KETAMINE

Hasanul Arifin,
BAGIAN ANESTESIOLOGI DAN REANIMASI
FAKULTAS KEDOKTERAN USU
M E D A N
TRIAS
ANESTHESIA
NARCOSIS
ANALGESIA
RELAXATION
K E T A M I N E
1959 the search of potent sedative
analgetic phenycyclidine (CI-395 and CI-
400)
1965 discovery of ketamine (Parke
Davis Co)
1970 introduced into clinical practice
Dissosiative anesthesia

KETAMINE
Merupakan derivat Phencyclidine yang
menyebabkan apa yang disebut dengan
dissosiative anesthesia, oleh karena
menimbulkan dissosiasi antara thalamus
dan sistim-limbic.
Mekanisme Kerja
Depresi selektif nucleus thalamicus medialis
Supressi lamina spinal cord yang
menghantarkan rangsang nyeri
Mengikat opioid receptor
Mempengaruhi neurotransmitter
(acetylcholine) di CNS

N- methyl - D - aspartate
The NMDA receptor is an ionotropic -- is stimulated by glutamate,
resulting excitatory neurotransmitter
The receptor includes of five sub-units nearby a central ion channel
permeable to Ca, Na and K. It needs glycine as an mandatory co-
agonist and is constrained by Mg.
Ketam. reduces stimulation of synaptic neuron in NMDA receptors.
Ketam. binds to phencycline receptor in the NMDA channel inhibi -
ting glutamate activation of channel in a noncompetitive manner.

DISSOCIATIVE STATE
Profound analgesia
Amnesia, but not necessarily hypnosis
Although not asleep, but unaware of the enviroment
Mechanisms :
- eletrophysiologic inhibition of thalamocortical
- stimulation of limbic system
Side effects :
- sympathomimetic
- psychomimetic reactions
The use of ketamine reduced, due to its side effects
(Kohrs R, Marcel E, Durieux. Anesth Analg 1998;87: 1186-93)
FARMAKOKINETIK
Rapid onset
Relative short duration
High lipid solubility
i.v. peak plasma concentration 1 menit
i.m. peak plasma concentration 5 menit
Adanya redistribusi dari otak ke jaringan yg inaktif
yang menyebabkan masa kerja yang pendek dan
mengakhiri masa tidak sadar
METABOLISME
Metabolisme oleh enzyme microsom di liver
Demethylasi oleh cytochrome P-450 menjadi
Nor-Ketamin
Menyebabkan enzyme-induction sehingga efek
menurun
Ekskresi melalui ginjal

Farmakodinamika
Suntikan I.V 2 mg/kgBB,onset of action
tercapai dalam 30 detik, masa kerja 5-10 menit.
Suntikan I.M 10 mg/kgBB, onset of action
tercapai dalam 3-4 menit, masa kerja 10-20
menit
Tanda masuk stadium anestesia adalah adanya
nystagmus(Vertical atau horizontal), yg diikuti
dengan Gaze (pandangan kosong ke depan) dan
tanda awal berakhirnya anestesia juga ditandai
dengan nystagmus.
Kardiovaskuler
TD meningkat 20-40 mmHg (Sistolik
maupun Diastolik, tetapi Diastolik
meningkat lebih sedikit)
Cardiac Output meningkat 30 %.
Beban Kerja Jantung naik 45 %.

Hal di atas dapat dikurangi dengan
Suntikan lambat
Drip i.v
Diazepam 0,3-0,5 mg/kgBB/iv.(pemberian 5-
10 mg diazepam i.v sdh dpt mengurangi efek
kardiovaskuler. Bila dosis lebih besar, maka
masa tidur akan lebih lama.
Kontra indikasi
TD > 160 mmHg
Coronary Insufficiency
Decompensasi Cordis

Central Nervous System
Peningkatan ICP o.k. CBF meningkat s/d 60
%. Hal ini dapat dikurangi dgn Premedikasi
Diazepam.
Kontra indikasi pada kasus- dengan
peninggian ICP (tumor otak, trauma
kepala)?

Respirasi
Reflex pharynx (+), hipersalivasi
(premedikasi dgn SA 0,25 mg).
Depresi respirasi dapat terjadi pada
kasus dgn dosis yang besar, suntikan
terlalu cepat, sebelumnya dapat
narkotika.
Mata
Pada mata menyebabkan peningkatan
TIO (Tek.intra okuli)
Penggunaan Klinik
1. Induksi Anestesi
2. Single iv. Anestesi
Operasi minor
Airway control sulit
Neurological-radio-diagnostic
Pasien syok
Luka bakar (debritement,necrotomi)
Negara berkembang
3. Sedasi di ICU
4. Supplemen bila regional inadekwat
5. Induksi pada pasien asma aktif

(Kohrs R, Marcel E, Duroeux E. Anesth Analg 1998; 87: 1186-93)
D O S I S
Sediaan yang beredar
100 mg/cc
50 mg/cc
Intra vena :
1 2 mg/kg BB solution 1 % (10 mg/cc)
dosis ulangan 0,5 mg/kgBB.
Intra Muskular :
5 10 mg/kgBB solution 5 % (50 mg/cc)
dosis ulangan setengah dosis awal.
Slow Infusion Drip :
2 4 mg/kgBB. Solution 0,1 % (1 mg/cc D5W)

INTRANASAL KETAMINE (IK)
Diaz (1997) IK preinduction of paediatric outpatients
Dose 3 mg /kg ; Cooperation index :
- 10 min separation from parents, monitor
- 15 min put the mask on the face
This trick did not prolonged recovery

Innovative Drug Delivery Systems (IDDS) reported IK study :
IK dose : 1/6
th
I.V. dose -- to treat moderate > severe pain
onset of action : 2 10 min
duration of action 60 90 min.

INTRANASAL KETAMINE
CHRISTENSEN et al (2002) : efficacy and safety IK for
acute pain; 80 patients undergoing the removal impacted
M3 with local anesthesia. At the postoperative period,
patients self-administered intranasal K or placebo :
Rapid onset 2 10 min
Analgesic effect started at dose of 10 mg
Analgesic efficacy was assessed over a 3 hour period.
Results:
VAS (next slide)
IK offers a safe nonopiate , analgesic alternatif
Side effects were observed at the higher dose.
(http://wwwampainsoc.org/abstract/2003/data/929)
VAS demontrated analgesic effect of
intranasal ketamin 10 mg, 30 mg and 50 mg
http://www.idds.com/images/ketamine.pdf
EFFICACY AND SAFETY IK FOR
BREAKTHROUGH PAIN IN CHRONIC PAIN
BTP (breakthrough pain) involves dosage increases of 24 h opioids
and or supplem. rescue of short acting opioids or fixed dose mixtures
with NSAIDs
20 patients with chronis pain, experiencing at least 2 BTP episodes
daily, received IK or placebo.
Patients self adminitered 10 mg each, up to 50 mg.
Intensity of BTP > 5 ; 0 10 numeric scale.
Result :
IK onset of pain 5 min; duration of action : 60 min
IK no patient required rescue analgesic
Placebo 35 % required rescue analgesic
No patients reported hallucinations
Goudas et al (2002 ASCO Annnual Meeting)
KETAMINE and PREEMPTIVE ANALGESIA
PA : the establishment of an analgesis system before the
onset of noxious stimuli, with the goal of preventing
sensitization of nervous system to subsequent stimuli that
could amplify pain.
Or, in another words, the goal of PA. is to decrease the
development of a memory of pain stimulus in the nervous
system.
The principle of PA, is to administer antinociceptive
treatment before surgical injury.
NMDA receptors are responsible for pain memory, and
their blockade contribute to the prevention of pain.
NMDA antagonists prevent the induction of central
sensitization and even abolish hypersensitivity.
KETAMINE is the only NMDA antagonist approved by FDA.


THE TRICKS USE KETAMINE
KETAMINE SUB
ANESTHETIC
( 0.1 - 0.5 mg / kg)
KETAMINE
ANESTHETIC
( > 2mg / kg )
CLINICAL USE Preemptive Analg
Supplement Analg
A n e s t h e s i a
E F F E C T S analgesia
no sedated
analgesia
unconciousness
SIDE EFFECTS no change hemody-
namic and respirat.
less nausea/vomit.
sympathomimetic
psychomimetic
24
THE OUTCOME STUDIES OF KETAMINE P.A.
SOMETIMES ARE CONTROVERSIAL ( I )
Fu et al (1997) : preemptive ketamine before
surgical incission, decreased postoperative opioid
requirement. (Anesth Analg 1997;84: 1086-90).
Kucuk et al (1998) : preem. ketam. epidurally (60 mg) did not ha-
ve analgesic effect in 98 upper abdominal surgery patients.
(Anesth Analg 1998;87:103-6.)
Stubhaug et al (1997): small dose ketam.
0.5mg/kg i.v. + infusion 2 mg/kg/min for
24 h and then 1 mg/kg/min for 48 h. These
result: Low dose i.v. ketam. during and after
surgery reduces hyperalgesia surrounding
surgical incission. Inhibiton of NMDA recep.
prevents the central sensitization due to
nociceptive in put during and after
surgery.(Acta Anaesthsiol Scand 1997;41:1124-32)

Adam et al (1999) : preemp. ketam. 0.15 mg/kg
given to 128 patients undergoing mastectomy before
and after surgery. Ketam. at the time closer of
surgery is more effective. (Anesth Analg 1999; 89: 444-)
KETAMINE AND NEUROSURGERY
KETAMINE
Used alone or high dose
ICP
contraindication
KETAMINE
ICP
Dose of 2 mg / kg
Barbiturate
Benzodiazepin
Propofol
Hyperventilation


K E T A M I N E
Ketamines place as a brain protectant is still
debatable (Baughman VL. Anesth Clin of North America. 2002)
Ketamine : both CMR and CBF controversial
in neuroanesthesia
Ketamine : ICP if the patients are in
spontaneous breathing.
No increase ICP, If patients are in controlled
ventilation. ( Mayberg TS et al. Anesth Analg 1995)
Ketamine + propofol : middle cerebral artery
flow velocity and CO2 reactivity are not
affected. (Sakai et al. Anesth Analg 2000)
K E T A M I N E
Ketamine has been deemed the drug of choice
for induciton and maitenance in severly ill
patients. (White PF, et al. Anesthesiology 1982).
Ketamine - sedated patients





Ketamine subanesthetic doses
Protective reflexes ( + )
Remain spontan. breathing
Sedation and analgesia
. .
Suitable outside operating room
(White PF, et al. Anesthesiology 1982)
(Kohrs R, et al. Anesth Analg 1998)
A global increase in rCBF but
no changes in rCMRO2.
Disturbed coupling of CBF and
metabolism were unlikely.
Only minor increase in rCBV
(Langsjo JW, et al. Anesthesiology 2003)
29
KETAMINE and BRAIN PROTECTION
KETAMINE may contribute to brain protection, because :
- it blocks the NMDA receptors which activated via
enhanced excitatory neurotransmitter release.
(Thompsone A et al. Natur 1985;313: 479-81)
- it also inhibit transmembrane calsium influx

KETAMINE can be neurotoxic (rats), but can be avoided
the application :
- anticholinergic drug
- diazepam
- barbiturate. (Olney JW, et al. Science 1989; 244: 1360-2)


KETAMINE and PALLIATIVE CARE
Patients with terminal stage of cancer crescendo pain .
Small dose ketamine, if :
opioid refractory pain
adverse effects
The protocol palliative care in last few years :
Ketam. 0.1 0.2 mg / kg or 0.5 mg/kg s.c. or i.m
Monitor, assess pain and vital sign
After 15 min, (30-45 min for s.c / i.m.), still pain , double
the dose of ketam.
Repeat monitoring and dosing steps until satisfactory pain
relief or side effects occur.
Decrease opioid dose by 50 % and halve again every 6-12 h.
Rebolus with ketam. or increase as needed, limited only due
to side effects such as psychomimetic.
(Mercadante S, Lodi F, Sapio M, Calligara M. J Pain Symptom Manage
1995;10: 564-8)
Side effect
Emergence Reaction
Post operatif Period
Visual,auditory,proprioceptive & confusional illusion.
Delirium
Vivid unpleasant dream
Halusinasi
Yang berlangsung s/d 24 jam post op.
Mekanismenya:
Depresi inf. Colliculus & nucl. Medial geniculatus yang
menyebabkan misinterpretasi.



Incidence : 5 30 % kasus
Faktor-faktor :
Usia > 16 tahun
Perempuan
Dosis > 2 mg/kgBB/iv.
History of frequent dreaming
Pencegahan :
Premedikasi dengan Benzodiazepin 0,15 0,3 mg /kgBB/iv.
Post op jangan dibangunkan
Pre-operatif psikoterapi

Emergence Reaction
(lanjutan)
Contoh Penggunaan Klinis
Laki-laki, 50 kg, mengalami kecelakaan lalu
lintas dgn fx terbuka cruris dextra yg akan
dilakukan debritement & reposisi cito.
Perkiraan waktu bedah 3 jam
Diputuskan utk menggunakan GA intra vena dgn
teknik Slow Infusion drip.

Persiapan
Kosongkan lambung dgn mempuasakan, pasang NGT
no besar & hisap aktif
Pra induksi beri premed diazepam 5 mg & SA 0,25
mg iv.
Pastikan TD < 160 mmHg, & tdk ada kontra indikasi
lain.
Gunakan dosis 3 mg/kg. oki. kebutuhan Ketamine
= 3x3x50 mg = 450 mg (4,5 cc Ketamine 10%)
Campurkan 5 cc Ketamine 10 % dlm 500 cc D5W
(larutan 0,1 %)
Infus sdh terpasang baik.
Pelaksanaan
Setelah 15 mt post premed, & semua persiapan bedah
sdh selesai
Induksi Ketamine 1 mg/kgBB/iv (= 50 mg Ketalar 1
%)
Drip larutan Ketamine 0,1 % dlm D5W 50 gtt/mt.(150
mg=150 cc habis dlm 1 jam)
Tindakan bedah dimulai bila tanda masuk nystagmus
atau gaze (+).
Durante Op. bila pasien bangun atau action sesuai
stimulus maka tetesan dipercepat atau bolus Ketamine
1 % 25 mg/iv.
Tetesan Ketamine dihentikan 15 -20 mt menjelang
operasi selesai (tanya operator).
Utk mencegah Emergence reaction pasien jangan
dibangunkan,biarkan bangun sendiri,usahakan
lingkungan yg tenang.
Utk tindakan operasi yg relatif singkat (s/d 1 jam)
lebih dipilih teknik iv bolus intermitten, dgn dosis 1-2
mg/kgBB & dosis ulangan 0,5 mg/kgBB.
MONITORING
Monitoring tetap dgn prinsip skala
prioritas emergensi, B1----B4.
Jaga jalan nafas tetap bebas (look,listen,feel)
Hemodinamik :TD, nadi, perfusi perifer
(pink,warm,dry)
Bangun ?
Urine cukup ? ( 1 cc/kgBB/jam ).
Kam shia
Ketamine
Ketamine has been a well known general anesthetic and
analgesic for the past 3 decades. Although high doses of
ketamine have been implicated in causing psychomimetic
effects (excessive sedation, cognitive dysfunction,
hallucinations, nightmares), subanesthetic or low doses of
ketamine have demonstrated significant analgesic efficacy
without these side effects. Low-dose ketamine has not been
associated with adverse pharmacological effects on respiration,
cardiovascular function, nausea, vomiting, urinary retention,
and constipation/prolonged adynamic postoperative ileus. There
is evidence that low-dose ketamine may play an important role
in postoperative pain management when used as an adjunct to
opioids, local anesthetics, and other analgesic agents [13,14].
Multimodal analgesia for controlling acute postoperative pain
Asokumar Buvanendran and Jeffrey S. Kroin
Current Opinion in Anaesthesiology 2009,
22:588593
In summary, adding an IV infusion of small-
dose ketamine to a continuous femoral block
for 48 hours after surgery decreased morphine
consumption by 35% and improved early
rehabilitation with similar incidence of adverse
effects. However, there were no long-term
improvements in the recovery of functional
outcome.
Small-Dose Ketamine Infusion Improves Postoperative
Analgesia and Rehabilitation After Total Knee Arthroplasty
Frederic Adam, MD, Marcel Chauvin, MD, Bertrand Du Manoir, MD, Mathieu
Langlois, MD,Daniel I. Sessler, MD, and Dominique Fletcher, MD
(Anesth Analg 2005;100:47580)
Conclusion:
The results suggest that for definitive preemptive
analgesia, blockade of opioid and N-methyl-D-aSpartate
receptors is necessary for upper abdominal surgery such
as gastrectomy; singly, either treatment provided
significant, but not definitive, postsurgical pain relief.
Epidural morphine may affect the spinal cord segmentally,
whereas intravenous ketamine may block brain stem
sensitization via the vagus nerve during upper abdominal
surgery. (Key words: Epidural analgesia; heterosegmenta
innervation; segmental innervation.)
Preemptive Analgesia by Intravenous Low-dose Ketamine and
Epidural Morphine in Gastrectomy
A Randomized Do u b Ze-6 Zind StudySumihisa Aida, M.D.,* Tomohiro Yamakura,
M.D.,t Hiroshi Baba, M.D.,t Kiichiro Taga, M.D.,SSatoru Fukuda, M.D., Koki
Shimoji, F.R.C.A., M.D.11
Anesthesiology, V 92, No 6, Jun 2000