The Use of Sedatives in the Critically Ill Adults (Amanda) Use of Sedatives in the Critically Ill...

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The Use of Sedatives in the Critically Ill Adults

Amanda Chan, PharmacistQueen Mary Hospital7 Jan 2009

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General ConceptsGuidelines for SedationOverview of Sedatives

DexmedetomidineRemifentanil

Sedation Practices & ManagementSummary

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Sedation and Analgesia in ICU

Sessler CN, Grap MJ, Brophy GM. Multidisciplinary management of sedation and analgesia in critical care. Semin Respir Crit Care Med 2001; 22:211-25

Acute Medical or Surgical Illness

Mechanical Ventilation

ICU Environmental Influences

Hospital Acquired Illness

MedicationsInvasive, Medical, & Nursing

InterventionsUnderlying Medical

Conditions

Predisposing and Causative Conditions

Management of predisposing &

causative conditions

Sedative, analgesic, antipsychotic, medicationsInterventions

Dangerous agitation

Deeply sedated

Lightly sedated

Calm Alert, Free of pain & anxiety

Pain, Anxiety

Agitation, ventilator dys-

synchronyUnresponsive

Spectrum of Distress / Comfort / Sedation

Anxiety, Pain, Delirium

E. Munch, The Scream 1893

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Levels of Sedation and Analgesia

Continuum of depth of sedation. Definition of general anesthesia and levels of sedation/analgesia. American Society of Anaesthesiologists website: http://www.asahq.org/publicationsAndServices/standards/20.pdf

May be impaired

Usually maintained

Usually maintainedUnaffectedCardiovascular function

**Reflex withdrawal from a painful stimulus is NOT considered purposeful response

Frequently inadequate

May be inadequateAdequateUnaffectedSpontaneous ventilation

Intervention often required

Intervention may be required

No intervention required

UnaffectedAirway

Unable to rouse even with painful stimulation

Purposeful response following repeated or painful stimulation**

Purposeful response to verbal or tactile stimulation**

Normal response to verbal stimulation

Responsiveness

General anaesthesia

Deep sedation/analgesia

Moderate sedation/analgesia (conscious sedation)

Minimal sedation (anxiolysis)

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Sedation Assessment Scale

Responsive to touch, name, or both

2Patient responds to a light glabellar tap

4Sedated

Responsive only to noxious stimuli

1Sluggish response to a light glabellartap

5

Patient responds to commands only

3

Restless and cooperative

4Agitated5Agitated5Very agitated6

Devlin JW, et al. CritCare Med1999;27(7):1271-5

0

3

6

Motor Activity Assessment Scale

DrowsyLight sedationModerateDeep sedationUnarousable

Alert and calm

CombativeVery agitatedAgitatedRestless

SedatedVery sedatedUnarousable

Calm and cooperative

Dangerously agitated

No response

Cooperative, oriented, and tranquil

Anxious, agitated, or both

Sessler CN, et al. Am J Respir Crit Care Med2002;166(10):1338-44

Riker R, et al. CritCare Med1994;22(3):433-40

Ramsay MA, et al. BMJ 1974;2(5920):656-9

Source

Unresponsive

-1-2-3-4-5

321

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Calm and cooperative

042Calm

Dangerously agitated, uncooperative

+4+3+2+1

71Agitated

Richmond Agitation-Sedation Scale

Sedation-Agitation Scale

Ramsay Scale

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Anxiety Sleep

AACN Sedation Assessment Scale

Vancouver Sedative Recovery Scale

Riker’s Sedation Agitation Scale

Eye contact

Richmond Agitation-Sedation Scale

AnxietyRamsay Sedation

New Sheffield Sedation Scale

Motor Activity Assessment Scale

Glasgow Coma Scale modified by Cook and Palma

Mean BP, HR

Muscle tone

Facial expression

Comfort scale

Physiologic Variable

OtherPainVentilator Synchrony

AgitationLevel of Consciousness

Instrument

Fuchs EM, Rueden KV. Sedation management in the mechanically ventilated critically ill patient. AACN Advanced Critical Care 2008;19(4):421-32

Validated in ventilated patients in ICU

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BIS Monitor

BIS Sensor

Objective measures of sedation, such as BispectralIndex, have not been completely evaluated and are not yet proven useful in the ICU


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Guidelines for Sedation

American College of Critical Care Medicine (2002)

Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult

Surviving Sepsis Campaign (2008)

International guidelines for management of severe sepsis and septic shock

1. Jacobi J, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30(1): 119-142.

2. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327. Erratum in: Crit Care Med. 2008;36(4):1394-6

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American College of Critical Care Medicine Sedation Guidelines (2002)

Jacobi J, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002; 30(1): 119-142.

Yes

Yes

Acute agitation:

Midazolam: 2-5mg IV push q 5-15min until acute event is controlled

Rule out and correct reversible causes

Use a delirium scale (CAM-ICU) to assess for

delirium

Use a sedation-assessment scale (SAS or other

sedation-assessment scale) to assess for anxiety and

agitation

Use a pain scale (numeric rating scale or other pain scale) to assess for pain

Use nonpharmacologictreatment, optimize the

environment

Is the patient comfortable and at her or his goal?

Reassess goal daily. If on medication titrate and taper drug to maintain goal; consider daily awakening trials; taper if >1wk high-dose

therapy and monitor for withdrawal symptoms

Hemodynamically unstable:Fentanyl: 25-100mcg IV push q 5-15min orHydromorphone: 0.25-0.75mg IV push q 5-15min

Hemodynamically stable:Morphine: 2-5mg IV push q 5-15minRepeat until pain is controlled, then scheduled doses + as needed for pain

Ongoing sedation:Lorazepam: 1-4mg IV push q 10-20min until at goal, then q 2-6hr scheduled + as needed orPropofol: start 5mcg/kg/min, titrate q 5min until at goal

Haloperidol: 2-10mg IV push q 20-30min, then 25% of loading dose every 6hr

Set goal for analgesia

Set goal for sedation

≥3days propofol? (except

neurosurgery patients) Convert to

lorazepam

Set goal for control of delirium

IV push doses more often than q

2hr?

Consider continuous infusion of opioid or

sedative

If lorazepam is given by infusion,

use a low rate and IV push loading dose

Benzodiazepine or opioid: taper

infusion rate by 10%-25% per day

Yes

1

2

3

4

No** Doses given are approximations

for a 70-kg adult

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International guidelines for management of severe sepsis and septic shock: 2008

Use sedation protocols with a sedation goal for critically ill mechanically ventilated patients (Grade 1B)Use either intermittent bolus sedation or continuous infusion sedation to predetermined end points (sedation scales), with daily interruption/lightening to produce awakening. Re-titrate if necessary (Grade 1B)Avoid neuromuscular blockers where possible. Monitor depth of block with train of four when using continuous infusions (Grade 1B)

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Overview of Sedating Agents

Sedative hypnoticsBenzodiazepines

DiazepemLorazepamMidazolam

BarbituratesThiopentalMethohexital

AnestheticsKetaminePropofol

Richards G, Schoch P, Haefely W. Benzodiazepine receptors: new vistas. Seminars in Neuroscience 1991;3:191–203

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Opioid AnalgesicsFentanylHydromorphoneMorphineRemifentanil

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Centrally acting alpha-2-agonistDexmedetomidine

NeurolepticsHaloperidol

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Sedatives SelectionConsideration of

etiology of patient distresspotential drug interactionsfactors that may influence pharmacokinetics

Ideal sedativefree of serious adverse effectsnot associated with significant drug interactionsdoes not accumulate with repeated dosing, even in the presence of organ dysfunctioneasy to administerhas a quick and predictable onset and dissipation of effectinexpensive

Schweickert WD, Kress JP. Strategies to optimize analgesia and sedation. Critical Care2008;12(suppl 3):S6

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Unacceptable sedatives in critically ill patients

2009 UpToDate®

Technical delivery problems (requires closed ventilation circuit); environmental toxicity; alertness when turned off for routine patient care (suctioning)

Volatile anesthetics (halothane, enflurane, isoflurane)

Risk of leukopenia and bone marrow depression secondary to methionine synthetase inhibition; environmental toxicity. Risk of hypoxia due to high concentrations (60-70%) needed for sedativeeffect

Nitrous oxide

Inhibits adrenal steroid production; long-term use associated with increased mortality

Etomidate

Hypotension secondary to alpha-adrenergic receptor blockade; risk of malignant neuroleptic syndrome

Chlorpromazine

Little amnestic effect; decrease cerebral blood flow and brain metabolic rate; potent hepatic microsomal enzyme inducers; cardiovascular toxicity; minimal efficacy

Barbiturates

No analgesic effect; anticholinergic effects may contribute to disorientation and confusion

Antihistamines

CommentsDrug

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Sedatives

↓ BP, ↓ HR; not approved for use >24h, some studies use longer

Very short duration; has some analgesic properties

LD: 0.5-1mcg/kg over 10minMD: 0.2-0.7mcg/kg/h for 24h

Immediate Appr. 6min; longer in liver failure

Heptaic Cyt. P450 and glucuronidation

Dexmedetomidine($$$$$)

↓BP, ↑ serum TG, pancreatitis, propofol infusion syndrome, zinc depletion

Short actingMD: 5-150mcg/kg/min30-50sAppr. 3-10min; dose dependent

ConjugationPropofol($$$$)

Many drug interactions, may increase midazolamlevels, active metabolite accumulates in renal failure

Shorter acting if preserved organ function; fast onset

LD: 2-5mg IVPMD: 1-20mg/h; start low in elderly

5-10min1-4h; longer in ESRD/CHF/liver failure

Cyt.P450 3A4; active metabolite excreted renally

Midazolam($$$)

Propylene glycol toxicity at high doses (anion gap metabolic acidosis, renal insufficiency)

Inexpensive, longer half-life

LD: 2-4mg IVPMD: 2-6mg IV q4h-q6hInfusion: 1-10mg/h; start low in elderly

5-20min6-8h; up to 24-72h in elderly/cirrhosis/ESRD

Hepatic conjugation to inactive metabolite

Lorazepam($$)

DisadvantagesAdvantagesDosing (IV)Onset / DurationEliminationDrug

Sessler CN, Varney K. Patient-focused sedation and analgesia in the ICU. Chest 2008;133:552-65

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Opioid Analgesics

↓ HR, ↓ BP, ↑ICP

No accumulation in hepatic or renal failureSedation:+++

LD: 1mcg/kg over 1minMD: 0.6-15mcg/kg/h for MV (unlabeled use); use ideal body weight if >30% over ideal body weight

1-3min10-20min

Tissue esterases

Remifen-tanil($$$)

↓ HR, ↓ BP, ↑ICP

LD: 1-2mcg/kg slowly over 3-5minMD: 8-50mcg as needed

1-3minDose dependent duration

HepaticSufentanil($)

↓ HR, ↓ BP, ↑ICP; 3A4 inhibitors may increase levels of alfentanil

Very short-acting agent

LD: 50-75mcg/kg slowly over 3-5minMD: 0.5-3mcg/kg/min (usual 1-1.5mcg/kg/min)

1min30-60min; dose dependent

Hepatic; active metabolites excreted renally

Alfentanil($$)

3A4 inhibitors may increase fentanyl; fever will increase patch fentanyllevels by 30%

Less hypotension than morphine

LD: 25-50mcg IVPMD: 0.7-10mcg/kg/h for ventilated patients

1-2min2-4h; longer in liver failure

Cyt. P450 3A4Fentanyl($$)

↓ BP, respiratory depression, accumulation in hepatic/renal failure

Reduces tachypneaSedation:++

LD: 2-4mg IVPMD: 2-30mg/h for ventilated patients

5-10min2-4h

Conjugation; active metabolite excreted renally

Morphine($)

DisadvantagesAdvantagesDosing (IV)Onset / DurationEliminationDrug

Sessler CN, Varney K. Patient-focused sedation and analgesia in the ICU. Chest 2008;133:552-65

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Propofol vs MidazolamA randomized, controlled trial demonstrates no difference in the duration of mechanical ventilation and length of stay in the ICU or hospital between midazolam and propofol in mechanically ventilated ICU patients

Kress JP, Pohlman AS, O’Connor MF, et al. Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000;342(20):1471-7

A systematic review demonstrates that propofol provides at least as effective sedation as midazolam and results in a faster time to extubation, with an increased risk of hypotension and higher cost. Insufficient data exist to determine effect on length of stay in the ICU

Ostermann ME, Keenan SP, Seiferling RA, et al. Sedation in the intensive care unit: a systematic review JAMA2000;283(11):1451-9

A multicenter randomized trial demonstrates that the use of propofol sedation allowed for more rapid tracheal extubation than when midazolam sedation was employed. This did not result in earlier ICU discharge

Hall RI, Sandham D, Cardinal P, et al. Propofol vs midazolam for ICU sedation : a Canadian multicenterrandomized trial. Chest 2001;119(4):1151-9

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Propofol vs LorazepamA randomized trial demonstrates that for medical patients requiring >48 hrs of mechanical ventilation, sedation with propofol results in significantly fewer ventilator days compared with intermittent lorazepam when sedatives are interrupted daily

Carson SS, Kress JP, Rodgers JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily interruption in mechanically ventilated patients. Crit Care Med 2006;34(5):1326-32

Large retrospective database analysis demonstrates that propofolis associated with a shorter duration of mechanical ventilation than intermittent lorazepam even when daily interruption is not used

Fong JJ, Kanji S, Dasta JF, et al. Propofol associated with a shorter duration of mechanical ventilation than scheduled intermittent lorazepam: a database analysis using Project IMPACT. Ann Pharmacother 2007;41:1986-91

A pharmacoeconomic study concludes that propofol, despite having an acquisition cost far greater than intermittent lorazepamtherapy is, on average, cheaper for sedation among the critically ill who require mechanical ventilation when used in the setting of daily sedative interruption

Cox Ce, Reed Sd, Govert JA, et al. Economic Economic evaluation of propofol and lorazepam for critically ill patients undergoing mechanical ventilation. Crit Care Med 2008;36(3):706-14

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Dexmedetomidine(Precedex®)

Alpha 2-adrenoceptor agonistFDA Approved in 1999 for continuous I.V. sedation of initially intubated and mechanically ventilated patients in the intensive-care setting for use up to 24 hours. It can be used before, during and after extubationNew indication approved by FDA in Oct 2008 for the use in non-intubated patients requiring sedation prior to and/or during surgical and other procedures

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DexmedetomidineAlpha-adrenoceptor agonist

PhenylephrineNorepinephrineEpinephrineDopamineClonidineGuanfacineDexmedetomidine

Alpha 2-adrenoceptor agonist Modulate sympathetic response ‘negative feedback loop’Control epinephrine, norepinephrine release

Harvey MA. Managing agitation in critically ill patients Am J Crit Care 1996;5:7-16

Alpha 1

Alpha 2

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Dexmedetomidine

Kamibayashi T, Maze M. Clinical uses of alpha2 -adrenergic agonists. Anesthesiology 2000;93(5):1345-9

Highly selective, centrally acting alpha-2-agonist

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DexmedetomidineSupplied as 2ml vial containing 200mcg

$210.5/vial2ml vial with 48ml NS (4mcg/ml)

Loading dose1mcg/kg over 10min

Continuous infusion0.2-0.7mcg/kg/hr

Reduced dose in elderly (>65yr), renal and hepatic impairmentCommon adverse effects

Hypotension, bradycardia, sinus arrest, transient hypertension (during loading dose), dry mouth

MonitoringLevel of sedation, heart rate, respiration, rhythm, blood pressure, pain controlpatients who receive an infusion for more than 6 hours should be informed to report nervousness, agitation, and headaches that may occur for up to 48 hours

Precedex ® Package Insert

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Dexmedetomidine has shown efficacy in decreasing the need for opioids, benzodiazepines, and propofol. Short-term sedation has been shown to be safe in studies

Carollo DS, Nossaman BD, Ramadhyani U. Dexmedetomidine: a review of clinical applications. Curr Opin Anaesthesiol 2008;21:457-61

In short-term sedation in surgical critically ill patients, similar times to extubation were observed; however, less opioids were required in the dexmedetomidine grouopwhen compared with the propofol group

Geriach At, Dasta J. Dexmedetomidine: an updated review. Ann Pharmacother 2007;41:245-52

There is no evidence that dexmedetomidine improves patient satisfaction compared to propofol

Corbett, SM, Rebuck, JA, Greene, CM, et al. Dexmedetomidine does not improve patient satisfaction when compared with propofol during mechanical ventilation. Crit Care Med 2005; 33:940.

Dexmedetomidine

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The MENDS randomized controlled trial(Dexmedetomidine vs Lorazepam)

Double-blind, randomized controlled trial of 106 adult mechanically ventilated medical and surgical ICU patients at 2 tertiary care centersSedation with dexmedetomidineresulted in

more days alive without delirium or coma (median days, 7.0 vs 3.0; P = .01) a lower prevalence of coma(63% vs 92%; P < .001) more time within 1 RASS point of their sedation goalcompared with patients sedated with lorazepam(median percentage of days, 80% vs 67%; P = .04).

Dexmedetomidine infused up to a maximum of 120hr

Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA2007;298(22):2644-53

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Remifentanil (Ultiva®)Potent selective μ-opioid receptor agoinistFDA indication

Analgesic for use during the induction and maintenance of general anesthesiaFor continued analgesia into the immediate postoperative periodAnalgesic component of monitored anesthesia

Unlabeled indicationManagement of pain in mechanically ventilated patients

Approval from European Medicines Agency in 2002Provision of analgesia for a duration of up to 3 days in mechanically ventilated ICU patients

Ultiva ® Package Insert

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Remifentanil (Ultiva®)

Supplied as 1mg & 2mg injection1mg inj: $64.6 ; 2mg inj: $113.1Prepare solution by adding 1ml of diluent per 1mg of remefentanil, then further dilute to a final conc. Of 20, 25, 50, or 250mcg/ml

Continuous infusion in critically-ill patients0.6-15mcg/kg/hr

Common adverse effectsHypotension, hypertension, and bradycardia

MonitoringRespiratory and cardiovascular status, blood pressure, heart rate

Ultiva ® Package Insert

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Remifentanil

Context-sensitive half-times of remifentanil and the other 4-anilido-piperidine opioids

1. Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in healthy adult male volunteers. Anesthesiology 1993;79:881–92

2. Wilhelm W, Kreuer Sascha. Review: The place for short-acting opioids: special emphasis on remifentanil. Critical Care2008;12(Suppl 3):S5

Decline of effect site concentration of different opioids after 24 hours of infusion

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Remifentanil

Extubation times in 46 intensive care unit patients after sedation with a remifentanil infusion (mean duration 9.8 hours, mean dosage 0.14 ± 0.08 mcg/kg per minute)Two-thirds of all patients could be extubated within 15 minutes and 87% within 45 minutes after cessation of remifentanilinfusion

Wilhelm W, Dorscheid E, Schlaich N, et al. The use of remifentanil in critically ill patients. Clinical findings and early experience. Anaesthesist 1999, 48:625–29

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Remifentanil

Analgesia-based sedation with remifentanil is a useful option for mechanically ventailated patients in the ICU settingRemifentanil is at least as effective as comparator opioids such as fentanyl, morphine and sufentanil in providing pain relief and sedation in mechanically ventilated ICU patients

Battershill AJ, Keating GM. Remifentanil: A review of its analgesic and sedative use in the intersive care unit. Drugs 2006;66(3):365-85

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Hypnotic-based sedation vs Analgesic based sedation in a general ICU

111 patients received Hypnotic-based sedation (HBS), where midazolam and/or propofol are used, with morphine or another analgesic added as needed 79 received Analgesia-based sedation (ABS) utilizing remifentanil, with hypnotics added only if neededRESULTS:

29 (37%) of the patients receiving remifentanil without the use of supplementary hypnotic agentsIn the remaining 63% the use of remifentanil was associated with a reduction in the amount and duration of propofol usedSignificantly more patients receiving ABS had satisfactory levels of sedation during synchronized intermittent mandatory ventilation (19 [2,55] vs 50 [14,83], P<0.001)

CONCLUSIONS: The use of ABS allowed patients to be managed more comfortably, either without a hypnotic drug or with less hypnotic drug, than using conventional HBS.

Park G, Lane M, Rogers S, et al. A comparison of hypnotic and analgesic based sedation in a general intensive care unit. Br J Anaesth 2007;98(1):76-82

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General ConceptsGuidelines for SedationOverview of Sedatives

DexmedetomidineRemifentanil

Sedation Practices & ManagementSummary

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Sedation Practices in the mechanically ventilated patients

Morphine, Lorazepam, Midazolam, Haloperidol, Propofol

Commonly used agents

36%29%33%Use of protocol

Remifentanil, DexmedetomidineOther agents

43%50%80%Use of sedation assessment tools

EuropeCanada US

US - Rhoney DH, Murry KR. National survey of the use of sedating drugs, neuromuscular blocking agents, and reversal agents in the intensive care unit. J Intensive Care Med. 2003 May-Jun;18(3):139-45Canada - Mehta S, Burry L, Fischer S, et al. Canadian survey of the use of sedatives, analgesics, and neuromuscular blocking agents in critically ill patients. Crit Care Med. 2006;34(2):374-80Europe – Payen JF, Chanques G, Mantz J, et al. Current practices in sedation and analgesia for mechanically ventilated critically ill patients. Anesthesiology 2007;106:687-95

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Sedation Practices in the mechanically ventilated patients

Wide variety in sedation management among US, Canada and EuropeSedation assessment tools and protocols or guidelines are utilized in less than 50% of patients receiving sedation

Fuchs EM, Von Rueden K. Sedation management in the mechanically ventilated critically ill patient. AACN Advanced Critical Care 2008; 19(4): 421-32

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Strategies to Optimize Sedation

Patient-targeted sedation protocolsContinuous versus intermittent sedative administration Daily interruption of sedative infusions

Schweickert WD, Kress JP. Review: Strategies to optimize analgesia and sedation. Critical Care2008;12(suppl 3):S6

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Protocol for Sedation Management

To ensure that sedation level is evaluated using an objective-scoring toolTo provide guidelines for medication use that will lead to prompt and adequate control of pain, agitation, and delirium, without causing oversedationTo provide an algorithm for medication management that enables more timely responsiveness to changes in patient’s medication requirementsPharmacists and Nurses could help to ensure the protocol-driven sedation

Shapiro MB, West MA, Nathens AB, et al. Guidelines for sedation and analgesia during mechanical ventilation general overview. J Trauma 2007;63(4):945-50

37Shapiro MB, West MA, Nathens AB, et al. Guidelines for sedation and analgesia during mechanical ventilation general overview. J Trauma 2007;63(4):945-50

Sedation Protocol

ANXIETY

Assess patient for pain, anxiety, and delirium

(Record sedation level with objective scale)

PAIN DELIRIUM

Fentanylbolus 25-100mcg q5min, continue bolus q30-60min

If pain not controlled after 3hr begin infusion

at 50mcg/hr doses

If pain not controlled in 1hr bolus with current

rate and increase infusion 25mcg/hr

PropofolBolus 0.5mg/kg IV, start infusion at 20mcg/kg/min

If goal not met in 15min, bolus with 0.5mg/kg and

increase infusion by 10mcg/kg/min q15min to max of 100mcg/kg/min

Propofol or Lorazepam

Haloperidol2-10mg IV q1hr prn

If goal not met in 6hr begin 5mg IV q6hr and continue

bolus doses

LorazepamBolus 1-2mg IV q15min

prn, continue bolus dose q24hr

If goal not met in 3hr begin 4mg IV q6hr and continue bolus doses

If goal not met in 24hr begin infusion at 2mg/hr

and continue bolus doses prn

If goal not met in 1hr increase infusion by 1mg/hr and continue

bolus doses prn

ANXIETY



PAIN DELIRIUM



at 50mcg/hr doses









bolus doses







bolus doses prn

ANXIETY



PAIN DELIRIUM



at 50mcg/hr doses









bolus doses







bolus doses prn

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Continuous versus intermittent sedative administration

Kollef, MH, Levy NT, Ahrens TB, et al. The Use of Continuous IV Sedation Is Associated With Prolongation of Mechanical Ventilation Chest 1998;114:541-48

* Values shown are means per patient and 95% CIs. Outcome variables have been adjusted for age, gender, severity of illness, mortality, indication for mecahnical ventilation, use of chemical paralysis, presence of a tracheostomy, and the number of acquired organ system derangements

<0.00113.8 (12.8, 14.9)19.4 (16.7, 22.1)Length of hospital stay, d

0.0077.2 (6.6, 7.7)9.6 (8.4, 10.9)Length of intensive care, d

<0.00178.7 (68.9, 88.6)148 (121, 175)Duration of mechanical ventilation, h

p ValueNo Continuous IV Sedation (n=149)Continuous IV Sedation (n=93)Variable

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Sedation InterruptionDaily interruption of sedation in ventilated patients decreased duration of mechanical ventilation and length of hospital stay.

Randomized, controlled study of 128 ptsDaily, stopped sedation until patient was awake or uncomfortable/agitatedMean duration of mechanical ventilation 4.9 days compared to 7.3 days control group (p=0.004)More complications (pulling out EG tube) occurred in control compared to intervention group (7% to 4%)

Benefit confirmed by subsequent studies

Kress JP, et al. Daily Interruption of Sedative Infusions in Critically Ill Patients Undergoing Mechanical Ventilation. NEJM 2000;342:1471-77.

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Sedation Interruption126 patients receiving mechanical ventilation and continuous infusions of sedative drugs in a medical intensive care unitPatients undergoing daily interruption of sedative infusions experienced 13 complications (2.8%) vs. 26 (6.2%) in those subjected to conventional sedation techniques (p =.04).

.Schweickert WD, et al. Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients.Crit Care Med 2004; 32(6):1272-76.

2613Total no.10sinusitis10cholestasis

52venous thromboembolic disease

30barotrauma

74bacteremia

45upper gastrointestinal hemorrhage

52ventilator-associated pneumonia

ControlInterventioncomplications associated with mechanical ventilation and critical illness

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Awakening and Breathing Controlled (ABC) trialIn four tertiary-care hospitals, 336 mechanically ventilated patients in intensive care were randomly assigned to management with a daily SAT followed by an SBT (intervention group; n=168) or with sedation per usual care plus a daily SBT (control group; n=168)Results of intervention group

spent more days breathing without assistance during the 28-day study period (14.7 days vs 11.6 days; p=0.02) discharged from intensive care (median time in intensive care 9.1 days vs 12.9 days; p=0.01) Discharged from hospital earlier (median time in the hospital 14.9 days vs 19.2 days; p=0.04)

A wake up and breathe protocol that pairs daily spontaneous awakening trials (ie, interruption of sedatives) with daily spontaneous breathing trials results in better outcomes for mechanically ventilated patients in intensive care than current standard approaches

.Girard TD; Kress JP; Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008;371(9607):126-34

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Awakening and Breathing Controlled (ABC) trial

A. Probability of successful extubationduring the first 28 days after randomization

B. Probability of discharge from intensive careduring the first 28 days after randomization

C. Probability of hospital discharge during the first 28 days after randomization

paired spontaneous awakening trials (SATs)-ie, daily interruption of sedatives-with spontaneous breathing trials (SBTs)

.Girard TD; Kress JP; Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008;371(9607):126-34

sedation per usual care plus a daily spontaneous breathing trials (SBTs)

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Sedative Dependence

Patients exposed to more than one week of high dose opioid or sedative may develop tolerance and/or dependence.Opioid withdrawal:

Pupillary dilation, sweating, lacrimation, rhinorrhea, yawning, tachycardia, irritability, anxiety

Benzodiazepine withdrawal:Dysphoria, tremor, headache, nausea, sweating, agitation, anxiety, sleep disturbances, myoclonus, delirium, seizures

Propofol withdrawal not well-described but reported to resemble BZD withdrawal

Schweickert WD, Kress JP. Review: Strategies to optimize analgesia and sedation. Critical Care2008;12(suppl 3):S6

44

Strategies to Optimize Sedation

Schweickert WD, Kress JP. Strategies to optimize analgesia and sedation. Critical Care2008;12(suppl 3):S6

Sedation Scale AssessmentReproducible. Well understood by all team membersAttends to level of consciousness, agitation and

subtle distress signals (grimacing, ventilator synchrony)

DISTRESS? Awake? Pain?

Protocol-Guided, Nurse-Initiated Behaviours

De-escalation of Sedation and Analgesia

Daily interruptionProtocol-guided

withdrawal

GOALPain-freeCalm patientAble to undergo complete cognitive and neuromuscular evaluation

Assess for Reversible FactorsVerbal reassurancePatient PositioningVentilator Manipulation

Assess for painAssess for Anxiety and Agitation

Drug AdministrationCommon Pairing of Analgesia and Sedation

Yes

Yes

No

YesNo

No

Sedation Scale AssessmentReproducible. Well understood by all team membersAttends to level of consciousness, agitation and

subtle distress signals (grimacing, ventilator synchrony)

DISTRESS? Awake? Pain?

Protocol-Guided, Nurse-Initiated Behaviours

De-escalation of Sedation and Analgesia

Daily interruptionProtocol-guided

withdrawal

GOALPain-freeCalm patientAble to undergo complete cognitive and neuromuscular evaluation

Assess for Reversible FactorsVerbal reassurancePatient PositioningVentilator Manipulation

Assess for painAssess for Anxiety and Agitation

Drug AdministrationCommon Pairing of Analgesia and Sedation

Yes

Yes

45

Summary

Successful management of analgesia and sedation in ICU patients requires the implementation of structured assessment tools for pain and depth of sedation, coupled with strategies to guide drug administration and withdrawalThe use of newer agents such as Dexmedetomidine and Remifentanil is increasing, which may have a role in promoting shorter time on mechanical ventilation and thus fewer ICU complications, however drug costs maybe a concern

46

Thank You

47

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Respir Crit Care Med 2001; 22:211-252. Continuum of depth of sedation. Definition of general anesthesia and levels of sedation/analgesia. American Society

of Anaesthesiologists website: http://www.asahq.org/publicationsAndServices/standards/20.pdf3. Fuchs EM, Rueden KV. Sedation management in the mechanically ventilated critically ill patient. AACN Advanced

Critical Care 2008;19(4):421-324. Jacobi J, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult.

Crit Care Med 2002; 30(1): 119-1425. Dellinger RP, Levy MM, Carlet JM, et al. Surviving Sepsis Campaign: international guidelines for management of

severe sepsis and septic shock: 2008. Crit Care Med. 2008;36(1):296-327. Erratum in: Crit Care Med. 2008;36(4):1394-6

6. Schweickert WD, Kress JP. Strategies to optimize analgesia and sedation. Critical Care 2008;12(suppl 3):S67. 2009 UpToDate®8. Sessler CN, Varney K. Patient-focused sedation and analgesia in the ICU. Chest 2008;133:552-659. Kress JP, Pohlman AS, O’Connor MF, et al. Daily interruption of sedative infusions in critically ill patients undergoing

mechanical ventilation. N Engl J Med 2000;342(20):1471-710. Ostermann ME, Keenan SP, Seiferling RA, et al. Sedation in the intensive care unit: a systematic review JAMA

2000;283(11):1451-911. Hall RI, Sandham D, Cardinal P, et al. Propofol vs midazolam for ICU sedation : a Canadian multicenter randomized

trial. Chest 2001;119(4):1151-912. Carson SS, Kress JP, Rodgers JE, et al. A randomized trial of intermittent lorazepam versus propofol with daily

interruption in mechanically ventilated patients. Crit Care Med 2006;34(5):1326-3213. Fong JJ, Kanji S, Dasta JF, et al. Propofol associated with a shorter duration of mechanical ventilation than scheduled

intermittent lorazepam: a database analysis using Project IMPACT. Ann Pharmacother 2007;41:1986-9114. Cox Ce, Reed Sd, Govert JA, et al. Economic Economic evaluation of propofol and lorazepam for critically ill patients

undergoing mechanical ventilation. Crit Care Med 2008;36(3):706-1415. Harvey MA. Managing agitation in critically ill patients Am J Crit Care 1996;5:7-16

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References16. Kamibayashi T, Maze M. Clinical uses of alpha2 -adrenergic agonists. Anesthesiology 2000;93(5):1345-9 17. Precedex ® Package Insert18. Carollo DS, Nossaman BD, Ramadhyani U. Dexmedetomidine: a review of clinical applications. Curr Opin

Anaesthesiol 2008;21:457-6119. Geriach At, Dasta J. Dexmedetomidine: an updated review. Ann Pharmacother 2007;41:245-5220. Corbett, SM, Rebuck, JA, Greene, CM, et al. Dexmedetomidine does not improve patient satisfaction when compared

with propofol during mechanical ventilation. Crit Care Med 2005; 33:940.21. Pandharipande PP, Pun BT, Herr DL, et al. Effect of sedation with dexmedetomidine vs lorazepam on acute brain

dysfunction in mechanically ventilated patients: the MENDS randomized controlled trial. JAMA 2007;298(22):2644-5322. Ultiva ® Package Insert23. Egan TD, Lemmens HJ, Fiset P, et al. The pharmacokinetics of the new short-acting opioid remifentanil (GI87084B) in

healthy adult male volunteers. Anesthesiology 1993;79:881–9224. Wilhelm W, Kreuer Sascha. Review: The place for short-acting opioids: special emphasis on remifentanil. Critical Care

2008;12(Suppl 3):S525. Wilhelm W, Dorscheid E, Schlaich N, et al. The use of remifentanil in critically ill patients. Clinical findings and early

experience. Anaesthesist 1999, 48:625–2926. Battershill AJ, Keating GM. Remifentanil: A review of its analgesic and sedative use in the intersive care unit. Drugs

2006;66(3):365-8527. Park G, Lane M, Rogers S, et al. A comparison of hypnotic and analgesic based sedation in a general intensive care

unit. Br J Anaesth 2007;98(1):76-8228. Rhoney DH, Murry KR. National survey of the use of sedating drugs, neuromuscular blocking agents, and reversal

agents in the intensive care unit. J Intensive Care Med. 2003 May-Jun;18(3):139-4529. Mehta S, Burry L, Fischer S, et al. Canadian survey of the use of sedatives, analgesics, and neuromuscular blocking

agents in critically ill patients. Crit Care Med. 2006;34(2):374-8030. Payen JF, Chanques G, Mantz J, et al. Current practices in sedation and analgesia for mechanically ventilated

critically ill patients. Anesthesiology 2007;106:687-9531. Shapiro MB, West MA, Nathens AB, et al. Guidelines for sedation and analgesia during mechanical ventilation general

overview. J Trauma 2007;63(4):945-5032. Girard TD; Kress JP; Fuchs BD, et al. Efficacy and safety of a paired sedation and ventilator weaning protocol for

mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet 2008;371(9607):126-34

49

Appendix

American College of Critical Care Medicine Sedation Guidelines (2002)Evidence-Based Sedation Management RecommendationAdministration of Remifentanil in clinical practiceDrug Cost

50

American College of Critical Care Medicine Sedation Guidelines (2002)Sedation indication:

Sedation of agitated critically ill patients should be started only after providing adequate analgesia and treating reversible physiological causes (Grade of recommendation = C)

Sedation assessment:A sedation goal or endpoint should be established and regularly redefined for each patients. Regular assessment and response to therapy should be systematically documented (Grade of recommendation = C)The use of validated sedation assessment scale (RSAS, MAAS) is recommended ((Grade of recommendation = B)Objective measures of sedation, such as BIS, have not been completely evaluated and are not yet proven useful in the ICU (Grade of recommendation = C)

Jacobi, J, Fraser, GL, Coursin, DB, et al. Clinical practice guidelines for the sustained use of sedatives and analgesics in the critically ill adult. Crit Care Med 2002;30:119

51


Sedatives selectionMidazolam or diazepam should be used for rapid sedation of acutely agitated patients (Grade of recommendation = C)Propofol is the preferred sedative when rapid awakening (e.g. for neurologic assessment or extubation) is important (Grade of recommendation = B)Midazolam is recommended for short-term use only, as it produces unpredicatble awakening and time to extubation when infusions continue longer than 48-72 hours (Grade of recommendation = A)Lorazepam is recommended for the sedation of most patients via intermittent IV administration or continuous infusion (Grade of recommendation = B)


52


Sedatives selectionThe titration of the sedative dose to a defined endpoint is recommended with systematic tapering of the dose or daily interruption with retitration to minimize prolonged sedative effects (Grade of recommendation = A)Triglyceride concentration should be monitored after two days of propofol infusion, and total caloric intake from lipids should be included in the nutrition support prescription (Grade of recommendation = B)The use of sedation guidelines, an algorithm, or a protocol is recommended (Grade of recommendation = B)


53


Sedation withdrawalThe potential for opioid, benzodiazepine, and propofol withdrawal should be considered after high doses or more than approximately seven days of continuous therapy. Doses should be tapered systematically to prevent withdrawal symptoms (Grade of recommendation = B)


54

Evidence-Based Sedation Management Recommendation

Sedation indicationDetermination of length of sedation (i.e. >24hr or <24hr)Consider severity and complexity of illnessConsider the presence of comorbid factors (i.e. history off substance abuse)

Sedation goalsSedation goals are established and evaluated daily by critical care team membersThe use of systematic, reliable, and valid sedation assessment scales is recommended to monitor level of sedation


55

Evidence-Based Sedation Management Recommendation

Sedative selectionThe sedative selection is consistent with the patient sedation needs and goalsThe sedative pharmacokinetics and pharmacodynamics are evaluated against existing comorbidities, severity of illness, and organ involvement

Sedation management strategyThe implementation of nurse-driven sedation protocol is recommendedThe incorporation of pharmacists in the development and enforcement of nurse-driven protocols is recommended to assist clinical decision making

Sedation weaning strategyProtocol-driven daily spontaneous awakening trial is the recommended sedation weaning strategy


56

Administration of Remifentanil in clinical practice1. Conduct a clinical evaluation of the patient2. Initiate a remifentanil infusion at an adequate dosage. The

recommended starting dose is between 0.1-0.15mcg/kg/min (6-9mcg/kg/hr), which is about 0.4-0.6mg/hr for a 70kg patient

3. Titrate remifentanil in increments of 0.025mcg/kg/min (1.5mcg/kg/hr) to achieve the desired level of analgesia (at intervals of at least 5min)

4. If a dosage of 0.2mcg/kg/min (12mcg/kg/hr) remifentanil is reached and further sedation is necessary, add a hypnotic agent (propofol or midazolam)

5. Adapt the required remifentanil and hypnotic dosage to the individual patient’s needs at any given time

Wilhelm W, Kreuer Sascha. Review: The place for short-acting opioids: special emphasis on remifentanil. Critical Care 2008;12(Suppl 3):S5

57

Administration of Remifentanil in clinical practice6. Because of the rapid offset of action of remifentanil, no

residual opiod activity will be present within 5 to 10 minutes after discontinuation, regardless of the duration of infusion. Therefore careful planning of the transition to longer acting analgesia is necessary (e.g. longer acting opioids should be given at an approprriate dose before discontinuation of remifentanil)

7. If the patient is ready for weaning, titrate the remifentanilinfusion down in adequate steps. Prior to extubation, the remifentanil infusion rate should be gradually titrated down to 0.1mcg/kg/min (6mcg/kg/hr)

8. After extubation, the remifentanil infusion rate should be further decreased in 25% decrements at intervals of at least 10min until the infusion is discontinued

9. Analgesia and sedation should be monitored closely during the entire procedure

Wilhelm W, Kreuer Sascha. Review: The place for short-acting opioids: special emphasis on remifentanil. Critical Care 2008;12(Suppl 3):S5

58

Drug Cost (Jan 2009)

Midazolam 15mg inj: $5.9Propofol 10mg/ml

20ml inj: $12.1 ; 50ml pre-filled syringe: $150.7Dexmedetomidine 200mcg vial: $210.5Morphine

10mg inj: $17.2 ; 15mg inj: $3.0Fentanyl

100mcg/2ml inj: $2.7 ; 500mcg/10ml inj: $8.9Remifentanil

1mg inj: $64.6 ; 2mg inj: $113.1

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