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INTRODUCTION

The intensive care unit (ICU) is a harsh environment where patient restlessness, discomfort, agitation, and delirium challenge caregivers on a daily basis. In the past, clinical success was defined by patient survival to hospital discharge. Over the last 2 decades, the health care system has increased attention on interventions to improve patient comfort and safety, with a positive impact on long-term patient functionality, cognition, and quality of life.¹ We now understand that sedative choice, administration, and the level of sedation achieved significantly impact patient outcomes. The use of benzodiazepines for sedation, for example, is associated with longer durations of mechanical ventilation and ICU length of stay (LOS).² Patients with deep sedation and drug-induced coma have higher ICU complication rates and a greater need for neurodiagnostic and delirium testing to evaluate altered mental status.³

The American College of Critical Care Medicine and the Society of Critical Care Medicine published updated clinical practice guidelines in 2018 for the management of pain, agitation/sedation, delirium, immobility and sleep disruption (PADIS) in adult critically ill patients.⁴ These revised guidelines use standardized, transparent methods, and include new evidence supporting practice advancements such as early mobility and sleep. Furthermore, in 2017, the American College of Chest Physicians in cooperation with the American Thoracic Society created a clinical practice guideline for liberation from mechanical ventilation, which included sedation strategies.⁵ A primary reason for the upsurge in pain, agitation, and delirium (PAD) guidelines is to disseminate recent data defining best practices to improve short- and long-term clinical outcomes in the critically ill. The existing gap between published clinical data and corresponding changes in clinical practice must be closed.^6,7

This article examines pharmacists' roles in managing PADIS in critically ill patients. By translating best evidence into clinical practice, pharmacists can help make the ICU a safer, more humane environment.

CHANGING CLINICAL PRACTICE

Successful efforts to change clinical practice consistently use a multifaceted, interdisciplinary team approach including these components:

• Education
• Real-time reminders such as protocols imbedded within order sets
• Electronic documentation
• Outcome assessments and monitoring with feedback to practitioners

Members of the PADIS writing panel published advice specific to the bedside implementation of their guidelines.⁸ A checklist for transforming the PADIS guidelines into practice includes these points:

• A gap analysis to determine which aspects of the guidelines are not currently in place.
• Creation of stakeholders and champions for the effort to lead and prioritize changes.
• Implementation with well-established milestones that can be monitored for compliance, success, and opportunities for further improvement.
• Sharing ideas and “borrowing” tools as appropriate (iculiberation.org).

Pharmacists are established members of the critical care provider team and can readily facilitate these efforts using their well-documented clinical expertise, process improvement skills, scholarly activities, and attention to financial resource issues.⁹

As a prerequisite to involvement, pharmacists should become familiar with all aspects of PADIS management within the guidelines.⁴ The guidelines do not provide a hierarchy of pharmacologic choices; instead, they offer general advice about management strategies.

One example of this approach is the recommendation to target light sedation over deep sedation, while leaving the choice of sedative agent to the prescriber. This was done intentionally since sedation choice is based on individual patient factors.⁴

The guidelines are sensitive to local practice patterns, cultures, and financial restraints when determining formulary decisions. Pharmacotherapy recommendations from 2013 PAD¹ and the 2018 PADIS guidelines⁴ are somewhat different (Table 1).

PAIN AND DISCOMFORT

Clinicians anticipate that patients experiencing surgery, trauma, certain disease states (e.g., pancreatitis), invasive procedures, or device insertion will likely suffer pain. Accordingly, these patients are routinely offered analgesia. Less appreciated is the high frequency of discomfort associated with routine ICU care, including prolonged immobility, repositioning in bed, central line insertion, arterial blood draws, wound dressing changes, endotracheal suctioning, and drain removal.¹⁰ Fewer than 50% of patients are offered analgesia before these potentially painful events.¹¹ This unfortunate reality has been consistently documented by postdischarge surveys suggesting that more than 40% of ICU patients felt that their pain was underestimated and they had unmet analgesia needs.¹²

Our commitment to provide compassionate care for the critically ill requires acknowledgment that unrelieved pain has a multitude of physiologic and psychologic consequences. Pain can initiate the stress response leading to sleep impairment, increased oxygen consumption, inadequate tissue perfusion, impaired wound healing, hemodynamic derangement, hyperglycemia, and altered immune system function.⁴ Compared with patients with adequate pain control, those who recalled ICU pain had a higher incidence of chronic pain, posttraumatic stress disorder (PTSD), and lower health-related quality of life.⁴ However, providing pain relief in the ICU is complicated as many patients are unable to communicate their analgesia needs. Systematic pain evaluations can reduce the need for sedative-hypnotic agents, ICU LOS, and frequency of moderate-to-severe pain by nearly 50%.^13,14 Despite this information, pain assessments are performed in fewer than 40% of patients, especially in patients unable to self-report.¹⁵ The PADIS guidelines recommend routinely offering assessment-driven therapies as a part of a protocol-based approach to the management of pain.⁴

Patient self-report using a numeric rating scale, or NRS, is considered the gold standard for pain assessment in the ICU.¹⁶ For patients unable to communicate because of lack of intact motor function, the guidelines recommend either the behavioral pain scale (BPS) or critical care pain observation tool (CPOT).⁴ Both the BPS and CPOT assess facial expression, body movements or muscle tension, and compliance with the ventilator; both have been tested for reliability and validity. Hemodynamic changes such as increasing heart rate or blood pressure are not considered within these assessment tools because fluctuations in vital signs do not correlate with self-reported or behavioral pain scores. They may serve, however, as prompts for more formal assessments of pain using BPS or CPOT.

Pain Management

Pain should be assessed within 30 minutes of pain identification and reassessed after intervention.⁴ Identification of the source of discomfort can guide the initial approach to pain relief. Targeted nonpharmacologic remedies such as relocating misplaced or migrating endotracheal tubes, adjusting the mode of ventilation, or stabilizing fractures are direct and effective therapies. Nonpharmacologic interventions are favored as they are analgesic-sparing, resource neutral, and typically devoid of adverse effects.

Of the nearly 3 dozen nonpharmacologic strategies for relief of discomfort and pain that have been published, music therapy, massage, deep breathing, and ice therapy seem to offer the most benefit; however, published results are inconsistent.^15,17 Many patients find that these interventions are inadequate, and this should prompt an analgesic trial (typically with an intravenous [IV] opioid as a part of a multimodal approach) with patient response guiding subsequent therapeutic decisions. The 2018 guidelines emphasize the utility as well as the paucity of supportive data for a multimodal approach for pain relief that employs nonopioid pharmacologic options. Recommendations for nonopioid management of pain are highlighted in Table 2.¹⁸

Opioid Therapy

Intravenous opioids – used as-needed, scheduled, or as continuous infusion – are recommended to treat nonneuropathic pain in the ICU. While all opioids share similar pharmacology and reduce pain by binding to μ-opioid receptors in the central nervous system (CNS), differences in pharmacokinetic variables should be considered when selecting the drug, dose, and frequency of administration.

With the exception of remifentanil, the liver metabolizes all opioids, posing a risk for overdose in hepatic disease. Additionally, some opioids have active metabolites that can accumulate in the setting of renal disease, potentially precipitating adverse events. For instance, accumulation of the 6-glucuronide salt of morphine causes excessive narcotic effect. Opioid choice in patients who have renal disease is largely determined by whether they need rapid onset (e.g., fentanyl) or prolonged activity (e.g., hydromorphone).⁴

Methadone has μ-opioid receptor agonist properties, but it is also an N-methyl-D-aspartate (NMDA) receptor antagonist. NMDA receptor antagonism may restore analgesic responsiveness to patients who have exhibited tolerance to high doses of standard opioids.¹⁹ In addition, methadone's good (~80%) oral bioavailability makes it a reasonable alternative to parenteral opioid administration. Along with patient comorbidities and pain control needs, context should be considered. Methadone can facilitate liberation from mechanical ventilation and shorten ICU LOS.²⁰

It is important to note that there are no dosing equivalence guidelines for ICU patients when transitioning patients from standard opioids to methadone. Because of the uncertainty in providing equivalent analgesic activity, an order for a "rescue" opioid, such as fentanyl, should be in place for breakthrough pain when transitioning patients to methadone. In addition to the expected risk of respiratory depression, methadone has been associated with dose-related QTc prolongation, ventricular arrhythmias, bradycardia, serotonin syndrome, and sudden death.^21,22

Safety concerns regarding the use of opioids — sedation, delirium, respiratory depression, ileus, and immunosuppression — may increase ICU LOS and worsen post-ICU patient outcomes.²³ Clinicians should use the lowest effective dose for procedural pain control and prevent well-known adverse events whenever possible. For example, constipation may be managed pre-emptively with routine administration of stool softeners and stimulant cathartics, and withdrawal can be prevented by gradually tapering doses with long-term therapy.

Clinicians may also consider adopting a multimodal analgesia approach by using nonopioid pain control agents adjunctively to improve analgesia effectiveness and spare the use of opioids (Table 3). Most adjunct medications have not been rigorously studied in the ICU population and have notable limitations to their use. For this reason, patient comorbidities, as well as drug, dose, and efficacy considerations, should be evaluated prior to implementation. Selecting an opioid for a particular patient should involve consideration of the distinctions within the opioid class.

The PADIS guidelines highlight differences in the management of nonneuropathic and neuropathic pain.⁴ For nonneuropathic pain, all IV opioids appear to be efficacious when titrated to a desired pain intensity score. Neuropathic pain should be treated with enteral administration of gabapentin or carbamazepine in addition to IV opioids.

Although the value of adjunctive pain medications including IV acetaminophen and IV nonsteroidal anti-inflammatory drugs (NSAIDs) has not been rigorously investigated in the ICU, they are recommended for use in select patients (Table 2).⁴ It should be appreciated that IV acetaminophen has been associated with reductions in blood pressure (decrease in mean arterial pressure >15 mm Hg) in up to 50% of patients and may limit its use in those with hemodynamic compromise.²⁴ These hemodynamic issues in conjunction with the added costs of the IV formulation support the use of enteral acetaminophen whenever possible.

Analgosedation

The PADIS guidelines suggest that since pain is a very common cause of patient distress, a protocolled, pain assessment–driven, analgesia-first approach (an analgesic is used before a sedative to reach comfort goal) or an analgesia-based approach (an analgesic is used instead of a sedative to reach comfort goal) should be the initial pharmacologic intervention for most adult ICU patients experiencing significant agitation. Several studies have compared a traditional sedative-hypnotic drug approach to an analgesia-first strategy in which opioids serve as first-line treatment for agitation and are supplemented only with sedatives for patients who do not achieve the goal sedation level.^25-27 The potential advantages associated with analgosedation include the following:

1. Offering an intervention that is effective against a common and troubling clinical issue (pain).
2. In approximately 50% of patients, obviating the need for standard sedative agents, such as benzodiazepines, propofol, and dexmedetomidine, along with their potential for adverse events.
3. Providing an alternative (sometimes with additional intermittent benzodiazepines) to propofol or dexmedetomidine for patients who are vasopressor dependent.⁴

Analgosedation should not be considered for patients experiencing drug or substance withdrawal (except opioids), drug-induced agitation (such as serotonin syndrome or delirium), or any agitation associated with a clear and reversible cause (other than pain). It should also be emphasized that a small fraction of ICU patients do not suffer significant discomfort and agitation and that pharmacologic interventions should be employed only when needed.⁴

AGITATION AND SEDATION

Agitation is a very common problem in the ICU and affects at least 50% of adult patients.^28,29 It is described as excess motor activity that can be either nonpurposeful (flailing in bed) or purposeful and counterproductive (removing medical devices or attempting to escape). ICU agitation can result in disruption of anastomotic sutures and removal of medical devices such as endotracheal, vascular, feeding, and drainage tubes—all of which carry varying morbidity and cost.³⁰ Other acute consequences of agitation are heightened risk for nosocomial infections, trauma resulting from falls, and caregiver injury from violent patient behaviors. The identification and treatment of possible underlying etiologies of pain, delirium, hypoxia, or substance withdrawal or toxicity form the foundation for ICU agitation management.⁴

Interestingly, clinicians find a cause of agitation in two-thirds of cases. Most cases are likely multifactorial, making the task of providing directed therapy an elusive goal. This issue is made even more complex because many ICUs do not systematically evaluate agitation, and as a result, extreme or dangerous behaviors are often the first sign of sedative need.

Assessment and Sedation Goals

Two assessment tools, the Richmond Agitation-Sedation Scale and the Sedation-Agitation Scale, have been extensively tested for reliability and validity in the ICU. The PADIS guidelines recommend targeting light sedation, though no definitions of light, moderate, or deep sedation are offered.^4,31 Nurses should monitor patients routinely for agitation and sedation four or more times per nursing shift and as needed. This strategy may prompt more timely remedial interventions and result in a 33% reduction in the frequency of dangerous agitation.¹³

Furthermore, the use of protocols incorporating sedation/agitation assessment tools to guide sedation titration significantly improves patient outcomes such as overall mortality, ICU and hospital LOS, and the need for tracheostomy.³² These benefits may be attributed to consistent provision of sedation that controls behavioral while avoiding drug-induced coma.

Sedation goals are dynamic and evolve as patient conditions and treatments change. For most patients, ideal sedative titration allows for comfort and wakefulness (the ability to purposefully perform 3 of the following: open eyes, maintain eye contact, squeeze hand, stick out tongue, and wiggle toes) with or without daily sedation interruption. It is, however, reasonable to offer sustained deep sedation for the small number of ICU patients who receive neuromuscular blocking agents or for those with elevated intracranial pressures, tenuous respiratory function, status epilepticus, or complex surgical wounds.⁴

Pharmacists should be involved in the creation and implementation of sedation and analgesia protocols that facilitate patient comfort and the ability to participate in care, while avoiding drug-induced coma.^33-35 Daily interruption of continuous sedation infusions has been shown to decrease the number of days of mechanical ventilation, duration of ICU LOS, and 1-year mortality rates in ICU patients.^36,37 It also allows daily assessment of patient mental status, reducing the need for neurologic testing.

Even in the face of these supportive data, fewer than 70% of ICUs use a protocol-based approach that includes embedded assessment tools to guide sedation titration.³⁸ Linking sedation interruption with spontaneous breathing trials (and increasing the potential for successful patient extubation) represents a clinically relevant way to encourage routine bedside incorporation of this strategy.³⁹

Without proper protocols in place, it is easy to understand why more than 40% of patients are more deeply sedated than necessary and that drug-induced coma may be a feature of ICU care in nearly one-third of patients.^40,41Additionally, many other factors sustain the practice that deep sedation is a reasonable therapeutic goal.

For example, a pervasive belief among caregivers is that it is cruel to allow patient awareness since the formation of factual memories of the ICU experience could lead to long-lasting psychologic sequelae, such as PTSD. In fact, PTSD in ICU survivors is associated with increased sedative use and the delusional memories that can occur during the provision of deeper levels of sedation.^42,43 Light sedation results in more ICU-specific memories, but it is less disturbing and may result in a lower incidence of PTSD symptoms.⁴⁴ Moreover, increased patient alertness in the ICU facilitates patient participation in early physical and occupational therapy, leading to less delirium, fewer ventilator days, and improved functional status after hospital discharge.⁴⁵

Lighter sedation strategies also allow more accurate pain and delirium assessments and enable patients to participate actively in decisions about interventions and desired levels of care. The majority of published data suggest that the benefits of maintaining a light level of sedation in ICU patients far outweigh any potential risks (e.g., patient-initiated device removal).⁴ Caregivers and family members must understand that drug-induced coma may result in patient behaviors suggestive of comfort, but this degree of sedation has serious consequences including prolonged ICU stay, greater mortality, and diminished long-term quality of life.⁴⁶

Treatment and Prevention of ICU Agitation

Similar to pain management, the identification and correction of the causes of agitation are the essential first steps in its management. Concurrent nonpharmacologic approaches include repositioning in bed to limit discomfort, music and massage therapy, verbal assurances and reorientation, facilitating natural sleep-wake cycles, frequent family visits, and removal of all nonessential invasive medical devices and tubes.

Most ICU patients, however, will require some pharmacologic intervention.⁴ Since pain and discomfort are common causes of ICU agitation, most agitated patients should receive analgosedation as the initial intervention. When this is not adequate, benzodiazepines, propofol, and dexmedetomidine can be used (Table 4). Patient variables help guide appropriate pharmacologic choices and include the presence of pain, substance use and withdrawal, neurologic function, seizure history, respiratory status, organ system dysfunction, and home medication use.⁴

Benzodiazepines

Benzodiazepine-based sedation is no longer considered first-line therapy as these agents negatively affect clinical outcomes and increase the risk for delirium.^3,4 A meta-analysis of moderate- to high-quality trials demonstrated that benzodiazepine-based sedation in ICU patients results in prolonged ventilator requirements (by approximately 2 days) and longer stays in the ICU (by approximately 1.6 days) compared with propofol or dexmedetomidine.² These differences in outcomes are likely related to benzodiazepine pharmacodynamic profiles and resultant difficulties in dose titration.

Nevertheless, benzodiazepines remain important sedative options in select circumstances. For instance, because of its rapid onset of action, midazolam may be useful to control dangerous behaviors quickly. Other indications for benzodiazepines include the treatment of seizures, elevated intracranial pressures, and any other condition requiring deep sedation with amnesia (such as during the administration of neuromuscular blockade). Limited data support benzodiazepine use in the setting of hemodynamic instability or for ethanol withdrawal.⁴⁷

For patients with renal failure, clinicians should generally avoid continuous infusion midazolam because its active metabolite accumulates. Lorazepam and diazepam require monitoring for a high anion gap metabolic acidosis, especially in renal failure, as a result of toxicity from propylene glycol, the diluent used in the parenteral formulation.⁴

Propofol

Propofol is the most commonly used sedative in ICUs and is an excellent choice for many different types of patients and clinical circumstances.⁴⁸ The rapid onset and offset, easy dose titration, and relatively low cost help to explain its widespread use. Propofol is preferred over benzodiazepines because it is associated with a shorter ICU LOS and has not been implicated in the development of delirium. One high-quality multicenter trial compared propofol with dexmedetomidine; no between-group differences were observed in the duration of mechanical ventilation or ICU/hospital LOS. Also, there were no differences in mortality or the prevalence of hypotension.⁴⁷

Propofol has some downsides: lack of analgesic activity, frequent hypotension, the requirement for mechanical ventilation, and the often-fatal but fortunately rare propofol-related infusion syndrome (PRIS).⁴ Although PRIS was originally identified in pediatric patients receiving continuous infusion propofol, the syndrome has also been recognized in adults. Risk factors have traditionally focused on exposure (doses exceeding 4 mg/kg/h and duration longer than 48 hours). More recent data support this finding and also suggest that PRIS can occur with lower doses and within hours of administration. Clinical findings (likely related at least in part to mitochondrial dysfunction) include metabolic acidosis, rhabdomyolysis, and cardiovascular collapse. There is no antidote for this syndrome other than early recognition with timely propofol discontinuance and provision of supportive measures.⁴⁹

In addition to these adverse effects, propofol is dissolved in a 10% lipid emulsion containing egg lecithin and soybean oil, which can precipitate allergic reactions in patients with egg or soybean allergies.

Dexmedetomidine

Dexmedetomidine is a central alpha-2 agonist approved by the U.S. Food and Drug Administration (FDA) in 1999 for ICU sedation. It has opioid-sparing properties and does not depress respiratory drive, even in high doses.⁴ These attributes are especially helpful for treating agitation in patients who are not mechanically ventilated or who develop agitation during spontaneous weaning trials.

Patients treated with dexmedetomidine are generally able to be awakened, follow commands, and participate in their care. It is associated with delirium less frequently than benzodiazepines.⁵⁰ Whether this represents a causal relationship between benzodiazepines and delirium, a protective effect against delirium with dexmedetomidine, or simply avoidance of sedative-induced artifact in delirium screening is unknown.

Dexmedetomidine does not have amnesic properties and should not be used when deep sedation is desired. Clinically important bradycardia and hypotension occur in as many as 15% of patients, prompting the following general safety rule: if beta-blockade is considered a risk for a patient, then dexmedetomidine should also be avoided.⁴

Compared with propofol, dexmedetomidine plays a much smaller role in routine sedation in the critically ill.⁴⁸ Limiting features include cost, inadequate FDA-approved dosing (more than 60% of patients may require more than 0.7 mcg/kg/h), a short FDA-approved treatment duration (less than 24 hours), and the potential for clinically important alterations in hemodynamic status.⁴ Calculating dexmedetomidine's true cost is not straightforward and is becoming even more complex with the availability of generic formulations. Dollars spent on this agent should be compared with the potential cost savings associated with a reduction in mechanical ventilation and ICU stay.⁵¹

If drug acquisition costs are a concern, an alternative alpha-2 agonist such as clonidine can be considered. Clonidine is approved for IV use in many countries for ICU sedation, yet in the United States, clonidine is only available as a patch, epidural solution, or enteral tablet. As a recent study demonstrated, nearly 75% of selected patients (those who have responded favorably to a stable dose of dexmedetomidine, have an accessible and functional gastrointestinal tract, and require continued alpha-2 therapy) could be successfully transitioned to enteral clonidine within 48 hours.⁵² The benefits of this strategy include a much lower cost and the ability to transfer patients to a non-ICU environment. Preliminary data describing dose titration, safety, and efficacy have been published.⁵²

DELIRIUM

As many as 80% of mechanically ventilated critically ill patients experience delirium, which manifests as an acute onset of disorganized thinking, inattention, and changes in mental status and consciousness. Delirium has been associated with increased hospital LOS and cognitive impairment at 3 and 12 months after ICU discharge.^53-56 It may also be associated with increased ICU LOS, functional decline, dependence, depression, and mortality, though these outcomes are inconsistent.

Delirium is a clinical diagnosis, and guidelines recommend using valid tools to regularly assess patients.⁴ Common validated screening tools include the Confusion Assessment Method for the ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC).^57,58 Delirium screening tools have detected an increased association with blood transfusions and benzodiazepine use and may be areas to mitigate patient risk.⁴ Nonmodifiable risk factors include increased age, dementia, prior coma, pre-ICU emergency surgery or trauma, and increasing Acute Physiologic Assessment and Chronic Health Evaluation (APACHE) or American Society of Anesthesiologists (ASA) scores.

The precise cause of delirium remains uncertain but related symptoms are thought to develop from numerous sources. Associated mechanisms include disruption of the balance of various CNS neurotransmitters and receptor function, the release of inflammatory cytokines that increase blood-brain barrier permeability, and diffuse brain injury. Of particular interest to pharmacists may be the high prevalence of drug-induced delirium in the critically ill. More than 100 medications have been characterized as deliriogenic. Most have been shown to affect CNS neurotransmitters or receptor function. Changes in mental status have been widely appreciated in medications possessing anticholinergic activity (e.g., diphenhydramine); however, there is an emerging appreciation for the neurotoxic potential of other classes, including antibiotics. Fluoroquinolones and cephalosporin antibiotics (e.g., cefepime) may contribute to the development of delirium in the ICU, especially when renal elimination is compromised.⁵⁹ Furthermore, withdrawal from various substances such as ethanol, benzodiazepines, opioids, selective serotonin reuptake inhibitors, and tobacco is associated with delirium.

These data highlight the importance of regular scrutiny of all medications and substance use before and during a patient’s ICU admission. Nonessential drugs should be discontinued when delirium becomes evident, and the pharmacist should document prehospital medication and substance use by interviewing the patient, friends, caregivers, and family members.⁴ If delirium is thought to be related to substance withdrawal, reinitiation of therapy should be carefully considered. Factors that may contribute to the manifestation of delirium (e.g., encephalopathy, hypoxemia, acidosis, infections, and metabolic or hemodynamic instability) should also be regarded as potentially reversible physiologic targets.⁴

Despite an abundance of data, the pathophysiology, assessment, and management of delirium is still in the discovery phase.

Delirium Assessment

The PADIS guidelines provide an ungraded “Good Practice Statement” that delirium assessment using validated scoring tools (such as the CAM-ICU and the ICDSC) should be regularly assessed.⁴ It remains uncertain if routine bedside application of such assessment tools actually improves patient outcomes. Nevertheless, delirium may serve as an initial manifestation of a significant infectious, metabolic, or CNS disease, and its identification may prompt appropriate diagnostic evaluations.⁴ In short, the benefits of regular assessment far outweigh any potential disadvantages.

The timing of delirium assessments in relationship to the degree of sedation is important. The frequency of positive delirium screening is approximately halved when patients are allowed to awaken before delirium evaluation compared with when they are assessed during sedation.⁶⁰ One-year outcomes for patients with sedation-related delirium (delirium that disappears when sedation is lightened) are nearly identical to those in patients who never experienced delirium.⁶¹ This suggests significant confounding by ongoing sedation. Delirium assessments with the CAM-ICU should be performed after sedation interruption or establishment of wakefulness to avoid inaccurate results.

Delirium Management

There are 3 components in the management of delirium in the ICU: prevention, treatment of the underlying disorder, and behavioral therapy with pharmacologic and/or nonpharmacologic interventions.

Pharmacologic and Nonpharmacologic Strategies for Delirium Prevention

Available data do not support pharmacologic prevention of delirium. Antipsychotics, dexmedetomidine, statins, and ketamine have not been shown to prevent delirium and may cause patient harm.⁴

In contrast, the PADIS guidelines strongly recommend early mobility as a means for reducing delirium frequency and duration. ICU-specific data involving early physical and occupational therapy (e.g., early mobilization) have shown promising results, including a 50% reduction in delirium duration.⁴⁵ Studies assessing the impact of environmental, acoustic, and visual stimulation (e.g., wall clocks, wearing glasses, or listening to music), sleep-wake cycle promotion (e.g., minimizing ambient noise and dimming hallway lights during the night), sedation disruption, and cognitive impairment (e.g., reorientation and mental stimulation) have shown favorable results when used in combination with mobilization efforts.

Using such interventions, the incidence of delirium in non-ICU settings may be reduced by rates of 40% or more. Supportive data are limited in the ICU population, but the PADIS guidelines recommend using multicomponent nonpharmacologic methods to reduce modifiable risk factors for delirium, improve cognition, and optimize sleep, mobility, hearing, and vision in critically ill adults.⁴

It is important to emphasize that combination strategies are likely more effective than any single intervention, reflecting the diverse etiologies associated with the syndrome. Further supporting the multimodal approach, incorporating the assessment, prevention, and management of pain along with coordination of awakening and breathing trials, delirium assessment/prevention/management, early mobility/exercise, and family engagement and empowerment (ABCDEF) has been shown to decrease mortality, duration of ICU and hospital stays, time on the ventilator, coma, and delirium frequency.⁶²

Treatment of Underlying Disorders

Once delirium has been identified, the mainstay of treatment is the simultaneous identification and correction of potential physiologic causes (e.g., metabolic derangements, hypoxia, hyperthermia, hypercarbia, pain, acidosis, hemodynamic instability, and infection), and control of potentially dangerous behaviors. The continued need for deliriogenic medications such as benzodiazepines, anticholinergics, corticosteroids, cephalosporins (especially cefepime), macrolides, or fluoroquinolones, should be evaluated and alternative agents suggested by pharmacists.⁵⁴

Pharmacologic Interventions for Delirium Treatment

No specific therapeutic options reduce symptom severity or delirium duration, or improve any clinically relevant delirium-related outcome in ICU patients with delirium. Haloperidol or second-generation (atypical) antipsychotic agents are often used for behavioral control but do not improve outcomes in published literature and are not currently endorsed for routine use in the PADIS guidelines.⁶³ Short courses of antipsychotics used to target feelings of severe distress — such as anxiety, fearfulness, hallucinations or agitation (especially when harmful to oneself or others) — may be appropriate, but the ongoing need for medication should be addressed regularly.

When comparing antipsychotics, it is important to consider differences among agents within the class. Haloperidol is the dopamine antagonist most frequently used to treat symptoms of ICU delirium. It has no significant effect on respiratory drive or hemodynamic function in euvolemic patients. Its onset of activity may be delayed for 15 to 20 minutes, even when administered intravenously. Many dose-escalation protocols exist; it is unclear which strategy is optimal, although there seems to be a relationship between dose and the potential for prolonging the corrected QT interval. It is prudent to ensure adequate serum potassium and magnesium levels and have electrocardiogram monitoring in place for haloperidol-treated patients. It may be wise to avoid haloperidol use altogether in patients with a history of heart disease or in those receiving other QTc-prolonging medications.

Because of a modest effect on repolarization, olanzapine, quetiapine, and risperidone may represent reasonable antipsychotic alternatives for these patients. On the other hand, it is increasingly apparent that these second-generation antipsychotics share many of haloperidol's adverse effects, including the potential for neuroleptic malignant syndrome.⁴ Agent-specific adverse event profiles should also be considered, including hyperglycemia, bradycardia, pancreatitis, and hypotension with olanzapine; prolongation of QTc with ziprasidone; agranulocytosis with clozapine; and sedation with quetiapine.

Inadvertent or inappropriate continuation of antipsychotic agents after ICU discharge is common and contributes to adverse events.⁶⁴ Pharmacists can minimize these events by diligently questioning the need for antipsychotic use.

Due to the potential for harm and a lack of supportive evidence, no pharmacologic treatments are currently recommended by the PADIS guidelines in nonmechanically ventilated patients. Conversely, in patients unable to wean from mechanical ventilation due to agitation, dexmedetomidine may decrease hours spent requiring ventilation and is recommended by the guidelines. Supporting evidence is weak – predominantly arising from a single randomized controlled trial – but the potential benefits of earlier ventilator liberation will outweigh ramifications in most patients.⁶⁵

IMMOBILITY

The previous iteration of the PAD guideline addressed immobility as a preventive strategy for delirium¹; however, the updated guidelines distinguish immobility as a standalone clinical issue.⁴ ICU-acquired muscle weakness (ICUAW), which occurs in 25% to 50% of patients, is associated with decreases in patients’ long-term survival, physical function, and quality of life.⁶⁶ Rehabilitation and mobilization should be performed in all stable critically ill patients. This is considered safe and feasible in stable patients (regardless of vasoactive infusion or mechanical ventilation requirements) and performed either in- or out-of-bed, as appropriate.

Pharmacists can support rehabilitation/mobilization efforts by complying with guideline recommended pain, sedation, and delirium minimization strategies. Opioid boluses, continuous infusion of sedatives, and the presence of delirium have all been associated with decreased physical therapy participation and are important targets for intervention.

SLEEP

Sleep architecture and circadian rhythm are severely disrupted during critical illness and remain a major complaint of ICU survivors. Abnormal sleep patterns may increase emotional distress and contribute to poor patient outcomes, including delirium, cognitive dysfunction, longer time on mechanical ventilation and deranged immune function.⁴ These worsening outcomes may reflect the manifesting sequelae of neurologic impairment in the critically ill, and it is difficult to quantify how extensively altered sleep contributes (independently) to these poor outcomes.

Risk factors that affect sleep quality in the ICU include a history of poor sleep quality at home and the outpatient use of pharmacologic sleep aids. ICU-acquired risks factors include the presence of pain; interruptions in the form of noise, medication, or procedural administration; and ambient lighting. Current guidelines recommend using several nonpharmacologic strategies to minimize the impact of these environmental factors, including adjusting the ventilator mode at nightfall (i.e., assist-control ventilation is recommended over pressure support), using light- and noise-reduction strategies, and adopting a multicomponent sleep promoting protocol, including earplugs, eyeshades, and (optionally) relaxing music (Table 5).^4,67 The supportive evidence is limited and low quality, but such interventions are low risk and easy to implement.

Evidence supporting pharmacologic agents to improve sleep quality is similarly absent. Melatonin supplementation may address a relative deficiency acquired through critical illness, which theoretically may improve circadian integrity and internal sleep-regulating mechanisms.⁶⁸ Melatonin supplements are inexpensive and pose few risks (mild sedation and headache), but their use has not been adequately evaluated for sleep in the ICU. Similarly, dexmedetomidine may favorably improve sleep architecture and stage 2 sleep in mechanical ventilated patients, but the generalizability of this data to the broad ICU population remains unknown. Consequently, the PADIS guidelines offer no recommendation for these agents, though considerations for cost and side effects must be made.⁴

Due to insufficient evidence, other sleep-promoting medications (e.g., tricyclic antidepressants, second generation antipsychotics, benzodiazepines, and benzodiazepine receptor agonists) are not addressed in the current iteration of the guidelines.⁴

CONCLUSION

Pain, agitation/sedation, delirium, immobility, and sleep disruption are fundamental complications of critical illness. The recommendations made by the PADIS guidelines can help facilitate good decision-making and aid pharmacists as they continue to serve as vital members of the critical care teams.

Features of the guidelines include the importance of systematic evaluation (with validated tools) for pain and agitation, analgosedation, and using a patient-centered approach to management decisions. Other key aspects include selecting a sedative based on patient-specific goals and conditions with consideration of pharmacokinetics, pharmacodynamics, and pharmacoeconomics; preferentially using propofol and dexmedetomidine rather than benzodiazepines; targeting light levels of sedation; mobilizing all stable critically ill patients; and promoting sleep quality with a sleep protocol based on nonpharmacologic interventions.

Applying guideline recommendations can improve outcomes and the patient experience. Many unknowns remain about the best management of PADIS topics such as the adequate treatment for delirium-related distress. Efforts to provide comfort and quality care to critically ill patients will continue to evolve as we improve our understanding.

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