Propofol Infusion Syndrome (PRIS)

Definition

Historical Background

• First described by Parke et al. (1992) in children receiving high-dose propofol infusions in the PICU.
• Subsequently recognized in critically ill adults.
• The name "PRIS" was coined by Bray in 1998.

Incidence and Risk Factors

Triggering Conditions

Predisposing Risk Factors

• Young age (children > adults, though adults are also affected)
• Critical illness - sepsis, severe TBI, status epilepticus
• Poor oxygen delivery / tissue hypoperfusion
• Low carbohydrate supply (fasting state, high catecholamine drive)
• Mitochondrial enzyme defects - e.g., medium-chain acyl-CoA dehydrogenase (MCAD) deficiency
• High catecholamine or glucocorticoid states
• Concurrent use of vasopressors or steroids (impair mitochondrial function further)

Pathogenesis

1. Inhibition of Mitochondrial Respiratory Chain

• Propofol inhibits Complex I (NADH-ubiquinone oxidoreductase) and Complex IV (cytochrome c oxidase) of the mitochondrial electron transport chain.
• This uncouples oxidative phosphorylation, causing failure of ATP synthesis.
• The result is cellular energy depletion, similar to a mitochondrial myopathy.

2. Impaired Fatty Acid Beta-Oxidation

• Propofol inhibits carnitine transport (carnitine palmitoyltransferase I - CPT-I), blocking entry of long-chain fatty acids into mitochondria.
• In states of low carbohydrate availability (fasting, catecholamine excess), fatty acids are the primary fuel source. Blocking their oxidation causes:
  • Accumulation of toxic acylcarnitines and acyl-CoA esters
  • Shift to anaerobic metabolism - lactic acidosis
• Predisposition is higher in patients with MCAD deficiency (a genetic inborn error of metabolism)

3. Cellular Energy Failure and Organ Toxicity

• Cardiac muscle: Energy-depleted cardiomyocytes develop conduction defects (Brugada-pattern ECG changes), cardiomyopathy, arrhythmias, and refractory bradycardia/asystole.
• Skeletal muscle: Rhabdomyolysis from ATP depletion and membrane instability.
• Liver: Hepatic lipid accumulation (hepatomegaly, fatty liver) due to failure of hepatic lipid regulation.
• Kidney: Acute kidney injury secondary to myoglobinuria and hypoperfusion.

4. Lipid Formulation Contribution

• Propofol is formulated in a 10% lipid emulsion (1.1 kcal/mL).
• High infusion rates deliver a significant exogenous lipid load, contributing to hypertriglyceridemia, pancreatitis risk, and worsening hepatic lipid overload.

Simplified Pathogenesis Diagram

High-dose propofol
       ↓
Inhibition of mitochondrial Complex I & IV
+ Inhibition of CPT-I (fatty acid entry into mitochondria)
       ↓
Impaired oxidative phosphorylation + Impaired β-oxidation
       ↓
ATP depletion + Toxic lipid metabolite accumulation
       ↓
Cell membrane failure, lipemia, lactic acidosis
       ↓
Rhabdomyolysis + Cardiac conduction failure + Hepatic failure
       ↓
PRIS: Refractory bradycardia → Asystole + Metabolic acidosis

Clinical Features

Diagnostic Criteria (Bray's criteria - modified)

1. Metabolic acidosis (base deficit >10 mmol/L)
2. Rhabdomyolysis (elevated CK, myoglobinuria)
3. Hyperlipidemia / lipemia
4. Enlarged or fatty liver (hepatomegaly)

Additional Features

• ECG changes: Brugada-type pattern (RBBB + ST elevation in V1-V3) - highly characteristic
• Widened QRS, ventricular arrhythmias
• New-onset cardiomyopathy / acute cardiac failure
• Hyperkalemia (from rhabdomyolysis + acidosis)
• Acute kidney injury (myoglobinuric AKI)
• Elevated lactate (Type B lactic acidosis)
• Elevated liver enzymes, hypertriglyceridemia
• Skeletal myopathy, limb weakness

Investigations

Treatment

1. Immediate: Discontinue Propofol

• Stop propofol infusion immediately - this is the single most important step.
• Switch to an alternative sedative: dexmedetomidine, midazolam, or ketamine.

2. Hemodynamic Support

• Vasopressors / inotropes for refractory hypotension and cardiac failure.
• Noradrenaline for vasodilatory shock.
• Dobutamine / milrinone for cardiogenic component.
• In refractory cardiac failure - consider IABP (intra-aortic balloon pump) or ECMO (veno-arterial) as a bridge to recovery - several case reports document successful use.

3. Management of Bradyarrhythmia

• Atropine for bradycardia (may be ineffective in severe cases).
• Temporary transvenous pacing for complete heart block or refractory bradycardia.
• CPR and ACLS for cardiac arrest.

4. Correction of Metabolic Acidosis

• IV sodium bicarbonate for severe acidosis (pH <7.1, bicarbonate <15 mmol/L).
• Address underlying cause - fluid resuscitation, ensure adequate oxygen delivery.

5. Glucose and Carbohydrate Loading

• IV dextrose infusion (10-20%) to provide carbohydrate substrate.
• Rationale: reverses the metabolic shift toward fatty acid dependence.
• Target blood glucose 6-10 mmol/L.

6. Renal Replacement Therapy (RRT)

• For myoglobinuric AKI - aggressive IV hydration first (target urine output >1 mL/kg/h).
• Urinary alkalinization with bicarbonate.
• Continuous RRT (CRRT) or hemodialysis for established AKI, severe hyperkalemia, or refractory acidosis.
• High-flux hemofiltration may also help clear propofol and its metabolites.

7. Supportive Organ Care

• Respiratory support - continue mechanical ventilation.
• Avoid additional nephrotoxins, manage electrolytes (hyperkalemia management: calcium gluconate, insulin-dextrose, salbutamol nebulization).
• Nutritional support - enteral feeding with adequate glucose.

8. Monitoring After Stopping Propofol

• Recovery can occur if PRIS is recognized early and propofol stopped promptly.
• Monitor ECG, cardiac enzymes, renal function, CK levels, ABG, lactate, and triglycerides closely.

Prevention - Key Points for Exam

Summary Table for Quick Revision

• Miller's Anesthesia, 10th ed. - Side Effects and Contraindications (Propofol); Management of Pain and Agitation (ICU chapter)
• Morgan & Mikhail's Clinical Anesthesiology, 7th ed.
• Fodale V, La Monaca E. Propofol infusion syndrome - an overview of a perplexing disease. Drug Saf. 2008;31:293-303.
• Krajcova A et al. Propofol infusion syndrome: a structured review. Br J Anaesth. 2019;122(4):448-459.

What This Note Covers

1. Definition - pH <7.35, HCO3- <21 mEq/L, compensatory low PaCO2
2. Normal buffer physiology - bicarbonate-CO2 system, three lines of defense
3. Pathophysiology - four mechanisms, cellular/organ effects, anaesthesia-specific implications (opioid potentiation, succinylcholine risk, arrhythmogenicity)
4. Anion Gap - calculation, albumin correction formula, urine anion gap, delta-delta ratio
5. Classification and full etiology - HAGMA (GOLD MARK mnemonic) and NAGMA (HARDUP) with complete cause lists
6. Respiratory compensation - Winter's formula with worked example
7. Stewart's Strong Ion Approach - SID, independent variables, practical relevance
8. Stepwise diagnostic algorithm - 8-step approach including osmolar gap
9. Specific high-yield causes - DKA, lactic acidosis Type A/B, RTA (all three types)
10. Management - cause-specific treatment, NaHCO3 formula, indications/contraindications, THAM, dialysis
11. Anesthetic considerations - induction, ventilation, fluid choice, NMB, post-op monitoring
12. Recent Advances (2020-2026) - BICAR-ICU trial, Lind 2026 meta-analysis, SMART/SALT-ED, fomepizole, THAM, updated cardiac arrest guidelines