Malignan Hipertermia

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Propofol History 1970's: from hypnotic substituted "hindered" phenols arose:

2,6-diisopropylphenol 1977: First clinical trial. Initially in cremaphor EL -> anaphylactoid reaction. So, new formulation developPhysicochemical Considerations

2,6-diisopropylphenol SAR: increasing length of 2,6 side chains up to about 7 or 8 C atoms:  increased sleep time

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increased potency

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decreased induction time

Further increase in length of side chains longer than about 8 C atoms:  decreased potency  slower induction 

prolonged recovery

Present form:  20 ml amps or 50 ml vials: o propofol 1% o

soybean oil 10%

o

glycerol 2.25%

o

egg phosphatide 1.2%

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pH 7-8

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isotonic

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no antimicrobial preservatives

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compatible with D5W

ed: emulsion in use today.

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Metabolism

Liver glucuronate & sulfate conjugation -> excreted in urine (70% in 24 hours, 90% in 5 days). Metabolites probably inactive. Cl exceeds hepatic blood flow. Extrahepatic metabolism has been shown during liver transplantation.

Pharmacokinetics 2 and/or 3 compartment models 3 compartment model (2 distribution phases)  T1/2(distrib) = 2-8 minutes  T1/2(redistrib) = 30-60 minutes 

T1/2(elim) = 4-7 hours ("deep" compartment allows accumulation with prolonged infusion)

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Vdss = 2-10 L/kg

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Vd(peak effect) = 300 ml/kg

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Cl = 20-30 ml/kg/min

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older age: decreased Cl (so reduce dose)

Pharmacodynamics CNS

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NOT an analgesic (but not antanalgesic as thiopental) in fact, causes local pain on injection

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hypnosis in 1 arm-brain time (2.5 mg/kg)

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Mechanism of Action: Probably related to action at or near the GABA receptor that enhances the inhibitory effect of GABA on neurotransmission.

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lower doses -> slower onset (but less bad side effects)

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duration 5-10 minutes (2-2.5 mg/kg)

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subhypnotic doses -> sedation and amnesia and antemesis

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alter mood less than thiopental

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general sense of well being; 'amorous' ideation reported

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hallucination and opisthotonus have been reported

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EEG: 2.5 mg/kg + infusion ->

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o

log blood concentration proportional to %delta/%beta

o

seizure effect unclear 

has been used effectively to treat seizures

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briefer seizure activity after ECT compared to Brevital

lowers ICP (normal and patients with high ICP) o

+ fentanyll -> less ICP response to ETT

o

normal CO2 response

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patients with high ICP: MAP may drop more than ICP -> decreasing CPP

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lowers IOP 35% acutely (> thiopental)

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relevant Cp's (depends also on age and concurrent medications) o

Cp50 for loss of response to verbal commands = 2.3 - 3.5 mcg/ml

o

maintenance: 1.5-6 mcg/ml

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awakening: < 1.6 mcg/ml

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orientation: < 1.2 mcg/ml

Uses, Doses Induction and Maintenance of General Anesthesia

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Induction: 1-2.5 mg/kg Maintenance: 50-200 mcg/kg/min +/- N2O or opioid or ketamine

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ED95 2.25-2.5 mg/kg

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Onset 1 arm-brain time

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Duration: 3-6 minutes

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Pediatrics: not much change

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o

maybe 3 mg/kg induction dose in healthy young children

o

slightly higher maintenance doses may be expected

Fast recovery and return of psychomotor function o

within 8-10 minutes after up to 2 hours infusion

o

almost as fast as desflurane and with less nausea and vomiting

Cardiac surgery o

not associated with hypotension if boluses are avoided

o

no change in coronary sinus flow, MVO2, or myocardial lactate extraction

Cp required: 2.5-6 mcg/ml

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TIVA: propofol + ketamine o

propofol:ketamine = 4:1 (or even 8:1 for less painful procedures)

o

stable hemodynamics

o

no negative dreaming or abnormal behavior

Sedation  

Readily titratable, rapid recovery, by infusion ICU: 4 days sedation -> o

10 minutes to recover

o

Cp for sedation stable 96 hours (no tolerance)

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25-60 mcg/kg/min

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amnesia - yes

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compared to midazolam

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o

equal or better control

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more rapid recovery (and extubation)

PCS, patient controlled sedation, has been reported effective

Precautions Side effects  Pain on injection o less than or equal to etomidate pain but greater than usually painless thiopental o

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minimize by mixing with lidocaine or pre-administering lidocaine (0.5-1 mg/kg)

Significantly increased risk of bradycardia compared with other anesthetics (Tramer et al, 1997) Overall NNH (number-needed-to-harm) = 11.3 Pediatric strabismus surgery: NNH = 4.1

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Myoclonus (thiopental < propofol < etomidate or methohexital) Apnea (less with infusion; avoid boluses)

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Hypotension (especially with narcotics; less with infusion)

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Phlebitis (rare)

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Reported to cause tissue necrosis on subcutaneous extravasation in small children *

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Respiratory  

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qualitatively similar to barbiturates apnea after induction dose: 25-40% o

more likely to last longer than 30 seconds

o

function of dose, speed of injection, other medications

2.4 mg/kg -> o

slower respiratory rate for 2 minutes

o

smaller VT for 4 minutes

100 mcg/kg/min ->

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o

slightly less CO2 response (compared to 3 mg/kg thiopental)

o

VT 40% less, respiratory rate 20% greater

200 mcg/kg/min -> o

only slightly more depression of VT

o

expect paCO2 low 50's

Cardiovascular System 

Induction bolus 2-2.5 mg/kg: o BP DOWN: systolic, diastolic, and mean: 24-40% o

CI, SV DOWN 15-20%

o

LVSWI down 30%

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HR little changed or significant bradycardia *

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vasodilation + myocardial depression

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Less depression of CI with spontaneous ventilation (compared to controlled ventilation)

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More CV depression in the elderly and debilitated

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Less CV depression with an induction infusion (avoid boluses)

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Maintenance o

systolic BP 25% less than preop

o

100 mcg/kg/min + spontaneous ventilation on room air: 

CI and SV unchanged

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HR relatively unchanged

o

MVO2 and myocardial blood flow lower

o

Myocardial O2 supply:demand ratio probably preserved

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ETT: returns BP to baseline

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Other -- some nice negatives: Does NOT:  potentiate NM blockers  trigger MH 

cause nausea or vomiting

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affect steroid synthesis or ACTH response

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alter hepatic or fibrinolytic function

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cause histamine release

Propofol - References Texts Hemelrijck JV and White PF: Nonopioid Intravenous Anesthesia. In Clinical Anesthesia, Third Edition. Lippincott-Raven, 1997 Reeves JG, Glass PSA, Lubarsky DA: Nonbarbiturate intravenous anesthetics. In Anesthesia, Fifth Edition. Churchill Livingstone, 2000

Journals 

Sebel PS: Propofol. Curr Rev Clin Anesth 12(14):113-120, 1992 White PF: Propofol: Pharmacokinetic and Pharmacodynamics. Seminars in Anesthesia VII(1,sup1):4-20, 1988 Roth W, Eschertzhuber S et al: Case report. Extravasation of propofol is associated with tissue necrosis in small children. Pediatric Anesthesia 16:887-889, 2006 Tramer MR, Moore RA, McQuay JH: Propofol and bradycardia: causation, frequency and severity. British Journal of Anaesthesia 78:642-651, 1997

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