Postoperative Delirium

Etiology

Delirium may be due to exacerbation of a primary injury or insult, or a potential new secondary insult or injury. Several studies have tried to identify risk factors predisposing to the development of delirium postoperatively. 

DSM-5 categorizes delirium as:

• Substance Intoxication delirium
• Substance withdrawal delirium
• Medication-induced delirium
• Delirium because of other medical conditions
• Delirium because of other etiologies

POD should be considered a separate category. The post-operative period is the time period right after surgery until the patient is discharged from the hospital. POD should not be diagnosed separately from emergence delirium although any lucid interval after emergence delirium should be noted.[1]

Factors that can predispose or precipitate post-operative delirium can be broadly divided into preoperative, intraoperative and postoperative causes.[2] 

Pre-Operative Factors

• Age over 65 years
• Male gender
• Baseline cognitive dysfunction
• Dementia
• Preoperative memory complaint
• Anxiety
• Depression
• Benzodiazepine use
• Intracranial stenosis
• Carotid stenosis
• Peripheral vascular disease
• Prior stroke/transient ischemic attacks
• Sensory impairments
• Diabetes mellitus
• Hypertension
• Atrial fibrillation
• Electrolyte abnormalities
• Alcohol abuse
• Sleep deprivation
• Smoking         

Intraoperative Factors 

• Hip surgery
• Cardiac surgery 
• Vascular surgery
  • Open greater than endovascular surgery
• Emergency surgery 
• Increased Surgical duration 
• Hypotension
• Shock
• Arrhythmias
• Hypothermia/hyperthermia
• Blood Transfusion

 Postoperative Factors

• Low hemoglobin 
• Hypoxemia
• Prolonged intubation
• Pain
• Hypoalbuminemia
• Liver failure
• Renal failure (BUN/Cr greater than 18)
• Sleep-wake disturbances

Alcohol and benzodiazepine withdrawal have also been known to cause POD.

Epidemiology

POD is common, and the prevalence increases with the severity of the surgical insult. According to DSM-5, the incidence of POD in non-cardiac surgery is anywhere between 15% and 54% depending on the screening test used. The incidence in the intensive care population is up to 70% to 80% during their entire stay. In cardiac surgery patients, the incidence is similarly high, between 26% and 52%.[1] 

While the incidence of POD is common and similar to other settings, there is a wide discrepancy in the literature regarding the incidence, partly due to the lack of clearly defined distinction between emergence delirium and POD. Prior studies have focused on hyperactive delirium, typically recognized as the patient in the PACU pulling at lines and tubes and being agitated, likely under-diagnosing hypoactive delirium, the most common, which is characterized by lethargy, decreased responsiveness and decreased activity level. This type will often go undiagnosed if routine delirium monitoring is not used.[3]

Despite these limitations, the incidence and risk factors of POD reported in the literature is strongly influenced by the severity of the surgical insult, comorbidities, and sedative and/or analgesic drug exposure.

Pathophysiology

Although the International Study of Post-Operative Cognitive Dysfunction 1 (ISPOCD1) concluded that general anesthesia is responsible for postoperative cognitive dysfunction (POCD), later studies showed a similar incidence in sedation and regional anesthesia cases.[4][5] Both surgery and anesthesia present patients with unique physiological conditions. Surgery causes the release of psychoactive inflammatory markers including interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha) and IL-1 beta that may contribute to the development of delirium through dopamine, GABA, or cholinergic-mediated pathways. On the other hand, general anesthesia exposes the brain to a myriad of cognitively active drugs that alter the chemical balance in the sleep/arousal pathway. The incidence of delirium is lower in patients exposed to light sedation compared to deep sedation.[6]

History and Physical

The patient can present with hyperactive psychomotor activity and frank psychosis in a hyperactive variety or as withdrawal and lethargy which can easily be mistaken for residual anesthetic effects, in hypoactive variety. Other common features include a fluctuating level of consciousness, disorientation, and impaired executive function.[7]

Evaluation

The first step in the evaluation of POD is to determine if the person is arousable to voice. If the person is not arousable to voice, then that person is considered to be in a coma. After the level of arousal has been determined, the delirium instruments can assess the content of the arousal by examining for fluctuating change in mental status highlighted by inattention and altered level of consciousness.[8]

The Richmond Agitation Sedation Scale (RASS) is the most commonly used assessment tool for the level of arousal.[9] Patients in a state of deep sedation or patients who are unarousable cannot be further assessed for delirium. 

Using the DSM-5 criteria, delirium is characterized by:

1. A disturbance in attention (reduced ability to direct, focus, sustain, and shift attention) and awareness (reduced orientation to the environment).
2. A disturbance that develops over a short period (usually hours to a few days) represents a change from baseline attention and awareness and fluctuates in severity during the day.
3. An additional disturbance in cognition (memory deficit, disorientation, language. visuospatial ability, or perception).
4. The disturbances in Criteria A and C are not better explained by another pre-existing established or evolving neurocognitive disorder and do not occur in a severely reduced level of arousal, such as coma.
5. There is evidence from the history, physical examination, or laboratory findings that the disturbance is a direct physiological consequence of another medical condition, substance intoxication or withdrawal (due to a drug of abuse or to a medication), or exposure to a toxin, or is due to multiple etiologies.

There are many assessment tools for delirium that have been validated for a variety of patient populations and hospital locations, including postoperatively on the ward or in the intensive care unit. 

These include:

• Confusion Assessment Method (CAM)
• Delirium Symptom Interview (DSI)
• Confusion Assessment Method for the intensive care unit (CAM-ICU) See Figure. The Confusion Assessment Method for the Intensive Care Unit (CAM-ICU).
• Intensive Care Delirium Screening Checklist (ICDSC)

CAM and variations of CAM are most commonly used. The CAM-ICU and 3D-CAM are brief versions of CAM that perform moment in time assessments for delirium. The Brief Confusion Assessment Method (bCAM) has been validated in the non-ICU setting. The CAM-ICU is validated for intubated patients on mechanical ventilation. See figure 1.

The Delirium Detection Scale (DDS) and the Memorial Delirium Assessment Scale (MDAS) can assess the severity of delirium.

Treatment / Management

Nonpharmacological followed by pharmacologic interventions should be employed early in the course of delirium to mitigate the risk of long-term adverse sequelae. Nonpharmacological interventions have been tried and have proven to be effective. Notable examples are the Hospital Elder Life Program (HELP) and modified HELP. These programs use multidisciplinary teams that work on reorienting the patient, socialization, daily visits from the family, feeding and nutrition balance, managing sleep-wake cycles, noise reduction, providing sensory aids and early mobilization. Using 3 protocols administered daily; i.e., orienting communication, oral and nutritional assistance, and early mobilization, Chen et al. demonstrated a significant reduction in the incidence of delirium in the intervention group.[10](A1)

The ABCDEF bundle used in the ICU has also been associated with improved brain function outcomes.[11] 

• A: Assess and manage pain
• B: Daily awakening and breathing trials
• C: Choice of sedation, light sedation, and avoidance of benzodiazepines
• D: Routine delirium assessment, non-pharmacologic intervention, and judicious use of medications to treat delirium
• E: Early mobility 
• F: Family involvement

Hayhurst et al. showed that patients receiving a daily goal-directed mobility program had more days alive and free of delirium, had shorter lengths of hospital stay, were more functionally independent at discharge and were more likely to discharge to home.[12](A1)

To institute prevention strategies, early intervention, and treatment, patients should be evaluated for their risk of POD. In the PACU, reorientation should be started immediately, for example, saying the patient name, current location, type of surgery and surgeon's name. Physical factors such as a distended bladder, hypoventilation, uncomfortable patient positioning, and pain should be addressed promptly.

Several pharmacologic agents have been used to prevent and treat delirium in a high-risk population. Continued delirium should be dealt with aggressively by reversing continued effects of anesthetic agents. Flumazenil (0.2-mg increments), naloxone (0.04-mg increments), and physostigmine because it crosses the blood-brain barrier (1- to 2-mg increments), can reverse the effects of benzodiazepines, opioids, and muscle relaxants. Haldol, which is often used for acute management of delirium, shortens the severity of delirium episodes but does not change the incidence and is also not effective for prophylaxis in high-risk elderly populations.[7] Dexmedetomidine has emerged as a useful adjunct to general anesthesia. Intraoperative infusion of dexmedetomidine was shown to reduce the incidence of POD in high-risk elderly population. Its use in children and in ICU patients has been shown to decrease the incidence of emergence agitation, nausea and vomiting, and postoperative pain. However, its optimal intraoperative dose, infusion or boluses, has not been established.[3][4] Dexmedetomidine was also found to accelerate resolution of delirium, use of fewer antipsychotics and earlier extubation in patients in the ICU in whom agitated delirium prevented extubation.[13] In another study, patients receiving dexmedetomidine had their delirium resolve faster, had less oversedation, less need for noninvasive ventilation and had shorter ICU stay compared to those on haloperidol.[14](A1)

Drugs that increase acetylcholinesterase availability, antipsychotic drugs such as haloperidol have shown no benefit over placebo for the treatment of delirium. Since benzodiazepine sedation has been strongly tied to delirium, propofol and dexmedetomidine have become the mainstay of ICU sedation. Djaiani et al. demonstrated that patients receiving dexmedetomidine had less incidence of and shorter duration of delirium compared to those receiving propofol.[15](A1)

Differential Diagnosis

• Hypoxia
• Hypercarbia
• Hypoglycemia
• Hypothermia
• Stroke
• Seizure
• Central cholinergic syndrome
• Acidemia
• Electrolyte disturbances
• micronutrients and vitamin deficiencies

The patient’s vitals should be checked promptly, and arterial blood gases with blood glucose levels checked while performing a complete physical exam. This would estimate hemoglobin, electrolytes, and blood glucose values. If signs of new focal neurologic deficits are present, a computed tomographic scan of the head should be strongly considered. An individualized panel of lab tests might be requested according to the specific clinical vignette. For instance, a previous history of alcohol abuse might result in thiamine deficiency. In the setting of an abnormal liver function test, along with compatible physical examination, further diagnostic steps are required. Increased carbohydrate metabolites, lactate, pyruvate, and decreased blood thiamine levels are confirmatory. [16]

Treatment Planning

Perioperative suggestions to reduce delirium and brain dysfunction include: 

• Avoiding medications that trigger deliria such as anticholinergic medications, benzodiazepines, and meperidine.
• Using light sedation whenever possible and safe  
• Ensuring adequate pain control with regional techniques and non-opioid adjuncts 
• Using multi-component bundles aimed at reducing delirium such as: 
  • Attention to hydration and electrolytes
  • Early mobility
  • Restoring hearing aids and eyeglasses postoperatively
• Using dexmedetomidine for sedation in the postoperative period if sedation is required.
• Treating only those with hyperactive symptoms refractory to non-pharmacologic approaches

Toxicity and Adverse Effect Management

No drug has gained FDA approval for the prevention and treatment of delirium. There are limited data on effective prophylactic agents as well as limited data on effective initial therapies. Haloperidol and atypical antipsychotics (olanzapine, quetiapine, risperidone) are commonly used despite limited data on efficacy.

Antipsychotics may cause oversedation, respiratory depression, QT prolongation, neuroleptic malignant syndrome, and hypoactive delirium. Dexmedetomidine requires an infusion and ICU stay.

Prognosis

POD is associated with significantly worse patient outcomes. There is emerging evidence that POD can lead to a higher likelihood of postoperative cognitive dysfunction, prolonged brain dysfunction, early dementia, and acceleration in the cognitive decline of Alzheimer's patients.[17][18] Delirium in the PACU is a sign of further brain dysfunction in the hospital, worse cognition at the time of discharge, and increased likelihood of being admitted at a nursing or rehabilitation facility as opposed to going home.[19] Most studies have shown an association between delirium and increased risk of death.[20]

Complications

Patients with postoperative delirium may be at a higher risk of aspiration, especially in emergency surgery where nil per os (NPO) guidelines were not followed.[21] POD is associated with a prolonged hospital stay and increased health care costs, increased risk of institutionalization after discharge and increased risk of disability.[7]