4KetamineKetamine, a non-competitive NMDA receptor antagonist, produces a dissociative anesthetic state (hypnosis, amnesia and analgesia).Phencyclidine (PCP) derivativeIntroduced in 1970Highly 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.
5Ketamine Pharmacokinetics Onset: IV: 30 seconds; IM: 3-4 minutes Duration: IV: 5-15 minutes; IM: minutesHalf-Life - Elimination half-life: 2.5 hours; Distribution half-life: hoursMetabolism: Hepatic via hydroxylation and N- demethylation; the metabolite norketamine is 33% as potent as parent compoundExcretion: primarily urine
7NMDA ReceptorNMDA 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.
9Ketamine Analgesia effects: Preventing central sensitization in the dorsal horn neurons (interfere with pain transmission in spinal cord)Inhibits nitric oxide synthaseS(+) enantiomer shown to have opioid mu receptor activityAnalgesia occurs at lower blood levels than loss of consciousness (subanesthetic doses produce analgesia)
10Ketamine 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 depressionNeurological - increases cerebral blood flow, metabolism and ICP. Seizure threshold unalteredCauses sensory and perceptual illusions, vivid dreams and “emergence reactions”
11CasesFirst case:80 y.o., 80 kg male presenting for a mediastinoscopy, left VATS with left lower lobe wedge resectionHistory: 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
12Ketamine 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 (pre- incision, 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.
13Ketamine 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).
14Ketamine as Adjunctive Analgesic to Opioids and Post-Operative Analgesia
15Ketamine 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 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.
16Ketamine 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.
17Importance of Pain Control Acute and Chronic Effects:Increase in morbidity and mortalityStimulation of neuroendocrine stress responseStimulation of SNSPoor patient satisfaction and health-related quality of lifePoorly controlled acute postoperative pain can be a predictive factor of chronic postoperative pain
18Cases 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.
19Ketamine + Propofol Infusion KETOFOLTHEORY 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.
20KETOFOLAndolfatto 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).
21KETOFOLSmischney 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.
22CasesThird Case: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 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.
23Combination 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: mg/kg; infusion: 6-25 mg/kg/hrCaution with magnesium use:- Can prolong neuromuscular blockade - avoid dosing near end of case- Increase sedation- Contribute to cardiac morbidity
24Combination 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 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!
25Other 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 mg/kg/hr, Dexmedetomidine mcg/kg/hr and Fentanyl 1-2 mcg/kg/hr + 60% Nitrous.Quick wake-up testMinimal 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)
26Contraindications to Ketamine Use Sole anesthetic in pts with ischemic heart diseaseOpen 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)
27ReferencesAndolfatto, 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);Baughman, V. L., Golembiewski, J., Gonzales, J. P., & Alvarez, W. (2011). Anesthesiology & critical care drug handbook (10th 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);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);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,Green, S. M., Andolfatto, G., & Krauss, B. (2010). Ketofol for procedural sedation? Pro and con. Ann Emerg Med, 57;Himmeslsher, S., & Durieux, M. E. (2005). Ketamine for perioperative pain management. Anesthesiology, 102;
28ReferencesJoshi, G. P., & White, P. F. (2001). Management of acute and postoperative pain. Current Opinion in Anesthesiology, 14;Katzung, B. G, Masters, S. B., & Trevor, A. J. (Eds.), (2009). Basic and clinical pharmacology (11th ed.). New York, NY: McGraw-Hill.Laskowski, K., & McKay, W. P. (2011). A systemic review of intravenous ketamine for postoperative analgesia. Canadian Journal of Anesthesia, 58;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;Loftus, et al., (2010). Intraoperative ketamine reduces perioperative opiate consumption in opiate-dependent patients with chronic back pain undergoing back surgery. Anesthesiology, 113;Lysakowski, C. et al. (2007). Magnesium as an adjuvant to postoperative analgesia: A systematic review of randomized trials. Anesthesia & Analgesia, 104(6);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);