Propofol-Related Infusion Syndrome (PRIS): A Comprehensive Review for Critical Care Practitioners

Dr Neeraj Manikath Claude.ai

Abstract

Background: Propofol-Related Infusion Syndrome (PRIS) is a rare but potentially fatal complication of prolonged propofol administration, characterized by metabolic acidosis, rhabdomyolysis, and cardiac dysfunction. Despite its rarity, the high mortality rate necessitates heightened awareness among critical care practitioners.

Objective: To provide a comprehensive review of PRIS pathophysiology, clinical presentation, risk factors, diagnostic approach, and management strategies, with practical pearls for critical care postgraduates.

Methods: Comprehensive literature review of published cases, case series, and mechanistic studies from 1992 to 2024.

Results: PRIS typically occurs with propofol doses >4 mg/kg/h for >48 hours, though cases have been reported with lower doses and shorter durations. The syndrome involves mitochondrial dysfunction leading to impaired fatty acid oxidation and cellular energy failure. Early recognition and immediate propofol discontinuation are crucial for survival.

Conclusions: While rare, PRIS carries significant mortality. Understanding risk factors, maintaining clinical suspicion, and implementing preventive strategies are essential for safe propofol use in critical care settings.

Keywords: Propofol, PRIS, metabolic acidosis, rhabdomyolysis, cardiac failure, critical care

Introduction

Propofol (2,6-diisopropylphenol) has revolutionized sedation practices in critical care since its introduction in the 1980s. Its favorable pharmacokinetic profile, rapid onset, and short duration of action have made it the sedative of choice for many critically ill patients¹. However, the recognition of Propofol-Related Infusion Syndrome (PRIS) in the early 1990s has tempered its unrestricted use, particularly in pediatric populations and prolonged sedation scenarios².

PRIS represents a constellation of metabolic derangements that can progress rapidly to multi-organ failure and death. The syndrome was first described by Bray in 1998, following reports of unexplained deaths in children receiving prolonged propofol infusions³. Despite increased awareness, PRIS continues to pose diagnostic and therapeutic challenges, with mortality rates ranging from 18% to 83% in reported series⁴.

This review aims to provide critical care practitioners with a comprehensive understanding of PRIS, emphasizing practical aspects of recognition, prevention, and management that are essential for postgraduate medical education.

Pathophysiology

Mitochondrial Dysfunction: The Central Mechanism

The pathogenesis of PRIS centers on mitochondrial dysfunction, specifically the uncoupling of oxidative phosphorylation and impaired fatty acid β-oxidation⁵. Propofol's phenolic structure allows it to integrate into mitochondrial membranes, disrupting the electron transport chain at Complex I and III⁶.

Pearl 1: Think of PRIS as "cellular energy bankruptcy" - when mitochondria can't produce ATP efficiently, cells switch to anaerobic metabolism, producing lactate and depleting energy stores.

Metabolic Cascade

The mitochondrial dysfunction triggers a cascade of metabolic events:

Impaired Fatty Acid Oxidation: Propofol inhibits carnitine palmitoyltransferase I, preventing fatty acids from entering mitochondria for β-oxidation⁷
Enhanced Lipolysis: Compensatory mechanisms increase lipolysis, flooding plasma with free fatty acids that cannot be efficiently metabolized⁸
Lactate Accumulation: Cells shift to anaerobic glycolysis, producing lactate and contributing to metabolic acidosis⁹
Cellular Energy Depletion: ATP stores become depleted, particularly affecting high-energy demand tissues like cardiac and skeletal muscle¹⁰

Cardiac-Specific Mechanisms

The heart is particularly vulnerable due to its high metabolic demands and dependence on fatty acid oxidation. Propofol-induced mitochondrial dysfunction leads to:

Reduced cardiac contractility
Conduction abnormalities
Potential for sudden cardiac death¹¹

Hack 1: Monitor troponin levels in patients on prolonged propofol - elevated troponins may be an early marker of cardiac involvement before overt heart failure develops.

Clinical Presentation

Classic Triad

PRIS classically presents with:

Metabolic Acidosis (often severe, pH <7.35)
Rhabdomyolysis (CK >1000 U/L, often >10,000 U/L)
Cardiac Dysfunction (heart failure, arrhythmias, or cardiac arrest)

Expanded Clinical Spectrum

Modern understanding recognizes a broader clinical spectrum:

Early/Mild PRIS:

Unexplained metabolic acidosis
Elevated lactate (>2 mmol/L)
Mild elevation in CK or troponin
Lipemic plasma

Established PRIS:

Severe metabolic acidosis (pH <7.2)
Rhabdomyolysis (CK >10,000 U/L)
Cardiac dysfunction (reduced EF, arrhythmias)
Acute kidney injury
Hepatomegaly/liver dysfunction

Fulminant PRIS:

Refractory acidosis
Cardiovascular collapse
Multi-organ failure
Cardiac arrest

Pearl 2: PRIS can present as a "biochemical emergency" before clinical signs become apparent. A high index of suspicion based on laboratory values is crucial.

Risk Factors

Established Risk Factors

Dose-Related:

Propofol infusion >4 mg/kg/h for >48 hours¹²
Cumulative dose >67 mg/kg¹³
Duration >48 hours (risk increases significantly after 72 hours)

Patient-Related:

Age <18 years (historically higher risk, though adult cases increasingly reported)
Critical illness with high catecholamine levels
Sepsis or systemic inflammation
Traumatic brain injury
Status epilepticus requiring high-dose propofol¹⁴

Concurrent Medications:

High-dose catecholamines (norepinephrine, epinephrine)
Corticosteroids
Other mitochondrial toxins

Emerging Risk Factors

Recent literature suggests additional considerations:

Genetic polymorphisms affecting fatty acid metabolism¹⁵
Pre-existing mitochondrial dysfunction
Malnutrition or prolonged fasting states
Concomitant use of other sedatives that may mask early signs

Oyster 1: Age is no longer protective - adult PRIS cases are increasingly reported, possibly due to higher survival rates allowing longer ICU stays and higher cumulative propofol doses.

Diagnostic Approach

Laboratory Investigations

Essential Tests:

Arterial blood gas (metabolic acidosis, elevated lactate)
Creatine kinase (often markedly elevated)
Troponin (cardiac involvement)
Comprehensive metabolic panel (anion gap, creatinine)
Liver function tests
Lipid panel (may show extreme hypertriglyceridemia)

Advanced Testing:

Echocardiography (assess cardiac function)
ECG (conduction abnormalities, ST changes)
Urinalysis (myoglobinuria)

Diagnostic Criteria

While no universally accepted diagnostic criteria exist, the following framework is practical:

Definite PRIS: ≥2 of the following in a patient receiving propofol:

Metabolic acidosis (pH <7.35, BE <-5)
Rhabdomyolysis (CK >1000 U/L)
Cardiac dysfunction (heart failure, arrhythmias, or cardiac arrest)

Probable PRIS: 1 major criterion + 2 minor criteria:

Major: Severe metabolic acidosis, rhabdomyolysis, cardiac dysfunction
Minor: Elevated lactate, lipemic plasma, hepatomegaly, acute kidney injury

Hack 2: Use the "4-4-8 Rule" as a screening trigger: Propofol >4 mg/kg/h for >48 hours in patients with ≥4 of the following: acidosis, elevated CK, elevated troponin, elevated lactate, lipemic plasma, or new cardiac dysfunction.

Management

Immediate Management

Step 1: Discontinue Propofol

Immediate cessation of propofol infusion
Switch to alternative sedatives (midazolam, dexmedetomidine, or ketamine)

Step 2: Supportive Care

Aggressive fluid resuscitation (monitor for fluid overload)
Correction of metabolic acidosis (bicarbonate if severe)
Electrolyte management (particularly potassium, phosphate)

Step 3: Cardiac Support

Inotropic support as needed
Continuous cardiac monitoring
Consider mechanical circulatory support in severe cases

Specific Interventions

Rhabdomyolysis Management:

Aggressive hydration (target urine output >2 mL/kg/h)
Alkalinization of urine (sodium bicarbonate)
Monitor for compartment syndrome
Early nephrology consultation

Metabolic Support:

High-dose insulin therapy (controversial but may improve cardiac function)¹⁶
Carnitine supplementation (theoretical benefit)¹⁷
Avoid lipid-containing medications

Renal Replacement Therapy:

Consider early initiation for:
- Severe acidosis refractory to bicarbonate
- Acute kidney injury with oliguria
- Electrolyte imbalances
- Fluid overload

Pearl 3: Early and aggressive intervention is key - once PRIS progresses to multi-organ failure, mortality approaches 80%.

Prevention Strategies

Dosing Guidelines

Recommended Limits:

Adults: <4 mg/kg/h for <48 hours when possible
Children: Avoid propofol for prolonged sedation (>48 hours)
ICU protocols should mandate automatic review at 48 hours

Monitoring Protocols

Daily Assessment:

Review propofol dose and duration
Monitor for unexplained metabolic acidosis
Check CK if infusion >48 hours
Assess cardiac function clinically

Weekly Laboratory Monitoring (for prolonged infusions):

CK, troponin, lactate
Comprehensive metabolic panel
Lipid panel

Alternative Sedation Strategies

Short-term Alternatives:

Dexmedetomidine (excellent for weaning protocols)
Midazolam (though accumulation is a concern)
Ketamine (particularly useful in hemodynamically unstable patients)

Long-term Strategies:

Daily sedation interruption
Early mobilization protocols
Multimodal analgesia to reduce sedation requirements

Hack 3: Implement a "Propofol Passport" - a bedside chart tracking cumulative dose, duration, and key laboratory values. This visual aid helps teams recognize when limits are approached.

Special Populations

Pediatric Considerations

The pediatric population remains at highest risk, leading to FDA warnings against prolonged propofol use in children. Special considerations include:

Avoid propofol for ICU sedation >48 hours in children
If unavoidable, use lowest effective dose with intensive monitoring
Consider alternative agents earlier in the sedation algorithm

Traumatic Brain Injury

TBI patients often require prolonged sedation for ICP control, creating a challenging scenario:

Balance ICP management with PRIS prevention
Consider burst suppression protocols to minimize total propofol exposure
Multimodal ICP management to reduce sedation requirements

Status Epilepticus

Refractory status epilepticus may require high-dose propofol:

Monitor closely for early signs of PRIS
Consider alternative antiepileptic strategies
Multidisciplinary team approach with neurology

Oyster 2: The populations at highest risk for PRIS are often those who benefit most from propofol's unique properties - this creates challenging risk-benefit decisions that require individualized approaches.

Prognosis and Outcomes

Mortality Rates

Published series report mortality rates of 18-83%, with several factors influencing outcomes:

Time to recognition and propofol discontinuation
Severity at presentation
Age (pediatric patients historically had higher mortality)
Presence of multi-organ failure

Predictors of Poor Outcome

High-Risk Features:

pH <7.2 at presentation
CK >50,000 U/L
Cardiac arrest as presenting feature
Delayed recognition (>24 hours after symptom onset)
Multi-organ failure at presentation

Recovery Patterns

Survivors typically show:

Gradual improvement in acid-base status over 24-48 hours
CK normalization over 5-7 days
Cardiac function recovery over days to weeks
Potential for complete recovery if recognized early

Pearl 4: The window for intervention is narrow - early recognition and immediate propofol cessation are the most important determinants of survival.

Future Directions and Research

Biomarkers

Research is ongoing to identify early biomarkers:

Specific fatty acid metabolites
Mitochondrial DNA fragments
Novel cardiac markers

Genetic Susceptibility

Understanding genetic factors may help identify high-risk patients:

Fatty acid oxidation enzyme polymorphisms
Mitochondrial DNA variants
Pharmacogenomic factors affecting propofol metabolism

Prevention Strategies

Emerging prevention approaches include:

Real-time monitoring devices
Improved sedation protocols
Alternative formulations of propofol

Practical Pearls and Clinical Hacks

For the Bedside Clinician

Pearl 5: Lipemic plasma in a patient on propofol should trigger immediate PRIS evaluation - it's often the first visible sign.

Pearl 6: If a patient on propofol develops unexplained acidosis, assume PRIS until proven otherwise - the cost of missing the diagnosis far outweighs the cost of false positives.

Hack 4: Use the "Traffic Light System": Green (<2 mg/kg/h for <24h), Yellow (2-4 mg/kg/h or 24-48h), Red (>4 mg/kg/h or >48h) - this helps teams visualize risk progression.

Hack 5: Create a "PRIS Bundle" including automatic CK orders at 48 hours, daily propofol dose calculations, and mandatory intensivist review at defined thresholds.

For Teaching and Education

Oyster 3: PRIS is a perfect case study for teaching about drug toxicity, mitochondrial biology, and the importance of systematic monitoring in critical care.

Teaching Point: Use PRIS cases to illustrate the concept of "therapeutic paradox" - how medications that provide excellent short-term benefits can cause long-term harm without proper monitoring.

Conclusion

Propofol-Related Infusion Syndrome remains a significant challenge in critical care practice. While rare, its high mortality rate and the increasing use of propofol in critically ill patients necessitate heightened awareness among critical care practitioners. The key to improving outcomes lies in prevention through adherence to dosing guidelines, systematic monitoring protocols, and early recognition of at-risk patients.

For postgraduate trainees in critical care, understanding PRIS provides valuable lessons in pharmacovigilance, the importance of systematic monitoring, and the need for individualized risk-benefit assessments in critically ill patients. As our understanding of the syndrome continues to evolve, maintaining clinical suspicion and implementing preventive strategies remain the cornerstones of safe propofol use.

The motto for PRIS should be: "Prevention is better than cure, early recognition is better than late intervention, and immediate action is better than delayed response."

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Conflicts of Interest: The authors declare no conflicts of interest.

Funding: This review received no external funding.

Saturday, June 28, 2025