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

Acute Medical or Surgical Illness Predisposing and Causative Conditions Mechanical Ventilation Invasive, Medical, & Nursing Interventions Medications Underlying Medical Conditions Hospital Acquired Illness ICU Environmental Influences Management of predisposing & causative conditions Anxiety Pain Delirium Interventions Agitation Sedative, analgesic, antipsychotic, medications

Dangerous agitation Agitation, vent dyssynchrony Pain, anxiety Calm Alert Free of pain and anxiety Lightly sedated Deeply sedated Unresponsive

Spectrum of Distress/Comfort/Sedation

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

Item Facial expression Upper limbs Compliance with ventilation Description Relaxed Partially tightened (eg, brow lowering) Fully tightened (eg, eyelid closing) Grimacing No movement Partially bent Fully bent with finger flexion Permanently retracted Tolerating movement Coughing but tolerating ventilation for most of the time Fighting ventilator Unable to control ventilation Score 1 2 3 4 1 2 3 4 1 2 3 4 Payen JF, et al.

Crit Care Med.

2001;29(12):2258-2263.

BPS Validation

Sedated Mechanically Ventilated Patients Is BPS Sensitive to Pain?

□ Not painful n = 104 ● Painful n = 134 ▲ Retested painful n = 31

Is BPS Reproducible?

Weighted  = 0.74,

P

< 0.01

*

P

†

P

< 0.05 vs rest period < 0.05 vs not painful Payen JF, et al.

Crit Care Med.

2001;29:2258 –2263.

Exposed to Pain

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 with Analgesic Administration in the ICU

• Fewer patients assessed for pain, more treated with analgesics in ICUs without analgesia protocols compared with ICUs with protocols 1 • Pain scoring used in 21% of surveyed ICUs in 2006 2 100 80 60 40 20 0

Assessed

60 87

Treated

25 * 92 *

Protocol No Protocol

* P

< 0.01 vs ICUs using a protocol 1. Payen JF, et al.

Anesthesiol.

2007;106:687-695.

2. Martin J, et al.

Crit Care.

2007;11:R124.

Assessing Pain Reduces Sedative/Hypnotic Use

Any sedative Midazolam Propofol Other What proportion of MV ICU patients received sedative or hypnotic medication?

Day 2 Pain Assessment?

No (n = 631) Yes (n = 513) 86% 65% 75% 57% 21% 6% 17% 4%

P-value

< 0.01

< 0.01

0.06

0.03

Payen JF, et al.

Anesthesiology

. 2009;111;1308-1316.

Assessing Pain Improves Some Outcomes

Outcome

ICU Mortality ICU LOS MV duration Vent-acquired pneumonia

Day 2 Pain Assessment?

No Yes 22% 18 d 11 d 19% 13 d 8 d 24% 16%

Unadj.

OR

0.91

1.70

1.87

0.61

P-value Adjusted OR P-value

0.69

< 0.01

< 0.01

< 0.01

1.06

1.43

1.40

0.75

0.71

0.04

0.05

0.21

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

Payen JF, et al.

Anesthesiology

. 2009;111:1308-1316.

Maintaining Patients at the Desired Sedation Goal

Sedation-Agitation Scale (SAS)

Score

7 6 5 4 3 2 1

State

Dangerous Agitation Very Agitated Agitated Calm and Cooperative Sedated Very Sedated Unarousable

Behaviors

Pulling at ET tube, climbing over bedrail, striking at staff, thrashing side-to-side Does not calm despite frequent verbal reminding, requires physical restraints Anxious or mildly agitated, attempting to sit up, calms down to verbal instructions Calm, awakens easily, follows commands Difficult to arouse, awakens to verbal stimuli or gentle shaking but drifts off Arouses to physical stimuli but does not communicate or follow commands Minimal or no response to noxious stimuli, does not communicate or follow commands Riker RR, et al.

Crit Care Med.

1999;27:1325-1329.

Brandl K, et al.

Pharmacotherapy.

2001;21:431-436.

Score

+ 4 + 3 + 2 + 1 0 -1 -2 -3 -4 -5

Richmond Agitation Sedation Scale (RASS)

State

Combative Very agitated Agitated Restless Alert and calm Drowsy Light sedation Moderate sedation Deep sedation Unarousable eye contact > 10 sec eye contact < 10 sec no eye contact physical stimulation no response even with physical

Verbal Stimulus Physical Stimulus

Ely EW, et al.

JAMA

. 2003;289:2983-2991.

Sessler CN, et al.

Am J Respir Crit Care Med.

2002;166(10):1338-1344.

SAS RASS Ramsay MAAS

Sedation Scale Reliability

Riker, 1999 Brandl, 2001

r 2

0.83

Sessler, 2002 Ely, 2003 Riker, 1999 Ely, 2003 Olson, 2007 Devlin, 1999 Hogg, 2001

Kappa

0.92

0.93

0.80

0.91

0.88

0.94

0.28

0.83

0.81

MSAT Weinert, 2004 0.72-0.85

Correlating Sedation Assessment with Sedative Administration in the ICU

• 1381 ICU patients included in an observational study of sedation and analgesia practices 1 • Fewer patients assessed, more treated with sedatives in ICUs without sedation protocols compared with ICUs with protocols 1 • Use of sedation protocols and scores increased between 2002 and 2006 2 80 70 60 50 40 30 20 10 0

Assessed

56 68

Protocol Treated

31 * 76 *

No Protocol

* P

< 0.01 vs ICUs using a protocol 1. Payen JF, et al.

Anesthesiol.

2007;106:687-695.

2. Martin J, et al.

Crit Care.

2007;11:R124.

The Importance of Preventing and Identifying Delirium

Cardinal Symptoms of Delirium and Coma

Morandi A, et al.

Intensive Care Med

. 2008;34:1907-1915.

ICU Delirium

• 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 Vasilevskis EE, et al.

Chest

. 2010;138(5):1224-1233.

Patient Factors

Increased age Alcohol use Male gender Living alone Smoking Renal disease

Less Modifiable Predisposing Disease

Cardiac disease Cognitive impairment (eg, dementia) Pulmonary disease

DELIRIUM Environment

Admission via ED or through transfer Isolation No clock No daylight No visitors Noise Use of physical restraints

More Modifiable

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.

Acute Illness

Length of stay Fever Medicine service Lack of nutrition Hypotension Sepsis Metabolic disorders Tubes/catheters Medications: - Anticholinergics - Corticosteroids - Benzodiazepines

Sequelae of Delirium

During the ICU/Hospital Stay

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

After Hospital Discharge

• 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

Kaplan-Meier Survival Curve

P

< 0.001

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

Am J Respir Crit Care Med

. 2009;180:1092-1097.

Confusion Assessment Method (CAM-ICU)

1. Acute onset of mental status changes or a fluctuating course and 2. Inattention and 3. Altered level of consciousness or 4. Disorganized thinking

= Delirium

Ely EW, et al.

Crit Care Med

. 2001;29:1370-1379.

Ely EW, et al.

JAMA

. 2001;286:2703-2710.

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 Score 1 point for each component present during shift • Score of 1-3 = Subsyndromal Delirium • Score of ≥ 4 = Delirium Bergeron N, et al.

Intensive Care Med

. 2001;27:859-864.

Ouimet S, et al.

Intensive Care Med.

2007;33:1007-1013.

Subsyndromal Delirium and Clinical Outcomes ICU Mortality ICU LOS Hospital LOS Severity of illness (APACHE II) No delirium (ND) Subsyndromal (SD) Clinical (CD)

2.4% 10.6% 15.9% 2.5 d 31.7 d 12.9 5.2 d 40.9 d 16.7

P value*

P

< 0.001

P

< 0.001

10.8 d 36.4 d 18.6

ND vs. SD,

P

= 0.002

ND vs. CD,

P

< 0.001

SD vs. CD,

P

= 0.137

ND vs. SD,

P

< 0.001

ND vs. CD,

P

< 0.001

SD 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

• • • • •

T

oxic Situations – CHF, shock, dehydration – Deliriogenic meds (

Tight Titration

) – New organ failure, eg, liver, kidney

H

ypoxemia; also, consider giving

H

aloperidol or other antipsychotics?

I

nfection/sepsis (nosocomial),

I

mmobilization

N

onpharmacologic 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

Patient Comfort and Ventilatory Optimization Undersedation

• • • • • •

Patient recall Device removal Ineffectual mechanical ventilation Initiation of neuromuscular blockade Myocardial or cerebral ischemia Decreased family satisfaction w/ care G O A L Oversedation

•

Prolonged mechanical ventilation

• • •

Increase length of stay

•

Increased risk of complications - Ventilator-associated pneumonia Increased diagnostic testing Inability to evaluate for delirium

Jacobi J, et al.

Crit Care Med.

2002;30:119-141.

Consequence of Improper Sedation

30.6% 15.4% 54.0%

• • • 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 patients 2 – $31,574 versus $12,931,

P

< 0.001

Sedation should be titrated to achieve a cooperative patient and daily wake-up, a JC requirement 1,2 Undersedated 3 Oversedated On Target 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.

Clinical Effects

• Analgesia • Sedation Fentanyl

Opioids

Adverse Effects

• Respiratory depression • Hypotension • Bradycardia • Constipation • Tolerance • Withdrawal symptoms • Hormonal changes Morphine Remifentanil Benyamin R, et al.

Pain Physician

. 2008;11(2 Suppl):S105-120.

Opioid Mechanisms

Neurotransmitters ACh Glu NE Acetylcholine Glutamate Norepinephrine Brown EN, et al.

N Engl J Med

. 2010;363(27):2638-2650.

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 Strøm T, et al.

Lancet

. 2010;375:475-480.

Analgosedation Results

• 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 Strøm T, et al.

Lancet

. 2010;375:475-480.

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 Agonist Benzodiazepine Midazolam

Clinical Effects Adverse Effects

• Sedation, anxiolysis, and amnesia • Rapid onset of action (IV) • May accumulate with hepatic and/or renal failure • Anterograde amnesia • Long recovery time • Synergy with opioids • Respiratory depression • Delirium Olkkola KT, Ahonen J.

Handb Exp Pharmacol.

2008;(182):335-360.

Riker RR, et al; SEDCOM Study Group.

JAMA

. 2009;301(5):489-499.

40 30 20 10 0 60

Midazolam Pharmacodynamics: It’s About Time

• Highly lipid soluble • α-OH midazolam metabolite • CYP3A4 activity decreased in critical illness • Substantial CYP3A4 variability

50

Extubation Alertness Recovery

< 1 1-7 > 7 Sedation Time (days)

Carrasco G, et al.

Chest.

1993;103:557-564.

Bauer TM, et al.

Lancet.

1995;346:145-147.

GABA Agonist Benzodiazepine Lorazepam

 

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 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

Medication Lorazepam Midazolam Fentanyl Morphine Propofol Transitioning to Delirium Only OR (95% CI)

P

Value 1.2 (1.1-1.4) 1.7 (0.9-3.2) 1.2 (1.0-1.5) 1.1 (0.9-1.2) 1.2 (0.9-1.7) 0.003

0.09

0.09

0.24

0.18

Lorazepam Dose, mg

Pandharipande P, et al.

J Trauma.

2008;65:34-41. Pandharipande P, et al.

Anesthesiol.

2006:104:21-26.

GABA Agonist Propofol

Clinical Effects Adverse Effects

• Sedation • Hypnosis • Anxiolysis • Muscle relaxation • Mild bronchodilation • Decreased ICP • Decreased cerebral metabolic rate • Antiemetic • Pain on injection • Respiratory depression • Hypotension • Decreased myocardial contractility • Increased serum triglycerides • Tolerance • Propofol infusion syndrome • Prolonged effect with high adiposity • Seizures (rare) Ellett ML.

Gastroenterol Nurs

. 2010;33(4):284-925.

Lundström S, et al.

J Pain Symptom Manage.

2010;40(3):466-470.

Central Mechanisms of Propofol

Brown EN, et al.

N Engl J Med

. 2010;363(27):2638-2650.

Monoaminergic pathways Cholinergic pathways Lateral hypothalamus neurons Neurotransmitters ACh Acetylcholine DA GABA GAL Glu His NE 5HT Dopamine γ-Aminobutyric acid Galanin Glutamate Histamine Norepinephrine Serotonin

Propofol Has Greater Sedation Efficacy Than Continuous Midazolam

Efficacy of Sedation* Duration of Adequate Sedation

n = 18 trials n = 15 trials * Avg adequate sedation time avg total sedation time Walder B, et al.

Anesth Analg.

2001;92:975-983.

Continuous Midazolam Has Longer Weaning Time From MV Than Propofol

Data from 8 RCT Walder B, et al.

Anesth Analg.

2001;92:975-983.

Scheduled Intermittent Lorazepam vs Propofol with Daily Interruption in MICU Patients Ventilator days ICU LOS APACHE II Daily sedation dose Morphine dose (mg/day) Use of haloperidol Lorazepam n = 64 8.4

10.4

22.9

11.5 mg 10.7

12% Propofol n = 68 5.8

8.3

20.7

24.4 mcg/kg/min 31.6

9% P value 0.04

0.20

0.05

_ 0.001

0.80

Carson SS, et al.

Crit Care Med.

2006;34:1326-1332.

a 2

Agonist Clonidine

Clinical Effects

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

Adverse Effects

• Bradycardia • Dry mouth • Hypotension • Sedation 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.

Physiology of

a 2

Adrenoceptors

a

2A

a

2A Anxiolysis

a

2C X

? a

2B

a

2A

a

2B X ?

a

2B

Adapted from Kamibayashi T, Maze M.

Anesthesiology

. 2000;93:1346-1349. a

2A

a 2

Agonist Dexmedetomidine

Clinical Effects Adverse Effects

• Antihypertensive • Sedation • Analgesia • Decreased shivering • Anxiolysis • Patient arousability • Potentiate effects of opioids, sedatives, and anesthetics • Decrease sympathetic activity • Hypotension • Hypertension • Nausea • Bradycardia • Dry mouth • Peripheral vasoconstriction at high doses 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 DA GABA GAL Glu His NE 5HT Acetylcholine Dopamine γ-Aminobutyric acid Galanin Glutamate Histamine Norepinephrine Serotonin Brown EN, et al.

N Engl J Med

. 2010;363(27):2638-2650.

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

P

= 0.011

P

= 0.086

P

< 0.001

  Dexmedetomidine resulted in more time spent within sedation goals than lorazepam (

P

= 0.04)  Dexmedetomidine resulted in more days alive without delirium or coma (

P

= 0.01) and a lower prevalence of coma (

P

< 0.001) than lorazepam Differences in 28-day mortality and delirium-free days were not significant Dexmedetomidine n = 52 Lorazepam n = 51

Delirium/Coma-Free Days Delirium-Free Days Coma-Free

Pandharipande PP, et al.

JAMA.

2007;298:2644-2653.

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

Outcome

Lowest SBP Ever hypotensive (SBP < 80) Days on vasoactive meds Sinus bradycardia (< 60/min)

Lorazepam (n = 50)

97 (88,102) 20% 0 (0,3) 4% Heart rate < 40 Self-extubations (reintubations) 2% 2 (2)

Dexmedetomidine (n = 51)

96 (88,105)

P-Value

0.58

25% 0.51

0 (0,2) 0.72

17% 2% 4 (3) 0.03

0.99

0.41

Pandharipande PP, et al.

JAMA.

2007;298:2644-2653.

SEDCOM: Dexmedetomidine vs Midazolam

• 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

Outcome Midazolam (n = 122) Dexmedetomidine (n = 244)

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

77.3

Duration of sedation, days Time to extubation, days Delirium prevalence Delirium-free days Patients receiving open-label midazolam 4.1

5.6

93 (76.6%) 1.7

60 (49%) 3.5

3.7

132 (54%) 2.5

153 (63%)

P-

Value

0.18

0.01

0.01

0.001

0.002

0.02

Riker RR, et al.

JAMA.

2009;301:489-499.

100

Reduced Delirium Prevalence with Dexmedetomidine vs Midazolam

SEDCOM

Dexmedetomidine versus Midazolam,

P

< 0.001

80 60

Midazolam Dexmedetomidine

40 20 0

Sample Size

Baseline

118 229

1

109 206 Riker RR, et al.

JAMA.

2009;301:489-499.

2

92 175

3 Treatment Day

77 134

4

57 92

5

42 60

6

44 34

SEDCOM Trial:

Safety Outcomes Outcome

Bradycardia Bradycardia needing treatment Tachycardia Hypertension requiring intervention Hyperglycemia Infections

Midazolam (n = 122)

18.9% 0.8% 44.3% 29.5% 42.6% 19.7%

Dexmedetomidine (n = 244)

P-

Value

42.2% 4.9% 25.4% 18.9% 56.6% 10.2% 0.001

0.07

0.001 0.02

0.02

0.02

Riker RR, et al.

JAMA.

2009;301:489-499.

Comparison of Clinical Effects

Benzodiazepines Propofol Opioids

a

2 Agonists Haloperidol X X X

Sedation Alleviate anxiety 1,2 Analgesic properties 1-4 Promote arousability during sedation 2-4 Facilitate ventilation during weaning 2-4 Control delirium 1-4

X X X X X X X X X X X

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.

Comparison of Adverse Effects

Benzodiazepines Propofol Opioids

a

2 Agonists Haloperidol

Prolonged weaning 1 Respiratory depression 1 Hypotension 1-3 Constipation 1 Deliriogenic Tachycardia 1 Bradycardia 1

X X X X X X X X X X * X X X X

morphine fentanyl

X X X X

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.

*Excluding remifentanil

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: • Midazolam 5 mg/hr $35 $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

Propofol less expensive 0.5

Ratio of propofol to lorazepam MV days Average duration of MV 2 ` Lorazepam more effective 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 Low $1,825 75% $1,892 20% 20% Lorazepam High $9,488 5% $631 0%c 0% Midazolam Low High Cost of propofol Daily propofol dose, mg Cost of lorazepam Daily lorazepam dose, mg $11.37

$60.77

4,347 949 $0.81

$7.82

23 4 -$35 -$30 -$25 -$20 -$15 -$10 -$5 $0 $5 Cost Difference Between Lorazepam and Propofol ($ Thousands) Cox CE, et al.

Crit Care Med.

2008;36:706-714.

$10 $15 $20 $25 $30 $35

MENDS Trial: Cost of Care

Component

Pharmacy Respiratory ICU cost

Lorazepam

20.6 (10,42) 2.9 (2,6) 59.5 (36,83)

Dexmedetomidine

27.4 (16,46) 3.5 (2,7) 61.4 (37,108) $ – Costs represented in thousands, US dollars (Median, IQR)

P-value

0.15

0.35

0.32

Pandharipande PP, et al.

JAMA.

2007;298:2644-2653.

60,000 50,000 40,000

SEDCOM Cost of Care

40,365 50,149

DEX MID

• Median drug costs • Dex $1,166 • Midazolam $60 36,571 40,501 • Total ICU patient savings with Dex: $9679 • Reduced ICU stay • Reduced MV 30,000 20,000 10,000 0

P

< 0.01

Total ICU cost

P

< 0.05

ICU component 7,022 10,885

P

< 0.01

Mechanical ventilation component Dasta JF, et al.

Crit Care Med.

2010;38:497-503.

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

10 9 8 7 6 5 4 3 2 1 0

5.2

P

Pharmacist-Led

Marshall J, et al.

Crit Care Med.

2008;36:427-433.

< 0.001

6.9

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 • 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 Kress JP, et al.

N Engl J Med.

2000;342:1471-1477.

ABC Trial: Objectives

 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 Girard TD, et al.

Lancet.

2008;371:126-134.

ABC Trial: Main Outcomes

Outcome*

Ventilator-free days Time-to-Event, days Successful extubation ICU discharge Hospital discharge Death at 1 year, n (%) Days of brain dysfunction Coma Delirium * Median, except as noted † SBT compared with SAT+SBT Girard TD, et al.

Lancet.

2008;371:126-134.

SBT

12 7.0

13 19 97 (58%) 3.0

2.0

SAT+SBT

15 5 9 15 74 (44%) 2.0

2.0

P-value †

0.02

0.05

0.02

0.04

0.01

0.002

0.50

ABC Trial: 1 Year Follow-Up

Girard TD, et al.

Lancet

. 2008;371:126-134.

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/opiate 4 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.

Barriers to Daily Sedation Interruption

(Survey of 904 SCCM members) Increased device removal Poor nursing acceptance Compromises patient comfort Leads to respiratory compromise Difficult to coordinate with nurse No benefit Leads to cardiac ischemia #1 Barrier #2 Barrier #3 Barrier Leads to PTSD 0 10 20 30 40 50 60 70 Number of respondents (%)

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.

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) Schweickert WD, et al.

Lancet.

2009;373:1874-1882.

Animation = Less Delirium

Variable

ICU/Hosp Delirium (days)

Intervention (n = 49)

2 33% Time in ICU with Delirium Time in Hosp. with Delirium 28%

Control (n = 55)

4 57% 41%

P-Value

0.03

0.02

0.01

Schweickert WD, et al.

Lancet.

2009;373:1874-1882.

Procedural Sedation Major Applications

• Surgical – CV surgery – Neurosurgery – Bariatric surgery • Endoscopic – Bronchoscopy – Fiberoptic intubation – Colonoscopy

Standardized Monitoring

• Hemodynamic – ECG – Blood pressure • Respiration – Oxygenation (SpO 2 oxygen) by pulse oximetry, supplemental – Ventilation (end tidal CO 2 , EtCO 2 ) • 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

Agent

Propofol

Advantages

• Short acting • Reduces cerebral metabolism, O 2 consumption • Improves ICP after 3d

Considerations

• Propofol infusion syndrome Barbiturates • Reduce ICP • Neuroprotection • Interfere with neuro exam • Hypotension, reduced CBF • OCs not improved with severe TBI Saiki RL.

Crit Care Nurs Clin North Am

. 2009;21:549-559.

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.

Dexmedetomidine in Bariatric Surgery

• 80 morbidly obese patients • Gastric banding or bypass surgery • Prospective dose ranging study • Medication – Celecoxib – Midazolam 400 mg 20 µg/kg po IV – Propofol – Desflurane 1.25 mg/kg 4% IV inspired – Dexmedetomidine 0, 0.2, 0.4, 0.8 µg/kg/h IV Tufanogullari B, et al.

Anesth Analg

. 2008;106:1741-1748.

Dexmedetomidine in Bariatric Surgery: Results

• 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 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 Sedation in Flexible Bronchoscopy

• Randomized non-inferiority trial • 200 diverse patients received propofol or midazolam/hydrocodone • 1 o endpoints – Mean lowest SaO 2 – Readiness for discharge at 1h • Result – No difference in mean lowest SaO 2 – 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

GABA agonist GABA agonist

Example

Benzodiazepine Midazolam Benzodiazepine Propofol Opioid a 2 Agonist Fentanyl Remifentanil Dexmedetomidine

Advantages Considerations

• Quick onset • Injection not painful • Short duration • Quick onset • Not analgesic • Airway reflexes persist • Respiratory depression • Unconsciousness • Decreased bp, cardiac output • Increased HR • Respiratory depression • Analgesic • Cough suppressive • 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

Clinical Effects Adverse Effects

• Hypnotic agent with antipsychotic properties 1 – For treatment of delirium in critically ill adults 1 • Does not cause respiratory depression 1 • Dysphoria 2 • Adverse CV effects include QT interval prolongation • Extrapyramidal symptoms, neuroleptic malignant syndrome (rare) 1 • Metabolism altered by drug-drug interactions 2 1. Harvey MA.

Am J Crit Care.

1996;5:7-16.

2. Crippen DW.

Crit Care Clin.

1990;6:369-392.

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.

90

Use of Atypical Antipsychotic Therapy Is Increasing

80 70 60 50 40 30 20 10 0 2001 2007 Ely EW, et al.

Crit Care Med.

2004;32:106-112.

Patel RP, et al.

Crit Care Med.

2009;37:825-832.

Antipsychotic Therapy

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

Drug Specificity: Comparative Receptor Binding Profiles

H1 Quetiapine D1D2 5HT2A 5HT1A A1 A2 5HT1A Ziprasidone A1 D2 D1 5HT1A A1 Risperidone A2 H1 D1 D2 M Olanzapine D1 D2 5HT2A H1 A2 A1 A1 Haloperidol D1 5HT1A 5HT2A D2 5HT2A 5HT2A

Adapted from Gareri P, et al.

Clin Drug Invest.

2003;23:287-322.

Rationale-based Pharmacotherapy Important Principles

Receptors Effects of Receptor Blockade

H 1 D 2 5-HT 2C 5-HT 2A α 1 -adrenergic M 1 Sedation, weight gain, postural dizziness EPS, prolactin elevation, antipsychotic Satiety blockade Anti-EPS?

Hypotension Deficits in memory and cognition, dry mouth, constipation, tachycardia, blurred vision Adapted from Weiden P, et al.

J Clin Psychiatry

. 2007;68:5-46.

Modifying the Incidence of Delirium (MIND) Trial

• 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] Girard TD, et al.

Crit Care Med.

2010;38:428-437.

MIND Trial Results

Outcome Haloperidol, n = 35

Delirium/coma-free days Delirium days 14.0

4 Delirium resolution on study drug, n(%) 24 (69) Coma days 2 % of days accurately sedated 70 7.8

Ventilator-free days Length of stay, days ICU Hospital 21-day mortality, n (%) Average extrapyramidal symptoms score 11.7

13.8

4 (11) 0

Ziprasidone, n = 30

15.0

4 23 (77) 2 64 12.0

9.6

13.5

4 (13) 0

Placebo, n = 36

12.5

4 21 (58) 2 71 12.5

7.3

15.4

6 (17) 0

P-value

0.66

0.93

0.28

0.90

0.91

0.25

0.70

0.68

0.81

0.56

Girard TD, et al.

Crit Care Med.

2010;38:428-437.

Quetiapine for Delirium Study Design

• 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.

258 patients with delirium (ICDSC ≥ 4) tolerating enteral nutrition 222 patients excluded 36 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 Titration Increase quetiapine or placebo dose by 50 mg every 12 hours daily if the subject received ≥ 1 dose of as needed haloperidol in prior 24 hours.

(Maximum dose = 200 mg every 12 hours) Discontinuation of study drug 1. No signs of delirium 2. 10 days of therapy had elapsed 3. ICU discharge prior to 10 days of therapy 4. Serious adverse event potentially attributable to the study drug Devlin JW, et al.

Crit Care Med.

2010;38:419-427.

Patients with First Resolution of Delirium

Log-Rank

P

= 0.001

Placebo Quetiapine Day During Study Drug Administration

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

Devlin JW, et al.

Crit Care Med

. 2010;38:419-427.

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 Jacobi J, et al.

Crit Care Med.

2002;30:119-141.

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