KETOFOL USE IN THE ED
By Carmen Lau
Pharmacy Year 4
December 27th, 2013
Procedural sedation and analgesia (PSA)
Definition: A technique of administering sedatives w/ or w/o
analgesics to induce a state that allows for unpleasant
procedures, also referred to as conscious sedation
Procedures
• Setting fractures
• Draining abscesses
• Reducing dislocations
• Endoscopy
• Cardioversion
• TEE and other imaging
Procedural sedation and analgesia (PSA)
• The ideal drug
• Easily titrated
• Rapid onset
• Brief duration of action
• Provides adequate sedation and analgesia
• Minimal respiratory and hemodynamic effects
Propofol
Class
Short acting sedative hypnotic
MOA
Not well defined, potentiation of GABAA receptor activity→slowing channel
closing time, also acts a sodium channel blocker
PK
Vd: 171-349L
Metabolism: hepatic
Excretion: 90% renal
Onset: 10-50sec
Duration after single dose: 3-10min
Dosing
Product: 1000mg in 100ml (10mg/ml) premixed in 10% fat
Procedural dose: 1mg/kg IV followed by 0.5mg/kg q3-5min
Monitoring
↓CO/Cl, ↓BP, ↓HR, ↓RR, SVR, PA, PCWP, CVP, UO
ECG changes (PVC’s, PAC’s, S-T depression, bigeminy, VF, heart block)
Adverse
Effects
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Allergies
Do not use in pts allergic to eggs or soybeans
Hypotension, bradycardia, ECG changes
Apnea, cough, hiccups
Pain at injection site
Myoclonic/clonic movement, hyperreflexia, twitching
N/V/cramping
HLD, pancreatitis
Propofol use in PSA
Pro’s
• Rapid onset, short duration of
action, antiemetic effects
Con’s
• Use limited to dose-dependent
respiratory depression and
hypotension
• Lack of analgesic effect: often coadministered with opioids but the
combination increases likelihood
of adverse airway events
Ketamine
Class
Dissociative sedative
MOA
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•
•
•
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Noncompetitive NMDA receptor antagonist which interferes with pain
transmission in spinal cord
Inhibits nitric oxide synthase
Binds to sigma and opioid receptors
Blocks Ca and Na channels
Acts a noradrenergic and serotonergic uptake inhibitor
PK
Metabolism: hepatic
Excretion: renal
Onset: 30-40sec
Duration after single dose: 5-10min
Dosing
Product: 10mg/ml, 50mg/ml, 100mg/ml
Procedural dose: 1-2mg/kg IV over 1-2min, then 0.25-0.5 mg/kg q5-10min
Dose reduction: Caution in hepatic impairment→longer duration of action
Monitoring ↑BP, ↑P, RR, pain score, sedative score
Adverse
Effects
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Dysphoria, hallucinations, visual changes (increased color)
Excessive sedation and salivation
Increased muscle tone, muscle movement abnormalities
HTN, N/V, ↑ICP
Memory disruptions
Ketamine in PSA
Pro’s
• Preservation of airway reflexes
• CV and respiratory stimulation
• Analgesia
Con’s
• Longer recovery time
• Recovery agitation and vomiting
Better together?
Propofol
Ketamine
Does not have analgesic
effects
Analgesic effects even at
subanesthetic concentrations
Respiratory depression
and ↓BP
Sympathomimetic effects leads
to respiratory stimulation and
↑BP
Antiemetic and sedative
Vomiting and hallucinations
Physically compatible when mixed in a single polypropylene
syringe and stable at room temperature with exposure to light
The case
23yo 60kg F is brought to the ED with a dislocated left
shoulder after a MVC. The physician decides to use ketofol
for the procedure and asks you, the pharmacist, for help
dosing the medication. How are you going to prepare this
medication?
Chem 7: Na 139, K 4.2, Cl 109, CO2 22, BUN 30, SCr 0.70, Glu 126
CBC: pending
VS: HR 98, RR 22, Temp 37.6, BP 122/88
The 1st ketofol study
(A prospective case series by Willman et al.)
Objective
Effectiveness and safety of IV ketofol for procedural sedation
and analgesia in the ED
Inclusion/
Exclusion
Any patient treated with ketofol between July 2005- Feb 2006
at Lions Gate Hospital in Vancouver, BC
Intervention
Ketofol prepared at 1:1 mixture of ketamine 10mg/ml and
propofol 10mg/ml in a 10 or 20ml syringe
Results
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•
•
•
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114 procedural sedation and analgesia events
Median dose= 0.75mg/kg of each drug
Median recovery time= 15min
Procedural success w/o adjunctive sedatives: 110 (96.5%)
8 pts (7%) had minor adverse events (most common= 3
airway malalignments)
• No cases of hypotension, vomiting, aspiration
Conclusion Ketofol is effective and safe for PSA. Few adverse
events occurred and recoveries were rapid.
Other ED ketofol case series
Sharieff, 2007
Andolfatto, 2010
Andolfatto, 2011
Patients
20 children for fracture
reduction
219 children for
mostly fracture
reduction
728 adults for
mostly fracture
reduction
Dose
ketamine 0.5mg/kg +
propofol 1.0mg/kg
0.8mg/kg of 1:1
mix in same
syringe
0.7mg/kg of 1:1 mix
in same syringe
Success
95%
100%
98%
Transient
hypoxia
3/20
3/219
17/728
Median
Recovery
38min
14min
14min
The case cont.
23yo 60kg F is brought to the ED with a dislocated left shoulder.
The physician decides to use ketofol for the procedure.
Chem 7: Na 139, K 4.2, Cl 109, CO2 22, BUN 30, SCr 0.70, Glu 126
CBC: pending
VS: HR 98, RR 22, Temp 37.6, BP 122/88
You start to prepare ketofol at a 1:1 mixture of
ketamine 10mg/ml and propofol 10mg/ml in a 10ml
syringe. How much are you going to draw up, and
how is the physician supposed to administer it?
Administration
Approach 1 (Andolfatto et al.)
• Initial dose= 0.375mg/kg of each ketamine and propofol
administered during 15-30sec
• Every minute thereafter, the physician assesses the pt’s
level of sedation and administers 0.188mg/kg of each
drug if needed until sedation
Approach 2
• Administer 1-3ml aliquots of 1:1 ketamine 10mg/ml and
propofol 10mg/ml at the physician’s discretion
How to gauge sedation?
• Physician assessment
• Loss of lid reflexes, verbal
response, tactile stimuli
• Ramsay Sedation Scale <5
• Bispectral index (BIS)
• Neurophysiological monitoring
device that analyzes a pt’s
electroencephalogram
• Mostly used to assess deep
anesthesia but is now studied
in the ED
The case cont.
23yo 60kg F is brought to the ED with a dislocated left shoulder.
The physician decides to use ketofol for the procedure.
Chem 7: Na 139, K 4.2, Cl 109, CO2 22, BUN 30, SCr 0.70, Glu 126
CBC: pending
VS: HR 98, RR 22, Temp 37.6, BP 122/88
• You mix 30mg (3ml) of ketamine and 30mg (3ml) of propofol in
a syringe
• The physician gives 3ml of the mixture (0.25mg/kg of each
drug) initially, followed in 1min by the remainder 3ml
• Adequate sedation was not reaches, so more ketofol was
prepared and the physician gives another 3ml
The case cont.
• A total of 9ml of the 1:1 mixture was administered
• 9ml= 45mg of each drug
• 45mg/60kg= 0.75mg/kg of each drug
Remember that the median dose for the Willman
et al. ketofol case series was 0.75mg/kg!!!
The case cont.
The shoulder reduction was successful and the physician
thanks you for your help. BP only dropped to 114/80 during
the procedure. The patient will be discharged in about 1
hour after she recovers.
The physician really likes ketofol, but wonders how it
compares to other PSA agents. You tell him that…
Ketofol vs Propofol RCT
Messenger, 2008
Patients
63 adults or teenagers for Fx reduction
Ketofol arm
Ketamine 0.3mg/kg followed 2min later by
titrated propofol
Propofol comparison
Titrated propofol followed 2min later by fetanyl
1.5µg/kg
Procedural success %
Ketofol 97, propofol 100
Transiet hypoxia %
Ketofol 38, propofol 77
Median recovery time
Ketofol 28min, propofol 37min
Primary outcome
Fewer adverse events including hypoxia
with ketofol
Secondary outcomes
• Similar satisfaction scores
• More propofol required with ketofol
Ketofol vs Propofol Case Series
• Phillips et al. 2010
• Prospective randomized case series of 28 patients >21yo
• Propofol 0.5-1.5mg/kg vs. ketofol 0.75mg/kg
• Measured procedural success, BIS score, adverse effects,
recovery time, and VS
Results
• Smaller % decline in SBP with ketofol (1.6% vs 12.5%)
• Smaller difference between baseline and goal sedation BIS
score with ketofol (18.78 vs 34.64)
• Lower mean propofol dose with ketofol (92.5mg vs 177.27mg)
• No respiratory depression in either group
Ketofol vs Propofol RCT
David, 2010
Patients
100 adults + 93 children for mostly Fx reduction
Ketofol arm
Ketamine 0.5mg/kg + propofol 1mg/kg, followed by
propofol 0.5mg/kg prn
Propofol comparison
Propofol 1mg/kg, followed by propofol 0.5mg/kg prn
Procedural success %
Ketofol 100, propofol 100
Transiet hypoxia %
Ketofol 7, propofol 12
Median recovery time
N/A
Primary outcome
Similar incidence of respiratory depression
Secondary outcomes • Ketofol had greater satisfaction scores
• Less propofol administered with ketofol
• More consistent sedation quality with ketofol
based on the Colorado Behavioral Numerical
Pain Scale
Ketofol vs Propofol RCT
Andolfatto, 2013
Patients
284 patients >14yo for mostly Fx reduction
Ketofol arm
•
•
Propofol comparison
•
•
0.375 mg/kg of each drug, every min thereafter if Ramsay Sedation
Score <5 give another 0.188mg/kg
Total dose= 0.7mg/kg of each
Propofol 0.75mg/kg, every min thereafter if Ramsay Sedation Score
<5 give another 0.375mg/kg
Total dose= 1.5mg/kg
Procedural success %
Ketofol 100, propofol 100
Adverse respiratory event
based on Quebec Criteria
Ketofol 43 (30%), propofol 46 (32%)
Median recovery time
Ketofol 8min, propofol 6min
Primary outcome
Similar incidence of respiratory depression
Secondary outcomes
•
•
Sedation depth based on Ramsay Sedation Score appeared to
be more consistent with ketofol (46% ketofol vs 65% propofol)
Other secondary outcomes and satisfaction scores are similar
Ketofol vs Propofol Recap
• SBP
• Less SBP % decrease with ketofol
• Respiratory Depression
• Similar if not fewer incidence of adverse respiratory events with ketofol
• Sedation depth
• Greater consistency based on Ramsay Scale and Colorado Behavioral
Numerical Pain Scale with ketofol
• Satisfaction score
• Similar if not higher with ketofol
• Mean propofol dose
• Conflicting data, with most studies indicating less propofol required with ketofol
Ketofol vs Ketamine RCT
Shah, 2011
Patients
131 children for Fx reduction
Ketofol arm
Ketamine + propofol each 0.5mg/kg, followed by
propofol 0.5mg/kg prn
Ketamine comparison
Ketamine 1mg/kg, followed by 0.25mg/kg prn
Procedural success %
Ketofol 96, ketamine 100
Transiet hypoxia %
Ketofol 5, ketamine 3
Median recovery time
Ketofol 10, ketamine 12
Primary outcome
Sedation time was 3min shorter with ketofol
Secondary outcomes • Similar efficacy and respiratory adverse events
• Ketofol had less vomiting
• Ketofol had greater provider and pt satisfaction
Ketofol vs Midazolam/Fentanyl RCT
Amir, 2011
Patients
62 patients >18yo for lacerations and Fx reduction
Ketofol arm
0.75mg/kg of each drug, then more prn
Midaz/fent comparison 0.04mg/kg midazolam and 2 µg/kg fetanyl
Procedural success %
Ketofol 96, ketamine 100
Transiet hypoxia %
Ketofol 5, ketamine 3
Median recovery time
Ketofol 10, ketamine 12
Primary outcome
• No difference in sedation time
• No difference in physician satisfaction
• Pain as measured by the Visual Analog Scale
was significantly lower with ketofol
Secondary outcomes • VS differences mostly not statistically sig.
• One pt from each group required bag-mask
Are the benefits clinically relevant?
• Safe sedation can be achieved with just propofol
• Induced hypotension is usually transient and self limiting
• Using “extra” propofol doesn’t necessarily mean lengthened
recovery time
• No compelling evidence showing that ketofol greatly reduces
respiratory depression compared to propofol
• Ketamine works well alone if dissociative sedation is desired
• Added complexity of administering 2 drugs and having to anticipate
the side effects of both
• It does not make sense pharmacokinetically to mix an ultrashort acting
medication with another that isn’t
Conclusion
• Ketofol provides adequate procedural sedation and
analgesia
• Ketofol is safe and effective: recovery times are short and
adverse events are limited
• Compared to other PSA agents, ketofol may have ↓
hypotension, ↓ respiratory depression, ↑ sedation quality,
and ↑ patient satisfaction
• It is still not certain whether ketofol offers clinically
relevant benefits over either agent alone
Questions?
Unrelated fun fact: Photofrin is a drug that requires lasers!!!
References
Baker SN and Weant KA. Procedural Sedation and Analgesia in the Emergency Department. J Pharm Pract.
2011; 24(2): 189-195.
Green SM, Andolfatto G, Krauss B. Ketofol for Procedural Sedation? Pro and Con. Ann Emerg Med. 2011;
57(5): 444-448.
Willman EV, Andolfatto G. A Prospective Evaluation of “Ketofol” (Ketamine/Propofol Combination) for
Procedural Sedation and Analgesia in the Emergency Department. Ann Emerg Med. 2007; 49(1): 23-30.
Andolfatto G, Willman E. A Prospective Case Series of Single-syringe Ketamine-Propofol (Ketofol) for
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Phillips W, Anderson A, Rosengreen M, et al. Propofol Versus Propofol/Ketamine for Brief Painful Procedures
in the Emergency Department: Clinical and Bispectral Index Scale Comparison. J Pain Palliat Care
Pharmacother. 2010; 24: 349-355.
Andolfatto G, Abu-Laban RB, Zed PJ, et al. Ketamine-Propofol Combination (Ketofol) Versus Propofol Alone
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504-512.
Nejati, A. Moharari S, Ashraf H, et al. Ketamine/Propofol Versus Midazolam/Fentanyl for Procedural Sedation
and Analgesia in the Emergency Department: A Randomized, Prospective, Double-blind Trial. Acad Emerg
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