Analgesia y Anestesia en UCI

DOI 10.1378/chest.07-2026 2008;133;552-565Chest

Curtis N. Sessler and Kimberly Varney

*the ICUPatient-Focused Sedation and Analgesia in

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Patient-Focused Sedationand Analgesia in the ICU*Curtis N. Sessler, MD, FCCP; and Kimberly Varney, PharmD

Patient-focused sedation and analgesia in the ICU encompasses a strategy of comprehensivestructured management that matches initial evaluation, monitoring, medication selection, andthe use of protocols with patient characteristics and needs. This is best accomplished throughinterdisciplinary management by physicians, nurses, and pharmacists. An early consideration isthat of the potential predisposing and precipitating factors, as well as prior sedative or analgesicuse, factors that may influence pharmacologic and supportive therapy. Frequent monitoringwith validated tools improves communication among clinicians and plays an important role indetecting and treating pain and agitation while avoiding excessive or prolonged sedation.Patient-focused management encompasses selecting medications best suited to patient charac-teristics, including the presence of organ dysfunction that may influence drug metabolism orexcessive risk for side effects. The use of protocols to optimize drug therapy has emerged as a keycomponent of management, resulting in reductions in the duration of sedation, mechanicalventilation, and ICU length of stay demonstrated with strategies to titrate medications to specifictargets, daily interruption of sedation, intermittent rather than continuous therapy, and analgesia-based therapy. While much attention is paid to the initiation and maintenance of therapy, greateremphasis must be placed on careful de-escalation of therapy in order to avoid analgesic orsedative withdrawal. Finally, more work is needed to explore the relationship of critical illnessand sedation management with long-term psychological outcomes.

(CHEST 2008; 133:552–565)

Key words: analgesia; delirium; medications; protocols; sedation

Abbreviations: ATICE � Adaptation to the Intensive Care Environment; BIS � bispectral index; DIS � daily interruptionof sedation; EMG � electromyography; ICDSC � Intensive Care Delirium Screening Checklist; LOS � length of stay;MSAT � Minnesota Sedation Assessment Tool; MV � mechanical ventilation; NMB � neuromuscular blockade;PTSD � posttraumatic stress disorder; RASS � Richmond Agitation-Sedation Scale; RCT � randomized controlled trial;SCCM � Society of Critical Care Medicine

C ritically ill patients, particularly those who arereceiving mechanical ventilation (MV), often have

pain, anxiety, dyspnea, and other forms of distress.1Core principles of ICU care are to provide comfort,to improve tolerance of the harsh ICU environment,and to provide relief from distress. This is oftenaccomplished through identifying and correctingpredisposing and precipitating factors, applying non-pharmacologic measures to enhance comfort, andadministering sedative and analgesic medications, asdepicted in a conceptual framework in Figure 1.2Patients report that the greatest stressors they en-counter include pain, sleep deprivation, and thepresence of tubes in the nose and mouth, factors thatare exceedingly common in the ICU setting.1,3,4

Accordingly, it is not surprising that the majority of

ICU patients require IV sedative and analgesic med-ications.5 It is important to recognize that theseunderlying conditions, including delirium and delu-sional memories, as well as therapeutic interventionsmay influence the likelihood of patients having long-term psychological effects.6

Interdisciplinary Management

It is noteworthy that effective sedation manage-ment is best accomplished through intradisciplinaryplanning and practice. By combining nurses’ bedsideexperience, skills, and continuous management ofsedation,7 pharmacists’ knowledge of medications,their interactions and proper role in critically illpatients,8 and physicians’ integration of sedation

CHEST Postgraduate Education CornerCONTEMPORARY REVIEWS IN CRITICAL CARE MEDICINE

552 Postgraduate Education Corner



issues into medical management,2,9 a comprehensiveplan can be implemented on a consistent basis. Anoverview of the principles of the management ofsedation and analgesia is displayed in Table 1. Effec-tive management is patient focused, encompassingmedication selection to avoid adverse effects orprolonged effects from the parent drug or its activemetabolite(s), and titrating sedative and analgesicmedications to specific targets for effectiveness (ie,tolerance of ICU environment, pain and anxietycontrol, patient/ventilator synchrony) while avoidingexcessive or unnecessarily prolonged sedation thatmight lead to longer ICU length of stay and theaccompanying complications of chronic critical illness.

Initial Evaluation and Management

An important starting place is to consider thepossible predisposing and precipitating factors forvarious forms of distress, plus issues that influencemanagement, as depicted in Figure 1. Underlyingmedical conditions such as chronic pain or arthritis,acute illness or injury, history of alcohol or substanceabuse, and psychiatric illness can influence medicationselection. Other issues such as postoperative factors,ICU interventions such as MV, medications, and sim-ple maneuvers like turning and suctioning, as well assleep deprivation related to excessive noise and light,can all can play a role.2 Recognition and managementof these factors are crucial. Medication reconciliation(ie, continuing a patient’s chronic home medicationregimen) is frequently forgotten in hospitalized pa-tients. Antidepressants, anxiolytics, and antipsychoticsare medications of particular concern if not restarted.Severe withdrawal or rebound of chronic symptomscan occur if these medications are withheld for toolong, and can lead to serious comorbid issues. Forexample, patients who appear delirious or severelyagitated in the ICU may become overmedicated withsedative drugs because their home medications havebeen temporarily discontinued. Recognition and man-agement of all of these factors early in their ICU stayare crucial to optimal management of sedation.

*From the Virginia Commonwealth University Health System,Medical College of Virginia Hospitals, Richmond, VA.Dr Sessler is the Orhan Muren Professor of Medicine, VirginiaCommonwealth University Health System.Dr. Sessler discloses receiving honoraria as a consultant fromHospira, Inc.Dr. Varney has no actual or potential conflicts of interest to disclose.Manauscript received August 10, 2007; revision accepted Octo-ber 31, 2007.Reproduction of this article is prohibited without written permissionfrom the American College of Chest Physicians (www.chestjournal.org/misc/reprints.shtml).Correspondence to: Curtis N. Sessler, MD, FCCP, Division ofPulmonary and Critical Care Medicine, Box 980050, VirginiaCommonwealth University Health System, Richmond, VA 23298;e-mail: [email protected]: 10.1378/chest.07-2026

Figure 1. Conceptual framework for the interactions among underlying and causative factors, thesensations of pain, anxiety, and delirium, pharmacologic and nonpharmacologic interventions, and thestate of a patient along the continuum from deep sedation to overt agitation. Reproduced withpermission from Sessler et al.2

www.chestjournal.org CHEST / 133 / 2 / FEBRUARY, 2008 553



Delirium, an acute reversible disorder of attentionand cognition, is a common occurrence among crit-ically ill patients, and may be a marker for worseoutcomes, including increased incidence of posttrau-matic stress disorder (PTSD) and increased long-term mortality.10,11 While classical hyperactive de-lirium is easily recognized by manifestations ofintermittent agitation, hallucinations, and disrup-tive behavior, a hypoactive form appears to be morecommon in the ICU setting.12 A wide variety ofmedical conditions (including CNS disorders, infec-tions, hypoxia, pain, withdrawal syndromes, electro-lyte and metabolic disorders, and various organdysfunctions) as well as a long list of medications canprecipitate delirium.2,11,13,14 There is emerging evi-

dence that many cases of hypoactive or mixed delir-ium in the ICU are related to the sedative effects ofanxiolytic and analgesic drugs, particularly loraz-epam, that ICU caregivers administer15; thus, strat-egies that emphasize using the lowest effective sed-ative drug dose may help avoid delirium.

Patient-focused sedation incorporates the conceptthat need for sedation and analgesia differs amongpatients and varies over time for individual patients.For example, patients who receive unusual forms ofventilatory support such as high-frequency oscillatoryventilation or prone positioning may require deepsedation, or even neuromuscular blockade (NMB), toachieve ventilator synchrony.16–18 Patients who arereceiving NMB require adequate sedation and anal-gesia, and periodic cessation of the NMB agent toassess adequacy of sedation and analgesia.19 In con-trast, low tidal volume ventilation per se does notrequire increased sedative drug therapy in compari-son to conventional ventilation for the ARDS.20–22

Converting the artificial airway from an endotrachealtube to a tracheostomy tube has been associated withuse of less sedative and analgesic medication andcorrespondingly fewer hours of deep sedation.23 Alco-hol and substance abuse is associated with greatersedative drug requirements.24 Importantly, require-ments for sedation are dynamic, generally decliningas illness improves, and thus must be reassessedfrequently.

Evaluation of Pain, Sedation, Agitation,and Delirium

Bedside evaluation of the level of consciousness orarousability, cognitive function, presence and inten-sity of pain, and presence and intensity of agitationis an integral component of daily patient care.2,9,25

The detection and quantification of pain or agitationis useful to prompt the initiation or escalation oftherapy as well as the reevaluation for reversiblecauses.26 The routine determination of the level ofconsciousness, which often incorporates the domainsof arousal and cognition, helps guide sedative drugdosing and avoidance of excessively deep sedation.Thus, utilization of tools—sedation scales and painevaluation instruments—is important for patient-focused therapy, typically by establishing a targetlevel of sedation to which medications are titrated toachieve, and to minimize pain.

Pain Evaluation

Evaluation of pain is relatively straightforward forpatients who are alert enough to “self-report” byspeaking, nodding, or pointing in response to ques-tions about severity of pain. This is often performed

Table 1—Key Concepts for Management of Sedationand Analgesia

1. Develop an interdisciplinary, structured approach for managingsedation and analgesia in the ICU

2. Perform patient assessment and optimize the ICU environmentA. Identify predisposing and precipitating factors; manage

treatable factorsB. Identify outpatient medications (medication reconciliation),

particularly psychiatric and pain medications; restartmedications as appropriate

C. Optimize patient comfort and tolerance of the ICUenvironment

D. Optimize MV settings for patient/ventilator synchrony3. Regularly perform and document structured patient evaluation

and monitoringA. Establish and communicate treatment goalsB. Assess presence and severity of pain, as well as response to

therapyC. Assess level of sedation using a validated sedation scale, as

well as response to therapyD. Assess presence and severity of agitation using a validated

agitation scaleE. Identify delirium, and consider regular assessment of

delirium, using a validated delirium assessment instrument4. Implement a structured patient-focused management strategy

A. Select analgesic and sedative drugs based upon patientneeds, drug allergies, organ dysfunction (particularly renal orhepatic dysfunction), need for rapid onset and/or offset ofaction, anticipated duration of therapy, and prior response totherapy

B. Focus first on analgesia, then sedationC. Titrate analgesic and sedative drugs to a defined target,

using the lowest effective doseD. Implement a structured strategy to avoid accumulation of

medications/metabolites: utilize scheduled interruption, orintermittent dosing of analgesic and sedative drugs

E. Evaluate and manage severe agitation, including search forcausative factors, and perform rapid tranquilization

F. Identify delirium, correct precipitating factors, and treat withhaloperidol or other neuroleptic drugs

G. Avoid potential adverse effects of analgesic and sedativedrugs; quickly identify and manage adverse effects thatoccur

5. Recognize and take steps to ameliorate analgesic and sedativedrug withdrawal during de-escalation of therapy




using an instrument such as a 10-cm visual analogscale, or a scale with extremes of measurement an-chored by numerical (0 to 10), descriptive (“no pain” to“worst pain ever”), or diagrammatic (smiling face tocrying face) variables, the patient indicating theirlevel of pain.27 Asking about pain should be per-formed frequently, particularly prior to administer-ing sedatives or when these agents are stoppedtemporarily. Assessment of pain is less reliable andless valid when inferred through observation ofpatient behaviors, although recent instruments suchas the Critical Care Pain Observation Tool28 showpromise. The components of Critical Care Pain Obser-vation Tool and other similar tools29–31 are based onrecognition of common behaviors, such as facialgrimacing, restless body movement, rigid limbs, andpatient/ventilator asynchrony observed during pain-ful procedures and validated against self-report.32,33

While hypertension, tachycardia, and tachypnea arealso commonly observed during painful stimuli, theirlack of specificity for pain34 has dampened enthusi-asm for routine use. These symptoms may be moretelling if combined with a positive history of chronicor acute pain, or use of chronic pain medications.

Sedation Evaluation

The level of sedation is assessed in many ICUsusing a sedation scale; however, surveys indicate theyare used by fewer than one half of practitioners,35

ICUs,36 and consecutive patients receiving MV.37

Useful features of a sedation scale include rigorousmultidisciplinary development; ease of administra-tion, recall, and interpretation; well-defined discretecriteria for each level; sufficiency sedation levels foreffective drug titration; assessment of agitation; dem-onstration of interrater reliability for relevant patientpopulations; and evidence of validity.25 Although anumber of sedation scales have been developed forICU use, the following sedation scales satisfy manyof these characteristics and have been tested forinterrater reliability in multiple patient populations atmultiple hospitals and validated against numerous mea-sures: the Ramsay Sedation Scale,38 the Sedation Agi-tation Scale,39 the Motor Activity Assessment Scale,40

the Richmond Agitation-Sedation Scale (RASS),41

the Adaptation to the Intensive Care Environment(ATICE) instrument,42 and the Minnesota SedationAssessment Tool (MSAT).43 A common approach totesting level of consciousness is to observe thepatient to see if they are awake, and if not, then tostimulate the patient using auditory stimulation(speaking to the patient), followed by more intensive(physical) stimulation if there is no response toauditory stimuli. The patient’s response to increasinglevels of stimulation is noted and a score assigned, as

with the Ramsay Sedation Scale, RASS, ATICE, andMSAT. In some scales, cognition—as the ability tofollow a command (ie, RASS, ATICE)—and sustain-ability (ie, RASS) are included in the testing.41,42

Additionally, agitation is identified and graded inseverity in Sedation Agitation Scale, Motor ActivityAssessment Scale, RASS, and ATICE.39–42 Finally,widespread integration into ICU practice has beendocumented for RASS, MSAT, and ATICE.41,44–47

Implementation of sedation evaluation with a scaleis an integral component of many treatment algo-rithms, and has been documented to result inmore precise dosing, reduced sedative and analgesicdrug use, shorter duration of MV, and reduced needfor vasopressor therapy,48 as well as reduced inci-dence of oversedation.49

Objective Measurement of Brain Activity

Objective assessment of brain activity can beperformed using EEG signals processed by propri-etary algorithms such as with the bispectral index(BIS),50 patient state index,51 cerebral state index,52

and Narcotrend index53 systems to yield a singlenumerical value from 0 (complete EEG suppression)to 100 (awake). These monitors offer advantages ofusing objective physiologic parameters, a simplifiednumerical display, and near-continuous measure-ment, yet are rarely utilized in the clinical ICUsetting today.50 Factors such as electromyography(EMG) or electrical current-related artifact, whichare less problematic in the operating room setting,increase variability of BIS in the critically ill patient.In fact, the administration of a NMB agent tosedated ICU patients led to remarkable decreases inBIS, averaging 24 U and 35 U in two studies,54,55

demonstrating the potential importance of EMGinterference. While EMG artifact may account inpart for the wide variability in correlation (r2 � 0.21to 0.93) between BIS and level of sedation as judgedby various sedation scales,50 the use of newer algo-rithms designed to reduce EMG influence may noteliminate BIS variability.56 Experts recommend us-ing BIS for selected cases, such as monitoring thelevel of consciousness of patients treated with NMBagents and for deep (pentobarbital-induced) coma57;however, routine use must await studies that dem-onstrate added value from better outcomes and/orcost savings. Additional approaches to brain moni-toring in the ICU include response entropy and stateentropy,58 and auditory-evoked potentials.59,60

Delirium Evaluation

Delirium is associated with worse outcomes10,11

and has been frequently found in ICU patients whenusing some10,61,62 but not all assessment tools11,63–65




and depending on the patient population. Detectionof delirium in the critically ill patient has beenchallenging because inability to speak and often towrite impairs testing, yet tools for use in ICUpatients have been developed.66 Many validatedtools are interventional, such as the Confusion As-sessment Method for the ICU,61 or the CognitiveTest for Delirium67 (or its abbreviated version),68 inwhich a rater directly tests state of consciousness,comprehension, memory, attention, and vigilance.Other validated instruments use observation with achecklist of behaviors such as level of consciousness,inattention, disorientation, hallucinations, agitation,inappropriate mood, sleep-wake cycle disturbance,and symptom fluctuation as in the Intensive CareDelirium Screening Checklist (ICDSC)63 or theNursing Rating Scale for ICU Delirium.67 The Con-fusion Assessment Method for the ICU and ICDSCare more recently developed and have been exten-sively validated. The ICDSC also allows identifica-tion of “subsyndromal” delirium that may progress toovert delirium.69 Although routine screening for thepresence of delirium is recommended in the 2002Society of Critical Care Medicine (SCCM) guide-lines for sedative and analgesic therapy,9 surveysindicate that delirium testing of ICU patients with avalidated tool is rarely performed.35,70

Other components of sedation-related monitoring ofthe ICU patient include detection and quantification ofconditions that influence sedation management deci-sions, including agitation,39–42 patient movement asa surrogate for agitation,43,71,72 and patient/ventilatorasynchrony.73,74 Future approaches will likely inte-grate multiple measurements in order to optimizepatient comfort and tolerance of the ICU setting.

Managing Sedation and Analgesia

Pharmacologic therapy is required in the majorityof ICU patients, particularly those who are receivingMV.5 Medications are often administered by contin-uous infusion for ease of use and to provide a smoothcourse; however, continuous infusion has been linkedto prolonged sedation and longer length of ICUstay.75 Accordingly, intermittent therapy or provisionof schedule daily interruption of sedation (DIS) isoften employed to avoid excessive and prolongedeffects.76–78 Often, multiple medications are admin-istered in order to treat both pain and anxiety, or toprovide synergy, thus allowing reduced dosing ofmedications.5,79,80 Several studies suggest that focus-ing first on providing analgesia rather than initiallyon anxiolysis may provide more effective79 andshorter duration of MV.81 In most cases, IV admin-istration is desirable since absorption from the GI

tract or following subcutaneous or IM injection isless reliable, and precise titration to the target effectis more accurate. However, administration of trans-dermal or enteral medications may have a role insome patients, particularly those who require longer-term sedation and analgesia management, resultingin elimination or reduction in IV dosages.82 Mea-sures must be taken to avoid long-term sedative oropioid medication dependence after ICU discharge;explicit plans for cessation or scheduled tapering ofthese drugs are necessary as the patient leaves theICU, particularly for patients with a history of alco-hol or substance dependency.

Medications for Sedation and Analgesia

The two major classes of medications used topromote comfort and tolerance of the ICU environ-ment are the sedative-hypnotic agents and opioidanalgesics, which provide anxiolysis, sedation, amne-sia, and analgesia to the patient. General consider-ations for medication selection include effectiveness;factors related to duration, onset, and offset of effect;presence of active metabolites; adverse effects; costsrelated to drug acquisition as well as to duration ofsedation; and any recent history of opioid or benzo-diazepine use. Characteristics of commonly used IVadministered sedative and analgesic drugs are dis-played in Table 2.

Sedative Medications

The benzodiazepines, midazolam and lorazepam, arecommonly administered by continuous infusion or in-termittent injection in the North American ICUs,35,83

whereas lorazepam is rarely used and midazolamenjoys widespread use in Europe.37,84 Lorazepamgiven by intermittent boluses or continuous IV infu-sion was recommended in the 2002 SCCM consen-sus guidelines as the preferred sedative drug for ICUpatients who require prolonged therapy, whereasmidazolam was recommended only for short-term(� 48 h) sedation because of concerns for unpredict-able awakening observed after prolonged infusion.9Some of the delayed emergence with midazolammay be attributable to accumulation of the parentcompound in hepatic failure, or an active metabo-lite, �-hydroxymidazolam, which is cleared by thekidney and may lead to prolonged sedation in pa-tients with renal insufficiency.85,86 In a series ofconsecutive patients with prolonged sedation aftercessation of midazolam infusion, many patients hadelevated serum levels of �-hydroxymidazolam (allpatients had serum creatinine � 1.5 mg/dL), ordetectable levels of midazolam many hours afterinfusion discontinuation.86 There are relative few




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randomized controlled trials (RCTs) in which loraz-epam and midazolam are compared for long-term(� 72 h) infusion. No significant difference in timeto awakening was noted in two studies,87,88 whereasBarr and coworkers89 found significantly shorteremergence time and time to extubation for midazo-lam vs lorazepam infusion in a double-blinded RCTof postoperative patients without significant renal,hepatic, or neurologic impairment. Additionally, pro-longed high-dose administration of lorazepam canresult in accumulation of the vehicle, propyleneglycol, resulting in worsening renal function, meta-bolic acidosis, and altered mental status.90 Toxicity istypically observed after prolonged (� 7 d), high-dose(average of 14 mg/h), continuous lorazepam infusion,and can be recognized by measuring an increasedosmolal gap.90 Lorazepam infusion was identified asan independent risk factor for transition to deliriumamong ICU patients receiving MV15; however, ex-amination of the odds ratios for other sedative andopioid analgesics agents used less frequently in thestudy suggests it may occur with other agents. Inlight of drug accumulation with continuous infusion,and concerns for propylene glycol toxicity, long-termhigh-dose lorazepam should be used with caution.Midazolam may be a better alternative if hepatic andrenal function is normal.

Despite consensus recommendations that admin-istration of propofol be limited to � 24 to 48 h,9 itremains widely used worldwide.5,35,83,84 Propofol in-fusion has been compared to midazolam infusion forsedation in the ICU in many RCTs. Walder andcolleagues91 demonstrated more effective sedation(higher percentage of time) and shorter weaningtime for short-term (� 36 h) infusion but higheradverse event rates with propofol compared to mi-dazolam in a systematic review of 27 RCTs. Durationof MV was similar for propofol and midazolaminfusions, however, when DIS was routinely usedwith both drugs.77 In contrast, duration of MV wassignificantly shorter with propofol infusion and DIScompared to intermittent lorazepam in a recentRCT.78 Propofol infusion has been linked to a num-ber of adverse effects,92 including hypertriglyceride-mia,93 dose-dependent hypotension,94 and thepropofol infusion syndrome, a rare clinical syndromeof rhabdomyolysis, metabolic acidosis, renal failure,and cardiac failure after high doses of propofol.95

Dexmedetomidine is a selective �2-adrenergic re-ceptor agonist with a short half-life of approximately2.3 h, and has sedative, analgesic, anxiolytic, andsympatholytic effects without depressing respiratorydrive. Dexmedetomidine currently has limited ap-proval by the US Food and Drug Administration forsedation in postoperative patients of � 24 h dura-tion, although other ICU settings are being investi-

gated. In small studies of short-term use in thepostoperative or trauma patients, dexmedetomidinehas been shown to decrease opiate use, and tofacilitate extubation in patients who have failedprevious ventilator weaning attempts due to severeagitation.96 Case reports have also documented suc-cess in preventing alcohol withdrawal in patients inthe perioperative period.97 Drug-related adverse ef-fects are primarily cardiovascular including hypoten-sion and bradycardia,98 particularly when loadingdoses are used. Tolerance to the drug has been seenand there are concerns for a rebound effect whenused beyond 24 to 48 h. Most studies find thathigher-than-recommended doses are needed for ef-ficacy but that a ceiling dose effect is reported at adose approximately 1.5 �g/kg/h.99 Dystonia hasbeen reported and may be due to its effect onacetylcholine release.99 Acquisition cost is higherthan for other sedative agents, although one ret-rospective outcomes study100 of � 10,000 cardiacsurgery patients suggests favorable clinical andeconomic outcomes when dexmedetomidine isadded to midazolam and propofol for sedation.Publication of additional research will help toclarify new roles for this drug.

Opioid Analgesic Medications

A variety of opioids used by IV administration inadults are available for use in ICUs throughout theworld; many of these are compared in Table 2.Surveys and prospective surveillance studies35–37,83,84

indicate widespread use of fentanyl and morphinesulfate, although sufentanil enjoys considerable usein Europe.37,84 The 2002 SCCM guidelines recom-mend the use of fentanyl, hydromorphone, or mor-phine if an IV opioid analgesic is required.9 Opioidsfunction through stimulation of receptors, principallyvia the �1 and �2 opioid receptors. All opioidsproduce a dose-dependent respiratory depression;other common side effects include muscle rigidity,hypotension, delayed GI transit, nausea, pruritus,and urinary retention.27 There are important differ-ence in regards to lipid solubility, volume of distri-bution, and metabolism that are reflected in datadisplayed in Table 2. Particularly noteworthy is thatmorphine is metabolized to several active metabo-lites, including morphine-6-glucuronide that is moreactive than the parent compound, and accumulatesin renal failure potentially resulting in prolongedsedation and respiratory depression.101 Morphineshould be avoided in patients who have renal insuf-ficiency. Fentanyl has a rapid onset of action as aresult of high lipophilicity and a short duration ofaction from redistribution.27 Elimination is delayed,




however, with prolonged administration as a result ofits large volume of distribution.

Often analgesic medications are added to a seda-tive infusion, so-called “co-sedation” or “analgoseda-tion,” with reduced doses of both agents and in somecases more effective therapy.79 European studiesdemonstrate shorter duration of MV with an analgesic-based vs sedative-based protocol.81 Remifentanil, adrug that has organ-independent metabolism, wassuccessfully used in this trial81; however, other clin-ical trials demonstrate similar results between remifen-tanil and fentanyl, except for a greater incidence of painduring drug de-escalation with remifentanil.102

Antipsychotic Agents

Therapy with antipsychotic agents such as haloper-idol may be necessary for effective management ofdelirium and agitation. For treatment of acute agita-tion, the butyrophenone haloperidol can be admin-istered in escalating doses from 1 mg to as much as20 mg by IV injection, often in combinations with abenzodiazepine, until calmness is achieved.103 Halo-peridol has been associated with extrapyramidal ef-fects, and cardiac conduction abnormalities, specifi-cally prolonged QTc-associated torsades de pointesarrhythmia.104 These tend to be dose-related adverseeffects. A baseline ECG should be documented andperiodically repeated with continued use of the drug.In addition to maintaining normal magnesium, po-tassium, and calcium levels, it is important to consultwith a pharmacist regarding drug interactions thatcould potentiate cardiac arrhythmias (ie, amiodaroneand other antiarrhythmics, antifungal azoles, quino-lones, macrolides, etc.). Haloperidol may be admin-istered as a scheduled medication for managementof delirium. Interestingly, in a retrospective study,use of haloperidol in ICU patients receiving MV wasassociated with a lower mortality rate in a dose-response fashion than nonuse, although the explana-tion(s) for this is not clear.105 While there is interestin examining newer antipsychotic agents for manage-ment of delirium, only olanzapine has been directlycompared to haloperidol thus far. Olanzapine wasfound to be of similar efficacy to haloperidol incontrolling delirium, but with fewer extrapyramidalside effects in a small prospective trial.106

Protocols and Algorithms To ImproveSedation Management

Structured approaches to the management of se-dation and analgesia have been demonstrated inprospective studies26,47,76–79,81,107–109 to reduce sideeffects of medications, decrease unnecessary testing,reduce the duration of MV and the frequency of

tracheostomy, shorten the ICU and hospital lengthof stay, decrease the likelihood of having ICU-relatedmedical complications, and reduce costs of hospitaliza-tion. A variety of strategies have been employed,including using medications with a shorter half-life,titrating medications to end-points identified bysedation scales, mandating temporary cessation ofsedative drug infusion, use of intermittent sedativetherapy, and employing algorithms that proactivelyidentify pain, agitation, and/or patient/ventilatorasynchrony. Several studies that tested strategiesusing a prospective controlled study design deservefurther comment (Table 3).

Following demonstration that continuous infu-sion of sedatives and analgesics was associatedwith prolonged ventilator time and with longerICU and hospital LOS,75 Brook and colleagues76

conducted a single-center RCT comparing a nursing-implemented algorithm with conventional practice.This algorithm emphasized the following: (1) earlydetection of pain, (2) use of intermittent therapywith fentanyl or lorazepam, reserving continuousinfusions for patients who had inadequate responseto intermittent therapy, and (3) de-escalation ofcontinuous infusions to intermittent therapy. Theydemonstrated shorter duration of MV, shorter ICUand hospital LOS, and lower rates of tracheostomy.

Daily Interruption of Sedation

Kress and colleagues77 tested a strategy of DIScompared to usual practice in an RCT, also compar-ing midazolam to propofol infusions in a 2 � 2factorial design. All DIS patients had sedative andanalgesic (morphine sulfate) infusions discontinuedeach morning until the patient was able to followthree or more of four simple commands or becameagitated. Infusions were restarted at one half theoriginal rate. They demonstrated significant reduc-tions in duration of MV and shorter ICU LOS, aswell as fewer diagnostic studies for unexplainedaltered mental status. There was no difference in anyoutcomes between the midazolam and propofolgroups, although DIS resulted in significantly lowerdaily doses of midazolam and morphine but notpropofol. This observation implies that more rapidextubation and ICU discharge may be related to acombination of reduced drug accumulation, andadditional opportunities for initiating weaning fromMV.110 This strategy has also been linked to areduction in ICU complications, largely as a result ofa shorter ICU LOS.111

In a two-center RCT, Carson et al78 comparedpropofol infusion vs intermittent therapy with loraz-epam; both groups received DIS and morphinesulfate for analgesia. The continuous infusion propo-




Tab

le3—

Pro

spec

tive

Tri

als

ofSe

dati

onP

roto

cols

inA

dult

ICU

Pat

ient

s*

Sour

cePa

tient

san

dSe

ttin

gSt

udy

Des

ign

Key

Com

pone

nts

ofPr

otoc

olM

ajor

Fin

ding

sC

omm

ents

Bro

oket

al76

321

MV

med

ical

ICU

patie

nts,

US

univ

ersi

tyho

spita

l

RC

T:p

roto

col-d

irec

ted

seda

tion

vsno

n-pr

otoc

ol–d

irec

ted

seda

tion

(con

trol

)

Nur

sing

-dir

ecte

dpr

otoc

olth

atem

phas

izes

usin

gin

term

itten

tth

erap

y;fe

ntan

yl,l

oraz

epam

Prot

ocol

grou

pha

dsh

orte

rdu

ratio

nof

MV

(56

hvs

117

h,p

�0.

008)

;sho

rter

ICU

LO

S(5

.7d

vs7.

5d,p

�0.

013)

;sh

orte

rho

spita

lLO

S(1

4.0

dvs

19.9

d,p

�0.

003)

;lo

wer

trac

heos

tom

yra

te(6

.2%

vs13

.2%

,p�

0.03

8)K

ress

etal

7712

8M

Vm

edic

alIC

Upa

tient

s;U

Sun

iver

sity

hosp

ital

RC

T:i

nter

vent

ion

vsco

ntro

lIn

terv

entio

ngr

oup

rece

ived

DIS

Inte

rven

tion

grou

pha

dsh

orte

rdu

ratio

nof

MV

(4.9

dvs

7.3

d,p

�0.

004)

;sho

rter

ICU

LO

S(6

.4d

vs9.

9d,

p�

0.02

);an

dfe

wer

diag

nost

icte

sts

for

chan

ges

inm

enta

lsta

tus

(9%

vs27

%,p

�0.

02)

2�

2fa

ctor

iald

esig

n;pa

tient

sal

sora

ndom

ized

tore

ceiv

em

idaz

olam

orpr

opof

olM

acL

aren

etal

107

158

MV

patie

nts

inm

edic

al-s

urgi

cal-

neur

olog

icC

anad

ian

ICU

Pros

pect

ive

two-

phas

est

udy:

empi

ric

befo

re/

prot

ocol

afte

r

Evi

denc

e-ba

sed

seda

tion

and

anal

gesi

apr

otoc

olPr

otoc

olgr

oup

had

less

“dis

com

fort

”(1

1%vs

220.

4%,

p�

0.00

1);l

ess

pain

(5.9

%vs

9.6%

,p�

0.05

);lo

wer

hour

lyse

datio

nco

st(C

anad

ian

$5.6

8vs

Can

adia

n$7

.69,

p�

0.01

);tr

end

for

long

erse

datio

ndu

ratio

n(1

22.7

hvs

88.0

h,p

�0.

1);t

rend

for

long

erdu

ratio

nof

MV

(61.

6h

vs39

.1h,

p�

0.13

)

Prot

ocol

adhe

renc

e�

83.7

%

Mas

cia

etal

108

158

MV

med

ical

and

surg

ical

ICU

patie

nts,

US

tert

iary

care

univ

ersi

tyho

spita

l

Pros

pect

ive

two-

phas

est

udy:

base

line

befo

re/

guid

elin

esaf

ter

Gui

delin

esba

sed

upon

“rat

iona

lcos

t-ef

fect

ive

use

ofdr

ugs”

Gui

delin

egr

oup

had

low

erdi

rect

drug

cost

s;sh

orte

rdu

ratio

nof

MV

(167

hvs

317

h)†;

shor

ter

ICU

LO

S(9

.2.d

vs19

.1d)

†;sh

orte

rho

spita

lLO

S(1

9.1

dvs

34.3

d)†

Bra

tteb

oet

al10

928

5M

Vsu

rgic

alIC

Upa

tient

s,N

orw

egia

nun

iver

sity

hosp

ital

Pros

pect

ive

two-

phas

est

udy:

base

line

befo

re/

guid

elin

eaf

ter

Smal

l-sca

lera

pid-

cycl

eim

prov

emen

tm

odel

;pr

otoc

ol,s

edat

ion

scal

e

Prot

ocol

grou

pha

dsh

orte

rdu

ratio

nof

MV

(5.3

dvs

7.4

d)†;

tren

dfo

rsh

orte

rIC

UL

OS

(8.3

dvs

9.3

d)†

De

Jong

heet

al47

102

MV

med

ical

ICU

patie

nts,

Fre

nch

univ

ersi

ty-a

ffili

ated

hosp

ital

Pros

pect

ive

two-

phas

est

udy:

cont

rolb

efor

e/al

gori

thm

afte

r

Alg

orith

m:r

egul

aras

sess

men

tof

cons

ciou

snes

san

dto

lera

nce

toIC

Uen

viro

nmen

tw

ithgo

alof

tole

ranc

ean

dhi

ghL

OC

Alg

orith

mgr

oup

had

shor

ter

time

toar

ousa

l(2

dvs

4d,

p�

0.00

6);s

hort

erdu

ratio

nof

MV

(4.4

dvs

10.3

d,p

�0.

014)

Bre

enet

al81

105

MV

med

ical

-su

rgic

alIC

Upa

tient

s,10

Eur

opea

nco

untr

ies

15-c

ente

rR

CT

:ana

lges

ic(r

emife

ntan

ilba

sed)

orse

dativ

e(m

idaz

olam

base

d)

Titr

atio

nof

anal

gesi

c(r

emife

ntan

il,fe

ntan

yl,

orm

orph

ine)

and

seda

tive

(mid

azol

am)

drug

sto

targ

ets

Ana

lges

ic-b

ased

grou

pha

dsh

orte

rtim

efr

omw

eani

ngto

extu

batio

n(0

.9h

vs27

.5h,

p�

0.00

1);s

hort

erdu

ratio

nof

MV

(94

hvs

147.

5h,

p�

0.03

3)

Car

son

etal

7813

2M

V,s

edat

edm

edic

alIC

Upa

tient

s,tw

oU

Sun

iver

sity

hosp

itals

RC

T:l

oraz

epam

byin

term

itten

tbo

lus,

orpr

opof

olby

cont

inuo

usin

fusi

on

Dai

lyin

terr

uptio

nof

seda

tion

was

perf

orm

edin

both

grou

ps

Con

tinuo

usin

fusi

onpr

opof

olgr

oup

had

shor

ter

dura

tion

ofM

V(5

.8d

vs8.

4d,

p�

0.04

);tr

end

for

mor

eve

ntila

tor-

free

surv

ival

(18.

5d

vs10

.2d,

p�

0.06

)

(Con

tinu

ed)




fol with DIS group had significantly shorter durationof MV. Thus, DIS is emerging as a useful techniqueto shorten duration of MV, and this “sedation vaca-tion” has been widely embraced.112

Questions arose regarding the neuropsychiatricimpact of repeated abrupt awakening on critically illpatients,113 yet subsequent research has demon-strated that patients randomized to DIS have fewersymptoms of PTSD compared to control subjects.114

Interruption of sedation is associated with a surge incirculating catecholamines; however, patients withcoronary artery disease subjected to DIS had noincrease in cardiac ischemia when taken off seda-tion.115 These studies are encouraging for the safetyof widespread use of DIS, although caution for selectedpatients, such as those with hypertensive crisis or statusasthmaticus, who might have significant consequencesfrom the resulting stress response or patient/ventila-tor asynchrony, should be exercised.110 Finally, thereare theoretical concerns with regards to the use ofDIS in patients who have a history of alcohol abusebecause precipitation of withdrawal could occur ifthe patient is not otherwise receiving medicationsthat protect for alcohol withdrawal.

Other protocol-based approaches to sedation man-agement have been demonstrated in a sequentialstudy design with comparison to an earlier controlperiod, to reduce duration of MV,47,81,108,109 improvethe quality of sedation,107 reduce patient/ventilatorasynchrony,79 and reduce drug costs,79 although oneprotocol that increased use of lorazepam was associ-ated with a trend for longer ventilator duration.107

Common themes for effective protocols includetargeting pain, agitation, and intolerance of the ICUenvironment,26,47 and focusing more on analgesictherapy than sedation.79,81

Sedative and Analgesic Drug Withdrawal

Development of signs and symptoms of acuteopioid and sedative drug withdrawal syndrome canfollow long-term administration of these medicationsin ICU patients. This phenomenon has been partic-ularly well studied in critically ill children.116–118

Cammarano et al119 reported that one third of adulttrauma patients who received � 1 week of ICU hospi-talization had clear evidence of acute withdrawal oncedrugs were discontinued. Longer duration and higherdoses of opioids, benzodiazepines, and propofol wereassociated with withdrawal, as was less haloperidoladministration. Recently, withdrawal was detected in13.2% of ICU patients and linked to delirium in theICU.6 Research suggests that CNS and sympatheticnervous system markers for withdrawal can peakwith 6 h of cessation of sedative (midazolam, propo-

Tab

le3—

Con

tinu

ed

Sour

cePa

tient

san

dSe

ttin

gSt

udy

Des

ign

Key

Com

pone

nts

ofPr

otoc

olM

ajor

Fin

ding

sC

omm

ents

Cha

nque

set

al26

230

MV

med

ical

-su

rgic

alIC

Upa

tient

s,F

renc

hun

iver

sity

hosp

ital

Pros

pect

ive

two

phas

est

udy:

cont

rolb

efor

e/pr

otoc

olaf

ter

Prot

ocol

emph

asis

onsy

stem

atic

eval

uatio

nof

pain

and

agita

tion

Prot

ocol

grou

pha

dlo

wer

inci

denc

eof

pain

(42%

vs63

%,

p�

0.00

2);l

ower

inci

denc

eof

agita

tion

(12%

vs29

%,

p�

0.00

2);s

hort

erdu

ratio

nof

MV

(65

hvs

120

h,p

�0.

05);

few

erno

soco

mia

linf

ectio

ns(8

%vs

17%

,p

�0.

05)

Ric

hman

etal

7930

MV

med

ical

ICU

patie

nts,

US

univ

ersi

tyho

spita

l

RC

T:s

edat

ion

with

benz

odia

zepi

ne,o

rco

-se

datio

nw

ithbe

nzod

iaze

pine

plus

opia

te

Nur

se-im

plem

ente

dpr

otoc

ol;m

idaz

olam

,fe

ntan

yl

Co-

seda

tion

grou

pha

dfe

wer

hour

with

“off

-ta

rget

”se

datio

n(4

.2h

vs9.

1h,

p�

0.00

2);f

ewer

epis

odes

ofpa

tient

/ven

tilat

oras

ynch

rony

(0.4

/hvs

1.0/

h,p

�0.

05)

Smal

lsam

ple

size

;tr

end

for

mor

eile

usw

ithco

-sed

atio

n;du

ratio

nof

MV

not

repo

rted

*LO

C�

leve

lof

cons

ciou

snes

s.†I

ndic

ates

pva

lues

not

repo

rted

.




fol) and opioid (sufentanil) drug infusion,120 havingpotential implications for interruption of sedation insusceptible patients. Importantly, clinicians mustmaintain a high index of suspicion for sedative andanalgesic drug withdrawal as a patient recovers fromcritical illness because many of the symptoms, suchas restlessness, insomnia, delirium, nausea, hyper-tension, tachycardia, diaphoresis, and fever, are non-specific and may be easily overlooked. Strategies forgradual weaning of sedative and analgesic agentsand/or substitution with orally or subcutaneouslyadministered drugs in high-risk patients may beuseful.117,118,121

Sedative and Analgesic Therapy and Long-term Psychological Outcomes

The impact of sedative and analgesic medicationson neuropsychological health after recovery fromcritical illness is a complex issue because of manyconfounding factors, such as interruption of seda-tion, withdrawal from these agents or other sub-stances, critical illness and organ dysfunction, preex-isting neuropsychological disorders, physical restraintand immobilization, pain, delirium, memory forma-tion, and amnesia. Nevertheless, the influence ofsedation on subsequent recall of real or imaginedevents as well as the development of PTSD anddepression is an important, yet underrecognizedissue. Nelson and colleagues122 observed a positiveassociation between duration of sedation and depres-sion-related and PTSD-related symptoms 6 to 41months after acute lung injury. No difference inPTSD was noted, however, between high and lowsedative drug doses.122 Samuelson and coworkers123

found that patients who had no recall for ICU eventswere more likely to have had heavy sedation withfewer periods of wakefulness. Patients who subse-quently had delusional memories had longer ICULOS, received higher doses of sedative drugs, andhad more periods of being alert or agitated.123

Interestingly, DIS was associated with less frequentPTSD and a trend for better psychosocial adjustmentto illness when tested months later.114 These DISpatients had shorter duration of MV and sedation,yet had more episodes of being alert or agitated, thancontrol patients. Some experts124 postulate that re-call for factual events, rather than internally gener-ated images such as hallucinations and nightmares,may be protective for developing subsequent PTSD.In recent work,6 these authors found associationsbetween prolonged sedation but also physical re-straint with little or no sedation and development ofPTSD. Although further research is needed, clini-cians should be aware that sedative and analgesia

drugs may play a role in subsequent psychologicalimpairment in the ICU setting. Further, they shouldbe alert for signs of emotional trauma and thepossible need for psychological interventions duringrecovery from critical illness.

Summary and Conclusions

The majority of critically ill patients receive seda-tive and/or analgesic medications to combat pain andanxiety and to improve tolerance of the ICU envi-ronment. Patient-focused care related to these issuesincludes assessment of predisposing and precipitat-ing factors, frequent monitoring, careful medicationselection, and use of strategies to precisely targettherapy to defined end points and avoid sedation thatis excessive or prolonged.

References1 Desbiens NA, Wu AW. Pain and suffering in seriously ill

hospitalized patients. J Am Geriatr Soc 2000; 48:S183–S1862 Sessler CN, Grap MJ, Brophy GM. Multidisciplinary man-

agement of sedation and analgesia in critical care. SeminRespir Crit Care Med 2001; 22:211–225

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DOI 10.1378/chest.07-2026 2008;133; 552-565Chest

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