Ketamine

1 Ketamine Ketamine, a phencyclidine derivative, is arguably our most ideal anesthetic agent!

History 1958: phencyclidine (phenyl cyclohexyl piperidine, PCP) introduced into clinical anesthesia * Phencyclidine produced an unacceptably high incidence of hallucinations, confusion and delirium, so its development for use in human anesthesia was discontinued. It became commercially available for use as a veterinary anesthetic in the 1960s under the trade name of Sernylan and was placed in Schedule III under the U.S. Federal Contolled Substances Act (CSA). In 1978, due to considerable abuse phencyclidine was transferred to Schedule II under the CSA and manufacturing of Sernylan was discontinued. Today, virtually all of the phencyclidine encountered on the illicit market in the U.S. is produced in clandestine laboratories. 1959: cyclohexamine tried * worse than PCP (similar adverse psychotomimetic effects with less analgesia) 1962: ketamine (Ketalar) synthesized by Stevens 1965: ketamine tried in humans * chosen to be most promising from 200 PCP derivatives tested in animals 1970: ketamine officially released for clinical use in U.S. 1999: ketamine becomes a schedule III substance under the CSA Ketamine - 2 Chemistry Ketamine is 2-(o-chlorophenyl)-2-(methylamino) cyclohexanone (hydrochloride):

2

In 3 dimensions:

Rotatable 3D model (download free MDL Chime plug-in to view): rotatable ketamine molecule

Ketamine has a chiral center and is presently marketed as the racemic mixture of its two (mirror-image) enantiomers or enantiomorphs:

3

S-(+)-ketamine Structure-activity relationship:

R-(-)-ketamine

Ketamine, molecular weight 238, is partially water soluble at pH 7.4 (pKa 7.5), and 5 to 10 times more lipid soluble than thiopental. The commercial preparation (Ketalar) is a racemic mixture of (SR)-ketamine in NaCl solution with pH 3.5 to 5.5 and is prepared in three concentrations of ketamine: 10, 50 and 100 mg/ml, with benzethonium chloride added as a preservative. Ketamine - 3 Metabolism Ketamine is metabolized by the hepatic microsomal system.

Major pathway:

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N-demethylation ->

ketamine

norketamine (metabolite I)

Norketamine, with 20-30% of the activity of ketamine, is hydroxlyated to hydoxynorketamine, conjugated with glucuronate and excreted in the urine. Norketamine, with t1/2(elimination) = 6 hours, probably contributes significantly to analgesia. Pharmacokinetics  

plasma disappearance fits a 2-compartment model t1/2(distribution) = 11 - 16 minutes

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Vdss = 3 L/kg (very lipid soluble)

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clearance (Cl) = 12 - 17 ml/kg/min

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t1/2(elimination) = 2 - 3 hours

Plasma levels needed for hypnosis and amnesia during surgery are approximately 0.7 to 2.2 mcg/ml (perhaps up to 4.0 mcg/ml in children). Awakening occurs below 0.5

5 mcg/ml. Pharmacodynamics Central Nervous System  

unconsciousness and analgesia "dissociative anesthesia" o

cataleptic appearance

o

profound analgesia

o

eyes may be open

o

reflexes may be intact (corneal, cough and swallow)

o

amnesia (but not as profound as with benzodiazepines)

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onset < 30 seconds

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max effect: 1 minute (after IV injection)

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pupils dilate

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nystagmus

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lacrimation, salivation common

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skeletal muscle tone may increase

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may be purposeless but coordinated movements

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good correlation between blood concentration and CNS effects o

need plasma level 0.6-2 mcg/ml for general anesthesia in adults

o

may need 0.8-4 mcg/ml in children

6

 

2 mg/kg -> 10-15 minutes of anesthesia with full orientation in 15-30 minutes (dose-related duration) S enantiomer: o

slightly lower dose adequate

o

10% faster hepatic biotransformation

o

slightly faster recovery

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analgesia occurs at concentrations above approximately 0.1 mcg/ml (ketamine provides built-in post-op analgesia!)

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cerebral functional disorganization o

thalamoneocortical projection system: decreased function of cortical association areas and thalamus

o

increased function of parts of limbic system, including hippocampus (memory)

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decreased transmission in medial medullary reticular formation (affective-emotional component of nociception from cord -> brain)

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a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist o

inhibits activation of NMDA receptor by glutamate (excitatory CNS neurotransmitter)

o

reduces presynaptic release of glutamate

o

potentiates effects of gamma-aminobutyric acid (GABA, inhibitory neurotransmitter)

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



o

may mediate general anesthetic effect

o

may explain part of the analgesic effect

o

may be responsible for elements of the "near death experience" (NDE) sometimes described

opiate receptors o

ketamine probably occupies mu and kappa opiate receptors in brain and spinal cord

o

S-(+)-ketamine has been reported to have mu opioid receptor activity

o

may explain some of analgesic effect

increases cerebral metabolism o

generalized EEG theta activity (signals analgesic activity)

o

petit mal seizure-like activity - hippocampus

o

increased CMRO2

o

increased CBF

o

thiopental or diazepam block the increases in CBF and CMRO2

o

questionably may increase ICP - clinical significance controversial 

In the clinical setting, level II evidence indicates that ketamine does not increase intracranial pressure when used under conditions of controlled ventilation, coadministration of a gamma-aminobutyric acid (GABA) receptor agonist, and without nitrous oxide. Ketamine may thus safely be used in neurologically impaired patients. Compared with other anesthetics or sedatives, level II and III evidence indicates that hemodynamic stimulation induced by ketamine may improve cerebral perfusion; this could make the drug a preferred choice in sedative regimes after brain injury. Himmelseher 2005

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Ketamine has generally beneficial effects on the respiratory system with no more than minimal respiratory depression. Ketamine does not trigger seizure activity; in fact, it much more likely prevents seizure activity by NMDA receptor antagonism. The preponderance of evidence favors a neuroprotective action of ketamine. It seems confirmed that ketamine does not increase ICP when blood pressure is controlled and mild hypocapnea is achieved. Kohrs 1998

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Eight patients with traumatic brain injury were studied. In all patients, ICP monitoring was instituted before the study. Ketamine, in all three doses studied (1.5, 3, and 5 mg/kg) was associated with a significant decrease in

8 ICP (mean +/- SD: 2 +/- 0.5 mmHg [P < 0.05], 4 +/- 1 mmHg [P < 0.05], and 5 +/- 2 mmHg [P < 0.05]) among the study patients regardless of the ketamine dose used. Albanese 1997 

Anterior fontanel pressure decreased 11% during isoflurane administration, 9% during halothane administration, 10% after fentanyl, and 10% after ketamine. These changes were statistically significant, but clinically mild, and AFP remained within the normal range. Friesen 1987

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cerebrovascular CO2 response intact (reducing PaCO2 attenuates rise in ICP)

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psychological effects ("emergence reactions") o

vivid dreaming

o

extracorporeal (floating "out-of-body") experience

o

misperceptions, misinterpretations, illusions

o

may be associated with euphoria, excitement, confusion, fear

o

occur from 1 to several hours post-op

o

10-30% of adults

o

adults > children

o

women > men

o

more with more drug (dose-related)

o

increased susceptibility: psychosis

o

best attenuated or eliminated with benzodiazepines and, probably, propofol

o

may be ameliorated by prior "preemptive" positive suggestion

Respiratory System 

ventilatory response to CO2 unaltered o 2 mg/kg may lead to brief (1-3 minutes) decrease in VE o

apnea rare and only at high doses

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no significant change in ABG's

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bronchodilation: bronchial smooth muscle relaxation (even in isolated bronchial muscle studies)

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increased salivation

9 

airway reflexes relatively intact: o

swallow

o

cough

o

sneeze

o

gag

Cardiovascular System 

Ketamine stimulates the cardiovascular system o blood pressure increases o

heart rate increases

o

cardiac output increases

o

increased MVO2 and work (associated with appropriately increased coronary artery dilation and flow)

o

relativley unrelated to dose (0.5 mg/kg = 1.5 mg/kg)

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increases central sympathetic outflow

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increases sympathoneuronal norepinephrine release (may block this effect with barbiturates, benzodiazepines, droperidol)

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inhibits catecholamine reuptake

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in vitro: direct negative inotropic effect on isolated myocardium

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tachycardia and hypertension reduced by

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o

prior benzodiazepines

o

delivering ketamine by continuous infusion rather than by boluses

o

using other general anesthetic agents concomitantly

o

beta-blockers

congenital heart disease: o

usually no significant change in shunt

o

usually no significant change in SPO2

o

some increase in pulmonary artery pressure

o

pulmonary vascular resistance may increase more than systemic vascular resistance

10 Other

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ketamine suppresses neutrophil production of inflammatory mediators, improving blood flow * reduces migration of leukocytes through endothelial cells *

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suppresses proinflammatory cytokine production in whole blood *

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inhibits activity of hepatic microsomal enzymes, CYP 2D1 and CYP 3A, by 10-20% *

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Uses of Ketamine Induction and Maintenance of General Anesthesia 1.

Poor risk ASA IV (or V) patients with respiratory or cardiovascular disease (not CAD), especially reactive airway disease or hemodynamic compromise based on hypovolemia or intrinsic myocardial disease (not CAD) 2. Reactive airway disease, asthma 3. Rapid-sequence induction in otherwise healthy trauma victims after significant hemorrhage 4. Patients with septic shock * 5. Cardiac tamponade and restrictive percarditis (ketamine maintains heart rate and filling pressures) 6. Congenital heart disease, especially with propensity for R -> L shunt 7. Malignant hyperthermia susceptible patient with large anterior mediastinal mass when spontaneous ventilation was required during induction and intubation * 8. Cardiac anesthesia for correction of valvular or ischemic heart disease: ketamine, plus diazepam or midazolam * (maybe plus sufentanil*), by continuous infusion o

minimal hemodynamic pertubations

o

profound analgesia

o

dependable amnesia

o

uneventful convalescence

9. Continuous infusion of ketamine plus propofol allows total intravenous anesthesia (TIVA) with profound analgesia and spontaneous ventilation Sedation and Analgesia 1.

Preoperative sedation/analgesia

11 2. Sedation (especially pediatric) away from the OR: o

Cardiac catheterization

o

Radiation treatment

o

Radiologic studies

o

Dressing changes (e.g. post burn injury)

o

Dental procedures

3. During primary propofol sedation/anesthesia with spontaneous ventilation, ketamine boluses provide good analgesia (without respiratory depression) during injection of local anesthetics. * 4. Supplement to regional anesthesia, prior to or after block 5. Postoperative analgesia * Other 1. Bronchodilation, treatment of status asthmaticus * 2. Inhibition of reflex hypertensive response to urinary bladder distension (rats) * 3. Treatment of restless leg syndrome * (ketamine 30-40 mg PO BID) 4. It has been suggested that ketamine may be useful as an adjunct to psychotherapy; e.g. it has been investigated as an aid in treatment of heroin addiction. Ketamine - 7 Doses, Routes of Administration Ketamine may be administered by the intravenous, intramuscular, oral, rectal, or nasal routes. (Ketamine has also been administered in the epidural and intrathecal spaces to achieve analgesia.)

General Anesthesia  

Intravenous induction: 0.5 - 2 mg/kg -> peak effect in 30-60 seconds Intramuscular induction: 4 - 10 mg/kg -> onset 5 minutes, peak 20 minutes

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Maintenance: 0.5 - 1 mg/kg IV prn Or, better: 20 - 90 mcg/kg/min IV infusion

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For TIVA may also be conveniently infused continuously IV in propofol:ketamine (4:1) mixture (e.g. propofol 200 mg + ketamine 50 mg)

12 

may be wise to reduce dose in elderly patients

Sedation/analgesia  

0.2 - 0.8 mg/kg IV 2 - 4 mg/kg IM

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5 - 10 mcg/kg/min IV infusion

Pediatric sedation-anesthesia:

Bioavailability * Route

% bioavailability

Nasal

50

Oral

20

IM

90

Rectal

25

Epidural

77

Precautions  

Emergence reactions Relative contraindications o

patient with intracranial mass lesion and elevated ICP

o

open eye injury (or whenever increased intraocular pressure would be harmful)

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o

sole agent in ischemic heart disease

o

patient with vascular aneurysm

o

psychotic disease

Other notes  

ketamine has been reported to potentiate nondepolarizing neuromuscular blockade ketamine's preservative may be neurotoxic, so epidural or subarachnoid administration may be unwise Ketamine - References

Texts Reeves JG, Glass PSA, Lubarsky DA: Nonbarbiturate intravenous anesthetics. In Anesthesia, Fifth Edition. Churchill Livingstone, 2000 Booker PD: Intravenous anesthetics. In Pediatric Anesthesia, Principles and Practice. McGraw-Hill, 2002

Journals J Albanese J, Arnaud S, Rey M, Thomachot L, Alliez B et al. Ketamine Decreases Intracranial Pressure and Electroencephalographic Activity in Traumatic Brain Injury Patients during Propofol Sedation. Anesthesiology 87(6):1328-1334, 1997 Allen CG, Byford LJ, Shamji FM: Anterior mediastinal mass in a patient susceptible to malignant hyperthermia. Can J Anaesth 40:46, 1993 Castroman PJ, Ness TJ: Ketamine, an N-methyl-D-aspartate antagonist, inhibits the reflex responses to distension of the rat urinary bladder. Anesthesiology 96:1401-9, 2002 Corssen G, Domino EF: Dissociative anesthesia: further pharmacologic studies and first clinical experience with the phencyclidine derivative CI-581. Anesth Analg 45: 29-40, 1966 Dich-Nielsen JO, Svendsen LB, Berthelsen P:Intramuscular low-dose ketamine versus pethidine for postoperative pain treatment after thoracic surgery. Acta Anaesthesiol Scand 36:583, 1992 Friedberg, BL: Propofol-Ketamine Technique: Dissociative Anesthesia for Office Based Surgery (A 5-Year Review of 1264 Cases). Aesth Plast Surg 23:70-75, 1999

14 Friesen RH, Thieme RE, Honda AT and Morrison JE Jr. Changes in anterior fontanel pressure in preterm neonates receiving isoflurane, halothane, fentanyl, or ketamine. Anesth Analg 66:431-434, 1987 Griefenstein FE, DeVault M, Yoshitake J et al: A study of a l-aryl cyclo hexyl amine for anesthesia.

Anesth Analg 37:283, 1958 Gutstein HB et al: Oral ketamine preanesthetic medication in children. Anesthesiology 76:28, 1992 Hatano S, Keane DM et al: Diazepam-ketamine anaesthesia for open heart surgery: a "micro-mini" drip administration technique. Can J Anaesth 23:648, 1976 Hofbauer R, Moser D, Hammerschmidt V, et al: Ketamine significantly reduces the migration of leukocytes through endothelial cell monolayers. Crit Care Med 26:1545-9, 1998 S. Himmelseher and M. E. Durieux. Revising a Dogma: Ketamine for Patients with Neurological Injury? Anesth Analg 101(2):524 - 534, 2005 Kapur N, Friedman R: Oral ketamine: a promising treatment for restless leg syndrome. Anesth

Analg 94:1558-9, 2002 Kawasaki T, Ogata M, Kawasaki C, et al: Ketamine suppresses proinflammatory cytokine production in human whole blood in vitro. Anesth Analg 89:665-9, 1999 Kohrs R and Durieux ME. Ketamine: teaching an old drug new tricks. Anesth Analg 87:1186-1193, 1998 Lear E, Suntay R, Pallin IM et al: Cyclohexamine (CI-400): A new intravenous agent. Anesthesiology 20:330, 1959 Loch JM, Potter J, Bachmann KA: The influence of anesthetic agents on rat hepatic cytochrome P450 in vivo. Pharmacology 50:146, 1995 Malinovsky JM et al: Ketamine and norketamine plasma concentrations after i.v., nasal and rectal administration in children. Br J Anaesth 77:203, 1996 Raza SM, Masters RW, Zsigmond EK: Haemodynamic stability with midazolam-ketamine-sufentanil analgesia in cardiac surgical patients. Can J Anaesth 36:617, 1989 Sarma VJ: Use of ketamine in acute severe asthma. Acta Anaesthesiol Scand 36:106, 1992

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Van der Linden P, Gilbart E, Engelman E et al: Comparison of halothane, isoflurane, alfentanil, and ketamine in experimental septic shock. Anesth Analg 70:608, 1990 Weigand MA, Schmidt H, Zhao Q, et al: Ketamine modulates the stimulated adhesion molecule expression on human neutrophils in vitro. Anesth Analg 90:206-12, 2000 Friedberg, BL: Cosmetic Surgery Anesthesia. http://www.drfriedberg.com