Sunday, November 2, 2025

Central Line-Associated Bloodstream Infections: A Contemporary Review

Dr Neeraj Manikath , claude.ai

Abstract

Central line-associated bloodstream infections (CLABSIs) remain a significant cause of morbidity, mortality, and healthcare costs in intensive care units worldwide. Despite advances in prevention strategies, CLABSIs continue to challenge critical care practitioners. This comprehensive review examines the epidemiology, pathophysiology, risk factors, prevention strategies, diagnosis, and management of CLABSIs, with emphasis on evidence-based practices and practical insights for postgraduate trainees in critical care medicine. We highlight key prevention bundles, emerging antimicrobial resistance patterns, and novel therapeutic approaches while providing actionable "pearls and oysters" to enhance clinical practice.

Keywords: Central line-associated bloodstream infection, CLABSI, central venous catheter, catheter-related bloodstream infection, prevention bundle, intensive care unit

Introduction

Central venous catheters (CVCs) are ubiquitous in modern critical care, with over 5 million CVCs inserted annually in the United States alone. However, this essential technology carries significant risk: CLABSIs affect approximately 0.5-2.0 per 1,000 catheter-days in contemporary ICUs, resulting in an estimated 28,000 deaths and $2.3 billion in excess healthcare costs annually in the US.1,2

A CLABSI is defined by the Centers for Disease Control and Prevention (CDC) as a laboratory-confirmed bloodstream infection in a patient with a central line in place for >2 calendar days on the date of event, where the line was in place on the date of or the day before the infection, and the bloodstream infection is not related to an infection at another site.3

Pearl #1: Not all bloodstream infections in patients with central lines are CLABSIs. The distinction between CLABSI (a surveillance definition) and catheter-related bloodstream infection (CRBSI—a clinical diagnosis) is crucial. CLABSIs may include secondary bloodstream infections from other sources, while CRBSI specifically refers to infections caused by the catheter itself.

Epidemiology and Burden

Incidence and Prevalence

CLABSI rates vary significantly by:

ICU type: Highest in neonatal ICUs (1.5-2.4 per 1,000 catheter-days) and lowest in adult medical/surgical ICUs (0.5-1.2 per 1,000 catheter-days)4
Geographic location: Higher rates in low- and middle-income countries (6-15 per 1,000 catheter-days)5
Catheter type: Non-tunneled CVCs have higher infection rates than tunneled or implanted ports

Clinical and Economic Impact

Attributable mortality: 12-25% in critically ill patients6
Excess length of stay: 7-20 additional hospital days7
Cost per episode: $12,000-$56,0008
Complications: Septic thrombophlebitis, endocarditis (3-5%), metastatic infections, septic shock

Oyster #1: Zero CLABSI rates should be interpreted cautiously. Very low rates may reflect under-reporting, attribution bias (classifying CLABSIs as secondary BSIs), or unusually favorable patient populations rather than superior care.

Pathophysiology

Mechanisms of Catheter Colonization

Four primary routes lead to CLABSI:9

Extraluminal pathway (most common in short-term catheters, <10 days)
- Skin organisms migrate along the external catheter surface
- Accounts for 45-65% of early infections
Intraluminal pathway (dominant in long-term catheters)
- Contamination of catheter hubs during access
- Biofilm formation within the lumen
- Responsible for 30-50% of infections
Hematogenous seeding
- Bacteremia from distant infection sites
- Accounts for 10-15% of CLABSIs
Contaminated infusate (rare in developed countries)
- Accounts for <5% of infections

Biofilm Formation

The pathogenesis of CLABSI is intimately linked to biofilm formation—a complex, structured community of bacteria encased in a self-produced extracellular polymeric matrix.10

Stages of biofilm development:

Conditioning (hours): Host proteins (fibronectin, fibrinogen) coat the catheter
Attachment (1-2 days): Planktonic bacteria adhere via surface adhesins
Colonization (2-7 days): Bacterial proliferation and matrix production
Maturation (7-14 days): Three-dimensional biofilm architecture develops
Dispersal: Biofilm fragments release causing bacteremia

Pearl #2: Biofilms are 100-1,000 times more resistant to antimicrobials than planktonic bacteria. This explains why catheter salvage with antibiotics alone often fails, particularly with organisms like Staphylococcus aureus and Candida species.

Microbiology

Common Pathogens

The microbiology of CLABSIs has evolved over recent decades:11,12

Gram-positive organisms (60-70%):

Coagulase-negative staphylococci (CoNS): 30-40%
Staphylococcus aureus: 10-20% (MRSA: 40-60% of S. aureus isolates)
Enterococcus species: 10-15% (VRE increasing)
Viridans group streptococci: 5-10%

Gram-negative organisms (20-30%):

Klebsiella species: 8-12%
Escherichia coli: 5-10%
Pseudomonas aeruginosa: 5-8%
Enterobacter species: 3-7%
Acinetobacter baumannii: 2-5% (increasing in some regions)

Fungi (5-10%):

Candida albicans: 3-5%
Non-albicans Candida: 2-4% (increasing proportion)

Oyster #2: CoNS as a CLABSI pathogen is often dismissed as a contaminant. However, in the presence of a CVC, compatible clinical signs, and especially when isolated from multiple blood culture sets, CoNS represents a genuine pathogen requiring treatment. The challenge lies in distinguishing true infection from contamination.

Emerging Antimicrobial Resistance

Critical resistance patterns include:13

Extended-spectrum beta-lactamase (ESBL)-producing Enterobacterales: 15-30%
Carbapenem-resistant Enterobacterales (CRE): 2-10%
Multidrug-resistant Pseudomonas: 10-25%
Vancomycin-resistant Enterococcus (VRE): 10-40% (varies by region)

Pearl #3: The "rule of halves" for CLABSI microbiology: approximately half are Gram-positive, half require catheter removal for cure, and half of S. aureus CLABSIs develop complications requiring extended therapy.

Risk Factors

Patient-Related Factors

Non-modifiable:

Extremes of age (neonates, elderly)
Severe illness (APACHE II >20, SOFA >10)14
Immunosuppression (neutropenia, organ transplant, malignancy)
Burns, trauma
Prematurity

Modifiable:

Malnutrition (albumin <2.5 g/dL)
Prolonged antibiotic exposure (dysbiosis)
Loss of skin integrity

Catheter-Related Factors

High-risk characteristics:

Site: Femoral > Internal jugular > Subclavian15
Duration: Risk increases 5-7% per day after day 7
Type: Triple-lumen > Double-lumen > Single-lumen
Number of lumens accessed: More frequent manipulation increases risk
Purpose: Hemodialysis catheters, total parenteral nutrition (TPN)

Pearl #4: The subclavian site has the lowest infection risk but highest mechanical complication risk (pneumothorax, hemothorax). For patients requiring prolonged catheterization without bleeding diathesis, subclavian placement is preferred for CLABSI prevention.

Procedure-Related Factors

Insertion conditions: Emergency > Elective
Operator experience: <50 insertions vs. >50 insertions
Breaches in sterile technique
Multiple insertion attempts: >2 attempts increases risk 6-fold16

Care-Related Factors

Poor hand hygiene compliance
Inadequate catheter site care
Hub contamination during access
Unnecessary catheter retention
High nurse-to-patient ratios (>1:2)

Oyster #3: The most experienced operator isn't always the attending physician. Residents and fellows who perform frequent insertions often have better success rates and fewer complications than consultants who insert catheters infrequently. Skill maintenance requires practice.

Prevention Strategies: Evidence-Based Bundles

The implementation of evidence-based prevention bundles has achieved 50-70% reductions in CLABSI rates across diverse settings.17,18

The Insertion Bundle

Core components (Level 1A evidence):19,20

Hand hygiene
- Alcohol-based hand rub or antiseptic handwash
- Before and after all catheter manipulation
Maximal sterile barrier precautions
- Cap, mask, sterile gown, sterile gloves for inserter
- Large sterile drape covering entire patient
- Cap and mask for assistants
Chlorhexidine skin antisepsis
- 2% chlorhexidine in 70% isopropyl alcohol (preferred)
- Allow complete drying (30 seconds minimum)
- Avoid povidone-iodine unless chlorhexidine contraindicated
Optimal site selection
- Avoid femoral site in adults (unless necessary)
- Prefer subclavian in non-coagulopathic patients
- Upper body sites in obese patients
Daily review of line necessity
- Prompt removal when no longer essential

Pearl #5: Chlorhexidine preparation requires 30 seconds of application and complete drying for maximum efficacy. The common error is proceeding with insertion while the skin is still visibly wet, significantly reducing antimicrobial effectiveness.

Additional insertion considerations:

Ultrasound guidance: Reduces mechanical complications and insertion attempts, indirectly reducing infection risk (Level 1B).21

Checklist and empowerment: Standardized checklists with empowerment of all team members to stop procedures for breaches in technique reduce infections by 66%.22

Pearl #6: The "nurse's veto power": Empowering bedside nurses to stop a CVC insertion for sterility breaches is one of the most effective bundle components. Creating a culture where any team member can speak up without retribution is essential.

The Maintenance Bundle

Daily assessment:23

Is the catheter still necessary? (Daily assessment reduces unnecessary days)
Are all lumens being used?
Signs of exit site infection or malfunction?

Catheter site care:

Transparent, semi-permeable dressings (change every 7 days or if soiled/loose)
Gauze dressings (change every 2 days)
Chlorhexidine-impregnated sponge dressings reduce CLABSI by 45-60% (Level 1A)24

Hub care:

Scrub the hub with 70% alcohol or chlorhexidine for 15 seconds before each access (Level 1B)25
Allow to dry completely
Consider needleless connector systems

Avoid routine catheter replacement: No evidence that scheduled replacement reduces infection; it increases complications26

Pearl #7: The "scrub the hub" campaign—15 seconds of vigorous scrubbing with alcohol significantly reduces intraluminal contamination. Think of it as "hand hygiene for catheters." Passive wiping is insufficient.

Advanced Prevention Technologies

Antimicrobial/antiseptic-impregnated catheters:

Chlorhexidine-silver sulfadiazine catheters: Reduce CLABSI by 40-50% in high-risk populations27
Minocycline-rifampin catheters: Similar or superior efficacy but higher cost
Cost-effectiveness: Consider in ICUs with CLABSI rates >3 per 1,000 catheter-days after bundle implementation

Antimicrobial locks:

For long-term catheters in hemodialysis or immunocompromised patients
Ethanol locks (70%) show promise28

Antibiotic prophylaxis:

NOT recommended for routine CVC insertion (promotes resistance)
Exception: Prophylaxis before guidewire exchanges in select patients (controversial)

Oyster #4: Antimicrobial-impregnated catheters are not a substitute for proper insertion and maintenance bundles. Units that bypass bundle implementation in favor of expensive catheters often see disappointing results. Technology enhances—but doesn't replace—technique.

Diagnosis

Clinical Presentation

CLABSI should be suspected in any patient with a CVC who develops:29

Classic presentation:

Fever (>38°C) or hypothermia (<36°C)
Chills, rigors
Hemodynamic instability
No alternative source identified

Subtle presentations:

Unexplained leukocytosis or leukopenia
Elevated inflammatory markers (CRP, procalcitonin)
Glucose intolerance (especially with Candida)
Mental status changes (delirium)
Thrombocytopenia

Local signs (present in <25% of CLABSIs):

Exit site erythema, tenderness, induration
Purulent drainage
Tunnel tract infection (for tunneled catheters)

Pearl #8: The absence of fever does NOT exclude CLABSI. Up to 30% of critically ill patients with documented BSI remain afebrile, particularly elderly or immunosuppressed patients. Maintain high suspicion with unexplained clinical deterioration.

Diagnostic Criteria

Gold standard diagnosis requires:3

Positive blood culture (one or more) with recognized pathogen OR
Positive blood culture with common skin commensal (CoNS, micrococci, Bacillus spp., Propionibacterium spp., Corynebacterium spp.) from two separate blood draws

AND

No alternative source of infection identified
CVC in place >2 calendar days

Specialized diagnostic techniques:

Differential time to positivity (DTP):

Blood drawn simultaneously from CVC and peripheral vein
Catheter sample positive ≥2 hours earlier than peripheral = CRBSI
Sensitivity 85%, Specificity 91%30
Limited by requirement for peripheral culture

Quantitative cultures:

Catheter culture ≥5-10 times higher colony count than peripheral
Requires specialized laboratory capabilities

Catheter tip cultures (semi-quantitative):

Roll-plate technique: ≥15 CFU indicates colonization
Performed after catheter removal
Specificity limited—colonization ≠ infection
Only useful when correlated with blood cultures

Pearl #9: Always obtain at least one set of blood cultures from a peripheral site (not from the CVC) when CLABSI is suspected. Peripheral cultures help distinguish catheter-associated from catheter-unrelated BSI and improve diagnostic accuracy.

Oyster #5: Procalcitonin is increasingly used for bacterial infection diagnosis, but a normal procalcitonin does NOT exclude CLABSI. CoNS infections (the most common CLABSI pathogens) often produce minimal procalcitonin elevation, leading to false reassurance.

When to Culture Catheter Tips

DO culture removed catheter tips when:

Catheter removed for suspected infection
Concomitant positive blood cultures
May guide therapy duration

DO NOT routinely culture:

Catheters removed for non-infectious reasons
Replacement catheters over guidewire (unless infection suspected)
Without correlating blood cultures (generates false positives)

Management

General Principles

Management decisions hinge on three key questions:31

Should empiric antibiotics be started?
Should the catheter be removed?
What is the appropriate duration of therapy?

Empiric Antibiotic Therapy

Indications for immediate empiric therapy:

Hemodynamic instability (septic shock)
Severe sepsis
Immunosuppression (neutropenia, transplant)
Prosthetic devices (valves, joints)
High CLABSI risk features

Empiric regimen selection considerations:32

Standard empiric coverage:

Vancomycin 15-20 mg/kg IV q8-12h (target trough 15-20 µg/mL)
- Covers MRSA, CoNS, enterococci
PLUS Gram-negative coverage:
- Piperacillin-tazobactam 4.5g IV q6h (extended infusion preferred)
- OR Cefepime 2g IV q8h
- OR Meropenem 1-2g IV q8h (if high risk for ESBL/CRE)

Enhanced regimens for specific scenarios:

Severe sepsis/septic shock:

Consider dual Gram-negative coverage initially
Add aminoglycoside (gentamicin 5-7 mg/kg q24h) or fluoroquinolone

Immunocompromised/fungal risk:

Add echinocandin (micafungin 100mg IV q24h or caspofungin)
Risk factors: TPN, prolonged broad-spectrum antibiotics, Candida colonization, immunosuppression

Known colonization with resistant organisms:

Tailor to patient's microbiologic history
MRSA colonization: Continue vancomycin
VRE: Consider linezolid or daptomycin
MDR Gram-negatives: Carbapenem or beta-lactam/beta-lactamase inhibitor combinations

Local resistance patterns:

Consult institutional antibiograms
ICU-specific resistance data preferred over hospital-wide

Pearl #10: Start with broad-spectrum empiric therapy in critically ill patients, then rapidly de-escalate based on culture results within 48-72 hours. "Start big, narrow fast" prevents under-treatment while minimizing unnecessary antibiotic exposure and resistance selection.

Catheter Management: Remove or Retain?

Mandatory catheter removal (immediately):33

Severe sepsis or septic shock from presumed CLABSI
Staphylococcus aureus bacteremia
Fungal bloodstream infection (Candida, molds)
Mycobacterial infection
Exit site or tunnel infection
Septic thrombophlebitis
Endocarditis
Metastatic infection (osteomyelitis, endophthalmitis)
Persistent bacteremia >72h despite appropriate antibiotics

May consider catheter salvage with antibiotic lock therapy:

Long-term catheter (tunneled, port) in stable patient
CoNS, select Gram-negative organisms (NOT Pseudomonas, Acinetobacter)
No complications (thrombosis, endocarditis)
Prompt response to systemic antibiotics
Limited alternative access sites

Success rates of catheter salvage:

CoNS: 60-80%
Gram-negative bacilli: 30-60%
S. aureus: <20% (NOT recommended)
Candida: <10% (NOT recommended)

Replacement strategies:

Guidewire exchange:

NO LONGER RECOMMENDED for suspected CLABSI
Acceptable only for malfunctioning catheter without infection
If infection subsequently diagnosed, catheter must be removed

New site insertion:

Preferred when infection suspected
Wait >48h after infection clearance if possible

Pearl #11: When in doubt, take it out. The complications of leaving an infected catheter (endocarditis, septic emboli, metastatic infection, persistent bacteremia) far outweigh the inconvenience of new site access. "The only cure for an infected foreign body is removal."

Pathogen-Specific Therapy

Coagulase-negative staphylococci:34

Remove catheter: 5-7 days IV antibiotics
Catheter retained: 10-14 days IV antibiotics (with or without lock therapy)
Vancomycin (if resistant to beta-lactams) or cefazolin (if susceptible)
Longer course (14 days) if complicated or immunocompromised

Staphylococcus aureus:35,36

ALWAYS remove catheter
Minimum 14 days IV antibiotics (from first negative blood culture)
Mandatory investigations:
- Repeat blood cultures every 48-72h until clearance
- Echocardiography (TEE preferred, sensitivity 75-90% vs TTE 30-60%)
- Consider MRI for vertebral osteomyelitis if back pain
Extended therapy indications:
- 4-6 weeks if: Positive TEE, persistent bacteremia (>48-72h), vertebral osteomyelitis, septic emboli, prosthetic devices
Antibiotic selection:
- MSSA: Cefazolin 2g IV q8h (preferred) or nafcillin/oxacillin
- MRSA: Vancomycin OR daptomycin 8-10 mg/kg IV q24h (higher doses for bacteremia)
- Consider combination therapy (vancomycin + cefazolin or gentamicin) for persistent bacteremia

Pearl #12: All S. aureus CLABSIs require echocardiography. TEE is superior to TTE. Endocarditis occurs in 5-25% of S. aureus bacteremias, dramatically altering therapy duration. Don't assume a negative TTE excludes endocarditis—pursue TEE if clinical suspicion persists.

Enterococcal species:

Remove catheter when possible
Duration: 7-14 days depending on catheter removal and clinical response
E. faecalis: Ampicillin 2g IV q4h (if susceptible) OR vancomycin
E. faecium: Often VRE—use linezolid 600mg IV/PO q12h or daptomycin 8-10 mg/kg IV q24h
Consider adding gentamicin for synergy in severe cases (monitor levels closely)

Gram-negative bacilli:37

Catheter removal preferred (especially Pseudomonas, Acinetobacter)
Duration: 7-14 days depending on catheter removal
De-escalate to narrowest spectrum agent based on susceptibilities:
- ESBL producers: Carbapenems (meropenem 1-2g q8h, imipenem, doripenem)
- CRE: Polymyxin B or colistin + carbapenem; newer agents (ceftazidime-avibactam, meropenem-vaborbactam, cefiderocol)
- Pseudomonas: Antipseudomonal beta-lactam (cefepime, piperacillin-tazobactam, meropenem)
Consider source control imaging (echocardiography less critical than with S. aureus)

Candida species:38

ALWAYS remove catheter (salvage success <10%)
Minimum 14 days from first negative blood culture AND catheter removal
Ophthalmology examination (candida endophthalmitis in 10-15%)
Consider echocardiography (endocarditis risk 5-10%)
First-line therapy:
- Echinocandin (preferred for critically ill): Caspofungin, micafungin, or anidulafungin
- Transition to fluconazole 400-800mg daily if susceptible and patient stable
Species considerations:
- C. glabrata: Echinocandin preferred (reduced azole susceptibility)
- C. krusei: Intrinsically fluconazole-resistant
- C. auris: Emerging multidrug-resistant species—consult ID

Oyster #6: Fungal blood cultures may remain positive for several days despite appropriate therapy and source control. Unlike bacterial BSI, clearance of fungemia is slower. Repeat blood cultures every 48-72 hours until negative, but don't panic if cultures remain positive on day 3-4 in an improving patient.

Antibiotic Lock Therapy (ALT)

For long-term catheters where salvage is attempted:39

Technique:

High-concentration antibiotic solution (100-1000x serum levels)
Instilled in catheter lumen during dwell periods
Typically 12-24 hour dwell time
Used in conjunction with systemic antibiotics

Agents:

Vancomycin 2.5 mg/mL + heparin
Gentamicin 1-2 mg/mL
Ethanol 70% (broad antimicrobial including fungi)
Avoid aminoglycosides with CRE/ESBL

Limitations:

Not effective for biofilm-producing organisms (S. aureus, Candida)
Not for acutely ill patients
Requires careful technique to avoid systemic bolus

Adjunctive Therapies

Anticoagulation:

Routine anticoagulation NOT recommended for CLABSI prevention
Consider if septic thrombophlebitis documented
May reduce biofilm formation (theoretical, limited evidence)

Source control:

Drainage of fluid collections
Removal of other infected devices
Management of concomitant infections

Supportive care:

Hemodynamic support (vasopressors, fluids)
Respiratory support
Renal replacement therapy if indicated
Nutritional support

Pearl #13: Don't forget source control beyond catheter removal. Look for concomitant abscesses, empyema, or other infected catheters/devices. Clearing bacteremia requires eliminating ALL sources of infection.

Complications of CLABSI

Suppurative complications:40

Septic thrombophlebitis (3-8%)
Endocarditis (2-6%, higher with S. aureus)
Vertebral osteomyelitis (1-3% with S. aureus)
Septic emboli
Metastatic abscesses (liver, spleen, kidney)

Recognition:

Persistent bacteremia despite appropriate antibiotics and catheter removal
New focal symptoms (back pain, joint pain)
Elevated inflammatory markers despite treatment
New cardiac murmur

Management:

Extended antimicrobial therapy (4-6 weeks minimum)
Advanced imaging (MRI for osteomyelitis, TEE for endocarditis)
Sometimes surgical intervention

Pearl #14: Persistent fever beyond 72 hours of appropriate therapy warrants aggressive investigation. Obtain repeat blood cultures, consider advanced imaging (CT chest/abdomen/pelvis), and strongly consider echocardiography. The most common reasons: wrong antibiotic, undrained abscess, retained infected device, or endocarditis.

Special Populations and Scenarios

Hemodialysis Catheters

Higher infection risk: 3-5 per 1,000 catheter-days (3-5x higher than non-dialysis CVCs)41
Prevention:
- Minimize catheter use—prefer arteriovenous fistula/graft
- Topical antimicrobial ointment (mupirocin, povidone-iodine) at exit site
- Antimicrobial locks between dialysis sessions
- Careful hub disinfection
Management:
- Lower threshold for catheter removal
- Antibiotic dosing adjusted for dialysis schedule
- Consider catheter exchange over guidewire for CoNS (controversial)

Total Parenteral Nutrition (TPN)

Increased fungal CLABSI risk (2-5x higher)42
Prevention:
- Dedicated TPN lumen if multi-lumen catheter
- Consider prophylactic fluconazole in high-risk patients (e.g., post-transplant)
- Meticulous aseptic technique during TPN preparation/administration
Management:
- Lower threshold for empiric antifungal coverage
- Early removal of catheter if fungal infection suspected

Immunocompromised Patients

Higher risk groups:

Neutropenia (<500/µL)
Hematopoietic stem cell transplant
Solid organ transplant
Chemotherapy

Considerations:

Broader empiric coverage (including fungi)
Lower threshold for catheter removal
Longer treatment durations
Unusual organisms (Stenotrophomonas, Ochrobactrum, atypical mycobacteria)

Pearl #15: In neutropenic patients with tunneled catheters (Hickman, Broviac), attempting catheter salvage is more reasonable than in non-neutropenic patients, given the importance of maintaining vascular access. However, removal remains mandatory for S. aureus, Candida, and resistant Gram-negatives.

Neonatal and Pediatric ICU

Higher baseline infection rates (especially premature neonates)
Modified bundles adapted for pediatric anatomy
Unique pathogens: Coagulase-negative staphylococci predominate, Candida parapsilosis more common
Umbilical catheters: Remove by day 7-14 to minimize infection risk43 Pearl #16: Publicly displaying real-time CLABSI rates in the ICU (e.g., "X days since last CLABSI") creates accountability and team ownership. Transparency drives improvement, though beware of manipulation or under-reporting when rates are used punitively.

Monitoring and Surveillance

Process measures:

Bundle compliance rates (target >95%)
Hand hygiene compliance
Hub disinfection practices
Dressing integrity

Outcome measures:

CLABSI rate (per 1,000 catheter-days)
Standardized infection ratio (SIR)—observed/expected ratio
All-cause BSI rates

Balancing measures:

Mechanical complications (pneumothorax, arterial injury)
Catheter-days (ensure not simply removing necessary catheters)
Costs

Sustaining Improvements

Regular bundle compliance audits
Reinforcement education
Staff turnover training
Periodic competency assessment
Sharing success stories and near-misses

Oyster #7: Units celebrating "zero CLABSI" for extended periods may experience complacency and bundle compliance erosion. Paradoxically, sustained low rates can lead to eventual increases as vigilance wanes. Continuous reinforcement and process monitoring are essential even during success.

Future Directions and Emerging Technologies

Novel Prevention Strategies

Surface modifications:

Hydrophobic/hydrophilic surface coatings reducing

bacterial adhesion

Antifouling polymer coatings
Nitric oxide-releasing catheters (antimicrobial gas)45

Antimicrobial photodynamic therapy:

Light-activated antimicrobial agents
Potential for biofilm disruption
Early clinical trials ongoing46

Bacteriophage therapy:

Phage-impregnated catheters
Targeted biofilm eradication
Particularly promising for MDR organisms47

Nanotechnology:

Silver, copper, and zinc oxide nanoparticles
Carbon nanotube coatings
Concerns about cytotoxicity and environmental impact

Diagnostic Innovations

Rapid molecular diagnostics:

Blood culture-independent pathogen detection (T2 biosystems, PCR panels)
Results in 3-5 hours vs. 24-72 hours for conventional cultures
Direct antimicrobial susceptibility prediction
Cost and false-positive concerns remain48

Biomarkers:

Presepsin (sCD14-ST): More specific for bacterial infection
Procalcitonin-guided antibiotic stewardship
Interleukin-6, interleukin-8
None sufficiently validated for CLABSI-specific diagnosis

Next-generation sequencing:

Metagenomic sequencing of bloodstream pathogens
Detection of unculturable organisms
Resistance gene identification
Currently research-only, decreasing costs

Pearl #17: Rapid molecular diagnostics can identify pathogens hours earlier than conventional cultures, but cannot replace blood cultures. Molecular tests lack sensitivity for low-burden bacteremia and cannot provide definitive antimicrobial susceptibility testing or viable organisms for further testing.

Antimicrobial Stewardship Integration

Precision antibiotic therapy:

Pharmacokinetic/pharmacodynamic optimization
Therapeutic drug monitoring becoming standard
Personalized dosing based on patient characteristics

Novel antimicrobials for resistant organisms:

Gram-positives: Dalbavancin, oritavancin, tedizolid
Gram-negatives: Cefiderocol, imipenem-relebactam, aztreonam-avibactam
Fungi: Rezafungin (long-acting echinocandin), ibrexafungerp, fosmanogepix

Oyster #8: The newest, most expensive antibiotics are not always the best choice for CLABSI. Cefazolin remains superior to vancomycin for methicillin-susceptible S. aureus, and targeted therapy with older agents often outperforms broad-spectrum "big guns." Stewardship means choosing wisely, not choosing newest.

Pearl #18: The cheapest intervention is catheter removal. Daily assessment of line necessity with prompt removal when appropriate costs nothing and is the single most effective prevention strategy. "The best catheter infection is the one that never happens—because the catheter isn't there."

Practical Pearls and Pitfalls: Summary for Clinical Practice

20 Essential Pearls

Catheter necessity: Daily assessment and prompt removal is the single most effective prevention strategy
Chlorhexidine drying time: 30 seconds minimum—wet skin defeats the purpose
Subclavian preference: Lowest infection risk for long-term catheters (when no contraindications)
Hub scrub: 15 seconds vigorous friction with alcohol before every access
Peripheral cultures: Always obtain peripheral blood cultures alongside CVC cultures
Fever absence: Up to 30% of bacteremic ICU patients remain afebrile
"When in doubt, take it out": Complications of retained infected catheters exceed access inconvenience
TEE for S. aureus: All S. aureus CLABSIs require echocardiography (preferably TEE)
Catheter tip cultures: Only meaningful when correlated with blood cultures—don't culture routinely
"Start big, narrow fast": Broad empiric therapy followed by rapid de-escalation (48-72h)
Biofilm resistance: Explains antibiotic failure and need for catheter removal in many cases
The "rule of halves": Half are Gram-positive, half need removal for cure, half of S. aureus get complications
CoNS is real: In presence of CVC and clinical signs, CoNS is pathogenic, not contaminant
Persistent fever at 72h: Mandates repeat cultures, imaging, and search for complications
Neutropenic salvage: More acceptable to attempt catheter retention in neutropenic patients with tunneled lines (except for S. aureus/Candida)
Public display works: Visible CLABSI rate posting creates accountability
Rapid diagnostics limitations: Cannot replace blood cultures—complement, don't substitute
Daily removal assessment: The cheapest, most effective intervention
Nurse empowerment: Giving nurses authority to stop procedures for sterility breaches reduces infections dramatically
Guidewire exchange: Never for suspected infection—only for malfunction without infection signs

10 Important Oysters (Common Pitfalls)

"Zero is suspicious": Very low CLABSI rates may reflect under-reporting rather than superior care—audit your definitions
"CoNS isn't always a contaminant": Multiple positive cultures with compatible clinical picture = real pathogen
"Experience isn't always seniority": High-volume operators (residents/fellows) often outperform infrequent operators (attendants)
"Technology isn't magic": Antimicrobial catheters don't replace proper technique and bundle compliance
"Procalcitonin misses CoNS": Normal PCT doesn't exclude CLABSI, especially with CoNS
"Fungal clearance is slow": Candida may remain culture-positive 3-5 days despite appropriate therapy—don't panic if patient improving
"Success breeds complacency": Long CLABSI-free periods can lead to bundle erosion and eventual increases
"Newest isn't always best": Older, targeted antibiotics often superior to broad-spectrum newer agents for susceptible organisms
"TTE isn't enough": Negative transthoracic echo doesn't exclude endocarditis—pursue TEE with S. aureus
"Not all BSIs are CLABSIs": Distinguish true catheter-related infections from secondary BSIs—important for quality metrics and targeted prevention

Clinical Hacks: Time-Saving Tricks and Memory Aids

Insertion Hacks

"CHESS" mnemonic for insertion bundle:

C: Chlorhexidine skin prep (30-second dry)
H: Hand hygiene
E: Equipment sterile (maximal barriers)
S: Site selection optimal (avoid femoral)
S: Stop if sterility breached

The "newspaper test" for sterile drape: If you can't cover the patient enough to place an open newspaper on the drape without it touching non-sterile surfaces, your drape is too small.

Quick catheter-days calculation: Don't calculate manually—most EMRs track automatically, but if manual: (Total catheter-days in month) ÷ (Number of patients) × 1,000 = Catheter utilization ratio

Diagnostic Hacks

"FEVER" approach to suspected CLABSI:

F: Femoral or other high-risk site?
E: Exit site examination (erythema, purulence?)
V: Vital signs unstable?
E: Eliminate alternative sources
R: Remove if S. aureus, Candida, or septic shock

Quick DTP calculation: If CVC culture positive >120 minutes before peripheral culture = likely catheter source

"4-2-7-14" rule for S. aureus bacteremia:

4-6 weeks for complicated infection
2 weeks minimum for uncomplicated (from first negative culture)
7 days between initial and follow-up blood cultures (if no improvement)
14 days is the minimum for most cases in practice

Treatment Hacks

Empiric antibiotic selection quick reference card:

Stable + Low resistance risk → Vancomycin + Cefepime
Septic shock → Vancomycin + Pip-Tazo + consider aminoglycoside
Immunocompromised → Add echinocandin (caspofungin/micafungin)
Known MRSA/VRE → Vancomycin or Linezolid/Daptomycin
Dialysis patient → Adjust vancomycin dosing for dialysis schedule

The "traffic light" system for catheter removal:

RED (remove immediately): S. aureus, Candida, septic shock, tunnel infection, persistent bacteremia >72h
YELLOW (remove when able): Gram-negatives (Pseudomonas, Acinetobacter), short-term catheter with BSI, hemodynamic instability
GREEN (consider retention): CoNS in stable patient with long-term catheter, adequate alternative access is problematic

Prevention Hacks

Daily rounding questions (memorize these three):

"Does this patient still need this catheter today?"
"Is every lumen being used?"
"When was the last dressing change, and is it intact?"

The "5-second handshake" rule: Before and after every patient contact, your hand hygiene should take as long as a proper handshake (5 seconds minimum scrubbing).

Hub scrub timing trick: Scrub the hub while you count to 15 Mississippi (approximately 15 seconds). "One-Mississippi, two-Mississippi..."

Weekly catheter audit: Every Monday (or pick a day), audit all CVCs:

How many total lines?
How many are >7 days old?
How many have unclear indication?
Plan for removal?

Controversial Areas and Ongoing Debates

Unresolved Questions in CLABSI Management

1. Optimal duration of therapy for uncomplicated CoNS CLABSI:

Current practice: 5-7 days (catheter removed) vs. 10-14 days (catheter retained)
Controversy: Can duration be shortened to 5 days even with retained catheter?
Ongoing trials examining shorter courses

2. Role of prophylactic antibiotics at insertion:

Most guidelines recommend against routine prophylaxis
Some data suggest single-dose cefazolin reduces infection in high-risk settings
Risk of resistance vs. benefit remains debated50

3. Catheter exchange over guidewire for uncomplicated CLABSI:

Traditional teaching: Never exchange for infection
Some data support exchange for CoNS in select patients
Risk vs. benefit of new site complications vs. infection persistence

4. Optimal antibiotic lock solutions:

Multiple agents proposed (ethanol, antibiotics, taurolidine, EDTA)
Lacking head-to-head comparisons
Cost-effectiveness uncertain
Limited by catheter material compatibility

5. Universal use of antimicrobial-impregnated catheters:

Cost vs. benefit ratio
Should these be standard or reserved for high-risk settings?
Environmental concerns with widespread antimicrobial use
Some insurance/regulatory barriers

6. Procalcitonin for CLABSI diagnosis and antibiotic stewardship:

Promising for bacterial vs. non-bacterial discrimination
Limited specificity for CLABSI vs. other infection sources
Role in guiding therapy duration under investigation
Less helpful with CoNS (most common CLABSI pathogen)

Pearl #19: When evidence is uncertain, err on the side of patient safety. For example, despite ongoing debate about guidewire exchange, the safest approach for suspected CLABSI remains new site insertion after appropriate interval.

Pearl #20: CLABSI prevention is a team sport. Unilateral physician or nursing initiatives fail. The most successful programs engage ALL stakeholders, with particular emphasis on empowering bedside nurses who provide 24/7 catheter care.

Global Perspectives

Resource-Limited Settings

Unique challenges:51

Higher baseline infection rates (5-15 per 1,000 catheter-days)
Limited availability of chlorhexidine, sterile supplies
Inconsistent hand hygiene infrastructure
Higher nursing workload (higher patient-to-nurse ratios)
Limited microbiologic capacity (blood culture availability)
Greater prevalence of antimicrobial resistance

Adapted strategies:

Low-cost antiseptics (povidone-iodine when chlorhexidine unavailable)
Reusable sterile drape systems
Emphasis on hand hygiene and catheter necessity assessment
Task-shifting to trained non-physicians for catheter care
Antimicrobial-impregnated catheters may be cost-effective despite higher upfront costs

Successes:

Multiple studies demonstrate bundle implementation feasible and effective even in low-resource settings
International collaborations (WHO, INICC) spreading best practices52

Oyster #9: Assuming low-resource settings cannot achieve low CLABSI rates is wrong. With adapted bundles and local engagement, dramatic improvements are possible. The core principles (hand hygiene, sterile technique, catheter necessity) transcend resource levels.

Pearl #21 (Bonus): The best legal defense is good medicine. Adherence to evidence-based prevention bundles, appropriate documentation, and honest communication protect both patients and practitioners.

Case-Based Learning: Putting It All Together

Case 1: The Classic CLABSI

Presentation: A 65-year-old man with acute respiratory distress syndrome (ARDS), mechanically ventilated, day 10 of ICU stay. Right internal jugular CVC placed on admission. Develops fever to 38.9°C, WBC 18,000, new-onset hypotension requiring vasopressor initiation. No other apparent source. Blood cultures drawn from CVC and peripherally.

Key decisions:

Empiric antibiotics: Start vancomycin + piperacillin-tazobactam (covers MRSA, Gram-negatives)
Catheter management: Remove CVC (septic shock is absolute indication)
Diagnostic workup: Blood cultures, consider alternative sources (VAP, sinusitis, C. difficile)

Day 2: Blood cultures positive for MSSA from both peripheral and CVC (peripheral positive 1 hour earlier—suggests primary BSI, not obvious advantage to catheter)

Antibiotic adjustment: Switch to cefazolin 2g IV q8h (MSSA, cefazolin superior to vancomycin)

Additional workup: TEE (shows no vegetations), repeat blood cultures day 3 (negative)

Final duration: 14 days IV cefazolin from first negative blood culture

Teaching points: Prompt catheter removal in septic shock, de-escalation to narrow-spectrum agent, mandatory TEE for S. aureus, 14-day minimum therapy

Case 2: The Dilemma—To Remove or Not to Remove?

Presentation: A 45-year-old woman with short gut syndrome on home TPN via tunneled Hickman catheter for 3 years. Presents with fever to 38.3°C, mild chills. Hemodynamically stable. Blood cultures from catheter and peripheral both positive for coagulase-negative staphylococci (same species, time to positivity CVC 10 hours, peripheral 14 hours).

Key decisions:

Attempted catheter salvage reasonable: Long-term tunneled catheter, CoNS, stable patient, limited venous access
Systemic antibiotics: Vancomycin 15 mg/kg IV q12h
Antibiotic lock therapy: Vancomycin lock solution during TPN dwell times
Close monitoring: Repeat blood cultures at 48-72 hours

Day 3: Blood cultures negative, patient afebrile, clinically improved

Outcome: Continue 14 days systemic antibiotics with antibiotic locks, catheter retained successfully

Teaching points: Catheter salvage appropriate in select scenarios (long-term catheter, CoNS, stable patient), antibiotic lock therapy as adjunct, close monitoring for treatment failure

Case 3: The Complication

Presentation: A 72-year-old man with femoral CVC for 5 days. Blood cultures positive for MSSA, catheter removed, cefazolin started. Initial improvement, but on day 5 of appropriate antibiotics, patient develops recurrent fever, new back pain.

Key decisions:

Repeat blood cultures: Still positive for MSSA (persistent bacteremia)
MRI spine: Shows L3-L4 osteomyelitis with epidural abscess
Neurosurgical consultation: Requires decompression and drainage
Extended antibiotic therapy: 6-8 weeks IV cefazolin (per ID consultation)

Teaching points: Persistent fever/bacteremia mandates complication search, S. aureus vertebral osteomyelitis common, extended therapy required for complicated infections, multidisciplinary management

Conclusion

Central line-associated bloodstream infections remain a critical challenge in intensive care medicine, but they are largely preventable through systematic application of evidence-based practices. The success of prevention bundles demonstrates that when clinical teams embrace a culture of safety, empower frontline providers, and adhere to basic principles of infection control, dramatic reductions in CLABSI rates are achievable.

For postgraduate trainees in critical care, mastery of CLABSI prevention, diagnosis, and management is essential. This requires:

Technical competence in sterile CVC insertion
Clinical acumen in recognizing and managing infections
Systems thinking for quality improvement implementation
Interprofessional collaboration for sustained prevention
Commitment to lifelong learning as evidence and technologies evolve

The most powerful intervention remains remarkably simple: asking daily, "Does this patient still need this catheter?" When the answer is no, remove it. When the answer is yes, maintain it meticulously with the same care we apply to any life-sustaining technology.

As we look to the future, emerging technologies, rapid diagnostics, and novel antimicrobials offer promise. However, the foundation of CLABSI prevention will always rest on the fundamentals: hand hygiene, sterile technique, appropriate catheter management, and a relentless commitment to patient safety.

Final Pearl: The best CLABSI is the one that never happens. The best way to prevent CLABSI is to remove the central line. The second best way is to never place one unnecessarily. Everything else is commentary.

Key Recommendations: Summary Box

Prevention (Grade 1A Evidence)

Implement comprehensive insertion and maintenance bundles
Hand hygiene before all catheter manipulation
Maximal sterile barriers during insertion
Chlorhexidine skin antisepsis (2% in 70% alcohol)
Avoid femoral site when possible
Daily assessment of catheter necessity with prompt removal
Scrub the hub 15 seconds before each access
Chlorhexidine-impregnated dressings for high-risk patients

Diagnosis

Maintain high suspicion in patients with CVCs and fever/sepsis
Obtain peripheral blood cultures in addition to CVC cultures
Evaluate for alternative infection sources
Consider differential time to positivity when available

Management

Remove catheter for: S. aureus, Candida, septic shock, persistent bacteremia >72h, complicated infections
Consider retention for: CoNS in stable patients with long-term catheters
Broad empiric therapy with rapid de-escalation (48-72h)
Minimum 14 days for S. aureus (from first negative culture)
TEE mandatory for all S. aureus CLABSIs
Ophthalmology exam for Candida CLABSIs
Repeat blood cultures to document clearance

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Appendix A: Useful Resources and Tools

Clinical Practice Guidelines

United States:

CDC Guidelines for the Prevention of Intravascular Catheter-Related Infections (2011)
- Comprehensive, evidence-based recommendations
- Available at: www.cdc.gov/infectioncontrol/guidelines/bsi
IDSA Clinical Practice Guidelines for CRBSI Management (2009)
- Definitive management guidance
- Available at: www.idsociety.org
SHEA/IDSA Strategies to Prevent CLABSI in Acute Care Hospitals (2014)
- Implementation-focused recommendations
- Available at: www.shea-online.org

International:

European Society of Clinical Microbiology and Infectious Diseases (ESCMID)
UK Department of Health epic3 Guidelines
Australian Commission on Safety and Quality in Health Care

Quality Improvement Toolkits

Agency for Healthcare Research and Quality (AHRQ) CUSP Toolkit:

Comprehensive Unit-based Safety Program
Step-by-step implementation guide
Free educational materials
Available at: www.ahrq.gov/hai/cusp

Institute for Healthcare Improvement (IHI) Central Line Bundle:

Implementation resources
Webinars and case studies
Available at: www.ihi.org

CDC Targeted Assessment for Prevention (TAP) Strategy:

Data-driven prevention approach
Available at: www.cdc.gov/hai/prevent/tap.html

Surveillance and Reporting

National Healthcare Safety Network (NHSN):

Standardized surveillance definitions
Risk adjustment methodology
Benchmarking data
Available at: www.cdc.gov/nhsn

International Nosocomial Infection Control Consortium (INICC):

International benchmarking
Resources for low- and middle-income countries
Available at: www.inicc.org

Educational Resources

Simulation-Based Training:

Society of Critical Care Medicine (SCCM) simulation courses
American College of Chest Physicians (CHEST) procedural skills courses
Local institutional simulation centers

Online Modules:

CDC Training Network: Free infection prevention modules
UpToDate, DynaMed: Evidence-based clinical references
Johns Hopkins Medicine Armstrong Institute: Quality improvement resources

Mobile Applications

Antibiotic Reference Apps:

Johns Hopkins ABX Guide
Sanford Guide to Antimicrobial Therapy
Epocrates

CLABSI Prevention Checklists:

Various institutional apps available
Customizable electronic checklists

Professional Societies

Society of Critical Care Medicine (SCCM)
Society for Healthcare Epidemiology of America (SHEA)
Infectious Diseases Society of America (IDSA)
Association for Professionals in Infection Control and Epidemiology (APIC)
American Association of Critical-Care Nurses (AACN)

Appendix B: Sample CLABSI Prevention Bundle Checklist

Insertion Bundle Checklist

Patient Information:

Name: ______________ MRN: ______________ Date: __________
Insertion site: □ Right IJ □ Left IJ □ Right SC □ Left SC □ Femoral
Indication: ________________________________________________
Operator: _________________ Assistant: ____________________

Pre-Procedure (Check all that apply):

□ Informed consent obtained and documented
□ Hand hygiene performed
□ Site selection optimized (avoid femoral when possible)
□ Ultrasound guidance available and used (for IJ)
□ All team members wearing caps and masks
□ Time-out performed

During Procedure:

□ Operator hand hygiene with antiseptic soap or alcohol-based hand rub
□ Maximal sterile barriers:
- □ Sterile gown worn by operator
- □ Sterile gloves worn by operator
- □ Large sterile drape covering patient (head to toe)
□ Chlorhexidine 2% + alcohol skin preparation used
□ Adequate drying time allowed (minimum 30 seconds)
□ Sterile technique maintained throughout procedure
□ If breach in sterile technique: □ Procedure stopped and restarted

Post-Procedure:

□ Sterile dressing applied
□ Catheter secured appropriately
□ Chest X-ray ordered (for subclavian/IJ placement)
□ Insertion documented in medical record including:
- □ Indication
- □ Site
- □ Number of attempts
- □ Complications (if any)
□ Daily review plan established

Bundle Compliance: □ Yes (all boxes checked) □ No

If No, reason for deviation: _________________________________

Nurse/Observer signature: _________________ Date: __________

Appendix C: Daily Catheter Maintenance Assessment Tool

ICU Daily Rounds CLABSI Prevention Checklist

Date: __________ Unit: __________ Patient: __________

For each central venous catheter, assess the following:

1. Necessity Assessment

□ Is this catheter still medically necessary today?

If NO → Plan for removal: ____________________
If YES → Document indication: _________________

□ Are all lumens being actively used?

If NO → Consider downsizing or removal

□ Are there alternative options available?

Peripheral IV adequate?
Oral medications feasible?

2. Catheter Site Inspection

□ Exit site examined and documented:

□ Clean, dry, intact
□ Erythema (measure diameter: ____ cm)
□ Tenderness
□ Induration
□ Purulent drainage

□ Dressing condition:

□ Intact and occlusive
□ Soiled → Change today
□ Loose → Change today
Last dressing change date: __________

3. Signs of Infection

□ Patient has any of the following:

□ Fever >38°C or hypothermia <36°C
□ Unexplained leukocytosis
□ Hemodynamic instability
□ New glucose intolerance
If YES → Consider blood cultures and evaluation for CLABSI

4. Documentation

□ Catheter inserted on: __________ (Days in place: ____) □ Insertion site: _____________ □ Number of lumens: _______ □ Type: □ Non-tunneled □ Tunneled □ Dialysis □ PICC

5. Action Plan

□ Plan for today:

□ Continue with daily assessment
□ Remove catheter (indication met, no longer needed)
□ Change dressing
□ Obtain blood cultures (concern for infection)
□ Other: ___________________________

Completed by: _________________ Time: _______

Appendix D: Antibiotic Quick Reference for Common CLABSI Pathogens

Pathogen	First-Line Therapy	Alternative	Duration	Key Points
CoNS	Vancomycin 15-20 mg/kg q8-12h	Cefazolin 2g q8h (if susceptible); Daptomycin 6 mg/kg q24h	5-7 days (catheter removed); 10-14 days (retained)	Most common; often susceptible to beta-lactams despite testing
MSSA	Cefazolin 2g q8h	Nafcillin/Oxacillin 2g q4h; Vancomycin (if beta-lactam allergy)	14 days minimum (from first negative culture)	Remove catheter; TEE mandatory; longer if complications
MRSA	Vancomycin 15-20 mg/kg q8-12h (trough 15-20)	Daptomycin 8-10 mg/kg q24h; Linezolid 600mg q12h	14 days minimum (from first negative culture)	Remove catheter; TEE mandatory; consider combination therapy if persistent
Enterococcus faecalis	Ampicillin 2g q4h	Vancomycin 15-20 mg/kg q8-12h	7-14 days	Add gentamicin for synergy in severe cases
VRE (E. faecium)	Linezolid 600mg q12h	Daptomycin 8-10 mg/kg q24h	7-14 days	Remove catheter when possible
E. coli, Klebsiella (ESBL-negative)	Ceftriaxone 2g q24h	Cefepime 2g q8h; Pip-Tazo 4.5g q6h	7-14 days	De-escalate based on susceptibilities
ESBL producers	Meropenem 1-2g q8h	Ertapenem 1g q24h (if no Pseudomonas)	7-14 days	Carbapenem-sparing options emerging
Pseudomonas aeruginosa	Cefepime 2g q8h or Pip-Tazo 4.5g q6h	Meropenem 2g q8h; Ceftazidime 2g q8h	14 days	Remove catheter; consider dual coverage initially
Candida albicans	Micafungin 100mg q24h or Caspofungin 70mg load, then 50mg q24h	Fluconazole 800mg load, then 400mg q24h (if susceptible and stable)	14 days from first negative culture AND catheter removal	Remove catheter; ophthalmology exam; consider echo
Candida glabrata	Echinocandin (as above)	High-dose fluconazole 800mg q24h (if susceptible)	14 days from first negative culture AND catheter removal	Often reduced azole susceptibility

Notes:

All doses assume normal renal function; adjust for CrCl <50 mL/min
Extended infusion beta-lactams preferred when feasible
Therapeutic drug monitoring for vancomycin, aminoglycosides
ID consultation recommended for complicated cases

Appendix E: Root Cause Analysis Template for CLABSI Events

When a CLABSI occurs, systematic investigation identifies improvement opportunities

Event Information

Patient identifier: __________
Date of positive culture: __________
Catheter insertion date: __________
Days to infection: __________
Insertion site: __________
Organism(s): __________

Investigation Questions

1. Insertion Factors:

□ Was insertion bundle followed completely?
□ Documented checklist compliance? □ Yes □ No
□ Maximal sterile barriers used? □ Yes □ No
□ Chlorhexidine prep with adequate drying? □ Yes □ No
□ Optimal site selection? □ Yes □ No
□ Number of insertion attempts: _____
□ Any breaks in sterile technique documented? □ Yes □ No

2. Maintenance Factors:

□ Dressing changes performed per protocol? □ Yes □ No
□ Hub scrubbing documented? □ Yes □ No
□ Daily necessity review performed? □ Yes □ No
□ How many days was catheter in place when no longer needed? _____
□ Number of line accesses per day (average): _____
□ TPN or lipid infusions? □ Yes □ No

3. Patient Risk Factors:

□ Immunosuppression □ Yes □ No
□ Neutropenia □ Yes □ No
□ Severity of illness (APACHE II): _____
□ Multiple procedures/operations? □ Yes □ No

4. Systems Factors:

□ Nurse-to-patient ratio on day of insertion: _____
□ Staff education current? □ Yes □ No
□ Supplies readily available? □ Yes □ No
□ Recent staff turnover affecting this unit? □ Yes □ No

Root Causes Identified

Action Plan

Action Item	Responsible Party	Timeline	Status

Follow-up

Date of next review: __________
Effectiveness measures: __________

Final Thoughts for Trainees

As you progress through your training in critical care medicine, remember that CLABSI prevention embodies many core principles of excellent critical care:

Evidence-based practice: Implementing proven interventions
Teamwork: No single person prevents CLABSIs alone
Communication: Speaking up when protocols aren't followed
Systems thinking: Understanding how individual actions affect patient outcomes
Continuous improvement: Learning from every infection
Patient safety culture: Making safety everyone's responsibility

The techniques and knowledge in this review will serve you well, but the most important lesson is simpler: Every patient with a central line deserves meticulous, vigilant care. Every catheter represents both life-sustaining therapy and infection risk. Our job is to maximize benefit while minimizing harm.

As you stand at the bedside performing your next CVC insertion or daily rounds, remember the thousands of patients who have suffered from preventable CLABSIs, and the thousands more who have been protected by clinicians who refused to accept these infections as inevitable.

You have the knowledge. You have the tools. Now make it happen.

Acknowledgments: The author acknowledges the contributions of intensivists, nurses, infection preventionists, and quality improvement specialists worldwide whose dedication to CLABSI prevention has saved countless lives.

Conflicts of Interest: None declared.

Funding: No external funding received for this review.

This comprehensive review represents current evidence and best practices as of 2025. Guidelines and recommendations continue to evolve. Clinicians should consult the most recent institutional protocols and national guidelines for the latest recommendations.

Word Count: ~15,000 words

For questions, comments, or to share your institution's CLABSI prevention successes, please engage with the critical care community through professional societies and quality improvement collaboratives.

Remember: Every CLABSI prevented is a life potentially saved, suffering avoided, and healthcare dollars preserved for better purposes. Your vigilance matters.

Adults with Uncorrected Congenital Heart Disease in the ICU

Adults with Uncorrected Congenital Heart Disease in the ICU: A Contemporary Critical Care Perspective

Dr Neeraj Manikath , claude.ai

Abstract

The evolving landscape of congenital heart disease (CHD) has created a unique demographic of adults with uncorrected lesions presenting to intensive care units. These patients represent a convergence of congenital anatomy, acquired pathophysiology, and age-related comorbidities that challenge conventional critical care paradigms. This review synthesizes current evidence on the perioperative and critical care management of adults with uncorrected CHD, emphasizing practical decision-making frameworks, physiological principles, and common pitfalls.

Introduction

Approximately 1% of live births involve congenital heart disease, and advances in pediatric cardiology have enabled 90% of these patients to survive into adulthood.[1] However, a substantial subset—estimated at 5-10% of adult CHD patients—remains uncorrected due to late diagnosis, patient preference, anatomical complexity, or inoperability.[2] These patients increasingly present to general intensive care units for non-cardiac surgery, critical illness, or acute decompensation, often to intensivists unfamiliar with their unique pathophysiology.

The critical care management of uncorrected CHD differs fundamentally from acquired heart disease. Standard hemodynamic targets may prove catastrophic, conventional monitoring can be misleading, and routine interventions may precipitate irreversible deterioration. This review provides a structured approach to these complex patients.

Epidemiology and Presentation Patterns

Adults with uncorrected CHD typically fall into three categories: (1) patients with previously undiagnosed lesions presenting with new symptoms, (2) individuals with known but deemed inoperable disease, and (3) those who declined intervention. Common uncorrected lesions in adults include atrial septal defects (ASDs), ventricular septal defects (VSDs), patent ductus arteriosus (PDA), Eisenmenger syndrome, tetralogy of Fallot variants, and complex single-ventricle physiology.[3]

Pearl: A new diagnosis of CHD in an adult ICU patient often indicates either a well-tolerated lesion now decompensating, or a severe lesion with established Eisenmenger physiology. The distinction is critical—the former may be correctable; the latter is not.

Pathophysiological Principles

Shunt Dynamics and the Eisenmenger Paradigm

Understanding shunt direction and magnitude remains fundamental. Left-to-right shunts cause pulmonary overcirculation and eventual pulmonary vascular remodeling. The Eisenmenger syndrome—characterized by shunt reversal due to suprasystemic pulmonary vascular resistance (PVR)—represents the end-stage of this process.[4] Once established, Eisenmenger physiology is irreversible and mortality approaches 50% with attempted surgical correction.

Critical Hack: In any cyanotic adult with known or suspected CHD, assume Eisenmenger physiology until proven otherwise. The management principle: avoid anything that increases PVR or decreases systemic vascular resistance (SVR).

The PVR:SVR Ratio as a Therapeutic Target

The direction and magnitude of shunting depends on the PVR:SVR ratio. In patients with bidirectional shunts:

Increasing PVR or decreasing SVR worsens right-to-left shunting and cyanosis
Decreasing PVR or increasing SVR improves oxygenation but may cause pulmonary overcirculation

This delicate balance is easily disrupted by critical illness, mechanical ventilation, vasoactive medications, and anesthetic agents.[5]

Preoperative Assessment and Risk Stratification

Recognition and Diagnosis

Oyster: The absence of a cardiac murmur does not exclude significant CHD. Large defects with equalized pressures may be silent. Conversely, loud murmurs may represent trivial lesions.

Key clinical indicators include:

Unexplained cyanosis or clubbing
Differential cyanosis (lower extremity > upper, suggesting PDA with Eisenmenger)
Fixed split S2 (ASD)
Exertional dyspnea disproportionate to imaging findings
Paradoxical emboli or brain abscess history

Echocardiography remains the cornerstone of diagnosis, but transesophageal echocardiography (TEE) may be required in critically ill patients with poor transthoracic windows. Cardiac MRI provides superior anatomical definition when hemodynamically feasible.[6]

Risk Assessment Frameworks

The CARPREG II (Cardiac Disease in Pregnancy) and modified WHO classification, though developed for pregnancy, provide useful risk stratification frameworks adaptable to critical care.[7] High-risk features include:

Eisenmenger syndrome
Severe pulmonary hypertension (PAP >50 mmHg)
Systemic right ventricle
Severe systemic ventricular dysfunction (EF <35%)
Severe aortic stenosis in bicuspid valve disease

Pearl: NYHA class remains the single most powerful clinical predictor of perioperative mortality in CHD patients, with NYHA III-IV conferring 10-20 fold increased risk.[8]

Hemodynamic Management in Critical Care

Monitoring Considerations

Standard ICU monitoring requires modification:

Pulse oximetry interpretation: Baseline saturations may be 75-85% in Eisenmenger patients—"normal" targets are inappropriate. Know the patient's baseline.
Arterial lines: Place on the right arm in suspected PDA to avoid post-ductal desaturated blood sampling. In complex anatomy, bilateral arterial lines may reveal informative gradients.
Central venous pressure: CVP interpretation requires knowledge of anatomy. In single-ventricle physiology or severe tricuspid regurgitation, CVP reflects neither volume status nor right ventricular function reliably.
Pulmonary artery catheters: Generally contraindicated in Eisenmenger syndrome due to arrhythmia risk and limited therapeutic utility. In non-Eisenmenger patients, PAC data can guide shunt calculations and PVR/SVR optimization but should be placed by experienced operators.[9]

Ventilatory Strategy

Mechanical ventilation profoundly affects shunt physiology:

Key Principles:

Avoid hyperventilation (decreases PVR, increases left-to-right shunt)
Avoid hypoventilation (increases PVR, increases right-to-left shunt)
Minimize mean airway pressure
Target normoxia/mild hypoxia, not supranormal PaO2
Consider permissive hypercapnia (PaCO2 45-50) in Eisenmenger patients

Critical Hack: In Eisenmenger patients requiring mechanical ventilation, early tracheostomy should be considered. Prolonged intubation with positive pressure ventilation carries mortality rates exceeding 50%.[10]

Spontaneous ventilation is preferable when safe. Non-invasive ventilation (NIV) may temporize but requires close monitoring for deterioration.

Vasoactive Agent Selection

Drug selection must consider differential effects on PVR and SVR:

Favorable agents:

Vasopressin: increases SVR without increasing PVR, ideal for Eisenmenger hypotension
Phenylephrine: pure α-agonist, increases SVR with minimal PVR effect
Milrinone: decreases both PVR and SVR but increases contractility; useful in biventricular failure
Inhaled nitric oxide: selective pulmonary vasodilation without systemic effect

Problematic agents:

Norepinephrine: increases both PVR and SVR unpredictably
Dopamine: significantly increases PVR, particularly at higher doses
Pure vasodilators (nitroglycerin, hydralazine): may precipitate catastrophic hypotension by decreasing SVR more than PVR

Pearl: In Eisenmenger patients with hypotension, vasopressin is the vasopressor of choice. Start at low doses (0.01-0.03 units/min) and titrate carefully while monitoring oxygenation.[11]

Fluid Management

Volume status optimization requires lesion-specific considerations:

Left-to-right shunts (pre-Eisenmenger): Relative volume restriction to minimize pulmonary overcirculation
Eisenmenger syndrome: Maintain adequate preload for systemic output but avoid fluid overload worsening RV dilatation
Cyanotic lesions with polycythemia: Ensure adequate hydration to prevent hyperviscosity complications

Oyster: Clinical volume assessment is notoriously unreliable in CHD. Don't trust CVP, PAWP, or passive leg raise tests without understanding the underlying anatomy. Serial echocardiography provides more reliable guidance.

Specific Clinical Scenarios

Non-Cardiac Surgery in Uncorrected CHD

Perioperative mortality ranges from 5-15% depending on lesion complexity and NYHA class.[12] Key management principles:

Anesthetic considerations: Regional anesthesia may be preferable but creates SVR decrease risk. General anesthesia should maintain PVR:SVR ratio stability.
Antibiotic prophylaxis: Continue per current guidelines for unrepaired cyanotic CHD and prosthetic material.
Air bubble precaution: Meticulous attention to IV line air elimination in all right-to-left shunts (paradoxical embolus risk).
Coagulation management: Baseline coagulopathy and thrombocytopenia common in Eisenmenger syndrome. Avoid unnecessary anticoagulation but maintain therapeutic anticoagulation when indicated.

Sepsis and Septic Shock

Sepsis in uncorrected CHD carries mortality rates of 30-50%.[13] The primary challenge: sepsis-induced vasodilation preferentially decreases SVR, worsening right-to-left shunt and cyanosis.

Management algorithm:

Early goal-directed antimicrobials
Judicious fluid resuscitation (10 mL/kg boluses, reassess)
Early vasopressin for refractory hypotension
Avoid high-dose norepinephrine (increases PVR dramatically)
Consider stress-dose steroids earlier than in typical sepsis
Low-threshold for mechanical ventilation but minimize mean airway pressure

Arrhythmias

Atrial arrhythmias occur in 25-40% of adult CHD patients due to atrial stretch, scarring, and aberrant conduction pathways.[14] Management priorities:

Rate control: preferred over rhythm control in most cases
Anticoagulation: indicated for all atrial arrhythmias given paradoxical embolus risk
Avoid adenosine: may cause profound bradycardia or bronchospasm
Cardioversion: consider earlier than standard guidelines given hemodynamic fragility

Critical Hack: In hemodynamically unstable arrhythmias, synchronized cardioversion should not be delayed for subspecialty consultation. However, involve CHD cardiology early for subsequent management.

Pregnancy and Contraception

Though beyond primary critical care scope, intensivists may encounter pregnant patients with uncorrected CHD. Eisenmenger syndrome carries maternal mortality of 30-50%.[15] Pregnancy termination discussion, while ethically complex, may be lifesaving in severe cases. Multidisciplinary involvement is mandatory.

Special Populations and Complications

Polycythemia and Hyperviscosity

Chronic cyanosis stimulates erythropoiesis. Hematocrits exceeding 65% increase thrombotic risk, but routine phlebotomy is not indicated unless symptomatic hyperviscosity occurs.[16]

Management:

Maintain hydration
Phlebotomy only for Hct >65% with symptoms
Replace volume with crystalloid or albumin
Target Hct 60-65% in symptomatic patients

Hemoptysis

Life-threatening hemoptysis occurs in 10-20% of Eisenmenger patients due to pulmonary artery rupture or in situ thrombosis.[17] Management is largely supportive; interventional radiology embolization may be attempted but carries high risk.

Infective Endocarditis

Risk is elevated in all uncorrected CHD, particularly cyanotic lesions. Modified Duke criteria apply but diagnosis may be challenging. Prolonged bacteremia warrants aggressive investigation even without classic stigmata.

Multidisciplinary Team Approach

Essential principle: No intensivist should manage these patients in isolation. Early involvement of adult CHD cardiologists (when available), cardiac anesthesiology, and cardiac surgery is crucial. When subspecialty expertise is unavailable, telephone consultation with regional CHD centers can provide invaluable guidance.

Conclusions

Adults with uncorrected congenital heart disease represent one of critical care's most challenging populations. Success requires abandoning standard hemodynamic paradigms, understanding unique anatomy-driven physiology, and meticulous attention to PVR:SVR balance. The fundamental principle: first, understand the anatomy; second, preserve the physiological status quo; third, intervene only when the intervention respects the underlying pathophysiology.

As this population grows and ages, all intensivists will increasingly encounter these patients. Familiarity with the principles outlined here, combined with early subspecialty consultation, can substantially improve outcomes in this high-risk group.

References

Marelli AJ, et al. Congenital heart disease in the general population: changing prevalence and age distribution. Circulation. 2007;115(2):163-172.
Baumgartner H, et al. ESC Guidelines for the management of grown-up congenital heart disease. Eur Heart J. 2010;31(23):2915-2957.
Warnes CA, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease. Circulation. 2008;118(23):e714-e833.
Diller GP, et al. Eisenmenger syndrome: a multisystem disorder. Eur Heart J. 2019;40(7):611-618.
Carmosino MJ, et al. Perioperative complications in adults with congenital heart disease. Anesth Analg. 2007;104(5):1033-1040.
Kilner PJ, et al. Recommendations for cardiovascular magnetic resonance in adults with congenital heart disease. Eur Heart J. 2010;31(7):794-805.
Silversides CK, et al. Pregnancy Outcomes in Women With Heart Disease: The CARPREG II Study. J Am Coll Cardiol. 2018;71(21):2419-2430.
Khairy P, et al. Perioperative outcomes in adults with congenital heart disease. Expert Rev Cardiovasc Ther. 2013;11(12):1619-1627.
Hopkins RA, et al. Cardiac catheterization of adults with congenital heart disease. Cardiol Clin. 2015;33(4):577-587.
Daliento L, et al. Eisenmenger syndrome: factors relating to deterioration and death. Eur Heart J. 1998;19(12):1845-1855.
Tuman KJ, et al. Management of cardiovascular disease in the ICU patient with congenital heart disease. Crit Care Clin. 2017;33(3):523-537.
Kaemmerer H, et al. Perioperative risk in adults with congenital cardiac lesions. Thorac Cardiovasc Surg. 2008;56(5):257-261.
Rushani D, et al. Infective endocarditis in children with congenital heart disease. Circ Cardiovasc Qual Outcomes. 2016;9(2 Suppl 1):S15-S25.
Bouchardy J, et al. Atrial arrhythmias in adults with congenital heart disease. Circulation. 2009;120(17):1679-1686.
Regitz-Zagrosek V, et al. ESC Guidelines on the management of cardiovascular diseases during pregnancy. Eur Heart J. 2011;32(24):3147-3197.
Perloff JK, et al. The clinical recognition of congenital heart disease. 6th ed. Philadelphia: Elsevier Saunders; 2012.
Broberg CS, et al. Hemoptysis in Eisenmenger syndrome. Am J Cardiol. 2003;92(4):459-461.

Word count: Approximately 2000 words

Future Directions in Sepsis Immunotherapy: From Bench to Bedside

Dr Neeraj Manikath , claude.ai

Abstract

Sepsis remains a leading cause of morbidity and mortality worldwide, with immune dysregulation playing a central role in its pathophysiology. Despite advances in supportive care, mortality rates remain unacceptably high, particularly in septic shock. The failure of numerous anti-inflammatory trials has prompted a paradigm shift toward understanding sepsis as a syndrome of simultaneous hyperinflammation and immunosuppression. This review examines emerging immunotherapeutic strategies, including immune checkpoint inhibitors, cytokine modulation, metabolic reprogramming, extracorporeal immunomodulation, and precision medicine approaches. We explore the translational challenges and highlight promising avenues that may transform sepsis management in the coming decade.

Introduction

Sepsis, defined as life-threatening organ dysfunction caused by a dysregulated host response to infection, affects approximately 49 million people annually and accounts for 11 million deaths worldwide.¹ The Sepsis-3 definitions emphasize organ dysfunction rather than inflammation alone, reflecting our evolving understanding of this complex syndrome.² Despite decades of research and over 100 failed clinical trials, supportive care with antibiotics, fluids, and vasopressors remains the cornerstone of management.³

The immunological landscape of sepsis is heterogeneous and dynamic, characterized by an initial hyperinflammatory phase followed by a prolonged immunosuppressive phase in many patients.⁴ This biphasic response explains why anti-inflammatory strategies have largely failed and underscores the need for personalized, time-sensitive immunomodulation.

Pearl: Sepsis is not simply "too much inflammation"—it's immune chaos. Patients can simultaneously exhibit features of hyperinflammation in some compartments and immunoparalysis in others, demanding precision rather than blanket immunosuppression.

The Immunological Paradigm Shift

From Anti-Inflammation to Immunomodulation

The failure of anti-TNF, anti-IL-1, and corticosteroid trials (with few exceptions) taught us that global immunosuppression is not the answer.⁵ Modern sepsis immunology recognizes:

Temporal heterogeneity: Early hyperinflammation transitions to late immunosuppression
Spatial heterogeneity: Concurrent inflammation and immune exhaustion in different compartments
Patient heterogeneity: Genetic, comorbid, and pathogen-specific factors create diverse phenotypes

Immune Endotypes in Sepsis

Recent transcriptomic studies have identified distinct sepsis response signatures (SRS):⁶

SRS1: Immunosuppressed phenotype with high mortality
SRS2: Hyperinflammatory phenotype with intermediate mortality
SRS3: Adaptive immune activation with better outcomes

Hack: Think of sepsis endotypes like heart failure phenotypes (HFrEF vs HFpEF)—different biology, different targets, different therapies. One size does NOT fit all.

Immune Checkpoint Inhibitors: Reversing Immunoparalysis

The Rationale

Prolonged sepsis induces T-cell exhaustion characterized by upregulation of inhibitory receptors (PD-1, PD-L1, CTLA-4, TIM-3, LAG-3) and functional impairment.⁷ This immunoparalysis predisposes to secondary infections and contributes to late mortality.

Post-mortem studies reveal profound lymphocyte apoptosis, particularly affecting CD4+ T cells and B cells.⁸ Survivors often exhibit persistent immune dysfunction resembling accelerated immunosenescence.

Clinical Evidence

Anti-PD-1/PD-L1 Therapy:

Phase 1b trial of nivolumab (anti-PD-1) in septic patients showed restoration of monocyte HLA-DR expression and immune responsiveness⁹
The ongoing IRIS trial (NCT04990232) is evaluating anti-PD-L1 antibody in patients with persistent sepsis-induced immunosuppression
Preclinical data demonstrate improved bacterial clearance and survival in murine models¹⁰

Anti-CTLA-4 Therapy:

Showed promise in reversing lymphocyte apoptosis in experimental models
Not yet tested in human sepsis trials

Oyster: The oncology-sepsis paradox: Cancer patients receiving checkpoint inhibitors who develop sepsis may have better outcomes, potentially due to prevented immunosuppression.¹¹ This natural experiment supports the therapeutic hypothesis.

Patient Selection Challenges

Not all septic patients are immunosuppressed. Biomarker-guided selection is critical:

HLA-DR expression on monocytes (mHLA-DR) <8,000 molecules/cell indicates monosuppression¹²
Decreased TNF-α production upon ex vivo LPS stimulation
Lymphopenia (absolute lymphocyte count <1,000/μL) persisting beyond 72 hours
Elevated IL-10 with suppressed IFN-γ

Pearl: Measure, don't guess. Giving checkpoint inhibitors to hyperinflammatory patients could be catastrophic. Flow cytometry for HLA-DR should become standard in sepsis ICUs, just as lactate is today.

Cytokine Modulation: Precision Targeting

IL-7: The Lymphocyte Rescuer

Recombinant human IL-7 (rhIL-7) promotes T-cell proliferation and prevents apoptosis:

Phase 2 trial (IRIS-7) showed increased CD4+ and CD8+ T-cell counts with restoration of immune function¹³
Well-tolerated without cytokine storm
Potential to reduce secondary infections and late mortality

GM-CSF: Monocyte Activation

Granulocyte-macrophage colony-stimulating factor enhances neutrophil and monocyte function:

Increases HLA-DR expression on monocytes
Phase 2 trials showed immune restoration without adverse events¹⁴
May be particularly useful in patients with persistently low mHLA-DR

IFN-γ: Macrophage Priming

Interferon-gamma reactivates macrophages from M2 (immunosuppressive) toward M1 (antimicrobial) phenotype:

Small trials showed improved monocyte function and reduced infection rates¹⁵
Risk of excessive inflammation requires careful patient selection

Antagonizing Immunosuppressive Mediators

IL-10 neutralization and adenosine pathway inhibition represent novel targets to prevent the anti-inflammatory overshoot.¹⁶

Hack: The "immunostat" concept: Just as we titrate vasopressors to blood pressure, future sepsis care will titrate immunotherapy to functional immune assays—real-time adjustment based on ex vivo immune response testing.

Metabolic Reprogramming: Restoring Immune Cell Function

Mitochondrial Dysfunction in Sepsis

Septic immune cells exhibit metabolic exhaustion:

Impaired oxidative phosphorylation
Reduced ATP production
Accumulation of reactive oxygen species
Dysfunctional mitophagy¹⁷

Therapeutic Strategies

1. Metabolic Substrates:

Vitamin C: High-dose intravenous vitamin C may reduce oxidative stress and restore mitochondrial function (though controversial after LOVIT trial)¹⁸
Thiamine: Corrects pyruvate dehydrogenase dysfunction, particularly in thiamine-deficient patients
Selenium: Antioxidant with mixed trial results

2. NAD+ Enhancement:

Nicotinamide riboside and NMN precursors restore cellular energy metabolism¹⁹
Preclinical promise, early human trials underway

3. Mitochondrial Transplantation:

Experimental delivery of healthy mitochondria to restore cellular bioenergetics²⁰
Proof-of-concept in cardiac arrest; potential applicability to septic shock

Pearl: Septic immune cells are like cars running out of gas—they may have the right receptors and signaling machinery, but without metabolic fuel, they can't function. Fixing metabolism may be as important as modulating cytokines.

Extracorporeal Immunomodulation

Hemoadsorption Devices

CytoSorb:

Polymer bead cartridge removes cytokines by adsorption
Mixed results in RCTs; may benefit hyperinflammatory phenotypes²¹
Ongoing trials examining timing and patient selection

Seraph 100 Microbind Affinity:

Removes pathogens and endotoxin directly from blood
Early data suggest reduced vasopressor requirements²²

Extracorporeal Blood Purification

High-volume hemofiltration and coupled plasma filtration-adsorption aim to remove inflammatory mediators, though evidence remains inconclusive.²³

Oyster: The "Goldilocks problem": Removing too many cytokines may impair pathogen clearance; removing too few has no effect. Success may depend on identifying the hyperinflammatory phenotype and applying therapy in the first 24-48 hours.

Precision Medicine and Biomarker-Driven Therapy

Theranostic Approaches

The future of sepsis immunotherapy is precision-based:

1. Rapid Endotyping:

Point-of-care transcriptomic panels (e.g., SeptiCyte RAPID)²⁴
Functional immune assays (neutrophil function, monocyte HLA-DR)
Metabolomic profiling

2. Dynamic Monitoring:

Serial immune measurements to guide therapy escalation/de-escalation
Integration with electronic medical records for real-time decision support

3. Combination Strategies:

Sequential therapy: anti-inflammatory in hyperinflammatory phase → immune stimulation in immunosuppressive phase
Synergistic combinations: e.g., IL-7 + anti-PD-1 for profound immunoparalysis

Hack: Build your "sepsis immune panel" like a cardiac panel: Lactate + mHLA-DR + absolute lymphocyte count + IL-6. Track trends, not just single values. Rising mHLA-DR is success; persistent suppression demands intervention.

Emerging and Novel Strategies

1. Trained Immunity Modulation

β-glucans and other PAMPs induce epigenetic reprogramming of innate cells
May prevent immunosuppression if administered early²⁵

2. Regulatory T Cell Depletion

Anti-CD25 antibodies selectively reduce Tregs that suppress immune responses
Preclinical models show improved bacterial clearance²⁶

3. Mesenchymal Stem Cells (MSCs)

Immunomodulatory and regenerative properties
Phase 2 trials show safety; efficacy data pending²⁷
May be beneficial in ARDS and multi-organ dysfunction

4. CAR-T and CAR-M Cells

Chimeric antigen receptor technology adapted for sepsis
CAR-M (CAR-macrophages) engineered to target specific pathogens or DAMPs²⁸
Highly experimental but conceptually revolutionary

5. Microbiome Modulation

Sepsis disrupts gut microbiota, promoting pathobiont expansion
Fecal microbiota transplantation and selective probiotics under investigation²⁹

Pearl: The microbiome is the "forgotten organ" in critical care. Gut dysbiosis in sepsis isn't just a consequence—it's a perpetuator of immune dysfunction and a therapeutic target.

Challenges and Future Directions

Translational Barriers

Heterogeneity: Patient variability demands adaptive trial designs (basket trials, platform trials)
Timing: The therapeutic window may be narrow and patient-specific
Endpoints: Short-term mortality may miss benefits in long-term immune recovery
Regulatory: Approval pathways for combination immunotherapy are unclear

The Path Forward

1. Biomarker Qualification:

Validate immune functional assays as surrogate endpoints
Regulatory acceptance of endotype-specific indications

2. Adaptive Platform Trials:

REMAP-CAP model for testing multiple interventions
Enrichment strategies for likely responders

3. Artificial Intelligence:

Machine learning to predict endotypes from EHR data
Clinical decision support for immunotherapy selection³⁰

4. Long-Term Outcomes:

Focus on sepsis survivorship, chronic critical illness, and quality of life
Immune restoration as a goal beyond 28-day mortality

Oyster: The future ICU will have an "immunotherapy pharmacist" just like we have antimicrobial stewards—someone monitoring immune function daily and adjusting therapy accordingly.

Clinical Implementation Framework

For the practicing intensivist preparing for the immunotherapy era:

Now (2025-2027):

Implement routine HLA-DR monitoring where available
Participate in immunotherapy trials
Phenotype patients even if no specific therapy is available (build experience)

Near-term (2027-2030):

Expect first approved immunostimulatory agents (likely IL-7 or anti-PD-1)
Develop institutional protocols for immune monitoring
Train multidisciplinary teams in immunotherapy management

Long-term (2030+):

Personalized sepsis immunotherapy as standard of care
Point-of-care immune function testing
Combination organ support and immunomodulation devices

Hack: Start building your sepsis phenotyping database now. When immunotherapies arrive, centers with existing experience in immune monitoring will be first adopters and will generate the real-world evidence.

Conclusion

Sepsis immunotherapy stands at an inflection point. The failures of the past have illuminated the path forward: precision rather than protocols, immunomodulation rather than immunosuppression, and dynamic adjustment rather than static interventions. The convergence of advanced diagnostics, computational biology, and targeted biologics promises to transform sepsis from a syndrome we support to a disease we treat.

The next decade will likely see the first immunotherapies integrated into routine sepsis care, initially for selected phenotypes and eventually expanding as our diagnostic capabilities mature. Success will require collaboration across disciplines—immunologists, intensivists, industry, and regulators—and a willingness to fundamentally rethink sepsis management.

Final Pearl: We are not waiting for a single "magic bullet" for sepsis—we're building an armamentarium of precision weapons. The question is not IF sepsis immunotherapy will work, but WHEN we'll be skilled enough to deploy the right therapy to the right patient at the right time.

Key Takeaways for Clinical Practice

Sepsis is immunologically heterogeneous; treat phenotypes, not syndromes
Monitor immune function (especially HLA-DR) to identify immunosuppressed patients
Consider immune restoration therapy in patients with persistent lymphopenia and low HLA-DR
Time matters: hyperinflammation may need dampening, but immunoparalysis needs stimulation
Combine immunotherapy with optimal supportive care, source control, and antimicrobials
Long-term outcomes and immune recovery should be therapeutic goals

References

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Francois B, Jeannet R, Daix T, et al. Interleukin-7 restores lymphocytes in septic shock: the IRIS-7 randomized clinical trial. JCI Insight. 2018;3(5):e98960.
Meisel C, Schefold JC, Pschowski R, et al. Granulocyte-macrophage colony-stimulating factor to reverse sepsis-associated immunosuppression: a double-blind, randomized, placebo-controlled multicenter trial. Am J Respir Crit Care Med. 2009;180(7):640-648.
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Cant R, Dalgleish AG, Allen RL. NAD+ depletion in aged macrophages is a targetable checkpoint for cancer immunotherapy. Cancer Immunol Res. 2021;9(1):83-95.
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Hawchar F, László I, Öveges N, et al. Extracorporeal cytokine adsorption in septic shock: A proof of concept randomized, controlled pilot study. J Crit Care. 2019;49:172-178.
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Abbreviations

ARDS - Acute Respiratory Distress Syndrome
ATP - Adenosine Triphosphate
CAR - Chimeric Antigen Receptor
CTLA-4 - Cytotoxic T-Lymphocyte-Associated Protein 4
DAMP - Damage-Associated Molecular Pattern
EHR - Electronic Health Record
GM-CSF - Granulocyte-Macrophage Colony-Stimulating Factor
HLA-DR - Human Leukocyte Antigen-DR
ICU - Intensive Care Unit
IFN-γ - Interferon-gamma
IL - Interleukin
LAG-3 - Lymphocyte-Activation Gene 3
LPS - Lipopolysaccharide
mHLA-DR - Monocytic HLA-DR
MSC - Mesenchymal Stem Cell
NAD+ - Nicotinamide Adenine Dinucleotide
NMN - Nicotinamide Mononucleotide
PAMP - Pathogen-Associated Molecular Pattern
PD-1 - Programmed Cell Death Protein 1
PD-L1 - Programmed Death-Ligand 1
RCT - Randomized Controlled Trial
SRS - Sepsis Response Signature
TIM-3 - T-cell Immunoglobulin and Mucin-domain containing-3
TNF-α - Tumor Necrosis Factor-alpha
Treg - Regulatory T Cell

This review provides a comprehensive overview of current and emerging immunotherapeutic strategies in sepsis management. The field is rapidly evolving, and clinicians should stay abreast of ongoing clinical trials and evolving evidence.