Dr. B. Uma University College of Medical Sciences & GTB Hospital, Delhi
Oct 24, 2015
Sedation• Sedation comes from the Latin word sedare.• Sedare = to calm or to allay fear• Conscious sedation: A minimally depressed
level of consciousness induced by the administration of pharmacologic agents in which a patient retains the ability to independently and continuously maintain an open airway and a regular breathing pattern, and to respond appropriately and rationally to physical stimulation and verbal commands
Why is sedation necessary?To improve patient comfortFacilitate interventionsTo allay fear, anxiety and agitationAdequate sleepAvoid painFacilitation of mechanical ventilation/airway
management/ weaningProtection against myocardial ischemiaAmnesia during neuromuscular blockade
Goals for sedation and analgesiaTo minimize physical discomfort or pain
during proceduresTo minimize psychological disturbanceTo maximize the potential for amnesiaTo guard patient safetyTo control behavior
Complications from pain and anxietyStimulation of the autonomic nervous
system and release of humoral factors → increased heart rate, blood pressure, and myocardial oxygen consumption → myocardial ischemia or infarction
Altered humoral response can lead to
hypercoagulability as a result of increased level of factor VIII, fibrinogen, platelet activity, and inhibition of fibrinolysis
Complications (contd.)Stress hormones also produce insulin
resistance, increased metabolic rate, and protein catabolism
Immunosuppression with reduction in number and function of lymphocytes and granulocytes
Psychological disturbances - memories of vivid nightmares, hallucinations, and paranoid delusions
Assessment of pain and anxiety Any scoring system should be simple, easily
performed, noninvasive, and reproducible. Six levels of sedation are used:
1. Anxious and agitated2. Cooperative, orientated, and tranquil3. Responds to verbal commands only4. Asleep but brisk response to loud auditory
stimulus/light glabellar tap5. Asleep but sluggish response to loud
auditory stimulus/light glabellar tap6. Asleep, no response
Commonly used sedation tools
Glasgow coma scale (GCS) – assessment of level of consciousness
6 point Ramsay scale – most commonly used sedation scale
Sedation Agitation Scale (SAS)Motor Activity Assessment scale (MAAS)Richmond Agitation–Sedation Scale
Richmond agitation sedation scaleScore Term Description
+4 Combative Violent; immediate danger to staff
+3 Very agitated Pulls/ removes tubes, catheters; aggressive
+2 Agitated Frequent non purposeful movement; patient ventilator asynchrony
+1 Restless Anxious or apprehensive
0 Alert and calm
-1 Drowsy Not fully alert but awakens for >10s, with eye contact, to voice
-2 Light sedation Briefly awakens (<10s), with eye contact, to voice
-3 Moderate sedation
Any movement to voice but no eye contact
-4 Deep sedation No response to voice but movement to physical stimulation
-5 Unarousable No response to voice or physical stimulation
Ramsay sedation scaleAwake1 Anxious and/or agitated2 Cooperative, oriented, and tranquil3 Responds to commandsAsleep4 Quiescent with brisk response to
light glabellar tap or loud auditory stimulus
5 Sluggish response to light glabellar tap or loud auditory stimulus
6 No response
Sedation agitation scale1: Unarousable 2: Very sedated 3: Sedated 4: Calm and cooperative 5: Agitated 6: Very agitated 7: Dangerous agitation
Bispectral indexA practical, processed EEG parameter that
measures the direct effects of sedatives on the brain
Provides objective information about a patient’s response to sedation
Numerical scale correlates to sedation endpoints
Optimizes sedation assessment and titration
Value of BIS in ICU
Minimize consequencesof over- and
under-sedation
Improve quality of sedation management
Objective sedation assessment
Optimize clinical and economic
outcomes
Recommendation for Assessment of SedationThe use of a validated sedation assessment
scale (SAS, MAAS, or Vancouver Interaction and Calmness Scale [VICS]) is recommended. (Grade of recommendation = B)
The SCCM guidelines state: Objective measures of sedation, such as Bispectral Index, have not been completely evaluated and are not yet proven useful in the ICU. (Grade of recommendation = C)
Sedation therapyNON PHARMACOLOGICAL THERAPY:Good communication with regular
reassurance from nursing staffEnvironmental control such as humidity,
lighting, temperature, and noiseExplanation prior to proceduresManagement of thirst, hunger,
constipation, and full bladderVariety for the patient e.g. radio
Pharmacologic therapyThe sedative agent should possess the
following qualities:Both sedative and analgesic propertiesMinimal cardiovascular side effectsControllable respiratory side effectsRapid onset/offset of actionNo accumulation in renal/hepatic
dysfunctionInactive metabolitesInexpensiveNo interactions with other ICU drugs
Pharmacologic therapyBenzodiazepinesPropofolEtomidateKetamineBarbiturate Short acting opioidsAlpha 2 agonistsInhalational agents
Benzodiazepines Anxiolytic, anticonvulsant, amnesic,
hypnotic and provide some muscle relaxation
Effects are mediated by depressing the excitability of the limbic system via reversible binding at GABA-benzodiazepine receptor complex
Minimal cardiorespiratory depressant effectThe common drugs in this class are
diazepam, midazolam, and lorazepam
Benzodiazepines: MidazolamWater-soluble Short elimination half life (1-4 hrs)No long acting metabolitesIn ICU patients, midazolam's elimination
half-life may be greatly prolonged and clinically important accumulation may occur
Minimal dose: 1 to 2 mg bolusInfusions@ 0.5 to 10 mg/hr
Benzodiazepines: Diazepam
Elimination half-life of 21 to 37 hours Major active metabolite,
desmethyldiazepam, has a half-life of 48 to 96 hours
In terms of cost, diazepam has a clear advantage, being one-tenth the price of midazolam.
Minimal dose: 5 to 10mg bolusInfusions not recommended
Benzodiazepines : Lorazepam
Lower lipid-solubility than midazolam Less hypotesnion Metabolised by liver to inactive
metabolites Lower cost Loading dose: 0.02-0.06 mg/kg Infusion dose: 0.01-0.1 mg/kg/hr
MIDAZOLM LORAZEPAM DIAZEPAM
LOADING DOSE 0.02-0.1 mg/kg 0.02-0.06 mg/kg
0.05-0.2 mg/kg
MAINTANENCE DOSE
0.04-0.2 mg/kg/hr
0.01-0.1 mg/kg/hr
Rarely used
ONSET 1-5 min 5-20 min 2-5 min
DURATION 1-2 hrs 2-6 hrs 2-4 hrs
CARDIAC EFFECTS
Minimal Minimal Present
RESPIRATORY EFFECTS
Important depressant effect
Important depressant effect
Important depressant effect
ANALGESIA None None None
AMNESIA Potent None None
ACTIVE METABOLITES
Yes No Yes
COST/24HRS 4 mg/hr: $37 2 mg/hr: $52 8 mg q 4h: $24
Flumazenil Benzodiazepine antagonistGiven in incremental doses of 0.2 to 0.5
mg upto 3 mgOnset – 2 minDuration- 30 to 60 min
Propofol The mode of action of propofol is via the GABA
receptorRapid onset of action; metabolized rapidly
hepatically and extrahepatically Recovery within 10 minutes of discontinuation,
can accumulate with prolonged use Ideally infused via a large or central veinProlonged infusions –increase triglyceride and
cholesterol levels A theoretical maximum recommended dose is
4 mg/kg/hour.
Propofol (contd.)Bolus dose – not recommendedInfusions @25 to 100μg/kg/hrTheoretical maximum dose- 4mg/kg/hrCautious about propofol infusion syndrome
Propofol: adverse effectsHypotension Reliable, dose-related Decreased SVR and contractility (CO)
Respiratory depression Apnea with bolus dosing
Synergistic CV and respiratory depression with opioids
Vehicle (soybean emulsion): Hypertriglyceridemia Venoirritation Infection
Propofol infusion syndromePropofol infusion syndrome is an adverse
drug event associated with high doses (>4 mg/kg per hour or >67 µg/kg per minute) and long-term (>48 hours) use of propofol.
Clinical features:- Cardiomyopathy with acute cardiac failure.- Myopathy.- Metabolic acidosis, K+ - Hepatomegaly.
Inhibition of FFA entry into mitochondria failure of its metabolism.
Management Supportive treatments addressing the clinical
manifestations The propofol infusion should be discontinued
immediately Alternative sedative should be started Intravenous crystalloid and colloid replacement
and vasopressor and/or inotropic support Cardiac pacing may be used for symptomatic
bradycardia Hemodialysis or continuous renal replacement
therapy to treat the acute renal failure
KetamineKetamine acts at the N-methyl-D-aspartate
(NMDA) receptorIn subanesthetic doses, sedative and analgesicGenerally not used because of the increase in
blood pressure, intracranial pressure (ICP), and pulse rate
Bronchodilatory properties, sometimes has a role in severe asthma
In the ICU conjunction with a narcoticDose : 5 to 30 μg/kg/min
Others ETOMIDATE :For maintenance of hypnosis, target
concentration of 300 to 500 ng/mL may be achieved by administration of a two- or three-stage infusion
BARBITURATES: Barbiturates such as Pentothal have been used in the ICU, especially in the management of patients with head injuries and seizure disorders. They cause significant cardiovascular depression and accumulate during infusions, leading to prolonged recovery times.
Others (contd.) BUTYROPHENONES AND PHENOTHIAZINESAn aggressive dosing regimen of haloperidol may
be useful in a patient with delirium to promote calm, 2 to 10 mg IV every 10 to 15 minutes until the desired response is achieved
VOLATILE AGENTSIsoflurane has been used in concentrations of up
to 0.6% for longterm sedation, with minimal cardiorespiratory side effects and rapid awakening.
Desflurane has been shown to be effective in sedation, with rapid offset of effects.
Others (contd.)Shorter acting opioidsFentanyl, alfentanyl, remifentanyl
Muscle relaxants
α2 agonistsClonidinedexmedetomidine
2 AgonistsClonidine
Selectivity: 2:1 250:1
Imidazole derivate 16:1
t1/2 10 hrsAntihypertensive
Dexmedetomidine
Selectivity: 2:1 1620:1
Imidazole derivate 31:1t1/2 2 hrs94% protein boundEliminated by
liver/kidneySedativeOnly available in IV form
Dexmedetomidine Pharmacology of dexmedetomidine
alpha 2 agonistMolecular targets + neural substrates
locus ceruleusnatural sleep pathways
Clinical paradigms for use of dextomed in anesthesiasedation + analgesia w/o respiratory depressionattenuation of tachycardiasmooth emergence + weaning from mechanical
ventilation
Pharmacokinetics Rapid redistribution: 6 minElimination half-life: 2 hVd steady state: 118 LClearance: 39 L/hProtein binding: 94%Metabolism: biotransformation in liver to
inactive metabolites + excreted in urineNo accumulation after infusions 12-24 hPharmacokinetics similar in young adults +
elderly
SedationTypical doses (target plasma levels 0.3-1.2
ng/ml):0.5 ug/kg load, 0.5 ug/kg/hr infusion1.0 ug/kg load, 0.7 ug/kg/hr infusionIncrease dose by bolus/infusionLoad only - short proceduresPatients with high sympathetic activity
may need very high doses
Clonidine Clonidine is synergistic with opioids and
acts at the spinal cord to inhibit nociceptive inputs, thus imparting analgesia
It is contraindicated in hypovolemia and can cause hypotension, bradycardia, and dry mouth
The Art of Sedation Under sedation:Fighting the ventilator.V/Q mismatch.Accidental extubation.Catheter
displacement.CV stress ischemia.Anxiety, awareness.Post-traumatic stress
disorder.
Over sedation:Tolerance,
tachyphylaxis.Withdrawal
syndrome.Delirium.Prolonged ventilation.CV depression. neuro testing.Sleep disturbance.
Propofol
Hypertriglyceridemia
CVS depression
Hypotension
2-agonists
Hypotension
Bradycardia
Benzodiazepines
Hypotension
Respiratory depression
Agitation/ConfusionKetamine
Hypertension
Secretions
Dysphoria
GeneralOver sedation
Delayed awakening/extubation
Analgesia in ICU Pain is ‘an unpleasant sensory and
emotional experience associated with actual or potential tissue damage, or described in terms of such damage’. Thus, perception of sensory events is a requirement, but actual tissue damage is not.
Although a majority of ICU patients receive parenteral analgesics routinely , 50% of patients discharged from the ICU remember pain as their worst experience while in the ICU. This emphasizes the need for effective pain control in the ICU.
Indices of pain severity applicable in the critically illSubjectiveVisual analogue scaleNumeric rating scaleVerbal descriptor scale
ObjectiveVital signs measurementsBehavioural responses
None mild moderate severe
Verbal rating scale
І─────────────────ІNo pain Worst pain
Visual analog scale
Recommendation for assessment of painUse of the numeric rating scale(NRS) is
recommended to assess pain. (Grade of recommendation = B)
Patients who cannot communicate should be assessed through subjective observation of pain and physiological indicators and the change in these parameters following analgesic therapy. (Grade of recommendation =B)
Analgesics used in ICUPain in the critically ill is best treated with
a pure opioid agonistIn a recent clinical guideline, the
recommended choices have been narrowed to morphine, fentanyl, and hydromorphone.
Other drugs with analgesic properties and variable use in critically ill patients are :
meperidine (pethidine) tramadol nonsteroidal anti-inflammatory drugs (NSAIDs) mixed opioid agonist-antagonist agents ketamine, a sedative drug with analgesic qualities α2 agonists.
Opioids :MorphinePlasma levels do not correlate with clinical
effect. Low lipid solubility causes slow equilibration
across BBB.Metabolized in the liver by conjugation.
Morphine-6-glucuronide active metabolite with sedative action.
The analgesic dose is highly variable, and may be delivered as an intermittent boluses or as a continuous infusion.
Minimal cardiovascular side effects Relatively contraindicated in asthma and renal
failure
MorphineCNS effects mediated via μ1 and μ2
receptorsAnalgesia: pain components Affective- greater effect Sensory
Euphoria SedationMood changeMental cloudiness
FentanylFentanyl : synthetic opioid derived from
meperidine (pethidine)Short-acting opioid with rapid onsetAfter prolonged infusion the duration of
action approaches that of morphineDoes not accumulate in renal failureIt does not cause histamine release and is
suitable for analgesia in the hemodynamically unstable patient
AlfentanylAlfentanil is a synthetic opioid Onset of action about five times faster
than fentanyl, due to the small volume of distribution
Less lipid solubleThe duration of action is about one-third
that of fentanyl Alfentanil has minimal cardiovascular
effects
RemifentanilRemifentanil, an ultra-short-acting opioid
metabolized by nonspecific tissue esterasesRapid onset of actionDoes not accumulate after infusions even in
organ dysfunction.Selective mu-receptor agonist.Potency similar to fentanyl.Terminal half-life < 10 min.Rapid blood-brain equilibrium. Can cause significant bradycardia
Morphine Hydromorphone
Fentanyl
Loading dose 5-10 mg 1-1.5 mg 50-100μg
Onset 10-20 min 5-15 min 1-2 min
Duration 2-3.5 hrs 2-3 hrs 30-60 min
Infusion rate 1-5 mg/hr 0.2-0.5 mg/hr 50-350μg/hr
Active metabolites
Yes Yes No
Histamine release
Yes No No
Cost / 24hrs 5mg/hr: $ 16 0.75 mg/hr: $ 10
100μg/hr: $ 5.50
Epidural analgesia Opioids Concentration
Morphine 20- 100 μg/ml
Fentanyl 2- 5 μg/ml
Adverse effects of epidural analgesia are more common with morphine than fentanyl. Epidural morphine can produce respiratory depression, and the onset can be delayed up to 12 hours . The incidence of respiratory depression is equivalent with epidural and intravenous morphine. More frequent side effects of epidural analgesia include pruritis, nausea, and urinary retention.
Other opioid agonistsTramadol
Synthetic 4-phenyl-piperidine analog of codeine
Stimulates the µ-receptor 1/5th to 1/10th as potent as morphine Analgesic doses of tramadol may produce
less respiratory depression and have minimal effects on gastrointestinal motor function
Naloxone Opioid antagonistUsed to restore spontaneous ventilation in
patients who breathe inadequately after opioid overdose
Onset of action is 1 -2 minDuration of effect is 30 -60 minDosage – 0.4 to 0.8mgSide effects: tachycardia, hypertension,
pulmonary edema
Non steroidal anti inflammatory drugsThere is only one NSAID approved for use in
the United States: ketorolac.Nonspecific inhibitor of cyclooxygenase with
strong analgesic activity and moderate anti inflammatory activity
Metabolized in the liver and excreted by the kidneys
Dose: 30 mg IV or 60 mg IM, f/b 30 mg IM or IV every 6 hours (maximum of 120 mg/day) for up to 5 days
iv paracetamolThe time course of action is quick with iv
paracetamol as it reaches peak concentration as soon as infusion is complete (about 15 minutes).
According to the product information, the analgesic effect starts within 5 minutes, peaks at 1 hour and lasts 4 to 6 hours.
Pain An assessment of pain and the response to
therapy should be regularly assessed using an appropriate pain scale.
Therapeutic plans and goals should be developed for all patients.
Recommended intravenous opioids are fentanyl for acute distress, fentanyl or hydromorphone for patients with hemodynamic instability or renal insufficiency, and morphine and hydromorphone for longer-term therapy.
Scheduled doses or continuous infusions are preferred over intermittent boluses.
Nonsteroidal anti-inflammatory drugs and acetaminophen can be useful adjuncts, but beware of renal insufficiency or gastrointestinal bleeding.
Sedation Treatment of pain and other reversible causes
should be conducted before sedating an agitated patient.
A treatment plan/goal should be established for each patient; therapy should be assessed with a sedation scale.
Midazolam or diazepam is useful for the acutely agitated patient.
Propofol is preferred when rapid awakening is crucial; triglyceride levels should be monitored for >2 d of continuous infusions.
Lorazepam is recommended for longer infusions.
Doses should be tapered daily to assess underlying mental status, and sedation protocols can be helpful and beneficial.
References Gabrielli A, Layon A, Joseph, et al. Anesthesia in
the ICU. Civetta, Taylor, & Kirby's: Critical Care,
4th Edition; Lippincott Williams & Wilkins:2009
Marino, PL. Analgesia and Sedation. ICU Book,
3rd Edition; Lippincott Williams & Wilkins:2007
Miller RD. Critical care protocols. Miller’s
Anaesthesia. 7th edition:2010