assessing and managing sedation in the intensive care and the perioperative settings

Assessing and Managing Sedation in the Intensive Care and the

Perioperative Settings

Assessing and Managing Sedation

SEDATION Curriculum Learning Objectives

• Manage adult patients who need sedation and analgesia while receiving ventilator support according to current standards and guidelines

• Use validated scales for sedation, pain, agitation and delirium in the management of these critically ill patients

• Assess recent clinical findings in sedation and analgesia management and incorporate them into the management of patients in the acute care, procedural, and surgical sedation settings

Predisposing and Causative Conditions

Anxiety Pain Delirium

Interventions

Managementof predisposing

& causative conditions

Sedative, analgesic,

antipsychotic,medications

Calm AlertFree of pain and anxiety

Lightlysedated

Deeplysedated

UnresponsivePain,

anxietyAgitation, vent dyssynchrony

Dangerousagitation

Spectrum of Distress/Comfort/Sedation

ICUEnvironmental

Influences

HospitalAcquired

IllnessMedications

Invasive,Medical, &

NursingInterventions

Underlying Medical

Conditions

Acute Medicalor Surgical Illness

MechanicalVentilation

Agitation

Sessler CN, Varney K. Chest. 2008;133(2):552-565.

Need for Sedation and Analgesia

• Prevent pain and anxiety

• Decrease oxygen consumption

• Decrease the stress response

• Patient-ventilator synchrony

• Avoid adverse neurocognitive sequelae– Depression, PTSD

Rotondi AJ, et al. Crit Care Med. 2002;30:746-752.Weinert C. Curr Opin in Crit Care. 2005;11:376-380.Kress JP, et al. Am J Respir Crit Care Med. 1996;153:1012-1018.

Potential Drawbacks of Sedative and Analgesic Therapy

• Oversedation:– Failure to initiate spontaneous breathing trials (SBT) leads to

increased duration of mechanical ventilation (MV)

– Longer duration of ICU stay

• Impede assessment of neurologic function

• Increase risk for delirium

• Numerous agent-specific adverse events

Kollef MH, et al. Chest. 1998;114:541-548.Pandharipande PP, et al. Anesthesiology. 2006;104:21-26.

American College of Critical Care Medicine Clinical practice guidelines for the sustained use of sedatives and

analgesics in the critically ill adult

• Guideline focus

– Prolonged sedation and analgesia

– Patients older than 12 years

– Patients during mechanical ventilation

• Assessment and treatment recommendations – Analgesia – Sedation– Delirium– Sleep

• Update expected in 2012

Jacobi J, et al. Crit Care Med. 2002;30:119-141.

Identifying and Treating Pain

FACES Pain Scale 0–10

Wong DL, et al. Wong’s Essentials of Pediatric Nursing. 6th ed. St. Louis, MO: Mosby, Inc; 2001. p.1301.

Behavioral Pain Scale (BPS) 3-12

Payen JF, et al. Crit Care Med. 2001;29(12):2258-2263.

Item Description Score

Facial expression

Relaxed 1

Partially tightened (eg, brow lowering) 2

Fully tightened (eg, eyelid closing) 3

Grimacing 4

Upper limbs

No movement 1

Partially bent 2

Fully bent with finger flexion 3

Permanently retracted 4

Compliance with ventilation

Tolerating movement 1

Coughing but tolerating ventilation for most of the time

2

Fighting ventilator 3

Unable to control ventilation 4

BPS ValidationSedated Mechanically Ventilated Patients

Payen JF, et al. Crit Care Med. 2001;29:2258–2263.

BP

S

□ Not painful n = 104

● Painful n = 134

▲ Retested painful n = 31

* P < 0.05 vs rest period†P < 0.05 vs not painful

Exposed to Pain

Re-

Exp

ose

d t

o P

ain

Is BPS Sensitive to Pain? Is BPS Reproducible?

Weighted = 0.74, P < 0.01

Critical Care Pain Observation Tool 0-8

Gélinas C, et al. Am J Crit Care. 2006;15:420-427.

Critical Care Pain Observation Tool

Sensitivity/Specificity DURING Painful Procedure

Gélinas C, et al. Am J Crit Care. 2006;15:420-427.

Correlating Pain Assessment withAnalgesic Administration in the ICU

• Fewer patients assessed for pain, more treated with analgesics in ICUs without analgesia protocols compared with ICUs with protocols1

• Pain scoring used in 21% of surveyed ICUs in 20062

1. Payen JF, et al. Anesthesiol. 2007;106:687-695.2. Martin J, et al. Crit Care. 2007;11:R124.

Pat

ient

s (%

)

Protocol No Protocol

Assessed Treated

* P < 0.01 vs ICUs using a protocol

0102030405060708090

100

60

25

8792*

*

Assessing Pain Reduces Sedative/Hypnotic Use

Payen JF, et al. Anesthesiology. 2009;111;1308-1316.

Day 2 Pain Assessment?P-value

No (n = 631) Yes (n = 513)

Any sedative 86% 75% < 0.01

Midazolam 65% 57% < 0.01

Propofol 21% 17% 0.06

Other 6% 4% 0.03

What proportion of MV ICU patients received sedative or hypnotic medication?

Assessing Pain Improves Some Outcomes

Payen JF, et al. Anesthesiology. 2009;111:1308-1316.

Outcome

Day 2 Pain Assessment? Unadj.

ORP-value

Adjusted OR

P-valueNo Yes

ICU Mortality 22% 19% 0.91 0.69 1.06 0.71

ICU LOS 18 d 13 d 1.70 < 0.01 1.43 0.04

MV duration 11 d 8 d 1.87 < 0.01 1.40 0.05

Vent-acquired pneumonia

24% 16% 0.61 < 0.01 0.75 0.21

Thromboembolic events, gastroduodenal hemorrhage, and CVC colonization were less than 10%, and not changed by pain assessment.

Maintaining Patients at the Desired Sedation Goal

Sedation-Agitation Scale (SAS)

Riker RR, et al. Crit Care Med. 1999;27:1325-1329.Brandl K, et al. Pharmacotherapy. 2001;21:431-436.

Score State Behaviors

7 Dangerous Agitation

Pulling at ET tube, climbing over bedrail, striking at staff, thrashing side-to-side

6 Very AgitatedDoes not calm despite frequent verbal reminding, requires physical restraints

5 AgitatedAnxious or mildly agitated, attempting to sit up, calms down to verbal instructions

4 Calm and Cooperative

Calm, awakens easily, follows commands

3 SedatedDifficult to arouse, awakens to verbal stimuli or gentle shaking but drifts off

2 Very SedatedArouses to physical stimuli but does not communicate or follow commands

1 UnarousableMinimal or no response to noxious stimuli, does not communicate or follow commands

Richmond Agitation Sedation Scale (RASS)

Score State

+ 4 Combative

+ 3 Very agitated

+ 2 Agitated

+ 1 Restless

0 Alert and calm-1 Drowsy eye contact > 10 sec

-2 Light sedation eye contact < 10 sec

-3 Moderate sedation no eye contact

-4 Deep sedation physical stimulation

-5 Unarousable no response even with physical

Ely EW, et al. JAMA. 2003;289:2983-2991.Sessler CN, et al. Am J Respir Crit Care Med. 2002;166(10):1338-1344.

Verbal Stimulus

Physical Stimulus

Sedation Scale Reliability r2

KappaSAS Riker, 1999 0.83 0.92

Brandl, 2001 0.93

RASS Sessler, 2002 0.80Ely, 2003

0.91

Ramsay Riker, 1999 0.88Ely, 2003 0.94

Olson, 20070.28

MAAS Devlin, 1999 0.83Hogg, 2001 0.81

MSAT Weinert, 2004 0.72-0.85

Correlating Sedation Assessment withSedative Administration in the ICU

• 1381 ICU patients included in an observational study of sedation and analgesia practices1

• Fewer patients assessed, more treated with sedatives in ICUs without sedation protocols compared with ICUs with protocols1

• Use of sedation protocols and scores increased between 2002 and 20062

1. Payen JF, et al. Anesthesiol. 2007;106:687-695.2. Martin J, et al. Crit Care. 2007;11:R124.

Pat

ient

s (%

)

Protocol No Protocol

Assessed Treated

* P < 0.01 vs ICUs using a protocol

*

*

0

10

20

30

40

50

60

70

80

56

31

6876

The Importance of Preventing and Identifying Delirium

Morandi A, et al. Intensive Care Med. 2008;34:1907-1915.

Cardinal Symptoms of Delirium and Coma

ICU Delirium

Vasilevskis EE, et al. Chest. 2010;138(5):1224-1233.

• Develops in ~2/3 of critically ill patients • Hypoactive or mixed forms most common

• Increased risk

– Benzodiazepines– Extended ventilation– Immobility

• Associated with weakness• Undiagnosed in up to 72%

of cases

Patient FactorsIncreased ageAlcohol useMale genderLiving aloneSmokingRenal disease

EnvironmentAdmission via ED or through transferIsolationNo clockNo daylightNo visitorsNoiseUse of physical restraints

Predisposing DiseaseCardiac diseaseCognitive impairment (eg, dementia)Pulmonary disease

Acute IllnessLength of stayFeverMedicine service Lack of nutritionHypotensionSepsisMetabolic disorders Tubes/cathetersMedications:- Anticholinergics- Corticosteroids- Benzodiazepines

Less Modifiable

More Modifiable

DELIRIUM

Van Rompaey B, et al. Crit Care. 2009;13:R77.Inouye SK, et al. JAMA.1996;275:852-857.Skrobik Y. Crit Care Clin. 2009;25:585-591.

After Hospital Discharge

During the ICU/Hospital Stay

Sequelae of Delirium

• Increased mortality• Longer intubation time• Average 10 additional days in hospital• Higher costs of care

• Increased mortality• Development of dementia • Long-term cognitive impairment• Requirement for care in chronic care facility• Decreased functional status at 6 months

Bruno JJ, Warren ML. Crit Care Nurs Clin North Am. 2010;22(2):161-178.Shehabi Y, et al. Crit Care Med. 2010;38(12):2311-2318.Rockwood K, et al. Age Ageing. 1999;28(6):551-556.Jackson JC, et al. Neuropsychol Rev. 2004;14:87-98.Nelson JE, et al. Arch Intern Med. 2006;166:1993-1999.

Delirium Duration and Mortality

Pisani MA. Am J Respir Crit Care Med. 2009;180:1092-1097.

Kaplan-Meier Survival Curve

Each day of delirium in the ICU increases the hazard of mortality by 10%

P < 0.001

Confusion Assessment Method(CAM-ICU)

or3. Altered level of

consciousness4. Disorganized

thinking

= Delirium

Ely EW, et al. Crit Care Med. 2001;29:1370-1379.Ely EW, et al. JAMA. 2001;286:2703-2710.

1. Acute onset of mental status changes or a fluctuating course

2. Inattention

and

and

Intensive Care Delirium Screening Checklist

1. Altered level of consciousness

2. Inattention

3. Disorientation

4. Hallucinations

5. Psychomotor agitation or retardation

6. Inappropriate speech

7. Sleep/wake cycle disturbances

8. Symptom fluctuation

Bergeron N, et al. Intensive Care Med. 2001;27:859-864.Ouimet S, et al. Intensive Care Med. 2007;33:1007-1013.

Score 1 point for each component present during shift • Score of 1-3 = Subsyndromal Delirium• Score of ≥ 4 = Delirium

Subsyndromal Delirium and Clinical Outcomes

No delirium

(ND)

Subsyndromal (SD)

Clinical (CD)

P value*

ICU Mortality

2.4% 10.6% 15.9% P < 0.001

ICU LOS 2.5 d 5.2 d 10.8 dP < 0.001

Hospital LOS

31.7 d 40.9 d 36.4 dND vs. SD, P = 0.002ND vs. CD, P < 0.001SD vs. CD, P = 0.137

Severity of illness (APACHE II)

12.9 16.7 18.6ND vs. SD, P < 0.001ND vs. CD, P < 0.001SD vs. CD, P < 0.016

*Pairwise comparison

Ouimet S, et al. Intensive Care Med. 2007;33:1007-1013.

What to THINK When Delirium Is Present

• Toxic Situations– CHF, shock, dehydration

– Deliriogenic meds (Tight Titration)

– New organ failure, eg, liver, kidney

• Hypoxemia; also, consider giving Haloperidol or other antipsychotics?

• Infection/sepsis (nosocomial), Immobilization• Nonpharmacologic interventions

– Hearing aids, glasses, reorient, sleep protocols, music, noise control, ambulation

• K+ or Electrolyte problems

See Skrobik Y. Crit Care Clin. 2009;25:585-591.

ICU Sedation: The Balancing Act

Oversedation

• Prolonged mechanical ventilation• Increase length of stay• Increased risk of complications - Ventilator-associated pneumonia• Increased diagnostic testing• Inability to evaluate for delirium

Undersedation

• Patient recall• Device removal• Ineffectual mechanical ventilation• Initiation of neuromuscular blockade• Myocardial or cerebral ischemia• Decreased family satisfaction w/ care

Patient Comfort and Ventilatory Optimization

GOAL


Consequence of Improper Sedation

• Continuous sedation carries the risks associated with oversedation and may increase the duration of mechanical ventilation (MV)1

• MV patients accrue significantly more cost during their ICU stay than non-MV patients2

– $31,574 versus $12,931, P < 0.001• Sedation should be titrated to achieve a

cooperative patient and daily wake-up, a JC requirement1,2

1. Kress JP, et al. N Engl J Med. 2000;342:1471-1477.2. Dasta JF, et al. Crit Care Med. 2005;33:1266-1271.3. Kaplan LJ, Bailey H. Crit Care. 2000;4(suppl 1):P190.

Undersedated3

Oversedated

On Target

15.4%

54.0%

30.6%

Opioids

• Hormonal changes

• Withdrawal symptoms

• Tolerance

• Constipation

• Bradycardia

• Hypotension• Sedation

• Respiratory depression• Analgesia

Adverse EffectsClinical Effects

Benyamin R, et al. Pain Physician. 2008;11(2 Suppl):S105-120.

Fentanyl

Morphine

Remifentanil

Opioid Mechanisms

Brown EN, et al. N Engl J Med. 2010;363(27):2638-2650.

Neurotransmitters

ACh AcetylcholineGlu GlutamateNE Norepinephrine

Analgosedation

• Analgesic first (A-1), supplement with sedative• Acknowledges that discomfort may cause agitation• Remifentanil-based regimen

– Reduces propofol use– Reduces median MV time – Improves sedation-agitation scores

• Not appropriate for drug or alcohol withdrawal

Park G, et al. Br J Anaesth. 2007;98:76-82. Rozendaal FW, et al. Intensive Care Med. 2009;35:291-298.

Analgosedation• 140 critically ill adult patients undergoing mechanical

ventilation in single center• Randomized, open label trial

– Both groups received bolus morphine (2.5 or 5 mg)– Group 1: No sedation (n = 70 patients)- morphine prn– Group 2: Sedation (20 mg/mL propofol for 48 h, 1 mg/mL

midazolam thereafter) with daily interruption until awake (n = 70, control group)

• Endpoints– Primary

• Number of days without mechanical ventilation in a 28-day period

– Other • Length of stay in ICU (admission to 28 days) • Length of stay in hospital (admission to 90 days)

Strøm T, et al. Lancet. 2010;375:475-480.

Analgosedation Intervention

Morphine prn at 2.5 or 5 mg for comfort

Physician consult if patient seemed uncomfortable

Haloperidol prn for delirium

If still uncomfortable, propofol infusion for 6 hours Transitioned back to prn morphine


AnalgosedationResults

• Patients receiving no sedation had – More days without ventilation (13.8 vs 9.6 days, P = 0.02)– Shorter stay in ICU (HR 1.86, P = 0.03)– Shorter stay in hospital (HR 3.57, P = 0.004)– More agitated delirium (N = 11, 20% vs N = 4, 7%, P = 0.04)

• No differences found in– Accidental extubations– Need for CT or MRI– Ventilator-associated

pneumonia


Options for Sedation: Recent Clinical Results

Characteristics of an Ideal Sedative

• Rapid onset of action allows rapid recovery after discontinuation

• Effective at providing adequate sedation with predictable dose response

• Easy to administer

• Lack of drug accumulation

• Few adverse effects

• Minimal adverse interactions with other drugs

• Cost-effective

• Promotes natural sleep

1. Ostermann ME, et al. JAMA. 2000;283:1451-1459.2. Jacobi J, et al. Crit Care Med. 2002;30:119-141.3. Dasta JF, et al. Pharmacother. 2006;26:798-805.4. Nelson LE, et al. Anesthesiol. 2003;98:428-436.

Consider Patient Comorbidities When Choosing a Sedation Regimen

• Chronic pain• Organ dysfunction• CV instability• Substance withdrawal• Respiratory insufficiency• Obesity • Obstructive sleep apnea

GABA AgonistBenzodiazepine Midazolam

• May accumulate with hepatic and/or renal failure

• Anterograde amnesia• Long recovery time• Synergy with opioids • Respiratory depression• Delirium

• Sedation, anxiolysis, and amnesia

• Rapid onset of action (IV)


Olkkola KT, Ahonen J. Handb Exp Pharmacol. 2008;(182):335-360.Riker RR, et al; SEDCOM Study Group. JAMA. 2009;301(5):489-499.

Midazolam Pharmacodynamics: It’s About Time

Carrasco G, et al. Chest. 1993;103:557-564.Bauer TM, et al. Lancet. 1995;346:145-147.

• Highly lipid soluble

• α-OH midazolam metabolite

• CYP3A4 activity decreased in critical illness

• Substantial CYP3A4 variability

0

10

20

30

40

50

60

< 1 1-7 > 7

Extubation

Alertness Recovery

Sedation Time (days)

Tim

e to

En

dp

oin

t (h

)

Clinical Effects Sedation, anxiolysis, and

amnesia Commonly used for long-

term sedation

Adverse Effects Metabolic acidosis (propylene glycol

vehicle toxicity) Retrograde and anterograde amnesia Delirium

GABA AgonistBenzodiazepine Lorazepam

Olkkola KT, Ahonen J. Handb Exp Pharmacol. 2008;(182):335-360.Wilson KC, et al. Chest. 2005;128(3):1674-1681.

Risk of Delirium With Benzodiazepines

Pandharipande P, et al. J Trauma. 2008;65:34-41. Pandharipande P, et al. Anesthesiol. 2006:104:21-26.

Lorazepam Dose, mgD

elir

ium

Ris

k

MedicationTransitioning to Delirium Only OR (95% CI)

P Value

Lorazepam 1.2 (1.1-1.4) 0.003

Midazolam 1.7 (0.9-3.2) 0.09

Fentanyl 1.2 (1.0-1.5) 0.09

Morphine 1.1 (0.9-1.2) 0.24

Propofol 1.2 (0.9-1.7) 0.18

GABA Agonist Propofol

• Sedation• Hypnosis• Anxiolysis• Muscle relaxation• Mild bronchodilation• Decreased ICP• Decreased cerebral metabolic rate• Antiemetic

Ellett ML. Gastroenterol Nurs. 2010;33(4):284-925.Lundström S, et al. J Pain Symptom Manage. 2010;40(3):466-470.

Clinical Effects Adverse Effects

• Pain on injection• Respiratory depression• Hypotension• Decreased myocardial contractility• Increased serum triglycerides• Tolerance• Propofol infusion syndrome• Prolonged effect with high adiposity• Seizures (rare)

Central Mechanisms of Propofol


Monoaminergic pathwaysCholinergic pathwaysLateral hypothalamus neurons

NeurotransmittersACh AcetylcholineDA DopamineGABA γ-Aminobutyric acidGAL GalaninGlu GlutamateHis HistamineNE Norepinephrine5HT Serotonin

Propofol Has Greater Sedation Efficacy Than Continuous Midazolam

Walder B, et al. Anesth Analg. 2001;92:975-983.

Efficacy of Sedation*Duration of

Adequate Sedation

* Avg adequate sedation time avg total sedation time

n = 18 trials n = 15 trials

Walder B, et al. Anesth Analg. 2001;92:975-983.

Continuous Midazolam Has Longer Weaning Time From MV Than Propofol

Data from 8 RCT

Scheduled Intermittent Lorazepam vs Propofol with Daily Interruption in MICU Patients

Lorazepam

n = 64

Propofol

n = 68

P value

Ventilator days 8.4 5.8 0.04

ICU LOS 10.4 8.3 0.20

APACHE II 22.9 20.7 0.05

Daily sedation dose

11.5 mg 24.4 mcg/kg/min _

Morphine dose (mg/day)

10.7 31.6 0.001

Use of haloperidol 12% 9% 0.80

Carson SS, et al. Crit Care Med. 2006;34:1326-1332.

a2 Agonist Clonidine

•Bradycardia•Dry mouth•Hypotension•Sedation

•Antihypertensive •Analgesia•Sedation•Decrease sympathetic activity•Decreased shivering


Kamibayashi T, et al. Anesthesiol. 2000;93:1345-1349.Bergendahl H, et al. Curr Opin Anaesthesiol. 2005;18(6):608-613. Hossmann V, et al. Clin Pharmacol Ther. 1980;28(2):167-176.

?

a2A

a2C

a2A

a2A

Anxiolysis

? a2B

a2B

X

a2B

X

Adapted from Kamibayashi T, Maze M. Anesthesiology. 2000;93:1346-1349.

Physiology of a2 Adrenoceptors

a2A

a2 Agonist Dexmedetomidine

•Hypotension•Hypertension•Nausea•Bradycardia •Dry mouth

• Peripheral vasoconstriction at high doses

•Antihypertensive•Sedation•Analgesia•Decreased shivering•Anxiolysis•Patient arousability•Potentiate effects of opioids,

sedatives, and anesthetics

•Decrease sympathetic activity


Kamibayashi T, et al. Anesthesiol. 2000;93:1345-1349.Bhana N, et al. Drugs. 2000;59(2):263-268.

Central Mechanisms of Dexmedetomidine

Neurotransmitters

ACh AcetylcholineDA DopamineGABA γ-Aminobutyric acidGAL GalaninGlu GlutamateHis HistamineNE Norepinephrine5HT Serotonin


Maximizing Efficacy of Targeted Sedation and Reducing Neurological Dysfunction (MENDS)

• Double-blind RCT of dexmedetomidine vs lorazepam• 103 patients (2 centers)

– 70% MICU, 30% SICU patients (requiring mechanical ventilation > 24 hours)

– Primary outcome: Days alive without delirium or coma

• Intervention– Dexmedetomidine 0.15–1.5 mcg/kg/hr– Lorazepam infusion 1–10 mg/hr– Titrated to sedation goal (using RASS) established by ICU team

• No daily interruption

Pandharipande PP, et al. JAMA. 2007;298:2644-2653.

MENDS: Dexmedetomidine vs Lorazepam


Dexmedetomidine resulted in more days alive without delirium or coma (P = 0.01) and a lower prevalence of coma (P < 0.001) than lorazepam

Dexmedetomidine resulted in more time spent within sedation goals than lorazepam (P = 0.04)

Differences in 28-day mortality and delirium-free days were not significant

Day

s

Lorazepam n = 51

Dexmedetomidine n = 5202

46

81

01

2

P = 0.011

Delirium/Coma-Free Days

Delirium-Free Days

P = 0.086 P < 0.001

Coma-Free Days

MENDS Delirium: All Patients

Pandharipande PP, et al. Crit Care. 2010;14:R38.

MENDS: Survival in Septic ICU Patients

Pandharipande PP, et al. Crit Care. 2010;14:R38.

MENDS Trial: Safety Profile

OutcomeLorazepam

(n = 50)Dexmedetomidine

(n = 51)P-Value

Lowest SBP 97 (88,102) 96 (88,105) 0.58

Ever hypotensive (SBP < 80) 20% 25% 0.51

Days on vasoactive meds 0 (0,3) 0 (0,2) 0.72

Sinus bradycardia (< 60/min) 4% 17% 0.03

Heart rate < 40 2% 2% 0.99

Self-extubations (reintubations) 2 (2) 4 (3) 0.41


OutcomeMidazolam(n = 122)

Dexmedetomidine(n = 244)

P-Value

Time in target sedation range, % (primary EP) 75.1 77.3 0.18

Duration of sedation, days 4.1 3.5 0.01

Time to extubation, days 5.6 3.7 0.01

Delirium prevalence 93 (76.6%) 132 (54%) 0.001

Delirium-free days 1.7 2.5 0.002

Patients receiving open-label midazolam 60 (49%) 153 (63%) 0.02

• Double-blind, randomized, multicenter trial comparing long-term (> 24 hr) dexmedetomidine (dex, n = 244) with midazolam (mz, n = 122)

• Sedatives (dex 0.2-1.4 μg/kg/hr or mz 0.02-0.1 mg/kg/hr) titrated for light sedation (RASS -2 to +1), administered up to 30 days

• All patients underwent daily arousal assessments and drug titration Q 4 hours

Riker RR, et al. JAMA. 2009;301:489-499.

SEDCOM: Dexmedetomidine vs Midazolam

Midazolam

Dexmedetomidine

Dexmedetomidine versus Midazolam, P < 0.001

Reduced Delirium Prevalence with Dexmedetomidine vs Midazolam

SEDCOM

Sample Size 118 229 109 206 92 175 77 134 57 92 42 60 44 34

Treatment Day

0

20

40

60

80

100

Baseline 1 2 3 4 5 6

Pa

tien

ts W

ith

De

liriu

m, %


SEDCOM Trial:Safety Outcomes

OutcomeMidazolam(n = 122)

Dexmedetomidine(n = 244)

P-Value

Bradycardia 18.9% 42.2% 0.001

Tachycardia 44.3% 25.4% 0.001

Hypertension requiring intervention 29.5% 18.9% 0.02

Hyperglycemia 42.6% 56.6% 0.02

Infections 19.7% 10.2% 0.02


Bradycardia needing treatment 0.8% 4.9% 0.07

Comparison of Clinical Effects

1. Blanchard AR. Postgrad Med. 2002;111:59-74.2. Kamibayashi T, et al. Anesthesiol. 2000;95:1345-1349.3. Maze M, et al. Anesthetic Pharmacology: Physiologic Principles and Clinical Practice. Churchill Livingstone; 2004.4. Maze M, et al. Crit Care Clin. 2001;17:881-897.

XXAlleviate anxiety1,2

XXControl delirium1-4

XFacilitate ventilation during weaning2-4

XPromote arousability during sedation2-4

XXAnalgesic properties1-4

XXXXXSedation

Haloperidola2 AgonistsOpioidsPropofolBenzodiazepines

X

Comparison of Adverse Effects

1. Harvey MA. Am J Crit Care. 1996;5:7-18.2. Aantaa R, et al. Drugs of the Future. 1993;18:49-56.3. Maze M, et al. Crit Care Clin. 2001;17:881-897.

XXXRespiratory depression 1

XXfentanylBradycardia 1

morphineTachycardia 1

XXXDeliriogenic

XConstipation 1

XXXXXHypotension 1-3

X *XXProlonged weaning 1

HaloperidolOpioidsPropofolBenzodiazepines

*Excluding remifentanil

X

a2 Agonists

Costs of Drug Therapy

• Acquisition• Waste disposal• Preparation• Distribution• Administration (Nursing time)• Toxicity cost (ADRs)• Monitoring (Time, lab, and diagnostic tests)• Downstream issues (infections, adverse events,

ICU stay, ventilator time, etc)

Dasta JF, Kane-Gill S. Crit Care Clin. 2009;25:571-583.

Drug Acquisition Cost(70 kg patient, per day)

• Lorazepam 3 mg/hr:$35

• Midazolam 5 mg/hr$42

• Propofol 30 mcg/kg/min:$150

• Dexmedetomidine 0.5 mcg/kg/hr: $274

Tufts Medical Center 2009 Pricing

Propofol Is More Cost-Effective Than Lorazepam

`

Cox CE, et al. Crit Care Med. 2008;36:706-714.

Propofol less expensive

Lorazepam moreeffective

2 0.5

HighLow

$9,488$1,825

$631

5%75%

$1,892

20% 0%c

0%20%

MidazolamLorazepam

High Low

$11.37 $60.77

4,347 949

$7.82$0.81

423

Ratio of propofol to lorazepam MV days

Average duration of MV

Cost of ICU day

Hospital mortality

Cost of hospital ward day

Probability of propofol intolerance

Probability of lorazepam intolerance

Crossover group from propofol

Physician costs

Cost of propofol

Daily propofol dose, mg

Cost of lorazepam

Daily lorazepam dose, mg

-$35 -$30 -$25 -$20 -$15 -$10 -$5 $0 $5 $10 $15 $20 $25 $30 $35

Cost Difference Between Lorazepam and Propofol ($ Thousands)

MENDS Trial: Cost of Care

Component Lorazepam Dexmedetomidine P-value

Pharmacy 20.6 (10,42) 27.4 (16,46) 0.15

Respiratory 2.9 (2,6) 3.5 (2,7) 0.35

ICU cost 59.5 (36,83) 61.4 (37,108) 0.32

$ – Costs represented in thousands, US dollars (Median, IQR)


40,36536,571

7,022

50,149

40,501

10,885

0

10,000

20,000

30,000

40,000

50,000

60,000

Total ICU cost ICU component Mechanical ventilationcomponent

Dol

lars

DEX MID

SEDCOM Cost of Care

Dasta JF, et al. Crit Care Med. 2010;38:497-503.

P < 0.01 P < 0.05

P < 0.01

• Median drug costs• Dex $1,166• Midazolam $60

• Total ICU patient savings with Dex: $9679

• Reduced ICU stay • Reduced MV

Strategies to Reduce the Duration of Mechanical Ventilation in Patients Receiving Continuous Sedation

Nurse-Driven Sedation Protocol• RCT of RN-driven protocol vs non-protocol sedation care in 321 MICU patients

requiring mechanical ventilation• The protocol:

– Assess pain first– Correct other etiologies for agitation– Use a sedation score to titrate sedatives– Use intermittent sedation first– Actively down-titrated sedation even when patient was at “goal”

Brook AD, et al Crit Care Med. 1999;27:2609-2615.

Pharmacist-Driven Sedation Protocol

• 156 MICU patients prescribed continuous sedation • Protocol encouraged 25% down-titration when patients more

sedated than goal• Before/after design evaluating impact of pharmacist promoting

protocol on at least a daily basis

Marshall J, et al. Crit Care Med. 2008;36:427-433.

Med

ian

Day

s o

f M

ech

anic

al V

enti

lati

on

5.2

6.9

P < 0.001

0123456789

10

Pharmacist-Led Control

Daily Sedation Interruption Decreases Duration of Mechanical Ventilation

• Hold sedation infusion until patient awake and then restart at 50% of the prior dose

• “Awake” defined as 3 of the following 4:– Open eyes in response to

voice– Use eyes to follow

investigator on request– Squeeze hand on request– Stick out tongue on request

Kress JP, et al. N Engl J Med. 2000;342:1471-1477.

• Fewer diagnostic tests to assess changes in mental status

• No increase in rate of agitated-related complications or episodes of patient-initiated device removal• No increase in PTSD or cardiac ischemia

To determine the efficacy and safety of a protocol linking:

spontaneous awakening trials (SATs) & spontaneous breathing trials (SBTs)

– Ventilator-free days– Duration of mechanical ventilation– ICU and hospital length of stay– Duration of coma and delirium– Long-term neuropsychological outcomes

ABC Trial: Objectives

Girard TD, et al. Lancet. 2008;371:126-134.

ABC Trial: Main Outcomes

Outcome* SBT SAT+SBT P-value†

Ventilator-free days 12 15 0.02

Time-to-Event, days

Successful extubation 7.0 5 0.05

ICU discharge 13 9 0.02

Hospital discharge 19 15 0.04

Death at 1 year, n (%) 97 (58%) 74 (44%) 0.01

Days of brain dysfunction

Coma 3.0 2.0 0.002

Delirium 2.0 2.0 0.50

*Median, except as noted†SBT compared with SAT+SBT


ABC Trial: 1 Year Follow-Up


Despite Proven Benefits of Spontaneous Awakening/Daily Interruption Trials, They Are Not

Standard of Practice at Most Institutions

Canada – 40% get SATs (273 physicians in 2005)1

US – 40% get SATs (2004-05)2

Germany – 34% get SATs (214 ICUs in 2006)3

France – 40–50% deeply sedated with 90% on

continuous infusion of sedative/opiate4

1. Mehta S, et al. Crit Care Med. 2006;34:374-380.2. Devlin J. Crit Care Med. 2006;34:556-557.3. Martin J, et al. Crit Care. 2007;11:R124.4. Payen JF, et al. Anesthesiology. 2007;106:687-695.

Number of respondents (%)

Barriers to Daily Sedation Interruption(Survey of 904 SCCM members)

Clinicians preferring propofol were more likely use daily interruption than those preferring benzodiazepines (55% vs 40% , P < 0.0001)

Tanios MA, et al. J Crit Care. 2009;24:66-73.

0 10 20 30 40 50 60 70

Leads to PTSD

Leads to cardiac ischemia

No benefit

Difficult to coordinate with nurse

Leads to respiratory compromise

Compromises patient comfort

Poor nursing acceptance

Increased device removal

#1 Barrier

#2 Barrier

#3 Barrier

Early Mobilization Trial Design

• 104 sedated patients with daily interruption – Early exercise and mobilization (PT & OT; intervention; n = 49)– PT & OT as ordered by the primary care team (control; n = 55)

• Primary endpoint: Number of patients returning to independent functional status at hospital discharge– Ability to perform 6 activities of daily living – Ability to walk independently

• Assessors blinded to treatment assignment • Secondary endpoints

– Duration of delirium during first 28 days of hospital stay – Ventilator-free days during first 28 days of hospital stay

Schweickert WD, et al. Lancet. 2009;373:1874-1882.

Early Mobilization Protocol: Result


Return to independent functional status at discharge– 59% in intervention group– 35% in control group (P = 0.02)

0.0141%28%Time in Hosp. with Delirium

0.0257%33%Time in ICU with Delirium

0.0342ICU/Hosp Delirium (days)

P-ValueControl

(n = 55)

Intervention

(n = 49)Variable


Animation = Less Delirium

Procedural SedationMajor Applications

• Surgical– CV surgery– Neurosurgery– Bariatric surgery

• Endoscopic– Bronchoscopy– Fiberoptic intubation– Colonoscopy

Standardized Monitoring• Hemodynamic

– ECG– Blood pressure

• Respiration– Oxygenation (SpO2 by pulse oximetry, supplemental oxygen)

– Ventilation (end tidal CO2, EtCO2)

• Temperature (risk of hypothermia)• Higher risk at remote locations

– Inadequate oxygenation/ventilation– Oversedation– Inadequate monitoring

Eichhorn V, et al. Curr Opin Anaesthesiol. 2010;23(4):494-499.

Factors Jeopardizing Safety

• Risk of major blood loss• Extended duration of surgery (> 6 h)• Critically ill patients (evaluate and document prior to

procedure) • Need for specialized expertise or equipment (cardio-

pulmonary bypass, thoracic or intracranial surgery)• Supply and support functions or resources are limited• Inadequate postprocedural care• Physical plant is inappropriate or fails to meet

regulatory standards

Eichhorn V, et al. Curr Opin Anaesthesiol. 2010;23(4):494-499.

Sedation/Analgesia for Traumatic Brain Injury

Goal: reduce ICP by decreasing pain, agitation

Saiki RL. Crit Care Nurs Clin North Am. 2009;21:549-559.

Agent Advantages Considerations

Propofol

• Short acting• Reduces cerebral

metabolism, O2 consumption

• Improves ICP after 3d

• Propofol infusion syndrome

Barbiturates• Reduce ICP• Neuroprotection

• Interfere with neuro exam• Hypotension, reduced CBF• OCs not improved with severe TBI

Fentanyl vs Dexmedetomidine in Bariatric Surgery

• 20 morbidly obese patients• Roux-en-Y gastric bypass surgery• All received midazolam, desflurane to maintain BIS at

45–50, and intraoperative analgesics– Fentanyl (n = 10) 0.5 µg/kg bolus, 0.5 µg/kg/h– Dexmedetomidine (n = 10) 0.5 µg/kg bolus, 0.4 µg/kg/h

• Dexmedetomidine associated with – Lower desflurane requirement for BIS maintenance– Decreased surgical BP and HR – Lower postoperative pain and morphine use (up to 2 h)

Feld JM, et al. J Clin Anesthesia. 2006;18:24-28.

• 80 morbidly obese patients• Gastric banding or bypass surgery• Prospective dose ranging study• Medication

– Celecoxib 400 mg po

– Midazolam 20 µg/kg IV– Propofol 1.25 mg/kg IV– Desflurane 4% inspired– Dexmedetomidine 0, 0.2, 0.4, 0.8 µg/kg/h IV

Dexmedetomidine in Bariatric Surgery

Tufanogullari B, et al. Anesth Analg. 2008;106:1741-1748.

• More dex 0.8 patients required rescue phenylephrine for hypotension than control pts (50% vs 20%, P < 0.05)

• All dex groups – Required less desflurane (19%–22%)– Had lower MAP for 45’ post-op– Required less fentanyl after awakening (36%–42%)– Had less emetic symptoms post-op

• No clinical difference – Emergence from anesthesia– Post-op self-administered morphine and pain scores – Length of stay in post-anesthesia care unit– Length of stay in hospital

Dexmedetomidine in Bariatric Surgery: Results

Tufanogullari B, et al. Anesth Analg. 2008;106:1741-1748.

Sedation for Endoscopy

• Desirable qualities– Permits complete

diagnostic exam– Safe – Diminishes memory of

the procedure– Permits rapid discharge

after procedure

• Risk factors– Depth of sedation– ASA status– Medical conditions– Pregnancy – Difficult airway mgt– Extreme age– Rapid discharge time

Runza M. Minerva Anestesiol. 2009;75:673-674.

Propofol vs Combined Sedationin Flexible Bronchoscopy

• Randomized non-inferiority trial• 200 diverse patients received propofol or midazolam/hydrocodone• 1o endpoints

– Mean lowest SaO2

– Readiness for discharge at 1h• Result

– No difference in mean lowest SaO2

– Propofol group had • Higher readiness for discharge score (P = 0.035)• Less tachycardia• Higher cough scores

• Conclusion: Propofol is a viable alternative to midazolam/ hydrocodone for FB

Stolz D, et al. Eur Respir J. 2009;34:1024-1030.

Fiberoptic Intubation

Agent Class

Example Advantages Considerations

GABA agonist

Benzodiazepine Midazolam

•Quick onset• Injection not painful•Short duration

• Not analgesic• Airway reflexes persist

GABA agonist

Benzodiazepine Propofol

•Quick onset • Respiratory depression• Unconsciousness• Decreased bp, cardiac

output• Increased HR

Opioid FentanylRemifentanil

•Analgesic•Cough suppressive

• Respiratory depression

a2 Agonist Dexmedetomidine •Pt easily arousable•Anxiolytic •Analgesic•No respir. depression

• Transient hypertension• Hypotension • Bradycardia

Summary courtesy of Pratik Pandharipande, MD.

Prevention and Treatment of Delirium in the ICU

Before Considering a Pharmacologic Treatment for Delirium…

• Have the underlying causes of delirium been identified and reversed/treated?

• Have non-pharmacologic treatment strategies been optimized?

• Does your patient have delirium?– Hyperactive– Hypoactive– Mixed hyperactive-hypoactive

Inouye SK, et al. N Engl J Med. 1999;340:669-676.

Dopamine Antagonist Haloperidol

• Adverse CV effects include QT interval prolongation

• Extrapyramidal symptoms, neuroleptic malignant syndrome (rare)1

• Does not cause respiratory depression1

• Dysphoria2• Hypnotic agent with antipsychotic properties1


1. Harvey MA. Am J Crit Care. 1996;5:7-16.2. Crippen DW. Crit Care Clin. 1990;6:369-392.

– For treatment of delirium in critically ill adults1

• Metabolism altered by drug-drug interactions2

Use of Haloperidol Is an Independent Predictor for Prolonged Delirium

Pisani MA, et al. Crit Care Med. 2009;37:177-183.

Potential Advantages of Atypical Antipsychotics vs Conventional Antipsychotics

• Decreased extrapyramidal effects

• Little effect on the QTc interval (with the exception of ziprasidone)

• Less hypotension/fewer orthostatic effects

• Less likely to cause neuroleptic malignant syndrome

• Unlikely to cause laryngeal dystonia

• Lower mortality when used in the elderly to treat agitation related to dementia

Tran PV, et al. J Clin Psychiatry. 1997;58:205-211.Lee PE, et al. J Am Geriatr Soc. 2005;53:1374-1379.Wang PS, et al. N Engl J Med. 2005;353:2235-2341.

Use of Atypical Antipsychotic Therapy Is Increasing

Ely EW, et al. Crit Care Med. 2004;32:106-112.Patel RP, et al. Crit Care Med. 2009;37:825-832.

01020

304050

607080

90

Atypical anti-psychotics

Benzodiazepines

Haloperidol

Propofol

2001

2007

http://www.canhr.org/ToxicGuide/Media/Articles/FDA%20Alert%20on%20Antipsychotics.pdf

Antipsychotic TherapyRule Out Dementia

• Elderly patients with dementia-related psychosis treated with conventional or atypical antipsychotic drugs are at an increased risk of death

• Antipsychotic drugs are not approved for the treatment of dementia-related psychosis. Furthermore, there is no approved drug for the treatment of dementia-related psychosis

• Physicians who prescribe antipsychotics to elderly patients with dementia-related psychosis should discuss this risk of increased mortality with their patients, patients’ families, and caregivers

Drug Specificity:Comparative Receptor Binding Profiles

Adapted from Gareri P, et al. Clin Drug Invest. 2003;23:287-322.

Olanzapine

Risperidone

Quetiapine

Ziprasidone

Haloperidol

D1D25HT2A

5HT1A

A1

A2

H1

D1D2

5HT2A

A1

A2H1

M

D2 D1

5HT2A

5HT1AA1 D1 D2

5HT2A

5HT1A

A1A2H1 D1

D2

5HT2A

5HT1A

A1

Rationale-based PharmacotherapyImportant Principles

Adapted from Weiden P, et al. J Clin Psychiatry. 2007;68:5-46.

Anti-EPS?5-HT2A

EPS, prolactin elevation, antipsychoticD2

Satiety blockade5-HT2C

Deficits in memory and cognition, dry mouth, constipation, tachycardia, blurred vision

M1

Hypotensionα1-adrenergic

Sedation, weight gain, postural dizzinessH1

Effects of Receptor BlockadeReceptors

• Design: Double-blind, placebo-controlled, randomized trial • Setting: 6 tertiary medical centers • Intervention:

– Haloperidol (5 mg) vs ziprasidone (40 mg) vs placebo – Max 14 days– Dose interval increased if CAM-ICU negative– Could give IM if NPO up to max 8 doses– Oversedation: ↓dose frequency when RASS ≥ 2 levels above target

(after holding sedation therapy)– If delirium reoccurred after d/c of study drug then restarted at last

effective dose (and weaned again as per above)• Primary outcome:

– Number of days patient alive without delirium or coma during the 21-day study period• Delirium = + CAM-ICU • Coma = RASS (-4) [ie, responsive to physical but not verbal stimulation] or RASS

(-5) [ie, not responsive to either]

Modifying the Incidence of Delirium (MIND) Trial

Girard TD, et al. Crit Care Med. 2010;38:428-437.

Girard TD, et al. Crit Care Med. 2010;38:428-437.

MIND Trial Results

0.56000Average extrapyramidal symptoms score

0.816 (17)4 (13)4 (11)21-day mortality, n (%)

0.70

0.68

7.3

15.4

9.6

13.5

11.7

13.8

Length of stay, days

ICU

Hospital

0.2512.512.07.8Ventilator-free days

0.91716470% of days accurately sedated

0.90222Coma days

0.2821 (58)23 (77)24 (69)Delirium resolution on study drug, n(%)

0.93444Delirium days

0.6612.515.014.0Delirium/coma-free days

P-valuePlacebo,

n = 36

Ziprasidone,

n = 30

Haloperidol, n = 35

Outcome

• Double-blind, placebo-controlled, randomized trial • 3 academic medical centers• Intervention

– Quetiapine 50 mg PO/NGT twice daily titrated to a maximum of 200 mg twice daily) vs placebo

– PRN IV haloperidol protocolized and encouraged in each group– Oversedation: hold study drug when SAS ≤ 2 (after holding sedation

therapy)

• Primary outcome – Time to first resolution of delirium (ie, first 12-hour period when

ICDSC ≤ 3)

Devlin JW, et al. Crit Care Med. 2010;38:419-427.

Quetiapine for DeliriumStudy Design

222 patients excluded36 subjects randomized

Quetiapine 50 mg NG bid(n = 18)

Placebo 50 mg NG bid(n = 18)

As-needed haloperidol, usual sedation and analgesia therapy at physician’s discretion

Dose TitrationIncrease quetiapine or placebo dose by 50 mg every 12 hours dailyif the subject received ≥ 1 dose of as needed haloperidol in prior 24 hours.(Maximum dose = 200 mg every 12 hours)

258 patients with delirium (ICDSC ≥ 4) tolerating enteral nutrition

Discontinuation of study drug1. No signs of delirium2. 10 days of therapy had elapsed3. ICU discharge prior to 10 days of therapy4. Serious adverse event potentially attributable to the study drug


TIME TO DELIRIUM RESOLUTION

Surv

ival

Dis

trib

utio

n Fu

nctio

n

0.00

0.25

0.50

0.75

1.00

daydelre

0 2 4 6 8 10

STRATA: DSMBassig=1Censored DSMBassig=1DSMBassig=2

Placebo

Quetiapine

Pro

po

rtio

n o

f P

atie

nts

wit

h D

elir

ium

Day During Study Drug Administration

Log-Rank P = 0.001

Quetiapine added to as-needed haloperidol results in faster delirium resolution, less agitation, and a greater rate of transfer to home or rehabilitation.


Patients with First Resolution of Delirium

The Interaction Between Sedation, Critical Illness and Sleep in the ICU

Sleep Abnormalities in the ICU

% time in light sleep increased (NREM stages 1 and 2) % time in deep sleep decreased [slow wave sleep (SWS) and REM sleep)

Sleep fragmentation increased

Friese R. Crit Care Med. 2008;36:697-705.Weinhouse GL, Watson PL. Crit Care Clin. 2009;25:539-549.

Effect of Common Sedatives and Analgesics on Sleep

There is little evidence that administration of sedatives in

the ICU achieves the restorative function of normal sleep

• Benzodiazepines

↑ Stage 2 NREM

↓ Slow wave sleep (SWS) and REM• Propofol

↑ Total sleep time without enhancing REM

↓ SWS• Analgesics

– Abnormal sleep architecture• Dexmedetomidine

↑ SWS

Weinhouse GL, et al. Sleep. 2006;29:707-716.Nelson LE, et al. Anesthesiology. 2003;98:428-436.

Strategies to Boost Sleep Quality in the ICU

• Optimize environmental strategies• Avoid benzodiazepines• Consider dexmedetomidine• Zolpidem and zopiclone are GABA receptor agonists

but do not decrease SWS like the benzodiazepines • Sedating antidepressants (eg, trazodone) or

antipsychotics may offer an option in non-intubated patients

• Melatonin may improve sleep of COPD patients in medical ICU (1 small RCT)

• Don’t disturb sleeping patients at night

Weinhouse GL, Watson PL. Crit Care Clinics. 2009;25:539-549.Faulhaber J, et al. Psychopharmacology. 1997;130:285-291.Shilo L, et al. Chronobiol Int. 2000;17:71-76.

American College of Critical Care Medicine (ACCM) Guidelines

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

• Pertains to patients older than 12 years during M V• Areas of focus

– Assessment for pain, delirium– Physiological monitoring – Pharmacologic tools

• Most recommendations grade B or C


Conclusions

• Oversedation in the ICU is common; associated with negative sequelae

• Monitor and treat pain and delirium prior to administering sedation therapy

• Analgosedation has been shown to improve outcomes; consider sedation only if necessary

• Titrate all sedative medications using a validated assessment tool to keep patients comfortable and arousable if possible

• Monitor for adverse events

Conclusions

• ICU sedation should use protocols that include a down-titration and/or daily interruption strategy coupled with a spontaneous breathing trial

• Multiple sedatives are available• Propofol and dexmedetomidine will liberate patients from

mechanical ventilation faster than benzodiazepine therapy (even when administered intermittently) and are associated with less delirium

• Use of benzodiazepines should be minimized

Conclusions

• Cost of care calculations should consider the overall costs, not just drug acquisition costs

• Early mobility in ICU patients decreases delirium and improves functional outcomes at discharge

• Consider non-pharmacological management of delirium and reduce exposure to risk factors

• Typical and atypical antipsychotic medications may be used to treat delirium if non-pharmacological interventions are not adequate

assessing and managing sedation in the intensive care and the perioperative settings

Documents

intensive care

j respir crit care

prolonged sedation

acute care setting

analgesiaprevent pain

analgesia management

pain8faces pain scale

behavioral pain scale