Pharmacotherapy

Non-Pharmacologic Management

• Early recognition and diagnosis of sepsis is critical. Patients should be screened for signs of infection and organ dysfunction. Common screening tools include the systemic inflammatory response syndrome (SIRS) criteria, quick Sequential Organ Failure Assessment (qSOFA) score, and lactate measurement.

• Early administration of intravenous (IV) fluids is a key part of initial resuscitation. A fluid challenge with 30 mL/kg of crystalloids should be given in the first 3 hours. Further fluid therapy should be guided by assessment of fluid responsiveness using dynamic parameters like passive leg raise, stroke volume variation, or pulse pressure variation.

• Timely administration of empiric broad-spectrum antibiotics is crucial, with a goal of administration within 1 hour of sepsis recognition. Antibiotic selection should be based on likely pathogens and local resistance patterns.

• Source control with drainage of infective sources is important when applicable. This includes draining abscesses, debridement of infected tissues, and removal of infected devices.

• Supportive care like mechanical ventilation for respiratory failure and vasopressors for refractory hypotension should be initiated when indicated.

---

IV Fluid Resuscitation

Introduction to Fluid Therapy in Sepsis

 Fluid resuscitation is a critical intervention in sepsis and septic shock, targeting the restoration of circulatory volume, enhancing tissue perfusion, and preventing organ dysfunction. The goals of fluid therapy in sepsis include achieving hemodynamic stability, optimizing oxygen delivery to tissues, and minimizing the risk of fluid overload.

Fluid Resuscitation Strategy

• Initial Approach: Early administration of fluids within the first hours of sepsis recognition is vital, typically starting with 30 ml/kg of isotonic crystalloids.
• Monitoring and Reassessment: Continuous assessment of fluid responsiveness guides further resuscitation efforts, employing dynamic measures such as passive leg raise tests or volume challenge responses to evaluate the need for additional fluids.
  
  

Types of Intravenous Fluids

• Crystalloids: These include isotonic solutions like normal saline and Lactated Ringer’s solution, preferred for their efficacy and safety. Balanced crystalloids may offer advantages by reducing the risk of chloride overload and acid-base imbalances.
• Colloids: Options like albumin may be considered in specific scenarios, such as in patients with significant hypoalbuminemia or when crystalloids alone are insufficient. However, their use is limited by higher costs and potential adverse effects.

• Balanced Solutions Advantages:
  • Minimize chloride overload, reducing the risk of hyperchloremic metabolic acidosis.
  • More closely mimic plasma electrolyte composition, promoting physiological acid-base balance.
  • Potential for improved clinical outcomes, including lower incidence of acute kidney injury (AKI) and reduced mortality in sepsis patients.
• Clinical Implications in Sepsis:
  • Supports hemodynamic stability with less potential for causing adverse electrolyte imbalances.
  • May influence fluid therapy choices, guiding clinicians towards options that align with patient-specific needs and current evidence.
• Evidence-based Recommendations for Crystalloid Use:
  • Balanced crystalloids may be preferred over saline in many sepsis and septic shock patients due to their association with better outcomes.
  • Guidelines suggest the early administration of crystalloids for fluid resuscitation in sepsis to improve survival rates.
  • Continuous assessment of volume status and responsiveness to guide further fluid administration, emphasizing the importance of personalized therapy based on dynamic indicators.

Fluid Management Strategies

• Comprehensive Monitoring: Incorporate both dynamic and static parameters to assess fluid responsiveness accurately. Utilize technologies such as ultrasound or passive leg raise tests to guide decisions.

• Individualized Fluid Therapy: Tailor fluid choices and volumes to the specific needs and conditions of the patient, considering factors such as underlying comorbidities and the stage of sepsis.
• Recognition and Management of Fluid Overload: Early identification of fluid overload through clinical examination and monitoring of input-output balances is essential. Implement strategies such as diuretic therapy or fluid restriction when necessary.
• Evaluation of Organ Function: Regularly assess organ function to ensure that fluid management strategies are not adversely affecting organ systems, particularly renal and cardiac functions.
• Adjustment Over Time: Fluid therapy in sepsis is dynamic; reassessment at regular intervals is critical to adapt to the changing clinical status of the patient.
• Collaboration Among Specialties: Engage a multidisciplinary team, including pharmacists, intensivists, and nurses, to ensure a cohesive approach to fluid management, leveraging different perspectives for optimal patient care.

---

Antimicrobials

Antimicrobial Selection in Sepsis

Introduction to Antimicrobial Selection in Sepsis

Timely and appropriate antimicrobial therapy is paramount in sepsis management to reduce morbidity and mortality. Empirical therapy, initiated based on the suspected source of infection and risk factors for specific pathogens, including multidrug-resistant organisms, is crucial for the early stages of sepsis treatment.

Empirical Antimicrobial Therapy by Suspected Source of Infection

• Respiratory Tract Infections: Differentiation between community-acquired pneumonia and hospital-acquired or ventilator-associated pneumonia guides the choice of empirical antibiotics, targeting common pathogens like Streptococcus pneumoniae for community-acquired cases and considering Pseudomonas aeruginosa in hospital-acquired cases.
• Abdominal Infections: Broad-spectrum antibiotics are recommended to cover gram-negative rods, gram-positive cocci, and anaerobes. Consideration of patient-specific factors such as recent antibiotic use or healthcare exposure is critical for selecting the most appropriate empirical therapy.
• Urinary Tract Infections: Empirical therapy should cover common pathogens such as Escherichia coli. In cases of complicated UTIs or urosepsis, broader coverage, including coverage for resistant organisms, may be necessary.
• Skin and Soft Tissue Infections: For necrotizing infections, broad-spectrum antibiotics, including MRSA coverage, are recommended. Diabetic foot infections require coverage for gram-positive cocci and, depending on severity, may also require coverage for gram-negative rods and anaerobes.
• Central Nervous System Infections: Empirical therapy for meningitis should consider age, potential pathogen exposure, and vaccination status to cover likely pathogens, including Streptococcus pneumoniae, Neisseria meningitidis, and Haemophilus influenzae.
• Catheter-Related Bloodstream Infections: Removal of the implicated catheter and initiation of antibiotics targeting common skin flora, including Staphylococcus aureus and coagulase-negative staphylococci, is recommended.

Tailoring Therapy Based on Risk Factors for Multidrug-Resistant Organisms

Evaluation of risk factors such as recent antibiotic use, healthcare exposure, and known local resistance patterns is essential for modifying empirical therapy to ensure adequate coverage of potential multidrug-resistant organisms.

• Common empiric therapy choices:Pseudomonal coverage with an antipseudomonal penicillin (piperacillin-tazobactam, ticarcillin-clavulanate), cephalosporin (cefepime, ceftazidime), or carbapenem (meropenem, imipenem-cilastatin). Can combine with an aminoglycoside or fluoroquinolone. MRSA coverage with vancomycin or linezolid. Should be added empirically in patients at high risk for MRSA.Antifungal coverage with fluconazole, echinocandins (caspofungin, micafungin), or amphotericin formulations in high risk patients.

Antimicrobial Stewardship in Sepsis

Principles of Antimicrobial Stewardship in Sepsis

The goal is to use antimicrobials judiciously to improve patient outcomes while minimizing the risk of resistance. This includes timely initiation of empirical therapy, de-escalation based on culture results, and optimization of antibiotic duration to balance efficacy with the risk of adverse effects and resistance development.

Monitoring and Adjusting Therapy

Pharmacokinetic and pharmacodynamic considerations are critical in the critically ill population, necessitating regular review and adjustment of antimicrobial therapy. Monitoring therapeutic drug levels, renal function, and markers of infection are key components of this process.

Role of the Pharmacist in Antimicrobial Stewardship

Pharmacists play a vital role in guiding antimicrobial therapy in sepsis, including selecting appropriate empirical therapy, dosing adjustments based on patient-specific factors, and promoting stewardship principles among the healthcare team.

Effective antimicrobial selection and stewardship are critical components of sepsis management. Pharmacists, leveraging their expertise in pharmacotherapy and stewardship principles, are essential to ensuring optimal antimicrobial use and improving patient outcomes in sepsis.

---

Vasopressors

• Vasopressors are medications used to increase blood pressure in patients with sepsis.
• Sepsis is a life-threatening condition characterized by organ dysfunction caused by a dysregulated response to infection.
• Vasopressors are used to maintain adequate tissue perfusion and oxygen delivery in septic patients.

Indications for Vasopressors in Sepsis

• Persistent hypotension despite adequate fluid resuscitation
• Mean arterial pressure (MAP) <65 mmHg
• Lactate >2 mmol/L
• Oliguria (<0.5 mL/kg/hr)

Choice of Vasopressor

• Norepinephrine is the first-line vasopressor for sepsis.
• Vasopressin may be added to norepinephrine if the patient remains hypotensive despite adequate doses of norepinephrine.
• Epinephrine may be used in patients with refractory hypotension or myocardial ventricular dysfunction.

Complications of Vasopressors

• Tachycardia
• Arrhythmias
• Hypertension
• Tissue ischemia
• Increased risk of thrombosis

Norepinephrine

• Starting Dosing: 8 to 12 mcg/min continuous IV infusion, or 0.01 to 0.1 mcg/kg/min
• Adverse effects: Tachycardia, arrhythmias, hypertension, tissue ischemia, increased risk of thrombosis
• Clinical pearls:
  • First-line vasopressor for sepsis
  • Titrate to achieve a MAP of 65-70 mmHg
  • Monitor for adverse effects, especially in patients with underlying cardiovascular conditions

Vasopressin

• Dosing: 0.03-0.04 units/min
• Adverse effects: Hypertension, tissue ischemia, increased risk of thrombosis
• Clinical pearls:
  • May be added to norepinephrine in patients with refractory hypotension
  • May be particularly beneficial in patients with diabetes insipidus or adrenal insufficiency

Epinephrine

• Dosing: 0.1-0.3 mcg/kg/min
• Adverse effects: Tachycardia, arrhythmias, hypertension, tissue ischemia, increased risk of thrombosis
• Clinical pearls:
• May be used in patients with refractory hypotension
• Should be used with caution in patients with underlying cardiovascular conditions

Clinical Pearls for All Vasopressors

• Vasopressors should be used in conjunction with other supportive measures, such as fluid resuscitation, antibiotics, and source control.
• The choice of vasopressor should be individualized based on the patient’s hemodynamic status and response to therapy.
• Vasopressors should be titrated to the lowest effective dose to minimize the risk of complications.
• Close monitoring of the patient’s hemodynamic status is essential to prevent complications and optimize outcomes.

Additional Considerations

• The use of vasopressors in sepsis is associated with improved survival.
• Vasopressors should be discontinued as soon as possible once the patient’s hemodynamic status has stabilized.
• Patients receiving vasopressors should be monitored closely for adverse effects, including tachycardia, arrhythmias, hypertension, tissue ischemia, and increased risk of thrombosis.

Vasopressor Administration and Monitoring

Administration Guidelines

• Vasopressors should be initiated early to achieve and maintain an initial target MAP of 65 mm Hg.
• Peripheral administration of vasopressors is acceptable temporarily until central venous access is established.

Monitoring Efficacy and Safety

• Continuous monitoring of hemodynamic parameters and response to therapy is essential to adjust vasopressor therapy appropriately.
• Awareness of potential adverse effects, such as arrhythmias or peripheral ischemia, is necessary for safe vasopressor use.

Role of the Pharmacist

Clinical Decision Support

• Pharmacists provide vital support in selecting appropriate vasopressors, dosing, and monitoring therapeutic and adverse effects.
• They play a key role in educating the healthcare team on best practices and latest evidence in vasopressor therapy.

---

Corticosteroids

• Mechanism of action: Corticosteroids have anti-inflammatory and immunosuppressive effects. They work by binding to glucocorticoid receptors in cells, which then leads to the production of proteins that inhibit inflammation and suppress the immune system.
• Indications: Corticosteroids are used to treat a wide variety of conditions, including sepsis, septic shock, and ARDS. In sepsis, corticosteroids are thought to improve outcomes by reducing inflammation, preventing capillary leak, and improving organ function.
• Dosing: The recommended dose of corticosteroids for sepsis is hydrocortisone 200 mg/day, given as either a continuous infusion or 50 mg every 6 hours.
• Duration of therapy: The optimal duration of corticosteroid therapy in sepsis is unknown. Some studies have shown that short-term therapy (3-5 days) is as effective as longer-term therapy (7-10 days), while other studies have shown that longer-term therapy may be associated with improved outcomes.
• Contraindications: Corticosteroids are contraindicated in patients with active untreated infection, peptic ulcer disease, uncontrolled diabetes, and severe liver or kidney disease.
• Adverse effects: The most common adverse effects of corticosteroids include hyperglycemia, fluid retention, hypertension, and immunosuppression.

---

Adjunctive Therapies

• Venous thromboembolism (VTE) prophylaxis with pharmacologic agents like heparin or enoxaparin is recommended unless contraindicated.
  • Stress ulcer prophylaxis with a proton-pump inhibitor or H2 blocker is suggested in at-risk patients.
  • Blood glucose levels should be maintained between 140-180 mg/dL with the use of insulin infusions.
  • Intravenous immunoglobulins and thrombomodulin have not shown clear benefit and are not routinely recommended.
  • Blood Products: – Transfuse packed red blood cells for a hemoglobin less than 7 g/dL. A higher threshold of 9 g/dL may be appropriate in myocardial ischemia, severe hypoxemia, or acute hemorrhage.

---

Clinical Pearls

• ICU admission is indicated for any septic patient requiring vasopressors or with lactate ≥4 mmol/L.

• Dynamic assessment of fluid responsiveness using tools like passive leg raise is superior to static parameters like central venous pressure.

• Norepinephrine is considered first-line for vasopressor support, with epinephrine and vasopressin as secondary agents. 

• Mean arterial pressure goal is typically 65 mm Hg but may be increased to 85 mm Hg in patients with chronic hypertension.

• Combination antibiotic therapy provides broader coverage for multidrug-resistant pathogens but should be de-escalated once culture data are available.

• Low-dose hydrocortisone has a limited role in advanced septic shock with hypotension poorly responsive to fluids/vasopressors.