Sedation in the ICU

Sedation and Delirium in the Intensive Care Unit

Sedation, analgesia, pain, anxiety, delirium, ICU psychosis

Introduction: sedation and delirium in critically ill patients

Sedation and analgesia are administered to critically ill patients to provide comfort and ensure safety, because unrelieved or unrecognized pain and anxiety contribute to patient distress, evoke the stress response, complicate the management of lifesaving devices, and negatively affect outcome. Unpredictable pharmacokinetics and pharmacodynamics secondary to hemodynamic instability, organ dysfunction, protein binding, and drug interactions lead to complications when sedative and analgesic medications are administered to critically ill patients.

Because most sedative agents are administered as continuous infusions, drug accumulation, redistribution, and tachyphylaxis also confound their utilization, and techniques to prevent systemic drug accumulation need to be employed. Recent studies have shown that continuous sedation is associated with increased times on mechanical ventilation and in the ICU, more radiological testing for altered mental status, ICU-acquired weakness and greater likelihood of delirium. Additionally the role of sedation and amnesia in the ICU has been questioned because studies have shown that sedative agents, especially benzodiazepines, may put patients at higher risk for post-traumatic stress disorder (PTSD) and potentially even cognitive impairment, months after ICU discharge. Furthermore, individual sedatives have drug-specific side effects such as hypotension, bradycardia, myocardial suppression, and rhabdomyolysis.

There has been a growing concern among health care providers about the potential of iatrogenic harm after studies have shown a temporal relationship between the administration of higher doses of benzodiazepines (a common occurrence in ICUs) and the development of acute brain dysfunction (delirium and coma), adding to the call among many to employ strategies to reduce the burden of unnecessary sedation in critically ill patients.

Delirium

Delirium is a manifestation of acute brain dysfunction, characterized by an acute disturbance of consciousness accompanied by inattention, disorganized thinking, and perceptual disturbances that fluctuates over a short period of time. Delirium is commonly under-diagnosed in the ICU and has a reported prevalence of 20% to 80%, depending on the severity of illness and the need for mechanical ventilation. Historically, delirium was considered an inconsequential occurrence during critical illness.

Unfortunately, recent investigations have shown that delirium is independently associated with worse outcomes as seen with other organ dysfunctions. The presence of delirium is a strong predictor of longer hospital stays, greater times on mechanical ventilation, higher costs and more alarmingly, increased risk of death. Each additional day with delirium increases the risk of dying by 10%. Longer periods of delirium are also associated with greater degrees of cognitive decline when patients are evaluated one year after hospital discharge.

Subtypes of delirium

Delirium can be categorized into subtypes according to psychomotor behavior manifested by patients. Hypoactive delirium patients are characterized by decreased physical and mental activity (lethargy) and inattention, are frequently overlooked by both physicians and nursing staff, and may have higher mortality and morbidity. On the other extreme are hyperactive delirium patients who are agitated and combative. Patients exhibiting both characteristics have mixed delirium. Evaluation of the subtypes of delirium has revealed that hypoactive delirium is often the more prevalent form of delirium in critically ill patients.

Pathophysiology of delirium

The pathogenesis of delirium is poorly understood. Numerous hypotheses exist and include neurotransmitter imbalance [e.g., dopamine, γ-aminobutyric acid (GABA), and acetylcholine], inflammatory perturbations (e.g., tumor necrosis factor-α, interleukin-1, and other cytokines/chemokines), impaired oxidative metabolism, cholinergic deficiency, and changes in various amino acid precursors.

Diagnosis of delirium

Until recently, evaluation for delirium required consultations with psychiatrists to utilize the DSM-IV criteria. Recent validation of 2 bedside delirium monitoring instruments, the Confusion Assessment Method for ICU (CAM-ICU) and the Intensive Care Delirium Screening Checklist (ICDSC), has made it easy for health care providers to evaluate patients for delirium, even when patients are non-verbal due to mechanical ventilation.

Delirium monitoring instruments

The Confusion Assessment Method for ICU (CAM – ICU): The CAM-ICU (Figure 1) is a reliable and validated instrument for diagnosing delirium. It has a high specificity and sensitivity, is easy to use, and takes approximately 60-90 seconds to administer. Patients are first evaluated for a level of consciousness, and if they respond to verbal commands (e.g., a Richmond Agitation-Sedation score of -3 or higher), then they are assessed for delirium. Large-scale implementation studies have been performed, including in trauma patients, showing good reliability and compliance of delirium monitoring by bedside nurses.

Intensive Care Delirium Screening Checklist: This is a validated, eight-item-based screening checklist for delirium (Table I). The patient is evaluated for inattention, disorientation, hallucination, delusion or psychosis, psychomotor agitation or retardation, inappropriate speech or mood, sleep/wake cycle disturbance, and fluctuation of the above symptoms. Each item is scored as absent or present (0 or 1, respectively) and summed. A score ≥ 4 indicates delirium, while 0 indicates no delirium. Patients with scores between 1 and 3 are considered to have subsyndromal delirium. Patients with subsyndromal delirium have some but not all features of delirium and have outcomes that are in between those of patients with and without delirium.

Table I.

Altered level of consciousness (A-E)	* See scoring for level of consciousness below
Inattention	Difficulty in following a conversation or instructions. Easily distracted by external stimuli. Difficulty in shifting focuses. Any of these scores 1 point.
Disorientation	Any obvious mistake in time, place or person scores 1 point.
Hallucinations-delusion-psychosis	The unequivocal clinical manifestation of hallucination or of behavior probably due to hallucination or delusion.Gross impairment in reality testing. Any of these scores 1 point.
Psychomotor agitation or retardation	Hyperactivity requiring the use of additional sedative drugs or restraints in order to control potential danger to oneself or others.Hypoactivity or clinically noticeable psychomotor slowing.
Inappropriate speech or mood	Inappropriate, disorganized or incoherent speech.Inappropriate display of emotion related to events or situation. Any of these scores 1 point.
Sleep/wake cycle disturbance	Sleeping less than 4 h or waking frequently at night (do not consider wakefulness initiated by medical staff or loud environment).Sleeping during most of the day. Any of these scores 1 point.
Symptom fluctuation	Fluctuation of the manifestation of any item or symptom over 24 h scores 1 point.
Total score (0-8)

*Level of consciousness:

A: No response, score: None.

B: Response to intense and repeated stimulation (loud voice and pain), score: None.

C: Response to mild or moderate stimulation, score 1.

D: Normal wakefulness, score: 0.

E: Exaggerated response to normal stimulation, score: 1.

(Adapted from Bergeron et al.)

The CAM-ICU and the ICDSC

Risk factors for delirium

Risk factors for the development of delirium are multifactorial and can be divided into host factors (age, baseline comorbidities, baseline cognitive impairment and genetic predisposition), factors of acute illness (sepsis, hypoxemia and metabolic disturbances) and iatrogenic and environmental factors (metabolic disturbances, anticholinergic medications, sedatives and analgesic medications and sleep disturbances).

Sedatives and analgesics as risk factors for delirium

Numerous studies have shown an association between benzodiazepine and opioid administration and the development of delirium. It is also true, however, that pain itself is a risk factor for delirium and hence needs to be appropriately addressed. In studies looking at the temporal association between sedative and analgesic exposure and the development of delirium, lorazepam and midazolam have been associated with development of delirium in medical, surgical, trauma, and burn ICU patients.

The association between opioid medications and delirium is inconsistent, with fentanyl being a risk factor for delirium in surgical ICU patients but not in trauma patients and morphine being associated with a lower risk of delirium in the trauma ICU patients. Similar to the trauma patients, exposure to both intravenous opiates and methadone were associated with lower odds of developing delirium, leading to the belief that appropriate pain control in populations at risk for severe pain (trauma, burn, etc.) reduces delirium risk.

Management of pain in critically ill patients

Pain assessment

The most valid and reliable indicator of pain is the patient’s self-report. Information about pain, including location, quality, and intensity, should be elicited routinely as part of the patient’s vital signs. Tools such as the visual analog scale or numeric rating scale can be used to document severity. It is not uncommon for ICU patients to be unable to communicate with caregivers, in which case behavioral and physiologic indicators must be used to assess pain intensity. The FACES scale and Behavioral Pain Scale (Table II) are validated tools for assessing pain, use of which has been associated with lower analgesic and sedative use and decreased time on the ventilator.

Table II.

Item	Description	Score
Facial expression	Relaxed	1
	Partial tightened (e.g. brow lowering)	2
	Full tightened (e.g. eyelid closing)	3
	Grimacing	4
Upper limb	No movement	1
	Partial bent	2
	Fully bent with finger flexion	3
	Permanently retracted	4
Compliance with ventilation	Tolerating movement	1
	Coughing but tolerating ventilation most of the time	2
	Fighting ventilator	3
	Unable to control ventilation	4

Pain management

In managing pain, nonpharmacologic methods should be attempted first. These include patient repositioning, injury stabilization, removal of noxious or irritating stimuli, and application of heat or cold. Repositioning and additional support, especially for the lumbar region, are increasingly important in obese patients. When nonpharmacologic approaches are insufficient to provide analgesia, regional or systemic therapy is indicated.

Regional therapy

Regional nerve blockade provides analgesia for specific areas of the body without the systemic effects of intravenous analgesia. These procedures are useful adjuncts to decrease exposure to side effects of potent analgesics, especially the respiratory depressant effects of opiates. Blockade of individual nerves or nerve plexus may provide relief of pain localized to one extremity, and placement of peripheral nerve catheters can prolong the benefit of this targeted action. Paravertebral blocks are useful for managing pain related to unilateral thoracic or abdominal procedures and traumatic rib fractures, and can help in improving pulmonary mechanics.

Epidural analgesia has become increasingly popular for the management of pain from thoracic, abdominal, or lower extremity operative procedures. Through a catheter, local anesthetics, opiates, and other pharmaceutical adjuncts such as clonidine can be infused in the epidural space to provide bilateral analgesia in specific dermatomes.

Systemic therapy

Systemic analgesics should be administered as part of a goal-directed sedation and analgesia protocol. Systemic therapies include nonsteroidal anti-inflammatory drugs and acetaminophen, but opioids are the most common ICU therapy secondary to their analgesic and sedative properties.

Commonly used analgesics and dosages in critically ill patients

The most commonly used opiates in the ICU are morphine, hydromorphone and fentanyl. Morphine and hydromorphone are typically utilized as intermittent intravenous (IV) injections. Morphine is given in doses of 2-5 mg IV every 5-15 minutes until the pain is controlled, followed by similar doses on a scheduled basis every 1-2 hours. Hydromorphone is preferred in patients with renal dysfunction, with typical dosing ranges of 0.2 mg-1 mg IV. Fentanyl is a synthetic opioid with a rapid onset (5-15 minutes) and a short duration of action (30-60 minutes). Its short half-life allows easy titration as a continuous infusion. It is relatively safe in patients with renal dysfunction as well. In general, loading doses of 25-100 mcg are given every 5-10 minutes until the pain is controlled, followed by infusion rates of 25-250 mcg/hr.

Remifentanil

Remifentanil is a derivative of fentanyl that is metabolized by nonspecific blood and tissue esterases. It is utilized primarily as an infusion (0.05-2 mcg/kg/hr) and has an elimination half-life of less than 10 minutes regardless of infusion duration. Hypotension and bradycardia are the most common side effects of remifentanil administration, and supplemental analgesic medication is usually required at the conclusion of a remifentanil infusion. Concerns about cost, withdrawal, and hyperalgesia after discontinuation of remifentanil have limited the widespread use of this agent.

Pharmacokinetics of commonly prescribed analgesic medications

Morphine is characterized by hepatic metabolism and renal excretion, so its effects can be prolonged in patients with renal or hepatic impairment. Hydromorphone is a more potent congener of morphine with similar pharmacokinetic and pharmacodynamic profiles. Its lack of histamine release and decreased incidence of central nervous system side effects make it a useful alternative to morphine. Both morphine and hydromorphone have intermediate volumes of distribution. Fentanyl causes less histamine release than morphine and does not undergo renal elimination; it is the preferred opioid analgesic in hemodynamically unstable patients and can be used safely in patients with renal insufficiency.

Side effects of systemic analgesic therapy

Opioids, however, have a number of adverse effects. Respiratory depression and decreased gastrointestinal motility are commonly seen, although their impact can be reduced through proper airway and ventilator management and stimulant laxative use, respectively. Hypotension may result from decreased sympathetic tone or vasodilation from histamine release, especially with morphine. Other side effects include pruritus, flushing, urinary retention, and delirium.

Management of sedation in critically ill patients

Assessment of level of sedation

Many scales are available to assess level of sedation and agitation, including the Ramsay scale, Riker sedation-agitation scale, motor activity assessment scale, and Richmond agitation-sedation scale (RASS). Their reliability and validity among adult ICU patients allow these to be used to set targets for goal-directed therapy. Only the RASS has been shown to detect variations in the level of consciousness over time or in response to changes in sedative and analgesic drug use.

Richmond Agitation-Sedation Scale (RASS)

The RASS is a 10-point scale with discrete criteria to distinguish levels of agitation and sedation (Table III). Numerous studies have shown that the use of a defined sedation target for the provision of protocol-based, goal-directed therapy reduces patient discomfort and improves outcome.

Table III.

+4	Combative	Combative, violent, immediate danger to staff
+3	Very agitated	Pulls or removes tubes or catheters; aggressive
+2	Agitated	Frequent nonpurposeful movement; fights ventilator
+1	Restless	Anxious, apprehensive, but movements not aggressive or vigorous
0	Alert and calm
−1	Drowsy	Not fully alert, but has sustained (>10 sec) awakening (eye opening/contact) to voice
−2	Light sedation	Drowsy, briefly (<10 sec) awakens to voice or physical stimulation
−3	Moderate sedation	Movement or eye opening (but no eye contact) to voice
−4	Deep sedation	No response to voice, but movement or eye opening to physical stimulation
−5	Unarousable	No response to voice or physical stimulation

Common sedative regimens

Benzodiazepine-based sedation

Benzodiazepines bind to GABA receptors in the central nervous system, thereby providing sedation, anxiolysis, hypnosis, muscle relaxation, anticonvulsant activity, and amnesia. Diazepam, midazolam, and lorazepam have traditionally been the benzodiazepines most frequently utilized in the ICU. Currently, benzodiazepine sedation in the ICU is decreasing in favor of other sedation regimens secondary to mounting evidence of increased morbidity, including increased delirium, time on mechanical ventilation, and ICU length of stay. Benzodiazepines, however, remain the drugs of choice for the treatment of delirium tremens and seizures.

Propofol-based sedation

Propofol is an intravenous anesthetic with a mechanism of action primarily at the GABA receptor. It has proven utility as a sedating agent in the ICU due to its rapid onset (1-2 minutes) and short duration of action (2-8 minutes). It is typically given as a bolus injection of 0.5-0.75 mg/kg IV followed by an infusion of 5-50 mcg/kg/min. Propofol is a respiratory depressant and can also cause significant hypotension by venodilation, vasodilation, and myocardial depression. Propofol has been associated with hypertrigylceridemia when infused for 7 days or greater, and propofol infusion syndrome at high doses.

Dexmedetomidine-based sedation

Dexmedetomidine is a selective alpha2 receptor agonist with a site of action that includes presynaptic neurons in the locus ceruleus and spinal cord, producing analgesia and sedation without respiratory suppression. The onset of action is within 15 minutes, and peak concentrations are achieved after one hour of continuous infusion. Sedation is often initiated with a bolus of 1 mcg/kg over 10-20 minutes, followed by an infusion of 0.2-0.7 mcg/kg/hr. Bradycardia is the most common side effect of dexmedetomidine, especially with rapid bolus administration, and both hypotension and hypertension may be seen during dexmedetomidine utilization. Dexmedetomidine infusion has been shown to decreases postoperative analgesic and antiemetic therapies.

Pharmacokinetics of dexmedetomidine

Dexmedetomidine is metabolized by the liver, and patients with severe liver disease require lower dosing, whereas there is no need for dose adjustment based on renal dysfunction, age, or gender.

Propofol infusion syndrome

Propofol infusion syndrome is characterized by severe lactic acidosis and rhabdomyolysis. While the majority of reports have been in the pediatric population, a few case reports have been published describing propofol infusion syndrome in adults associated with high-dose (>75 mcg/kg/min) and prolonged (>72 hours) infusions. Consequently, providers should consider alternative sedative agents for any patient receiving high-dose propofol infusions who develops unexplained metabolic acidosis, arrhythmia, or cardiac failure.

Basic principles of management of sedation and delirium in the ICU

Target -based sedation with use of nurse-driven protocols has been shown to reduce exposure to sedative medications and to improve patient outcomes. Additionally, daily interruption of sedation, as well as linking these spontaneous awakening trials to daily spontaneous breathing trials, has been shown to improve time off mechanical ventilation, shorten ICU stays and reduce12-month mortality without any associated increase in long-term neuropsychological outcomes. An increased rate of self-extubation was witnessed with these protocols but without a difference in re-intubation rates. Delirium should be evaluated in all patients and non-pharmacological treatments focused on reorientation, decreasing exposure to deliriogenic medications and improving sleep should be tried before symptom relief is attempted with typical or atypical antipsychotics. At this time, no clear evidence exists on which antipsychotic is beneficial for treating delirium though quetiapine has shown promise in one small study. Dexmedetomidine has been associated with reducing delirium duration and prevalence. Additionally early exercise or physical therapy in ICU patients has been associated with reduction in duration and prevalence of delirium, while improving functional status at discharge.

What's the evidence for sedation and delirium management in the ICU?

We present an evidence-based organizational approach referred to as the ABCDE bundle (Awakening and Breathing trials, Choice of appropriate sedation, Delirium management and Early mobility and Exercise) to assist clinicians in incorporating best practice guidelines into their care of patients.

Awaken the patient daily

Benzodiazepines are known to increase the risk of delirium in a dose-dependent manner. Multiple studies have shown that protocolized target-based sedation and daily spontaneous awakening trials reduce the number of days on mechanical ventilation. This strategy also exposes the patient to smaller cumulative doses of sedatives. Patients should be screened daily, and if they do not have specific contraindications to stopping sedation, the sedative agents need to be discontinued until they follow simple commands; thereafter, sedation can be restarted at half the dose if indicated.

Coordination of daily awakening and daily breathing trials

The Awakening and Breathing Controlled trial combined spontaneous awakening trial with the spontaneous breathing trials. This combination showed shorter duration of mechanical ventilation, a 4-day reduction in hospital length of stay, a remarkable 15% decrease in 1-year mortality, and no long-term neuropsychological consequences of waking patients during critical illness.

Choosing the right sedative regimen in critically ill patients

Numerous studies have identified that benzodiazepines are associated with worse clinical outcomes, necessitating attention to the choice of sedation one decides to use for one’s patients. In a study comparing propofol to intermittent lorazepam, Carson et al. found that in patients requiring >48 hrs of mechanical ventilation, sedation with propofol resulted in lower ventilator times than lorazepam, even when sedatives were interrupted daily.

Breen et al. compared a sedation regimen using remifentanil to midazolam and found that the remifentanil-based sedation regimen decreased duration of mechanical ventilation. Two studies comparing sedation protocols using dexmedetomidine to benzodiazepine infusions showed similar results. The MENDS study showed more days alive without delirium or coma (7.0 vs. 3.0;
P= .01), with a lower risk of developing delirium on subsequent days if dexmedetomidine was used instead of lorazepam. The SEDCOM study also showed a decrease in delirium prevalence in the dexmedetomidine group (54% vs. 76.6%; P< .001), with shorter times on mechanical ventilation.

Delirium management

The Society of Critical Care Medicine (SCCM) has published guidelines recommending routine monitoring for delirium in all ICU patients. Pharmacologic therapy for delirium should be attempted only after correcting any contributing factors or underlying physiologic abnormalities. Patients who manifest delirium should be treated with a traditional antipsychotic medication (haloperidol), per the SCCM guidelines. A recommended starting dose is 2-5 mg every 6-12 hours (IV or PO); the maximal effective doses are usually around 20 mg/day. Newer “atypical” antipsychotic agents (e.g., risperidone, ziprasidone, quetiapine, and olanzapine) also may prove helpful for the treatment of delirium.

While the MIND study showed no difference in the duration of delirium between haloperidol, ziprasidone or placebo, when used for prophylaxis and treatment, a smaller study done by Devlin et al. showed that quetiapine was more effective than placebo in resolution of delirium when supplementing ongoing haloperidol therapy. Data from the MENDS study and the SEDCOM trial support the view that dexmedetomidine can decrease the duration and prevalence of delirium when compared to lorazepam or midazolam.

Exercise and early mobility

Morris et al. showed that initiating physical therapy early during the patient’s ICU stay was associated with decreased length of stay both in the ICU as well as in the hospital. In this prospective cohort study the investigators assessed the effect of introducing a mobility protocol in the ICU. They found that patients in the study group received at least one more physical therapy session than the control group, were out of bed earlier, had therapy initiated more frequently and had no differences in the complication rates.

Schweikert et al. examined the efficacy of combining daily interruption of sedation with physical and occupational therapy to see if it had an impact on the development of ICU-acquired weakness and delirium in mechanically ventilated patients. They found that patients who underwent early mobilization had a significant improvement in functional status at hospital discharge. These patients also had a significant decrease in the duration of delirium (approximately 50%) in the ICU as well as during the hospital stay. At 28 days patients also had more ventilator-free days in the physical therapy group.

Conclusion

Analgesia and sedation is frequently required in critically ill patients, but can also be associated with worse clinical outcomes such as longer times on mechanical ventilation, longer ICU stays and delirium, which itself is an independent predictor of worse outcomes. Clinicians should strive to minimize these medications through use of targeted sedation and via protocols that incorporate awakening and breathing trials, reduce benzodiazepine exposure and encourage early mobilization.

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Critical Care Medicine