Assessing and Managing Sedation

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

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: Weinert C. Curr Opin in Crit Care. 2005;11: Kress JP, et al. Am J Respir Crit Care Med. 1996;153:

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: 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:

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; p.1301.

Behavioral Pain Scale (BPS) 3-12
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 Partially bent Fully bent with finger flexion Permanently retracted Compliance with ventilation Tolerating movement Coughing but tolerating ventilation for most of the time Fighting ventilator Unable to control ventilation Payen JF, et al. Crit Care Med. 2001;29(12):

BPS Validation Sedated Mechanically Ventilated Patients
Is BPS Sensitive to Pain? Is BPS Reproducible? □ Not painful n = 104 Weighted  = 0.74, P < 0.01 ● Painful n = 134 ▲ Retested painful n = 31 BPS Re-Exposed to Pain Exposed to Pain * P < 0.05 vs rest period †P < 0.05 vs not painful Payen JF, et al. Crit Care Med. 2001;29:2258–2263.

Critical Care Pain Observation Tool 0-8
Gélinas C, et al. Am J Crit Care. 2006;15:

Critical Care Pain Observation Tool
Sensitivity/Specificity DURING Painful Procedure Gélinas C, et al. Am J Crit Care. 2006;15:

Correlating Pain Assessment with Analgesic Administration in the ICU
Assessed Treated Fewer patients assessed for pain, more treated with analgesics in ICUs without analgesia protocols compared with ICUs with protocols1 * Patients (%) * Pain scoring used in 21% of surveyed ICUs in 20062 Protocol No Protocol * P < 0.01 vs ICUs using a protocol 1. Payen JF, et al. Anesthesiol. 2007;106: 2. Martin J, et al. Crit Care. 2007;11:R124.

Assessing Pain Reduces Sedative/Hypnotic Use
What proportion of MV ICU patients received sedative or hypnotic medication? Day 2 Pain Assessment? P-value No (n = 631) Yes (n = 513) Any sedative 86% 75% < 0.01 Midazolam 65% 57% Propofol 21% 17% 0.06 Other 6% 4% 0.03 Payen JF, et al. Anesthesiology. 2009;111;

Assessing Pain Improves Some Outcomes
Day 2 Pain Assessment? Unadj. OR P-value Adjusted OR No 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 1.40 0.05 Vent-acquired pneumonia 24% 16% 0.61 0.75 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:

Maintaining Patients at the Desired Sedation Goal

Sedation-Agitation Scale (SAS)
Score State Behaviors 7 Dangerous Agitation Pulling at ET tube, climbing over bedrail, striking at staff, thrashing side-to-side 6 Very Agitated Does not calm despite frequent verbal reminding, requires physical restraints 5 Agitated Anxious or mildly agitated, attempting to sit up, calms down to verbal instructions 4 Calm and Cooperative Calm, awakens easily, follows commands 3 Sedated Difficult to arouse, awakens to verbal stimuli or gentle shaking but drifts off 2 Very Sedated Arouses to physical stimuli but does not communicate or follow commands 1 Unarousable Minimal or no response to noxious stimuli, does not communicate or follow commands Riker RR, et al. Crit Care Med. 1999;27: Brandl K, et al. Pharmacotherapy. 2001;21: 19

Richmond Agitation Sedation Scale (RASS)
Score State + 4 Combative + 3 Very agitated + 2 Agitated + 1 Restless 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 Verbal Stimulus Physical Stimulus Ely EW, et al. JAMA. 2003;289: Sessler CN, et al. Am J Respir Crit Care Med. 2002;166(10):

Sedation Scale Reliability
r2 Kappa SAS Riker, Brandl, RASS Sessler, Ely, Ramsay Riker, Ely, Olson, MAAS Devlin, Hogg, MSAT Weinert,

Correlating Sedation Assessment with Sedative 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 Assessed Treated * Patients (%) * Protocol No Protocol * P < 0.01 vs ICUs using a protocol 1. Payen JF, et al. Anesthesiol. 2007;106: 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:

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):

DELIRIUM Less Modifiable More Modifiable Patient Factors
Increased age Alcohol use Male gender Living alone Smoking Renal disease Predisposing Disease Cardiac disease Cognitive impairment (eg, dementia) Pulmonary disease Less Modifiable Acute Illness Length of stay Fever Medicine service Lack of nutrition Hypotension Sepsis Metabolic disorders Tubes/catheters Medications: Anticholinergics Corticosteroids - Benzodiazepines 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: Skrobik Y. Crit Care Clin. 2009;25:

During the ICU/Hospital Stay After Hospital Discharge
Sequelae of Delirium Increased mortality Longer intubation time Average 10 additional days in hospital Higher costs of care During the ICU/Hospital Stay Increased mortality Development of dementia Long-term cognitive impairment Requirement for care in chronic care facility Decreased functional status at 6 months After Hospital Discharge Bruno JJ, Warren ML. Crit Care Nurs Clin North Am. 2010;22(2): Shehabi Y, et al. Crit Care Med. 2010;38(12): Rockwood K, et al. Age Ageing. 1999;28(6): Jackson JC, et al. Neuropsychol Rev. 2004;14:87-98. Nelson JE, et al. Arch Intern Med. 2006;166: 27

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:

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 4. Disorganized thinking or = Delirium Ely EW, et al. Crit Care Med. 2001;29: Ely EW, et al. JAMA. 2001;286:

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

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 d Hospital LOS 31.7 d 40.9 d 36.4 d ND vs. SD, P = 0.002 ND vs. CD, P < 0.001 SD vs. CD, P = 0.137 Severity of illness (APACHE II) 12.9 16.7 18.6 ND vs. SD, P < 0.001 SD vs. CD, P < 0.016 *Pairwise comparison Ouimet S, et al. Intensive Care Med. 2007;33:

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:

ICU Sedation: The Balancing Act and Ventilatory Optimization
Patient Comfort and Ventilatory Optimization Oversedation Prolonged mechanical ventilation Increase length of stay Increased risk of complications - Ventilator-associated pneumonia Increased diagnostic testing Inability to evaluate for delirium G O A L Undersedation Patient recall Device removal Ineffectual mechanical ventilation Initiation of neuromuscular blockade Myocardial or cerebral ischemia Decreased family satisfaction w/ care Jacobi J, et al. Crit Care Med. 2002;30: 33 33

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 30.6% 15.4% 54.0% Undersedated3 Oversedated On Target 1. Kress JP, et al. N Engl J Med. 2000;342: 2. Dasta JF, et al. Crit Care Med. 2005;33: 3. Kaplan LJ, Bailey H. Crit Care. 2000;4(suppl 1):P190.

Opioids Clinical Effects Adverse Effects Analgesia
Respiratory depression Sedation Hypotension Bradycardia Constipation Fentanyl Tolerance Withdrawal symptoms Hormonal changes Morphine Remifentanil Benyamin R, et al. Pain Physician. 2008;11(2 Suppl):S

Opioid Mechanisms Neurotransmitters ACh Acetylcholine Glu Glutamate NE Norepinephrine Brown EN, et al. N Engl J Med. 2010;363(27):

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:

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:

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:

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:

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: 2. Jacobi J, et al. Crit Care Med. 2002;30: 3. Dasta JF, et al. Pharmacother. 2006;26: 4. Nelson LE, et al. Anesthesiol. 2003;98:

Consider Patient Comorbidities When Choosing a Sedation Regimen
Chronic pain Organ dysfunction CV instability Substance withdrawal Respiratory insufficiency Obesity Obstructive sleep apnea

Benzodiazepine Midazolam
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): Riker RR, et al; SEDCOM Study Group. JAMA. 2009;301(5):

Midazolam Pharmacodynamics: It’s About Time
Highly lipid soluble α-OH midazolam metabolite CYP3A4 activity decreased in critical illness Substantial CYP3A4 variability 60 50 40 Time to Endpoint (h) 30 Extubation Alertness Recovery 20 10 < 1 1-7 > 7 Sedation Time (days) Carrasco G, et al. Chest. 1993;103: Bauer TM, et al. Lancet. 1995;346:

Benzodiazepine Lorazepam
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): Wilson KC, et al. Chest. 2005;128(3):

Risk of Delirium With Benzodiazepines
Medication Transitioning to Delirium Only OR (95% CI) P Value Lorazepam 1.2 ( ) 0.003 Midazolam 1.7 ( ) 0.09 Fentanyl 1.2 ( ) Morphine 1.1 ( ) 0.24 Propofol 1.2 ( ) 0.18 Delirium Risk Lorazepam Dose, mg Pandharipande P, et al. J Trauma. 2008;65: 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): Lundström S, et al. J Pain Symptom Manage. 2010;40(3):

Central Mechanisms of Propofol
Monoaminergic pathways Cholinergic pathways Lateral hypothalamus neurons Neurotransmitters ACh Acetylcholine DA Dopamine GABA γ-Aminobutyric acid GAL Galanin Glu Glutamate His Histamine NE Norepinephrine 5HT Serotonin Brown EN, et al. N Engl J Med. 2010;363(27):

Propofol Has Greater Sedation Efficacy Than Continuous Midazolam
Duration of Adequate Sedation Efficacy of Sedation* n = 18 trials n = 15 trials * Avg adequate sedation time avg total sedation time Walder B, et al. Anesth Analg. 2001;92: 50

Continuous Midazolam Has Longer Weaning Time From MV Than Propofol
Data from 8 RCT Walder B, et al. Anesth Analg. 2001;92: 51

Scheduled Intermittent Lorazepam vs Propofol with Daily Interruption in MICU Patients
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: 52

a2 Agonist Clonidine Clinical Effects Adverse Effects Antihypertensive
Analgesia Sedation Decrease sympathetic activity Decreased shivering Bradycardia Dry mouth Hypotension Sedation Kamibayashi T, et al. Anesthesiol. 2000;93: Bergendahl H, et al. Curr Opin Anaesthesiol. 2005;18(6): Hossmann V, et al. Clin Pharmacol Ther. 1980;28(2):

Physiology of a2 Adrenoceptors
Anxiolysis a2A a2C X ? a2B a2A a2B X a2A ? a2B Adapted from Kamibayashi T, Maze M. Anesthesiology. 2000;93:

a2 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: Bhana N, et al. Drugs. 2000;59(2):

Central Mechanisms of Dexmedetomidine
Neurotransmitters ACh Acetylcholine DA Dopamine GABA γ-Aminobutyric acid GAL Galanin Glu Glutamate His Histamine NE Norepinephrine 5HT Serotonin Brown EN, et al. N Engl J Med. 2010;363(27):

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:

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 P = 0.011 P = 0.086 P < 0.001 12 10 8 Days 6 4 2 Dexmedetomidine n = 52 Lorazepam n = 51 Delirium/Coma-Free Days Delirium-Free Days Coma-Free Days Pandharipande PP, et al. JAMA. 2007;298:

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 Lorazepam (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 Pandharipande PP, et al. JAMA. 2007;298:

Dexmedetomidine vs Midazolam
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 μg/kg/hr or mz 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) 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 Riker RR, et al. JAMA. 2009;301:

Reduced Delirium Prevalence with Dexmedetomidine vs Midazolam SEDCOM
100 Dexmedetomidine versus Midazolam, P < 0.001 80 Midazolam Dexmedetomidine 60 Patients With Delirium, % 40 20 Baseline 1 2 3 4 5 6 Treatment Day Sample Size 57 92 42 60 44 34 Riker RR, et al. JAMA. 2009;301:

SEDCOM Trial: Safety Outcomes
Midazolam (n = 122) Dexmedetomidine (n = 244) P-Value Bradycardia 18.9% 42.2% 0.001 Bradycardia needing treatment % % Tachycardia 44.3% 25.4% 0.001 Hypertension requiring intervention 29.5% 18.9% 0.02 Hyperglycemia 42.6% 56.6% Infections 19.7% 10.2% Riker RR, et al. JAMA. 2009;301:

Comparison of Clinical Effects
Benzodiazepines Propofol Opioids a2 Agonists Haloperidol Sedation X X X X X Alleviate anxiety1,2 X X Analgesic properties1-4 X X Promote arousability during sedation2-4 X Facilitate ventilation during weaning2-4 X X Control delirium1-4 X X 1. Blanchard AR. Postgrad Med. 2002;111:59-74. 2. Kamibayashi T, et al. Anesthesiol. 2000;95: 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:

Comparison of Adverse Effects
Benzodiazepines Propofol Opioids a2 Agonists Haloperidol Prolonged weaning 1 X X X * Respiratory depression 1 X X X Hypotension 1-3 X X X X X Constipation 1 X Deliriogenic X X X Tachycardia 1 morphine Bradycardia 1 X fentanyl X X *Excluding remifentanil 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:

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: 67

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 68

Propofol Is More Cost-Effective Than Lorazepam
Propofol less expensive 2 ` 0.5 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 Low High Lorazepam more effective $1,825 $9,488 75% 5% $1,892 $631 20% 0%c 20% 0% Lorazepam Midazolam High Low $11.37 $60.77 4,347 949 $0.81 $7.82 23 4 -$35 -$30 -$25 -$20 -$15 -$10 -$5 $0 $5 $10 $15 $20 $25 $30 $35 Cost Difference Between Lorazepam and Propofol ($ Thousands) Cox CE, et al. Crit Care Med. 2008;36:

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) Pandharipande PP, et al. JAMA. 2007;298:

SEDCOM Cost of Care Median drug costs Dex $1,166 Midazolam $60
Total ICU patient savings with Dex: $9679 Reduced ICU stay Reduced MV P < 0.01 P < 0.05 P < 0.01 Dasta JF, et al. Crit Care Med. 2010;38:

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:

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 Median Days of Mechanical Ventilation 10 P < 0.001 9 8 7 6 6.9 5 4 5.2 3 2 1 Pharmacist-Led Control Marshall J, et al. Crit Care Med. 2008;36:

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:

ABC Trial: Objectives spontaneous awakening trials (SATs) &
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:

ABC Trial: Main Outcomes
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 Girard TD, et al. Lancet. 2008;371:

ABC Trial: 1 Year Follow-Up
Girard TD, et al. Lancet. 2008;371:

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 ( )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: 2. Devlin J. Crit Care Med. 2006;34: 3. Martin J, et al. Crit Care. 2007;11:R124. 4. Payen JF, et al. Anesthesiology. 2007;106:

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 #1 Barrier Leads to cardiac ischemia #2 Barrier #3 Barrier Leads to PTSD 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 < ) Tanios MA, et al. J Crit Care. 2009;24:66-73. 80

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:

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:

Animation = Less Delirium
Variable Intervention (n = 49) Control (n = 55) P-Value ICU/Hosp Delirium (days) 2 4 0.03 Time in ICU with Delirium 33% 57% 0.02 Time in Hosp. with Delirium 28% 41% 0.01 Schweickert WD, et al. Lancet. 2009;373:

Procedural Sedation Major 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):

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):

Sedation/Analgesia for Traumatic Brain Injury
Goal: reduce ICP by decreasing pain, agitation 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 Saiki RL. Crit Care Nurs Clin North Am. 2009;21:

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 mg po Midazolam 20 µg/kg IV Propofol mg/kg IV Desflurane 4% inspired Dexmedetomidine 0, 0.2, 0.4, 0.8 µg/kg/h IV Tufanogullari B, et al. Anesth Analg. 2008;106:

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:

Sedation for Endoscopy
Desirable qualities Risk factors Permits complete diagnostic exam Depth of sedation ASA status Safe Medical conditions Diminishes memory of the procedure Pregnancy Difficult airway mgt Permits rapid discharge after procedure Extreme age Rapid discharge time Runza M. Minerva Anestesiol. 2009;75:

Propofol vs Combined Sedation in 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:

Fiberoptic Intubation
Agent Class Example Advantages Considerations GABA agonist Benzodiazepine Midazolam Quick onset Injection not painful Short duration Not analgesic Airway reflexes persist Benzodiazepine Propofol Respiratory depression Unconsciousness Decreased bp, cardiac output Increased HR Opioid Fentanyl Remifentanil Analgesic Cough suppressive a2 Agonist Dexmedetomidine Pt easily arousable Anxiolytic 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:

Dopamine Antagonist Haloperidol
Clinical Effects Adverse Effects Hypnotic agent with antipsychotic properties1 Dysphoria2 Adverse CV effects include QT interval prolongation For treatment of delirium in critically ill adults1 Extrapyramidal symptoms, neuroleptic malignant syndrome (rare)1 Does not cause respiratory depression1 Metabolism altered by drug-drug interactions2 1. Harvey MA. Am J Crit Care. 1996;5:7-16. 2. Crippen DW. Crit Care Clin. 1990;6:

Use of Haloperidol Is an Independent Predictor for Prolonged Delirium
Pisani MA, et al. Crit Care Med. 2009;37: 97

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: Lee PE, et al. J Am Geriatr Soc. 2005;53: Wang PS, et al. N Engl J Med. 2005;353: 98

Use of Atypical Antipsychotic Therapy Is Increasing
90 80 70 60 2001 50 2007 40 30 20 10 Propofol Haloperidol Benzodiazepines Atypical anti-psychotics Ely EW, et al. Crit Care Med. 2004;32: Patel RP, et al. Crit Care Med. 2009;37:

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

Drug Specificity: Comparative Receptor Binding Profiles
Quetiapine Olanzapine D1 D2 5HT2A 5HT1A A1 A2 H1 D1 D2 5HT2A A1 A2 H1 M Ziprasidone Risperidone Haloperidol D2 D1 5HT2A 5HT1A A1 D1 D2 5HT2A 5HT1A A1 A2 H1 D1 D2 5HT2A 5HT1A A1 Adapted from Gareri P, et al. Clin Drug Invest. 2003;23: 4 1

Rationale-based Pharmacotherapy Important Principles
Anti-EPS? 5-HT2A EPS, prolactin elevation, antipsychotic D2 Satiety blockade 5-HT2C Deficits in memory and cognition, dry mouth, constipation, tachycardia, blurred vision M1 Hypotension α1-adrenergic Sedation, weight gain, postural dizziness H1 Effects of Receptor Blockade Receptors 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: 103

Girard TD, et al. Crit Care Med. 2010;38:428-437.
MIND Trial Results Outcome Haloperidol, n = 35 Ziprasidone, n = 30 Placebo, n = 36 P-value Delirium/coma-free days 14.0 15.0 12.5 0.66 Delirium days 4 4 4 0.93 Delirium resolution on study drug, n(%) 24 (69) 23 (77) 21 (58) 0.28 Coma days 2 2 2 0.90 % of days accurately sedated 70 64 71 0.91 Ventilator-free days 7.8 12.0 12.5 0.25 Length of stay, days ICU Hospital 11.7 13.8 9.6 13.5 7.3 15.4 0.70 0.68 21-day mortality, n (%) 4 (11) 4 (13) 6 (17) 0.81 Average extrapyramidal symptoms score 0.56 Girard TD, et al. Crit Care Med. 2010;38:

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: 105

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) 222 Excluded 46 Prior antipsychotic use within 30 days 38 Not receiving enteral nutrition 28 Primary neurological condition 16 Encephalopathy or end-stage liver disease 12 Alcohol withdrawal 12 Inability to conduct ICDSC 11 No delirium 11 Inability to obtain informed consent 10 Moribund 8 Irreversible brain disease (e.g. dementia) 5 Baseline QTc interval ≥ 500msec 5 Attending physician refusal for enrollment 7 Other Discontinuation of study drug No signs of delirium 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: 106

Patients with First Resolution of Delirium
Log-Rank P = 0.001 Proportion of Patients with Delirium 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: 107

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: Weinhouse GL, Watson PL. Crit Care Clin. 2009;25:

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: Nelson LE, et al. Anesthesiology. 2003;98:

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: Faulhaber J, et al. Psychopharmacology. 1997;130: 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:

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 113

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 114

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

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