Principles and Practice of Sedation in Intensive Care Unit (ICU)

Principles and Practice of Sedation in Intensive Care Unit

(ICU)

Review Article

Anxiety

Is defined as a sustained state of apprehension &autonomic arousal in response to real or perceived threats[1]. Fear of suffering, fear of death, loss of control &frustation due to inability to effectively communicate aretypical causes of anxiety in critically ill patients. Symptoms& signs include headache, nausea, insomnia, anorexia,dyspnoea, palpitations, dizziness, dry mouth, chest pain,hyperventilation, pallor, tachycardia, tremulousness and /or hyper vigilance.

Pain

Routine patient care (suctioning, repositioning,physiotherapy), immobility, trauma, surgery, endotrachealtubes & other monitoring devices can all produce pain.Clinical evidence of pain may include grimacing,withdrawal, combativeness, diaphoresis, hyperventilation&/or tachycardia.

Delirium

Is an organic mental syndrome defined as an acute,potentially reversible impairment of consciousness &cognitive function that fluctuates in severity [1]. Deliriumis rather common in ICU patients but is frequently underrecognized especially in older individuals & is mostlyunder treated [3,4]. Delirious patients have impaired shortterm memory, abnormal perception & intermittentdisorientation which is usually worse at night. EEG mayshow diffuse slowing of electrical activity of brain. It is arisk factor for prolonged hospitalization & mortality incritically ill patients [5]. Risk factors for delirium include:

13 Apollo Medicine, Vol. 8, No. 1, March 2011

PRINCIPLES AND PRACTICE OF SEDATION IN INTENSIVE CARE UNIT (ICU)

AJIT VIGGHead, Department of Respiratory Medicine & Director, Institute of Sleep Medicine, Apollo Hospitals,

Jubilee Hills, Hyderabad 500 033,India.e-mail:[email protected]

Distress is common amongst critically ill patients in ICU, especially those who are intubated or have difficultycommunicating with their caregivers [1]. Distress in ICU generally presents as agitation. It needs to be treatedfor patient comfort & if left untreated increases sympathetic tone with untoward physiologic effects [2].

Before a sedative agent is initiated to manage agitation, the cause of distress should be identified & treated.Common causes of distress in critically ill patients include:- anxiety, pain, delirium, dyspnoea andneuromuscular paralysis. These etiologies may occur separately or in combination.

Key words: Anxiety, Pain, Delirium, Dyspnoea, Neuromuscular Paralysis,Sedation Protocol control agitation.

Electrolyte disturbances (hyponatremia, hypocalcemia),hyper-glycemia, hyper amylasemia, azotemia, hepaticdisease, infections, drug withdrawal, alcohol withdrawal,mal-nutrition, cancer, cerebrovascular disease, cardiopul-monary disease, advanced age & certain drugs (benzo-diazepines, corticosteroids, antihistamines, betablockers,anti arrhythmics, atropine, digoxin) [6].

Dyspnoea

Is a sensation of air hunger or a feeling of suffocation.Clinical evidence of dyspnoea include tachypnea, shallowbreathing, diaphoresis, tachycardia, hypoxemia. It mayexist despite acceptable blood gas parameters.

Neuromuscular paralysis

All patients undergoing neuromuscular blockaderequire pharmacological sedation because neuromuscularparalysis without sedation or adequate pain control is anextremely frightening & unpleasant sensation. Identifyingdistress in patients on neuromuscular blocking agents isoften difficult because the typical physiological responsesassociated with stress may not correlate with patientdiscomfort in this setting.

Treat the cause of distress

Initial treatment of agitation should target the presumedcause of underlying distress. As an example, a patient whois agitated due to hypoxemia should receive supplementaloxygen as a priority.

Non pharmacological strategies

For managing agitation should begin simultaneously

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with therapy targeting the cause of distress. These includereassurance, frequent communication with the patient,regular family visits, establishment of normal sleep cycle inthe ICU & cognitive – behavioral therapies (music therapy,relaxation techniques, guided imagery) [7].

This strategy of using non pharmacologicalintervention to control agitation rather than immediatelyinitiating pharmacological sedation is supported byevidence from literature. A randomized trial of 140mechanically ventilated patients compared no sedationwith continuous sedative infusion with daily interruption[8]. It found that patients managed with a strategy of nosedation (and continuous verbal comforting & reassurance)had more ventilator free days & decreased length of ICUstay, decreased length of hospital stay and decreasedincidence of delirium [8].

Initiation of sedation protocol

Sedative analgesic medication is indicated whentreatment of the cause of distress & nonpharmacologicalinterventions cannot sufficiently control the agitation.

Commonly used agents

Drugs commonly used to control agitation in the ICUinclude Benzodiazepines, Opoid analgesics, propofol andneuroleptics (Table 1). They differ in their amount ofanxiolysis, analgesia, amnesia & hypnosis.

Barbiturates (thiopental, methohexital) could be used tomanage agitation in critically ill patients if patient is nottolerating or responding to any of the above agents.However, they are not ideal because they do not have potentsedative effects & can cause profound cardiovascular &respiratory depression as well as diminished cerebral bloodflow.

Selection of an agent

No sedative – analgesic agent is sufficiently superior to

other agents to warrant its use in all clinical situations.Therefore selection of an agent must be individualizedaccording to patient characteristics & the given clinicalsituation. Important considerations when selecting an idealsedative include the etiology of the distress, expectedduration of therapy & potential interaction with other drugs[9].

Etiology of the distress

The appropriate sedative to be used is determined by theunderlying cause of distress. Thus, for distress due toanxiety, benzodiazepines are optimal. For distress due todyspnoea or pain, opoids are the agents of choice whereasfor distress due to delirium, neuroleptics (Haloperidol) arepreferred. Combination therapy is appropriate for patientswith more than one cause of distress; has an example, abenzodiazepine & an opoid is appropriate for a patientwhose agitation is due to anxiety & pain.

Duration of therapy

Drugs with a shorter duration of effect (midazolam,propofol) should be used if a brief duration of sedation (<24 hours) is anticipated or if patient needs to be frequentlyawakened for neurological evaluation. In contrast, drugswith a longer duration of action (eg. Lorazepam) arepreferred if a longer duration of sedation (>48 hrs) isexpected [10]. Pharmacokinetic modifying variables (e.g.,age, body weight, renal & hepatic function) and the desireddepth of sedation should be considered whenever a sedativeanalgesic agent is selected. Abnormal pharma-cokineticmodifying variables can magnify differences among thesedative agents (eg; onset, peak, duration of sedation)especially during deep sedation.

Initial loading dose

The initial dose of a sedative should account for thedesired level of sedation as well as factors that may affectdrug metabolism (i.e patient age, body weight, renalfunction, hepatic function, h/o. alcoholism, drug abuse).For exact initial doses of various sedatives see Table 2[11,12].

The advantages & disadvantages of various sedativesused in ICU are shown below

Fentanyl

Advantages: Potent analgesic sedative with immediateonset, minimal Venodilation, less hypotension; Hepati-cally metabolized by Cytochrome P 450 3A4 to inactivemetabolites.

Disadvantages: Highly Lipophilic; tolerance may develop

Table 1 Drugs for sedation in critically ill patients

Analgesics : Fentanyl, Morphine,HydromorphoneRemifentanil

Sedative – Hypnotics : Diazepam, Lorazepam,MidazolamBenzodiazepines

Anesthetic – Sedatives : PropofolAlpha -2- Agonists : DexmedetomidineNeuroleptics : Haloperidol, Olanzepine,

Quetiapine, Risperidone

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requiring dose escalation. Withdrawal syndrome uponabrupt discontinuation; Chest wall rigidity can occuroccasionally.

Morphine

Advantage: No consistent advantage over Fentanyl.

Disadvantage: Hepatically metabolized to active &inactive metabolites which can accumulate in organ failure;May precipitate bronchospasm due to histamine release.

Remifentanil

Advantage: Ultra short acting; cleared by nonspecificplasma esterases. No accumulation in renal or hepaticinsufficiency.

Disadvantage : Pain & discomfort upon abrupt cessation.

Midazolam

Advantage: Potent amnestic & anxiolytic agent with

immediate onset of action & short duration of effect whenadministered for short term (<48 hrs). Only IVbenzodiazepine not delivered in propylene glycol.

Disadvantage : Metabolized to active metabolites that mayaccumulate & cause prolonged sedation if administeredlong term. Drug interaction with multiple ICU drugs & onemust be aware about these drug interactions.

Lorazepam

Advantage: Sedative, annestic, potent anxiolysis with anticonvulsant properties. Hepatically metabolized. Low riskof drug interactions; safe in mild to moderate hepatic &renal insufficiency.

Disadvantage: Relatively slow onset of action; Risk ofover sedation when titrating due to delayed response& accumulation in peripheral tissues; IV incompatibilities& risk of line precipitate; Propylene glycol solventmay accumulate with high dosing & cause metabolicacidosis.

Table 2 Drugs for various sedatives & their initial doses

Drug Loading Maintenance Onset Duration ofdose dose (Min.) action

Fentanyl 1-2 microgram/kg 0.7-10 microgram/ <0.5 30-60 mins(50-200 micrograms) kg/hr infusion

Morphine 0.05-0.2 mg/kg 0.1-0.5 mg/ 5-10 mins 240 minsSulphate (2-10 mgm) kg/hr infusion

Remifentanil None 0.6-15 micrograms/ 1-3 min 5-10 minskg/hr infusion

Midazolam 0.02-0.08 mg/kg 1-2 mg intermittent 1-5 min 30 mins(1-5 mgs) infusion or 2-8 mg/hr

continuous infusionLorazepam 0.02-0.06 mg/kg 0.02-0.06 mg/kg 5-20 mins 360 to 480 mins

(1-4 mgs) every 3-6 hrsor0.5010 mg/hr ascontinuous infusion

Propofol Loading dose 5-80 micrograms/ < 1 min 3-10 minnot recommended kg/min. Initiate at

5 micrograms/kg/min & titrate every10 min. in incrementsor 5 micrograms/kg/min

Dexmede- Not 0.2 to 1.4 microgram/ > 5-10 60-120 min tomidine recommended kg/hr initiate at 0.2

micrograms/kg/hr &titrate every 30 minutes

Haloperidol 0.03-0.15 0.03-0.15 mg/kg 30-60 min 30-360 minmg/kg (2-10 mg) every 30 min. to to 6 hrs

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Maintenance: Once initiation of sedative agent achieves acalm state, attention should be directed towards monitoring& avoiding excess sedation.

Monitoring of sedation: Patients should be reassesseddaily to determine whether their agitation & underlyingdistress are being adequately managed. To facilitate thisevaluation, various scoring systems have been developed.

Scoring systems: Are used to assess pain, sedation &delirium. They use multiple criteria to determine theamount of pain, depth of sedation and severity of delirium.An important limitation of scoring systems is that referencestandards do not exist [14].

Pain scales: There are unidimensional scales (verbal ratingscale, visual analogue scale, numeric rating scale) & multidimensional scales (McGill pain questionnaire, Wisconsinbrief pain questionnaire) to assess a patient’s level of pain.The unidimensional scales can be quickly & easily appliedin ICU if patient is communicative. Multidimensionalscales are more complex & take longer to administer &often not appropriate for ICU use.

Sedation scales: There are numerous scoring systems toassess the depth of sedation. The Riker Sedation-Agitationscale (SAS), motor activity assessment scale (MASS),Minnesota sedation assessment tool (MSAT) & RichmondAgitation-Sedation Scale (RASS) (Table 3) are all valid &reliable in adults who are mechanically ventilated &critically ill [15-19]. Alternative scoring systems includeRamsay Sedation Scale, Comfort Scale, Sheffield Scale &Bizek Agitation Scale [20-22)]. The comfort scale is a valid& reliable system for children [21].

Delirium scales: Many scales & diagnostic instrumentshave been developed to identify & evaluate delirium butmost exclude critically ill patients due to difficultycommunicating with them [10]. However a rapid bedsideinstrument that can identify delirium in critically ill patientsis the confusion assessment method for the ICU (CAM-ICU) [23]. Another validated scoring system used inEurope is the ICDSC tool (Intensive Care DeliriumScreening Checklist). Both assess patients for acute mentalstatus changes or fluctuating mental status changes,inattention, disorganized thinking &/or altered level ofconsciousness. The CAMICU can identify new orpersistent delirium, but does not quantify the severity ofdelirium.

Limitations of scoring systems: For patients who arepharmacologically paralyzed, monitoring is challengingbecause scoring systems cannot determine level of pain,depth of sedation or delirious state. Heart rate & bloodpressure have historically been used as indicators of

Propofol

Advantage : Potent sedative hypnotic with immediateonset & rapid awakening upon discontinuation. Un alteredmetabolism in renal or hepatic insufficiency; no major druginteractions.

Disadvantage : With long term use, no specific advantageover midazolam regarding the duration of vent weaning;can cause hypotension, hypertriglyceredemia, propofolinfusion syndrome, which is characterized by refractorybrady-cardia, severe metabolic acidosis cardiovascularcollapse, rhabdomyolysis & renal failure.

Dexmedetomidine

Advantage: Effective sedative, sympatholytic (central,alpa-2-agonist), moderate anxiolysis & analgesia; nosignificant effect on respiratory drive; less likely to causedelirium than other sedatives.

Disadvantage: Hypotension, bradycardia, Hypertension,hepatically metabolized by cytochrome P450 -2A6; dosereduction required in renal & hepatic insufficiency.

Haloperidol

Advantage: Sedative dopamine 2-antagonist; controlspositive symptoms of delirium & ICU psychosis. Minimalcardio respiratory effects in hemodynamically stablepatients.

Disadvantage: Complex hepatic metabolism bycytochrone P450-3A4 & 2D6; transformations can causedose dependent QT prolongation & hypotension.

Administration: The evidence indicates that continuousinfusion of a sedative prolongs the duration of mechanicalventilation [13]. As a result, current practice favorsintermittent infusions or daily interruption of continuousinfusions. The Society of Critical Care Medicine’s 2002clinical practice guidelines for the sustained use ofsedatives & analgesics in critically ill adults endorse theinitial use of intermitted infusion, with the initiation ofcontinuous infusions with daily interruption in patients whorequire intermittent infusions more often than every twohours [10].

Sedation goal: A goal depth of sedation should bedetermined prior to beginning the sedation, since this is thetarget to which initial therapy is titrated. The goal depth ofsedation should be frequently reassessed & adjusted as thepatient’s sedation requirement becomes more apparent. Asexamples, lighter sedation may be desired when serialneurological exams are required, while deeper sedationmay be desired during severe hypoxemic respiratoryfailure.

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cardiovascular depression. Co administration with an opoidanalgesc may potentiate respiratory & cardiovasculardepression.

Properties

Potency is determined by its binding affinity for GABAreceptor. Lorazepam has highest binding affinity & greatestpotency. Midazolam has lower binding affinity & lowerpotency when compared to Lorazepam [31].

Rapidity of action

Is related to how quickly it crosses the blood brainbarrier. Midazolam is highly lipophilic & readily crossesthe blood brain barrier & therefore rapid onset of action (2-5 mins.) Lorazepam is less lipophilic & has a slower onsetof action (5-20 minutes).

Duration of effect

Initially both lorazepam & midazolam have a shortduration of effect because there is rapid redistribution fromCNS to peripheral tissue sites. With repeated dosing,however both accumulate in adipose tissue & this increasethe duration of effect because there is more drug that needsto be mobilized for elimination. Obese patients may storemore drug than lean patients & are at greater risk forprolonged effects. Midazolam has a short duration of effect(2-4 hrs) when it is given short term (<48 hrs) byintermittent infusion to a patient with intact hepaticfunction because it has rapid hepatic clearance & there israpid redistribution to peripheral tissue sites. However, if

Table 3 Richmond agitation - sedation scale (RASS)

SCORE TERM DESCRIPTION

+ 4 Combative Overtly combative/violent, immediate danger to ICU staff

+ 3 Very agitated Pulls on or remove tubes/catheters aggressive behaviour towards staff

+ 2 Agitated Frequent nonpurposeful movement. Patient ventilator asynchrony

+ 1 Restless Anxious or Apprehensive but movements are not aggressive or vigorous

0 Alter & calm

– 1 Drowsy No fully alert, sustained (>10secs) awakening has eye contact to voice

– 2 Light sedation Briefly awakens (<10 secs) with eye contact to voice

– 3 Moderate sedation Any movement to voice but no eye contact

– 4 Deep sedation No response to voice, any movement to physical Stimulation

– 5 Unrousable No response to voice or physical stimulation

distress in this situation, but these vital signs are neithersensitive nor specific. I am of the opinion that there are tworeasonable approaches. Firstly, pharmacologicallyparalyzed patients can be given higher than usual doses ofboth an anxiolytic/amnestic and an analgesic to ensure deepsedation. Secondly, a newer EEG form of Bispectral index(BIS) monitoring can be used. Although there areconflicting data regarding its benefit [24-29], I believe, BISmonitoring is a reasonable approach to assess depth ofsedation in ICU patients receiving neuromuscularparalysis. However, BIS monitoring cannot replace theclinical assessment of sedation in routine management ofICU patients until further favorable data are available fromthe literature.

Since midazolam, lorazepam and dexmedetomidine arethe most commonly used sedatives in ICU, further detailsabout their mechanism of action & their properties shall bediscussed.

Both Midazolam & Lorazepam can be administered byeither intermittent or continuous infusion & have arelatively short duration of effect.

Mechanism of action

They blind to specific receptors in the Gammaaminobutyric acid (GABA) receptor complex whichenhances the binding of this inhibitory neurotransmitter[30]. Anxiolysis is achieved at low doses. Higher doses areassociated with sedation, muscle relaxation, anterogradeamnesia, anti convulsant effects & both respiratory &

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midazolam is administered over a longer duration (> 48 hrs)it may cause prolonged sedation because it has a largevolume of distribution, binds to peripheral tissues & has anactive metabolite alpha hydroxy midazolam [32]. Thisactive metabolite is most likely to accumulate in patientswith poor hepatic or renal function or in those patients whoare receiving drugs that inhibit cytochrome CYP 3A4metabolism (fluconazole, macrolide antibiotics,amiodarone, & metronidazole).

Lorazepam has a moderate duration of effect (6-8 hrs)when administered over short term (<48 hrs) byintermittent infusion. This reflects lorazepam’s low hepaticclearance, small volume of distribution & absence of activemetabolites [33]. Lorazepam is a good choice for longerterm sedation because of its low risk of drug interactions &because its metabolism does not form active metabolites[10]. Tolerance i.e. the need for an increased dose toachieve the same therapeutic effect with continuedadministration, occurs with all benzo diazepines. It mayreflect changes in volume of distribution, binding affinity&/or occupancy of bendiazepine receptor.

Adverse effects

Respiratory& cardiovascular depression are wellknown dose dependent complications of both lorazepam &midazolam. Delayed awakening occurs in those patientswho are sedated for > than 48 hrs. This is associated withprolonged mechanical ventilation [34]. Delirium may occurwith both lorazepam & midazolam [35-38]. In anobservational study of 198 mechanically ventilated patientsreceiving pharmacologic sedation, lorazepam wasidentified as an independent risk factor for delirium [35]. Itappears to be more common among those who receive deepsedation, elderly ICU patients, & those who have dementia[36,38]. Delirium is associated with a longer duration ofmechanical ventilation, ICU stay, hospital stay & increasedmortality [37].

Propylene glycol toxicity

Propylene glycol is the carrier (solvent) that is used toadminister intravenous lorazepam or diazepam. Infusion ofeither drug may be complicated by propylene glycoltoxicity [39-42], which is characterized by hyper-osmolality and an anion gap metabolic acidosis which isoften accompanied by kidney injury & can progress tomulti system organ failure if severe [39-42].

Dexmedetomidine is a highly selective centrally actingalpha-2 agonist with anxiolytic, sedative & mild analgesiceffects. It has no deleterious effects on respiratory drive.According to FDA, dexmedetomidine is indicated forinitial sedation of mechanically ventilated patients for upto

24 hrs. The rationale for 24 hrs limit is that the longer usemay increase the risk of withdrawal effects (hyper-tension)although these effects have not been consistently found inother studies [43,44]. The evidence from literature suggeststhat dexmedetomidine decreases the need for alternativesedatives [45]. It increases days without delirium [46] &decreases time to extubation [47] when compared tomidazolam.

COMPARISONS

There is insufficient evidence to recommend anysedation regimen over another since relatively few trialshave directly compared sedative agents. Comparing agentsacross trials is invalid because there are differences in theseverity of illness, type of cases, therapeutic goals, durationof therapy & techniques to assess sedation [48]. Thefollowing direct comparisons are among the few that havebeen reported in the recent literature:-

Midazolam Vs Propofol

Several studies have compared midazolam to propofolwith both drugs providing adequate sedation[48-53].Recovery time was longer for midazolam than propofolafter short term use; however the recovery time wasprolonged for both drugs with long term administration.

Lorazepam Vs Propofol

In an open label study, 132 mechanically ventilatedpatients were randomized to receive lorazepam byintermittent IV bolus or propofol by continuous infusion[54]. Median days on ventilator were lower in the propofolgroup (6 vs 8 days). There was no mortality difference. Thistrial has been criticized for its design because it is unclearwhether the results are due to different drugs or differenttypes of administration (intermittent boluses vs continuousinfusion).

Dexmedetomidine Vs Propofol

A randomized trial assigned 89 post operative patientswith an expected length of intubation of < 24 hours toreceive dexmedetomidine or propofol for sedation [55].The dexmedetomidine group was less deeply sedated &had a shorter duration of intubation but also had morediscomfort.

Dexmedetomidine Vs Midazolam

A multicentre trial randomized 375 patients expected tobe mechanically ventilated for more than 24 hrs to receivemidazolam or dexmedetomidine for either 30 days or untilextubation [48]. There was no difference in the amount oftime spent within the goal sedation range, the trials primary

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end point. The dexmedetomidine group had a significantlylower prevalence of delirium (54 vs 77%) & shorterduration until extubation (3.7 vs 5.6 days) although thesecame at a cost of more frequent bradycarda (42% vs 19%)[48].

Dexmedetomidine Vs Lorazepam

In a double blind trial, 106 adults who were beingmechanically ventilated in a medical & surgical ICU wererandomized to receive Dexmedetomidine or lorazepam forupto 120 hrs [48]. The dexmedetomidine group were lessagitated, & had more days without delirium or coma.

Dexmedetomidine Vs Haloperidol

In an open label trial, 20 medical or surgical ICUpatients with agitation and delirium that preventedextubation were randomized to receive haloperidol ordexmedetomidine [56]. Dexmedetomidine shortened themedian time to extubation & decreased the ICU length ofstay.

AVOID EXCESS SEDATION

Sedative agent should not be overused because excesssedation may prolong duration of mechanical ventilation[13]. Two strategies have been shown in randomized trialsto reduce duration of mechanical ventilation & reducecomplication related to prolonged ventilation :-

(a) Intermittent infusions [13,57].

(b) daily interruption of continuous infusions [58-60].

INTERMITTENT INFUSIONS

An observational study of 242 patients compared theduration of mechanical ventilation among patients whoreceived a continuous infusion to those who received eitherintermittent sedative infusion or no sedative [48,57]. Thegroup that received intermittent infusion or no sedation hada shorter duration of mechanical ventilation (median of 56hours) than the group that received a continuous infusion(median 185 hrs).

DAILY INTERRUPTION OF SEDATION

Refers to discontinuing the continuous sedativeinfusion until the patient is awake & is followinginstructions or until the patient is uncomfortable or agitated& deemed to require resumption of sedation. The rationalefor daily interruption of sedation is that it facilitatesassessment of patient’s underlying neurologic status as wellas the patient’s need for ongoing sedation. This practice issupported by evidence from recent robust clinical trialsmentioned below.

In a trial of 128 patients on mechanical ventilation andcontinuous sedative infusion, patients were randomlyassigned to continue conventional management or toundergo daily spontaneous awakening trials [60]. Thegroup whose continuous sedative infusion was interrupteddaily had a shorter duration of mechanical ventilation (4.9Vs 7.3 days) and shorter length of ICU stay (6.4 Vs 9.9days). Limitations of the trial (which were criticized bymany) include that it was performed in a single centre,ventilator weaning protocol was not standardized &spontaneous awakening techniques were monitored closelyby study personnel, which is not practically feasible in mostICU’s.

A similar trial (ABC trial) randomly assigned 336patients to a daily spontaneous breathing trial & either adaily spontaneous awakening trial or conventional sedationmanagement [61]. The daily spontaneous awakening trialgroup had decreased one year mortality (but not 28 daymortality), increased number of vent free days, decreasedlength of ICU & hospital stay. The group also had lesscognitive impairment at three months (ARR: 20%)although there was no difference at 12 months [62].

While these trials indicate that daily interruption ofcontinuous sedative infusion are beneficial, the benefit maybe less or absent if a sedation protocol is also being used.This was illustrated by a 3-centre trial in which 65 patientswere randomly assigned to receive either protocolizedsedation (PS) alone or Ps plus daily interruption ofcontinuous sedative infusion (DI) [63]. Although thepatients in the PS & DI group received significantly lowerdoses of midazolam, than patients in the Ps group, therewere no significant differences in duration of ventilation,ICU stay, hospital length of stay, mortality rates & organdysfunction [63].

Despite the evidence that daily interruption ofcontinuous sedative infusion is beneficial, may intensivistshave not incorporated this into daily clinical practice inmost of the ICUs [64,65]. Concerns related to patient safetyremain a significant obstacle to routine implementation[66,67]. These concerns include the possibility of long-term psychological sequelae (post traumatic stressdisorder) [68] & myocardial ischemia [69]. There is littleevidence to support these concerns as demonstrated byvarious trials [70].

WITHDRAWAL

When pharmacologic sedation is no longer necessary,the sequence & rate of discontinuing the sedation must bedetermined: For patients receiving more than one sedativeanalgesic medication (e.g. a benzodiazepine & an opioid),the opioid should be tapered last so that the patient doses

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not wake up in pain. The rate of reduction should beindividualized. Abrupt discontinuation is acceptable ifsedation has been given for a short duration (less than 48hrs), but a gradual reduction over several days is required ifsedation has been given for a longer duration (> than 7days).

During the reduction of sedative dose, patient should beclosely observed for withdrawal symptoms. Acutewithdrawal symptoms are common. In an observationalstudy of 28 mechanically ventilated patients in ICU formore than one week, nine patients (32%) developed acutewithdrawal symptoms when their sedative was reduced[71]. Higher doses of benzodiazepines & opiates are morecommonly associated with acute withdrawal symptoms.

Benzodiazepine withdrawal symptoms include agi-tation, confusion, anxiety, tremors, tachycardia, hyper-tension & fever. Administration of intermittent intra-venous or oral lorazepam (1mg every 6-12 hrs) often helpsto protect patients from developing withdrawal symptomsas the continuous benzodiazepine infusion is reduced.

Opiate withdrawal symptoms include agitation, anxiety,confusion, rhinorrhoea, lacrimation, mydriasis, stomachcramps, diarrhoea, tremor, nausea, vomiting, tachycardia,hypertension & fever. Several strategies have beenproposed to prevent opioid withdrawal, including de-escalation of dose, addition of alpha -2-agonist (clonidine,dexmedetomidine) converting to a long acting barbiturate[72]. However, there is no consensus as to the best availablestrategy.

SUMMARY

• Distress in critically ill patients is common in the ICUsetting, particularly amongst those who are intubatedor who have difficulty communicating with their caregivers.

• Before a sedation is initiated to treat agitation due todistress, the underlying cause of distress should beidentified & treated appropriately. Non pharma-cological strategies should be implementedsimultaneously.

• Pharmacological sedation is necessarily indicatedwhen treatment of the cause of distress & non-pharmacological interventions cannot sufficientlycontrol the agitation.

• Sedative agent & its initial dose are selected on thebasis of several factors: the etiology of the distress,expected duration of sedation, potential druginterations, desired depth of sedation andpharmacokinetic modifying variables.

• There is a strong recommendation from currentguidelines to prefer intermittent infusions or dailyinterruption of continuous infusions (Grade 1BRecommendation)

• All patients should be frequently reassessed todetermine whether their underlying distress andagitation are being adequately managed scoringsystems should be routinely used to assess the degreeof pain, level of sedation & state of delirium.

• Once the decision has been made to begin reducingsedation, the rate of reduction must be individua-lized; for those patients on more than one sedativeanalgesic combination it is prudent to taper the opioidlast so that the patient dose not wake up in pain.During the reduction of sedation, special attentionshould be paid for withdrawal symptoms.

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