Version May 2024
INTRODUCTION — Distress generally presents as agitation. It is common among critically ill patients, especially those who are intubated [1]. Distress needs to be treated for patient comfort and to decrease sympathetic tone, which may have untoward physiologic effects [2].
The management of distress in critically ill adults, including the initiation, maintenance, and withdrawal of pharmacologic sedation, is reviewed here. The mechanism, pharmacokinetics, and adverse effects of common sedative-analgesic medications, the treatment of pain, and the use of neuromuscular blocking agents in critically ill patients are discussed elsewhere.
●(See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects".)
●(See "Pain control in the critically ill adult patient".)
INITIAL ASSESSMENT AND TREATMENT — The cornerstone of treating agitation involves treating the underlying critical illness and reason for distress (eg, pain anxiety, delirium) and use of nonpharmacologic interventions.
Treat underlying critical illness — Several conditions and their associated symptoms can lead to distress, including, but not limited to, drug withdrawal, infection, dyspnea, hypoxemia, and shock. Strategies to alleviate distress due to the underlying illness include simple maneuvers, such as adjusting ventilator settings for dyssynchrony and/or derangements in gas exchange, antipyretics for high fever, hemodynamic support with fluids and/or vasopressors for shock, antimicrobials for suspected infection, and/or heart rate control for arrythmias. Evaluation and management of respiratory distress in mechanically ventilated patients are discussed separately. (See "Assessment of respiratory distress in the mechanically ventilated patient".)
Identify the etiology of distress — As an initial strategy, we identify the cause of the distress so that targeted treatment can be administered. Not uncommonly, there may be more than one reason for distress, necessitating combination therapy. (See 'Combination therapy' below.)
General history and examination — The primary causes of distress in critically ill patients include anxiety or fear, pain, dyspnea, and delirium. These etiologies can be assessed more readily in awake and nonintubated patients, with assessment being more challenging in intubated and/or sedated patients. Thus, in a newly intubated patient, we often use clinical judgement based upon the patient's previous history or reason for intubation to make this assessment. We ask simple "yes or no" questions, such as the following:
●Are you in pain or discomfort?
●Are you afraid?
●Do you feel anxious?
●Do you feel short of breath?
●Are you thirsty?
●Do you know where you are?
We may also use other cues, such as facial expressions (eg, grimacing on palpation), vital signs, and response to analgo-sedative therapy, to assess the presence and severity of symptoms.
When patients are unable to report their symptoms, validated tools for pain and delirium can supplement clinical history and examination for objective assessment. (See 'Assessment anxiety, pain, delirium' below.)
Assessment anxiety, pain, delirium — We also specifically evaluate for anxiety, pain, or delirium, which facilitates directed therapy.
●Anxiety – Reports suggest a wide range of intensive care unit (ICU) patients experience anxiety (12 to 80 percent) [3,4].
•Source – Fear of suffering or death, loss of control, and frustration due to the inability to effectively communicate are typical causes of anxiety in critically ill patients.
•Manifestations – Symptoms and signs include headache, nausea, insomnia, dyspnea, palpitations, dizziness, dry mouth, chest pain, diaphoresis, hyperventilation, pallor, tachycardia, tremulousness, and/or hypervigilance.
•Assessment tools – Self report and clinical evaluation are the most widely used methods for evaluating anxiety. While patient and provider assessment tools for anxiety have been reported in the literature including the Visual Analog Scale-Anxiety (VAS-A) and the Faces Anxiety Scale [5], they are not commonly used in routine clinical practice.
●Pain – Pain is likely underreported in ICU patients, and a significant proportion of ICU survivors report experiencing moderate to severe pain during ICU care [6].
•Source – Pain can be due to routine patient care (eg, suctioning, repositioning, physical therapy), immobility, trauma, surgery, endotracheal tubes, and other monitoring devices.
•Manifestations – Patients may report pain or have evidence of pain, including grimacing, withdrawal, combativeness, diaphoresis, hyperventilation, and/or tachycardia.
•Assessment tools – While self-reporting is preferred over behavioral pain scales, we use unidimensional scales in patients who can communicate or multidimensional scales in nonverbal patients.
-Patients who can communicate – The unidimensional scales can be quickly and easily applied in the ICU if the patient is communicative. As an example, the numeric pain rating scale is a 0 to 10-point scale on which 10 represents the worst pain and 0 is no pain (figure 1); patients choose the number that best describes their pain. Other alternatives include the verbal rating scale or visual analogue scale.
-Nonverbal patients – Multidimensional scales are more complex than unidimensional scales and take longer to administer but can be used in nonverbal patients, which is common in the ICU. Most commonly used and recommended by guideline groups are the Behavioral Pain Scale (BPS) (table 1) and the Critical Care Pain Observation Tool (CPOT) (table 2) since they are simple, valid, and reliable in critically ill patients [7].
A more detailed assessment of pain in critically ill patients is provided separately. (See "Pain control in the critically ill adult patient", section on 'Assessment for pain'.)
●Delirium – Delirium occurs in up to 80 percent of ICU patients. It is frequently unrecognized in older individuals and in patients who have hypoactive delirium [8,9]. Hyperactive delirium is more readily apparent (eg, delirium due to drug or alcohol withdrawal) [10]. Delirium is a risk factor for prolonged hospitalization and mortality in critically ill patients [11-13].
•Risk factors – Risk factors for delirium include electrolyte imbalances (hypocalcemia, hyponatremia), hyperamylasemia, hyperglycemia, azotemia, hepatic disease (hyperbilirubinemia, elevated hepatic enzymes), infections, drug or alcohol withdrawal, malnutrition, cancer, cerebrovascular disease, cardiopulmonary disease, advanced age, and some medications (eg, benzodiazepines, corticosteroids, antihistamines, beta blockers, antiarrhythmics, digitalis glycosides, atropine) [14].
•Manifestations – In the acute phase, delirious patients have impaired short-term memory, abnormal perception, and intermittent disorientation, which is usually worse at night.
•Assessment tools – Many scales and diagnostic instruments have been developed to identify and evaluate delirium, but most exclude critically ill patients due to difficulty communicating with them. Nonetheless, society guidelines promote the regular assessment of critically ill patients with a delirium assessment tool, understanding that the level of arousal may affect accurate assessment. This includes the confusion assessment method for the intensive care unit (CAM-ICU) scale (the original CAM table (table 3) was modified for ICU patients) [15] and the Intensive Care Delirium Screening Checklist (ICDSC) [16]. Both scales assess patients for acute mental status changes or fluctuating mental status changes, inattention, disorganized thinking, and/or an altered level of consciousness. Both scales can identify new or persistent delirium, but neither quantify the severity of the delirium. (See "Diagnosis of delirium and confusional states", section on 'Recognizing the disorder'.)
Further details on the evaluation of delirium are provided separately. (See "Diagnosis of delirium and confusional states", section on 'Evaluation'.)
Nonpharmacologic approaches — We apply nonpharmacologic strategies prior to or in combination with pharmacologic treatment. Combination therapy is common since the cause of the distress is rarely quickly reversible. (See 'Initiating sedative-analgesics' below and 'Combination therapy' below.)
Initial nonpharmacologic strategies include reassurance and frequent communication with the patient [17]. Over the course of the ICU stay, it also includes regular caregiver visits, establishment of normal sleep cycles, correction of sensory deficits, noise reduction, minimizing use of lines and tubes, relaxation therapy (eg, massage) and cognitive-behavioral therapies (eg, music), physical and occupational therapies, and caregiver interaction [18-25].
Even when both nonpharmacologic and pharmacologic interventions are employed, use of physical restraints may be required if the perceived risk of self or caregiver harm cannot be minimized. Restraints should never be the sole method employed for managing patients in the ICU, and when employed, every effort should be made to discontinue them as soon as possible. Further discussion is provided separately. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Nonpharmacologic interventions'.)
Data to support nonpharmacologic interventions include the following:
●Verbal reassurance – One trial randomly assigned 140 mechanically ventilated patients to receive either a strategy of continuous verbal comforting and reassurance without sedation ("no sedation") or continuous sedation with daily interruption of sedatives [20]. For the no sedation group, only when nonpharmacologic interventions failed were patients treated with a continuous sedative infusion with daily interruption. Patients managed with a strategy of no sedation had more ventilator-free days, decreased length of ICU and hospital stay, and decreased incidence of delirium. There was no difference in posttraumatic stress disorder, quality of life, depression, or recall of the ICU experience in survivors approximately two years after randomization [21].
●Music therapy – Another randomized trial of 373 mechanically ventilated patients reported that patient-directed self-initiated music therapy (PDM) with patient-preferred selections tailored by a music therapist resulted in a reduction in the visual analog scale for anxiety when compared with usual care or noise-cancelling headphones (52 versus 33) [22]. PDM also reduced sedation intensity (sedation intensity score 4.4 versus 2.8) and frequency (5 versus 3 doses of study-approved sedative). These findings were confirmed in a meta-analysis of 14 trials examining the impact of music in mechanically ventilated patients [23]. Reductions in patient distress has also been reported in those receiving noninvasive ventilation [24].
●High quality sleep – Although many ICUs implement programs to promote high quality sleep (eg, limiting noise and dimming the lights at night), supporting data are lacking. Disordered sleep in critically ill patients is discussed separately. (See "Clinical and physiologic complications of mechanical ventilation: Overview", section on 'Disordered sleep'.)
INITIATING SEDATIVE-ANALGESICS — For patients in whom treatment of the underlying critical illness and nonpharmacologic strategies have failed to achieve an appropriate level of sedation (eg, calm, cooperative), pharmacologic agents should be administered. This approach reduces the risk of acute and chronic physical and emotional harm, if distress is treated adequately. Once sedative agents are selected and initiated, the dose and/or frequency are titrated to a set target. (See 'Selection of agent(s)' below and 'Set sedation-analgesia targets (scoring systems)' below.)
For the most part, the administration of sedative-analgesic medications should be based on observed agitation and not on anticipated distress (unless the patient is on neuromuscular blockers [NMB]). This reduces the risk of over sedation, which can prolong length of stay and duration of mechanical ventilation. (See 'Avoiding oversedation' below.)
Patients undergoing neuromuscular blockade should empirically receive pharmacologic sedation and analgesia since neuromuscular paralysis without sedation or adequate pain control is an extremely frightening and unpleasant sensation. Additionally, assessing and treating underlying delirium, pain, or anxiety is impossible in paralyzed patients. Indications for neuromuscular blockade in critically ill patients are discussed in detail separately. (See "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects".)
Sedative-analgesic medications that are commonly used in the intensive care unit (ICU) include opioid analgesics (eg, fentanyl, hydromorphone, morphine, remifentanil, methadone), nonopioid analgesics (eg, acetaminophen, nonsteroidal anti-inflammatory drugs), propofol, dexmedetomidine, benzodiazepines (eg, diazepam, lorazepam, midazolam), and antipsychotics (eg, haloperidol, quetiapine, ziprasidone). Other less commonly used agents include barbiturates and ketamine [10,26]. All these agents differ in their amount of anxiolysis, analgesia, amnesia, and hypnosis (table 4). Their mechanisms, properties, dosage regimens, and potential adverse effects are listed on the table (table 5) and reviewed separately. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects".)
Our approach, for the most part, is consistent with The Society of Critical Care Medicine (SCCM) guidelines and Intensive Care Medicine Rapid Practice Guideline (ICM-RPG) [7,27].
Selection of agent(s) — Selection of agent(s) must be individualized since no sedative-analgesic agent is sufficiently superior to other agents to warrant its use in all clinical situations. In practice, observing the response to a specific medication may also help choose an effective agent.
When selecting agents, the following applies:
●We select an agent that targets the etiology of the distress – (See 'Target etiology of the distress' below.)
●We then identify any modifying variables that may influence that choice (ie, pharmacologic and nonpharmacologic factors, such as potential interactions with other drugs and clinical status of the patient) – (See 'Modifying variables' below.)
●In most cases, more than one agent is needed (eg, anxiolytic/sedative and analgesic agents) – (See 'Combination therapy' below.)
●We administer the agent with set targets in mind – (See 'Set sedation-analgesia targets (scoring systems)' below and 'Administration' below.)
Target etiology of the distress — The appropriate initial pharmacologic agent for managing agitation should target the cause of the distress [7]. In practice, more than one agent is typical, and the regimen may contain an agent for pain as well as an agent for anxiety/agitation and/or delirium. These agents are discussed below:
●(See 'Pain or dyspnea' below.)
●(See 'Anxiety/agitation' below.)
●(See 'Delirium' below.)
●(See 'Substance withdrawal' below.)
Pain or dyspnea — For distress due to dyspnea or pain, opioids are the agents of choice (eg, fentanyl or hydromorphone). Fentanyl is generally the most commonly used opioid for intermittent or continuous use due to its rapid onset and short duration of action.
Opioids — Further details on opioid use for pain management are provided separately. (See "Pain control in the critically ill adult patient".)
Anxiety/agitation — Our approach to managing anxiety/agitation is the following:
●For patients with anxiety who do not need a continuous infusion (eg, some patients with mild to moderate alcohol withdrawal), intermittent dosing with benzodiazepines is appropriate. (See "Management of moderate and severe alcohol withdrawal syndromes", section on 'Drug selection'.)
●For severe agitation due to anxiety requiring a continuous infusion, we use propofol or dexmedetomidine rather than a benzodiazepine [7]. We agree with the SCCM who favor nonbenzodiazepine agents. Exceptions include patients in whom benzodiazepines are first-line therapy for the underlying illness (eg, alcohol or substance withdrawal). (See 'Substance withdrawal' below.)
The avoidance of benzodiazepine infusions is supported by evidence that reports increased risk of delirium, mechanical ventilation days, and ICU length of stay when continuous infusions of benzodiazepines are used [7]. Data also suggest that all three parameters are reduced by dexmedetomidine while mechanical ventilation days and ICU length of stay are reduced by propofol. These data are discussed below. (See 'Propofol' below and 'Dexmedetomidine' below and 'Benzodiazepines' below.)
Propofol — Propofol appears to reduce ICU length of stay and mechanical ventilation days but not mortality compared with benzodiazepines [28-30].
●A 2018 network meta-analysis of 31 randomized trials (4491 patients) reported that benzodiazepines increase ICU length of stay compared with propofol (hazard ratio [HR] 3.62, 95% credible interval [CrI] 0.834-6.2) [30]. Mortality rates were similar.
●In one large, randomized, open label trial (included in the above meta-analysis), propofol infusions with daily infusion interruption (mean dose 24.4±16.3 mcg/kg/minute) resulted in a lower number of mechanical ventilation days compared with intermittent bolus lorazepam (median dose 11.5 mg/day) [28].
Dexmedetomidine — Dexmedetomidine may reduce mechanical ventilation days, ICU length of stay, and delirium compared with other agents (including benzodiazepines), but has no impact on mortality [31-51]. As examples:
●A 2022 meta-analysis of 77 randomized trials reported that compared with other sedatives, dexmedetomidine reduced the duration of mechanical ventilation (mean difference [MD] -1.8 hours, 95% CI -2.89 to -0.71), ICU length of stay (MD -0.32 days, 95% CI -0.42 to -0.22), and the risk of delirium (risk reduction 0.67, 95% CI 0.55-0.81) [40]. However, dexmedetomidine also increased the risk of bradycardia by 6 percent and hypotension by 4 percent.
●A 2018 network meta-analysis of 31 randomized trials (4491 patients) reported that compared with dexmedetomidine, propofol and benzodiazepines were associated with an increased risk of delirium (HR 2.4, 95% CrI 0.304-21 and HR 2.59, 95% CrI 1.08-7.4, respectively) [30]. Mortality rates were similar among all agents including propofol, benzodiazepines, and dexmedetomidine [30].
Dexmedetomidine may also decrease the need for alternative sedatives especially in patients withdrawing from alcohol where it may serve as a useful adjunct to benzodiazepines [52-54], the details of which are discussed separately. (See "Management of moderate and severe alcohol withdrawal syndromes", section on 'Alternative and contraindicated agents'.)
The comparative sedative activity of dexmedetomidine versus clonidine, another systemic central alpha-2-adrenoceptor agonist, in mechanically ventilated critically ill adults is being evaluated in an ongoing randomized clinical trial [44].
Benzodiazepines — Benzodiazepines are first-line agents for alcohol withdrawal. (See "Management of moderate and severe alcohol withdrawal syndromes", section on 'Drug selection'.)
For other critically ill patients, benzodiazepines are effective anxiolytics but increase the risk of delirium (see "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Adverse effects'), may prolong mechanical ventilation and ICU length of stay, and result in excess sedation for prolonged periods due to metabolite storage in adipose tissue. Benzodiazepine efficacy compared with propofol and dexmedetomidine are discussed above. (See 'Propofol' above and 'Dexmedetomidine' above.)
Delirium — Antipsychotics can be used intermittently as supplements to other sedatives for the treatment of hyperactive (agitated) delirium. While anti-psychotics are effective at treating delirium, they do not prevent or decrease the duration of delirium or mortality and are, therefore, not administered prophylactically. These data are discussed below. (See 'Antipsychotics' below.)
Choosing among the antipsychotics is individualized. For example, when rapid control of agitation is needed for acute hyperactive psychosis, we use intravenous (IV) haloperidol. In contrast, we use enteral agents (ie, atypical antipsychotics, such as quetiapine) when chronic control is needed (eg, nocturnal psychosis or "sundowning," delirium limiting the ability of the patient to wean off sedative infusions in preparation for extubation). Further details regarding the efficacy of antipsychotics and treatment of delirium are provided separately. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Antipsychotic medications'.)
Antipsychotics — Haloperidol is the most common antipsychotic used to treat delirium in the ICU. Despite its widespread use in the past for delirium prevention, evidence among mechanically ventilated patients suggests that routine use of haloperidol does not prevent or decrease the duration of delirium and has no impact on mortality [55-59]:
●One randomized trial of 1789 critically ill patients at risk of delirium (defined as an anticipated ICU stay of at least two days) reported that 2 mg of haloperidol administered intravenously three times a day had no impact on the incidence of delirium, survival, duration of mechanical ventilation, length of stay, or any other measured outcome compared with placebo [57].
●In another randomized trial of 566 ICU patients with hyperactive or hypoactive delirium, haloperidol or the atypical antipsychotic ziprasidone had no impact on the number of days alive without delirium or coma, 30- or 90-day mortality, duration of mechanical ventilation, or time to ICU or hospital discharge compared with placebo [58].
●In a randomized trial of 1000 mechanically ventilated patients, treatment of delirium with haloperidol did not alter the number of days alive outside the hospital at 90 days compared with placebo [59]. The overall adverse event rate was low and was no different between the groups.
Atypical antipsychotics (quetiapine, olanzapine, risperidone, ziprasidone) are oral agents that have also been used in adult ICU patients to treat delirium. While there is some evidence that oral atypical antipsychotics improve delirium in critically ill patients [60,61], there is a paucity of studies that examine outcomes or compare the efficacy and safety of oral atypical antipsychotics with haloperidol or with one another. The few studies that exist suggest that the efficacy and safety of oral atypical antipsychotics may be similar to that of haloperidol [60,62,63] and may reduce the use of other sedative agents [64].
Substance withdrawal — Patients with agitation due to withdrawal syndromes should be treated consistent with the cause of withdrawal. As examples:
●For patients experiencing alcohol or benzodiazepine withdrawal, treatment may consist of benzodiazepines, phenobarbital, dexmedetomidine, or clonidine. Limited but contradictory evidence supports the use of phenobarbital for management of alcohol withdrawal syndrome in the ICU. A meta-analysis reported that phenobarbital may reduce length of hospital stay and intubation rates, but had no effect on ICU length of stay [65]. Management of alcohol withdrawal is discussed separately. (See "Management of moderate and severe alcohol withdrawal syndromes".)
●For patients experiencing opioid withdrawal, treatment should include reintroduction of an opioid, with level of use prior to admission and current organ function facilitating choice and dose of opioid. Other medications, such as clonidine and loperamide, may be used for additional symptomatic relief. Management of opiate withdrawal is discussed separately. (See "Opioid withdrawal in the emergency setting".)
Modifying variables — Other factors that we consider when selecting a sedative-analgesic agent include the following:
●Pharmacokinetic modifying variables (eg, age, body weight, renal and hepatic function, drug interactions, history of alcohol or drug use). These variables affect onset, peak, and duration of sedation as well as potentiate adverse effects, particularly during deep or long-term sedation.
●Nonpharmacokinetic variables include the desired depth of sedation (eg, light or deep) and clinical status of the patient (eg, eg, presence of bradycardia, hypotension, obesity, long QTc).
How these factors influence agent choice is variable. As examples:
●For patients with bradycardia, dexmedetomidine is generally avoided since bradycardia is a common side effect of this agent. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Dexmedetomidine'.)
●For patients with obesity, prolonged and high-dose benzodiazepines are often avoided since metabolites accumulate in adipose tissue, prolonging sedation and increasing length of stay and mechanical ventilation. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Benzodiazepines' and "Intensive care unit management of patients with obesity", section on 'Sedatives, analgesics, and neuromuscular blockers'.)
●For patients with prolonged QTc interval or on agents that prolong the QTc interval (table 6), antipsychotics are avoided to decrease the risk of ventricular arrythmias. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Antipsychotics' and "Acquired long QT syndrome: Clinical manifestations, diagnosis, and management".)
●For patients with significant hypotension, propofol and dexmedetomidine are often avoided or dosing limited since hypotension is a common adverse effect. A small degree of hypotension ("soft" blood pressure) is sometimes tolerated if the desired sedative effect is achieved and the patient is receiving vasopressors for another reason such as sepsis. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Propofol'.)
●For patients with severe hypertriglyceridemia, propofol is contraindicated. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Propofol'.)
●For patients in whom rapid sedation is required (eg, immediately following intubation, shivering during hypothermia) or rapid awakening is desirable (eg, patients who require frequent neurologic examinations), propofol is useful because it has a rapid onset and short duration of effect. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Properties'.)
●The depth of sedation required for individual patients varies. While "light" sedation is the level recommended for most patients, deeper sedation may be required in patients with severe hypoxemic respiratory failure and ventilator dyssynchrony, patients undergoing procedures or transport, patients with cardiac devices, patients with elevated intracranial pressure, patients receiving medication for treatment of status epilepticus, or patients receiving NMBs. Propofol is the agent of choice for deep sedation because it allows relatively rapid emergence from deep levels of sedation. Recovery from deep sedation with benzodiazepines may be prolonged, and deep sedation may not be easily attained in many patients with dexmedetomidine alone. (See 'Set sedation-analgesia targets (scoring systems)' below.)
●For patients with renal insufficiency, high dose lorazepam should be avoided since the diluent, polypropylene glycol, can accumulate and cause lactic acidosis. This adverse effect is discussed separately. (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects", section on 'Propylene glycol toxicity'.)
The pharmacologic properties of individual agents are provided separately (table 5). (See "Sedative-analgesia in ventilated adults: Medication properties, dose regimens, and adverse effects".)
Combination therapy — Pharmacologic needs range widely. While some patients require minimal or no sedation (eg, severe traumatic brain injury), others require deep sedation to be mechanically ventilated without discomfort, agitation, or asynchrony (eg, severe acute respiratory distress). If the clinician has trouble achieving the set target, dosing is maximized as tolerated and additional agents are administered. Importantly, we avoid polypharmacy such that daily evaluation of both routine and as-needed sedatives is important. (See 'Continuous reassessment' below.)
In practice, most patients often need more than one class of drug (typically two) since the etiology of distress is multifactorial. As an example, for a patient whose agitation is due to anxiety and pain, propofol plus an intermittent opioid is appropriate. For patients who are intubated and mechanically ventilated and not able to clearly communicate the source of agitation, we also often administer propofol with an intermittent analgesic agent (eg, fentanyl) [7]. Patients with alcohol withdrawal may require benzodiazepines (or phenobarbital) and supplemental atypical antipsychotic for heightened periods of delusional agitation; dexmedetomidine infusion may also be a useful adjunct in this population for difficult to control symptoms.
The value of combination therapy was supported by a trial that randomly assigned 30 mechanically ventilated patients to receive midazolam alone or midazolam plus fentanyl [66]. Midazolam plus fentanyl maintained sedation level goals better, decreased the dose of the primary agent, added analgesia, and did not appreciably increase the likelihood of prolonged sedation. There were no differences in hemodynamic or respiratory adverse effects. Two patients treated with the combination regimen developed ileus, compared with none in the midazolam group.
Set sedation-analgesia targets (scoring systems) — We use scoring systems for the presumed cause of distress to target a set sedation level. As an example, if the distress is due to pain and an opioid is initiated, then assessment using a pain scale is appropriate. If the goal of therapy is anxiolysis/sedation, then a scale assessing level of sedation should be used. On many occasions, more than one scoring system is used since agitation/distress is often multifactorial.
Once the appropriate scoring system(s) is selected, we titrate or taper the sedative-analgesic medication to meet the therapeutic goals. One caveat of scoring systems is that reference standards do not exist, underscoring the importance of simultaneous clinical evaluation [67].
●Anxiety/sedation scale – There are numerous scoring systems to assess anxiety/agitation that are valid and reliable in adults who are critically ill and mechanically ventilated [68-72]. The most common scale used is the Richmond Agitation-Sedation Scale (RASS) (table 7), although the Riker Sedation-Agitation Scale is an alternative [7,10]. Other scoring systems include the Motor Activity Assessment Scale, Minnesota Sedation Assessment Tool, Ramsay Sedation Scale (table 8), Bizek Agitation Scale, Sheffield Scale, and COMFORT Scale [73-76].
For most patients, we target a "light" level of sedation. However, there is no consensus regarding the definition of "light" sedation. While in intubated patients the ideal sedation goal is for the patient to be awake and comfortable with minimal to no distress (eg, 0 on the RASS scale) (table 7), a target range from 0 (alert and calm) to -1 (drowsy) is more realistic. Data that support "light" sedation targets are derived from an SCCM meta-analysis of eight studies where light sedation was associated with a shorter time to extubation (mean difference -0.77 days, 95% CI -2.04 to -0.50) and a reduced tracheostomy rate (risk ratio [RR] 0.57, 95% CI 0.41-0.8) [7]. Light sedation was not associated with a reduction in 90-day mortality, delirium (RR 0.96, 95% CI 0.80-1.16), posttraumatic stress disorder, depression, or self-extubation.
However, some critically ill mechanically ventilated patients require a very deep level of sedation-analgesia to control agitation or pain. As examples, deeper sedation may be desired in patients with severe hypoxemic respiratory failure and ventilator dyssynchrony, patients undergoing procedures or transport, patients with cardiac devices, patients with elevated intracranial pressure, patients receiving medication for treatment of status epilepticus, or patients receiving NMBs.
The goal for depth of sedation should be frequently reassessed and adjusted as the patient's sedation requirement becomes more apparent and the critical illness evolves. (See 'Continuous reassessment' below.)
●Pain scales – The primary goal of analgesia is to provide optimal patient comfort, which is highly subjective. We assess the response to analgesia using similar assessment tools to those used for the initial evaluation. These details are described separately. (See "Pain control in the critically ill adult patient".)
●Delirium scales – The primary goal of treating delirium is that the patient be calm and cooperative or back to their baseline mental status. We assess the response to treatment using similar assessment tools to those used for the initial assessment. These tools are described separately. (See 'Assessment anxiety, pain, delirium' above and 'Delirium' above.)
●Targets during paralysis – For patients receiving NMBs (which are not sedatives), deep levels of sedation and assurance of analgesia should be established prior to the administration of paralytics if feasible. Although neuromuscular monitoring (eg, train-of-four) is used routinely during paralysis, clinical targets should additionally guide NMB dosing (eg, ventilator synchrony, avoidance of shivering during hypothermia). Setting targets and monitoring patients on NMBs is discussed separately. (See "Monitoring neuromuscular blockade".)
Administration — Once an agent(s) is chosen, the initial dose and route of administration is selected.
●Initial dosing – Suggested initial and continuous infusion dosing for common agents are shown in the table (table 5).
The initial dose of a sedative-analgesic agent depends upon the desired level of sedation, ability to tolerate the drug (including hemodynamic and respiratory status), and factors that may affect drug metabolism (ie, patient age, body weight, renal function, hepatic function, drug interactions (see 'Modifying variables' above)). Higher doses are appropriate for deeper sedation, larger patients, and patients with a history of alcohol or drug use while lower doses are appropriate for lighter sedation, smaller patients, patients with advanced age, and diminished renal or hepatic function.
●Route of administration – We typically initiate sedatives intravenously. Whether a continuous infusion or intermittent IV dosing is administered is an individualized decision. Although more labor intensive, intermittent IV bolus dosing is less likely to result in drug accumulation compared with continuous infusions. Some experts switch to a continuous infusion when patients require intermittent dosing more often than every two hours. Infusion strategies that prioritize protocolized titrations to light level of sedation or daily interruption are appropriate. Protocolization, daily interruption, and sedation targets are discussed separately. (See 'Set sedation-analgesia targets (scoring systems)' above and 'Avoiding oversedation' below.)
The number of agents required to achieve adequate sedation vary. For some patients, intermittent IV bolus sedation is sufficient to maintain light sedation and patient cooperation with care (eg, mild to moderate alcohol withdrawal, patients with severe hypoxic encephalopathy following resuscitation from cardiac arrest, hypoactive delirium). In contrast, other patients require a continuous infusion to manage severe agitation (eg, patients with hyperactive delirium, severe agitation from opiate withdrawal, coronavirus disease 2019 [COVID-19]-related delirium). Some patients with severe agitation may also need several agents with more than one continuous infusion with or without supplemental bolus infusions (eg, COVID-19 patients). (See 'Combination therapy' above.)
MAINTENANCE AND MONITORING
Role of the pharmacist — Although not universally available, we advocate for the involvement of a critical care pharmacist, particularly during daily rounds [77,78]. Since agent selection can be complex given the multitude of modifying variables in critically ill patients, the clinical pharmacist can optimize therapy, help to reduce drug interactions, improve patient monitoring, and avoid adverse effects. Pharmacists are also key in recognizing discontinued home medications that may exacerbate anxiety, delirium, and pain or agitation in critically ill patients.
Data support the role of the pharmacist. One meta-analysis of 14 studies reported that intervention of critical care pharmacists as part of the multidisciplinary intensive care unit (ICU) team reduced the likelihood of mortality compared with no intervention (odds ratio 0.78, 95% CI 0.73-0.83) [77]. Pharmacist involvement also reduced length of stay and drug-related adverse events.
Continuous reassessment — Once the target goal of sedation is reached, attention should be directed towards monitoring and avoiding excess sedation. This involves frequent reassessment of sedative-analgesic requirements to achieve simultaneous patient comfort in an awake and alert patient. The assessment systems described above allow the clinician to taper sedation when the sedation level is too deep and to titrate sedation when it is too light (see 'Assessment anxiety, pain, delirium' above and 'Set sedation-analgesia targets (scoring systems)' above). This requires hourly bedside assessment by nursing staff as well as daily assessment during rounds that are focused on avoiding oversedation and weaning sedation to the lowest achievable effective dose. As the critical illness is treated, the sedative requirement should fall.
Avoiding oversedation — Excess sedation prolongs the duration of mechanical ventilation [79-81]. Three strategies have been shown to reduce the impact of oversedation on prolonged mechanical ventilation. Although the optimal method is unknown, many ICUs practice one of these approaches and the Society of Critical Care Medicine state that "light" sedation can be achieved in most patients most of the time using any one of these methods [7]:
●Intermittent intravenous (IV) boluses of medication (including analgesia without sedatives, sometimes referred to as "no sedation"). (See 'Intermittent bolus' below.)
●Daily sedation interruption (DSI) of continuous infusions. (See 'Daily interruption of sedation' below.)
●Detailed protocols that incorporate one or both of the above approaches. (See 'Nursing protocolized sedation' below.)
Benefits may be limited if two methods are being concurrently used. This was illustrated by a multicenter trial in which 430 mechanically ventilated patients were randomly assigned to receive protocolized sedation (PS) alone or PS plus daily interruption of their continuous sedative-analgesic infusion (PS+DI) [82]. Time to extubation, rates of unintentional removal of medical devices, ICU delirium, diagnostic neuroimaging, and tracheostomy rates were similar. This study suggests PS alone can effectively achieve the minimal effective sedative dose requirement for patients; there is likely no benefit associated with interrupting the minimal effective dose.
Intermittent bolus — Intermittent bolus sedation involves only administering boluses of IV sedation, typically opiates or benzodiazepines, on a regular basis or when needed. For example, patients with alcohol withdrawal can often be managed successfully with an around-the-clock intermittent benzodiazepine supplemented with as-needed doses of the same benzodiazepine.
Limited older data support intermittent boluses of sedatives to decrease the risk of prolonged mechanical ventilation due to oversedation. One observational study of 242 patients compared the duration of mechanical ventilation among patients who received a continuous sedative-analgesic infusion (not targeted to any specific level of sedation) with those who received either intermittent or no sedative-analgesic infusions, based on a nursing protocol [79]. The group that received intermittent or no medication had a shorter duration of mechanical ventilation than the group that received a continuous infusion (median 56 versus 185 hours). However, sedation level in the continuous infusion group was not targeted to a "light" level with DSI. This may explain why no difference was found in a separate study when intermittent sedation was compared with "light" sedation [83]. These data are discussed below. (See 'Daily interruption of sedation' below.)
Daily interruption of sedation — DSI refers to discontinuation of the continuous sedative-analgesic infusion until the patient is awake and following instructions or uncomfortable/agitated and deemed to require the resumption of sedation. The rationale for DSI is that it facilitates assessment of the patient's underlying neurologic status as well as the patient's need for ongoing sedation.
Randomized trials and meta-analyses report possible benefit from DSI with regard to reducing duration of mechanical ventilation and length of stay [28,79-82,84-93]. However, there is considerable heterogeneity among trials that limits their interpretation. As examples:
●A 2014 meta-analysis of nine trials reported that compared with strategies that do not utilize DSI, DSI resulted in marginal reductions in the duration of mechanical ventilation (13 percent), ICU and hospital length of stay (10 and 6 percent, respectively) [92]. The risk of death, rate of accidental endotracheal tube removal, incidence of new onset delirium, and doses of sedative administered were similar. The confidence intervals were wide, which indicates imprecision and limits interpretation of the analysis.
●A subsequent trial compared daily interruption of "light sedation" (defined as -2 to -3 on the Richmond Agitation and Sedation Scale (table 7) with "no sedation" (intermittent analgesia with IV morphine) in 710 mechanically ventilated patients [83]. There were similar rates of 90-day mortality (37 versus 42 percent), the number of ICU- and ventilator-free days, and days free from coma or delirium. Although the thromboembolic event rate was higher in the sedation group, the total event rate was low (1.5 percent). The inclusion criteria were very specific (among 2300 screened, only 710 underwent randomization) suggesting that the approach of "no sedation" is not generalizable to all mechanically ventilated patients. In addition, the trial may have been underpowered to detect a difference in mortality.
While initially there were concerns related to patient safety during DSI [94,95], such as posttraumatic stress disorder, self-extubation or line removal, and myocardial ischemia, newer data do not support these concerns [90,91,96,97].
Nursing protocolized sedation — Nursing protocolized-sedation is defined as a bedside sedation protocol implemented by nurses that directs sedative choices and medication titration to achieve targeted sedation scores. They usually incorporate components of intermittent bolus infusions and/or DSI.
Data support protocol use [93,98-101]. A meta-analysis of six randomized trials of mechanically ventilated patients in closed nonspecialty ICUs reported that compared with usual care, protocolized sedation was associated with a rate reduction in overall mortality (15 percent), length of hospital stay (3.5 days), and tracheostomy (31 percent) [93]. The duration of mechanical ventilation and rate of self-extubation or reintubation were similar.
REFRACTORY AGITATION — For patients with refractory agitation, three or four agents from different classes may be required. In this population, second-line agents, such as barbiturates and ketamine, may also need to be considered. Use of paralysis is rare (eg, persistent ventilator dyssychrony, hypothermia-induced shivering despite deep sedation).
●Ketamine is a US Food and Drug Administration-approved anesthetic agent. Off-label uses include procedural sedation/analgesia, treatment of extreme agitation, and treatment of pain as an adjunct to opioids [7]. Use of ketamine as an adjunctive analgo-sedative in critically ill mechanically ventilated patients was common during the COVID-19 pandemic [102,103].
Since ketamine has analgesic properties, it has been shown to reduce opioid requirements [104,105]. Small randomized studies of patients with burns also suggested that during painful procedures, oral ketamine provided better analgesia than dexmedetomidine or the combination of midazolam, acetaminophen, and codeine (eg, dressing changes) [106,107]. (See "Pain control in the critically ill adult patient", section on 'Ketamine' and "Management of burn wound pain and itching", section on 'Nonopioid analgesics'.)
The role of ketamine as an induction agent for intubation is discussed in detail separately. (See "Induction agents for rapid sequence intubation in adults for emergency medicine and critical care", section on 'Ketamine'.)
●Use of phenobarbital is rarely needed to manage agitation, although limited but contradictory evidence supports its use for management of alcohol withdrawal syndrome in the intensive care unit (ICU). A meta-analysis reported that phenobarbital may reduce length of hospital stay and intubation rates compared with benzodiazepines, but had no effect on ICU length of stay [65]. Management of alcohol withdrawal is discussed separately. (See "Management of moderate and severe alcohol withdrawal syndromes".)
●For patients who exhibit dyssynchrony despite appropriate adjustments to ventilator settings and deep sedation, the addition of a neuromuscular blocker is sometimes needed, ensuring that patients remain deeply sedated with analgo-sedatives. Sedation targets during paralysis and indications for paralysis are discussed separately. (See 'Set sedation-analgesia targets (scoring systems)' above and "Neuromuscular blocking agents in critically ill patients: Use, agent selection, administration, and adverse effects".)
DISCONTINUATION — When pharmacologic sedation is no longer necessary, we wean sedatives with a goal of discontinuation. General principles include the following:
●Order of medication weaning – For patients receiving more than one sedative-analgesic medication (eg, propofol and an opioid) and in whom pain can be assessed, the opioid should be tapered last so that the patient does not awake in pain. For patients in whom pain is able to be assessed, agents may be weaned simultaneously and pain treated.
●Rate of weaning – The rate of medication reduction should be individualized and depends upon the duration of sedation and manifestations of potential addiction (ie, tachyphylaxis [increased dosage required over time to achieve the same level of sedation]). Generally speaking, the following applies:
•If the sedative-analgesic agent has been administered for a short duration (≤7 days), discontinuation over a short period of time is acceptable (eg, over hours).
•If the sedative-analgesic agent has been administered for >7 days and the patient exhibits evidence of tachyphylaxis, a gradual reduction may be necessary (eg, approximately 10 to 25 percent per day).
In some patients who have received significant amounts of sedation for >7 days who are deeply sedated from prolonged accumulation of medication, abrupt discontinuation may be appropriate. The rationale for this approach is that there may be a delay (ie, days) between the moment that reduction of the sedative-analgesic agent begins, and the patient begins to awaken, particularly following long-term therapy. This is because lipophilic drugs accumulate in tissue stores and must be mobilized for elimination (eg, benzodiazepines and opiates).
●Observation for withdrawal symptoms – During sedative-analgesic medication weaning, the patient should be closely observed for withdrawal symptoms, which are common in this setting (up to one-third of patients) [108]. In general, higher doses of benzodiazepines and opiates confer a higher risk of withdrawal.
Our approach is the following:
•Benzodiazepine withdrawal – For those with troublesome benzodiazepine withdrawal, transitioning to intermittent intravenous or oral lorazepam (eg, 0.5 to 1 mg every 6 to 12 hours) may help protect the patient from developing withdrawal symptoms as the continuous benzodiazepine infusion is being reduced.
•Opiate withdrawal – Several strategies have been proposed for preventing opioid withdrawal, including de-escalating the dose, converting to a longer-acting oral equivalent, converting to a long-acting barbiturate (eg, phenobarbital), and adding an alpha-2-agonist (clonidine, dexmedetomidine) [109,110]. However, there are no controlled trials of any strategy and there is no consensus as to the best strategy. Data are limited to case reports, including two reports in which dexmedetomidine was initiated at a dose of 0.7 mcg/kg/hour (with or without a loading dose) and successfully facilitated opioid withdrawal [111,112]. (See "Opioid tapering for patients with chronic pain", section on 'Opioid tapering strategy'.)
•Dexmedetomidine withdrawal – For those with troublesome dexmedetomidine withdrawal (eg, agitation, delirium, tachycardia, elevated systolic blood pressure) transitioning to oral clonidine, a centrally acting alpha-2-agonist may be a safe way to minimize symptoms and signs of withdrawal. Clonidine is initiated at a dose of 0.2 to 0.3 mg every six hours and then tapered by increasing the dosage interval every 24 hours over the next several days (eg, five to six days) [113-115].
The value of institutional policies is unclear. One observational study reported that most institutions do not have a policy/protocol for sedative weaning and when available, they are used in only a small percentage of patients [116].
INVESTIGATIONAL AGENTS — Sevoflurane and baclofen are investigational agents that have been studied as analgo-sedatives in critically ill patients.
●Data describing sevoflurane use in critically ill patients are limited. A trial randomly assigned 60 mechanically ventilated intensive care unit (ICU) patients to sedation with sevoflurane, propofol, or midazolam [117]. All of the patients received remifentanil for analgesia, most were relatively young trauma patients, and 47 completed the trial. The median duration of sedation in the sevoflurane group was 50 hours (range 39 to 71 hours). Wake-up time and time to extubation were significantly shorter in the sevoflurane group compared with the propofol or midazolam groups. The study had too few events to conclusively detect differences in ICU length of stay or mortality.
●Early data suggested that baclofen may mitigate alcohol craving in patients with alcohol use disorder [118,119]. A subsequent randomized trial used high-dose oral baclofen (50 to 150 mg per day) for the management of agitation in 314 mechanically ventilated patients who had unhealthy alcohol use [120]. Baclofen reduced the proportion of patients who experienced at least one agitation-related event compared with placebo (19.7 versus 29.7 percent; eg, self-extubation, removal of venous catheters). Baclofen had no impact on 28-day ICU mortality and was associated with a longer duration of mechanical ventilation and ICU length of stay. The most common adverse effect was delayed awakening; others included stroke, seizure, and bradycardia. Several flaws in study design, including the lack of standardized baclofen dosing and inaccurate assessment of alcohol consumption, limit interpretation and generalization of this study.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Nonprocedural sedation".)
SUMMARY AND RECOMMENDATIONS
●Initial management – Before a sedative-analgesic agent is initiated, the underlying critical illness should be treated and the etiology of the distress identified and addressed (eg, anxiety, pain, and/or delirium). Nonpharmacologic strategies should be implemented simultaneously (eg, reassurance and frequent communication with the patient, music therapy). (See 'Initial assessment and treatment' above.)
●Pharmacologic sedation – For patients in whom treatment of the underlying illness and nonpharmacologic interventions do not sufficiently control the agitation, pharmacologic sedation is appropriate. (See 'Initiating sedative-analgesics' above.)
•Agent selection – Selection of an agent must be individualized according to the etiology of distress and any existing modifying variables, such as interactions with other drugs and clinical status of the patient. In most cases, more than one agent is needed (eg, anxiolytic/sedative plus analgesic agents) (table 5). (See 'Selection of agent(s)' above and 'Combination therapy' above.)
-For most patients with agitation due to anxiety that requires a continuous intravenous (IV) sedative infusion, we suggest propofol or dexmedetomidine rather than a benzodiazepine (Grade 2B). This choice is based upon evidence that suggests increased risk of delirium, mechanical ventilation days, and intensive care unit (ICU) length of stay when continuous infusions of benzodiazepines are used. Data also suggest that all three parameters are reduced by dexmedetomidine while mechanical ventilation days and ICU length of stay are reduced by propofol. (See 'Anxiety/agitation' above.)
The exception is patients with alcohol withdrawal in whom benzodiazepines are first-line therapy; these details are provided separately (See "Management of moderate and severe alcohol withdrawal syndromes".)
-Most patients who are mechanically ventilated have pain and many have dyspnea. For patients with distress due to dyspnea or pain, short-acting titrating bolus or continuous opioids are required. Requirements are variable, ranging from an intermittent bolus or continuous infusion. Fentanyl is the most common agent used, although hydromorphone, remifentanil, and morphine are alternatives. Further details on opioids for pain management are provided separately. (See "Pain control in the critically ill adult patient".)
-Agitated delirium is typically treated with antipsychotics. For patients with distress due to acute psychosis, we suggest a trial of haloperidol rather than other agents (Grade 2C).The IV formulation, administered intermittently, is often required since continuous infusions are not available. For patients with less acute psychosis (eg, nocturnal psychosis or "sundowning"), we suggest using longer-acting enteral agents (Grade 2C). Options include atypical antipsychotics, such as quetiapine, respiridone, and olanazepine. Further details regarding the efficacy of antipsychotics and treatment of delirium are provided separately. (See "Delirium and acute confusional states: Prevention, treatment, and prognosis", section on 'Antipsychotic medications'.)
-Patients with agitation due to withdrawal syndromes should be treated consistent with the cause of withdrawal, the details of which are discussed separately. (See "Management of moderate and severe alcohol withdrawal syndromes" and "Opioid withdrawal in the emergency setting".)
●Sedation goals – Clinical evaluation and scoring systems are used to set sedation targets and to follow the response to therapy. (See 'Set sedation-analgesia targets (scoring systems)' above.)
•Anxiety/sedation – In most mechanically ventilated patients, we suggest targeting a "light" level of sedation (Grade 2B). The most common scale used is the Richmond Agitation-Sedation Scale (RASS) (table 7); we typically target a RASS score of 0 to -1). In this population, a light sedation level has been shown to decrease mechanical ventilation days and tracheostomy rates. However, some patients require a very deep level of sedation-analgesia (eg, patients with refractory hypoxemia and ventilator dyssynchrony, with intracranial hypertension, undergoing diagnostic procedures). (See 'Set sedation-analgesia targets (scoring systems)' above.)
•Pain – In patients who can communicate, we use unidimensional scales (eg, a 0 to 10-point scale on which 10 represents the worst pain (figure 1)). In nonverbal patients, we use multidimensional scales, such as the Behavioral Pain Scale (BPS) (table 1) and the Critical Care Pain Observation Tool (CPOT) (table 2). The goal of pain control is to ensure comfort. Further details regarding pain control are provided separately. (See 'Set sedation-analgesia targets (scoring systems)' above and "Pain control in the critically ill adult patient", section on 'Goals of pain control'.)
•Delirium – We use the confusion assessment method for the intensive care unit (CAM-ICU) scale or the Intensive Care Delirium Screening Checklist (ICDSC) to detect delirium. The goal is to have the patient be calm and cooperative and return back to their baseline mental status. (See 'Set sedation-analgesia targets (scoring systems)' above and 'Assessment anxiety, pain, delirium' above.)
●Maintenance and monitoring – Our approach is the following:
•All patients should be frequently reassessed to determine whether their sedative-analgesic medication needs to be titrated or tapered. This requires hourly bedside assessment by nursing staff as well as daily assessment during rounds. (See 'Continuous reassessment' above.)
•Although the optimal method is unknown, choosing one of the following approaches should help avoid oversedation (see 'Avoiding oversedation' above):
-Intermittent boluses rather than continuous dosing of medication (including analgesia without sedatives, sometimes referred to as "no sedation"). (See 'Intermittent bolus' above.)
-Daily sedation interruption (DSI) of continuous infusions. (See 'Daily interruption of sedation' above.)
-Protocolized sedation that incorporates components of intermittent bolus sedation or DSI. (See 'Nursing protocolized sedation' above.)
●Weaning – When pharmacologic sedation is no longer necessary, we wean sedatives with a goal of discontinuation. The rate of reduction must be individualized and depends upon the duration of sedation and manifestations of potential addiction (eg, tachyphylaxis). Tapering agents in parallel is often performed except when opioids are coadministered and are generally tapered last so that the patient does not awake in pain. If there is difficulty weaning due to withdrawal symptoms, transitioning to an oral or intermittent agent of the same class may be useful. (See 'Discontinuation' above.)
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