S. Scott Sutton
LEARNING OBJECTIVES
Upon completion of the chapter, the reader will be able to:
1. Compare and contrast the definitions of syndromes related to sepsis.
2. Identify the pathogens associated with sepsis.
3. Discuss the pathophysiology of sepsis as it relates to pro- and anti-inflammatory mediators.
4. Identify patient symptoms as early or late sepsis and evaluate diagnostic and laboratory tests for patient treatment and monitoring.
5. Assess complications of sepsis and discuss their impact on patient outcomes.
6. Design desired treatment outcomes for septic patients.
7. Formulate a treatment and monitoring plan (pharmacologic and nonpharmacologic) for septic patients.
8. Evaluate patient response and devise alternative treatment regimens for nonresponding septic patients.
KEY CONCEPTS
Sepsis is a continuum of physiologic stages defined by physiologic measures and signs and symptoms of sepsis process.
Gram-positive and gram-negative bacteria, fungal species, and viruses may cause sepsis.
Inflammation is the key factor in the development of sepsis. Patients with severe infections, trauma, debilitating conditions, or an immunocompromised status may experience an imbalance between inflammatory mediators that progresses to sepsis.
The cumulative burden of sepsis complications is the leading factor of mortality. The risk of death increases 20% with failure of each additional organ. Severe sepsis averages two failed organs, with a mortality rate of 40%.
Treatment is aimed at early goal-directed resuscitation; reducing or eliminating organ failures; treating and eliminating the source of infection; avoiding adverse reactions of treatment; and providing cost-effective therapy.
Appropriate empiric anti-infective therapy administered within 1 hour of the recognition of sepsis decreases complications and 28-day mortality.
Drotrecogin alfa may be utilized for patients at a high risk of mortality (as defined by Acute Physiology, Age, and Chronic Health Evaluation II [APACHE II] scores).
Sepsis is a continuum of physiologic stages characterized by infection, systemic inflammation, and hypoper-fusion with widespread tissue injury.1 The American College of Chest Physicians and the Society of Critical Care Medicine developed definitions to utilize for sepsis (Table 82–1).2 Physiologic parameters categorize patients as having: bacteremia, infection, systemic inflammatory response syndrome (SIRS), sepsis, severe sepsis, septic shock, or multiple-organ dysfunction syndrome (MODS).2 Standardized definitions have been developed for infections in critically ill patients.3
EPIDEMIOLOGY AND ETIOLOGY
Sepsis is the leading cause of morbidity and mortality for critically ill patients, and the tenth leading cause of death overall.1,4 Sepsis causes 660,000 to 750,000 cases annually, a fourfold increase from 1979.1,4,5 Care of septic patients costs $17 billion in the United States annually ($22,000–$50,000 per patient).4,6
Table 82–1 Definitions Related to Sepsis
Bacteremia (fungemia): Presence of viable bacteria or fungi in the bloodstream
Infection: Inflammatory response to invasion of normally sterile host tissue by microorganisms
SIRS: A systemic inflammatory response to a variety of clinical insults which can be infectious, but can have a noninfectious etiology. The response is manifested by two or more of the following conditions: temperature greater than 38°C (100.4°F) or less than 36°C (96.8°); pulse greater than 90 bpm; respiratory rate greater than 20 breaths/min or PaCO2 less than 32 torr; WBC count greater than 12 × 103/mm3 (12 × 109/L), less than 4 × 103/mm3 (4 × 109/L), or greater than 10% immature (band) forms
Sepsis: The SIRS and documented infection (culture or Gram stain of blood, sputum, urine, or normally sterile body fluid positive for pathogenic microorganisms
Severe sepsis: Sepsis associated with organ dysfunction, hypoperfusion, or hypotension (systolic blood pressure less than 90 mm Hg). Hypoperfusion and perfusion abnormalities may include, but are not limited to, lactic acidosis, oliguria, or acute alteration in mental status
Septic shock: Sepsis with hypotension, despite fluid resuscitation, along with the presence of perfusion abnormalities. Patients who are on inotropic or vasopressor agents may not be hypotensive at the time perfusion abnormalities are measured
MODS: Presence of altered organ function requiring intervention to maintain homeostasis
MODS, multiple-organ dysfunction syndrome; PaCO2, partial pressure of carbon dioxide; SIRS, systemic inflammatory response syndrome.
From Ref. 2.
Risk factors for sepsis include: age, cancer, immunodeficiency, chronic organ failure, genetic factors (male, and nonwhite ethnic origin in North America), bacteremic patients, and polymorphisms in genes that regulate immunity.4,7–10 Pulmonary, GI, genitourinary, and bloodstream infections account for the majority of sepsis cases.4,7,8
Gram-positive and gram-negative bacteria, fungal species, and viruses cause sepsis (Table 82–2). Gram-positive infections account for 30% to 50% of sepsis and septic shock cases.4,7,8 The percentages of gram-negative, polymicrobial, and viral sepsis cases are 25%, 25%, and 4%, respectively.4,7,8,11 Multidrug resistant (MDR) bacteria are responsible for approximately 25% of sepsis cases, are difficult to treat, and increase mortality.7,8 The rate of fungal infections increased 200% from 1979 to 2000.4 Candida albicans is the most common fungal species; however, nonalbicans species (C. glabrata, C. krusei, and C. tropicalis) have increased from 24% to 46%.4,11,12 Other fungi identified as causes of sepsis include Cryptococcus, Coccidioides, Fusarium, and Aspergillus.
Table 82–2 Pathogens in Sepsis
PATHOPHYSIOLOGY
The development of sepsis is complex and multifactorial. The normal host response to infection is designed to localize and control bacterial invasion and initiate repair of injured tissue through phagocytic cells and inflammatory mediators.1 Sepsis results when the inflammatory response becomes exaggerated and extends to normal tissue distant from the initial tissue site.
Pro- and Anti-inflammatory Mediators
The key factor in the development of sepsis is inflammation, which is intended to be a local and contained response to infection or injury. Infection or injury is controlled through pro- and anti-inflammatory mediators. Proinflammatory mediators facilitate clearance of the injuring stimulus, promote resolution of injury, and are involved in processing of damaged tissue.1,13–16 In order to control the intensity and duration of the inflammatory response, anti-inflammatory mediators are released that act to regulate proinflammatory mediators.15–16 The balance between pro- and anti-inflammatory mediators localizes infection/injury of host tissue.13–16 However, systemic responses ensue when equilibrium in the inflammatory process is lost.
The inflammatory process in sepsis is linked to the coagulation system. Proinflammatory mediators may be procoagulant and antifibrinolytic, whereas anti-inflammatory mediators may be fibrinolytic. A key factor in the inflammation of sepsis is activated protein C, which enhances fibrinolysis and inhibits inflammation. Protein C levels are decreased in septic patients.
CLINICAL PRESENTATION AND DIAGNOSIS
The clinical presentation of sepsis varies and the rate of development of clinical manifestations may differ from patient to patient. Immunosuppressed patients, those with meningococcemia or Pseudomonas aeruginosa infections may progress to late sepsis more rapidly.
A physical examination should be performed rapidly and efficiently, with efforts directed toward uncovering the most likely cause of sepsis. The patient may not provide any medical history; therefore historical data may be obtained from medical records and/or family. The patient’s medical condition, recent illnesses, infections, or activities may provide valuable information about the cause of sepsis.
Diagnostic and Laboratory Tests
Microbiologic cultures should be obtained before anti-infective therapy is initiated. However, cultures take 6 to 48 hours for results to be returned and may be negative (no growth of bacterial organisms). Negative cultures do not rule out infection. Administering anti-infectives prior to obtaining cultures may lead to a false negative culture.
Two sets of blood cultures should be obtained to rule out contamination. At least one set should be drawn percutaneously and one drawn through each vascular access device, unless the device was recently (less than 48 hours) inserted.
Physical Examination Results in Sepsis
HEENT: Scleral icterus, dry mucous membranes, pinpoint pupils, dilated and fixed pupils, nystagmus
Neck: Jugular venous distention, carotid bruits
Lungs: Crackles (rales), consolidation, egophony, absent breath sounds
CV: Irregular rhythm, S3 gallop, murmurs
Abd: Tense, distended, tender, rebound, guarding, hepatosplenomegaly
Rectal: Decreased tone, bright red blood
Exts: Swollen calf, disparity of blood pressure between upper extremities
Neurologic: Agitation, confusion, delirium, obtundation, coma
Skin: Cold, clammy, or warm; hyperemic skin; rashes
Clinical Presentation and Diagnosis of Sepsis
The signs and symptoms of septic patients are referred to as early and late sepsis.
Signs and Symptoms
The initial clinical signs and symptoms represent early sepsis, and they include: fever, chills, and change in mental status. Other signs and symptoms include:
• Tachycardia
• Tachypnea
• Nausea and vomiting
• Hyperglycemia
• Myalgias
• Lethargy and malaise
• Proteinuria
• Leukocytosis
• Hypoxia
• Hyperbilirubinemia
Septic patients may have an elevated, low, or normal temperature. The absence of fever is common in neonates and elderly patients. Hypothermia is associated with a poor prognosis. Hyperventilation may occur before fever and chills and may lead to respiratory alkalosis. Disorientation and confusion may develop early in septic patients, particularly in the elderly and patients with pre-existing neurologic impairment. Disorientation and confusion may be related to the infection or due to sepsis signs and symptoms (e.g., hypoxia).
Late sepsis represents a slow process that develops over several hours of hemodynamic instability. Signs and symptoms of late sepsis include:
• Lactic acidosis
• Oliguria
• Leukopenia
• Thrombocytopenia
• Myocardial depression
• Pulmonary edema
• Hypotension
• Hypoglycemia
• GI hemorrhage
Oliguria often follows hypotension because of decreased perfusion. Metabolic acidosis ensues because of diminished clearance by the kidneys and liver of lactic acid.
Patient Encounter, Part 1
A 67-year-old man with a history of chronic obstructive pulmonary disease presents to the emergency department with high fevers, shaking chills, severe chest pain, and shortness of breath. His family members state that he has been confused all day. He started having a severe cough 2 days ago, with excessive sputum production. He received doxycycline 100 mg twice daily for an upper respiratory tract infection 7 days ago.
What information is suggestive of infection and/or sepsis?
Does this patient have factors that could lead to the development of sepsis?
What information do we need in order to confirm or diagnose sepsis in this patient?
Cultures to obtain if clinical situation suggests infection of specific fluids, tissues, or organs include:
• Urine culture and urinalysis, respiratory secretions, cerebrospinal fluid, wounds
• Laboratory tests to evaluate infection or complications of sepsis include: CBC with differential; coagulation parameters; basic metabolic panel; serum lactate concentration; arterial blood gas.
The use of biomarkers of sepsis have been controversial. Measurement of endotoxin, procalcitonin, or other markers in blood or serum is not routinely recommended. Concentrations of procalcitonin in serum are usually increased in sepsis, but fail to differentiate between infection and inflammation. However, procalcitonin has a high negative predictive value and could allow for the discontinuation of antibiotics.
Complications of Sepsis
Recognition and treatment of sepsis complications, particularly organ failure is essential to improve outcomes. The cumulative burden of sepsis complications is the leading factor of mortality. The risk of death increases 20% with failure of each additional organ. Severe sepsis averages two failed organs, with a mortality rate of 40%. The most common complications are: disseminated intravascular coagulation, acute respiratory distress syndrome (ARDS), acute renal failure (ARF), and hemodynamic compromise.
Disseminated Intravascular Coagulation
Disseminated intravascular coagulation (DIC) complicates 25% to 50% of septic patients, and is an independent predictor of mortality.17 DIC is a syndrome characterized by coagulation and activation and production of proinflammatory cytokines, culminating in intravascular fibrin formation and deposition in the microvasculature. Bleeding results from consumption and exhaustion of coagulation proteins and platelets, because of continued activation of the coagulation system.17 DIC may produce ARF, hemorrhagic necrosis of the GI mucosa, liver failure, acute pancreatitis, ARDS, and pulmonary failure.17
Acute Respiratory Distress Syndrome
ARDS is an acute and persistent lung inflammatory process with increased vascular permeability leading to severe hypoxia that can affect 20% of septic shock patients.18,19 Lung deterioration is a multiphase process that begins after infection, injury, or exacerbation of the medical condition. The patient appears stable; however, the chest radiograph reveals parenchymal infiltrates. At this time the patient has pulmonary edema and may be hyperventilating.18,19During the next phase the patient develops respiratory insufficiency and pulmonary edema can be seen on chest radiographs. Severe hypoxia may ensue, leading to mechanical ventilation.
Acute Renal Failure
ARF occurs in 19% of septic patients, 25% of severe septic patients, and 51% of septic shock patients.20 Sepsis and ARF together have a 70% mortality, compared to 45% among patients with ARF alone.20ARF leads to fluid in the extravascular space, including the lungs, followed by impairment in gas exchange and severe hypoxemia. The hypoxemia will exacerbate ischemia and organ damage. Renal replacement therapy with the use of continuous venovenous hemofiltration and intermittent hemodialysis can be used to facilitate volume and electrolytes.20
Hemodynamic Compromise
Arterial vasodilatation is the hallmark of hemodynamic effects related to sepsis. High cardiac output and low systemic vascular resistance characterize arterial vasodilation. Inflammatory cytokines (i.e., tumor necrosis factor-α [TNF-α]) and endotoxin directly depress cardiovascular function. Persistent hypotension offsets the delivery of oxygen to tissues (DO2) and oxygen consumption by tissues (VO2).21 Certain tissues may receive adequate oxygen during sepsis; however, in other tissues oxygen demands may not be met because of decreased perfusion. This perfusion defect is accentuated by increased precapillary atrioventricular shunt. If perfusion decreases, oxygen extraction increases, and the atrioventricular oxygen gradient widens. Cellular DO2 is decreased, but VO2 remains unchanged. If perfusion decreases significantly, reserve DO2 will be exceeded, and tissue ischemia results. Tissue ischemia leads to organ failure. Therefore, increasing oxygen delivery or decreasing oxygen consumption in a hypermetabolic patient should optimize systemic DO2 relative to VO2.21
TREATMENT AND OUTCOME EVALUATION
Desired Outcomes
The primary treatment goal of sepsis is to prevent morbidity and mortality. Treatment is aimed at early goal-directed resuscitation; reducing or eliminating organ failures; treating and eliminating the source of infection; avoiding adverse reactions of treatment; and providing cost-effective therapy.22-28
General Approach to Treatment
The speed and appropriateness of therapy administered in the initial hours after sepsis develops influences outcome, as is the case for acute myocardial infarction and cerebrovascular accidents.22
Pertinent issues in the management of septic patients are (Fig. 82–1):24
1. Early goal-directed resuscitation of septic patients during the first 6 hours after recognition.
2. Early administration of broad-spectrum anti-infective therapy.
3. Activated protein C in patients with severe sepsis and high risk of death (Acute Physiology, Age, and Chronic Health Evaluation II [APACHE II] score greater than 25).
4. Hydrocortisone for septic shock patients refractory to resuscitation and vasopressors.
FIGURE 82–1. Therapeutic approach to sepsis. (C&S, culture and sensitivity.)
5. Glycemic control via infusion of insulin and glucose, to maintain a glucose level less than 150 mg/dL (8.3 mmol/L).
6. Adjunctive therapies: nutrition, deep vein thrombosis (DVT) prophylaxis, stress ulcer prophylaxis, and sedation for mechanically ventilated patients.
Pharmacologic Therapy
Treatment for sepsis focuses on infection, inflammation, hypo-perfusion, and widespread tissue injury. Septic patients may require multiple simultaneous treatment regimens to achieve desired outcomes of decreased morbidity and mortality.
Initial Resuscitation
Early goal-directed resuscitation decreases 28-day mortality in septic patients. The treatment goals of sepsis-induced hypoperfusion (hypotension or lactic acidosis) during the first 6 hours include24,27–29:
• Central venous pressure: 8 to 12 mm Hg (12–15 mm Hg for intubated patients)
Patient Encounter, Part 2: Medical History, Physical Exam, and Diagnostic Tests
PMH: Chronic obstructive pulmonary disease; hypertension; diabetes mellitus; chronic renal insufficiency (baseline serum creatinine 1.6 mg/dL [141 μmol/L])
FH: Father had stroke at age 59; mother has history of hypertension and diabetes mellitus
SH: Construction worker; smoker with a 35 pack-year history Allergies: NKDA
Meds: No know drug allegies; albuterol/ipratropium inhaler two puffs every 6 hours; glipizide 10 mg once daily; hydrochlorothiazide 25 mg once daily; lisinopril 20 mg once daily
ROS: Unable to obtain; patient has become more confused
PE:
VS: BP 87/53 mm Hg, P 97 bpm, RR 34/min, T 39.3°C (102.7oF)
Lungs: Decreased breath sounds
Labs: Serum creatinine 2.7 mg/dL (239 μmol/L); glucose 298 mg/dL (16.5 mmol/L); white blood cells: leukocytosis with left shift. APACHE II score 27
Cultures: Blood, urine, and respiratory cultures pending.
Radiology: Chest x-ray shows infiltrates in left lower lobe
According to the patient’s parameters what does he have (i.e., systemic inflammatory response syndrome, sepsis, or septic shock)?
Identify treatment goals (nonpharmacologic and pharmacologic).
• Mean arterial pressure greater than or equal to 65 mm Hg
• Urine output greater than or equal to 0.5 mL/kg/h
• Central venous or mixed venous oxygen saturation greater than or equal to 70% or 65%, respectively.
Crystalloid (such as 0.9% sodium chloride or lactated Ringer’s solutions) or colloid fluids (5% albumin or 6% hetastarch) are used for resuscitation and clinical studies comparing the fluids found them to be equivalent.29Crystalloids require more fluids, which may lead to more edema (utilize caution in patients at risk for fluid overload, e.g., congestive heart failure and ARDS); however, colloids are significantly more expensive. Most patients require aggressive fluid resuscitation during the first 24 hours because of persistent venodilation and capillary leak.24
Monitoring Parameters and Alternative Treatment for Resuscitation24,27–29
• An elevated serum lactate concentration may be an early marker for tissue hypoperfusion.
• Administer a fluid challenge to hypovolemic patients (hypotension or lactic acidosis): crystalloids 500 to 1,000 mL; colloids 300 to 500 mL. Administer over 30 minutes and repeat based on response (increase in blood pressure and urine output).
• Patients may require maintenance fluid therapy.
Anti-infective Therapy
Appropriate empiric anti-infective therapy decreases 28-day mortality compared to inappropriate empiric therapy (24% versus 39%).22,23,30 Additionally, appropriate therapy administered within 1 hour of sepsis recognition also decreases complications and mortality.22,23,30 Empiric anti-infective therapy should include one, two, or three drugs, depending on the site of infection and causative pathogens (Table 82–3). Anti-infective clinical trials in sepsis and septic shock patients are scarce and have not demonstrated differences among agents; therefore, factors that determine selection are:
• Site of infection
• Causative pathogens
• Community- or nosocomial-acquired infection
• Immune status of patient
• Antibiotic susceptibility and resistance profile for the institution. Clinicians should be cognizant of growing prevalence of bacterial resistance in community and health care setting.
• Patient history (underlying disease, previous cultures or infections, and drug intolerance)
• Adverse reactions
• Cost
Anti-infective regimens should be broad-spectrum since there is little margin for error in critically ill patients.
Table 82–3 Empirical IV Antimicrobial Regimens in Sepsis
Monitoring and Treatment Strategies to Maximize Efficacy and Minimize Toxicity for Anti-infectives
• Administer broad-spectrum anti-infectives for initial therapy, as early as possible and within first hour of recognition of sepsis.
• Appropriate cultures should be obtained before initiating antibiotic therapy, but should not prevent prompt administration of treatment.
• Administer antibiotics that concentrate at the site of infection.
• Monitor patient parameters to ensure adequate dosing.
• Abnormal renal and hepatic function will increase drug concentration and predispose the patient to toxicity.
• Septic patients may have altered volume of distribution due to initial resuscitation.
• Reevaluate the initial regimen daily to optimize activity, prevent development of resistance, reduce toxicity, and decrease costs.
• Initiate step-down therapy based on microbiologic cultures to: prevent resistance, reduce toxicity, and cost.
• Monotherapy is equivalent to combination therapy once a causative pathogen has been identified. Empiric therapy should include combination regimens to ensure coverage of causative organisms.
Clinical Parameters for Aminoglycosides
Tobramycin is more active against Pseudomonas aeruginosa than gentamicin, whereas gentamicin is more active against Serratia species. Amikacin is the most potent aminoglycoside against the Enterobacteriaceae; however, it should be reserved for bacterial organisms resistant to gentamicin and tobramycin. Select an aminoglycoside based on:
• Local susceptibility patterns
• Patient parameters (infection and microbiologic culture history)
• Cost
Aminoglycosides may be administered by traditional methods (1.5-2 mg/kg every 8 hours) or by an extended dosing interval method (4-7 mg/kg every 24 hours). The extended dosing method maximizes the pharmacodynamic properties of aminoglycosides (concentration-dependent killing and postantibiotic effect) and reduces the incidence of nephrotoxicity. Extended dosing interval aminoglycosides have prolonged drug-free periods, during which the saturable uptake of aminoglycosides into the proximal renal tubular cells can be completed. Extended dosing interval aminoglycosides should not be used in pediatric patients, burn victims, pregnant patients, patients with pre-existing or progressive renal insufficiency, or for synergy with gram-positive organisms.38
Selection of Antimicrobial Agents
Urinary Tract Infections
Septic patients with a community-acquired urinary tract infection should be treated with a third-generation cephalosporin (ceftriaxone or cefotaxime) or a fluoro-quinolone (ciprofloxacin or levofloxacin). The causative pathogen is commonly an enteric gram-negative bacilli (i.e., Escherichia coli). Nosocomially-acquired urinary tract infections are often related to catheters and are caused by fermenting and nonfermenting (Pseudomonas) gramnegatives, and enterococci (see Table 82–3). β-Lactam/β-lactamase inhibitors (i.e., piperacillin-tazobactam), an antipseudomonal cephalosporin (i.e., cefepime or ceftazidime), or an antipseudomonal carbapenem (imipenem, meropenem, or doripenem), plus an aminoglycoside are recommended treatment options until susceptibilities are known (see Table 82–3).31
Community-Acquired Pneumonia
Septic patients with community-acquired pneumonia (CAP) are treated with a third-generation cephalosporin (ceftriaxone or cefotaxime) plus a macrolide (azithromycin or clarithromycin) or doxycycline, or a respiratory fluoroquinolone (levofloxacin, moxifloxacin, gemifloxacin) (see Table 82–3).32 The causative organisms for CAP are Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, and atypical organisms (Mycoplasma pneumoniae, Chlamydia pneumoniae, and Legionella pneumophila). S. pneumoniae accounts for 60% of the deaths associated with CAP, and is resistant to penicillin and macrolides (multidrug resistant S. pneumoniae; MDRSP) 30% to 40% of the time.32,33 Controversy exists relating to the clinical significance of this resistance for nonmeningitis infections. Respiratory fluoroquinolones (levofloxacin, moxifloxacin, and gemifloxacin) may be utilized for MDRSP; however, clinical data have not shown them to be superior to cephalosporins plus a macrolide or doxycycline. The Centers for Disease Control and Prevention recommends reserving fluoroquinolones as last-line options in order to maintain their broad-spectrum antibacterial activity.33 Treatment of methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa is a potential reason to modify the standard empirical regimen for CAP. Risk factors for the development of these pathogens are listed in Table 82–4.
Hospital-, Ventilator-, and Health Care–Associated Pneumonia
Treatment for septic patients with hospital-acquired, ventilator-acquired, and health care–associated pneumonia is dependent on risk factors for MDR organisms (Fig. 82–2). Recommended treatment for patients with no MDR risk factors are: third-generation cephalosporins (ceftriaxone or cefotaxime), fluoroquinolones (levofloxacin and moxifloxacin), ampicillin-sulbactam, or ertapenem (see Table 82–3).34Recommended treatment for patients with MDR risk factors are: β-lactam/β-lactamase inhibitors (piperacillin/tazobactam), antipseudomonal cephalosporin (cefepime or ceftazidime), or an antipseudomonal carbapenem (imipenem, meropenem, or doripenem), plus an aminoglycoside, plus vancomycin or linezolid (see Table 82–3).34 If an aminoglycoside is undesirable, a antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin) may be utilized with a antipseudomonal β-lactam (piperacillin/tazobactam, cefepime, ceftazidime, imipenem, meropenem, or doripenem).
Table 82–4 Risk Factors for MRS A, Pseudomonas, and Gram-Negatives in CAP
Methicillin-Resistant Staphylococcus aureus
End stage renal disease
Injection drug abuse
Prior influenza
Prior antibiotic therapy (especially fluoroquinolones)
Pseudomonas aeruginosa
Structural lung disease
Exacerbations of severe chronic obstructive pulmonary diseases leading to frequent steroid and/or antibiotic use, as well as prior antibiotic therapy
Other Gram-negatives (Klebsiella pneumoniae or Acinetobacter species)
Chronic alcoholism
From Ref. 33.
Skin and Soft-Tissue Infections
Community-acquired skin and soft-tissue infections are caused by Streptococcus pyogenes and S. aureus. Treatment with nafcillin or cefazolin is recommended (see Table 82–3).35 Soft-tissue infections caused by S. pyogenes can lead to streptococcal toxic shock syndrome. Although penicillins and cephalosporins are efficacious, experimental models show clindamycin to be more effective than penicillin.31Hospital-acquired skin and soft-tissue infections are caused by S. pyogenes, S. aureus, and enteric gram-negatives. Recommended treatment is a third-generation cephalosporin (cefotaxime or ceftriaxone), ampicillin-sulbactam, or ertapenem, plus vancomycin (see Table 82–3).35
Intra-abdominal Infections
Intra-abdominal infections are polymicrobial, including enteric aerobes and anaerobes. Patients with community-acquired intra-abdominal infections of mild to moderate severity should be administered antibiotics with activity against enteric gram-negative bacilli, gram-negative anaerobes, and gram-positive cocci. Recommended treatment for mild to moderate community-acquired intra-abdominal infections are: ampici-llin/sulbactam; cephalosporins (ceftriaxone or cefotaxime) plus metronidazole; fluoroquinolones (levofloxacin, ciprofloxacin, or moxifloxacin) plus metronidazole; and ertapenem (see Table 82–3).36 Patients with nosocomial-acquired, high-severity intra-abdominal infections or immunosuppression should receive empiric treatment with broad-spectrum antibiotics. Broad-spectrum antibiotics such as antipseudomonal β-lactam/β-lactamase in hibitors (piperacillin/tazobactam), carbapenems (imipenem, meropenem, or doripenem), antipseudomonal cephalosporins (cefepime or ceftazidime) plus metronidazole, or antipseudomonal fluoroquinolones (ciprofloxacin or levofloxacin) plus metronidazole are recommended (see Table 82–3).36
FIGURE 82–2. Risk factors for multidrug resistant pathogens and causative pathogens for hospital, ventilator, and health care-associated pneumonia.34 (ESBL, extended spectrum β-lactamase; MDR, multidrug resistant; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-sensitive Staphylococcus aureus)
Clinical Dilemma About MRSA
MRSA is a common hospital-acquired pathogen and is also increasing in the community. MRSA has presented a problem in the past because it required treatment with vancomycin. Community-acquired MRSA presents a major therapeutic challenge. MRSA can cause pneumonia, cellulitis, and other infections. Clinicians should be aware of the rate of hospital and community MRSA in your geographic area. New treatment options are available for MRSA. They include linezolid, tigecycline, and daptomycin. Prospective clinical trials have not demonstrated benefits of these agents over vancomycin.39,40
Patient Encounter, Part 3
Treatment and Outcome Evaluation
The patient has continued hypotension despite previous intervention. Continued hypoxia has led to mechanical ventilation. The patient’s serum creatinine has risen to 6.8 mg/dL (601 μmol/L). Blood cultures reveal gram-positive cocci and lactose-negative oxidase-positive gram-negative rods.
Design a therapeutic regimen for this patient. Include all necessary medications.
Antifungal Therapy
Septic patients not responding to conventional antibiotics should be evaluated for fungal infections. Candida albicans is the most common fungal species; however, the prevalence of nonalbicans species is increasing. Amphotericin B is utilized in septic patients with fungal or suspected fungal infections because of greater activity against nonalbicans Candida compared to fluconazole.37 However, amphotericin B has a significantly higher rate of adverse reactions. Lipid formulations of amphotericin B (amphotericin B cholesteryl sulfate complex, lipid complex, and liposomal amphotericin B) are available that are less nephrotoxic and have decreased infusion-associated side effects. Efficacy among the amphotericin products is equivalent, but the lipid formulations are significantly more expensive. Lipid products are recommended for patients intolerant of conventional amphotericin. Other alternatives for treatment of fungal infections include voriconazole and echinocandins (anidulafungin, caspofungin, micafungin). Data are lacking that demonstrate clinical superiority between agents.
Duration of Therapy
Average duration of anti-infective therapy for septic patients is 7 to 10 days. However, the durations vary depending on the site of infection and response to therapy. Step-down therapy from IV to oral anti-infectives is recommended for:
• Hemodynamically stable patients
• Patients afebrile for 48 to 72 hours
• Patients with normalized WBC
• Patients able to take oral medications
Vasopressors and Inotropic Therapy
When fluid resuscitation does not provide adequate arterial pressure and organ perfusion, vasopressors and/or inotropic agents should be initiated. Vasopressors are recommended in patients with a systolic blood pressure less than 90 mm Hg or mean arterial pressure (MAP) lower than 60 to 65 mm Hg, after failed treatment with crystalloids.24,27,28 Vasopressors and inotropes are effective in treating life-threatening hypotension and improving cardiac index, but complications such as tachycardia and myocardial ischemia require slow titration of the adrenergic agents to restore MAP without impairing stroke volume. Vasopressor therapy may also be required transiently to sustain life and maintain perfusion in the face of life-threatening hypotension, even when fluid resuscitation is in progress and hypovolemia has not yet been corrected. Agents commonly considered for vasopressor or inotropic support include dopamine, dobutamine, norepinephrine, phenylephrine, and epinephrine. Norepinephrine or dopamine are first-line vasopressors to correct hypotension in septic shock.24,27,28
Clinical Controversy
Enterococcus species are normal inhabitants of the GI tract, but should empiric treatment of intra-abdominal infections have activity against Enterococcus species? Empiric treatment that covered Enterococcus species in intra-abdominal infections was equivalent to empiric treatment that lacked enterococcal coverage. Routine coverage for Enterococcus is not necessary for patients with community-acquired intra-abdominal infections. However, in patients with nosocomial or high-severity infections, enterococcal coverage may be warranted.36
Norepinephrine is a potent α-adrenergic agent with less pronounced β-adrenergic activity. Doses of 0.01 to 3 mcg/kg/min can reliably increase blood pressure with small changes in heart rate or cardiac index. Norepinephrine is a more potent agent than dopamine in refractory septic shock.24,27,28
Dopamine is a α- and β-adrenergic agent with dopa-minergic activity. Low doses of dopamine (1-5 mcg/kg/min) maintain renal perfusion, higher doses (greater than 5 mcg/kg/min) exhibit and β-adrenergic activity and are frequently utilized to support blood pressure and to improve cardiac function. Low doses of dopamine should not be used for renal protection as part of the treatment of severe sepsis.24,27,28
Dobutamine is a β-adrenergic inotropic agent that can be utilized for improvement of cardiac output and oxygen delivery. Doses of 2 to 20 mcg/kg/min increase cardiac index; however, heart rate increases significantly. Dobutamine should be considered in septic patients with adequate filling pressure and blood pressure, but low cardiac index. If used in hypotensive patients, dobutamine should be combined with vasopressor therapy.24,27,28
Phenylephrine is a fast-acting, short-duration α1 agonist. Phenylephrine has primarily vascular effects, and does not impair cardiac or renal function. Phenylephrine is useful when tachycardia limits the use of other vasopressors.24,27-28
Epinephrine is a nonspecific α and β-adrenergic agonist. Epinephrine can increase cardiac index and produce significant peripheral vasoconstriction. However, it can also increase lactate levels and impair blood flow to the splanchnic system. Because of these undesirable effects, epinephrine should be reserved for patients who fail to respond to traditional therapies.24,27,28
Vasopressin levels are increased during hypotension to maintain blood pressure by vasoconstriction. However, there is a vasopressin deficiency in septic shock. Low doses of vasopressin increase MAP, leading to the discontinuation of vasopressors. However, routine use of vasopressin is not recommended because of lack of evidence of efficacy. Vasopressin is a direct vasoconstrictor without inotropic or chronotropic effects and may result in decreased cardiac output and hepatosplanchnic flow. Vasopressin use may be considered in patients with refractory shock despite adequate fluid resuscitation and high-dose vasopressors.24,27,28
Recombinant Human Activated Protein C
Recombinant human activated protein C (drotrecogin alfa) is recommended for patients at a high risk of death (APACHE II score greater than or equal to 25, multiple-organ failure, septic shock, or ARDS) and no absolute contraindications related to bleeding.41 Drotrecogin alfa has antithrombotic, anti-inflammatory, and profibrinolytic properties. The Recombinant Human Activated Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) trial evaluated the effects of a 96-hour continuous infusion of drotrecogin alfa. Drotrecogin alfa decreased 28-day mortality compared to placebo (30.8% versus 24.7%). A higher incidence of serious bleeding occurred during the 28-day period in the drotrecogin alfa group (3.5%) than in the placebo group (2.0%). An analysis of secondary endpoints suggested that the incidence of multiple-organ dysfunction was lower in patients treated with drotrecogin alfa, and that therapy was associated with more rapid recovery of cardiac and pulmonary function. A second study of patients with severe sepsis, Extended Evaluation of Recombinant Human Activated Protein C (ENHANCE) trial noted that 28-day all cause mortality for patients treated with drotrecogin alfa was similar to that observed in PROWESS. ENHANCE also found that patients treated within the first 24 hours of their first sepsis-induced organ dysfunction had significantly lower mortality than those treated after 24 hours (22.9-27.4%). Cost-effectiveness models have found that for septic patients with a APACHE II score greater than or equal to 25, the cost per year of life saved with drotrecogin alfa is $24,000 to $27,000, suggesting that this is a cost-effective therapy in patients with severe sepsis and septic shock. The effect of drotrecogin alfa on long-term survival was evaluated in a retrospective analysis of patients in PROWESS. The mortality benefit of drotrecogin alfa persisted up to hospital discharge; however, there were no mortality differences between drotrecogin alfa and placebo thereafter.42
Drotrecogin alfa is not recommended for severe sepsis patients at low risk for death. The Administration of Drotrecogin Alpha in Early Stage Severe Sepsis (ADDRESS) trial evaluated the effects of a 96-hour continuous infusion of drotrecogin alfa. There were no statistically significant differences between drotrecogin alfa and placebo in 28-day mortality (18.5% versus 17.0%).43 The rate of serious bleeding was higher for drotrecogin alfa during the 96-hour infusion and the 28-day study period.
Steroids
Stress-induced adrenal insufficiency complicates 9% to 24% of septic patients and is associated with increased mortality. Septic shock patients refractory to resuscitation and vasopressors should be administered IV hydrocortisone 200 to 300 mg/day in three divided doses.24,44 Patients should be weaned from steroid therapy when vasopressors are no longer required.
Patient Encounter, Part 4
During medical rounds, you are asked to discuss clinical trials.
What antibiotics are found to be superior in septic patients?
What are the results of the PROWESS and ADDRESS trials?
Is this patient a candidate for drotrecogin alfa?
Sedation and Neuromuscular Blockade
Patients with ARDS and progressive hypoxia require mechanical ventilation. Critically ill patients may require sedation when high ventilator settings are used or when patients fight the ventilator. Mechanically ventilated patients should receive sedation by a protocol that includes a daily interruption or lightening of a sedative infusion until the patient is awake.24 The utilization of sedation protocols decreases the duration of mechanical ventilation, length of hospitalization, and tracheostomy rates.
Paralysis usually is reserved for patients in whom sedation alone does not improve the effectiveness of mechanical ventilation. Neuromuscular blockers may lead to prolonged skeletal muscle weakness and should be avoided if possible. Patients requiring neuromuscular blockade should be monitored and intermittent boluses or continuous infusion should be utilized. Monitor depth of neuromuscular blockade with train-of-four stimulation when using continuous infusion.
Glucose Control
Glycemic control improves survival in postoperative surgical patients and is recommended in septic patients. Following initial stabilization of septic patients, maintain blood glucose concentrations less than 150 mg/dL (8.3 mmol/L).24,45 Septic patients with high glucose concentrations should receive insulin and glucose with frequent blood glucose monitoring (every 1 to 2 hours until glucose values and insulin infusion rates are stable, then every 4 hours).
Adjunctive Therapies
Enteral nutrition is recommended in septic patients to meet the increased energy and protein requirements. Protein requirements are increased to 1.5 to 2.5 g/kg/day. Nonprotein caloric requirements range from 25 to 40 kcal/kg/day (105–168 kJ/kg/day).24
DVT prophylaxis is recommended for septic patients. Low-dose unfractionated heparin or low-molecular-weight heparin (such as enoxaparin or dalteparin) may be utilized. Graduated compression stockings or an intermittent compression device is recommended for patients with a contraindication to heparin products (thrombocytopenia, severe coagulopathy, active bleeding, or recent intracerebral hemorrhage).24Patients with severe sepsis and history of DVT, trauma, or orthopedic surgery should receive a combination of pharmacologic and mechanical therapy unless contraindicated or not practical.
Stress ulcer prophylaxis is recommended in septic patients. Patients at greatest risk for stress ulcers are: coagulopathic, mechanically ventilated, and hypotensive. Histamine-receptor antagonists (such as ranitidine) are more efficacious than sucralfate, and proton pump inhibitors (such as omeprazole) have not been compared to histamine-receptor antagonists. However, they do demonstrate equivalence in the ability to increase gastric pH.24 The benefit of prophylaxis must be weighed against the potential effect of an increased stomach pH and development of hospital-acquired pneumonia.
Nonpharmacologic Therapy
Evaluate septic patients for the presence of a localized infection amenable to source control measures. Common source control measures include drainage and debridement, device removal, and prevention.24–26 Implementation of source control methods should be instituted as soon as possible following initial fluid resuscitation. The selection of optimal source control methods must weigh benefits and risks of the intervention. Source control measures may cause complications (bleeding, fistulas, and organ injury), therefore the method with the least risk should be employed.24
Prognosis
There are various factors that influence outcome. Gramnegative bacteria are more likely to produce septic shock than gram-positive bacteria (50% versus 25%) and have a higher mortality than other pathogens. This may be related to the severity of the underlying condition. Patients with rapidly fatal conditions, such as leukemia, aplastic anemia, and burn patients have a worse prognosis than patients with nonfatal underlying conditions, such as diabetesme llitus or chronicrenal insufficiency. Other factors that worsen the prognosis of septic patients are: advanced age, malnutrition, resistant bacteria, utilization of medical devices, and immunosuppression. Data for long-term mortality are lacking (it is estimated that the mortality for sepsis survivors within the first year is 20%).5 Patients may have prolonged physical disability related to muscle weakness and posttraumatic stress.
Patient Care and Monitoring
1. Evaluate patient parameters and classify as infection, SIRS, sepsis, severe sepsis, septic shock, or MODS.
2. Review available diagnostic and laboratory data.
3. Evaluate early goal-directed resuscitation therapy. Understand what parameters define efficacy and failure of initial therapy. Recommend alternative resuscitation therapy if the patient does not respond to initial fluid challenge.
4. Evaluate the source of infection and make recommendations to remove potential source(s).
5. Analyze anti-infective therapy (dose, frequency, and duration) and revise as necessary based on clinical response and culture and sensitivity reports. Prepare an appropriate step-down therapy for the patient.
6. Determine the risk of sepsis complications and construct recommendations for treatment and monitoring.
7. Formulate appropriate doses of medications involved in patient therapy and revise as needed. Patient parameters may change frequently, thus requiring different doses and/or medications. Examples include: antibiotic therapy, sedatives, insulin, fluids, or vasopressors.
8. Continually monitor patient parameters to ensure optimal therapy to maximize outcomes.
Abbreviations Introduced in This Chapter
Self-assessment questions and answers are available at http://www.mhpharmacotherapy.com/pp.html.
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