sedation analgesia and neuromuscular blockade in the adult icu
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Sedation, Analgesia, and Neuromuscular Blockade in the Adult ICU. Giuditta Angelini , MD University of Wisconsin Madison, WI Gil Fraser, PharmD , FCCM Maine Medical Center Portland, ME Doug Coursin , MD, FCCM University of Wisconsin Madison, WI.

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sedation analgesia and neuromuscular blockade in the adult icu

Sedation, Analgesia, and Neuromuscular Blockade in the Adult ICU

GiudittaAngelini, MD

University of Wisconsin

Madison, WI

Gil Fraser, PharmD, FCCM

Maine Medical Center

Portland, ME

Doug Coursin, MD, FCCM

University of Wisconsin

Madison, WI

what we know about icu agitation discomfort
What We Know About ICU Agitation/Discomfort
  • Prevalence
    • 50% incidence in those with length of stay > 24 hours
  • Primary causes: unrelieved pain, delirium, anxiety, sleep deprivation, etc.
  • Immediate sequelae:
    • Patient-ventilator dyssynchrony
    • Increased oxygen consumption
    • Self (and health care provider) injury
    • Family anxiety
  • Long-term sequelae: chronic anxiety disorders and post-traumatic stress disorder (PTSD)
recall in the icu
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
need for sedation


Acute confusional status

Mechanical ventilation

Treatment or diagnostic procedures

Psychological response to stress

Need for Sedation
goals of sedation in icu
Goals of Sedation in ICU
  • 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
characteristics of an ideal sedation agents for 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
The Challenges of ICU Sedation
  • Assessment of sedation
  • Altered pharmacology
  • Tolerance
  • Delayed emergence
  • Withdrawal
  • Drug interaction

Causes for Agitation




Causes for Agitation

Agitation & anxiety

Pain and discomfort

Catheter displacement

Inadequate ventilation




Myocardial ischemia

Wound disruption

Patient injury


Causes for Agitation


Prolonged sedation

Delayed emergence

Respiratory depression



Increased protein breakdown

Muscle atrophy

Venous stasis

Pressure injury

Loss of patient-staff interaction

Increased cost

correctable causes of agitation
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
Causes of Agitation Not to be Overlooked
  • Hypoxia
  • Hypercarbia
  • Hypoglycemia
  • Endotracheal tube malposition
  • Pneumothorax
  • Myocardial ischemia
  • Abdominal pain
  • Drug and alcohol withdrawal
daily goal is arousable comfortable sedation
Daily Goal is Arousable, Comfortable Sedation
  • Sedation needs to be protocolized and 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
Protocols and Assessment Tools
  • SCCM practice guidelines can be used as a template for institution-specific protocols.
  • Titration of sedatives and analgesics guided by assessment tools:
    • Validated sedation 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.)
strategies for patient comfort
Strategies for Patient Comfort
  • Set treatment goal
  • Quantitate sedation and pain
  • Choose the right medication
  • Use combined infusion
  • Reevaluate need
  • Treat withdrawal
overview of sccm algorithm
Overview of SCCM Algorithm





Jacobi J, Fraser GL, Coursin D, et al. Crit Care Med. 2002;30:119-141.

visual pain scales
Visual Pain Scales

0 1 2 3 4 5 6 7 8 9 10

Worst possible


No pain

signs of pain
Signs of Pain
  • Hypertension
  • Tachycardia
  • Lacrimation
  • Sweating
  • Pupillary dilation
principles of pain management
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
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
  • 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
Opiate Analgesic Options: Fentanyl, Morphine, Hydromorphone

* Offset prolonged after long-term use

** Active metabolite accumulation causes excessive narcosis

sample analgesia protocol
Sample Analgesia Protocol

Numeric Rating Scale

sedation scoring scales
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;2:656-659

Crit Care Med 1999;27:1325-1329

J Clin Psychopharmacol 1990;10:244-251

Crit Care Med 1999;27:1271-1275

what sedation scales do
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
What Sedation Scales Don’t Do
  • Assess anxiety
  • Assess pain
  • Assess sedation in paralyzed patients
  • Predict outcome
  • Agree with each other
bis range guidelines
BIS Range Guidelines




Responds to normal voice



Responds to loud commands

or mild prodding/shaking




Low probability to explicit recalls

Unresponsive to verbal stimuli


Burst suppression

Deep Sedation


Flat line EEG


choose the right drug
Choose the Right Drug
  • Benzodiazepines
  • Propofol
  • -2 agonists
sedation options benzodiazepines midazolam and lorazepam
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
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
Sample Sedation Protocol

Sedation-agitation Scale

Riker RR et al. Crit Care Med. 1999;27:1325.

sedation options dexmedetomidine
Sedation Options: Dexmedetomidine
  • Alpha-2-adrenergic agonist like clonidine but with much less imidazole activity
  • Has been shown to decrease the need for other sedation in postoperative ICU patients
  • Potentially useful while decreasing other sedatives to prevent withdrawal
  • Benefits
    • Does not cause respiratory depression
    • Short-acting
    • Produces sympatholysis which may be advantageous in certain patients such as postop cardiac surgery
  • Risks
    • No amnesia
    • Small number of patients reported distress upon recollection of ICU period despite good sedation scores due to excessive awareness
    • Bradycardia and hypotension can be excessive, necessitating drug cessation and other intervention
propofol dosing
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
use continuous and combined infusion
Use Continuous and Combined Infusion





repeated bolus
Repeated Bolus



choose the right drug1
Choose the Right Drug









Patient Comfort

-2 agonists

altered pharmacology midazolam and age
Altered PharmacologyMidazolam and Age

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

delayed emergence
Delayed Emergence
  • Overdose (prolonged infusion)
    • pK derived from healthy patients
    • Drug interaction
    • Individual variation
  • Delayed elimination
    • Liver (Cp450)
    • Kidney dysfunction
    • Active metabolites
opiate and benzodiazepine withdrawal
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
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
  • Acute onset of mental status changes or a fluctuating course
  • &
  • 2. Inattention
  • &

3. Disorganized


4. Altered level of



Courtesy of W Ely, MD

risk factors for delirium
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
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
    • Cognitive Test for Delirium
    • Abbreviated Cognitive Test for Delirium
    • CAM-ICU
  • Ely. JAMA. 2001;286: 2703-2710.
delirium screening checklist
Delirium Screening Checklist
  • No Patient Participation
    • Delirium Screening Checklist

Bergeron. Intensive Care Med. 2001;27:859.

treatment of delirium
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
  • No treatment FDA approved
  • 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
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
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
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
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
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
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 agents1
Neuromuscular Blocking Agents
  • Nondepolarizing muscle relaxants
    • Pancuronium, vecuronium, cisatracurium
    • All rapid onset (2 - 3 minutes)
    • Differ in duration (pancuronium 1 - 2 hours, vecuronium 0.5 hours, cisatracurium 0.5 hours)
    • Differ in route of elimination (pancuronium = renal/liver, vecuronium = renal/bile, cisatracurium = Hoffman degradation)
neuromuscular blocking agents2
Neuromuscular Blocking Agents
  • Infusion doses
    • Pancuronium 0.05 - 0.1 mg/kg/h
    • Vecuronium 0.05 - 0.1 mg/kg/h
    • Cisatracurium 0.03 - 0.6 mg/kg/h
  • Other distinguishing features
    • Pancuronium causes tachycardia
    • Vecuronium has neutral effects on hemodynamics but has severalrenally excreted active metabolites
    • Elimination of cisatracurium is not affected by organ dysfunction, but it is expensive
monitoring nmbas
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
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
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.

  • 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
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
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
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
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
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
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.
  • Withdrawal from preoperative drugs
  • Sudden cessation of sedation
    • Return of underlying agitation
  • Hyperadrenergic syndrome
    • Hypertension, tachycardia,sweating
  • Opioid withdrawal
    • Salivation, yawning, diarrhea