6. Sedation and Analgesia in ICU Final

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Dr. B. Uma University College of Medical Sciences & GTB Hospital, Delhi

Transcript of 6. Sedation and Analgesia in ICU Final

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Dr. B. Uma

University College of Medical Sciences & GTB Hospital, Delhi

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Sedation• Sedation comes from the Latin word sedare.• Sedare = to calm or to allay fear• Conscious sedation: A minimally depressed

level of consciousness induced by the administration of pharmacologic agents in which a patient retains the ability to independently and continuously maintain an open airway and a regular breathing pattern, and to respond appropriately and rationally to physical stimulation and verbal commands

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Why is sedation necessary?To improve patient comfortFacilitate interventionsTo allay fear, anxiety and agitationAdequate sleepAvoid painFacilitation of mechanical ventilation/airway

management/ weaningProtection against myocardial ischemiaAmnesia during neuromuscular blockade

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Goals for sedation and analgesiaTo minimize physical discomfort or pain

during proceduresTo minimize psychological disturbanceTo maximize the potential for amnesiaTo guard patient safetyTo control behavior

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Complications from pain and anxietyStimulation of the autonomic nervous

system and release of humoral factors → increased heart rate, blood pressure, and myocardial oxygen consumption → myocardial ischemia or infarction

Altered humoral response can lead to

hypercoagulability as a result of increased level of factor VIII, fibrinogen, platelet activity, and inhibition of fibrinolysis

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Complications (contd.)Stress hormones also produce insulin

resistance, increased metabolic rate, and protein catabolism

Immunosuppression with reduction in number and function of lymphocytes and granulocytes

Psychological disturbances - memories of vivid nightmares, hallucinations, and paranoid delusions

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Assessment of pain and anxiety Any scoring system should be simple, easily

performed, noninvasive, and reproducible. Six levels of sedation are used:

1. Anxious and agitated2. Cooperative, orientated, and tranquil3. Responds to verbal commands only4. Asleep but brisk response to loud auditory

stimulus/light glabellar tap5. Asleep but sluggish response to loud

auditory stimulus/light glabellar tap6. Asleep, no response

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Commonly used sedation tools

Glasgow coma scale (GCS) – assessment of level of consciousness

6 point Ramsay scale – most commonly used sedation scale

Sedation Agitation Scale (SAS)Motor Activity Assessment scale (MAAS)Richmond Agitation–Sedation Scale

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Glasgow coma scale

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GCS modified by Cook and Palma

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Richmond agitation sedation scaleScore Term Description

+4 Combative Violent; immediate danger to staff

+3 Very agitated Pulls/ removes tubes, catheters; aggressive

+2 Agitated Frequent non purposeful movement; patient ventilator asynchrony

+1 Restless Anxious or apprehensive

0 Alert and calm

-1 Drowsy Not fully alert but awakens for >10s, with eye contact, to voice

-2 Light sedation Briefly awakens (<10s), with eye contact, to voice

-3 Moderate sedation

Any movement to voice but no eye contact

-4 Deep sedation No response to voice but movement to physical stimulation

-5 Unarousable No response to voice or physical stimulation

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Ramsay sedation scaleAwake1 Anxious and/or agitated2 Cooperative, oriented, and tranquil3 Responds to commandsAsleep4 Quiescent with brisk response to

light glabellar tap or loud auditory stimulus

5 Sluggish response to light glabellar tap or loud auditory stimulus

6 No response

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Sedation agitation scale1: Unarousable 2: Very sedated 3: Sedated 4: Calm and cooperative 5: Agitated 6: Very agitated 7: Dangerous agitation

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Bispectral indexA practical, processed EEG parameter that

measures the direct effects of sedatives on the brain

Provides objective information about a patient’s response to sedation

Numerical scale correlates to sedation endpoints

Optimizes sedation assessment and titration

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BIS monitor BIS sensor

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BIS range guidelines

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Value of BIS in ICU

Minimize consequencesof over- and

under-sedation

Improve quality of sedation management

Objective sedation assessment

Optimize clinical and economic

outcomes

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Recommendation for Assessment of SedationThe use of a validated sedation assessment

scale (SAS, MAAS, or Vancouver Interaction and Calmness Scale [VICS]) is recommended. (Grade of recommendation = B)

The SCCM guidelines state: Objective measures of sedation, such as Bispectral Index, have not been completely evaluated and are not yet proven useful in the ICU. (Grade of recommendation = C)

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Sedation therapyNON PHARMACOLOGICAL THERAPY:Good communication with regular

reassurance from nursing staffEnvironmental control such as humidity,

lighting, temperature, and noiseExplanation prior to proceduresManagement of thirst, hunger,

constipation, and full bladderVariety for the patient e.g. radio

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Pharmacologic therapyThe sedative agent should possess the

following qualities:Both sedative and analgesic propertiesMinimal cardiovascular side effectsControllable respiratory side effectsRapid onset/offset of actionNo accumulation in renal/hepatic

dysfunctionInactive metabolitesInexpensiveNo interactions with other ICU drugs

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Pharmacologic therapyBenzodiazepinesPropofolEtomidateKetamineBarbiturate Short acting opioidsAlpha 2 agonistsInhalational agents

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Benzodiazepines Anxiolytic, anticonvulsant, amnesic,

hypnotic and provide some muscle relaxation

Effects are mediated by depressing the excitability of the limbic system via reversible binding at GABA-benzodiazepine receptor complex

Minimal cardiorespiratory depressant effectThe common drugs in this class are

diazepam, midazolam, and lorazepam

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Benzodiazepines: MidazolamWater-soluble Short elimination half life (1-4 hrs)No long acting metabolitesIn ICU patients, midazolam's elimination

half-life may be greatly prolonged and clinically important accumulation may occur

Minimal dose: 1 to 2 mg bolusInfusions@ 0.5 to 10 mg/hr

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Benzodiazepines: Diazepam

Elimination half-life of 21 to 37 hours Major active metabolite,

desmethyldiazepam, has a half-life of 48 to 96 hours

In terms of cost, diazepam has a clear advantage, being one-tenth the price of midazolam.

Minimal dose: 5 to 10mg bolusInfusions not recommended

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Benzodiazepines : Lorazepam

Lower lipid-solubility than midazolam Less hypotesnion Metabolised by liver to inactive

metabolites Lower cost Loading dose: 0.02-0.06 mg/kg Infusion dose: 0.01-0.1 mg/kg/hr

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MIDAZOLM LORAZEPAM DIAZEPAM

LOADING DOSE 0.02-0.1 mg/kg 0.02-0.06 mg/kg

0.05-0.2 mg/kg

MAINTANENCE DOSE

0.04-0.2 mg/kg/hr

0.01-0.1 mg/kg/hr

Rarely used

ONSET 1-5 min 5-20 min 2-5 min

DURATION 1-2 hrs 2-6 hrs 2-4 hrs

CARDIAC EFFECTS

Minimal Minimal Present

RESPIRATORY EFFECTS

Important depressant effect

Important depressant effect

Important depressant effect

ANALGESIA None None None

AMNESIA Potent None None

ACTIVE METABOLITES

Yes No Yes

COST/24HRS 4 mg/hr: $37 2 mg/hr: $52 8 mg q 4h: $24

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Flumazenil Benzodiazepine antagonistGiven in incremental doses of 0.2 to 0.5

mg upto 3 mgOnset – 2 minDuration- 30 to 60 min

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Propofol The mode of action of propofol is via the GABA

receptorRapid onset of action; metabolized rapidly

hepatically and extrahepatically Recovery within 10 minutes of discontinuation,

can accumulate with prolonged use Ideally infused via a large or central veinProlonged infusions –increase triglyceride and

cholesterol levels A theoretical maximum recommended dose is

4 mg/kg/hour.

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Propofol (contd.)Bolus dose – not recommendedInfusions @25 to 100μg/kg/hrTheoretical maximum dose- 4mg/kg/hrCautious about propofol infusion syndrome

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Propofol: adverse effectsHypotension Reliable, dose-related Decreased SVR and contractility (CO)

Respiratory depression Apnea with bolus dosing

Synergistic CV and respiratory depression with opioids

Vehicle (soybean emulsion): Hypertriglyceridemia Venoirritation Infection

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Propofol infusion syndromePropofol infusion syndrome is an adverse

drug event associated with high doses (>4 mg/kg per hour or >67 µg/kg per minute) and long-term (>48 hours) use of propofol.

Clinical features:- Cardiomyopathy with acute cardiac failure.- Myopathy.- Metabolic acidosis, K+ - Hepatomegaly.

Inhibition of FFA entry into mitochondria failure of its metabolism.

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Management Supportive treatments addressing the clinical

manifestations The propofol infusion should be discontinued

immediately Alternative sedative should be started Intravenous crystalloid and colloid replacement

and vasopressor and/or inotropic support Cardiac pacing may be used for symptomatic

bradycardia Hemodialysis or continuous renal replacement

therapy to treat the acute renal failure

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KetamineKetamine acts at the N-methyl-D-aspartate

(NMDA) receptorIn subanesthetic doses, sedative and analgesicGenerally not used because of the increase in

blood pressure, intracranial pressure (ICP), and pulse rate

Bronchodilatory properties, sometimes has a role in severe asthma

In the ICU conjunction with a narcoticDose : 5 to 30 μg/kg/min

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Others ETOMIDATE :For maintenance of hypnosis, target

concentration of 300 to 500 ng/mL may be achieved by administration of a two- or three-stage infusion

BARBITURATES: Barbiturates such as Pentothal have been used in the ICU, especially in the management of patients with head injuries and seizure disorders. They cause significant cardiovascular depression and accumulate during infusions, leading to prolonged recovery times.

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Others (contd.) BUTYROPHENONES AND PHENOTHIAZINESAn aggressive dosing regimen of haloperidol may

be useful in a patient with delirium to promote calm, 2 to 10 mg IV every 10 to 15 minutes until the desired response is achieved

VOLATILE AGENTSIsoflurane has been used in concentrations of up

to 0.6% for longterm sedation, with minimal cardiorespiratory side effects and rapid awakening.

Desflurane has been shown to be effective in sedation, with rapid offset of effects.

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Others (contd.)Shorter acting opioidsFentanyl, alfentanyl, remifentanyl

Muscle relaxants

α2 agonistsClonidinedexmedetomidine

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N

N

H

N

Cl

Cl

Clonidine

CH3

CH3

N

N

CH3H

Dexmedetomidine

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2 AgonistsClonidine

Selectivity: 2:1 250:1

Imidazole derivate 16:1

t1/2 10 hrsAntihypertensive

Dexmedetomidine

Selectivity: 2:1 1620:1

Imidazole derivate 31:1t1/2 2 hrs94% protein boundEliminated by

liver/kidneySedativeOnly available in IV form

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Dexmedetomidine Pharmacology of dexmedetomidine

alpha 2 agonistMolecular targets + neural substrates

locus ceruleusnatural sleep pathways

Clinical paradigms for use of dextomed in anesthesiasedation + analgesia w/o respiratory depressionattenuation of tachycardiasmooth emergence + weaning from mechanical

ventilation

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Pharmacokinetics Rapid redistribution: 6 minElimination half-life: 2 hVd steady state: 118 LClearance: 39 L/hProtein binding: 94%Metabolism: biotransformation in liver to

inactive metabolites + excreted in urineNo accumulation after infusions 12-24 hPharmacokinetics similar in young adults +

elderly

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SedationTypical doses (target plasma levels 0.3-1.2

ng/ml):0.5 ug/kg load, 0.5 ug/kg/hr infusion1.0 ug/kg load, 0.7 ug/kg/hr infusionIncrease dose by bolus/infusionLoad only - short proceduresPatients with high sympathetic activity

may need very high doses

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Clonidine Clonidine is synergistic with opioids and

acts at the spinal cord to inhibit nociceptive inputs, thus imparting analgesia

It is contraindicated in hypovolemia and can cause hypotension, bradycardia, and dry mouth

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The Art of Sedation Under sedation:Fighting the ventilator.V/Q mismatch.Accidental extubation.Catheter

displacement.CV stress ischemia.Anxiety, awareness.Post-traumatic stress

disorder.

Over sedation:Tolerance,

tachyphylaxis.Withdrawal

syndrome.Delirium.Prolonged ventilation.CV depression. neuro testing.Sleep disturbance.

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Propofol

Hypertriglyceridemia

CVS depression

Hypotension

2-agonists

Hypotension

Bradycardia

Benzodiazepines

Hypotension

Respiratory depression

Agitation/ConfusionKetamine

Hypertension

Secretions

Dysphoria

GeneralOver sedation

Delayed awakening/extubation

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Analgesia in ICU Pain is ‘an unpleasant sensory and

emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. Thus, perception of sensory events is a requirement, but actual tissue damage is not.

Although a majority of ICU patients receive parenteral analgesics routinely , 50% of patients discharged from the ICU remember pain as their worst experience while in the ICU. This emphasizes the need for effective pain control in the ICU.

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Indices of pain severity applicable in the critically illSubjectiveVisual analogue scaleNumeric rating scaleVerbal descriptor scale

ObjectiveVital signs measurementsBehavioural responses

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None mild moderate severe

Verbal rating scale

І─────────────────ІNo pain Worst pain

Visual analog scale

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Recommendation for assessment of painUse of the numeric rating scale(NRS) is

recommended to assess pain. (Grade of recommendation = B)

Patients who cannot communicate should be assessed through subjective observation of pain and physiological indicators and the change in these parameters following analgesic therapy. (Grade of recommendation =B)

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Analgesics used in ICUPain in the critically ill is best treated with

a pure opioid agonistIn a recent clinical guideline, the

recommended choices have been narrowed to morphine, fentanyl, and hydromorphone.

Other drugs with analgesic properties and variable use in critically ill patients are :

meperidine (pethidine) tramadol nonsteroidal anti-inflammatory drugs (NSAIDs) mixed opioid agonist-antagonist agents ketamine, a sedative drug with analgesic qualities α2 agonists.

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Opioids :MorphinePlasma levels do not correlate with clinical

effect. Low lipid solubility causes slow equilibration

across BBB.Metabolized in the liver by conjugation.

Morphine-6-glucuronide active metabolite with sedative action.

The analgesic dose is highly variable, and may be delivered as an intermittent boluses or as a continuous infusion.

Minimal cardiovascular side effects Relatively contraindicated in asthma and renal

failure

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MorphineCNS effects mediated via μ1 and μ2

receptorsAnalgesia: pain components Affective- greater effect Sensory

Euphoria SedationMood changeMental cloudiness

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FentanylFentanyl : synthetic opioid derived from

meperidine (pethidine)Short-acting opioid with rapid onsetAfter prolonged infusion the duration of

action approaches that of morphineDoes not accumulate in renal failureIt does not cause histamine release and is

suitable for analgesia in the hemodynamically unstable patient

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AlfentanylAlfentanil is a synthetic opioid Onset of action about five times faster

than fentanyl, due to the small volume of distribution

Less lipid solubleThe duration of action is about one-third

that of fentanyl Alfentanil has minimal cardiovascular

effects

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RemifentanilRemifentanil, an ultra-short-acting opioid

metabolized by nonspecific tissue esterasesRapid onset of actionDoes not accumulate after infusions even in

organ dysfunction.Selective mu-receptor agonist.Potency similar to fentanyl.Terminal half-life < 10 min.Rapid blood-brain equilibrium. Can cause significant bradycardia

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Morphine Hydromorphone

Fentanyl

Loading dose 5-10 mg 1-1.5 mg 50-100μg

Onset 10-20 min 5-15 min 1-2 min

Duration 2-3.5 hrs 2-3 hrs 30-60 min

Infusion rate 1-5 mg/hr 0.2-0.5 mg/hr 50-350μg/hr

Active metabolites

Yes Yes No

Histamine release

Yes No No

Cost / 24hrs 5mg/hr: $ 16 0.75 mg/hr: $ 10

100μg/hr: $ 5.50

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Epidural analgesia Opioids Concentration

Morphine 20- 100 μg/ml

Fentanyl 2- 5 μg/ml

Adverse effects of epidural analgesia are more common with morphine than fentanyl. Epidural morphine can produce respiratory depression, and the onset can be delayed up to 12 hours . The incidence of respiratory depression is equivalent with epidural and intravenous morphine. More frequent side effects of epidural analgesia include pruritis, nausea, and urinary retention.

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Respiratorydepression

ConfusionVasodilation

Gut motilitydepression

Opioids

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Other opioid agonistsTramadol

Synthetic 4-phenyl-piperidine analog of codeine

Stimulates the µ-receptor 1/5th to 1/10th as potent as morphine Analgesic doses of tramadol may produce

less respiratory depression and have minimal effects on gastrointestinal motor function

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Naloxone Opioid antagonistUsed to restore spontaneous ventilation in

patients who breathe inadequately after opioid overdose

Onset of action is 1 -2 minDuration of effect is 30 -60 minDosage – 0.4 to 0.8mgSide effects: tachycardia, hypertension,

pulmonary edema

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Non steroidal anti inflammatory drugsThere is only one NSAID approved for use in

the United States: ketorolac.Nonspecific inhibitor of cyclooxygenase with

strong analgesic activity and moderate anti inflammatory activity

Metabolized in the liver and excreted by the kidneys

Dose: 30 mg IV or 60 mg IM, f/b 30 mg IM or IV every 6 hours (maximum of 120 mg/day) for up to 5 days

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iv paracetamolThe time course of action is quick with iv

paracetamol as it reaches peak concentration as soon as infusion is complete (about 15 minutes).

According to the product information, the analgesic effect starts within 5 minutes, peaks at 1 hour and lasts 4 to 6 hours.

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Pain An assessment of pain and the response to

therapy should be regularly assessed using an appropriate pain scale.

Therapeutic plans and goals should be developed for all patients.

Recommended intravenous opioids are fentanyl for acute distress, fentanyl or hydromorphone for patients with hemodynamic instability or renal insufficiency, and morphine and hydromorphone for longer-term therapy.

Scheduled doses or continuous infusions are preferred over intermittent boluses.

Nonsteroidal anti-inflammatory drugs and acetaminophen can be useful adjuncts, but beware of renal insufficiency or gastrointestinal bleeding.

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Sedation Treatment of pain and other reversible causes

should be conducted before sedating an agitated patient.

A treatment plan/goal should be established for each patient; therapy should be assessed with a sedation scale.

Midazolam or diazepam is useful for the acutely agitated patient.

Propofol is preferred when rapid awakening is crucial; triglyceride levels should be monitored for >2 d of continuous infusions.

Lorazepam is recommended for longer infusions.

Doses should be tapered daily to assess underlying mental status, and sedation protocols can be helpful and beneficial.

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Guidelines for sedation and analgesia in ICU

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References Gabrielli A, Layon A, Joseph, et al. Anesthesia in

the ICU. Civetta, Taylor, & Kirby's: Critical Care,

4th Edition; Lippincott Williams & Wilkins:2009

Marino, PL. Analgesia and Sedation. ICU Book,

3rd Edition; Lippincott Williams & Wilkins:2007

Miller RD. Critical care protocols. Miller’s

Anaesthesia. 7th edition:2010

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