Sedation, Analgesia, and
Neuromuscular Blockade in the
Adult ICU
Division of Critical Care Medicine
University of Alberta
Objectives

SCCM guidelines for sedation, analgesia, and chemical paralysis

Benefits of daily awakening/lightening and sedation titration programs

Devise a rational pharmacologic strategy based on treatment goals and
comorbidities
Agitation/Discomfort : The Problem
Prevalence
•
50% incidence in those with length of stay > 24 hours
Causes: uncontrolled pain, delirium, anxiety, sleep
deprivation, etc.
Immediate Sequelae:
•
•
•
•
Patient-ventilator dys-synchrony > respiratory failure
Increased oxygen consumption
Self (and health care provider) injury
Family anxiety
Long-term Sequelae: chronic anxiety disorders and posttraumatic stress disorder (PTSD)
Recall in the ICU
Some degree of recall occurs in up to 70% of ICU
patients.
•
Anxiety, fear, pain, panic, agony, or nightmares reported in 90% of
those who did have recall.
Potentially cruel:
•
Up to 36% recalled some aspect of paralysis.
Associated with PTSD in ARDS?
•
41% risk of recall of two or more traumatic experiences.
Associated with PTSD in cardiac surgery
Appropriate Recall May be Important
Factual memories (even unpleasant ones) help to put
ICU experience into perspective
Delusional memories risk panic attacks and PTSD
The optimal level of sedation for most patients is that
which offers comfort while allowing for interaction with
the environment. This IS NOT THE SAME AS COMA.
Daily Goal is Arousable,
Comfortable Sedation
Sedation needs to be titrated to goal:
•
Lighten sedation to appropriate wakefulness daily
Effect of this strategy on outcomes:
•
•
•
One- to seven-day reduction in length of sedation and
mechanical ventilation needs
50% reduction in tracheostomies
Three-fold reduction in the need for diagnostic evaluation of CNS
Protocols and Assessment Tools
Titration of sedatives and analgesics guided by
assessment tools:
•
Ramsay Sedation Scale [RSS], Sedation-Agitation Scale [SAS],
Richmond Sedation-agitation Scale [RSAS], etc.
- No evidence that one is preferred over another
•
Pain assessment tools - none validated in ICU (numeric rating scale
[NRS], visual analogue scale [VAS], etc.)
Sedating/Analgesia Options
Rule out reversible causes of discomfort/anxiety such as
hypoxemia, hypercarbia, and toxic/drug side effect.
Assess comorbidities and potential side effects of drugs
chosen.
Target irreversible etiologies of pain and agitation
Overview of SCCM Algorithm
ALGORITHM FOR SEDATION AND ANALGESIA OF MECHANICALLY VENTILATED PATIENTS
Is the Patient Comfortable & at Goal?
Yes
No
Reassess goal daily,
Titrate and taper therapy to maintain goal,
Consider daily wake-up,
Taper if > 1 week high-dose therapy & monitor
for withdrawal
Rule out and Correct Reversible Causes
1
2
3
Use Non-pharmacologic Treament,
Optimize the Environment
*
Use Pain Scale to
Assess for Pain
Use Sedation Scale
to Assess for
Agitation/Anxiety
**
Hemodynamically Unstable
Fentanyl 25 - 100 mcg IVP Q 5-15 min, or
Hydromorphone 0.25 - 0.75 mg IVP Q 5 - 15 min
Hemodynamically stable
Morphine 2 - 5 mg IVP Q 5 - 15 min
Set Goal
for
Analgesia
Ongoing Sedation #
Lorazepam 1 - 4 mg IVP Q 10-20 min until
at goal then Q 2 - 6 hr scheduled + prn, or
Propofol start 5 mcg/kg/min, titrate Q 5 min
until at goal
(except neuro pt.)
Use Delirium Scale *** to
Assess for Delirium
Consider continuous
infusion opiate or
sedative
Lorazepam via
infusion?
Use a low rate and IVP
loading doses
Acute Agitation #
Midazolam 2 - 5 mg IVP Q 5 - 15 min until
acute event controlled
> 3 Days Propofol?
4
Yes
Repeat until pain controlled, then scheduled doses
+ prn
Set Goal
for
Sedation
Yes
IVP Doses
more often than Q
2hr?
Benzodiazepine or Opioid:
Taper Infusion Rate by
10-25% Per Day
Convert to
Lorazepam
Set Goal
for Control
of Delirium
Haloperidol 2 - 10 mg IVP Q 20 - 30 min,
then 25% of loading dose Q 6hr x 2-3 days,
then taper
Jacobi J, Fraser GL, Coursin D, et al. Crit Care Med. 2002;30:119-141.
Doses
approximate for
70kg adult
Address Pain
Is the Patient Comfortable & at Goal?
Reassess goal daily,
Titrate and taper therapy to maintain goal,
Consider daily wake-up,
Taper if > 1 week high-dose therapy & monitor
for withdrawal
Use Pain Scale * to
Assess for Pain
Set Goal
for
Analgesia
Hemodynamically Unstable
Fentanyl 25 - 100 mcg IVP Q 5-15 min, or
Hydromorphone 0.25 - 0.75 mg IVP Q 5 - 15 min
Hemodynamically stable
Morphine 2 - 5 mg IVP Q 5 - 15 min
Repeat until pain controlled, then scheduled doses
+ prn
Opiates
Benefits
•
•
Relieve pain or the sensibility to noxious stimuli
Sedation trending toward a change in sensorium, especially with more lipid
soluble forms including morphine and hydromorphone.
Risks
•
•
•
•
•
•
•
•
Respiratory depression
NO amnesia
Pruritus
Ileus
Urinary retention
Histamine release causing venodilation predominantly from morphine
Morphine metabolites which accumulate in renal failure can be analgesic
and anti-analgesic.
Meperidine should be avoided due to neurotoxic metabolites which
accumulate, especially in renal failure, but also produces more sensorium
changes and less analgesia than other opioids.
Opiate Analgesic Options: Fentanyl,
Morphine, Hydromorphone
Fentanyl
Rapid onset
X
Rapid offset
X*
Hydromorphone
Avoid in renal disease
Morphine
X**
Preload reduction
X
Avoid in hemodynamic
instability
X
Equivalent doses
100 mcg
* Offset prolonged after long-term use
** Active metabolite accumulation causes excessive narcosis
1.5 mg
10 mg
Sample Analgesia Protocol
Numeric Rating Scale
Address Sedation
Is the Patient Comfortable & at Goal?
Reassess goal daily,
Titrate and taper therapy to maintain goal,
Consider daily wake-up,
Taper if > 1 week high-dose therapy & monitor
for withdrawal
IVP Doses
more often than Q
2hr?
Consider continuous
infusion opiate or
sedative
Use Sedation Scale **
to Assess for
Agitation/Anxiety
Set Goal
for
Sedation
Ongoing Sedation #
Lorazepam 1 - 4 mg IVP Q 10-20 min until
at goal then Q 2 - 6 hr scheduled + prn, or
Propofol start 5 mcg/kg/min, titrate Q 5 min
until at goal
> 3 Days Propofol?
(except neuro pt.)
Yes
Acute Agitation #
Midazolam 2 - 5 mg IVP Q 5 - 15 min until
acute event controlled
Convert to
Lorazepam
Lorazepam via
infusion?
Use a low rate and IVP
loading doses
Benzodiazepine or Opioid:
Taper Infusion Rate by
10-25% Per Day
Sedation Options: Benzodiazepines
(Midazolam and Lorazepam)
Pharmacokinetics/dynamics
•
•
Lorazepam: onset 5 - 10 minutes, half-life 10 hours, glucuronidated
Midazolam: onset 1 - 2 minutes, half-life 3 hours, metabolized by cytochrome
P450, active metabolite (1-OH) accumulates in renal disease
Benefits
•
•
•
Anxiolytic
Amnestic
Sedating
Risks
•
•
•
•
Delirium
NO analgesia
Excessive sedation: especially after long-term sustained use
Propylene glycol toxicity (parenteral lorazepam): significance uncertain
- Evaluate when a patient has unexplained acidosis
- Particularly problematic in alcoholics (due to doses used) and renal failure
•
Respiratory failure (especially with concurrent opiate use)
•
Withdrawal
Sedation Options: Propofol
Pharmacology: GABA agonist
Pharmacokinetics/dynamics: onset 1 - 2 minutes, terminal
half-life 6 hours, duration 10 minutes, hepatic metabolism
Benefits
•
•
•
Rapid onset and offset and easily titrated
Hypnotic and antiemetic
Can be used for intractable seizures and elevated intracranial pressure
Risks
•
•
•
•
•
•
Not reliably amnestic, especially at low doses
NO analgesia!
Hypotension
Hypertriglyceridemia; lipid source (1.1 kcal/ml)
Respiratory depression
Propofol Infusion Syndrome
- Cardiac failure, rhabdomyolysis, severe metabolic acidosis, and renal failure
- Caution should be exercised at doses > 80 mcg/kg/min for more than 48 hours
- Particularly problematic when used simultaneously in patient receiving
catecholamines and/or steroids
Sample Sedation Protocol
Sedation-agitation Scale
Riker RR et al. Crit Care Med. 1999;27:1325.
Opiate and Benzodiazepine Withdrawal
Frequency related to dose and duration
•
32% if receiving high doses for longer than a week
Onset depends on the half-lives of the parent drug and its active
metabolites
Clinical signs and symptoms are common among agents
•
•
•
CNS activation: seizures, hallucinations,
GI disturbances: nausea, vomiting, diarrhea
Sympathetic hyperactivity: tachycardia, hypertension, tachypnea, sweating,
fever
No prospectively evaluated weaning protocols available
•
•
10 - 20% daily decrease in dose
20 - 40% initial decrease in dose with additional daily reductions of 10 20%
Consider conversion to longer acting agent or transdermal
delivery form
Significance of ICU Delirium
Seen in > 50% of ICU patients
Three times higher risk of death by six months
Five fewer ventilator free days (days alive and off
vent.), adjusted P = 0.03
Four times greater frequency of medical device removal
Nine times higher incidence of cognitive impairment at
hospital discharge
Delirium
1. Acute onset of mental status changes or
a fluctuating course
&
2. Inattention
&
3. Disorganized
Thinking
or
Courtesy of W Ely, MD
4. Altered level of
consciousness
Risk Factors for Delirium
Primary CNS Dx
Infection
Metabolic derangement
Pain
Sleep deprivation
Age
Substances including tobacco (withdrawal as well as
direct effect)
Diagnostic Tools: ICU
Routine monitoring
recommended by SCCM
•
Only 6% of ICUs use
Confusion Assessment
Method (CAM-ICU) or
Delirium Screening Checklist
(DSC)
Requires Patient
Participation
•
•
•
Ely. JAMA. 2001;286: 2703-2710.
Cognitive Test for Delirium
Abbreviated Cognitive Test
for Delirium
CAM-ICU
Delirium Screening Checklist
No Patient Participation
•
Delirium Screening Checklist
Bergeron. Intensive Care Med. 2001;27:859.
Treatment of Delirium
Correct inciting factor, but as for pain…relief need not be
delayed while identifying causative factor
Control symptoms?
•
•
•
No evidence that treatment reduces duration and severity of
symptoms
Typical and atypical antipsychotic agents
Sedatives?
-
Particularly in combination with antipsychotic and for drug/alcohol
withdrawal delirium
Haloperidol
No prospective randomized controlled trials in ICU
delirium
> 700 published reports involving > 2,000 patients
The good:
•
•
Hemodynamic neutrality
No effect on respiratory drive
The bad:
•
•
•
QTc prolongation and torsades de pointes
Neuoroleptic malignant syndrome - only three cases with IV
haloperidol
Extrapyramidal side effects - less common with IV than oral
haloperidol
Atypical Antipsychotics: Quetiapine,
Olanzapine, Risperidone, Ziprasidone
Mechanism of action unknown
Less movement disorders than haloperidol
Enhanced effects on both positive (agitation) and negative
(quiet) symptoms
Efficacy = haloperidol?
•
One prospective randomized study showing equal efficacy of olanzapine
to haldol with less EPS
Issues
•
•
•
Lack of available IV formulation
Troublesome reports of CVAs, hyperglycemia, NMS
Titratability hampered
- QTc prolongation with ziprasidone IM
- Hypotension with olanzapine IM
Neuromuscular Blockade (NMB)
(Paralytics) in the Adult ICU
Used most often acutely (single dose) to facilitate
intubation or selected procedures
Issues
•
•
•
•
NO ANALGESIC or SEDATIVE properties
Concurrent sedation with amnestic effect is paramount (analgesic as
needed)
Never use without the ability to establish and/or maintain a definitive
airway with ventilation
If administering for prolonged period (> 6 - 12 hours), use an objective
monitor to assess degree of paralysis.
Neuromuscular Blockade in the ICU
Current use in ICU limited because of risk of prolonged
weakness and other complications
•
Maximize sedative/analgesic infusions as much as possible prior to
adding neuromuscular blockade
Indications
•
•
•
•
•
Facilitate mechanical ventilation, especially with abdominal
compartment syndrome, high airway pressures, and dyssynchrony
Assist in control of elevated intracranial pressures
Reduce oxygen consumption
Prevent muscle spasm in neuroleptic malignant syndrome, tetanus, etc.
Protect surgical wounds or medical device placement
Neuromuscular Blocking Agents
Two classes of NMBS:
•
Depolarizers
- Succhinylcholine is the only drug in this class
- Prolonged binding to acetylcholine receptor to produce depolarization
(fasciculations) and subsequent desensitization so that the motor endplate
cannot respond to further stimulation right away
•
Nondepolarizers
- Blocks acetylcholine from postsynaptic receptor competitively
- Benzylisoquinoliniums
•
Curare, atracurium, cisatracurium, mivacurium, doxacuronium
- Aminosteroids
•
Pancuronium, vecuronium, rococuronium
Quick Onset Muscle Relaxants for
Intubation
Patients with aspiration risk need rapid onset paralysis
for intubation.
Not usually used for continuous maintenance infusions
Rocuronium
•
•
Nondepolarizer with about an hour duration and 10% renal elimination
Dose is 1.2 mg/kg to have intubating conditions in 45 seconds
Succinylcholine
•
•
•
Depolarizer with a usual duration of 10 minutes
All or none train of four after administration due to desensitization (can
be prolonged in patients with abnormal plasma cholinesterase)
Dose is 1 - 2 mg/kg to have intubating conditions in 30 seconds
Potential Contraindications of
Succinylcholine
Increases serum potassium by 0.5 to 1 meq/liter in all
patients
Can cause bradycardia, anaphylaxis, and muscle pain
Potentially increases intragastric, intraocular, and
intracranial pressure
Severely elevates potassium due to proliferation of
extrajunctional receptors in patients with denervation
injury, stroke, trauma, or burns of more than 24 hours
Neuromuscular Blocking Agents
Nondepolarizing muscle relaxants
•
•
•
•
Pancuronium, vecuronium, rocuronium, cisatracurium
All rapid onset (2 - 3 minutes)
Differ in duration (pancuronium 1 - 2 hours, rocuronium 0.5 hours,
cisatracurium 0.5 hours)
Differ in route of elimination (pancuronium = renal/liver, vecuronium =
renal/bile, cisatracurium = Hoffman degradation)
Neuromuscular Blocking Agents
Infusion doses
•
•
•
Pancuronium 0.05 - 0.1 mg/kg/h
Rocuronium 0.05 - 0.1 mg/kg/h
Cisatracurium 0.03 - 0.6 mg/kg/h
Other distinguishing features
•
•
•
Pancuronium causes tachycardia
Rocuronium is neutral
Elimination of cisatracurium is not affected by organ dysfunction, but it
is expensive
Monitoring NMBAs
Goal - To prevent prolonged weakness associated with
excessive NMBA administration
Methods:
•
•
•
Perform NMBA dose reduction or cessation once daily if possible
Clinical evaluation: Assess skeletal muscle movement and respiratory
effort
Peripheral nerve stimulation
- Train of four response consists of four stimulae of 2 Hz, 0.2 msec in
duration, and 500 msec apart.
- Comparison of T4 (4th twitch) and T1 with a fade in strength means that
75% of receptors are blocked.
- Only T1 or T1 and 2 is used for goal in ICU and indicates up to 90% of
receptors are blocked.
Monitoring Sedation During Paralysis
Bispectral index is based on cumulative observation of a large
number of clinical cases correlating clinical signs with EEG
signals.
While used to titrate appropriate sedation (and amnesia) in
anesthetized patients to the least amount required, not proven
to achieve this goal.
Increased potential for baseline neurologic deficit and EEG
interference in ICU patients
No randomized controlled studies to support reliable use in ICU.
Other neuromonitoring (awareness) modalities are likely to be
developed.
Cessation of NMB as soon as safe in conjunction with other
patient parameters should be a daily consideration.
Complications of Neuromuscular Blocking
Agents
Associated with inactivity:
•
Muscle wasting, deconditioning, decubitus ulcers, corneal drying
Associated with inability to assess patient:
•
Recall, unrelieved pain, acute neurologic event, anxiety
Associated with loss of respiratory function:
•
Asphyxiation from ventilator malfunction or accidental extubation,
atelectasis, pneumonia
Other:
•
Prolonged paralysis or acute NMBA related myopathy
- Related to decreased membrane excitability or even muscle necrosis
- Risk can be compounded by concurrent use of steroids.
Sample NMBA Protocol
References
Jacobi J, et al. Crit Care Med. 2002;30:119-141.
Jones, et al. Crit Care Med. 2001;29:573-580.
Cammarano, et al. Crit Care Med. 1998;26:676.
Ely, et al. JAMA. 2004;292:168.
Case Scenario #1
22-year-old male with isolated closed head injury who was
intubated for GCS of 7
He received 5 mg of morphine, 40 mg of etomidate, and 100
mg of succinylcholine for his intubation.
He is covered in blood spurting from an arterial catheter that
was just removed, and he appears to be reaching for his
endotracheal tube.
What sedative would you use and why?
What are the particular advantages in this situation?
How could you avoid the disadvantages of this drug?
Case Scenario #1 - Answer
Propofol will rapidly calm a patient who is displaying
dangerous behavior without need for paralysis.
Titratable and can be weaned quickly to allow for neurologic
exam
Can treat seizures and elevated ICP which may be present in
a head trauma with GCS of eight or less
Minimizing dose and duration will avoid side effects.
Case Scenario #2
54-year-old alcoholic who has been admitted for Staph sepsis
Intubated in the ICU for seven days and is currently on
midazolam at 10 mg/hour
His nurse was told in report that he was a “madman” on the
evening shift.
Currently, he opens his eyes occasionally to voice but does
not follow commands nor does he move his extremities to
deep painful stimulation.
Is this appropriate sedation?
What would you like to do?
How would you institute your plan of action?
Case Scenario #2 - Answer
This patient is oversedated. Not only can a neurologic exam
not be performed, but it would be unlikely to be able to
perform a wakeup test within one 24-hour period.
Given the need to examine the patient, midazolam should be
stopped immediately.
Rescue sedatives including midazolam should be available if
agitation develops.
Flumazenil should be avoided.
Case Scenario #3
62-year-old, 65-kg woman with ARDS from aspiration pneumonia
Her ventilator settings are PRVC 400, RR 18, PEEP 8, and FIO2
100%. She is dyssynchronous with the ventilator and her
plateau pressure is 37 mm Hg.
She is on propofol at 50 mcg/kg/min, which has been ongoing
since admit four days ago.
She is also on norepinephrine 0.1 mcg/kg/min and she was just
started on steroids.
What do you want to do next?
Do you want to continue the propofol?
Why or why not?
What two iatrogenic problems is she likely at risk for?
Case Scenario #3 - Answer
This patient needs optimization of her sedatives, and
potentially chemical paralysis to avoid complications of
ventilator dyssynchrony and high airway pressures.
If you continue to use propofol, higher doses are required and
the patient is already on norepinephrine. In addition, if
paralysis is used, you do not have reliable amnesia.
She is at risk for propofol infusion syndrome and critical illness
polyneuropathy.