Emergence Delirium and Agitation in the Perioperative Period

Emergence delirium (ED) and emergence agitation (EA) are abnormal mental states that develop as a result of anesthesia administration during the transition from unconsciousness to complete wakefulness. Inadequate emergence from anesthesia can present with either hyperactivity or hypoactivity. Key points in the management of these conditions include the following:

• The estimated incidence of ED is 4-31% overall but can be as high as 50-80% in children
• Extremes of age, male gender, and preexisting mental disorders (eg, depression, anxiety, and posttraumatic stress disorder [PTSD]) are among the patient factors contributing to ED; preoperative anxiety and, in children, poor adaptability and sociability predispose to ED
• The use of volatile anesthetics (particularly shorter-acting ones), higher postoperative pain level, specific types of surgical procedures (otorhinolaryngeal and ophthalmic surgery in children; intra-abdominal and breast surgery in adults), longer duration of preoperative fasting (particularly in children), and longer duration of the surgical procedure are associated with a higher incidence of ED
• The pathophysiology of ED is not well understood; imbalance between excitatory and inhibitory pathways and differential effects of hypnotic agents on cortical and subcortical networks may play roles
• The clinical presentation is characterized by impaired awareness and abnormal cognitive function, confusion, and verbal and physical agitation or hypoactivity
• The diagnostic distinction between ED and EA is based on the time from the offending anesthetic
• Neurocognitive assessment with the Pediatric Anesthesia Emergence Delirium (PAED) scale, the Richmond Agitation-Sedation Scale (RASS), and the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) is used for the diagnosis of ED
• The impact of ED is evident in the psychological distress of patients and caregivers, the increased risk of adverse postoperative events, and the potential for long-term complications, as well as the diminished patient satisfaction, the prolonged recovery time, the longer hospital stay, and the increased cost of care
• An essential component of the management of ED is a preemptive strategy that involves nonpharmacologic interventions, selection of appropriate anesthesia and multimodal analgesia regimens, and pharmacologic therapy using premedication and intraoperative administration of various agents (eg, propofol, dexmedetomidine, clonidine, fentanyl, midazolam, and dexamethasone); combinations of pharmacotherapeutic agents are more successful than monotherapy in preventing ED
• Treatment of ED includes control of pain and agitation via supportive measures and pharmacotherapy so as to avoid complications

The terminology used to describe abnormal emergence from anesthesia varies in the literature. The term emergence delirium is often applied to the state of agitation and hyperactivity occurring when a patient wakes from anesthesia, whereas the term hypoactive emergence is often applied to delayed recovery from anesthesia with reduced arousal and attentiveness. In this article, ED is considered to encompass both types of inadequate emergence.

ED is demonstrated in patients of all ages, though it has been more extensively recognized and studied in the pediatric population. The average estimated incidence of ED in children is in the range of 18-30%; however, estimates have ranged from as low as 2% to as high as 80% in some studies. ^[1]  In the adult population, ED in the postanesthesia care unit (PACU) is identified in 4-31% of cases, depending on the assessment criteria used and the timing of the evaluation. ^{[2, 3, 4]} In combat-injured veterans and those with preexisting mental health issues (eg, anxiety, depression, and PTSD), the incidence may be as high as 20-50%. ^{[5, 6]}

Etiology and risk factors

ED occurs in the setting of sedation and general anesthesia, and the specific anesthetic agents administered have an impact on its incidence. Shorter-acting volatile agents (eg, sevoflurane and desflurane) are associated with a higher incidence of ED than longer-acting agents (eg, halothane and isoflurane) are. Intravenous (IV) hypnotic agents such as propofol have consistently been shown to confer a lower risk ^[1] ; however, the use of etomidate, ^[7] as compared with propofol or thiopental, has been associated with an increased incidence of ED.

The effect of depth of anesthesia on the incidence of ED remains unclear. Premedication with benzodiazepines, as compared with no benzodiazepines, appears to increase the risk of ED in adults. ^{[2, 4]}  In children, some studies indicate increased risk, whereas others suggest a beneficial role in prevention of ED.

A higher level of postoperative pain has been identified as a precipitating factor, one that is more significantly linked to hyperactive ED. ^[7] Some studies have suggested an association between the total dose of perioperative opiate analgesia administered and the incidence of ED, ^[4]  but the apparent cause-and-effect relation may in part reflect the contribution of postoperative pain. It is important to note that impaired emergence also occurs after nonpainful procedures (eg, imaging under anesthesia), especially in children.

A longer procedure duration has been correlated with an increased incidence of ED, particularly for hypoactive emergence. ^[7] Associations between specific procedures and ED have been identified. Otorhinolaryngeal and ophthalmic surgery in children have been linked to abnormal emergence, as have musculoskeletal, intra-abdominal, and breast surgery in adults. ^{[2, 7]}

Other potential predisposing factors (eg, longer duration of preoperative fasting, higher surgical risk, lower core temperature, residual neuromuscular blockade, presence of an endotracheal tube, presence of a urinary catheter, and urinary retention) have been proposed, albeit with less consistent evidential support. ^[8]

Patient characteristics associated with ED include extremes of age and male gender. Preschool children and adult patients younger than 40 years or older than 65 years are at higher risk. ^{[4, 7]} In the pediatric population, certain psychosocial characteristics (eg, patient and parental preoperative anxiety, poor adaptability, and decreased sociability) increase the risk of ED. ^{[9, 10]} Preexisting anxiety, psychiatric disorders, PTSD, use of psychotropic medications, and substance abuse may also predispose patients to ED. ^{[5, 6]}

Research into other metabolic and neurotransmitter imbalances continues, with the aim of further elucidating the contribution of potentially modifiable factors to the development of ED. ^[11]  

Pathophysiology

Various hypotheses have been proposed to explain the genesis of ED; however, a clear understanding of the underlying mechanisms remains elusive. No single hypothesis explains all cases or is able to reconcile the differing clinical observations.

Faster emergence from anesthesia has been postulated to contribute to ED. Although the increase in ED with the use of modern shorter-acting anesthetic agents lends some support to this hypothesis, the evidence is inconsistent with respect to the different volatile agents. Furthermore, the literature suggests that short-acting IV agents such as propofol are associated with a lower incidence of ED.

Hypnotic agents alter the balance between excitatory and inhibitory neural pathways and affect the cortical networks responsible for higher-order processing, including emotional and memory functions. Depending on the level of sedation these agents induce, the lower-order sensory networks display preserved connectivity, increased connectivity in sensory-motor networks, and altered cross-modal sensory interactions. ^[12]

Delayed recovery of cognitive function; lagging recovery of vision, audition, and locomotion; and imbalance between the different brain functions may in part explain the development of ED. In children, immaturity of neuropsychological development and differences in cognitive control may contribute to the higher incidence of ED. ^[13]

Presentation

Symptoms of ED include the following:

• Confusion
• Disorientation
• Irritability
• Crying
• Inconsolability
• Involuntary movements such as kicking and writhing
• Violent verbal or physical behavior
• Avoidance of eye contact
• Lack of cooperation
• Lack of awareness of surroundings
• Inability to recognize familiar persons

Patients with PTSD may experience flashbacks and hallucinations and may display specific behavior related to their prior experience. Hypoactive emergence is characterized by depressed mental status and reduced responsiveness. Because this form of ED tends to attract less attention, its presence may be underrecognized.

The onset of ED symptoms usually comes shortly (typically 14 ± 11 minutes) after the end of anesthesia; however, delayed ED can occur as long as 45-60 minutes after the end of anesthesia. Although the duration of ED is usually short (average, 5-20 minutes), patients may exhibit signs for 1 hour or longer.

Diagnosis

To date, studies have not consistently defined clear diagnostic criteria for hyperactive and hypoactive delirium. Furthermore, in children, it may be challenging to distinguish between agitated emergence and pain or behavioral events (eg, temper tantrums). In adults, it may be challenging to differentiate residual anesthetic effects from hypoactive emergence.

Several assessment tools have been studied in the pediatric population, including the Pediatric Confusion Assessment Method for the Intensive Care Unit (p-CAM-ICU) and the revised Cornell Assessment of Pediatric Delirium (CAP-DR); however, the Pediatric Anesthesia Emergence Delirium (PAED) scale (see Table 1 below) is considered to be better validated and is more widely utilized. ^[14]  A PAED score of 10 or higher is considered to be diagnostic of ED, but a score of 12 or higher is more sensitive and specific. The degree of ED is directly correlated with the total PAED score.

Table 1. Pediatric Anesthesia Emergence Delirium (PAED) Scale (Open Table in a new window)

In adults, the Richmond Agitation-Sedation Scale (RASS; see Table 2 below) and the CAM-ICU (see Table 3 below) are used extensively for the purposes of both clinical practice and research. They are best applied in conjunction; an RASS score of 0, coupled with positive results on the CAM-ICU, can aid in identifying hypoactive emergence. 

Table 2. Richmond Agitation-Sedation Scale (RASS) (Open Table in a new window)

Table 3. Confusion Assessment Method for Intensive Care Unit (CAM-ICU) (Open Table in a new window)

The mainstay of diagnosis of ED is clinical assessment in conjunction with with application of the neurocognitive assessments. Some experimental evidence suggests that additional diagnostic tests may be available, such as pupillometry and assessment of pupillary light reflex. ^[15] Further validation of such testing is needed.

Outcomes

ED can pose a significant danger to both patients and caregivers and can result in potentially life-threatening complications. In hyperactive emergence, adverse events include the following:

• Infliction of injury
• Disruption of the surgical field and bleeding
• Accidental removal of noninvasive and invasive monitoring and therapeutic devices, including loss of IV access and airway and respiratory therapy appliances

Respiratory compromise and hemodynamic instability may result from either hyperactive or hypoactive states of inadequate emergence.

ED can lead to prolonged PACU and hospital stays and may necessitate additional interventions. It has a negative impact on the quality of patient care and cost-effectiveness. Delirium in the PACU is linked to an increased likelihood of subsequent postoperative hospital delirium, which in turn is associated with long-term cognitive impairment and increased morbidity and mortality. ^[16]

Parental and caregiver distress is an additional consideration. In children, there may be a link between ED and late postoperative behavioral alterations such as temper tantrums, fear of abandonment, and attention-seeking, as well as disturbed sleep, bedwetting, and various postdischarge behavioral changes. ^[17] The long-term psychological impact of ED in children is unclear.

Addressing the problem

The optimal strategy for management of ED should focus primarily on prevention and mitigation of modifiable risk factors. ED is of short duration and often self-limiting. Nonpharmacologic interventions have been shown to be effective, especially in the pediatric population, for alleviating preoperative anxiety and reducing postoperative delirium.

Preoperative education of children and their parents, distraction with age-appropriate interventions (eg, toys, games, videos, or clowns), music therapy, and hypnosis are all potentially beneficial. A dedicated induction room can provide a calming and less overwhelming environment. The advantage of parental presence is more consistently demonstrated in the preoperative area and is less consistently evident during induction; however, it appears to have a stronger positive impact if coupled with a comprehensive program aimed at preparing children and parents jointly. ^[9]  

A study that compared recordings of a maternal voice to recordings of a stranger's voice or no recordings in the PACU demonstrated reductions in ED among the pediatric patients who listened to the maternal-voice recordings. ^[18]  

In one study, although a virtual reality tour in children failed to reduce ED, it did alleviate anxiety, suggesting that further study into its potential role is warranted. ^[19] In ophthalmic surgery, visual preconditioning (application of an eyepatch over the eye to be operated) has been suggested to help with ED. ^[20]

Reduction of the time of preoperative fasting in accordance with preoperative societal guidelines, particularly in children, may have a positive impact on the incidence of ED. ^[8]

Evaluation and adjustment of the anesthesia plan with careful selection of hypnotic agents, when feasible, are important. Administration of premedication and the choice of specific agents and their route of administration are also important, particularly in pediatric patients. ^[21] In high-risk settings, total IV anesthesia should be considered; evidence indicates that propofol, as compared with volatile agents, reduces the risk of ED. ^[1] The use of anesthetic agents with analgesic properties (eg, ketamine and dexmedetomidine) confers added benefits. Dexmedetomidine has been shown to be effective as a premedication, as well as a perioperative adjunct to anesthesia. ^{[21, 22, 23, 24]}

The benefit of electroencephalography (EEG)-guided anesthesia management (vs usual anesthesia care) in reducing ED has been suggested. It has been inconsistently supported in a meta-analysis and was not supported in a randomized controlled trial. ^{[25, 26]}  However, a single-center randomized trial of adults undergoing carotid endarterectomy indicated benefit in reducing postoperative delirium. ^[27]

Optimal pain control is essential. Consistent pain control must be maintained intraoperatively and through the postoperative period. Short-acting continuous opiate infusion with remifentanil may have a role through the recovery stay in the PACU. ^[28]  A multimodal pain regimen should be instituted, with the use of regional anesthesia, opiate and nonopiate agents (eg, nonsteroidal anti-inflammatory drugs [NSAIDs]), and gabapentin.

Additional pharmacologic preventive options include premedication and intraoperative use of midazolam, clonidine, and dexamethasone, as well as melatonin and magnesium infusion. ^{[29, 30, 31, 32]} The advantages of dexmedetomidine and dexamethasone lie in their antiemetic and analgesic properties. In addition, propofol has an antiemetic effect, and ketamine confers an analgesic benefit.

The use of benzodiazepines should be judicious. These agents are selectively indicated, in that they may help mitigate abnormal emergence in children ^{[30, 33]} ; however, in adults, benzodiazepines are associated with an increased risk of ED. ^{[2, 4]}

Pharmacologic regimens utilizing a combination of medications have greater success in reducing ED than monotherapies do. A meta-analysis has supported the addition of midazolam and antiemetics to improve the efficacy of other medications ^[34] ; specifically, the combinations of dexmedetomidine-midazolam-antiemetic and midazolam-propofol-antiemetic were associated with the lowest incidence of ED. Among the monotherapies, high-dose melatonin (0.4 mg/kg) and nalbuphine had the highest benefit in preventing ED. ^[34]

Psychological interventions are also employed in the treatment of ED, with the following aims:

• To reduce undesirable stimulation and calm down agitated patients
• To maintain an appropriate level of arousal in hypoactive emergence
• To assist in reorientation and improvement of the cognitive function

Parental presence in the PACU, when clinically appropriate, can be effective in quieting children. Physical restraints should be avoided; they are relatively ineffective and may increase the risk of injury. Adjustment of respiratory devices and removal of catheters and appliances that are no longer needed may help reduce stimulation.

In addition to optimization of pain control, clinicans should emphasize treatment of untoward events such as nausea, emesis, hypothermia, and shivering.

The goals of pharmacologic therapy are to control agitation and reduce the risk of injury. In choosing a specific agent and determining an optimal dosage, it is necessary to balance the expected therapeutic benefits against the potential adverse effects on hemodynamics, respiratory status, and other organs, as well as the possibility of a prolonged PACU stay. ^[35]  (See Table 4 below.)

Table 4. Pharmacologic Agents for Prevention and Treatment of Emergence Delirium (Open Table in a new window)

Clinical scenario

A 4-year-old 18-kg boy presents for a tonsillectomy. He is an only child, raised at home, and the parents are extremely anxious. As the anesthesiologist introduces herself to the family and discusses the patient’s medical history and the plan of anesthetic care, the child is becoming agitated and uncooperative. The anesthesiologist prepares midazolam 8 mg in a sip of clear syrup, and the parents coax the child to drink it.

The anesthesia team proceeds to perform inhalation induction with sevoflurane in the specialized induction room, while the parent holds the crying child. After induction, the child is moved to the operating room (OR). The anesthesiologist proceeds with general anesthesia with sevoflurane and administers IV dexamethasone, acetaminophen, fentanyl, and ondansetron. The case proceeds smoothly, and the child is extubated and promptly transferred to the PACU.

On arrival in the PACU, the child starts crying inconsolably. He is not making eye contact or focusing at all and is kicking and moving purposelessly, with resultant disconnection of the monitors and the supplemental oxygen. He is observed to cough up a small amount of blood-tinged secretions.

Resolution

The anesthesiologist promptly administered 10 mg of IV propofol and 15 μg of IV fentanyl. The child became sleepy, and the nurse was able to place him on his side and replace the monitors and blow-by oxygen. A call was placed to the waiting area to bring the parent to the bedside. While being held by the parent, the child slowly woke up with a small cry, but he was calmed down by the parent, and recovery then proceeded uneventfully. The patient was discharged home when he met the discharge criteria.

Clinical scenario

A 26-year-old 73-kg man, who has recently returned from overseas military service with multiple injuries sustained in a military operation, presents for exploratory laparotomy and reversal of a colostomy. He states that he has been under a significant amount of stress and has been experiencing persistent debilitating pain. He also reports that he has undergone two surgical procedures in the field hospital and that after both of them, he woke up from anesthesia with agitation and hallucinations. During one of these episodes, he accidentally removed his urinary catheter.

Resolution

The anesthesiologist administered gabapentin 300 mg orally with a sip of water in the preoperative area. In the OR, the monitors were placed and IV induction performed with propofol 2 mg/kg and a muscle relaxant. Total IV anesthesia was initiated with infusion of propofol 200 μg/kg/min and dexmedetomidine 0.2 μg/kg/min, along with intermittent IV doses of fentanyl. Dexamethasone and IV acetaminophen were administered intraoperatively, and at the end of the procedure, ondansetron and fentanyl bolus were given.

After the extubation criteria were met, the endotracheal tube was successfully removed and the patient transferred to the stretcher. During transport to the PACU, the patient became slightly agitated and started attempting to remove his gown. The anesthesiologist reoriented the patient verbally and, after inquiring about the patient’s level of pain, administered an additional 75-μg dose of fentanyl. The patient was admitted to the PACU and completed his recovery uneventfully.