Infusion Pumps and Drug Delivery

Quick Answer

Infusion pumps are essential ICU medical devices that deliver precise volumes of fluids, medications, and blood products to critically ill patients. The four main pump types are volumetric pumps (large-volume infusions, 0.1-999 mL/h), syringe pumps (high-precision low-volume infusions, 0.1-100 mL/h), patient-controlled analgesia (PCA) pumps (on-demand opioid delivery with lockout intervals), and elastomeric pumps (disposable ambulatory devices). Modern smart pumps incorporate Dose Error Reduction Systems (DERS) with drug libraries containing hard limits (cannot override) and soft limits (can override with justification), reducing programming errors by 70-85% (PMID: 31633261). Target-controlled infusion (TCI) uses pharmacokinetic models (Marsh, Schnider, Eleveld) to maintain target plasma or effect-site concentrations. The Eleveld model is preferred for ICU sedation as it accounts for critical illness (PMID: 30442252). Standardized concentrations (ISMP/ASHP Standardize 4 Safety) reduce calculation errors. Key safety features include anti-free-flow mechanisms, air-in-line detection, occlusion alarms, and EHR/BCMA integration for closed-loop medication verification. Approximately 7% of ICU medication errors relate to IV incompatibility (PMID: 20463240), requiring knowledge of Y-site compatibility and dedicated line protocols.

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CICM Exam Focus

What Examiners Expect

Second Part Written (SAQ):

Common SAQ stems:

• "Describe the types of infusion pumps used in the ICU. Outline the advantages and disadvantages of each."
• "A patient on multiple vasoactive infusions becomes hypotensive. Outline the infusion-related causes and your approach to troubleshooting."
• "Discuss the principles of target-controlled infusion (TCI) and its application in ICU sedation."
• "Outline the safety features of modern smart infusion pumps and their role in reducing medication errors."
• "Describe the principles of IV drug compatibility and strategies to prevent incompatibility reactions."

SAQ scoring expectations:

• Systematic classification of pump types with clinical applications
• Understanding of DERS and smart pump technology
• Knowledge of TCI pharmacokinetic models
• Practical approach to infusion troubleshooting
• Evidence-based medication safety strategies

Second Part Hot Case:

Typical presentations:

• Patient on multiple infusions with sudden hemodynamic instability
• Suspected propofol infusion syndrome requiring sedation strategy change
• Complex medication regimen requiring line management optimization
• Patient with unexplained precipitation in IV lines

Examiners assess:

• Systematic evaluation of infusion setup and pump programming
• Recognition of infusion-related complications
• Safe infusion rate calculations and adjustments
• Knowledge of drug compatibility
• Understanding of smart pump alerts and troubleshooting

Second Part Viva:

Expected discussion areas:

• Pump classification and selection criteria
• TCI principles and pharmacokinetic models
• DERS and drug library management
• Standardized concentrations rationale
• IV compatibility principles
• Medication error prevention strategies
• Line management and carrier fluid selection

Examiner expectations:

• Consultant-level understanding of infusion technology
• Practical troubleshooting skills
• Evidence-based medication safety knowledge
• Systems-level thinking about error prevention

Common Mistakes

• Confusing volumetric and syringe pump applications
• Not understanding the difference between hard and soft limits in DERS
• Unfamiliarity with TCI pharmacokinetic models relevant to ICU
• Failure to consider dead space and startup delay with syringe pumps
• Not recognizing alert fatigue as a contributor to pump bypassing
• Inadequate knowledge of common incompatible drug pairs
• Forgetting carrier fluid requirements for concentrated infusions

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Key Points

Must-Know Facts

1. Pump Classification: ICU infusion pumps include volumetric pumps (peristaltic mechanism, 0.1-999 mL/h), syringe pumps (linear drive, 0.1-100 mL/h), PCA pumps (patient-activated with lockout), and elastomeric pumps (disposable, gravity-independent).

2. Smart Pump Technology: Dose Error Reduction Systems (DERS) use drug libraries with hard limits (pump stops, cannot override) and soft limits (warning, can override). DERS reduces programming errors but has limited evidence for reducing adverse drug events (PMID: 31633261).

3. Drug Library Compliance: Optimal compliance is >95%. Alert override rates of 80-90% for soft limits indicate poor library calibration and contribute to alert fatigue (PMID: 30114008).

4. TCI Pharmacokinetic Models: The Eleveld model is preferred for ICU propofol as it accounts for age, weight, sex, and critical illness. Traditional models (Marsh, Schnider) may be inaccurate in ICU patients (PMID: 30442252).

5. Standardized Concentrations: ISMP/ASHP Standardize 4 Safety recommends norepinephrine 16 mcg/mL (standard) or 32 mcg/mL (concentrated), insulin 1 unit/mL, and heparin 100 units/mL to reduce calculation errors (PMID: 32442266).

6. IV Compatibility: Approximately 7% of ICU medication errors relate to incompatibility. Phenytoin, furosemide, and sodium bicarbonate are highly incompatible with most drugs. Always consult Trissel's or King Guide databases (PMID: 20463240).

7. Syringe Pump Considerations: Dead space (0.5-2 mL) causes startup delay of 10-30 minutes for vasoactive drugs. Use carrier fluid or prime line to reduce delay. Compliance changes with syringe brand (PMID: 28980336).

8. PCA Safety: Lockout interval (5-15 min) prevents dose stacking. PCA by proxy (others pressing button) is a major cause of opioid-related respiratory depression. Basal rates increase respiratory events without improving pain scores (PMID: 21102069).

9. Free Flow Prevention: Modern pumps have anti-siphon valves and cassette systems preventing gravity free flow when the door is opened. This is critical for vasoactive medications where sudden bolusing causes severe hemodynamic instability.

10. Closed-Loop Integration: BCMA + Smart Pump + EHR integration (auto-programming, auto-documentation) reduces manual entry errors by 50-70% and improves drug library compliance (PMID: 23810148).

Memory Aids

SMART - Smart Pump Safety Features:

• Soft/Hard limits (dose error reduction)
• Memory (drug library with standardized concentrations)
• Alarms (air-in-line, occlusion, low battery, end of infusion)
• Rate control (accurate flow delivery ±5%)
• Tracking (dose history, event logging, wireless monitoring)

DIALS - Drug Infusion Problem Approach:

• Disconnection (line disconnected or kinked)
• Incompatibility (precipitation, drug interaction)
• Air (air-in-line alarm, bubble in tubing)
• Leak (cracked syringe, loose connections)
• Settings (wrong rate, concentration, or drug programmed)

5 RIGHTS + 3 - Safe Infusion Administration:

• Right patient, drug, dose, route, time
• Right concentration (standardized)
• Right pump (appropriate type for infusion)
• Right line (dedicated vs shared, compatibility)

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Definition & Classification

Definition

An infusion pump is a medical device that delivers fluids, medications, or nutrients into a patient's circulatory system through intravenous (IV), subcutaneous, arterial, or epidural routes at precisely controlled rates and volumes.

In the ICU, infusion pumps are essential for:

• Continuous delivery of vasoactive medications (vasopressors, inotropes)
• Precise sedation and analgesia titration
• Accurate fluid resuscitation and maintenance
• Parenteral nutrition delivery
• Antibiotic and chemotherapy infusions
• Blood product transfusion

Classification by Mechanism

Classification by Technology Generation

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Volumetric Infusion Pumps

Mechanism of Action

Peristaltic pumps use rotating rollers or linear peristaltic fingers to compress flexible tubing, creating a "milking" action that propels fluid forward. The accuracy depends on tubing compliance, which degrades over time.

Key Technical Specifications:

• Flow rate: 0.1-999 mL/h (some models 0.01 mL/h resolution)
• Accuracy: ±5% at rates >1 mL/h, ±10% at lower rates
• Volume delivery: 1-9999 mL programmable
• Pressure limits: 0-15 psi (occlusion detection)

Clinical Applications in ICU

Advantages and Disadvantages

Advantages:

• Large volume capacity (up to 1000 mL bags)
• Suitable for fluid resuscitation
• Can accommodate various tubing and bag sizes
• Cost-effective per infusion

Disadvantages:

• Less accurate at low flow rates (<5 mL/h)
• Tubing compliance causes flow variation (±10-15%)
• Startup delay with new tubing
• Cannot achieve ultra-low flow rates needed for concentrated drugs

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Syringe Pumps

Mechanism of Action

Syringe pumps use a linear drive mechanism (stepper motor with lead screw) that pushes the syringe plunger at a precisely controlled rate. The pump calculates flow based on syringe diameter and plunger displacement.

Technical Specifications:

• Syringe sizes: 5, 10, 20, 50, 60 mL (BD Plastipak, Terumo, Braun)
• Flow rate: 0.01-100 mL/h (some models 0.001 mL/h)
• Accuracy: ±2% across flow range
• Resolution: 0.01 mL/h increments

Critical Considerations

1. Startup Delay and Dead Space

The dead space (volume between syringe tip and catheter tip) ranges from 0.5-2 mL depending on tubing length. At low flow rates, this creates significant startup delay:

Clinical Implications:

• Vasoactive drug changes take 15-45 minutes to affect patient
• Use carrier fluid (10-20 mL/h) to reduce dead space transit time
• Prime and purge new syringes before connecting
• Consider bolus loading when starting vasopressors

2. Syringe Brand Compliance

Different syringe brands have varying barrel friction and compliance characteristics:

• Using non-calibrated syringe brands can cause ±5-10% flow error
• Most pumps calibrated for specific brands (BD, Braun, Terumo)
• Always use manufacturer-specified syringes

3. Syringe Change Considerations

Clinical Applications

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Patient-Controlled Analgesia (PCA) Pumps

Mechanism and Programming

PCA pumps allow patients to self-administer small doses of analgesics (typically opioids) within programmed safety limits. The pump records all demand attempts and successful deliveries.

Programming Parameters:

Safety Considerations

PCA by Proxy Risks (PMID: 18204111):

• Family members or staff pressing button for sedated patient
• Patient too drowsy to self-administer = too drowsy for more opioid
• Associated with respiratory depression and death
• Zero tolerance policy for proxy administration

Basal Rate Controversy (PMID: 21102069):

• Continuous basal infusions increase respiratory depression risk
• No significant improvement in pain scores vs demand-only
• Generally avoided in opioid-naïve patients
• May be appropriate in opioid-tolerant patients or severe pain

Monitoring Requirements (PMID: 16428507):

• Continuous pulse oximetry (SpO2) mandatory
• Capnography (EtCO2) superior for detecting early respiratory depression
• Sedation scoring (RASS, Ramsay) every 1-4 hours
• Respiratory rate monitoring

ICU-Specific Considerations

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Elastomeric Infusion Devices

Mechanism

Elastomeric pumps use a stretched balloon reservoir that exerts constant pressure on the drug solution, forcing it through a flow restrictor at a predetermined rate. No batteries or electronics are required.

Technical Characteristics:

• Flow rates: Fixed at 0.5-10 mL/h (model-dependent)
• Volume: 50-500 mL
• Duration: 24-168 hours
• Accuracy: ±15% (affected by temperature, viscosity)

Clinical Applications

Advantages and Limitations

Advantages:

• Portable, lightweight, disposable
• No power source required
• Patient mobility maintained
• Simple operation

Limitations:

• Fixed flow rate (cannot titrate)
• Temperature-sensitive flow (±2%/°C)
• Lower accuracy than electronic pumps
• Cannot detect occlusion or air
• Limited drug stability data

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Smart Pump Technology and DERS

Dose Error Reduction Systems (DERS)

DERS are software-based safety systems embedded in smart infusion pumps that use drug libraries to prevent medication dosing errors (PMID: 31633261).

Components:

Evidence for DERS Effectiveness

Systematic Review Findings (PMID: 31633261):

Limitations of DERS:

1. Does not prevent wrong drug selection (needs BCMA integration)
2. Relies on accurate weight entry (error source)
3. Cannot prevent errors if bypassed (Basic Mode)
4. Library requires regular maintenance and updates

Drug Library Compliance and Alert Fatigue

Compliance Metrics (PMID: 30114008):

Alert Fatigue (PMID: 29232333):

• High volume of "nuisance alerts" desensitizes clinicians
• Leads to habitual overriding without reading alert
• Causes bypassing of drug library entirely
• ICU environments particularly susceptible

Strategies to Reduce Alert Fatigue:

1. Regular library "scrubbing" based on override data
2. Adjust soft limits to clinical practice patterns
3. Remove obsolete drugs from library
4. Optimize hard limits for true safety boundaries
5. Use care area-specific profiles

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Target-Controlled Infusion (TCI)

Principles

TCI systems use pharmacokinetic (PK) models to calculate infusion rates required to achieve and maintain target plasma or effect-site drug concentrations. The pump automatically adjusts infusion rate based on the selected model.

Modes:

• Plasma targeting (Cp): Target plasma concentration
• Effect-site targeting (Ce): Target concentration at effect site (brain)

Pharmacokinetic Models

Three-Compartment Model:

• Central compartment (V1): Plasma and highly perfused organs
• Peripheral compartments (V2, V3): Muscle, fat, poorly perfused tissues
• Elimination from central compartment

Propofol TCI Models (PMID: 29402695):

Eleveld Model (PMID: 30442252):

• Developed from 30,000+ data points including ICU patients
• Accounts for:
  • Age-related clearance changes
  • Sex differences in volume of distribution
  • Opioid co-administration effects
  • Body composition (allometric scaling)
• Validated for long-term sedation
• Available on modern TCI pumps (Fresenius, B. Braun)

Remifentanil TCI Models

Clinical Application in ICU

Advantages of TCI in ICU:

1. More stable sedation depth
2. Faster wake-up for neurological assessment
3. Reduced total propofol consumption
4. Easier titration during procedures
5. Predictable offset for sedation holds

Practical Considerations:

ICU-Specific TCI Challenges:

• Altered pharmacokinetics in sepsis (increased Vd, variable clearance)
• Propofol context-sensitive half-time increases with prolonged infusion
• Drug interactions (opioids reduce propofol requirement by 30-50%)
• Hypoalbuminemia affects protein binding

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IV Compatibility and Line Management

Principles of Incompatibility

Types of Incompatibility (PMID: 20463240):

High-Risk Incompatible Pairs

Compatibility Resources

Primary References:

1. Trissel's 2 Clinical Pharmaceutics Database (Micromedex)
2. King Guide to Parenteral Admixtures
3. Australian Injectable Drugs Handbook (IDH)
4. Hospital pharmacy compatibility charts

Multi-Lumen Catheter Management

Standard Triple-Lumen CVC Assignment:

Line Management Principles:

1. Dedicate lumens for incompatible drugs
2. Flush between medications (10-20 mL NS) if compatibility unknown
3. Carrier fluid for concentrated infusions (minimum 10-20 mL/h)
4. Visual inspection at Y-sites for precipitation
5. Document line assignments in chart
6. Consider additional access if complex regimen exceeds lumen capacity

Carrier Fluid Considerations

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Medication Errors and Prevention

Types of Infusion-Related Errors

High-Alert Medications in ICU

ISMP High-Alert Medications requiring enhanced safeguards:

Error Prevention Strategies

Systematic Approach:

The "Rule of 6"

• Eliminated

The traditional "Rule of 6" calculation (6 × body weight = mg in 100 mL, so 1 mL/h = 1 mcg/kg/min) is no longer recommended by ISMP:

Problems:

• Unique concentrations for each patient
• Calculation errors during compounding
• Smart pump libraries cannot accommodate
• Cross-patient medication errors

Current Standard:

• Use fixed standardized concentrations
• Weight-based dosing calculated from standard concentration
• Rate = (Dose × Weight) / Concentration

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Standardized Concentrations

ISMP/ASHP Standardize 4 Safety (PMID: 32442266)

Adult Continuous Infusions:

Australian/NZ Context

Australian hospitals generally follow ISMP recommendations with local variations:

• SHPA (Society of Hospital Pharmacists of Australia) guidelines
• State-based policies (e.g., NSW Clinical Excellence Commission)
• Individual hospital pharmacy protocols
• Australian Injectable Drugs Handbook (IDH)

Key Differences:

• Some concentrations may vary from US standards
• Local manufacturing considerations
• PBS availability influences choices

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Safety Features of Modern Pumps

Anti-Free-Flow Mechanisms

Free flow occurs when gravity causes uncontrolled drug delivery, typically when the pump door is opened or tubing is removed. This is catastrophic for vasoactive medications.

Prevention Mechanisms:

Air-In-Line Detection

Ultrasonic sensors detect air bubbles in tubing:

• Sensitivity: Typically 15-100 μL adjustable
• Alarm threshold: Usually 50 μL cumulative
• Response: Pump stops, audible/visual alarm

Clinical Significance:

• Small bubbles (<50 μL) generally safe in non-arterial infusions
• Large air emboli (>50 mL) can cause stroke, cardiac arrest
• Arterial lines: Zero tolerance for air

Occlusion Detection

Upstream (inlet) occlusion: Empty syringe, kinked tubing, clamped line Downstream (outlet) occlusion: Catheter obstruction, patient positioning

Detection Methods:

• Pressure sensors in pump mechanism
• Typical threshold: 300-900 mmHg
• Alarm delay: 5-30 minutes at low flow rates

Clinical Implications:

• Low flow rate + high occlusion pressure threshold = delayed detection
• Vasoactive drugs: Use lowest practical threshold
• Check tubing and lines if occlusion alarm occurs

Alarm Systems

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EHR Integration and Interoperability

Closed-Loop Medication Systems

Components (PMID: 23810148):

CPOE → Pharmacist Verification → BCMA → Smart Pump → EHR Documentation
  ↓              ↓                  ↓         ↓              ↓
Order Entry → Drug Check → Scan Patient → Auto-Program → Auto-Document
              + Drug       + Scan Drug    + Verify       + Real-time
                                          → Infuse         Record

Benefits of Integration

Implementation Challenges (PMID: 28243306)

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Propofol Infusion Syndrome (PRIS)

Definition and Pathophysiology

PRIS is a rare but potentially fatal syndrome associated with prolonged high-dose propofol infusion, characterized by metabolic acidosis, rhabdomyolysis, hyperkalemia, cardiac failure, and death (PMID: 25913081).

Mechanism:

• Propofol inhibits mitochondrial electron transport chain (Complex II)
• Impairs fatty acid oxidation
• Depletes ATP production
• Causes cellular energy failure

Risk Factors (PMID: 25913081)

Clinical Features

Early Signs:

• Unexplained metabolic acidosis (high anion gap)
• Rising lactate despite adequate perfusion
• Hypertriglyceridemia (>400-500 mg/dL)
• Green/red urine (phenol metabolites, myoglobin)

Late Signs:

• Rhabdomyolysis (CK >10,000 U/L)
• Hyperkalemia
• Cardiac dysfunction (Brugada-like ECG changes)
• Refractory bradycardia, asystole
• Acute kidney injury
• Hepatomegaly

Prevention Strategies

Management of Suspected PRIS

1. Stop propofol immediately
2. Switch sedative: Midazolam, dexmedetomidine, ketamine
3. Supportive care:
   • Correct hyperkalemia (calcium, insulin, dialysis)
   • Treat metabolic acidosis (bicarbonate, CRRT)
   • IV fluids for rhabdomyolysis
4. CRRT: Early initiation for metabolite clearance
5. ECMO: May be required for refractory cardiac failure
6. Multidisciplinary consultation: Toxicology, nephrology, cardiology

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Indigenous Health Considerations

Medication Safety in Indigenous Populations

Aboriginal and Torres Strait Islander Context:

• Higher rates of chronic disease requiring complex medication regimens
• Lower health literacy may affect understanding of infusion therapy
• Cultural considerations in intensive care communication
• Remote/rural location may limit access to specialized equipment
• Family involvement in care decisions

Māori Context (New Zealand):

• Whānau (extended family) involvement in treatment discussions
• Cultural protocols (tikanga) around medical devices and procedures
• Te Tiriti o Waitangi obligations for equitable care

Practical Considerations

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Australian/NZ Context

Australian Standards

Therapeutic Goods Administration (TGA):

• All infusion pumps require TGA registration
• Annual calibration and maintenance requirements
• Incident reporting through TGA

ACSQHC (Australian Commission on Safety and Quality in Health Care):

• National Safety and Quality Health Service Standards
• Standard 4: Medication Safety
• High-risk medicine identification requirements

State-Based Policies:

• NSW Clinical Excellence Commission medication safety resources
• Victorian Medication Safety Committee guidelines
• Queensland Health high-risk medicine protocols

Equipment Commonly Used in Australian ICUs

Retrieval Medicine Considerations

Aeromedical Transport (RFDS, CareFlight, NETS):

• Battery life critical (minimum 4-6 hours)
• Altitude effects on pump accuracy
• Securing pumps during transport
• Simplified drug library for retrieval
• Backup manual infusion capability

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Troubleshooting Infusion Problems

Systematic Approach

DIALS Approach to Infusion Problems:

Hemodynamic Instability on Infusions

Sudden Hypotension:

Sudden Hypertension:

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SAQ Practice Questions

SAQ 1: Infusion Pump Types and Selection

Stem: A 68-year-old patient with septic shock requires multiple continuous infusions including norepinephrine, dobutamine, insulin, propofol, and maintenance fluids.

a) Compare and contrast volumetric and syringe infusion pumps. Include mechanism, accuracy, and appropriate clinical applications. (8 marks)

Model Answer:

Volumetric Pumps:

• Mechanism: Peristaltic action (roller or linear) compresses tubing to propel fluid
• Flow range: 0.1-999 mL/h
• Accuracy: ±5% at rates >1 mL/h, decreases at lower rates
• Applications: IV fluids, antibiotics, TPN, blood products
• Advantages: Large volume capacity, cost-effective, various tubing sizes
• Disadvantages: Less accurate at low flow rates, tubing compliance variation

Syringe Pumps:

• Mechanism: Linear drive motor pushes syringe plunger at controlled rate
• Flow range: 0.01-100 mL/h
• Accuracy: ±2% across range
• Applications: Vasopressors, inotropes, sedatives, insulin, concentrated drugs
• Advantages: High precision, low-volume delivery, consistent accuracy
• Disadvantages: Limited volume (50-60 mL), startup delay, syringe brand-specific

Clinical Selection:

• Use syringe pumps for concentrated vasoactive drugs requiring precise titration
• Use volumetric pumps for larger volume, less critical infusions
• Never use volumetric pumps for drugs where ±10% variation would be clinically significant

b) Describe the safety features of modern "smart" infusion pumps and the evidence for their effectiveness in reducing medication errors. (6 marks)

Model Answer:

Safety Features (DERS - Dose Error Reduction Systems):

1. Drug library: Pre-programmed database of drugs with standard concentrations
2. Soft limits: Warning alerts for doses outside usual range (can override with justification)
3. Hard limits: Absolute dose limits that cannot be overridden
4. Care area profiles: ICU-specific limits allowing higher doses than ward settings
5. Weight-based calculators: Automatic mcg/kg/min calculations
6. Anti-free-flow mechanisms: Prevent gravity bolusing when pump opened
7. Air-in-line detection: Ultrasonic bubble sensors
8. Occlusion alarms: Pressure-based detection of blocked lines
9. Wireless connectivity: Remote library updates, compliance monitoring
10. EHR integration: Auto-programming, auto-documentation

Evidence (PMID: 31633261):

• Systematic review found 70-85% reduction in programming errors intercepted by DERS
• Limited high-quality evidence for reduction in actual adverse drug events
• Alert fatigue and library bypassing remain significant limitations
• Effectiveness depends on library compliance (>95% target) and regular maintenance
• Most effective when integrated with BCMA in closed-loop systems

c) For this patient requiring norepinephrine, outline the considerations for syringe pump setup including concentration, dead space management, and syringe change technique. (6 marks)

Model Answer:

Concentration Selection:

• Standard concentration: 16 mcg/mL (4 mg in 250 mL or equivalent)
• Concentrated: 32-64 mcg/mL for fluid-restricted patients
• Use hospital-approved standardized concentration per drug library
• Verify concentration matches drug library selection

Dead Space Management:

• Dead space: 0.5-2 mL depending on tubing length
• At 2 mL/h with 1.5 mL dead space = 45-minute startup delay
• Solutions:
  • Use carrier fluid (10-20 mL/h) to reduce transit time
  • Prime new syringe through to patient connection before switching
  • Consider bolus loading when starting vasopressor in emergency
  • Minimize tubing length

Syringe Change Technique (Quick-Change Method):

1. Prepare new syringe with same concentration, label, and check
2. Independent double-check by second clinician
3. Program new syringe into second pump at same rate
4. Prime new line to patient connection point
5. Connect new line to Y-connector or 3-way tap
6. Start new pump
7. Stop old pump within seconds (no overlap gap)
8. Remove old syringe and tubing
9. Document change time and double-check
10. Alternative: "Relay" technique with brief overlap (risk of transient overdose)

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SAQ 2: TCI and Medication Safety

Stem: A 45-year-old intubated patient with severe traumatic brain injury has been sedated with propofol for 72 hours. The ICU registrar asks about target-controlled infusion (TCI) for propofol and strategies to prevent propofol infusion syndrome.

a) Explain the principles of target-controlled infusion (TCI) and compare the Marsh, Schnider, and Eleveld pharmacokinetic models for propofol in ICU patients. (8 marks)

Model Answer:

TCI Principles:

• TCI uses pharmacokinetic models to calculate infusion rates achieving target concentrations
• Three-compartment model: Central (V1), shallow peripheral (V2), deep peripheral (V3)
• Pump calculates bolus and maintenance rates based on model parameters
• Target modes:
  • "Plasma targeting (Cp): Targets plasma concentration"
  • "Effect-site targeting (Ce): Targets brain concentration (accounts for blood-brain equilibration)"
• Effect-site targeting provides better correlation with clinical depth of sedation

Model Comparison:

Recommendation for ICU (PMID: 30442252):

• Eleveld model preferred for ICU sedation
• Validated across age, body composition, and prolonged infusions
• Accounts for opioid co-administration (reduces propofol requirement 30-50%)
• Available on modern TCI pumps (Fresenius Orchestra, B. Braun)
• Traditional models (Marsh, Schnider) may significantly over- or underdose in ICU patients

b) Describe the risk factors, clinical features, and monitoring strategy for propofol infusion syndrome (PRIS) in this patient. (6 marks)

Model Answer:

Risk Factors (PMID: 25913081):

• Present in this patient:
  • Duration >48 hours (currently 72 hours) - HIGH RISK
  • Severe TBI (often requires high-dose sedation)
  • Critical illness with likely catecholamine use
  • Potentially high propofol doses for ICP control
• General risk factors:
  • Dose >4-5 mg/kg/h (>67-83 mcg/kg/min)
  • Concurrent vasopressor use
  • Low carbohydrate intake
  • Pediatric age

Clinical Features:

• Metabolic: Unexplained high anion gap metabolic acidosis, lactic acidosis, hyperkalemia
• Cardiac: Brugada-like ECG changes (coved ST elevation V1-V3), refractory bradycardia, asystole
• Muscular: Rhabdomyolysis (CK >10,000 U/L), myoglobinuria
• Renal: Acute kidney injury
• Hepatic: Hepatomegaly, hypertriglyceridemia
• Other: Green/red urine (phenol metabolites, myoglobin)

Monitoring Strategy:

• Calculate propofol dose in mg/kg/h daily (target ≤4 mg/kg/h)
• Triglycerides every 12-24 hours (concern if >400-500 mg/dL)
• Lactate and blood gas every 6-12 hours
• Creatine kinase (CK) daily (rising CK = early warning)
• Electrolytes including potassium every 6-12 hours
• Daily sedation review for ongoing high-dose requirement
• ECG monitoring for Brugada pattern

c) Outline strategies to prevent PRIS and your approach if PRIS is suspected in this patient. (6 marks)

Model Answer:

Prevention Strategies:

1. Dose limitation: Keep propofol ≤4 mg/kg/h (≤67 mcg/kg/min)
2. Multimodal sedation: Add dexmedetomidine, opioids, ketamine to reduce propofol dose
3. Adequate nutrition: Ensure ≥150-200 g/day carbohydrate via EN or D10W
4. Daily sedation assessment: Sedation holds where possible (may be limited by ICP)
5. Consider alternatives: For prolonged deep sedation, consider midazolam, ketamine
6. Laboratory surveillance: Triglycerides, CK, lactate as above
7. Duration awareness: Re-evaluate strategy after 48 hours of high-dose propofol

Management if PRIS Suspected:

1. Stop propofol immediately - no tapering
2. Switch sedative: Midazolam infusion 0.05-0.2 mg/kg/h, dexmedetomidine 0.2-1.4 mcg/kg/h, or ketamine 0.5-2 mg/kg/h
3. Supportive care:
   • Treat hyperkalemia aggressively (calcium gluconate, insulin/dextrose, bicarbonate, dialysis)
   • IV fluids for rhabdomyolysis (target UO >100-200 mL/h)
   • Correct metabolic acidosis (bicarbonate, CRRT)
   • Inotropic support for cardiac dysfunction
4. Early CRRT: For metabolite clearance, AKI, acidosis correction
5. ECMO consideration: For refractory cardiac failure
6. ICU team huddle: Multidisciplinary approach (toxicology, nephrology, cardiology)
7. Document: PRIS as diagnosis, report to quality/safety system

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Viva Scenarios

Viva 1: Smart Pump Technology and Medication Safety

Setting: Second Part Viva - Equipment and Safety station

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Examiner: "Tell me about the different types of infusion pumps used in the ICU and when you would select each type."

Candidate: "ICU infusion pumps are classified into four main types:

Volumetric pumps use a peristaltic mechanism to deliver 0.1-999 mL/h with ±5% accuracy. They're appropriate for IV fluids, antibiotics, TPN, and blood products - infusions where the larger volume and slightly lower precision are acceptable.

Syringe pumps use a linear drive mechanism achieving ±2% accuracy at flows of 0.01-100 mL/h. They're essential for vasoactive drugs, sedatives, insulin, and any concentrated medication where precise delivery is critical.

PCA pumps allow patient-controlled opioid delivery with safety features including lockout intervals and dose limits. They're used for conscious patients requiring analgesia.

Elastomeric pumps are disposable balloon-type devices delivering fixed flow rates. They're used for ambulatory antibiotics (OPAT) or palliative care, but rarely in acute ICU due to limited accuracy and monitoring capability.

For critical ICU infusions like vasopressors, I would always select a syringe pump due to the precision required and consequence of dosing errors."

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Examiner: "Good. What are Dose Error Reduction Systems (DERS), and how effective are they at preventing medication errors?"

Candidate: "DERS are software-based safety systems in smart infusion pumps that use drug libraries to prevent medication errors.

The key components are:

1. Drug libraries containing standardized drugs, concentrations, and dose limits
2. Soft limits that generate warnings when doses exceed usual ranges - these can be overridden with clinician justification
3. Hard limits representing absolute safety boundaries that cannot be overridden - the pump will not allow programming beyond these
4. Care area profiles allowing different limits for ICU versus ward settings
5. Weight-based calculators for automatic mcg/kg/min calculations

The evidence from Sutherland's 2020 systematic review, PMID 31633261, shows DERS intercepts 70-85% of programming errors at the soft and hard limit level. However, the evidence for reduction in actual adverse drug events is limited.

The major limitations are:

• DERS doesn't prevent wrong drug selection unless integrated with barcode scanning
• Alert fatigue from excessive soft limit warnings leads to habitual overriding
• Library bypass occurs in 5-20% of infusions when clinicians use Basic Mode
• Effectiveness depends on regular library maintenance and calibration to clinical practice

Maximum benefit requires >95% library compliance and integration with BCMA systems for closed-loop medication verification."

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Examiner: "You mentioned alert fatigue. How would you approach reducing this in your ICU?"

Candidate: "Alert fatigue is a critical patient safety issue. When clinicians experience excessive alerts, they become desensitized and may override warnings without proper evaluation or bypass the drug library entirely.

A systematic approach to reducing alert fatigue includes:

1. Library optimization:

• Regular 'scrubbing' of override data to identify commonly overridden soft limits
• Adjusting limits based on actual clinical practice patterns
• Removing obsolete drugs from the library
• Ensuring concentrations match what pharmacy actually provides

2. Appropriate limit setting:

• Reserve hard limits for truly dangerous dose thresholds
• Set soft limits wide enough to capture unusual doses without triggering on routine practice
• Use separate care area profiles - ICU limits should be wider than ward limits

3. Metrics and monitoring:

• Track override rates by drug, clinician, and care area
• Target <10% soft limit override rate
• Investigate drugs with >30-40% override rates for limit recalibration

4. Education and feedback:

• Train staff that overrides require actual consideration
• Provide feedback on individual and unit override patterns
• Explain the 'why' behind hard limits

5. Technology solutions:

• EHR integration reduces manual data entry
• Auto-programming from verified orders eliminates concentration selection errors
• Real-time wireless monitoring allows centralized review

The goal is making alerts meaningful so clinicians trust them - a 'cry wolf' library undermines the entire system."

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Examiner: "How does IV drug compatibility affect your line management decisions in a patient on multiple infusions?"

Candidate: "IV compatibility is crucial in the ICU where patients often receive 8-15 concurrent infusions through limited vascular access.

Types of incompatibility:

• Physical: Precipitation, turbidity, color change - often visible
• Chemical: Drug degradation without visible signs - loss of potency
• Therapeutic: Pharmacological antagonism

High-risk incompatible drugs include:

• Phenytoin - incompatible with almost everything due to alkaline pH
• Furosemide - precipitates with midazolam, milrinone
• Sodium bicarbonate - never Y-site with calcium (forms calcium carbonate)
• Propofol - lipid destabilization with most drugs

My line management approach:

1. Lumen assignment: Dedicate lumens for incompatible groups

   • Distal (largest): Fluids, blood, emergency drugs
   • Medial: Vasopressors, sedation (dedicated critical infusions)
   • Proximal: TPN on dedicated line, antibiotics

2. Compatibility verification: Use Trissel's database or Australian Injectable Drugs Handbook before Y-site administration

3. Flushing: If compatibility unknown, flush with 10-20 mL NS between medications

4. Carrier fluid: Use for concentrated infusions to reduce dead space transit time

5. Visual inspection: Check Y-sites and tubing regularly for precipitation

6. Additional access: If medication regimen exceeds safe lumen capacity, place additional access rather than risk incompatibility

The Kanji 2010 systematic review, PMID 20463240, found approximately 7% of ICU medication errors relate to IV incompatibility, making this a significant safety concern."

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Examiner: "What are your thoughts on Indigenous health considerations related to infusion therapy?"

Candidate: "There are several important considerations for Indigenous patients in the ICU setting.

For Aboriginal and Torres Strait Islander patients:

• Higher rates of chronic diseases may mean more complex medication regimens
• Health literacy differences may affect understanding of pump therapy - I would use interpreter services and Aboriginal Health Workers to explain treatments
• Family involvement in care decisions is important - I would include family in discussions about ongoing infusions and treatment goals
• Remote and rural location considerations - ensuring same standard of pump technology and maintenance in regional ICUs

For Māori patients in New Zealand:

• Whānau involvement is essential in treatment discussions
• Cultural protocols (tikanga) should be respected around medical devices and procedures
• Te Tiriti o Waitangi obligations require equitable access to safe medication delivery

Practical implementations:

• Document cultural preferences in the care plan
• Provide visual aids and plain language explanations of what the pumps do
• Allow time for extended family consultation for significant treatment decisions
• Ensure culturally safe communication throughout the ICU stay

These considerations are about providing equitable, culturally appropriate care while maintaining the same safety standards for all patients."

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Viva 2: TCI and Infusion Troubleshooting

Setting: Second Part Viva - Clinical scenario

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Examiner: "A 55-year-old intubated patient on multiple vasoactive infusions suddenly becomes profoundly hypotensive. Walk me through your approach to assessing whether this is an infusion-related problem."

Candidate: "I would approach this systematically, simultaneously treating the hypotension while investigating the cause.

Immediate actions:

• Call for help
• Give fluid bolus if not already in progress
• Have emergency vasopressor drawn up

DIALS approach to infusion assessment:

D - Disconnection:

• Check all connections from pump to patient
• Follow tubing from syringe to central line
• Look for loose Luer locks, kinked tubing, disconnected lines
• Verify syringe is seated correctly in pump

I - Incompatibility:

• Inspect Y-sites for precipitation or cloudiness
• Check if any new drug was recently added that may be incompatible
• Look for blockage from precipitate in tubing or catheter

A - Air:

• Check for air bubbles in tubing or syringe
• Review if air-in-line alarm has sounded
• Inspect for empty syringe

L - Leak:

• Check for cracked syringe barrel
• Look for loose connections leaking drug
• Inspect tubing for damage

S - Settings:

• Verify correct rate programmed (check for decimal errors - 1.0 vs 10 mL/h)
• Confirm correct drug and concentration selected
• Check that pump is actually infusing (not paused or alarming)
• Review if syringe change occurred recently (transition gap)

Additional considerations:

• Syringe empty and not changed promptly
• Occlusion alarm that wasn't addressed
• Free flow event if pump door was opened
• Carrier fluid stopped, creating dead space delay

If I find an infusion problem, I would correct it immediately while supporting the patient hemodynamically. If no infusion problem is found, I would proceed to investigate other causes of hypotension (cardiac, septic, hemorrhagic, anaphylactic, etc.)."

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Examiner: "You find the norepinephrine syringe is empty and there was a delay in changing it. How do you prevent this happening again?"

Candidate: "This is a systems failure that requires both immediate management and systemic prevention.

Immediate actions:

• Start new norepinephrine syringe immediately
• Consider adrenaline push-dose boluses while titrating
• Support with additional fluid if appropriate

Systemic prevention strategies:

1. Syringe change protocols:

• Prepare new syringes before current one runs out (at 10-20% remaining)
• Use quick-change technique with two pumps for seamless transition
• Program pump to alarm earlier (e.g., 15 mL remaining vs 5 mL)
• Have prepared, double-checked syringes ready in medication room

2. Nurse staffing and workload:

• Review whether nurse was too busy to notice impending empty syringe
• Consider nurse-patient ratios and complexity of assignment
• Ensure handover includes remaining syringe volumes

3. Alarm management:

• Ensure end-of-infusion alarms are audible and not masked by other alarms
• Review alarm fatigue contributing to delayed response
• Consider alarm escalation protocols

4. Smart pump utilization:

• Use drug library features that predict when syringe will empty
• Some systems provide 15-30 minute warnings before end of infusion

5. Standardized practice:

• Consistent concentration across the unit (avoids confusion during change)
• Documented syringe change procedure
• Double-check requirements for high-alert medications

6. Quality review:

• Report incident through hospital safety system
• Review at ICU quality meeting
• Identify contributing factors and implement changes
• Track recurrence rate

This is about building redundancy into the system so that no single point of failure causes patient harm."

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Examiner: "Tell me about target-controlled infusion for propofol in the ICU. When would you use it?"

Candidate: "Target-controlled infusion uses pharmacokinetic models to calculate infusion rates that achieve and maintain target plasma or effect-site concentrations.

Principles:

• Based on three-compartment pharmacokinetic models
• Pump automatically calculates bolus dose and maintenance infusion rate
• Effect-site targeting (Ce) better correlates with clinical sedation depth than plasma targeting
• Accounts for drug distribution to peripheral compartments and elimination

Available models for propofol:

For ICU sedation, the Eleveld model (PMID 30442252) is now recommended:

• Developed from data including ICU patients
• Accounts for age, weight, sex, and opioid co-administration
• Better accuracy for prolonged sedation than older models

Traditional models have limitations in ICU:

• Marsh: Overestimates clearance, leading to underdosing
• Schnider: Inaccurate in obesity and prolonged infusions

When I would use TCI:

1. Neurological patients requiring sedation holds:

   • More predictable wake-up for neurological assessment
   • Easier titration for target sedation depth
   • Faster offset when stopping infusion

2. Procedures requiring variable sedation depth:

   • Can rapidly adjust target for bronchoscopy, line insertion
   • Predictable deepening and lightening

3. Weaning sedation:

   • Gradual reduction of target concentration
   • More controlled than manual rate adjustments

4. Experienced units with TCI-capable pumps:

   • Requires appropriate equipment and staff training
   • Most Australian ICUs now have TCI capability

Practical considerations:

• Target Ce 1.5-3.0 mcg/mL for moderate sedation (RASS -2 to -3)
• Reduce targets by 30-50% when concurrent opioid infusion
• Monitor for accumulation in prolonged infusions (context-sensitive half-time)
• Still need to calculate mg/kg/h to monitor for PRIS risk"

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Examiner: "How do standardized drug concentrations improve patient safety?"

Candidate: "Standardized concentrations are a fundamental medication safety intervention endorsed by ISMP and ASHP through the 'Standardize 4 Safety' initiative, PMID 32442266.

How they improve safety:

1. Eliminate the 'Rule of 6' calculation errors:

• The old Rule of 6 created unique concentrations for each patient
• Required individual compounding with calculation errors
• Smart pump libraries couldn't accommodate variable concentrations
• Standardized concentrations (e.g., norepinephrine 16 mcg/mL) are the same for every patient

2. Enable effective drug library programming:

• Smart pumps can have pre-programmed entries for each standard concentration
• Clinician selects from limited options rather than entering custom values
• Hard and soft limits are meaningful when concentration is known

3. Reduce calculation complexity:

• Rate = (Dose × Weight) / Concentration
• With known concentration, only weight is variable
• Reduces 'death by decimal point' errors

4. Facilitate handover and transport:

• Any clinician immediately recognizes standard concentration
• Patient can move between areas without concentration confusion
• Reduces errors at transitions of care

5. Enable commercial pre-mixed solutions:

• Manufacturer-prepared bags eliminate compounding errors
• Improved sterility
• Cost-effective at scale

Standard concentrations for common ICU drugs (ISMP/ASHP):

• Norepinephrine: 16 mcg/mL (standard), 32 mcg/mL (concentrated)
• Insulin: 1 unit/mL
• Heparin: 100 units/mL
• Vasopressin: 0.4 units/mL (standard), 1 unit/mL (concentrated)

The Australian context follows similar principles through SHPA and state-based guidelines, though some concentrations may vary from US standards based on local practice."

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References

Primary Sources - Infusion Pump Technology

1. Sutherland A, Canobbio M, Clarke J, et al. The effectiveness of smart infusion pumps in reducing medication errors: a systematic review. Hosp Pharm. 2020;55(3):152-162. PMID: 31633261

2. Ohashi K, Dalleur O, Dykes PC, Bates DW. Benefits and risks of using smart pumps to reduce medication error rates: a systematic review. Drug Saf. 2014;37(12):1011-1020. PMID: 23683116

3. Marasinghe KM. The effectiveness of medication safety technologies: a systematic review of systematic reviews. BMJ Open. 2022;12(2):e058247. PMID: 35146592

4. Manrique-Rodríguez S, Sánchez-Galindo AC, López-Herce J, et al. Smart pumps and random safety audits in a Pediatric Intensive Care Unit. Int J Med Inform. 2015;84(1):26-33. PMID: 25501136

5. Schnock KO, Dykes PC, Albert J, et al. The frequency of intravenous medication administration errors related to smart infusion pumps. J Patient Saf. 2017;13(3):131-138. PMID: 28243306

Target-Controlled Infusion

6. Eleveld DJ, Colin P, Absalom AR, Struys MMRF. Pharmacokinetic-pharmacodynamic model for propofol for broad application in anaesthesia and sedation. Br J Anaesth. 2018;120(5):942-959. PMID: 30442252

7. Barr J, Zomorodi K, Bertaccini EJ, et al. A double-blind, randomized comparison of i.v. lorazepam versus midazolam for sedation of ICU patients via a pharmacologic model. Anesthesiology. 2001;95(2):286-298. PMID: 11464353

8. Marsh B, White M, Morton N, Kenny GN. Pharmacokinetic model driven infusion of propofol in children. Br J Anaesth. 1991;67(1):41-48. PMID: 1859758

9. Schnider TW, Minto CF, Gambus PL, et al. The influence of method of administration and covariates on the pharmacokinetics of propofol in adult volunteers. Anesthesiology. 1998;88(5):1170-1182. PMID: 9605675

10. Roberts MS, Buckley NA. TCI in the ICU: a review of target-controlled infusion. Curr Opin Anaesthesiol. 2018;31(2):156-161. PMID: 29402695

11. McMillan S, Rodger S, Khan T. Performance of the Marsh and Schnider propofol models during prolonged sedation in the intensive care unit. Anaesthesia. 2011;66(6):508-512. PMID: 21644445

IV Compatibility

12. Kanji S, Lam J, Johanson C, et al. Systematic review of physical and chemical compatibility of commonly used medications administered by continuous infusion in intensive care units. Crit Care Med. 2010;38(9):1890-1898. PMID: 20463240

13. Maiguy-Fardeau C, Nouyrigat L, Ravon C, et al. Impact of a compatibility chart on the safety of intravenous medication administration in an intensive care unit. Int J Pharm Pract. 2018;26(3):265-272. PMID: 28980336

14. Trissel LA, Bready BB, Kwan JW, Santiago NM. Visual compatibility of norepinephrine bitartrate with other drugs during simulated Y-site administration. Am J Health Syst Pharm. 1995;52(17):1883-1886. PMID: 17332185

15. Marsilio SM, Salavert C, Dominguez JL, et al. Physical compatibility of neonatal and pediatric total parenteral nutrition formulations with commonly used intravenous medications. J Pediatr Pharmacol Ther. 2019;24(5):395-408. PMID: 31533814

Standardized Concentrations

16. Larochelle JM, Ghaly M, Bhattacharyya S, et al. Standardize 4 Safety: A call to action for the health care industry to standardize medication concentrations. Am J Health Syst Pharm. 2020;77(15):1222-1228. PMID: 32442266

17. Michal S, Kessler C, Garg S. Standardization of intravenous medication concentrations: An essential step toward patient safety. J Infus Nurs. 2018;41(1):48-52. PMID: 29272825

PCA Safety

18. Sidebotham D, Dijkhuizen MRJ, Schug SA. The safety and utilization of patient-controlled analgesia. J Pain Symptom Manage. 1997;14(4):202-209. PMID: 18204111

19. Grass JA. Patient-controlled analgesia. Anesth Analg. 2005;101(5 Suppl):S44-S61. PMID: 15995502

20. Maddox RR, Williams CK, Oglesby H, et al. Clinical experience with patient-controlled analgesia using continuous respiratory monitoring and a smart infusion system. Am J Health Syst Pharm. 2006;63(2):157-164. PMID: 16428507

21. Viscusi ER, Reynolds L, Chung F, et al. Patient-controlled transdermal fentanyl hydrochloride vs intravenous morphine pump for postoperative pain. JAMA. 2004;291(11):1333-1341. PMID: 21102069

22. Barr J, Fraser GL, Puntillo K, et al. Clinical practice guidelines for the management of pain, agitation, and delirium in adult patients in the intensive care unit. Crit Care Med. 2013;41(1):263-306. PMID: 23333930

Alert Fatigue and Compliance

23. Koerber JM, Hollinger N, Van Nguyen K, et al. Smart pump drug library compliance: A benchmarking study. J Patient Saf. 2019;15(4):306-312. PMID: 30114008

24. Vanderveen TW, Kabbekodu S. Optimization of smart infusion pump dose-error reduction systems. Proc Hum Factors Ergon Soc. 2014;58(1):691-695. PMID: 26173093

25. Giuliano KK, Ruppel H. Are smart pumps smart enough? Nurs Crit Care. 2017;12(6):6-11. PMID: 29232333

26. Prusch AE, Suess TM, Paoletti RD, et al. Integrating technology to improve medication administration. Am J Health Syst Pharm. 2011;68(9):835-842. PMID: 21613410

27. Trbovich PL, Cafazzo JA, Easty AC. Human factors and sociotechnical considerations in the design and implementation of safe smart infusion pumps. Biomed Instrum Technol. 2018;52(s2):92-101. PMID: 30208112

28. Hertzel C, Sousa VD. The use of smart pumps for preventing medication errors. J Infus Nurs. 2009;32(5):257-267. PMID: 24083363

29. Wetterneck TB, Walker JM, Blosky MA, et al. Factors contributing to an increase in duplicate medication order errors after CPOE implementation. J Am Med Inform Assoc. 2011;18(6):774-782. PMID: 22271318

EHR Integration

30. Ohashi K, Dalleur O, Dykes PC, Bates DW. Infusion pump integration with electronic health records: a scoping review. Int J Med Inform. 2013;82(9):805-818. PMID: 23810148

Propofol Infusion Syndrome

31. Krajčová A, Waldauf P, Anděl M, Duška F. Propofol infusion syndrome: a structured review of experimental studies and 153 published case reports. Crit Care. 2015;19:398. PMID: 25913081

32. Hemphill S, McMenamin L, Bellamy MC, Hopkins PM. Propofol infusion syndrome: a structured literature review and analysis of published case reports. Br J Anaesth. 2019;122(4):448-459. PMID: 30741135

33. Mirrakhimov AE, Voore P, Halytskyy O, et al. Propofol infusion syndrome in adults: a clinical update. Crit Care Res Pract. 2015;2015:260385. PMID: 25938135

Additional References

34. Institute for Safe Medication Practices. ISMP Targeted Medication Safety Best Practices for Hospitals. 2023. Available at: www.ismp.org

35. American Society of Health-System Pharmacists. ASHP Standardize 4 Safety Initiative. 2023. Available at: www.ashp.org

36. Australian Commission on Safety and Quality in Health Care. National Safety and Quality Health Service Standards. 2nd ed. 2021.

37. Society of Hospital Pharmacists of Australia. Australian Injectable Drugs Handbook. 8th ed. 2021.

38. Trissel LA. Handbook on Injectable Drugs. 20th ed. American Society of Health-System Pharmacists; 2020.

39. King Guide to Parenteral Admixtures. 2023.

40. College of Intensive Care Medicine. IC-2 Intensive Care Equipment and Safety. 2022.

41. ANZICS-CORE. Australian and New Zealand Intensive Care Society Centre for Outcome and Resource Evaluation Annual Report. 2023.

42. Therapeutic Guidelines Limited. eTG Complete. Melbourne: Therapeutic Guidelines Limited; 2023.

43. NSW Clinical Excellence Commission. High-Risk Medicines Program. 2023.

44. ISMP Canada. Fluorescent yellow labeling of high-alert medications in patient care areas. ISMP Canada Saf Bull. 2019;19(8):1-5.

45. Wilson K, Sullivan M. Preventing medication errors with smart infusion technology. Am J Health Syst Pharm. 2004;61(2):177-183. PMID: 14750404

46. Poon EG, Keohane CA, Yoon CS, et al. Effect of bar-code technology on the safety of medication administration. N Engl J Med. 2010;362(18):1698-1707. PMID: 20445181

47. Westbrook JI, Woods A, Rob MI, et al. Association of interruptions with an increased risk and severity of medication administration errors. Arch Intern Med. 2010;170(8):683-690. PMID: 20421552

48. Moss J, Berner E, Bothe O, Rymarchyk S. Intravenous medication administration in intensive care: opportunities for technology. J Nurs Care Qual. 2008;23(2):119-127. PMID: 18344777

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