Sedation, Analgesia and Paralysis in ICU

Mazen Kherallah, MD, FCCP

ICU Sedation

• ICU sedation is a complex clinical problem

• Current therapeutic approaches all have potential adverse side effects

• Agitated patients are often hypertensive, increase stress hormones, and require more intensive nursing care

The Need for Sedation

• Anxiety• Pain• Acute confusional status• Mechanical ventilation• Treatment or diagnostic procedures• Psychological response to stress

• Patient comfort and • Control of pain• Anxiolysis and amnesia• Blunting adverse autonomic and

hemodynamic responses• Facilitate nursing management• Facilitate mechanical ventilation• Avoid self-extubation• Reduce oxygen consumption

Goals of sedation in the ICU

Characteristics of an ideal sedation agents for the ICU

• Lack of respiratory depression• Analgesia, especially for surgical patients• Rapid onset, titratable, with a short

elimination half-time• Sedation with ease of orientation and

arousability• Anxiolytic• Hemodynamic stability

The Challenges of ICU Sedation

• Assessment of sedation• Altered pharmacology• Tolerance• Delayed emergence• Withdrawal• Drug interaction

Sedation

SedativesCauses for Agitation

Undersedation

Sedatives

Causes for AgitationAgitation & anxietyPain and discomfortCatheter displacementInadequate ventilationHypertensionTachycardiaArrhythmiasMyocardial ischemiaWound disruptionPatient injury

Oversedation

Sedatives

Causes for Agitation

Prolonged sedationDelayed emergenceRespiratory depressionHypotensionBradycardiaIncreased protein breakdownMuscle atrophyVenous stasisPressure injuryLoss of patient-staff interactionIncreased cost

Correctable Causes of Agitation• Full bladder• Uncomfortable bed position• Inadequate ventilator flow rates• Mental illness• Uremia• Drug side effects• Disorientation• Sleep deprivation• Noise• Inability to communicate

Causes of Agitation Not to be Overlooked

• Hypoxia• Hypercarbia• Hypoglycemia• Endotracheal tube malposition• Pneumothorax• Myocardial ischemia• Abdominal pain• Drug and alcohol withdrawal

Altered PharmacologyMidazolam and Age

00.5

11.5

22.5

33.5

44.5

5

10 20 30 40 50 60 70 80

Age (y)

T 1 / 2

hou

rs

Harper et al. Br J Anesth, 1985;57:866-871

Delayed Emergence

• Overdose (prolonged infusion)– pK derived from healthy patients– Drug interaction– Individual variation

• Delayed elimination– Liver (Cp450)– Kidney dysfunction– Active metabolites

Morphine Metobolism

M orp h in e-3 -GA n tian a lg es ic

N orm orp h in eN eu ro toxic ity

M orp h in e-6 -GA n a lg es ic (4 0 X )

M orp h in eTyp e t it le h e re

80% 10%

Withdrawal

• Withdrawal from preoperative drugs• Sudden cessation of sedation

– Return of underlying agitation• Hyperadrenergic syndrome

– Hypertension, tachycardia,sweating• Opioid withdrawal

– Salivation, yawning, diarrhea

Drug InteractionsDiazepam-Morphine Interaction

Synergism

Antagonism

Morphine

Diazepam

ED50 isobologramRighting reflexIn rats

Kissin et al. Anesthesiology. 1989, 70:689-694

Strategies for Patient Comfort

• Set treatment goal• Quantitate sedation and pain• Choose the right medication• Use combined infusion• Reevaluate need• Treat withdrawal

Set Treatment Goal

Sedation Analgesia

Amnesia AnxiolysisHypnosis

Patient Comfort

Quantitate Sedation & Analgesia

• Subjective measure• Objective measures

Sedation Scoring Scales

• Ramsay Sedation Scale (RSS)• Sedation-agitation Scale (SAS)• Observers Assessment of

Alertness/Sedation Scale (OAASS)• Motor Activity Assessment Scale (MAAS)

BMJ 1974;2:656-659Crit Care Med 1999;27:1325-1329J Clin Psychopharmacol 1990;10:244-251Crit Care Med 1999;27:1271-1275

The Ramsay Scale

Scale Description1 Anxious and agitated or restless, or both

2 Cooperative, oriented, and tranquil

3 Response to commands only

4 Brisk response to light glabellar tap or loud auditory stimulus

5 Sluggish response to light glabellar tap or loud auditory stimulus

6 No response to light glabellar tap or loud auditory stimulus

The Riker Sedation-Agitation ScaleScore Description Definition

7 Dangerous agitation Pulling at endotracheal tube, trying to strike at staff, thrashing side to side

6 Very agitated Does not calm despite frequent verbal commands, biting ETT

5 Agitated Anxious or mildly agitated, attempting to sit

4 Calm and cooperative

Calm, awakens easily, follows commands

3 Sedated Difficult to arouse, awakens to verbal stimuli, follows simple commands

2 Very sedated Arouse to physical stimuli, but does not communicate spontaneously

1 Unarousable Minimal or no response to noxious stimuli

The Motor Activity Assessment Scale

Score Description Definition6 Dangerous agitation Pulling at endotracheal tube, trying to strike

at staff, thrashing side to side

5 Agitated Does not calm despite frequent verbal commands, biting ETT

4 Restless and cooperative

Anxious or mildly agitated, attempting to sit

3 Calm and cooperative

Calm, awakens easily, follows commands

2 Responsive to touch or name

Opens eyes or raises eyebrows or turns head when touched or name is loudly spoken

1 Responsive only to noxious stimuli

Opens eyes or raises eyebrows or turns head with noxious stimuli

0 Unresponsive Does not move with noxious stimuli

What Sedation Scales Do

• Provide a semiquantitative “score”• Standardize treatment endpoints• Allow review of efficacy of sedation• Facilitate sedation studies• Help to avoid oversedation

What Sedation Scales Don’t Do

• Assess anxiety• Assess pain• Assess sedation in paralyzed patients• Predict outcome• Agree with each other

BIS Monitoring

BIS Monitoring

                 

BIS Range GuidelinesAwake

Responds to loud commands or mild prodding/shaking

Low probability to explicit recallsUnresponsive to verbal stimuli

Burst suppression

Flat line EEG

Responds to normal voice Axiolysis

Moderatesedation

Deep Sedation

100

80

60

40

20

0

BIS

Pain

Assess Pain Separately

Visual Pain Scales

0 1 2 3 4 5 6 7 8 9 10

No pain Worst possible pain

Signs of Pain

• Hypertension• Tachycardia• Lacrimation• Sweating• Pupillary dilation

Principles of Pain Management• Anticipate pain• Recognize pain

– Ask the patient– Look for signs– Find the source

• Quantify pain • Treat:

– Quantify the patient’s perception of pain– Correct the cause where possible– Give appropriate analgesics regularly as required

• Remember, most sedative agents do not provide analgesia• Reassess

Nonpharmacologic Interventions

• Proper position of the patient• Stabilization of fractures• Elimination of irritating stimulation• Proper positioning of the ventilator tubing

to avoid traction on endotracheal tube

Choose the Right Drug

• Benzodiazepines• Propofol• Opioids-2 agonists

Choose the Right Drug

Sedation Analgesia

Amnesia AnxiolysisHypnosis

Benzodiazepines

Benzodiazepines

Onset Peaks Duration

Diazepam 2-5 min 5-30 min >20 hr

Midazolam 2-3 min 5-10 min 30-120 min

Lorazepam 5-20 min 30 min 10-20 hr

Choose the Right Drug

Sedation Analgesia

Amnesia AnxiolysisHypnosis

Propofol

Propofol

Onset Peaks Duration

Propofol 30-60 sec 2-5 min short

Propofol Dosing

• 3-5 g/kg/min antiemetic• 5-20 g/kg/min anxiolytic• 20-50 g/kg/min sedative hypnotic• >100 g/kg/min anesthetic

Choose the Right Drug

Sedation Analgesia

Amnesia AnxiolysisHypnosis

Opioids

Pharmacology of Selected Analgesics

Agent Dose (iv) Half-life Metabolic pathway Active metabolites

Fentanyl 200 g 1.5-6 hr Oxidation NoneHydromorphone 1.5 mg 2-3 hr Glucuronidation None

Morphine 10 mg 3-7 hr Glucuronidation Yes (Sedation in RF)

Meperidine 75-100 mg

3-4 hr Demethylation & hydroxylation

Yes (neuroexcitation in RF)

Codeine 120 mg 3 hr Demethylation & Glucuronidation

Yes ( analgesia, sedation)

Remifentanil 3-10 min Plasma esterase NoneKeterolac 2.4-8.6 hr Renal None

Opioids

Lipid Solubility

Histamine Release

Potency

Morphine +/- +++ 1

Hydromorphone + + 5

Fentanyl +++ - 50

Opioids

Onset Peaks Duration

Morphine 2 min 20 min 2-7 hr

Fentanyl 30 sec 5-15 min 30-60 min

Problems with Current Sedative Agents

Midazolam Propofol OpioidsProlonged weaning X - XRespiratory depression X - XSevere hypotension X X -Tolerance X - XHyperlipidemia - X -Increased infection - X -Constipation - - XLack of orientation and cooperation

X X X

Choose the Right Drug

Sedation Analgesia

Amnesia AnxiolysisHypnosis

-2 agonists

Alpha-2 Receptors

Brain(locus ceruleus)

Spinal Cord

Peripheral vasculature

SedationAnxiolysis

Sympatholysis

Analgesia

Vasoconstriction

DEX: Dosing

Loading infusion0.25-1 g/kg(10-20 min)

Maintenance infusion0.2-0.7 g/kg/hr

Use Continuous and Combined Infusion

Plasma Level

Load

Maintenance

Repeated Bolus

Plasma levels

Opioid + Hypnotic Infusion

Fentanyl + Midazolam or Propofol

Analgesia AmnesiaAnxiolysisHypnosis

Continuous Infusion Regimens

Fentanyl 25-250 g/h

Midazolam 0.5-5 mg/hr

Propofol 15-50 g/kg/min

Choose the Right Drug

Sedation Analgesia

Amnesia AnxiolysisHypnosis

-2 agonistsPrimary

Adjunct sedation Propofol

Choose the Right Drug

Sedation Analgesia

Amnesia AnxiolysisHypnosis

-2 agonistsPrimary

Adjunct sedation Midazolam

Choose the Right Drug

Sedation Analgesia

Amnesia AnxiolysisHypnosis

-2 agonistsPrimary

Adjunct analgesia Morphine

Choose the Right Drug

Sedation Analgesia

Amnesia AnxiolysisHypnosis

-2 agonistsPrimary

Adjunct analgesia Fentanyl

Reassess Need

• Use sedation score as endpoint• Initiate sedation incrementally to desired

level• Periodically (q day) titrate infusion rate

down until the patient begins to emerge• Gradually increase infusion rate again to

desired level of sedation

Barr, Donner. Crit Care Clin. 1995;11827

Treat Withdrawal

• Acute management– Resume sedation– Beta-blockade, dexmedetomidine

• Prolonged management– Methadone 5-10 mg VT bid– Clonidine 0.1-0.2 mg VT q8h– Lorazepam 1-2 mg IV q8h