Ketamine: Another
Useful Tool in the OR
Katie Cass, SRNA
March 23rd, 2013
MoANA Conference
KETAMINE
Ketamine
Ketamine, a non-competitive NMDA receptor antagonist, produces a
dissociative anesthetic state (hypnosis, amnesia and analgesia).
Phencyclidine (PCP) derivative
Introduced in 1970
Highly lipophilic (44% non-ionized at physiological pH)
Racemic mixture of two stereoisomers: S(+) and R(-)
S(+) isomer has 4x greater affinity for the NMDA receptor than R(-)
isomer. S(+) ketamine has greater anesthetic and analgesic potency.
MOA: Acts on thalamocortical pathway and limbic system in the CNS and
blocks the membrane effects of the excitatory neurotransmitter glutamate at
the NMDA receptor subtype. Produces a dissociative state of anesthesia.
Pt awake but unaware of environment, eyes open with intact corneal and
light reflexes with a slow nystagmic gaze. Produces profound analgesia
and amnesia.
Ketamine
Pharmacokinetics
Onset: IV: 30 seconds; IM: 3-4 minutes
Duration: IV: 5-15 minutes; IM: 12-25 minutes
Half-Life - Elimination half-life: 2.5 hours;
Distribution half-life: 11-16 hours
Metabolism: Hepatic via hydroxylation and Ndemethylation; the metabolite norketamine is 33% as
potent as parent compound
Excretion: primarily urine
Ketamine
Dosing:
Sedation/analgesia IV: 0.2-0.75 mg/kg IM: 2-4 mg/kg
Induction IV: 0.5-2 mg/kg
Infusion 15-90 mcg/kg/min
IM: 4-10 mg/kg
NMDA Receptor
NMDA receptor (N-Methy-D-Aspartate), a specific inotropic glutamate receptor,
mediates neuronal signaling and regulates gene expression.
Present in all neurons in the CNS - specifically in the dorsal horn of the spinal
cord.
Highly permeable to and allows flow of Na+ and Ca2+ into cell and K+ out of cell.
Mg2+ blocks NMDA channels.
NMDA signaling is important in anesthesia: involved in pain processing,
neuronal plasticity and generation of central sensitization (wind-up pain) after
nocioceptive stimuli.
What is wind-up pain? A perceived increase in pain intensity over time from
repeated stimulation - caused by group C peripheral nerve fibers.
NMDAR antagonists reduce neuropathic, wind-up and spontaneous pain.
NMDA Receptor
Ketamine
Analgesia effects:
Preventing central sensitization in the dorsal horn neurons (interfere
with pain transmission in spinal cord)
Inhibits nitric oxide synthase
S(+) enantiomer shown to have
opioid mu receptor activity
Analgesia occurs at lower blood
levels than loss of
consciousness (subanesthetic
doses produce analgesia)
Ketamine
Other effects:
CV - inhibits reuptake of catecholamines (NE) at nerve terminals,
resulting in increase HR, BP, CO. It is thought ketamine attenuates
baroreceptor function by affecting NMDA receptors in the nucleus
tractus solitarius (central nervous system effect).
Pulmonary - Stimulation of B2 adrenergic receptors -> results in
bronchial smooth muscle relaxant (bronchodilation); increases salivary
and tracheobronchial secretions (esp in kids). Does not lead to
ventilatory depression
Neurological - increases cerebral blood flow, metabolism and ICP.
Seizure threshold unaltered
Causes sensory and perceptual illusions, vivid dreams and “emergence
reactions”
Cases
First case:
80 y.o., 80 kg male presenting for a
mediastinoscopy, left VATS with left lower lobe wedge resection
History: HTN, CAD, old MI with revascularization and DES in
RCA, PPM for sick sinus syndrome, EF 50-60%, COPD, lung Ca,
HLD, GERD, BPH.
Case went well, treating patient periodically with both long and
short -acting narcotics. Surgeons needed better exposure and had
difficulty with gaining access, so a thoracotomy was performed.
At the end of the case, before emergence: Ketamine 20 mg IV (0.25
mg/kg), Dexmetetomidine 40 mcg IVP, Tylenol 1 gram IV
Ketamine as Adjunctive Analgesic to Opioids and
Post-Operative Analgesia
Laskowski et al. (2011) reviewed over 70 studies involving more than 4700 patients
(ketamine vs placebo -> no regional anesthesia use).
Most studies received less than 1 mg/kg of Ketamine at various times (preincision, post incision, etc) and modes of delivery (bolus, PCA, infusion, etc).
Greatest efficacy with use of ketamine as analgesic adjunct was for thoracic,
upper abdominal and major orthopedic cases.
Ketamine’s analgesic effect was independent of intraoperative opioid used,
timing of ketamine administration and dose.
Ketamine as Adjunctive Analgesic to Opioids and Post-Operative
Analgesia
Himmelseher and Durieux (2005) highlighted several studies that utilized the effects of a
subanesthetic dose of intravenous ketamine as an analgesia adjunct to general anesthesia.
Conclusion: Intra-operative use of IV ketamine reduced postoperative pain and opioid
requirements (from out-patient surgeries to major abdominal procedures).
Ketamine as Adjunctive Analgesic to Opioids and
Post-Operative Analgesia
Ketamine as Adjunctive Analgesic to Opioids and
Post-Operative Analgesia
Bell et al. (2006) reviewed 37 RCT (over 2240 participants) use of periop ketamine or placebo. Subanesthetic doses of
ketamine (ranging from 10 mg - 270 mg) given at all
different time periods (pre-induction, induction, intraop, first
hour post op, etc).
27/37 trials found periop ketamine reduces rescue
analgesic requirements or pain intensity or both ->
ketamine in subanesthetic doses is effective in reducing
morphine requirements in the first 24 hours after surgery.
Ketamine as Adjunctive Analgesic to Opioids and
Post-Operative Analgesia
Loftus et al. (2010) found intraop ketamine reduces opioid consumption (morphine) in
the 48 hour postop peroid in opioid-dependent patients with chronic back pain. (dose
0.5 mg/kg IV at induction followed by 10 mcg/kg/min infusion until wound closure).
What does this mean for us? Antagonism of NMDA receptors aids in
postoperative pain relief.
- Use of ketamine can block receptors unaffected by opioids
- Blockade of multiple receptors can reduce opioid loads
- Opioid sparing
- Reduce side effects associated with opioids.
Importance of
Pain Control
Acute and Chronic Effects:
Increase in morbidity and mortality
Stimulation of neuroendocrine stress response
Stimulation of SNS
Poor patient satisfaction and health-related quality of life
Poorly controlled acute postoperative pain can be a predictive
factor of chronic postoperative pain
Cases
Second Case:
30 year old male presenting for
I&D right hand.
History of anxiety, smoker (1 PPD for 12 years),
marijuana use (everyday use) and ETOH use (40 beers
a week). Pt had crush injury to right hand devascularization injury. During hospitalization, pt had
multiple washouts, nerve transplantation and finger
amputations.
Our case: MAC with ketofol gtt (Propofol 150 mg
mixed with Ketamine 50 mg) at 50 mcg/kg/hr. Plus,
Fentanyl 100 mcg, Hydromorphone 0.5 mg.
KETOFOL
Ketamine + Propofol
Infusion
THEORY OF KETOFOL:
PRO ARGUMENT:
Ketamine preserves respiratory function -> counterbalance the respiratory
depression associated with propofol.
Ketofol reduces required amount of propofol -> less respiratory depression.
Less hypotensive episodes with ketofol versus propofol alone (ketamine
preserves BP).
Ketofol leads to a reduction in opioid requirements.
Ketofol has fewer side effects (than ketamine).
CON ARGUMENT:
Ketofol is nothing more than propofol sedation where fentanyl analgesia is
replaced with dissociative ketamine.
Ketofol does not reduce respiratory depression or is a superior sedative as
compared to either drug when used alone.
KETOFOL
Andolfatto et al (2010) performed a randomized, double-blind trial, utilizing ketofol (1:1 mixture of ketamine
and propofol) for ED procedural sedation.
Ketofol does not result in reduced incidence of adverse respiratory events compared to propofol as a sole
agent. Induction time, efficacy and sedation time were similar between ketofol and propofol, but sedation
depth appeared more consistent with ketofol.
David and Shipp (2010): RCT comparing propofol versus propofol/ketamine for procedural sedation analyzing respiratory depression, provider satisfaction, amount of propofol administered and sedation quality.
Ketamine dose was 0.5 mg/kg or placebo was given, then followed by propofol 1 mg/kg with repeated doses of
0.5 mg/kg PRN.
Difference of respiratory depression between the two groups was not statistically significant. However, the
ketamine/propofol combination resulted in greater provider satisfaction, less propofol administration and
better sedation quality (all were measured using appropriate scales/tools).
KETOFOL
Smischney et al. (2012) concluded that the use of ketofol is
associated with improved hemodynamic stability (BP, SV, CI
using noninvasive cardiac output monitors) during the first
ten minutes after induction as compared to the sole agent,
propfol.
What does this mean for us? Ketofol can be a great induction
agent, can provide excellent sedation and reduce propofol use.
Third Case:
Cases
62 yr old female presenting for left AKA wound washout and wound vac
change.
History: PVD, HLD, smoker ( 2 PPD for 30 years) and chronic pain.
Past Surgical History: multiple femoral popliteal bypass grafts, aortic
bifemoral bypass graft, femoral artery stent palcement, femoral to anterior
tibial bypass, left AKA and several subsequent washouts and wound vac
changes.
Chronic pain: Baclofen 20 mg TID, Gabapentin 1200 mg TID,,
Oxycodone ER 60 mg BID, Oxycodone 10-20 mg Q2h PRN,
Hydromorphone 1 mg IVP Q2h PRN, Lidocaine patches PRN.
Previous washouts and wound vac changes: High doses of
hydromorphone and fentanyl and one case received a requested
epidural.
My case: LMA with Ketamine 30 mg, Magnesium 2 grams,
Hydromorphone 3 mg, Ketorolac 30 mg.
Combination of Ketamine
and Magnesium
Lysakowski et al. (2007) determined that supplementation of magnesium alone
may decrease postoperative pain.
Albrecht et al. (2013) performed a quantitative systemic review, concluding that
perioperative magnesium reduced morphine consumption by 24% in first 24 hours.
Dosing - bolus: 30-50 mg/kg; infusion: 6-25 mg/kg/hr
Caution with magnesium use:
- Can prolong neuromuscular blockade - avoid dosing near end of case
- Increase sedation
- Contribute to cardiac morbidity
Combination of Ketamine
and Magnesium
- Liu et al. (2001) determined a super-additive (>90%) effect when coadministered
-> reduction of doses of each drug and postoperative morphine use.
- Potential recipe: Magnesium 20-30 mg/kg and ketamine 0.25 mg/kg,
reduction in NMBA by 25%
What does this mean for us?
- Ketamine and magnesium can individually reduce
postoperative pain and opioid consumption and are even better
together!
Other findings and uses....
Dale et al. (2012): Systematic review and meta-analysis and concluded that intraoperative
ketamine significantly inhibits the early postoperative IL-6 inflammatory response.
Penny (2010) submitted a case report to the AANA - utilized ketamine and
dexmedetomidine infusions during a scoliosis repair with EP monitoring.
Gtt rates: Ketamine 0.4-0.6 mg/kg/hr, Dexmedetomidine 0.9-1.2 mcg/kg/hr and
Fentanyl 1-2 mcg/kg/hr + 60% Nitrous.
Quick wake-up test
Minimal vasoactive support requirements (only 250 mcg of phenylephrine for
nine hours of anesthesia time)
Ketamine enhances MEP signals (while volatiles produce a dose-dependent
increase in latency and decrease in amplitude during SSEP monitoring)
Contraindications to
Ketamine Use
Sole anesthetic in pts with ischemic heart disease
Open eye injuries or other ophthalmic disorders where an
increase in IOP would be detrimental.
Vascular aneurysms (sudden change in arterial pressure)
Postoperative delirium is expected and where the delirium
associated with ketamine would confuse differential
diagnoses (DTs, head injuries, etc).
Neonates (apoptosis in newborn animal brains)
References
Andolfatto, et al., (2012). Ketamine-propofol combination (ketofol) versus propofol alone for emergency department
procedural sedation and analgesia: A randomized double-blind trial. American College of Emergency Physicians,
59(6); 504-512.
Baughman, V. L., Golembiewski, J., Gonzales, J. P., & Alvarez, W. (2011). Anesthesiology & critical care drug
th
handbook (10 ed.). Hudson, OH: Lexi-Comp.
Bell, R. F., Dahl, J. B. Moore, R. A. & Kalso, E. (2006). Perioperative ketamine for acute postoperative pain. The
Cochrane Database of Systemic Reviews, 3; 1-61.
Dale, O., Somogyi, A., Li, Y., Sullivan, T., & Shavit, Y. (2012). Does intraoperative ketamine attenuate
inflammatory reactivity following surgery? A systematic review and meta-analysis. Anesthesia & Analgesia, 115(4);
934-943.
David, H., & Shipp, Joseph, J. (2010). A randomized controlled trial of ketamine/propofol versus propofol alone for
emergency department procedural sedation. Annals of Emergency Medicine, 57(5); 435-441.
Fuchs-Buder, T., Wilder-Smith, O., Borgeat, A., & Tassonyi, E. (1995). Interaction of magnesium sulphate with
vecuronium-induced neuromuscular block. British Journal of Anaesthesia, 74, 405-409.
Green, S. M., Andolfatto, G., & Krauss, B. (2010). Ketofol for procedural sedation? Pro and con. Ann Emerg Med,
57; 444-448.
Himmeslsher, S., & Durieux, M. E. (2005). Ketamine for perioperative pain management. Anesthesiology, 102; 211220.
References
Joshi, G. P., & White, P. F. (2001). Management of acute and postoperative pain. Current Opinion in
Anesthesiology, 14; 417-421.
Katzung, B. G, Masters, S. B., & Trevor, A. J. (Eds.), (2009). Basic and clinical pharmacology (11
York, NY: McGraw-Hill.
th
ed.). New
Laskowski, K., & McKay, W. P. (2011). A systemic review of intravenous ketamine for postoperative
analgesia. Canadian Journal of Anesthesia, 58; 911-923.
Liu, H., Hollmann, M. W., Liu, W., Hoenemann, C. W., & Durieux, M. E. (2001). Modulation of NMDA
receptor function by ketamine and magnesium: Part 1. Anesth Analg, 92; 1173-1181.
Loftus, et al., (2010). Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent
patients with chronic back pain undergoing back surgery. Anesthesiology, 113; 639-646.
Lysakowski, C. et al. (2007). Magnesium as an adjuvant to postoperative analgesia: A systematic review of
randomized trials. Anesthesia & Analgesia, 104(6); 1532-1539.
Miller R.D. (Ed.). (2009). Miller's anesthesia edition (7th ed.). Philadelphia, PA: Churchill Livingstone.
Ouellette, R. G., & Joyce, J. A. (Eds.). (2010). Pharmacology for nurse anesthesiology. Sudbury, MA: Jones &
Barlett.
Penny, R. (2010). Use of dexmedetomidine and ketamine infusions during scoliosis repair surgery with
somatosensory and motor-evoked potential monitoring: A case report. AANA Journal, 78(6); 446-450.
QUESTIONS?