Review ArticleCritical Care Medicine

Sedation and Delirium in the Intensive Care Unit

List of authors.
  • Michael C. Reade, M.B., B.S., D.Phil.,
  • and Simon Finfer, G.D.

Introduction

Patients in intensive care units (ICUs) are treated with many interventions (most notably endotracheal intubation and invasive mechanical ventilation) that are observed or perceived to be lamentable. Pain is the most mutual memory patients have of their ICU stay.1 Agitation can precipitate accidental removal of endotracheal tubes or of intravascular catheters used for monitoring or administration of life-sustaining medications. Consequently, sedatives and analgesics are among the most commonly administered drugs in ICUs.

Early intensive care practise evolved from intraoperative anesthetic care at a time when mechanical ventilation was delivered by rudimentary machines that were non capable of synchronizing with patients' respiratory efforts. Equally a result, deep sedation was unremarkably used until a patient was able to breathe without assistance. Developments over the past 30 years, including microprocessor-controlled ventilators that synchronize with patients' own respiratory efforts and new, shorter-acting sedative and analgesic medications, have dramatically changed this approach. As important has been the recognition that pain, oversedation, and delirium are bug that if undetected and untreated are sad to patients and associated with increased morbidity and mortality.

Figure 1. Figure ane. Causes and Interactions of Hurting, Agitation, and Delirium.

Drugs and other treatments for pain, agitation, and delirium form an "ICU triad" cognitive management analogous to the "triad of anesthesia," which highlights interactions among hypnotics, analgesics, and muscle relaxants to encourage balanced anesthesia. The "ICU triad" concept highlights that changing one element is unlikely to exist as effective as a coordinated approach.

Just as the concept of the "triad of anesthesia" underscores the pharmacodynamic interactions among hypnotics, analgesics, and muscle relaxants and the recognition that the simultaneous administration of agents of each form permits the utilise of lower doses of drugs of all classes, the concept of the "ICU triad" recognizes that hurting, agitation, and delirium — and therefore approaches to their management — are inextricably linked (Effigy 1). According to the principle that information technology is meliorate to treat disease than to mask it, sedatives should exist used but when pain and delirium have been addressed with the use of specific pharmacologic and nonpharmacologic strategies.

Hurting, Analgesia, and Sedation in the ICU

Prospective studies ostend that the majority of patients who are treated in ICUs have hurting,1 which makes the assessment of pain and provision of adequate analgesia essential components of ICU care. The brusque-term consequences of untreated pain include higher free energy expenditure and immunomodulation.ii,iii Longer-term, untreated pain increases the gamble of post-traumatic stress disorder.iv Assessing whether a patient in the ICU is in pain may be difficult. The reference standard for the assessment of hurting is self-reporting by the patient, but patients in the ICU may not be sufficiently interactive to give valid responses. Physiological indicators such as hypertension and tachycardia correlate poorly with more intuitively valid measures of pain,5 but pain scales such as the Behavioral Pain Scale6 and the Disquisitional Care Pain Observation Tool7 provide structured and repeatable assessments and are currently the all-time bachelor methods for assessing pain.

A minority of ICU patients accept an indication for continuous deep sedation, for reasons such as the treatment of intracranial hypertension, astringent respiratory failure, refractory condition epilepticus, and prevention of sensation in patients treated with neuromuscular blocking agents. This review will focus on the remaining overwhelming majority of patients undergoing mechanical ventilation for whom the use of sedatives and analgesics should exist minimized, with the goal that they be calm, lucid, pain-gratuitous, interactive, and cooperative with their care.

Show from randomized, controlled trials consistently supports the use of the minimum possible level of sedation. In a landmark trial that compared routine daily interruption of sedative infusions with discretionary interruption by treating clinicians, patients whose sedation was routinely interrupted received less sedation overall and spent fewer days undergoing mechanical ventilation and fewer days in the ICU. 8 Although the trial was too small to appraise differences in mortality or discharge destination, the observed reductions in the elapsing of mechanical ventilation and length of stay in the ICU were associated with a nonsignificant reduction in bloodshed and a nonsignificant increase in the proportion of patients who were discharged to their own homes.8 A subsequent larger multicenter trial combined the daily interruption of sedation with daily spontaneous breathing trials.nine Daily break of sedation was associated with reduced administration of a benzodiazepine sedative, reduced duration of mechanical ventilation, reduced length of stay in the ICU, and significantly increased survival. In dissimilarity, when daily interruption of sedation was added to a protocol for sedation practice that already sought to minimize the level of sedation, the total allaying dose was increased and there was no clinical benefit.10

These conflicting results are open up to a number of interpretations, including that daily interruption is beneficial just when information technology results in a reduction in the full dose of sedative administered. The alien findings likewise highlight that the results of daily suspension of sedation may be context-specific and volition depend on the population existence studied, protocol adherence, and management of the control group. A randomized, controlled trial in which all patients undergoing mechanical ventilation received morphine for the treatment of pain in an "analgesia first" approach compared a protocol of no sedation with the routine utilize of sedation with daily pause.11 Patients who were assigned to the protocol of no sedation had shorter stays in the ICU and the hospital and more than days without mechanical ventilation.

The consistent message from all these sedation-interruption trials is that minimizing sedation among patients in the ICU provides clinical benefit. Farther support comes from a prospective, multicenter, longitudinal cohort report showing that the depth of sedation was independently associated with the duration of mechanical ventilation, in-hospital mortality, and rates of death within 180 days.12 In a randomized, controlled trial, the use of lighter sedation resulted in more ventilator-gratuitous and ICU-free days.13 In comparing with deep sedation, the use of lighter sedation did not increment the charge per unit of short-term agin events, and long-term psychiatric outcomes were either unaffected or improved. 13-16

Selection of Allaying Amanuensis

Table 1. Table ane. Sedatives and Analgesics in Common Utilize in the ICU.

Despite at to the lowest degree xc trials comparing sedative regimens,17 in general, no sedative drug is clearly superior to all others. Sedatives that are normally used in the ICU are the benzodiazepines midazolam and lorazepam (and to a bottom extent, diazepam), the brusk-interim intravenous coldhearted agent propofol, and dexmedetomidine.12 Remifentanil, an opioid, is besides used equally a sole amanuensis because of its allaying effects. Benzodiazepines act through γ-aminobutyric acrid type A (GABAA) receptors, as in part does propofol, whereas dexmedetomidine is an α2-adrenoceptor agonist, and remifentanil is a μ-opioid receptor agonist (Table 1). Marked differences in prescribing patterns among countries suggest that the selection of agent is determined more by tradition and familiarity than by evidence-based exercise.

If minimizing the depth and duration of sedation is accepted equally a desirable goal, then the use of a curt-acting agent with an effect that can be rapidly adapted such as propofol or remifentanil should offer advantages over longer-interim agents or agents with active metabolites. Every bit compared with benzodiazepines, propofol has not been shown to reduce mortality simply may result in a reduction in the length of stay in the ICU.18 Dexmedetomidine may also accept advantages over benzodiazepines, since it produces analgesia, causes less respiratory depression, and seemingly provides a qualitatively different type of sedation in which patients are more interactive and then potentially improve able to communicate their needs.19 Equally compared with lorazepam and midazolam, dexmedetomidine resulted in less delirium and a shorter elapsing of mechanical ventilation but not reduced stays in the ICU or hospital. nineteen-21 When ii short-acting and titratable drugs such equally propofol and dexmedetomidine were compared, there was no significant departure in the time spent at the target sedation level and no difference in either the duration of mechanical ventilation or ICU stay.19

Remifentanil has a half-life of iii to 4 minutes that is independent of the infusion duration or organ function. It has been investigated as a sedative agent in ICUs predominantly among surgical patients. Information technology has been compared with midazolam alone, midazolam with fentanyl, fentanyl alone, and morphine.22-25 Although remifentanil has been associated with a reduced duration of mechanical ventilation and ICU stay in these small trials, it has non yet been evaluated in a big, heterogeneous population of critically ill patients and is currently non a common choice in most ICUs.

Prevention and Treatment of Delirium

The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-Four),26 lists four domains of delirium: disturbance of consciousness, modify in cognition, development over a short period, and fluctuation. Delirium is defined past the National Institutes of Health as "sudden severe confusion and rapid changes in brain office that occur with concrete or mental disease." The most common feature of delirium, thought by many to be its key sign, is inattention. Delirium is a nonspecific but generally reversible manifestation of acute disease that appears to have many causes, including recovery from a sedated or oversedated state.

The pathophysiology of delirium that is associated with critical disease remains largely uncharacterized and may vary depending on the cause. The increased chance associated with the utilize of GABAA agonists and anticholinergic drugs led to the suggestion that the GABAergic and cholinergic neurotransmitter systems play a contributory role. In item, central cholinergic deficiency may be a final mutual pathway. Alternative hypotheses include excess dopaminergic activeness and direct neurotoxic effects of inflammatory cytokines. Currently, these hypotheses are unproven, making pharmacologic management strategies largely empirical.

Studies using magnetic resonance imaging have shown a positive association between the elapsing of delirium in the ICU and both cerebral atrophy and cerebral white-matter disruption.27,28 These preliminary investigations indicate either that delirium in the ICU gives ascent to alterations in brain structure or that the presence of such cognitive atrophy and white-matter disruption renders patients more susceptible to delirium.

Regardless of the crusade and the underlying pathophysiology, delirium is at present recognized as a frequent and serious event in critically ill patients. In that location is no diagnostic blood, electrophysiological, or imaging exam for delirium, which therefore remains a clinical diagnosis. Estimates for the incidence of delirium in the ICU range from 16%29 to 89%,xxx with the reported incidence afflicted both past the characteristics of the population being studied and by the diagnostic criteria used. Risk factors that have been identified include an advanced age and the presence of more than ane condition associated with coma, followed by treatment with allaying medications, a neurologic diagnosis, and increased severity of illness.31 A diagnosis of delirium is associated with increased mortality (estimated every bit a 10% increase in the relative risk of death for each day of delirium32) and decreased long-term cognitive function. 33

In that location are two distinct forms of delirium, hypoactive and agitated (or hyperactive). When individual patients intermittently have both forms, it is termed mixed delirium. The hypoactive form is characterized by inattention, matted thinking, and a decreased level of consciousness without agitation. Pure agitated delirium affects less than two% of patients with delirium in the ICU.34 Patients with hypoactive delirium are the least probable to survive, but those who practice survive may have meliorate long-term office than those with agitated or mixed delirium.33 Separating the effects of delirium status from those of illness severity with respect to the risk of decease is difficult, since patients with more serious illnesses are at increased hazard for both delirium and death. Association studies typically adjust for illness severity on admission to the ICU rather than at the time that delirium is diagnosed. Although the association betwixt delirium and a worse consequence is articulate, a causal relationship has not been established. Currently, the evidence that specific handling of delirium may improve outcomes is tenuous.

Cess and Monitoring of Sedation and Delirium

Although ICU practice is characterized by close monitoring of carefully administered care, surveys that accept been conducted in various countries take shown that the depth of sedation oftentimes goes unmonitored.35 This finding is surprising and unacceptable, since evidence suggests that the routine monitoring of sedation may amend patients' outcomes.36

Sedation Scales

Tabular array two. Tabular array 2. Sedation Scales for Patients in the ICU.

Of the sedation scales described, the Riker Sedation–Agitation Scale37 and the Richmond Agitation–Sedation Scale38 are the almost normally reported, only in caput-to-head comparison, neither is demonstrably superior39 (Tabular array 2). For the majority of patients undergoing mechanical ventilation in an ICU, an advisable target is a score of 3 to 4 on the Riker Sedation–Agitation Scale (which ranges from one to 7, with scores of <4 indicating deeper sedation, a score of four indicating an appearance of calm and cooperativeness, and scores of ≥v indicating increasing agitation) or a score of −2 to 0 on the Richmond Agitation–Sedation Calibration (which ranges from −5 to +4, with more negative scores indicating deeper sedation and more positive scores indicating increasing agitation, and with 0 representing the appearance of calm and normal alertness).

Identifying Delirium

Table 3. Table 3. Scoring Systems for the Diagnosis of Delirium in Critically Sick Patients.

In routine practice, ICU staff members typically do non diagnose delirium in almost three quarters of their patients who accept the condition, whereas active screening by research nurses identified delirium in up to 64% of patients who were considered to be delirious past a psychiatrist, a geriatrician, or a neurologist.40 Scales with respect to delirium in the ICU apply the iv DSM-Iv domains defining delirium in general medical and psychiatric patients to those in the ICU whose severity of illness can rapidly fluctuate, who receive multiple analgesics and sedatives, and who are unable to speak attributable to endotracheal intubation. Two scales are in mutual use, the Confusion Assessment Method for the ICU (CAM-ICU)41 and the Intensive Care Delirium Screening Checklist (ICDSC)29 (Table 3). The CAM-ICU reports a dichotomous assessment at a single time indicate, whereas the ICDSC lists signs that tin be observed over a period of time. Although such scales are essential in objectively diagnosing delirium for inquiry purposes, it is not clear that the use of these scales is more sensitive than unstructured assessments made past trained bedside nurses who are prompted to expect for delirium. Some studies take shown a high sensitivity when such assessments are performed past bedside nurses,42 whereas other studies have shown conflicting results.43 Used solitary (without an accompanying sedation scale), none of the published scales distinguish hyperactive from hypoactive delirium, and none of the published scales quantify the relative importance of individual elements of the scales despite recognition that specific treatments may shorten the duration of some elements and prolong the duration of others. All the scales dichotomize delirium as being either present or absent-minded, although it would seem to exist intuitive that delirium has dissimilar degrees of severity. The CAM-ICU and ICDSC are currently the two accepted methods for identifying a condition that otherwise frequently goes undiagnosed.44

Prevention and Treatmentof Delirium

Prevention

At that place is some prove that delirium can exist prevented. Outside the ICU, repeated reorientation, noise reduction, cognitive stimulation, vision and hearing aids, adequate hydration, and early mobilization can reduce the incidence of delirium in hospitalized patients.45 Haloperidol prophylaxis in patients undergoing hip surgery reduced the severity and elapsing of delirium.46 Among patients in the ICU, the duration of delirium was cut in half with early mobilization during interruptions in sedation.47

Pharmacologic studies of delirium prevention include trials comparing one sedative–analgesic regimen with some other and studies of antipsychotic drugs administered with the specific intent of preventing delirium. Four placebo-controlled trials have evaluated pharmacologic prophylaxis of delirium; low-dose haloperidol48 and depression-dose risperidone49 both reduced the incidence of delirium, every bit did a single low dose of ketamine during the induction of anesthesia.l However, these trials were conducted amid patients undergoing elective surgical procedures, and it is non clear whether their results tin can be extrapolated to the general ICU population. In contrast, the cholinesterase inhibitor rivastigmine was ineffective in preventing delirium.51

Sedation with dexmedetomidine rather than benzodiazepines appears to reduce the incidence of delirium in the ICU. In a multicenter, randomized trial predominantly involving medical patients in the ICU, the administration of dexmedetomidine or midazolam resulted in like proportions of time inside the target range of −ii to +1 on the Richmond Agitation–Sedation Scale amongst patients, but those assigned to receive dexmedetomidine had a reduced risk of delirium and spent less time undergoing mechanical ventilation.21 Every bit compared with a lorazepam infusion, sedation with dexmedetomidine resulted in more time at the target level of sedation and longer survival without delirium or blackout.20 In a multicenter European trial, patients were randomly assigned to go on treatment with their current sedative (midazolam or propofol) or to switch to sedation with up to 1.4 μg of dexmedetomidine per kilogram of body weight per hour.19 At that place were no betwixt-grouping differences in the proportion of time at the target level of sedation. The rates of the blended end point of agitation, anxiety, or delirium were lower with dexmedetomidine than with propofol, but the rates with dexmedetomidine were equivalent to those with midazolam. When delirium was assessed with the use of the CAM-ICU 48 hours afterwards sedation was discontinued, there were no significant differences among the groups.

Handling

In that location is very little evidence to guide the management of established delirium, and most existing trials were categorized by the investigators as pilot studies. Only ane small placebo-controlled trial supports the efficacy of a drug handling for established delirium in patients in the ICU. In a study of 36 patients who were randomly assigned to treatment with quetiapine or placebo, delirium resolved faster in patients who received quetiapine. The utilize of quetiapine too increased the number of patients who were discharged to their own home or to rehabilitation.52 A study of 103 patients who were randomly assigned to receive regular haloperidol, ziprasidone, or placebo showed no significant differences in the number of days that patients survived without delirium or coma.53 The single study comparing haloperidol with an atypical antipsychotic (olanzapine) showed equivalent efficacy.54 None of these trials distinguished between hyperactive and hypoactive delirium.

In a pilot written report comparison dexmedetomidine with haloperidol in patients with hyperactive delirium, dexmedetomidine was associated with a shorter fourth dimension to extubation and shorter length of stay in the ICU.55 This finding is supported by a randomized trial of dexmedetomidine versus midazolam in which patients with delirium at the time of enrollment had a more rapid resolution of delirium if they were assigned to receive dexmedetomidine than if they were assigned to receive midazolam.21 Nonetheless, definitive evidence supporting the use of dexmedetomidine for the treatment of delirium is not currently bachelor.

Quality Improvement Techniques

Frameworks that facilitate the aforementioned approaches have been adult. These include the "hurting, agitation, and delirium" (PAD) guidelines44 and the "spontaneous awakening and breathing coordination, attention to the choice of sedation, delirium monitoring, and early mobility and do" (ABCDE) packet.56 These guidelines emphasize improving team communication in the ICU, standardizing care processes, and prioritizing methods to lighten sedation and facilitate early mobilization and extubation. Each guideline recognizes the conceptual evolution from spontaneous-breathing trials and pause of sedation to a comprehensive approach to monitoring and managing pain, agitation, and delirium.

Conclusions

Figure 2. Effigy two. Algorithm for the Coordinated Management of Pain, Agitation, and Delirium.

The awarding of this algorithm — which combines the use of analgesics, antidelirium agents, sedatives, and nonpharmacologic techniques — volition depend on the individual situation for each patient. For example, patients undergoing surgery who are suitable candidates for rapid extubation and who accept little take a chance of delirium may be treated merely with analgesia and chop-chop diminishing sedation. RASS denotes Richmond Agitation–Sedation Scale, which ranges from −v to +4, with more than negative scores indicating deeper sedation and more positive scores indicating increasing agitation, and with 0 representing the appearance of at-home and normal alacrity.

Accumulating show suggests that the management of sedation and delirium can take an important effect on the outcomes of patients who are treated in ICUs. Currently bachelor data suggest that the all-time outcomes are achieved with the employ of a protocol in which the depth of sedation and the presence of pain and delirium are routinely monitored, pain is treated promptly and effectively, the assistants of sedatives is kept to the minimum necessary for the comfort and safety of the patient, and early mobilization is achieved whenever possible (Effigy two).

Funding and Disclosures

Dr. Reade reports receiving grant back up through his institution from Hospira. Dr. Finfer reports receiving grant support through his institution from Fresenius Kabi; existence a fellow member of the International Sepsis Forum (ISF) council, which has received funding from Eisai, Siemens, Agennix, AstraZeneca, BD Diagnostics, bioMérieux, BRAHMS/Thermo Fisher, Eli Lilly, Roche, Spectral, Toray, Philips, Apex, Ferring, BioCritica, and Plasma Protein Therapeutics Association during his membership; and receiving consulting fees from Edwards (paid to ISF), lecture fees from Eli Lilly and PPTA (donated to ISF), and travel back up from the ISF. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Author Affiliations

From the Burns, Trauma and Critical Care Research Heart, University of Queensland, and Joint Wellness Command, Australian Defence Strength, Brisbane (M.C.R.); and the George Institute for Global Health, and Majestic North Shore Hospital, University of Sydney, Sydney (Southward.F.) — all in Australia.

Address reprint requests to Dr. Reade at Level nine, University of Queensland Health Sciences Building, Royal Brisbane and Women'southward Hospital, Brisbane, QLD 4029, Australia, or at [email protected].

Supplementary Cloth

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