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
- Colonoscopy (see Colonoscopy, [[Colonoscopy]])
- Esophagogastroduodenoscopy (EGD) (see Esophagogastroduodenoscopy, [[Esophagogastroduodenoscopy]])
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

Cardiomyopathy/Cardiogenic Shock (see Cardiogenic Shock, [[Cardiogenic Shock]])
- Clinical Data
  - Propofol Inhibits β-Adrenergic Receptor Responsiveness to Catecholamines, Which May Result in Higher Doses of Required Exogenous Catecholamines (Anesthesia and Analgesia, 1999) [MEDLINE]
    - Demonstrated in Animal (Rat) Studies
  - Propofol Has Calcium Channel Blocking Properties on the Heart (Anesthesiology, 1997) [MEDLINE]):
    - Demonstrated in Animal (Rat) Studies
    - May Decrease Cardiac Performance and Promote Cardiac Inflammation
Inability to Protect Airway/Inability to Provide Mechanical Ventilation
Sensitivity to Egg Lecithin
Soy Allergy

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

IV Bolus (Induction)
- Healthy, Age <55 y/o: 2-2.5 mg/kg (given as 40 mg q10 min)
- Elderly, Debilitated or ASA P3-P4: 1-1.5 mg/kg (given as 20 mg q10 min)
IV Drip (ICU Sedation): 5-60 μg/kg/min
- Elderly: decrease dose by 20%
- Elderly: slow rate of administration

Dose Adjustment

Hepatic
Renal

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

xxxx

Use in Lactation

xxxx

Adverse Effects

Cardiovascular Adverse Effects

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

xxx

Hypotension (see Hypotension, [[Hypotension]])

Physiology: due to vasodilation and negative inotropy

Endocrinologic Adverse Effects

Hypertriglyceridemia (see Hypertriglyceridemia, [[Hypertriglyceridemia]])

Epidemiology: common
Risk Factors
- Co-Administration of Lipid Infusion
Monitoring: probably should monitor triglycerides at least twice per week while on propofol
Prognosis: not usually associated with adverse outcome

Neurologic Adverse Effects

Dystonia (see Dystonia, [[Dystonia]])

xxx

Pulmonary Adverse Effects

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

xxxx

Other Adverse Effects

Injection Site Pain

Epidemiology: especially if injected into a small vein

Priapism (see Priapism, [[Priapism]])

xxx

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
  - Asystole (see Asystole, [[Asystole]])
  - Atrial Fibrillation (AF) (see Atrial Fibrillation, [[Atrial Fibrillation]])
  - Sinus Bradycardia (see Sinus Bradycardia, [[Sinus Bradycardia]])
  - Bundle Branch Block (see Left Bundle Branch Block, [[Left Bundle Branch Block]] and Right Bundle Branch Block, [[Right Bundle Branch Block]])
  - Supraventricular Tachycardia (SVT) (see Supraventricular Tachycardia, [[Supraventricular Tachycardia]])
  - Ventricular Tachycardia (VT) (see Ventricular Tachycardia, [[Ventricular Tachycardia]])
- 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

Practice parameters for intravenous analgesia and sedation for adult patients in the intensive care unit: an executive summary. Crit Care Med. 1995;23:1596-1600
Effect on the duration of mechanical ventilation of identifying patients capable of breathing spontaneously. N Engl J Med 1996; 335:1864-1869 [MEDLINE]
The use of continuous IV sedation is associated with prolongation of mechanical ventilation. Chest 1998; 114:541-548
Sedation, where are we now? Intensive Care Med 1999; 25:137-139
Daily interruption of sedative infusions in critically ill patients undergoing mechanical ventilation. N Engl J Med 2000; 342:1471-1477 [MEDLINE]
The long-term psychological effects of daily sedative interruption on critically ill patients. Am J Respir Crit Care Med. 2003;168:1457-1461 [MEDLINE]
Daily interruption of sedative infusions and complications of critical illness in mechanically ventilated patients. Crit Care Med. 2004;32:1272-1276 [MEDLINE]
Efficacy and safety of a paired sedation and ventilator weaning protocol for mechanically ventilated patients in intensive care (Awakening and Breathing Controlled trial): a randomised controlled trial. Lancet. 2008 Jan 12;371(9607):126-34 [MEDLINE]
Sedation Management in Australian and New Zealand Intensive Care Units: Doctors’ and Nurses’ Practices and Opinions”. Am J Crit Care 2009; 19 (3): 285–95 [MEDLINE]
Dexmedetomidine vs midazolam or propofol for sedation during prolonged mechanical ventilation: two randomized controlled trials. JAMA. 2012 Mar 21;307(11):1151-60 [MEDLINE]
American College of Critical Care Medicine: Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med 2013, 41:263-306 [MEDLINE]
Drug absorption, distribution, metabolism and excretion considerations in critically ill adults. Expert Opin Drug Metab Toxicol. 2013 Sep;9(9):1067-84. doi: 10.1517/17425255.2013.799137. Epub 2013 May 17 [MEDLINE]
Safety of Propofol as an Induction Agent for Urgent Endotracheal Intubation in the Medical Intensive Care Unit. J Intensive Care Med. 2015 Dec;30(8):499-504. doi: 10.1177/0885066614523100. Epub 2014 Feb 17 [MEDLINE]

Pharmacology

Modulation of cardiac calcium channels by propofol,” Anesthesiology, vol. 86, no. 3, pp. 670–675, 1997 [MEDLINE]
Propofol-induced alterations in myocardial beta-adrenoceptor binding and responsiveness,” Anesthesia and Analgesia, vol. 89, no. 3, pp. 604–608, 1999 [MEDLINE]
Lipid metabolism disturbances and AMPK activation in prolonged propofol-sedated rabbits under mechanical ventilation,” Acta Pharmacologica Sinica, vol. 33, no. 1, pp. 27–33, 2012 [MEDLINE] – RETRACTED ARTICLE

Adverse Effects

Propofol infusion syndrome. Anaesthesia. 2007;62:690-701 [MEDLINE]
Propofol infusion syndrome: an overview of a perplexing disease. Drug Saf. 2008;31(4):293-303 [MEDLINE]
Propofol infusion syndrome: case report and literature review. Am J Health Syst Pharm. 2009 May 15;66(10):908-15 [MEDLINE]
Propofol infusion syndrome. Am J Ther. 2010 Sep-Oct;17(5):487-91 [MEDLINE]
Hypertriglyceridemia: a potential side effect of propofol sedation in critical illness. Intensive Care Med. 2012 [MEDLINE]
Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports. Crit Care. 2015 Nov 12;19:398. doi: 10.1186/s13054-015-1112-5 [MEDLINE]
Propofol infusion syndrome in adults: a clinical update. Crit Care Res Pract. 2015; 2015:260385 [MEDLINE]