Propofol (Diprivan, Propoven)


Indications

Intensive Care Unit Sedation (see Sedation, [[Sedation]])

  • Sedation While on Mechanical Ventilation

Procedural Sedation (see Sedation, [[Sedation]])

  • Bone Marrow Biopsy (see Bone Marrow Biopsy, [[Bone Marrow Biopsy]])
  • Bronchoscopy (see Bronchoscopy, [[Bronchoscopy]])
  • Cardioversion of Atrial Fibrillation (see Atrial Fibrillation, [[Atrial Fibrillation]])
  • Dental Procedure
  • Endoscopy
  • Endotracheal Intubation
    • Clinical Data
      • Propofol is Safe and Effective for Use in Endotracheal Intubation (J Intensive Care Med, 2015) [MEDLINE]
        • Adverse Effects: oxygen desaturation, hypotension, difficult intubation, esophageal intubation, aspiration, and oropharyngeal injury
        • Average Propofol Dose: 99 mg (standard deviation 7.39)
  • Fine Needle Aspiration (FNA) of Mass/Lesion
  • Foreign Body Extraction
  • Surgery

Contraindications


Pharmacology

Metabolic Activity of Propofol

  • Propofol Inhibits Carnitine Palmitoyl Transferase I Enzyme
    • Carnitine Palmitoyl Transferase I Enzyme is an Outer Mitochondrial Enzyme Which Functions to Transfer the Fatty Acyl Group to Carnitine to Form Fatty-Acyl Carnitine
    • Fatty-Acyl Carnitine Can Then Be Transported Through the Inner Mitochondrial Membrane Where its Metabolites Participate in the Citric Acid Cycle, Ketone Body Synthesis, and the Electron Transport Chain
    • In Propofol Infusion Syndrome, Acylcarnitine Can Accumulate and Free Fatty Acids Accumulate in Various Organs (Liver, etc)
      • Free Fatty Acids May Promote Cardiac Arrhythmogenicity in Propofol Infusion Syndrome
  • Propofol Inhibits the Mitochondrial Electron Transport Chain
    • Propofol Uncouples Oxidative Phosphorylation: in animal studies
    • Propofol Inactivates Cytochrome C and Cytochrome A/A3: in animal studies
    • Propofol Decreases Electron Complex Chain Complex II, Complex III, and Coenzyme Q Activity: in animal studies
    • Propofol Decreases Cytochrome C Oxidase Activity: in clinical studies
    • Propofol Decreases Electron Transport Chain Complex IV Activity: in clinical studies
  • Propofol Has Calcium Channel Blocking Properties on the Heart: demonstrated in animal (rat) studies
    • May Decrease Cardiac Performance and Promote Cardiac Inflammation
  • Other Factors Which May Predispose the Development of Propofol Infusion Syndrome
    • Decreased Carbohydrate Stores: low carbohydrate stores decrease citric acid levels, which acts to slow lipid metabolism
    • Catecholamine Administration
      • Propofol Inhibits β-Adrenergic Receptor Responsiveness to Catecholamines, Which May Result in Higher Doses of Required Exogenous Catecholamines: demonstrated in animal (rat) studies
      • Increased Catecholamines Also Result in Increased Propofol Clearance
      • Catecholamines are Stress Hormones Which Enhance Lipolysis
    • Stress
    • Use of Glucocorticoids
      • Glucocorticoids May Potentiate Protein Degradation in Skeletal and Cardiac Muscle Cells, Which May Contribute to Cellular Death
      • Glucocorticoids are Stress Hormones Which Enhance Lipolysis

Sedative Effects of Propofol

  • Potentiation of GABA-A Receptor Activity: slowing the channel-closing time
  • Sodium Channel Blocker
  • Effect on Glutamate Receptors
  • Effect on Endocannabinoid System

Clinical Effects of Propofol

  • Amnesia (see Amnesia, [[Amnesia]])
  • Lack of Analgesia
  • Lack of Association with Malignant Hyperthermia (see Malignant Hyperthermia, [[Malignant Hyperthermia]])
  • Effect on Sleep (see Sleep, [[Sleep]])
    • Suppression of REM Sleep Stage
    • Worsening of Sleep Quality

Formulation

  • Contains Egg Lecithin
  • Contains Soybean Oil

Pharmacokinetics

  • Half-Life (with Infusion): 30-60 min
    • Longer Half-Life is Observed After Prolonged Infusion, Due to Redistribution from Fat Stores
    • However, the Duration of the Clinical Effect is Typically Minutes, as Propofol is Rapidly Distributed into Peripheral Tissues

Metabolism

  • Hepatic Glucuronidation and Hydroxylation

Administration

Dose Adjustment

Use in Pregnancy (see Pregnancy, [[Pregnancy]])

Use in Lactation


Adverse Effects

Cardiovascular Adverse Effects

Sinus Bradycardia/Asystole (see Sinus Bradycardia, [[Sinus Bradycardia]])

Hypotension (see Hypotension, [[Hypotension]])

Endocrinologic Adverse Effects

Hypertriglyceridemia (see Hypertriglyceridemia, [[Hypertriglyceridemia]])

Neurologic Adverse Effects

Dystonia (see Dystonia, [[Dystonia]])

Pulmonary Adverse Effects

Respiratory Depression/Apnea (see Acute Hypoventilation, [[Acute Hypoventilation]])

Other Adverse Effects

Injection Site Pain

Priapism (see Priapism, [[Priapism]])

Propofol Infusion Syndrome

  • Epidemiology
    • Case Review of 153 Published Cases of Propofol Infusion Syndrome (Crit Care. 2015) [MEDLINE]
      • Propofol Infusion Syndrome (as Manifested by Cardiac Failure, Metabolic Acidosis, Fever, and Possibly Hypotension) Occurred More Frequently with Higher Infusion Rates, Irrespective of the Duration of Infusion
        • Cardiac Failure and Metabolic Acidosis Appeared to Be More Frequent in Cases Associated with Shorter Durations of Propofol Infusion
      • Propofol Infusion Syndrome (as Manifested by Arrhythmias, and EKG Changes) Occurred More Frequently with Longer Durations of Propofol Infusion, Irrespective of the Infusion Rate
      • Propofol Infusion Syndrome (as Manifested by Rhabdomyolysis and Hypertriglyceridemia) Occurred More Frequently with Both Longer Durations and Higher Infusion Rates of Propofol Infusion
        • Rhabdomyolysis and Hypertriglyceridemia Occur Most Frequently with Higher Propofol Infusion Rates After 96 hrs of Administration
      • Idiosyncratic Signs of Propofol Infusion Syndrome (AKI and Hepatomegaly) Occur Independent of the Infusion Rate or Duration of Infusion: however, hepatomegaly appears to show a trend to associate with the cumulative propofol dose
  • Risk Factors
    • Concomitant Use of Catecholamines
    • Concomitant Use of Glucocorticoids (see Corticosteroids, [[Corticosteroids]])
    • High-Dose, Long-Term Propofol Administration
  • Clinical
    • General Comments
      • Propofol Infusion Syndrome Has Been Described as an “All or None” Syndrome with Sudden Onset and a Probable Fatal Outcome
      • Literature Does Not Suggest Any Evidence of Degree of Symptoms or Range of Severity During the Clinical Course
    • Acute Kidney Injury (AKI) (see Acute Kidney Injury, [[Acute Kidney Injury]])
    • Arrhythmias
    • Congestive Heart Failure (CHF) (see Congestive Heart Failure, [[Congestive Heart Failure]] and Cardiogenic Shock, [[Cardiogenic Shock]])
      • Mechanism: rhabdomyolysis of cardiac muscle
    • Electrocardiographic (EKG) Changes (see Electrocardiogram, [[Electrocardiogram]])
      • Downsloping ST-Segment Elevation
    • Hepatomegaly (see Hepatomegaly, [[Hepatomegaly]])
    • Increased Troponin-I (see Troponin, [[Troponin]])
    • Lactic (Metabolic) Acidosis (see Lactic Acidosis, [[Lactic Acidosis]])
    • Rhabdomyolysis (see Rhabdomyolysis, [[Rhabdomyolysis]])
      • Mechanism: rhabdomyolysis of skeletal muscle
      • Myoglobinuria (see Myoglobinuria, [[Myoglobinuria]])
  • Prevention
    • Avoid Doses Exceeding 4-5 mg/kg/h for Long Periods (>48 h)
    • However, Fatal Cases Have Been Reported at Infusion Rates as Low as 1.9-2.6 mg/kg/h (Drug Saf, 2008) [MEDLINE] and (Crit Care, 2015) [MEDLINE]
  • Treatment
    • Cessation of Propofol Infusion
    • Supportive Care
  • Prognosis
    • Mortality Rate: 51% (and has decreased over time) (Crit Care, 2015) [MEDLINE]
    • Predictors of Death (Crit Care, 2015) [MEDLINE]
      • Cumulative Propofol Dose
      • Presence of Traumatic Brain Injury (TBI) (see Traumatic Brain Injury, [[Traumatic Brain Injury]])
      • Presence of Fever (see Fever, [[Fever]])

References

General

Pharmacology

Adverse Effects