Vicken Y. Totten MD, FACEP MS With help from Drs. David Cheng, Kelly Abbrescia, Tonya M. Thompson, and many others. Sedation. Historical notes. Alcohol probably the earliest analgesic Lousy analgesic, poor therapeutic window Opiates x 1000s years Highly valued, scarce
Review a few relevant definitions.
Review goals of procedural sedation
Review sedative agents
Pain: Noxious sensation transmitted by the nervous system to the brain; influenced by cognition and emotion.
Sedation: a spectrum of reduced responsiveness to one’s environment
Anesthesia: “no sensation” -- No response to environment, sometimes including own body needs
Analgesia: “No pain” - relief of pain without anesthesia.
“Anxiolysis” – breaking anxiety. Reducing anxiety without producing sedation (ie. without reducing LOC)More definitions
It’s a continuum!
Reassurance general anesthesia.
To the extent that you take control away from the patient, be prepared to substitute for those functions
Sedation is NOT analgesia
Minimal sedation / anxiolysis only
no depression of consciousness
Moderate sedation / moderately depressed LOC;
still responds purposefully to verbal commands or light touch
Deep sedation / markedly depressed LOC;
responds purposefully only to intense or painful stimuli
airway and respiratory function may be depressed
No purposeful response to any kind of stimuli. May have unconscious awareness of very painful stimuli (ie. HR RR BP ICP)
airway and respiratory function profoundly depressed; typically require airway and ventilation assistance
Autonomic & cardiovascular functions may be depressed
We don’t want to go here.
No anxiety before event. (Anxiolysis)
No pain during event. (Analgesia)
No memory of event. (Amnesia)
And, complete function of all protective reflexes during the entire procedure
Short duration of action.
Rapid offset (ie. zero residual action).
No hemodynamic effects.
Easy to use and administer
Wide therapeutic window
Well tolerated (ie. minimal side-effects.)
Analgesia: Local or General
+/- amnesia for the event
Protective reflexes usually diminished.
How much diminution of reflexes is tolerable?
maintenance of airway, respiratory function, and cardiovascular function
A-Allergies- Foods, medications, latex, act.
M-Medications, including prior sedations
and how tolerated.
P-Past medical history
L-Last PO intake
E-Events leading to why patient is having sedation
The agent’s specific procedural role
Its onset / duration / offset
The standard: benzodiazepines
Benzos (BZP’s) bind to and potentiate GABA (CNS inhibitory neurotransmitter)
in smaller doses: 1) anxiolysis
in larger doses:
3) respiratory and CV depression
Short acting, potent, reversible, safe. Hydroxylated by the liver. 1 active & 2 inactive metabolites.
Metabolites are conjugated and excreted in the urine.
Chronic alcoholics: potentiated metabolism,shortened duration of action
Cirrhosis or renal failure: decreased metabolism,prolonged duration of action
Highly lipid soluble at physiological pH rapid CNS uptake
Peak effect within 1-5 minutes when given IV
Duration of effect variable 30-60 minutes…
Longer in the obese because of lipophilic distribution.
Activity sub-therapeutic after 7-15 mins.
Has a wide therapeutic window.
1 mg -20 mg
In large doses, or with sedatives such as alcohol, opioids, can produce…
Give initial dose & repeat q 3-5 minutes to desired effect
Healthy adults: 1- 2 mg IV
Drunk, high, elderly, cirrhotic, or RF pts: 0.5- 1 mg IV
Chronic alcoholics — not currently drunk: 2 – 4 mg IV initially, then 1 – 2 mg IV prn
Remember, a variable amount of analgesic is going to be added.
This may variably increase the level of sedation
increase the potential for airway, respiratory, and cardiovascular compromise
The role of midazolam is
Anxiolysis Sedation & Amnesia
Just because they aren’t kicking and screaming does not mean that they are pain free
Unique class of drug (structure is 1,6-diisopropylphenol)
Multifaceted mechanism of action:
reduced excitability of sensory and motor neurons
inhibition of the acetylcholine receptor channel
Emulsified in Protein-free soybean oil with egg phosphatide
Painful on intravenous injection (mechanism unclear)
No preservatives — must be refrigerated, stored and handled properly
in theory, most egg-allergic patients should tolerate this protein-free emulsion
Liver inactive conjugates.
Interestingly, chronic hepatic or renal failure has minimal effect on diprivan kinetics
Propofol metabolism in the face of acute hepatic or renal failure has not been studied.
Very short half-life
3-5 minutes for effect (we’re impatient!)
If dose overshoot Profound sedation / respiratory depression and/or apnea
Frequent hypotension (pre-hydrate!)
Worse with alcohol, opioids, or other sedatives;
Caution: elderly or impaired hemodynamic status
Works better when injected slowly
Need to give with lidocaine
Has no analgesic properties
Sedation potentiated by analgesia
Amnesia somewhat inconsistent
Infusion dosing: slower, but safer
0.3 mg / kg / min IV in adults (15 to 20 mg / min)
0.5 mg / kg / min IV in children
Infuse at this rate until patient is adequately sedated, and then continue at this rate until the procedure is nearing completion
Bolus dosing: Faster. Greater risk of apnea, hypotension
Bolus of 0.75 mg / kg IV in adults (40 to 65 mg) and 1 mg / kg IV in children
If needed, give second ½ bolus in 2-3 mins
Q 2-4 min, give 10-20 mg in adults (0.5 mg / kg in children) to maintain sedation.
A derivative of PCP (animal tranquilizer / general anesthetic)
Drug of abuse (“Special K”)
Decouples incoming sensation from neurologic processing
The patient has only internal or no stimuli to respond to.
neural discontinuity between the cortico-thalamic system…
responsible for higher-level functioning
and the limbic system.
responsible for emotions, motivations, and memory
Return of coupling can be variable. This is turn is responsible for “emergence phenomena”
Muscle tone and many reflexes maintained (eg. breathing, coughing, swallowing, corneal reflexes)
Analgesia. Possibly greater analgesia for somatic (ie. body wall) pain as opposed to visceral (ie. organ) pain
P-450 cytochrome 3A4 to Norketamine
Mildly active 20-30% activity. Does not cross Brain-Blood Barrier sufficiently to cause dissociation
Metabolites conjugated and excreted in the urine
Because the conjugated metabolites have so little activity, Ketamine’s duration of action is not greatly increased in renal failure.
Metabolism increased (duration reduced) with use of drugs that induce Cytochrome P-450 3A4:
chronic alcohol consumption
- chronic INH use
- St. John’s Wort
Anticonvulsants: Tegretol, Dilantin, Phenobarb
Metabolism decreased (duration prolonged) by
acute alcohol consumption
macrolides (ie. erythromycin, Biaxin, azithromycin)
HIV protease inhibitors
Complex hemodynamic effects:
Direct myocardial depressant and systemic vasodilator
Indirectly stimulates the sympathetic system (possibly through inhibition of NE reuptake)
myocardial excitation O2 use, HR
systemic vasoconstriction BP
Typically indirect sympathetic stimulation predominates ( HR BP)
If decreased sympathetic reserve, direct effects predominate ( HR BP):
patients in toxic, septic, or hemodynamic shock
pts on prolonged catecholamine infusions
bronchodilation (use in asthmatics)
laryngospasm (contraindicated in: children <3mo old & respiratory illnesses (?)
salivation and bronchorrhea (pre-medicate with Atropine)
cerebral vasodilation (increased ICP)
Emergence is not rare. TOTAL 7%
Bad dreams 2%
Patients <10yrs old less likely; >16yrs old more likely, to experience emergence.
Anecdotal evidence suggests that emergence reactions may be reduced by avoiding visual, verbal, or tactile stimulation during the recovery period (until the patient is fully conscious).
Therefore, have patients recover from Ketamine administration in a quiet, dark room whenever possible.
Age < 3months
Upper respiratory infections
Procedures involving post. pharynx
Ischemic heart disease
Elevated ICP or IOP
Initial bolus below (peds & adults)
Highly lipid solubility rapid CNS uptake (eg. peak effect in 1-5mins IV)
Second ½ bolus PRN to maintain desired level of sedation.
Sedation + Analgesia + Amnesia
Can be sole agent for procedural sedation.
Typically, no need for additional analgesia.
½ procedural dose can be used to provide analgesia without sedation.
Consider theoretical need for additional analgesia in procedures involving predominantly visceral (as opposed to somatic) painful stimuli.
5 major opioid receptors: mu, kappa, sigma, delta, epsilon
Opioid agonists (such as Morphine and Fentanyl) operate predominantly at the mu (u) receptors
perception of pain is mediated by u1- and u2-receptors, both:
centrally in the brain & supraspinally (by inhibiting sensory dorsal horn pathways in the spinal cord)
There are many different opioids (and many different ways of classifying them), but for the purposes of procedural sedation in the ED, one opioid in particular has emerged as the agent of choice.
Semisynthetic, phenyl-piperidine derivative.
Highly lipid soluble rapid CNS uptake
Rapidly redistributed from the CNS into the adipose tissue
Short duration of effect except… in Obese patients, large doses significant drug-reservoir can be created in the adipose tissue, leading to a greatly prolonged (albeit mild) duration of effect.
Dealkylated in the liver by our friend, Cytochrome P-450 3A4 Norfentanyl
Drug activity will be reduced by Cyt P-450 3A4 inducers
Drug activity will be prolonged by Cyt P-450 3A4 inhibitors
Agent of choice for ED procedural sedation:
Rapid onset: peak activity in 2-5 mins IV
Short duration of action: sub-therapeutic within 10 mins
High potency (100 x Morphine)
Favourable cardiovascular profile
Low complication rate
Itchy nose quite common, quite inconsequential
Hypotension (low risk).
Fentanyl, unlike Morphine, does not release histamine; therefore the risk of BP is low (unless combined with sedatives or alcohol)
Respiratory depression (low risk)
risk is once again low unless drug is combined with sedatives or alcohol
Chest wall rigidity
Rare <15 ug / kg (i.e. 7X the dose used for ED sedation)
Only given IV (given over 30 secs)
1-2 ug / kg IV in adults, and 1-3 ug / kg IV in peds
Use higher doses if patient:
has an induced P-450 (eg. boozer)
Use lower doses if patient:
has an inhibited P-450 (eg. on Azithromycin)
If getting a sedative or is is <6 months old