Sedation

Sedation, Analgesia, and Sedation, Analgesia, and Neuromuscular Blockade in the Neuromuscular Blockade in the

Adult ICU Adult ICU

Giuditta Angelini, MDGiuditta Angelini, MDUniversity of Wisconsin

Madison, WI

Gil Fraser, PharmD, FCCMGil Fraser, PharmD, FCCMMaine Medical Center

Portland, ME

Doug Coursin, MD, FCCMDoug Coursin, MD, FCCMUniversity of Wisconsin

Madison, WI

ObjectivesObjectives

Participants should be able to:Describe the SCCM guidelines for sedation, analgesia, and chemical paralysis

Describe the benefits of daily awakening/lightening and sedation titration programs

Devise a rational pharmacologic strategy based on treatment goals and comorbidities Participants should be able to:

Describe the SCCM guidelines for sedation, analgesia, and chemical paralysis

Describe the benefits of daily awakening/lightening and sedation titration programs

Devise a rational pharmacologic strategy based on treatment goals and comorbidities

What We Know About ICU What We Know About ICU Agitation/DiscomfortAgitation/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 ICURecall 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 ImportantAppropriate 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.

Daily Goal is Arousable, Daily Goal is Arousable, Comfortable SedationComfortable 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 ToolsProtocols 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.)

Sedating/Analgesia OptionsSedating/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 AlgorithmOverview of SCCM Algorithm

Yes

Reassess goal daily,Titrate and taper therapy to maintain goal,Consider daily wake-up,Taper if > 1 week high-dose therapy & monitorfor withdrawal

No

Set Goalfor

Analgesia

Hemodynamically UnstableFentanyl 25 - 100 mcg IVP Q 5-15 min, orHydromorphone 0.25 - 0.75 mg IVP Q 5 - 15 min

Hemodynamically stableMorphine 2 - 5 mg IVP Q 5 - 15 min

Repeat until pain controlled, then scheduled doses + prn

Set Goalfor

Sedation

Acute Agitation #

Midazolam 2 - 5 mg IVP Q 5 - 15 min untilacute event controlled

Ongoing Sedation #

Lorazepam 1 - 4 mg IVP Q 10-20 min untilat goal then Q 2 - 6 hr scheduled + prn , orPropofol start 5 mcg/kg/min, titrate Q 5 minuntil at goal

Set Goalfor Controlof Delirium

Haloperidol 2 - 10 mg IVP Q 20 - 30 min,then 25% of loading dose Q 6hr x 2-3 days,then taper

IVP Dosesmore often than Q

2hr?

Consider continuousinfusion opiate or

sedative

> 3 Days Propofol?(except neuro pt.)

Convert toLorazepam

Yes

Benzodiazepine or Opioid:Taper Infusion Rate by

10-25% Per Day

Yes

Dosesapproximate for

70kg adult

Rule out and Correct Reversible Causes

Use Non-pharmacologic Treament,Optimize the Environment

ALGORITHM FOR SEDATION AND ANALGESIA OF MECHANICALLY VENTILATED PATIENTS

Use Pain Scale * toAssess for Pain

Use Sedation Scale **

to Assess forAgitation/Anxiety

Use Delirium Scale *** toAssess for Delirium

Is the Patient Comfortable & at Goal?

Lorazepam viainfusion?

Use a low rate and IVPloading doses

1

2

3

4

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

Address PainAddress Pain

Set G oalfor

Analgesia

Hem odynam ically UnstableFentanyl 25 - 100 m cg IVP Q 5-15 m in, orHydromorphone 0.25 - 0.75 m g IVP Q 5 - 15 m in

Hem odynam ically stableMorphine 2 - 5 m g IVP Q 5 - 15 m in

Repeat until pain controlled, then scheduled doses + prn

Use Pain Scale * toAssess for Pain

Reassess goal daily,T itrate and taper therapy to m aintain goal,Consider daily wake-up,Taper if > 1 week high-dose therapy & m onitorfor withdrawal

Is the Patient Com fortable & at Goal?

OpiatesOpiates

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, Opiate Analgesic Options: Fentanyl, Morphine, HydromorphoneMorphine, Hydromorphone

Fentanyl Hydromorphone Morphine

Rapid onset X

Rapid offset X*

Avoid in renal disease X**

Preload reduction X

Avoid in hemodynamic instability

X

Equivalent doses 100 mcg 1.5 mg 10 mg

* Offset prolonged after long-term use

** Active metabolite accumulation causes excessive narcosis

Sample Analgesia ProtocolSample Analgesia Protocol

Numeric Rating Scale

Address SedationAddress Sedation

Set G oalfor

Sedation

Acute Agitation #

Midazolam 2 - 5 m g IVP Q 5 - 15 m in untilacute event controlled

Ongoing Sedation #

Lorazepam 1 - 4 m g IVP Q 10-20 m in untilat goal then Q 2 - 6 hr scheduled + prn, orPropofol start 5 m cg/kg/m in, titrate Q 5 m inuntil at goal

IVP Dosesm ore often than Q

2hr?

Consider continuousinfusion opiate or

sedative

> 3 Days Propofol?(except neuro pt.)

Convert toLorazepam

Benzodiazepine or Opioid:Taper Infusion Rate by

10-25% Per Day

Use Sedation Scale **

to Assess forAgitation/Anxiety

Lorazepam viainfusion?

Use a low rate and IVPloading doses

Yes

Reassess goal daily,T itrate and taper therapy to m aintain goal,Consider daily wake-up,Taper if > 1 week high-dose therapy & m onitorfor withdrawal

Is the Patient Com fortable & at Goal?

Sedation Options: Benzodiazepines Sedation Options: Benzodiazepines (Midazolam and Lorazepam)(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: PropofolSedation Options: PropofolPharmacology: 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 ProtocolSample Sedation Protocol

Sedation-agitation Scale

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

Sedation Options: DexmedetomidineSedation Options: DexmedetomidineAlpha-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

Opiate and Benzodiazepine WithdrawalOpiate 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 DeliriumSignificance 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

DeliriumDelirium

1. Acute onset of mental status changes or a fluctuating course

&2. Inattention

&

or

Courtesy of W Ely, MD

3. Disorganized Thinking

4. Altered level of consciousness

Risk Factors for DeliriumRisk Factors for Delirium

Primary CNS Dx

Infection

Metabolic derangement

Pain

Sleep deprivation

Age

Substances including tobacco (withdrawal as well as direct effect)

Diagnostic Tools: ICUDiagnostic 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 ChecklistDelirium Screening Checklist

No Patient Participation• Delirium Screening Checklist

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

Treatment of DeliriumTreatment 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

HaloperidolHaloperidol

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, Atypical Antipsychotics: Quetiapine, Olanzapine, Risperidone, ZiprasidoneOlanzapine, 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) Neuromuscular Blockade (NMB) (Paralytics) in the Adult ICUin 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 ICUNeuromuscular 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 AgentsNeuromuscular 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 Quick Onset Muscle Relaxants for IntubationIntubation

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 Potential Contraindications of SuccinylcholineSuccinylcholine

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


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)


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 several renally excreted active metabolites

• Elimination of cisatracurium is not affected by organ dysfunction, but it is expensive

Monitoring NMBAsMonitoring 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 ParalysisMonitoring 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 Complications of Neuromuscular Blocking AgentsAgents

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 ProtocolSample NMBA Protocol

ReferencesReferences

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 #1Case 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 - AnswerCase 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.


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?


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.


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?


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.

Sedation

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