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Propofol Infusion Syndrome (PRIS)

Definition

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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.

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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)

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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

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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

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Investigations

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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.

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Prevention - Key Points for Exam

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Summary Table for Quick Revision

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• 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.

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Metabolic Acidosis - Detailed Notes for MD Anaesthesiology

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1. Definition

• pH < 7.35 (acidemia)
• Serum HCO3- < 21 mEq/L (primary decrease)
• Compensatory decrease in PaCO2 (secondary respiratory alkalosis)

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2. Normal Physiology - Buffer Systems

Primary Buffers

Three Lines of Defense

1. Chemical buffers - immediate (seconds)
2. Respiratory compensation - minutes to hours (Kussmaul breathing)
3. Renal compensation - hours to days (H+ excretion, HCO3- regeneration)

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3. Pathophysiology

A. Mechanisms of Metabolic Acidosis

• Lactic acid (anaerobic glycolysis in shock/hypoxia)
• Ketoacids (β-hydroxybutyrate + acetoacetate) in DKA, starvation, alcoholism
• Uremic acids (sulfates, phosphates) in renal failure

• Renal tubular acidosis (RTA) - failure to excrete H+ or reabsorb HCO3-
• Advanced CKD - inability to excrete sulfuric and phosphoric acids

• Gastrointestinal loss: diarrhea, pancreatic/biliary fistulas
• Renal loss: RTA Type 2 (proximal), carbonic anhydrase inhibitors

• Methanol → formic acid (via alcohol dehydrogenase)
• Ethylene glycol → glycolic acid → oxalic acid
• Salicylates → salicylic acid + organic acid intermediates
• Paraldehyde, propylene glycol

B. Cellular Effects of Acidemia

• Decreased myocardial contractility (Ca2+ handling impairment, decreased cardiac output)
• Arteriolar vasodilation (hypotension) - but venoconstriction increases central venous pressure
• Decreased response to catecholamines (reduced receptor sensitivity)
• Predisposes to arrhythmias (especially with halothane - increases arrhythmogenicity)
• Bradycardia in severe acidosis (pH <7.1)

• Kussmaul respiration - deep, rapid, sighing breaths (compensatory hyperventilation)
• Respiratory muscle fatigue in prolonged severe acidosis
• Shift of oxygen-hemoglobin dissociation curve rightward (Bohr effect) - decreased Hb-O2 affinity, increased O2 delivery to tissues (initially beneficial)

• Altered consciousness, obtundation, coma (severe acidosis)
• Reduced seizure threshold

• Hyperkalemia - H+ shifts into cells in exchange for K+ (transcellular shift): approximately 0.6 mEq/L rise in K+ for each 0.1 unit fall in pH
• Increased ionized calcium (H+ competes with Ca2+ for protein binding)
• Insulin resistance

• Opioids (weak bases): acidosis increases non-ionized fraction → enhanced CNS penetration → potentiated sedation
• Volatile and IV anesthetic agents: circulatory depressant effects amplified
• Rapid reduction of sympathetic tone (induction) can unmask severe hemodynamic compromise
• Succinylcholine is relatively contraindicated in hyperkalemic acidosis (risk of fatal hyperkalemia)
• Protein binding of drugs altered - more free drug available

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4. Classification and Etiology

The Anion Gap (AG) - The Central Diagnostic Tool

AG = [Na+] - ([Cl-] + [HCO3-])

Corrected AG = Measured AG + 2.5 × (4.0 - measured albumin in g/dL)

• Albumin is the largest component of the anion gap (~11 mEq/L contribution)
• Every 1 g/dL drop in albumin lowers the AG by ~2.5 mEq/L - failure to correct leads to missed AG acidosis

Urine AG = (Urine Na+ + Urine K+) - Urine Cl-

• Negative UAG = increased NH4+ excretion = appropriate renal response = GI cause (diarrhea)
• Positive UAG = impaired NH4+ excretion = renal cause (RTA, renal failure)

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Classification of Metabolic Acidosis

A. HIGH Anion Gap Metabolic Acidosis (HAGMA)

• Methanol, Uremia, DKA, Paraldehyde, Isoniazid/Iron, Lactic acidosis, Ethylene glycol, Salicylates

Lactic Acidosis (Type A vs Type B)

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B. NORMAL Anion Gap Metabolic Acidosis (NAGMA)

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Delta-Delta Ratio (Δ-Δ or Delta Ratio) - Detecting Mixed Disorders

Delta ratio = ΔAG / ΔHCO3- = (AG - 12) / (24 - HCO3-)

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5. Respiratory Compensation

PaCO2 = 1.5 × [HCO3-] + 8 ± 2 mmHg

ΔPaCO2 = 1.1 × ΔHCO3- (PaCO2 falls 1.1 mmHg for each 1 mEq/L fall in HCO3-)

• Compensation begins within minutes, maximizes within 12-24 hours
• If measured PaCO2 > predicted: additional respiratory acidosis present
• If measured PaCO2 < predicted: additional respiratory alkalosis present

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6. Stewart's Strong Ion Approach (Modern Framework)

1. PaCO2 (respiratory)
2. Strong Ion Difference (SID) = [Na+ + K+ + Ca2+ + Mg2+] - [Cl- + lactate-]
   • Normal SID ≈ 40-44 mEq/L
   • Decreased SID = acidosis (e.g., hyperchloremic, lactic acidosis)
   • Increased SID = alkalosis
3. Total weak acids [Atot] = albumin + phosphate
   • Increased Atot → acidosis
   • Decreased Atot (hypoalbuminemia) → alkalosis

• Normal saline causes acidosis: large Cl- load → narrows SID → acidosis
• Hypoalbuminemia causes alkalosis: low Atot → alkalosis (and may mask an underlying AG acidosis)

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7. Stepwise Diagnosis of Metabolic Acidosis

• Correct for albumin if hypoalbuminemia

• Osmolar gap = Measured Osm - Calculated Osm
• Calculated Osm = 2[Na] + [Glucose/18] + [BUN/2.8]
• Gap >10 mOsm/kg = suggests unmeasured osmoles (methanol, ethylene glycol, isopropanol)

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8. Specific Important Causes (Examination High-Yield)

Diabetic Ketoacidosis (DKA)

• Absolute/relative insulin deficiency → unrestrained lipolysis → ketoacid accumulation
• Triad: hyperglycemia + ketosis + HAGMA
• Treatment: IV fluids, insulin infusion, K+ replacement, phosphate/magnesium monitoring
• Transition from HAGMA to NAGMA during treatment is normal and expected

Lactic Acidosis

• Most common cause of HAGMA in ICU
• Type A: correct underlying hypoperfusion (fluids, vasopressors, source control in sepsis)
• Elevated lactate (>2 mmol/L) = independent predictor of mortality in critically ill

Renal Tubular Acidosis (RTA)

Hyperchloremic Acidosis from Saline

• 0.9% NaCl (154 mEq/L Na+ and 154 mEq/L Cl-) has supraphysiologic Cl-
• Causes NAGMA by reducing SID (Stewart mechanism)
• Buffered crystalloids (Lactated Ringer's, Plasma-Lyte) have lower Cl- and are preferred for large-volume resuscitation

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9. Management

Principle: Treat the underlying cause first

Sodium Bicarbonate Therapy - Detailed

NaHCO3 (mEq) = Base Deficit (mEq/L) × Bicarbonate space (0.3 × body weight in kg)

Bicarbonate space = 25-60% body weight (varies with severity; use 0.3 as conservative estimate)

In practice: give only 50% of calculated dose, reassess ABG, then re-titrate

NaHCO3 = 10 × 0.3 × 70 = 210 mEq → give 105 mEq first, recheck ABG

• pH < 7.1 (most guidelines agree)
• Severe hyperkalemia with metabolic acidosis (buying time)
• Tricyclic antidepressant overdose (NaHCO3 is specific treatment - alkalinization + Na loading)
• Salicylate poisoning (urinary alkalinization to trap ionized salicylate)
• RTA (chronic supplementation)

• Worsens intracellular acidosis (CO2 generated crosses cell membranes more readily than HCO3-)
• Paradoxical CSF and intracellular acidosis
• Sodium and water overload (hypernatremia, volume overload)
• Hypokalemia (alkalosis drives K+ intracellularly)
• Hypocalcemia
• Shifts ODC leftward - impairs O2 unloading at tissues
• Should not be used routinely in lactic acidosis (treats the pH, not the cause)

Ventilatory Management

• If patient is mechanically ventilated: maintain appropriate respiratory compensation (set minute ventilation to preserve compensatory low PaCO2)
• Permissive hypercapnia in ARDS may worsen acidosis - tolerate if pH >7.20
• After treating metabolic acidosis with NaHCO3, the CO2 generated needs adequate ventilation to be excreted - ensure adequate MV

Alternative Buffer Agents

Dialysis / Renal Replacement Therapy

• For severe refractory metabolic acidosis (especially in AKI/CKD)
• CRRT preferred in hemodynamically unstable patients
• Removes uremic acids, restores HCO3-

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10. Anesthetic Considerations in Patients with Metabolic Acidosis

1. Preoperative optimization - correct severe acidemia (pH <7.2) before elective surgery
2. Succinylcholine - avoid in hyperkalemic metabolic acidosis (K+ already elevated; succinylcholine raises K+ by 0.5-1 mEq/L further)
3. Induction drugs - reduce doses (propofol, thiopentone, opioids all have amplified effects due to hemodynamic vulnerability and altered protein binding)
4. Maintenance - avoid halothane (arrhythmogenic in acidosis); prefer isoflurane/sevoflurane
5. Ventilator settings - maintain respiratory compensation; set RR/TV to achieve appropriate PaCO2 per Winter's formula
6. Fluid choice - use balanced crystalloids (Lactated Ringer's, Plasma-Lyte) rather than normal saline to avoid worsening hyperchloremic acidosis
7. Neuromuscular blockers - acidosis may prolong some NMB agents; monitor with TOF
8. Post-operatively - monitor ABG, lactate, electrolytes closely

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11. Recent Advances (2020-2026)

1. BICAR-ICU Trial (2018, Jaber et al., NEJM) - Landmark

• Multicenter RCT: NaHCO3 infusion (target pH ≥7.30) vs. no bicarbonate in ICU patients with metabolic acidosis (pH 7.15-7.20 + AKI)
• Primary outcome (Day 28 mortality/organ failure): No significant difference overall
• Subgroup: In patients with AKIN stage 2 or 3 AKI, bicarbonate therapy significantly reduced 28-day mortality (66% vs 46%, p=0.0283) and reduced need for RRT
• Conclusion: NaHCO3 may be beneficial specifically in severe AKI with acidosis (pH <7.2)

2. 2026 Systematic Review and Meta-Analysis (Lind et al., Acta Anaesthesiol Scand 2026) - Most Recent

• 15 manuscripts/14 RCTs, including ICU patients, out-of-hospital cardiac arrest, intraoperative acidosis
• ICU patients with AKI: Buffer therapy (mostly bicarbonate) likely reduces need for RRT and rate of bloodstream infections (moderate certainty); probably no large effect on survival (low certainty)
• Out-of-hospital cardiac arrest: Buffering therapy likely has no effect on survival (very low to low certainty)
• Takeaway: Bicarbonate beneficial for reducing RRT in AKI; survival benefit not established

3. Balanced vs. Unbalanced Crystalloids - SMART & SALT-ED Trials (2018)

• Balanced crystalloids (LR, Plasma-Lyte) vs. normal saline in ICU and ED patients
• Balanced crystalloids associated with lower rates of major adverse kidney events (MAKE30), lower incidence of AKI, lower rate of RRT need
• Recommended for large-volume resuscitation to prevent dilutional hyperchloremic acidosis

4. Strong Ion Difference Concept in Practice

• SID-based approach increasingly used in ICU to explain complex mixed acid-base disorders (e.g., "hyperchloremic acidosis post-resuscitation")
• Guides fluid choice, albumin replacement, and bicarbonate therapy decisions in modern ICU practice

5. Fomepizole for Toxic Alcohol Poisoning (Expanded)

• Now first-line over ethanol infusion for methanol and ethylene glycol poisoning
• More predictable pharmacokinetics, fewer side effects, does not require intubation for administration
• Early hemodialysis + fomepizole for severe poisoning (methanol level >50 mg/dL, ethylene glycol with AKI)

6. Sodium Bicarbonate in Cardiac Arrest - Updated Evidence

• Most recent evidence (2026 meta-analysis, Lind et al.) confirms no survival benefit in OHCA with routine bicarbonate
• Current AHA/ACLS guidelines: NaHCO3 NOT routinely recommended during CPR; only in specific situations (hyperkalemic arrest, TCA overdose, pre-existing severe metabolic acidosis)

7. THAM (Tromethamine) - Renewed Interest

• Growing interest in THAM in patients with combined respiratory and metabolic acidosis (e.g., ARDS with permissive hypercapnia + metabolic acidosis)
• Does not generate CO2, penetrates cells - potentially superior in these specific scenarios
• Awaiting large RCT evidence

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12. Summary Table - Quick Revision

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• Barash's Clinical Anesthesia, 9e - Chapter 16 (Table 16-4, Winter's formula, treatment)
• Morgan & Mikhail's Clinical Anesthesiology, 7e - Chapter 50 (AG, bicarbonate space, anesthetic implications)
• Harrison's Principles of Internal Medicine, 22e (2025) - Step-by-step diagnostic approach
• Jaber S et al. Sodium bicarbonate therapy for patients with severe metabolic acidaemia in the intensive care unit (BICAR-ICU): a multicenter, open-label, randomised controlled, phase 3 trial. Lancet. 2018;392:31-40.
• Lind PC et al. Bicarbonate and Other Buffer Therapies in Acute Metabolic Acidosis: A Systematic Review and Meta-Analysis. Acta Anaesthesiol Scand. 2026. [PMID: 41808275]This is a comprehensive, exam-ready note covering everything an MD Anaesthesiology candidate needs. Here is a structured summary of what was covered:

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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