I. Introduction

Venous thromboembolism (VTE), stress-related mucosal bleeding, ICU delirium, and ventilator-associated pneumonia (VAP) are common and serious complications of invasive mechanical ventilation. Critical care pharmacists lead risk assessment, prophylaxis selection, dosing adjustments, and interdisciplinary stewardship to improve outcomes.

Scope and Impact

• Immobilization and inflammation drive a high VTE risk.
• Splanchnic hypoperfusion and acid hypersecretion cause stress ulcers.
• Delirium prolongs ventilation and hospital stays.
• VAP increases morbidity, antibiotic exposure, and costs.

Pharmacist’s Role

• Stratify risk using validated tools.
• Select agents, individualize dosing in organ dysfunction.
• Monitor for adverse events and adjust therapy.
• Champion antimicrobial stewardship and protocol adherence.

II. Pharmacotherapy Strategies

A. Venous Thromboembolism (VTE) Prophylaxis

Early pharmacologic prophylaxis with unfractionated heparin (UFH) or low-molecular-weight heparin (LMWH) reduces VTE incidence but requires balancing bleeding and heparin-induced thrombocytopenia (HIT) risk.

Mechanism of Action

• Unfractionated Heparin (UFH): Potentiates antithrombin III, leading to inhibition of factors Xa and IIa (thrombin), with a more pronounced effect on factor IIa.
• Low-Molecular-Weight Heparin (LMWH) (e.g., enoxaparin): Primarily inhibits factor Xa through antithrombin III, with less effect on factor IIa. Offers more predictable pharmacokinetic and pharmacodynamic profiles.

Risk Stratification

Validated tools like the Padua Prediction Score or the IMPROVE VTE Risk Model help identify patients at high risk. Key risk factors include active cancer, history of VTE, immobility, recent surgery or trauma, and certain inherited or acquired thrombophilias.

Contraindications & Precautions

• Active, clinically significant bleeding.
• Severe thrombocytopenia (e.g., platelet count < 50,000/µL).
• Recent or suspected intracranial hemorrhage.
• History of HIT.
• Monitor platelet counts regularly (e.g., every 2-3 days for the first 2 weeks); evaluate for HIT if platelet count drops by >50% from baseline or if new thrombosis occurs.

B. Stress Ulcer Prophylaxis (SUP)

Critically ill, ventilated patients with specific risk factors for stress-related mucosal disease (SRMD) benefit from targeted prophylaxis with proton pump inhibitors (PPIs) or histamine-2 receptor antagonists (H2RAs).

Major Risk Factors for SRMD

• Mechanical ventilation for >48 hours
• Coagulopathy (platelets <50,000/µL, INR >1.5, or PTT >2x normal)
• History of gastrointestinal ulceration or bleeding within the past year
• Traumatic brain injury, traumatic spinal cord injury, or severe burns
• Sepsis or shock
• Two or more minor risk factors (e.g., corticosteroid therapy, ICU stay >1 week, occult GI bleeding)

Route & Duration

Enteral administration is preferred if gastrointestinal function is intact. Prophylaxis should be discontinued once the patient is no longer mechanically ventilated or major risk factors resolve.

Monitoring

Monitor for signs of GI bleeding (hematemesis, melena, significant unexplained drop in hemoglobin). Be vigilant for potential infectious complications like Clostridioides difficile infection or pneumonia, particularly with PPIs.

C. Delirium Prevention and Management

Delirium affects up to 80% of ventilated ICU patients. Multicomponent non-pharmacologic strategies and optimization of sedation are the cornerstones of prevention and management.

Non-Pharmacologic Interventions (The “ABCDEF Bundle”)

• Assess, Prevent, and Manage Pain: Regular pain assessment and multimodal analgesia.
• Both Spontaneous Awakening Trials (SATs) and Spontaneous Breathing Trials (SBTs): Daily interruption of sedation and assessment for extubation readiness.
• Choice of Analgesia and Sedation: Prioritize non-benzodiazepine sedatives; target light sedation (e.g., RASS -2 to 0).
• Delirium: Assess, Prevent, and Manage: Routine screening (e.g., CAM-ICU, ICDSC).
• Early Mobility and Exercise: Reduce immobility.
• Family Engagement and Empowerment: Involve family in care and reorientation.
• Additional strategies: Sleep hygiene protocols (noise/light reduction, earplugs, eye masks), reorientation, and provision of sensory aids (glasses, hearing devices).

Sedation Strategy

Minimize the use of benzodiazepines due to their association with increased delirium. Prefer propofol or dexmedetomidine for sedation when needed, aiming for the lightest possible level of sedation that ensures patient safety and comfort.

Evidence Limitations for Antipsychotics

Routine use of antipsychotics for delirium treatment or prevention is not supported by strong evidence for improving mortality or delirium duration. Pharmacologic agents should be reserved for managing severe agitation or distress that is refractory to non-pharmacologic interventions and poses a safety risk.

D. Antimicrobial Stewardship for Ventilator-Associated Pneumonia (VAP)

Appropriate empiric antibiotic selection based on patient risk factors and local resistance patterns, followed by culture-guided de-escalation and optimal treatment duration, is essential to minimize resistance and toxicity.

Risk Assessment for Multidrug-Resistant (MDR) Pathogens

• Prior intravenous antibiotic use within 90 days.
• Current hospitalization of ≥5 days before VAP onset.
• Septic shock at time of VAP.
• ARDS preceding VAP.
• Acute renal replacement therapy prior to VAP onset.
• High local prevalence of MDR organisms (refer to institutional antibiogram).

Empiric Therapy Principles

Empiric therapy should cover Staphylococcus aureus (including MRSA if risk factors present or high local prevalence), Pseudomonas aeruginosa, and other Gram-negative bacilli. Double Gram-negative coverage may be considered in high-risk patients or those with prior MDR Gram-negative infections.

• Time-dependent agents (e.g., beta-lactams): Maximize the duration the drug concentration remains above the MIC. Consider extended or continuous infusions for agents like piperacillin-tazobactam or meropenem in severe infections or with less susceptible pathogens.
• Concentration-dependent agents (e.g., aminoglycosides, fluoroquinolones): Optimize peak concentrations. Use high-dose, once-daily regimens for aminoglycosides to maximize efficacy and minimize nephrotoxicity.

Dosing & Therapeutic Drug Monitoring (TDM)

• Vancomycin: Target an AUC/MIC ratio of 400–600 for MRSA. Perform AUC-based monitoring or trough-based monitoring (target 15-20 mg/L as a surrogate, though AUC is preferred). Adjust dosing based on renal function and TDM results.
• Aminoglycosides (e.g., gentamicin, tobramycin, amikacin): Monitor peak levels (for efficacy) and trough levels (to minimize toxicity, especially nephrotoxicity and ototoxicity). Utilize pharmacokinetic dosing services where available.

Culture-Driven De-escalation

Reassess antibiotic therapy at 48–72 hours, once culture and susceptibility results are available and clinical response can be evaluated. Narrow the spectrum of antibiotics or discontinue redundant agents. Procalcitonin trends can be used as an adjunct to clinical judgment to support de-escalation or discontinuation of antibiotics, but should not replace clinical assessment.

Duration of Therapy

A standard 7-day course of therapy is recommended for most patients with VAP who demonstrate good clinical response. Longer durations (e.g., up to 14 days) may be considered for infections caused by Pseudomonas aeruginosa or other non-fermenting Gram-negative bacilli, or in cases of slow clinical response or bacteremia.

III. Implementation and Monitoring

Embedding prophylaxis and stewardship strategies into standardized order sets, interprofessional communication, and real-time outcome tracking ensures consistent application of best practices.

Order Sets & Protocols

• Integrate risk assessment tools (e.g., Padua for VTE, specific criteria for SUP, CAM-ICU for delirium) directly into electronic health record order sets to prompt appropriate prophylaxis.
• Develop and implement institutional protocols for VTE prophylaxis, SUP, sedation/analgesia management, and empiric VAP therapy.
• Automate renal and hepatic dose adjustments for relevant medications where feasible and safe.

Communication & Education

• Conduct daily multidisciplinary rounds that explicitly include review of VTE prophylaxis, SUP appropriateness, sedation goals, delirium screening, and antibiotic therapy.
• Provide regular, targeted education to medical, nursing, and pharmacy staff on current guidelines, institutional protocols, and recognition of adverse drug events.
• Foster a culture of antimicrobial stewardship through pharmacist-led interventions and collaborative decision-making.

Outcome Tracking

• Monitor key process measures: adherence to prophylaxis guidelines, rates of appropriate delirium screening, timeliness of antibiotic de-escalation.
• Track clinical outcomes: incidence of VTE, clinically significant GI bleeding, delirium prevalence and duration, VAP rates, and rates of infection with MDR organisms.
• Utilize audit-and-feedback cycles to identify areas for improvement and refine protocols based on local data.

IV. Summary and Key Pearls

Effective pharmacologic strategies are crucial for preventing common and serious complications in mechanically ventilated patients. A proactive, evidence-based, and multidisciplinary approach is essential.

• VTE Prophylaxis: Initiate UFH or LMWH within 24 hours for at-risk patients unless contraindicated. Utilize mechanical methods when pharmacologic options are unsafe, and combine when appropriate in very high-risk individuals.
• Stress Ulcer Prophylaxis: Reserve PPIs or H2RAs for patients with significant risk factors for stress-related mucosal bleeding. Reassess need daily and discontinue when risk factors resolve to minimize adverse effects.
• Delirium Prevention & Management: Prioritize non-pharmacologic interventions (ABCDEF bundle). Optimize sedation by minimizing benzodiazepines and targeting light sedation. Use dexmedetomidine or antipsychotics judiciously for agitation refractory to non-pharmacologic measures.
• VAP Stewardship: Tailor empiric antibiotic therapy to patient-specific risk factors for MDR pathogens and local antibiograms. Obtain appropriate cultures and de-escalate therapy based on results and clinical response. Aim for a 7-day course of therapy in most responders.
• Systematic Implementation: Embed these strategies into institutional protocols, facilitate interprofessional communication through daily rounds, and monitor outcomes to drive sustained practice improvement and enhance patient safety.