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Management of Pain, Agitation, and Delirium in Critically Ill Adult Patients

INTRODUCTION

The intensive care unit (ICU) is an inhumane environment where patient restlessness, discomfort, agitation, and delirium are arguably the most common clinical issues challenging caregivers on a daily basis. In the past, clinical success was defined by patient survival resulting in hospital discharge. Over the last 2 decades, the health care system has focused on increasing attention interventions focused on improving patient comfort and safety and their impact on long-term patient functionality, cognitive function, and quality of life.1

We now understand that sedative choice, the method by which it is administered, and the level of sedation that is achieved significantly impact patient outcomes. The use of benzodiazepines for ICU sedation, for example, is associated with longer durations of mechanical ventilation and ICU lengths of stay.2 We also know that patients receiving 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 (ACCCM) and the Society of Critical Care Medicine published updated clinical practice guidelines in 2013 for the management of pain, agitation, and delirium (PAD) in adult critically ill patients.4 These revised guidelines used standardized, transparent methods, and included data supporting practice advancements that occurred since the last guideline publication in 2002. Despite their publication within the last 2 years, the current PAD guidelines are being revised again. They will be expanded to include a greater focus on early mobilization and sleep, with an anticipated release in 2018. Furthermore, the American College of Chest Physicians in cooperation with the American Thoracic Society has published a clinical practice guideline for liberation from mechanical ventilation that included sedation strategies. This guideline https://www.thoracic.org/statements/resources/cc/weaning-exec-summary.pdf was published in 2017.

A primary reason for the upsurge in PAD guideline publications is the need to disseminate recent data defining best practices to improve short-term and long-term clinical outcomes in the critically ill. The current gap between published clinical data and resulting changes in clinical practice must be remedied.5,6 This article examines pharmacists' roles in managing PAD 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 employ a multifaceted, interdisciplinary team approach. They often include

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

Members of the ACCCM guideline development team have published advice specific to the bedside implementation of the PAD guidelines.7 A checklist for transforming the PAD guidelines into practice includes

  • A gap analysis to determine which aspects of the guidelines are not currently in place
  • Creation of a group of stakeholders and champions for the effort who will lead and prioritize changes to be made
  • Implementation with well-established milestones that can be monitored for compliance, success, and opportunities for further improvement

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.

As a prerequisite to involvement, pharmacists need to become familiar with all aspects of PAD management within the guidelines.4 The guidelines' nonprescriptive approach to the recommendations can be challenging since they 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 context.4 The guideline writers were also sensitive to local practice patterns, cultures, and financial restraints when determining formulary decisions. Pharmacotherapy recommendations from 2013 PAD guidelines are summarized below in Table 1.

Table 1. Pain, Agitation, and Delirium Pharmacotherapy Recommendations
Pain
Recommendation (grade)a Use opioids as first-line therapy for treatment of nonneuropathic pain (+1c)

Consider using nonopioid analgesics in conjunction with opioids to reduce opioid administration and opioid-related adverse effects (+2C)

Use enteral gabapentin or carbamazepine, in addition to intravenous opioids, for treatment of neuropathic pain (+1A)

Use thoracic epidural anesthesia/analgesia for postoperative analgesia in abdominal aortic surgery patients (+1B)

Consider thoracic epidural analgesia for patients with traumatic rib fractures (+2B)
No recommendationb (grade)a Using a lumbar epidural over parenteral opioids for postoperative analgesia in patients undergoing abdominal aortic aneurysm surgery, because of a lack of benefit of epidural over parenteral opioids in this patient population (0,A)

Using thoracic epidural analgesia in patients undergoing either intrathoracic or nonvascular abdominal surgical procedures, because of insufficient and conflicting evidence for this mode of analgesic delivery in these patients (0,B)

Using neuraxial/regional analgesia over systemic analgesia in medical ICU patients, because of lack of evidence in this patient population (0, No Evidence)
Agitation
Recommendation (grade)a Suggest using analgesia‐first sedation for intubated and mechanically ventilated ICU patients (+2B)

Suggest using nonbenzodiazepines for sedation (either propofol or dexmedetomidine) rather than benzodiazepines (either midazolam or lorazepam)in mechanically ventilated adult ICU patients (+2B)
No recommendationb No preferred nonbenzodiazepine indicated for first-line sedation
Delirium
Recommendation (grade)a Consider using dexmedetomidine instead of benzodiazepines in ICU patients with delirium unrelated to alcohol/benzodiazepine withdrawal (+2B)

Avoid using rivastigmine to reduce the duration of delirium in ICU patients (–1B)

Avoid using haloperidol or second-generation (atypical) antipsychotics administered to prevent delirium in adult ICU patients (–2C)

Avoid using antipsychotics in patients who are at risk for torsades de pointes (–2B)
No recommendationb (grade)a There is no published evidence that treatment with haloperidol reduces the duration of delirium in adult ICU patients (No Evidence)

For the use of dexmedetomidine to prevent delirium in adult ICU patients, as there is no compelling evidence regarding its effectiveness in these patients (0,C)
Adapted from Reference 4
aThe quality of evidence for each statement and recommendation is ranked in the following manner: high (A), moderate (B), or low/very low (C). The strength of recommendations is ranked as: strong (1) or weak (2), and either in favor of (+) or against (–) an intervention.
bNo recommendation equates to not enough evidence or a lack of consensus among subcom­mittee members.

Pain and Discomfort

Clinicians easily accept and anticipate that patients experiencing prototypical noxious stimuli and having conditions or diseases such as surgery, trauma, pancreatitis, invasive procedures, or device insertion will likely suffer pain. These patients are routinely offered analgesia. Less well appreciated is the high frequency of discomfort associated with routine ICU care: prolonged immobility, repositioning in bed, central line insertion, arterial blood draws, wound dressing changes, endotracheal suctioning, and drain removal.8 Data suggest that fewer than 50% of patients are offered analgesia before initiation of these potentially painful events.9 This unfortunate reality has been consistently documented by postdischarge surveys suggesting that more than 40% of ICU patients felt that clinicians underestimated their pain and they had unmet analgesia needs.10

In addition to our commitment to provide humane care for the critically ill, we should be mindful 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 When compared with patients with good pain control, those who recalled ICU pain have a higher incidence of chronic pain and posttraumatic stress disorder (PTSD) and have a lower health-related quality of life.4 However, providing pain relief in the ICU is complicated because many patients are unable to communicate their analgesia needs.

The PAD guidelines recommend that nurses assess patients' pain 4 or more times per shift and additionally as needed. This recommendation is based on recent data suggesting that systematic pain evaluations can reduce the need for sedative–hypnotic agents and ICU length of stay and diminish the frequency of moderate-to-severe pain by nearly 50%.11,12 Despite this information, fewer than 40% of nurses routinely perform pain assessments, especially in patients unable to self-report.13 This represents an important gap in clinical practice that needs to be evaluated locally and rectified when necessary.

Patient self-report using a numeric rating scale (NRS) is considered the gold standard for pain assessment in the ICU.14 For patients unable to communicate but who retain 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 either patient self-report of pain nor behavioral pain scores. They may serve, however, as prompts for more formal assessments of pain using BPS or CPOT.

PAIN MANAGEMENT

Pain should be addressed pharmacologically or with other interventions within 30 minutes of its identification and then reassessed after the 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 represent direct and effective therapy. These (and other) nonpharmacologic interventions are favored since 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, family presence, deep breathing, and ice therapy seem to offer the most benefit; however, published results are inconsistent.13,15 Many patients find that these interventions are inadequate, and this should prompt an analgesic trial (typically with an intravenous opioid) with patient response guiding subsequent therapeutic decisions.

Opioid Therapy
The opioids are the most frequently used analgesics in the critically ill. All opioids share similar pharmacology, interacting with various opiate receptors in the body. Although pain relief is generally opioid agents' desired pharmacologic effect, clinicians should anticipate 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. Withdrawal symptoms should be prevented by gradual tapering of doses for patients receiving long-term therapy. Opioids are also sometimes administered to induce respiratory depression in patients who are mechanically ventilated.4

Distinctions among the opioids can help guide drug choice for a particular patient (Table 2). The liver metabolizes all opioids with the exception of remifentanil; some opioids have active metabolites that can accumulate in the setting of renal disease, leading to potentially 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.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 opiates.16 In addition, methadone's good oral bioavailability makes it a reasonable alternative to parenteral opioid administration. Methadone can facilitate liberation from mechanical ventilation and shorten ICU length of stay.17 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. Besides the expected risk of respiratory depression, methadone has been associated with dose-related QTc prolongation, ventricular arrhythmias, bradycardia, and sudden death.18

Table 2. Characteristics of Commonly Used Opiate Analgesics in the ICU
Drugs Onset (IV) Half-life Metabolic Pathway Useful Information
Fentanyl 1–2 min 2–4 h N-dealkylation
CYP3A4/5 substrate
  • Less hypotension than morphine
  • Accumulation with hepatic impairment
Hydromorphone 5–15 min 2–3 h Glucuronidation
  • Therapeutic option in patients tolerant to morphine and fentanyl
  • Accumulation in hepatic and renal impairment
Morphine 5–10 min 3–4 h Glucuronidation
  • Active metabolites: 6- and 3-glucoronide
  • Histamine release
  • Accumulation with hepatic and renal impairment
Methadone 1–3 d 15–60 h N-demethylation
CYP3A4/5, 2D6, 2B6, 1A2 substrate
  • Active metabolite: N-demethylated derivative
  • Unpredictable pharmacokinetics
  • Unpredictable pharmacodynamics in opiate naïve patients
  • Monitor QTc
Remifentanil 1–3 min 3–10 min Hydrolysis by plasma esterases
  • No accumulation in renal or hepatic failure
  • Use IBW if body weight is greater than 130% IBW
Adapted from reference 4.
Abbreviations: ICU, intensive care unit; CYP450, cytochrome P450; IBW, ideal body weight.

Ketamine is another NMDA receptor antagonist that may be helpful for patients who have become tolerant to the opioids. Unfortunately, supportive ICU-based data are sparse and confounded by potential neurotoxicity with prolonged use.

The PAD guidelines highlight differences in the management of nonneuropathic and neuropathic pain.4 For nonneuropathic pain, all intravenous (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.4

Analgosedation
The PAD guidelines suggest that since pain is a very common cause of patient distress, an analgesia-first approach (also known as analgosedation) 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 this 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.19-21 There are many potential advantages associated with analgosedation including: 1) offering an intervention that is effective against a common and troubling clinical issue (pain); 2) obviating the need in approximately 50% of patients for standard sedative agents, such as benzodiazepines, propofol, and dexmedetomidine, along with their potential for adverse events; and 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.22,23 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.24 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.4

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 and are recommended within the PAD guidelines.4,25 Nurses should monitor patients routinely for agitation and sedation 4 or more times per nursing shift and as needed. Data suggest that this strategy may prompt more timely remedial interventions and result in a 33% reduction in the frequency of dangerous agitation.11 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 lengths of stay, and the need for tracheostomy.26 These benefits may be attributed to consistent provision of sedation that controls behavioral while avoiding drug-induced coma.

Sedation goals are extremely complex since they 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.4 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, and 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.27-29 Maintaining light sedation may be associated with increased physiologic stress (e.g., increased catecholamine levels or increased oxygen consumption). However, no clinical evidence indicates that light sedation leads to an increased incidence of myocardial ischemia, PTSD, or bad ICU memories; even in those patients with coronary artery disease.30 Daily interruption of continuous sedation infusions has been shown to decrease the number of days of mechanical ventilation, duration of ICU length of stay, and 1-year mortality rates in ICU patients.31,32 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. 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.32 The PAD guidelines did not distinguish between sedation interruption and titration to light sedation since there are no good data suggesting superiority of 1 approach over another.

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 nearly one third of the time.33,34 Additionally, 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.35,36 Data suggest that light sedation results in more ICU-specific memories, but that they are less disturbing and may result in a lower incidence of PTSD symptoms.37

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.38 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.

Management

Treatment and Prevention of ICU Agitation
Similar to pain management, the identification and correction of the causes of agitation represent 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 3). Patient variables help guide appropriate pharmacologic choices and include the presence of pain, substance use and withdrawal, neurologic function, seizure history, respiratory status, any other organ system derangement, and home medication use.4

Table 3. Characteristics of Commonly Used Sedative Medications in the ICU
Drugs Onset After IV Loading Dose Half-life (h) Active Metabolites Adverse Effects
Diazepam 2–5 min 20–120 Yes
  • Respiratory depression, hypotension, phlebitis
Lorazepam 20 min 8–15 None
  • Respiratory depression, hypotension, propylene glycol-related metabolic acidosis resulting in nephrotoxicity
Midazolam 2–5 min 3–11 Yes
  • Respiratory depression, hypotension
Propofol 1–2 min 3–12a
50 ± 19b		 None
  • Hypertriglyceridemia, pancreatitis, respiratory depression, propofol-related infusion syndrome
  • Deep sedation associated with significantly longer emergence times than light sedation
Dexmedetomidine 5–10min 1.8–3.1 None
  • Bradycardia, hypotension, loss of airway reflexes; hypertension (if a loading dose used)
Adapted from Reference 4
Abbreviation: ICU, intensive care unit.
aShort-term use.
bLong-term use.

Benzodiazepines
Benzodiazepine-based sedation is no longer considered first-line therapy since these agents negatively affect important clinical outcomes and because they are a potential risk factor for delirium.3,4 A meta-analysis of moderate-quality 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 the benzodiazepines' 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.39 For patients with renal failure, clinicians should generally avoid continuous infusion midazolam because its active metabolite accumulates. They should also avoid lorazepam because of the toxicity risk 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.40 Its 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 length of stay 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 lengths of stay. Also, there were no differences in mortality or the prevalence of hypotension.39

Propofol has some downsides including its 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 (exceeding 4 mg/kg/h and duration longer than 48 h). 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.41 Also, 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.4

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. Data suggest that it is associated with delirium less frequently than the benzodiazepines.42 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.40 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 h), and the potential for clinically important alterations in hemodynamic status.4

Calculating dexmedetomidine's true cost is not straightforward. Dollars spent on this agent should be compared with the potential cost savings associated with a reduction in mechanical ventilation and ICU stay.43 However, if drug acquisition costs are a concern, an alternative alpha-2 agonist such as clonidine can be considered. Intravenous clonidine is approved in many countries for ICU sedation, but in the United States, it 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.44 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.44

ICU DELIRIUM

As many as 80% of mechanically ventilated critically ill patients experience delirium, which is manifested by an acute onset of changes in mental status, changes in consciousness, disorganized thinking, and inattention. Delirium is associated with increases in mortality, ICU and hospital length of stay, and cost of care.4 A recent trial confirmed that delirium duration is associated with worse cognitive and executive function (similar to early Alzheimer disease) as long as 12 months after discharge.45 It is unknown if delirium has direct toxic effects or if it simply represents brain dysfunction as a result of acute illness. For example, recent data suggest that there is little, if any, attributable mortality directly related to delirium when daily severity of illness is considered.46

Patients at risk for ICU delirium include those with dementia, a history of hypertension or alcohol abuse, or those who have a high severity of illness. The etiology of delirium has not been fully described but is probably associated with many factors, including disruption of the delicate balance of various central nervous system neurotransmitters and receptor function, the release of inflammatory cytokines that increase blood-brain barrier permeability, and diffuse brain injury. Encephalopathy, hypoxemia, acidosis, infections, and metabolic and hemodynamic instability are potentially reversible physiologic conditions associated with delirium.4

Approximately 30% of delirium cases have a pharmacologic basis.4 More than 100 medications have been characterized as deliriogenic. Most have been shown to affect central nervous system neurotransmitter or receptor function. Prototypically, these agents have overt anticholinergic activity (i.e., diphenhydramine). Furthermore, withdrawal from various substances such as ethanol, benzodiazepines, opioids, selective serotonin reuptake inhibitors, and tobacco is associated with delirium.

These data underscore the importance of regular scrutiny of all medications and substances patients ingest before ICU admission and discontinuance of any nonessential drugs when delirium becomes evident. The pharmacist should document prehospital medication and substance use by interviewing the patient, friends, caregivers, and family members, and having all medications available for inspection. If delirium is thought to be related to home medication withdrawal, re-initiation of therapy should be carefully considered.4

Despite an abundance of data, we remain in the discovery phase of understanding the pathophysiology, appropriate assessment, and management of delirium.

Assessment

The PAD guidelines strongly recommend delirium assessment using validated scoring tools (Confusion-Assessment Method for the ICU [CAM-ICU] and the Intensive Care Delirium Screening Checklist [ICDSC]) during every shift and as needed.4 Despite advances in identification of ICU delirium, 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 central nervous system disease, and its identification may prompt appropriate diagnostic evaluations.4

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.47 One-year outcome data for patients with sedation-related delirium (delirium that disappears when sedation is lightened) are nearly identical to patients who never experienced delirium.48 This suggests significant confounding by ongoing sedation. Delirium assessments with the CAM-ICU should be performed during sedation interruption or establishment of wakefulness to avoid introducing inaccurate results.

Management

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

Delirium Prevention
Pharmacologic prevention of delirium with antipsychotics is a topic of current research. A study completed after publication of the PAD guidelines found that intravenous prophylactic haloperidol had no impact on the duration of delirium, coma, or other clinical outcomes.49 These data support the guidelines’ recommendation that no pharmacologic options effectively prevent delirium.4

In contrast, the PAD 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 the most promising results, including a 50% reduction in delirium duration.38

Other nonpharmacologic interventions should be considered, but supportive data are limited in the ICU population. The use of environmental, acoustic, and visual stimulation (e.g., wall clocks, wearing glasses, or listening to music) has been examined. Promotion of the sleep-wake cycle by minimizing ambient noise and dimming hallway lights during the night may be beneficial. Using such interventions, the incidence of delirium in non-ICU settings can be reduced by at least 40%. This makes it prudent to offer these and other preventive strategies routinely50:

  • Updating patient care information boards with names of team members and the day’s schedule
  • Communicating with patients to reorient to surroundings
  • Initiating cognitively stimulating activities 3 times daily (e.g., discussion of current events, structured reminiscence, word games)
  • Providing warm drinks, relaxation tapes, and back massage at bedtime
  • Using unitwide noise reduction strategies
  • Making schedule adjustments to allow for sleep (e.g., reschedule procedures, medications)

Treatment of Underlying Disorders
Once delirium has been identified, the mainstay of treatment is the simultaneous identification and correction of potential physiologic causes (metabolic derangements, hypoxia, hyperthermia, hypercarbia, pain, acidosis, hemodynamic instability, and infection), and control of potentially dangerous behaviors. The continued need for deliriogenic medications— benzodiazepines, anticholinergics, corticosteroids, cephalosporins (especially cefepime), macrolides, or fluoroquinolones—should be evaluated and alternative agents suggested by pharmacists.51

Pharmacologic Interventions
There are no prospective ICU data suggesting that once a patient becomes delirious any specific therapeutic option reduces symptom severity or delirium duration, or improves any clinically relevant delirium-related outcome. As a result, the PAD guidelines make no recommendation for the use of haloperidol or second-generation (atypical) antipsychotic agents.4 Despite a lack of data, intensive care practitioners often prescribe antipsychotic medications for behavioral control in these patients.

Haloperidol is the dopamine antagonist most frequently used to treat symptoms of ICU delirium.4 Haloperidol has no significant effect on respiratory drive and 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.4

Because they have 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 They have agent-specific adverse event profiles as well: 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.52 Although patients older than 65 years with dementia have a greater risk of cardiovascular and infectious sequelae when treated with second-generation antipsychotics, it is unclear if this risk extends to short-term treatment in similar patients with ICU delirium.4

It is difficult to define an appropriate role for second-generation antipsychotics in patients with ICU delirium at this time since randomized data are limited to a single trial involving 36 patients.53 The PAD guidelines concluded that too few data support their use and therefore offered no formal recommendation.4

CONCLUSION

Medical science has made remarkable advances over the past decade in the understanding about how to provide comfort to ICU patients. Management decisions for ICU agitation should always be patient-centered and based on availability of clinical resources; common themes have emerged over the last few years. We now know, for example, that simply evaluating pain and agitation in a systematic fashion significantly reduces their occurrence.

Pain management should be the first priority for agitated patients with sedation added only if needed. Sedative choices should be based on patient-specific goals and conditions and with consideration of pharmacokinetics, pharmacodynamics, and pharmacoeconomics. The nonbenzodiazepines (propofol and dexmedetomidine) are preferred. Light levels of sedation are recommended for a number of reasons, including the ability to assess pain and delirium more accurately, facilitation of early mobility efforts, patient participation in decisions about levels of care, and improvement in a multitude of important clinical outcomes.

Unfortunately, a clear gap exists between published evidence, guideline recommendations, and actual ICU practice. For example, surveys indicate that fewer than 50% of ICUs interrupt sedation on a daily basis, use protocols or guidelines for sedation or analgesia use, or employ validated sedation scoring systems for patient evaluation. The greatest challenge facing critical care practitioners is the routine bedside application of important management strategies. Pharmacists can play a pivotal role in facilitating these changes.

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