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 Description

1 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 Definition

6 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 Guidelines

Awake

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 None

Hydromorphone 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 None

Keterolac 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 Opioids

Prolonged weaning X - X

Respiratory depression X - X

Severe hypotension X X -

Tolerance X - X

Hyperlipidemia - X -

Increased infection - X -

Constipation - - X

Lack 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