, insensitivity to pain, and superhuman strength.1 ExDS is associated with an increase in mortality and represents a true medical emergency that requires immediate attention.
TABLE 57.1 Differential Diagnosis for Acute Undifferentiated Agitation
MANAGEMENT GUIDELINES
Although sedation is a critical component of the management of acute agitation in the emergency department (ED), health care professionals should be mindful that these patients are experiencing personal, psychological, and medical crises and that they deserve respect and dignity. Prior to administering sedative agents, de-escalation techniques both verbal and environmental (i.e., turning the lights down, minimizing ambient noise) should be attempted. Such techniques may fail in the severely agitated (or combative) patients, some of whom may require physical restraint prior to chemical sedation. If physical restraint is used, it should be for the shortest time possible; positioning a restrained patient in the prone position should be avoided as this has been associated with increased mortality.2
Benzodiazepines and antipsychotic medications are the most commonly-used pharmacologic agents for the sedation of the agitated patient (Table 57.2). Although intravenous (IV) administration of these medications allows for rapid onset, this dosing route may be challenging and unsafe in the combative and uncooperative patient. For this reason, intramuscular (IM) formulations are often used initially until an IV can be established. Oral administration of benzodiazepines and antipsychotics is rarely given in acutely agitated patients, but can be considered in those who are cooperative.3
TABLE 57.2 Agents for Acute Undifferentiated Agitation in the Emergency Department
IV, intravenous; IM, intramuscular; PO, oral. Consider using lower doses for elderly patients. Adapted from Vilke GM, et al. J Forensic Leg Med. 2012;19:117–121; and Wilson MP, et al. West J Emerg Med. 2012;13:26–34.
MEDICATIONS USED FOR SEDATION OF THE SEVERELY AGITATED EMERGENCY DEPARTMENT PATIENT
Benzodiazepines have a long history of use in the treatment of agitation. This drug class binds to the gamma–aminobutyric acid β (GABA-β)-subtype receptor—the primary inhibitory neurotransmitter of the central nervous system—and exerts sedative, hypnotic, anxiolytic, anticonvulsant, amnestic, and muscle relaxant effects.4 Lorazepam and midazolam are the most commonly used and best studied benzodiazepines for the management of acute agitation because they have predictable onset of action when given in the IM form. Diazepam, chlordiazepoxide, and clonazepam are infrequently used in the acute management of agitation because they have longer half-lives and have inconsistent IM absorption.5 Midazolam has a faster onset and shorter duration of action than lorazepam, especially when given IM; however, patients receiving midazolam may require more frequent redosing because of its shorter half-life.6,7
The dosing of IM and IV midazolam and lorazepam is listed in Table 57.2. Protocols recommend dosing midazolam 2 to 5 mg IV every 5 to 10 minutes.8,9 Serial dosing, however, must be used cautiously, as it may increase the risk of respiratory depression, which was reported to be as high as 13% with use of this protocol.9 Fortunately, this serious side effect is usually transient;5,9,10 it may, however, be more common in patients with ethanol or opiate intoxication and so should be used with caution in this population. Additional side effects of benzodiazepines include ataxia, dizziness, and decreased blood pressure, especially in patients who are hypovolemic.
Benzodiazepines should be reserved for patients whose agitation is severe and who present an immediate threat to themselves or others. They may also be useful in patients who are withdrawing from ethanol or benzodiazepines or those who have taken stimulants such as amphetamines or cocaine.11 For agitated patients with delirium, the risks and benefits of benzodiazepine use, which can exacerbate delirium, must be carefully weighed.12
Typical, or first-generation, antipsychotics have a long history of use in the treatment of agitation. Haloperidol and droperidol are high-potency butyrophenone antipsychotics that primarily antagonize the D2 dopamine receptor. Despite their side effects (discussed below), and the availability of newer generation atypical antipsychotics, haloperidol and droperidol are still widely used for the management of agitation. They have relatively little effect on hemodynamics13 and can be given orally, intramuscularly, and intravenously.
Although haloperidol is more commonly used for agitation, droperidol offers several advantages. Droperidol may have a more rapid onset of action and a shorter half-life when given intramuscularly.14 In one randomized controlled study comparing droperidol 5 mg IM with haloperidol 5 mg IM, droperidol achieved more rapid control of the patient's agitation without any relative increase in side effects.15 Compared with IM haloperidol, IM droperidol may also last longer and be less likely to require repeat dosing.16 The dosages for haloperidol and droperidol are listed in Table 57.2. Serial dosing (i.e., every 5 to 10 minutes) can be required to achieve adequate sedation; total doses exceeding 20 mg are associated with increased side effects and have limited incremental benefit.6,17,18
One of the most feared side effects of both droperidol and haloperidol is QT prolongation and torsades de pointes, especially when theses drugs are given intravenously and at higher doses.19,20 Because of reports of cardiac death secondary to torsades de pointes, the FDA issued a black box warning on droperidol in 2001 that has curtailed its use in the clinical setting. This warning is not without controversy. Many have argued that the adverse events observed with droperidol were at doses much higher than typically used for agitation. Several studies have also shown droperidol to be safe for use at doses typically administered for agitation.21,22 Regardless, special care should be taken when using either haloperidol or droperidol in patients with a known prolonged QT interval, who take other QT prolonging medications, or have medical conditions that cause QT prolongation. A 12-lead electrocardiogram should be obtained if possible prior to IV administration. If the patient's QTc interval is >500 milliseconds, the IV route should be avoided.
Haloperidol and droperidol can also cause extrapyramidal symptoms (EPS)—including acute dystonic reactions, akathisia, and pseudoparkinsonism—due to their blockade of dopamine receptors in the basal ganglia. Because haloperidol and droperidol have relatively little anticholinergic activity, EPS occurs in up to 20% of patients treated with these medications.23 Anticholinergic agents such as diphenhydramine (25 to 50 mg), benztropine (1 to 2 mg), and promethazine (25 to 50 mg) are usually effective in treating acute EPS, though severe akathisia may require benzodiazepines.
Droperidol and haloperidol have also been shown to decrease seizure threshold and should be used with caution in patients with a history of seizures. Finally, neuroleptic malignant syndrome (NMS) is a rare but potentially fatal complication of these medications.
Olanzapine, risperidone, aripiprazole, and ziprasidone have been extensively evaluated for the treatment of acute agitation in the psychiatric patients; their role in the ED patient with undifferentiated agitation is less clear. Most atypical antipsychotics have oral and IM formulations, although the IM formulation may be less readily available in the ED.
Compared to typical antipsychotics, second-generation, or atypical, antipsychotics have a favorable side effect profile. Atypical antipsychotics also antagonize the dopamine D2 receptor, but unlike typical psychotics, they also antagonize the serotonin 5-HT2, histamine, alpha, and muscarinic receptors to variable degrees. They are less likely to cause oversedation, EPS, QT prolongation, and vital sign abnormalities. Some concerns, however, have been raised about hypotension and oxygen desaturation caused by parenteral olanzapine used in combination with benzodiazepines, especially in patients intoxicated with ethanol.25–27 Similar to typical antipsychotics, NMS has also been reported in patients receiving atypical antipsychotics.28
CHOICE OF MEDICATION FOR SEDATION OF THE AGITATED PATIENT
The choice of medication for sedating the agitated ED patient can depend on how quickly sedation needs to be achieved and on the desired length of sedation. Several randomized controlled trials of typical antipsychotics have explored how they compare with benzodiazepines as monotherapy for controlling agitation. In one study, 111 ED patients with severe agitation were treated with either midazolam 5 mg IM, lorazepam 2 mg IM, or haloperidol 5 mg IM; midazolam was reported as having the shortest time to adequate sedation and shorter times to awakening compared with haloperidol and lorazepam.7 A second study compared midazolam 5 gm IV with droperidol 5 mg IV in 153 agitated ED patients and allowed these medications to be redosed every 5 minutes until adequate sedation was achieved.8 The study observed that more patients in the midazolam group achieved adequate sedation within 5 minutes (45% vs. 17%), suggesting that midazolam may have faster onset of action than droperidol. Both medications had side effects; there was a trend toward increased respiratory depression in the midazolam group (4.1% vs. 0.0%) and dystonic reactions in the droperidol group (0.0% vs. 3.8%). A third study compared droperidol IV (2.5 mg for patients <50 kg, 5.0 mg for patients >50 kg) with lorazepam IV (2.0 mg for patients <50 kg, 4.0 mg for patients >50 kg) in 202 agitated ED patients; repeat dosing was allowed in 30 minutes.28 Though sedation was similar for both medications at 5 minutes, a larger proportion of the droperidol group achieved adequate sedation at subsequent time intervals. In addition, more patients in the lorazepam arm required redosing compared with the droperidol arm. No major adverse events occurred in either group.
The role of atypical antipsychotics in the management of the acutely agitated ED patient is less well established. To date, most research has been conducted in patients whose agitation has a psychiatric cause; in this population, atypical antipsychotics such as olanzapine, aripiprazole, and risperidone are as effective as haloperidol and show a lower incidence of EPS.29–31 Only one randomized controlled trial has evaluated the role of atypical antipsychotic medications in the ED patient with undifferentiated agitation. This study randomized 144 agitated ED patients to receive midazolam 5 mg IM, droperidol 5 mg IM, or ziprasidone 20 mg IM.17 Only 39% of the ziprasidone group achieved adequate sedation within 15 minutes compared to 69% of the midazolam group and 60% of the droperidol group.17 As result, IM ziprasidone is not recommended for rapid sedation of the agitated patient.
In the agitated patient with a psychiatric etiology, several studies have demonstrated that a butyrophenone in combination with a benzodiazepine results in improved sedation with less EPS than monotherapy.23,32,33 In ED patients, the role of combination therapy in the patient with undifferentiated agitation remains unclear. One randomized controlled trial compared droperidol 10 mg IM, midazolam 10 mg IM, and the combination of droperidol 5 mg IM + midazolam 5 mg IM in 91 violent and agitated ED patients.34 The study did not observe any differences in the duration of agitation between the three groups. However, the midazolam group required more redosing to maintain adequate sedation; this group also experienced a nonsignificant tendency to develop oxygen desaturations, especially in patients with ethanol intoxication. A second randomized controlled trial compared midazolam IV alone with midazolam IV used in conjunction with either droperidol 5 mg IV or olanzapine 5 mg IV.24 The combination of droperidol + midazolam or olanzapine + midazolam was associated with significantly shorter times to adequate sedation compared with midazolam alone. More patients in the midazolam-only group required additional sedation within 60 minutes. There were no differences in adverse events or ED length of stay. Several retrospective studies, however, raise concerns that combining olanzapine with a benzodiazepine may result in lower oxygen saturations when given to patients with ethanol intoxication.35,36 As a result, additional research is needed to determine the safety and efficacy of combining antipsychotics and benzodiazepine in the treatment of agitation in the ED.
SUMMARY RECOMMENDATIONS
Based on the abovementioned studies, the following general conclusions can be made:
Ketamine is a dissociative anesthetic that antagonizes the N-methyl-D-aspartate receptor. It is commonly used in the ED for procedural sedation and induction of intubation and minimally affects respiratory drive. Several case reports have shown that ketamine may be useful in the treatment of severe agitation refractory to antipsychotics or benzodiazepines.37–39
Dexmedetomidine is an alpha-2 agonist sedative that produces minimal respiratory depression; an advantage of this agent is that patients remain easily arousable, even while their agitation is adequately controlled. The evidence supporting its use is limited to case reports in patients with delirium tremens.40 Further research is needed to establish the role and safety of both ketamine and dexmedetomidine in treating agitation in the ED.
CHOICE OF SEDATIVES BASED UPON CAUSE OF AGITATION
Recently, the American Association for Emergency Psychiatry released a consensus statement on the management of agitation in the ED including specific types of agitation that may warrant specific sedatives.11 In a busy ED, however, it is often challenging to determine the cause of agitation, especially early in a patient's course. With this caveat, for agitation secondary to stimulants, benzodiazepines are considered the first-line agent. Benzodiazepines should also be used for agitation secondary to alcohol and benzodiazepine withdrawal. For alcohol-intoxicated patients, benzodiazepines should be avoided because of increased risk of respiratory depression; haloperidol or a second-generation antipsychotic should be used instead. For agitation secondary to a psychiatric illness, antipsychotics are preferred over benzodiazepines, and atypical antipsychotics are preferred over typical antipsychotics. Benzodiazepines may be used if the initial dose of antipsychotic medications is insufficient to control agitation. For agitation secondary to hyperactive delirium not caused by a stimulant, ethanol withdrawal, or benzodiazepine withdrawal, haloperidol is recommended if immediate pharmacologic control is required. Benzodiazepines can exacerbate the delirium component of hyperactive delirium and should be avoided in those instances.41
CONCLUSION
The management of severe acute agitation in the ED is challenging and requires a coordinated effort between emergency physicians, nurses, and staff. When non-pharmacological methods fail to calm the patient, intervention with chemical sedation can to ensure patient and staff safety and facilitate the diagnostic workup. Familiarity with the summary recommendations provided in this chapter can help guide selection of the most appropriate sedative agent.
LITERATURE TABLE
RCT, randomized control trials; IV, intravenous; IM, intramuscular; ED, emergency department; 95% CI, 95% confidence intervals; LOS, length of stay.
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