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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
Neuromuscular Blocking AgentsNeuromuscular 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 AgentsNeuromuscular 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 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.
Case Scenario #2Case 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 - AnswerCase 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 #3Case 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 - AnswerCase 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.