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Apr.02.2021

Sepsis

Synopsis

Key Points

  • Sepsis is a life-threatening systemic syndrome caused by a microbial infection and dysregulated physiologic response
    • Characterized by cascade effect of sepsis, including endothelial damage, vascular permeability, microvascular dysfunction, and coagulopathies, which, if not treated promptly and adequately, can lead to multiorgan failure and death
  • Presentation varies depending on source of infection, but it often includes fever, tachypnea, tachycardia, hypotension, and signs of tissue hypoperfusion
  • Diagnosis is based on history and clinical presentation, together with laboratory results providing evidence for an inflammatory process and microbial infection. CBC with differential and other cultures are useful in determining the pathogen responsible; imaging may be done as an adjunct to identify the anatomic site of infection
  • Treatment includes immediate stabilization, fluid resuscitation, collection of blood and other relevant cultures, and initiation of antimicrobial treatment, hemodynamic support, and source control; treatment should proceed rapidly (within 1 hourr1), regardless of setting
  • Complications include ventilator-associated pneumonia; end-organ dysfunction; deep vein thrombosis; stress ulcers; and physical, cognitive, and emotional disabilities
  • Prognosis depends on early identification and treatment, response to treatment, and severity at presentation
    • Severe sepsis has a mortality rate of 25% to 30% r2r3
    • Septic shock has a mortality rate of 40% to 70% r2r3

Urgent Action

  • Initial treatment needs to proceed rapidly (within 1 hour), regardless of setting. Focus on immediate stabilization, fluid resuscitation, initiation of antimicrobials, hemodynamic support, and source control r4
  • In septic shock, risk of death increases every hour that appropriate antimicrobial medications are delayed; it is imperative to start treatment upon recognition r2
  • Early lactate measurement is key to recognizing sepsis; delay is associated with increased mortality r5
  • Surviving Sepsis Campaign bundle (2018) recommends doing the following within the first hour when diagnosis is suspected: r1
    • Measure lactate level
    • Take blood culture specimens
    • Administer broad-spectrum antibiotics
    • For patients with hypotension or lactate levels of 4 mmol/L or higher:
      • Administer isotonic crystalloid fluids; goal is 30 mL/kg)
      • If hypotension occurs or persists during or after fluid resuscitation, add vasopressors

Pitfalls

  • Signs and symptoms of sepsis are highly variable, and hypoperfusion may be subtle in healthy adults; maintain a high degree of suspicion because prompt identification and treatment are crucial to recovery r3
  • Presentation of sepsis in elderly people is often different from presentation in younger people, which may delay diagnosis and treatment r6
    • Be aware of subtle signs of sepsis in elderly people, including delirium, urinary incontinence, weakness, malaise, anorexia, and falls
    • Elderly patients are less likely to present with fever, tachycardia, and hypoxemia than younger patients

Terminology

Clinical Clarification

  • Sepsis is a life-threatening syndrome of organ dysfunction caused by microbial infection in conjunction with a dysregulated host response r7
  • Characterized by a cascade of endothelial damage, vascular permeability, microvascular dysfunction, and coagulopathies, which can lead to multiorgan failure and death if not treated promptly and adequately or if not responsive to treatment r8

Classification

  • Sepsis r7
    • Life-threatening organ dysfunction caused by dysregulated host response to infection
    • Organ dysfunction is defined by increase from baseline in SOFA score of 2 or more (Sequential Organ Failure Assessment; originally the Sepsis-Related Organ Failure Assessment) r7r9
  • Septic shock r7
    • Subset of sepsis with profound circulatory and cellular/metabolic dysfunction and with significantly greater mortality risk
    • Defined as need for administration of vasopressor medication to maintain mean arterial pressure of at least 65 mm Hg and serum lactate level more than 2 mmol/L in the absence of hypovolemia r7r9

Diagnosis

Clinical Presentation

History

  • Presentation varies, depending on causative agent and portal of entry r2
  • Low threshold of suspicion and early recognition of sepsis are essential for successful outcomes r2
  • Thorough and timely history focuses on symptoms, comorbidities, recent surgery, recent antibiotic use, presence of medical devices, and travel r2
  • Common generalized symptoms of sepsis include: r2
    • Fever, chills; rigors may be reported c1c2c3
    • Confusion, anxiety c4c5
    • Fatigue, malaise c6c7
    • Myalgia c8
    • Dyspnea c9
    • Nausea and vomiting c10c11
    • Decreased urination c12
  • Localizing symptoms may include: r2
    • Headache and stiff neck when meningitis is the cause of sepsis c13c14
    • Cough and pleuritic chest pain with pneumonia c15c16
    • Abdominal pain with gastrointestinal or genitourinary source c17
    • Diarrhea in gastrointestinal luminal infections, such as Clostridium difficile or toxigenic Escherichia coli infection c18
    • Flank pain and dysuria with kidney infection c19c20
    • Bone or joint pain with osteomyelitis or septic arthritis c21c22
    • Skin or soft tissue pain with abscesses, wounds, or other soft tissue infections c23c24c25
  • Elderly persons may have limited or nonspecific symptoms (eg, poor oral intake, inanition) r2c26c27

Physical examination

  • Physical examination focuses on detecting generalized signs of sepsis and on determining the source; a careful and thorough examination may uncover an unexpected site
  • Generalized evidence of sepsis is highly variable but commonly includes:
    • Fever (more than 38.5 °C) or hypothermia (less than 36 °C) c28
      • Fever is the most common sign of sepsis
    • Hypotension (systolic blood pressure lower than 90 mm Hg and/or mean arterial pressure lower than 70 mm Hg) c29c30
      • Presenting sign in 40% of patients with sepsis r2
    • Tachycardia (heart rate more than 90 beats per minute) c31
    • Tachypnea (respiratory rate more than 20 breaths per minute) c32
    • Rigors may be observed c33
    • Altered mental status; older patients may present with irritability or agitation c34c35c36
    • Increased capillary refill time (more than 3 seconds) c37
    • Mottled skin on inspection; petechiae may be seen with severe thrombocytopenia or meningococcemia c38c39
    • Diaphoresis; clammy skin c40c41
  • Respiratory, gastrointestinal, and genitourinary systems and skin and soft tissue are the most common sites of infection leading to sepsis; signs specific to affected system include:
    • Respiratory
      • Cough; production of purulent or foul-smelling sputum may be observed by clinician or reported by patient c42c43
      • Hemoptysis may be observed by clinician or reported by patient with severe pneumonia, including tuberculosis c44
      • Dullness to percussion may indicate pleural effusion (parapneumonic effusion or empyema) or consolidation c45
      • Rhonchi and/or rales on auscultation c46
      • Egophony on auscultation indicates consolidation c47
    • Gastrointestinal
      • Abdominal distention on inspection c48
      • Decreased bowel sounds on auscultation owing to ileus c49
      • Abdominal pain with guarding on palpation; rigidity and rebound indicate peritonitis c50c51c52
        • Localization of tenderness may indicate source (eg, right upper quadrant for liver or gallbladder infection) c53
    • Genitourinary
      • Costovertebral tenderness and suprapubic pain on palpation c54c55
      • Vaginal discharge or bleeding c56c57
    • Skin and soft tissue
      • Wounds, ulcerations, furuncles, or carbuncles on inspection c58c59c60
        • In currently or recently hospitalized patients, surgical incisions and IV sites c61c62
      • There may be erythema and/or edema on inspection c63c64
      • Drainage may be evident, either spontaneous or expressed c65
      • Crepitus or fluctuancy may be palpable; an indurated tender phlebitic cord may be noted at site of infected peripheral IV line c66c67
      • Lymphadenopathy may be detected proximal to infection c68
    • Other less common findings may include:
      • Meningismus, Kernig sign, or Brudzinski sign in meningitis c69c70c71
      • Point tenderness over a vertebral body may indicate spinal osteomyelitis and/or epidural abscess c72
      • Warm, swollen joint may be a site of septic arthritis c73c74
      • New heart murmur or change in character of a murmur suggesting endocarditis c75

Causes and Risk Factors

Causes

  • Microbial pathogens breach skin and/or mucosal barriers to cause systemic infection c76
    • Wide range of microbial pathogens may be implicated, depending on site of primary infection, community patterns, and host characteristics
      • Most sepsis cases are caused by bacteria; fungi and viruses are less common causes but are significant causes of sepsis in immunocompromised patients c77c78
        • Gram-positive bacteria are responsible for most cases of septic shock in the acute care setting, followed by gram-negative and mixed bacterial infections
      • Candidal species are commonly implicated in neutropenic patients and in infections associated with indwelling catheters (eg, bloodstream, urinary) and other devices c79
      • Influenza virus may cause sepsis directly or may predispose to secondary bacterial infection and sepsis c80
    • Respiratory, gastrointestinal, and genitourinary systems and skin and soft tissue are the primary sites in most infections leading to sepsis (about 80%) r2
      • Common source infections leading to sepsis include:
        • Respiratory tract infections (account for 35% of sepsis cases) r10c81
          • Community-acquired pneumonia d1
            • Streptococcus pneumoniae and Staphylococcus aureus are commonly implicated in sepsis caused by pneumonia c82c83
            • Either may occur de novo or after influenza
          • Hospital-acquired and ventilator-associated pneumonias d2
            • Commonly associated with antibiotic-resistant pathogens c84
        • Genitourinary tract infections (account for 25% of sepsis cases) r10c85d3
          • Usually gram-negative or enterococcal c86c87
            • Pyelonephritis c88
            • Cystitis c89
          • Infections related to indwelling urinary catheters d4
            • Antibiotic-resistant organisms are often implicated in hospital and long-term care settings c90
            • Candidal species are common causes in patients with diabetes and in patients who have received broad-spectrum antibiotics c91
          • Obstruction of infected urine owing to impacted kidney stones or prostatic hypertrophy increases the risk of severe infection c92c93
        • Gastrointestinal tract infections (account for 11% of sepsis cases): often polymicrobial, involving enteric gram-negative bacilli, streptococcal species, and anaerobes r10c94c95c96c97
          • Appendicitis, with or without perforation and abscess c98d5
          • Cholecystitis, cholangitis; biliary obstruction caused by gallstone impaction increases the risk of severe infection c99c100d6
          • Bowel infarction or perforation with peritonitis c101c102c103d7
          • Diverticulitis, with or without diverticular abscess c104c105d8
          • Pancreatitis may cause sepsis due to infection or may cause an inflammatory response that mimics sepsis c106d9
        • Skin and soft tissue infections (account for 11%r10 of sepsis cases) c107c108
          • Cellulitis c109d10
            • Usually caused by Staphylococcus aureus or streptococci c110c111
              • Community-acquired MRSA infection is prevalent in many areas c112
              • Presentation of MRSA is often characterized by deep red or violaceous erythema surrounding a necrotic center, resembling a spider bite
          • Carbuncles c113
            • Usually Staphylococcus aureusc114
          • Wounds (traumatic or surgical) c115c116
            • Traumatic wounds can be infected with a variety of organisms, depending on the circumstances
              • Highly resistant Acinetobacter baumannii infections have been associated with combat wounds c117
            • Surgical wound infections may reflect nature of surgery (eg, colon surgery may be complicated by infection caused by enteric pathogens) or may be caused by common skin organisms c118
              • Antibiotic resistance is common
          • Infections related to intravascular access devices c119
            • May be isolated to insertion site, but secondary bacteremia is common in sepsis
            • Usually gram-positive organisms (Staphylococcus aureus, coagulase-negative staphylococci), but gram-negative bacilli or yeast are also common pathogens c120c121c122c123c124
          • Necrotizing fasciitis c125d11
            • Group A Streptococcus or synergistic polymicrobial infections are the most common causes of this unusual life-threatening condition c126c127c128
        • Less common but important sources of sepsis include:
          • Bone and joint infections
            • Osteomyelitis c129d12
              • Wide variety of pathogens, depending on cause (hematogenous versus contiguous focus)
            • Septic arthritis c130
              • Common causes vary with age; overall, Staphylococcus aureus and streptococci are the most common causes c131c132
          • Central nervous system infections c133
            • Meningitis c134d13
              • Typical pathogens vary by age range; Streptococcus pneumoniae and Neisseria meningitidis are the most common c135c136
            • Encephalitis c137d14
              • Usually viral; HSV and West Nile virus have been associated with sepsis c138c139
            • Epidural abscess c140
              • Uncommon; spinal epidural abscesses are usually secondary to bacteremia, with Staphylococcus aureus as the most frequent pathogen r11c141

Risk factors and/or associations

Age
  • Elderly people are at increased risk for sepsis and sepsis-associated hospitalizations owing to comorbidities, medical interventions, institutionalization, immunosenescence, functional disability, and malnutrition r6
    • About half of patients with sepsis are aged 65 years or older r12
    • Sepsis hospitalization rate increases with age r13
      • Younger than 65 years: about 10 per 10,000 population r13c142
      • Aged 65 years or older: about 120 per 10,000 population r13c143
      • Aged 85 years or older: about 270 per 10,000 population r13c144
  • Infants are at increased risk for sepsis r14
    • Incidence of sepsis in infants is higher than in overall population and pediatric population (about 50 per 10,000 population) r15c145
    • Associated with prematurity, low birth weight, and maternal group B streptococcal infection r14c146
Sex
  • Males are 25% to 30% more likely to develop sepsis than females r16c147
  • Males are more likely to develop sepsis due to respiratory tract infection than females; females are more likely to develop sepsis due to genitourinary tract infection r16c148c149
Genetics
  • Interleukin 1β-511 homozygosity is associated with increased risk of mortality from sepsis r3c150
  • Genetic mutations leading to deficiency of mannose-binding lectin are associated with increased risk of sepsis, particularly pneumococcal sepsis r3
  • Other hypotheses related to genetic predisposition to sepsis have been considered but are as yet unproven r3
Ethnicity/race
  • Black Americans are twice as likely to develop sepsis compared with White Americans; Black Americans have a higher case fatality rate than White Americans r16r17c151
    • Likely caused by interaction between differences in incidence of chronic comorbidities, socioeconomic factors, and genetics r16r17
  • Hispanic ethnicity is associated with a lower incidence of sepsis and a lower case fatality rate compared with Black Americans; rates among Hispanic Americans are similar to those of White Americans r17
Other risk factors/associations
  • Factors that breach natural barriers to pathogen invasion or compromise immune function increase the risk of sepsis r2r3r16r18
    • Recent surgery or hospitalization c152c153
    • Indwelling urinary catheters c154
    • Intravascular access devices c155
    • Endotracheal tubes c156
    • Malnutrition c157
    • Burns and/or trauma c158c159
    • Chronic illness (eg, cancer, diabetes) c160c161c162
    • Immunosuppression (eg, immunosuppressive medical therapy, HIV infection) c163c164c165
    • IV drug use r18c166
    • Pregnancy or recent childbirth, miscarriage, or pregnancy termination—particularly if the following are present: r18c167c168c169
      • Immunodeficiency c170
      • Diabetes or gestational diabetes c171
      • Invasive procedures such as cesarean or forceps delivery c172
      • Prolonged rupture of membranes c173
      • Close contact with people with group A streptococcal infection
      • Continued vaginal bleeding or offensive discharge c174

Diagnostic Procedures

Primary diagnostic tools

  • Diagnosis is based primarily on history and physical examination, coupled with laboratory results providing evidence for an inflammatory process and a microbial infection c175
  • Presence of organ dysfunction, integral to the diagnosis of sepsis, can be identified as an increase from baseline of 2 points or more in SOFA score (Sequential Organ Failure Assessment; originally the Sepsis-Related Organ Failure Assessment) r7
    • qSOFA score (Quick Sequential Organ Failure Assessment or Quick Sepsis-Related Organ Failure Assessment) does not require laboratory testing and is as accurate as the full tool in non-ICU patients c176
    • Score is more specific than sensitive: a negative test result does not rule out sepsis and should not be considered a barrier to further testing and monitoring when diagnosis is suspected r19
  • Initial laboratory tests in all patients include a CBC with differential; a metabolic panel; creatinine, bilirubin, and lactate levels; coagulation tests; blood gas levels; and urinalysis r2r7c177c178c179c180c181
    • Elements of SOFA score include platelet count, bilirubin level, creatinine level, and PaO₂ r7
    • Obtain results promptly; in particular, measure lactate level within 1 hour of presentation of patient with possible sepsis r1
  • In all patients, obtain blood cultures and cultures from any suspected source of infection. Do this before the first dose of antimicrobial therapy if that can be done without significant delay (less than 45 minutes) r4c182
  • Additional laboratory tests may provide etiologic information (eg, rapid influenza antigen testing; 1,3-β-D-glucan assay; legionella and pneumococcal antigens) r2r4c183c184c185
  • Perform imaging (eg, radiography, ultrasonography, CT, MRI) to confirm suspected anatomic site of infection; specific imaging mode to select depends on suspected site r20
  • Measurement of mean arterial pressure is indicated in patients with persistent hypoperfusion after fluid challenge r4
    • May provide support for the diagnosis of sepsis, and forms a baseline to guide fluid and vasopressor treatment
  • Several serum markers have been suggested as indicators of sepsis (eg, procalcitonin, C-reactive protein), but their role remains unclear in both diagnosis and management r21r22c186c187

Laboratory

  • CBC r20c188
    • Infection is suggested by a WBC count higher than 12,000 cells/mm³ or lower than 4000 cells/mm³, or by immature WBCs constituting more than 10% of the total
    • Platelet count lower than 100,000 cells/mm³ suggests hypoperfusion and organ dysfunction; may precede disseminated intravascular coagulation
  • Metabolic and chemistry panels r20c189c190
    • Blood glucose level higher than 140 mg/dL in a patient without diabetes suggests injury or illness (including sepsis)
    • Creatinine level increase of 0.5 mg/dL or more suggests renal impairment and hypoperfusion; level greater than 2 mg/dL suggests sepsis
    • Elevated liver enzyme levels and/or bilirubin level greater than 2 mg/dL suggest hepatic impairment and hypoperfusion
  • Lactate level c191
    • Elevated serum lactate level is both diagnostic and prognostic for sepsis, as it suggests end-organ dysfunction
      • Obtain within 1 hour of clinical suspicion of sepsis; longer intervals are associated with delays in administration of fluids and antibiotics and with higher mortality rates r1
      • Followed serially in protocols for goal-directed therapy for sepsis
    • In adults, blood lactate greater than 2 mmol/L is a defining criterion of septic shock r23
      • Low lactate level (0-2.5 mmol/L) is associated with a mortality rate of 4.9% r8
      • Intermediate lactate level (2.5-3.9 mmol/L) is associated with a mortality rate of 9% r8
      • High lactate level (greater than 4 mmol/L) is associated with a mortality rate of 28.4% r8
    • In children, elevated blood lactate levels also are associated with increased mortality in septic shock, but the optimal threshold has not been established r23
  • Coagulation tests r20c192
    • INR greater than 1.5 suggests coagulopathy associated with organ dysfunction
    • Activated partial thromboplastin time greater than 60 seconds suggests coagulopathy associated with organ dysfunction
  • Urinalysis and urine output c193c194
    • Provides assessment of renal function and fluid balance
    • Pyuria suggests urinary tract infection as the source of sepsis
    • Urine output less than 0.5 mL/kg/hour for more than 2 hours despite fluid resuscitation suggests hypoperfusion and/or renal dysfunction r20
  • Cultures to determine pathogen and susceptibility to antibiotics
    • Blood cultures c195
      • Obtain specimens before starting broad-spectrum antimicrobial therapy provided that obtaining them does not cause a significant delay in administration of antimicrobials (ie, 45 minutes) r4r23
        • Sensitivity of blood cultures is significantly reduced if obtained even shortly after initiation of empiric antimicrobial therapy r24
      • Draw 2 sets of blood culture specimens, each for both aerobic and anaerobic incubation, from separate sites r4
      • If vascular access devices are present and have been in place for 48 hours or more, draw culture specimens from each device if possible, as well as at least 1 peripheral set r4
        • If the peripherally drawn specimen and the vascular access device–drawn specimen develop the same pathogen on culturing, the vascular access device is likely the source of sepsis
          • Culture positivity more than 2 hours earlier in the blood drawn from the device compared with the blood drawn simultaneously from another site has been suggested as evidence of device infection, but data are not conclusive
        • If the vascular access device was placed within 48 hours, culture from that site is not necessary
      • Blood culture results may be negative in 50% to 65% of patients with sepsis r2
    • Urine cultures c196
      • Performed in conjunction with urinalysis in patients with suspected sepsis if urine is a possible source r20
    • Stool culture c197
      • May be performed in patients with diarrhea who have been in the hospital for fewer than 72 hours; patients who have been in the hospital for more than 72 hours are not likely to have diarrhea caused by enteric pathogens
      • Additionally, consider tests for Clostridium difficile toxin in patients with diarrhea and recent antibiotic use
    • Sputum culture c198
      • Performed in conjunction with Gram stain for suspected respiratory source of sepsis r20
      • Mechanical ventilator use is associated with pneumonia and may be the source of sepsis
        • Quantitative cultures may help to discriminate between infection and colonization
    • Skin and soft tissue culture c199
      • Performed in conjunction with Gram stain on drainage from abscesses or surgical sites r20
      • Culture of intact skin (eg, in cellulitis) is of little value and should not be done
    • Cerebrospinal fluid cultures c200
      • Done in conjunction with cell count and differential, chemistry, Gram stain, and other special tests as indicated
  • Rapid influenza molecular testing on nasopharyngeal secretions is recommended for suspected influenza during periods of high influenza activity r25c201
  • Urine testing for legionella and pneumococcal antigens is advisable for patients with severe community-acquired pneumonia r25c202c203
  • Serum 1,3-β-D-glucan assay and mannan and antimannan antibody assays are recommended for suspected fungal sepsis r4c204

Imaging

  • Radiography
    • Chest radiography is used to confirm the presence of pneumonia c205
    • Abdominal radiography identifies bowel perforation by the presence of free air; it may also provide preliminary imaging clues for other causes of sepsis by demonstrating the presence of gallstones, kidney stones, or other abnormalities that can be further explored with other tests c206
    • Plain radiographs also may be of value in demonstrating presence of air in soft tissues (eg, necrotizing infections) or osteomyelitis c207
  • Ultrasonography
    • Abdominal ultrasonography is used to identify abdominal infections (eg, appendicitis, cholecystitis, pancreatitis) r26c208
    • Renal ultrasonography is used to identify renal obstruction or pyelonephritis c209
    • Echocardiography is used to identify endocarditis in patients with a cardiac murmur or suspected IV drug use c210
  • CT
    • CT of chest is used to confirm pneumonia as the source infection if chest radiography is not diagnostic c211
    • CT of abdomen and pelvis is used to identify abdominal or pelvic abscesses (eg, pancreatic abscess, renal abscess) or ischemic bowel c212
    • CT also may be used to determine depth and extent of some serious soft tissue infections (eg, necrotizing fasciitis) c213
  • MRI
    • MRI of brain and/or spine is used in evaluation of meningitis, encephalitis, and epidural abscess c214c215

Functional testing

  • SOFA score (Sequential Organ Failure Assessment; originally the Sepsis-Related Organ Failure Assessment) r7c216
    • Either the standard score or the quick version (qSOFA) is recommended for all patients to identify organ dysfunction, a defining feature of sepsis
    • In the standard version, assign points (0-4) for each of the following parameters:
      • PaO₂/FiO₂ ratio
        • 0 points: 400 or higher
        • 1 point: less than 400
        • 2 points: less than 300
        • 3 points: less than 200 with respiratory support
        • 4 points: less than 100 with respiratory support
      • Platelet count (×10³ cells/mm³)
        • 0 points: 150 or higher
        • 1 point: less than 150
        • 2 points: less than 100
        • 3 points: less than 50
        • 4 points: less than 20
      • Bilirubin level (mg/dL)
        • 0 points: less than 1.2
        • 1 point: 1.2 to 1.9
        • 2 points: 2 to 5.9
        • 3 points: 6 to 11.9
        • 4 points: 12 or higher
      • Mean arterial pressure/vasopressor requirement (given over at least 1 hour)
        • 0 points: 70 mm Hg or higher
        • 1 point: lower than 70 mm Hg
        • 2 points: dopamine dosage less than 5 mcg/kg/minute or any dose of dobutamine
        • 3 points: dopamine dosage 5.1 to 15 mcg/kg/minute or any dose of epinephrine
        • 4 points: dopamine dosage higher than 15 mcg/kg/minute or epinephrine dosage higher than 0.1 mcg/kg/minute or norepinephrine dosage higher than 0.1 mcg/kg/minute
      • Glasgow Coma Scale score
        • 0 points: 15
        • 1 point: 13 to 14
        • 2 points: 10 to 12
        • 3 points: 6 to 9
        • 4 points: less than 6
      • Creatinine level (mg/dL)
        • 0 points: lower than 1.2
        • 1 point: 1.2 to 1.9
        • 2 points: 2 to 3.4
        • 3 points: 3.5 to 4.9
        • 4 points: 5 or higher
      • Urine output (mL/day)
        • 3 points: less than 500
        • 4 points: less than 200
    • An increase from baseline of 2 points or more indicates presence of organ failure; if baseline is unknown, assume it to be 0
  • qSOFA score (Quick Sequential Organ Failure Assessment or Quick Sepsis-Related Organ Failure Assessment)
    • Consists of 3 parameters. Presence of any 2 is indicative of organ dysfunction and possible sepsis:
      • Respiratory rate of 22 breaths per minute or faster
      • Altered mentation
      • Systolic blood pressure of 100 mm Hg or lower
  • Measurement and monitoring central vein hemodynamic parameters is appropriate for patients with evidence of hypoperfusion (eg, hypotension that persists after fluid challenge) r4c217
    • Mean arterial pressure
      • Calculation of average pressure in 1 cardiac cycle and a measure of organ perfusion
      • Mean arterial pressure of less than 60 mm Hg suggests that tissue oxygen and nutrient needs are not being met

Differential Diagnosis

Most common r2

  • Hypovolemic or hemorrhagic shock c218c219
    • Rapid fluid loss resulting in inadequate circulating volume and hypoperfusion; most often caused by burns, trauma, gastrointestinal bleeding, and ruptured abdominal aortic aneurysm
    • Similar features: tachypnea, tachycardia, malaise, hypotension, hypoxia, decreased capillary refill, mottled skin, oliguria, pallor, and altered mental status
    • Differentiating features: absence of fever; abnormalities in WBC count are usually absent or minimal
    • Diagnosed by: history, physical examination, and imaging indicate source of hemorrhage or other volume loss
  • Pulmonary embolism r27c220d15
    • Sudden occlusion of a pulmonary artery, most often caused by a dislodged thrombus
    • Similar features: dyspnea, tachypnea, hypoxia
    • Differentiating features: onset of symptoms is abrupt; pleuritic chest pain is common
    • Diagnosed by: multidetector-row CT angiography or CT pulmonary angiography detects pulmonary emboli; D-dimer levels are usually elevated
  • Myocardial infarction c221d16
    • Myocardial necrosis resulting from occlusion of a coronary artery
    • Similar features: dyspnea, fatigue
    • Differentiating features: retrosternal chest pain and/or pressure radiating to neck, jaw, shoulder, and/or arm
    • Diagnosed by: ECG shows ST elevation, ST depression, or T-wave inversion; cardiac troponin level is elevated
  • Acute pancreatitis r28c222d9
    • Sudden onset of parenchymal and pancreatic fat necrosis with inflammation of pancreas
    • Similar features: fever, diaphoresis, nausea, vomiting
    • Differentiating features: sudden onset of constant epigastric or left upper quadrant pain that may radiate to the back, chest, or flanks
    • Diagnosed by: serum amylase and lipase levels more than 3 times the upper reference limit, with confirmatory findings from abdominal imaging
  • Diabetic ketoacidosis r29c223d17
    • Decompensated state of diabetes that presents with the biochemical triad of hyperglycemia, ketonemia, and metabolic acidosis
    • Similar features: tachycardia, hypotension, weakness, nausea, vomiting
    • Differentiating features: polyuria, polydipsia, polyphagia, absence of fever, Kussmaul respirations, acetone breath
    • Diagnosed by: hyperglycemia, positive urine and serum ketones, decreased arterial pH, elevated anion gap, decreased serum bicarbonate level
  • Adrenal insufficiency r30c224d18
    • Cortisol and mineralocorticoid deficiency in primary adrenal insufficiency, or suppression of hypothalamic-pituitary axis in secondary adrenal insufficiency
    • Similar features: tachycardia, weakness, vomiting, hypotension, altered mental status
    • Differentiating features: increased skin pigmentation, salt craving, weight loss, more gradual progression of symptoms
    • Diagnosed by: decreased serum cortisol level, elevated adrenocorticotropic hormone level
  • Transfusion reaction r31c225
    • Adverse reaction to blood or blood product transfusion
    • Similar features: fever, rigors, dyspnea
    • Differentiating features: pruritus, urticaria, angioedema, evidence of hemolysis
    • Diagnosed by: history of blood transfusion and analysis of pretransfusion and posttransfusion blood samples

Treatment

Goals

  • Initial respiratory and hemodynamic stabilization to promote perfusion and maintain vital organ function
    • Within the first hour diagnosis is suspected: r1
      • Begin fluid resuscitation for patients who are hypotensive or who have serum lactate levels of 4 mmol/L or higher
      • If hypotension persists during or after fluid resuscitation, start vasopressors immediately
  • Initial antimicrobial treatment with broad-spectrum agents until the underlying infection is identified; tailored antimicrobial treatment once causative pathogen is identified
    • Within the first hour that diagnosis is suspected, begin empiric therapy r1
  • Source control within the first 12 hours, if possible
  • Prevention of complications and sequelae

Disposition

Admission criteria

Sepsis requires inpatient acute care for monitoring, IV antimicrobial therapy, and supportive care

Criteria for ICU admission
  • Septic shock with hemodynamic instability requires ICU admission for hemodynamic monitoring and treatment r32

Recommendations for specialist referral

  • Refer to infectious disease specialist to identify cause and direct appropriate antimicrobial therapy
  • Consult clinical pharmacologist to optimize dosing regimen
  • Refer to critical care specialists to guide resuscitative efforts in septic shock
  • Additional specialist referral depends on cause of sepsis and/or organ dysfunction resulting from sepsis; may include cardiologist, pulmonologist, nephrologist, or gastroenterologist
  • Surgical referral may be required for source control of abdominal or necrotizing infections

Treatment Options

Initial treatment often occurs in the emergency department and is continued in the inpatient setting; treatment should proceed rapidly (within 1 hourr1), regardless of setting r4

  • Implementation of multidisciplinary sepsis bundles that promote early identification and provide management protocols may result in improved outcomes r1r33

Treatment includes immediate stabilization, fluid resuscitation, initiation of antimicrobials, hemodynamic support, and source control r4

  • Ensure patency of airway and provide supplemental oxygen; support ventilation mechanically if necessary to improve oxygenation, protect airway, or prevent imminent respiratory failure r2
  • Invasive monitoring of hemodynamic parameters is recommended for patients with septic shock, and it can be used in patients without shock to monitor response to fluids
    • Intra-arterial blood pressure monitoring is recommended for patients with sepsis who are not responsive to initial fluid therapy or who require vasopressor treatment r34
  • Establish adequate IV access (2 large-gauge IV devices, preferably 18-gauge or larger) and begin infusing crystalloid solution immediately upon suspicion of sepsis and either hypotension or a lactate level of 4 mmol/L or higher; the recommended goal is 30 mL/kg within 3 hours r1r4
    • Early goal-directed therapy, a core component of previous sepsis guidelines, has not been shown to improve mortality in more recent studies r4r35r36r37
    • Nevertheless, adequate fluid resuscitation is essential, and many patients require large volumes, depending on hemodynamic response
      • Normalization of lactate levels also may be used as a guide to adequate fluid resuscitation r38r39
      • Bedside cardiac ultrasonography and other techniques may be used to assess initial fluid responsiveness; serial follow-up studies may help to determine fluid repletion and indication for inotropic therapy r34r40
    • Evidence and guidelines suggest that crystalloids should be used as first line fluid therapy; albumin may be needed for patients requiring large volumes of crystalloids r4r41r42
    • Normal saline has typically been the primary IV fluid given; however, balanced crystalloid solutions (eg, lactated Ringer solution) may have fewer adverse metabolic effects and a lower rate of complications r43
  • After collecting blood and other specimens for culture, but within the first hourr1 of recognizing septic shock or sepsis, begin antimicrobial therapy r4r23
    • Immediate (within 1 hour) administration of antibiotics may reduce mortality by as much as 33% compared with later administration r44r45
    • Infectious Diseases Society of America does not endorse recommending a rigid 1-hour time frame; instead, they recommend prompt administration of antibiotics once the presumptive diagnosis is made r46
    • International guidelines for children recommend starting antibiotic therapy as soon as possible after appropriate evaluation and: r23
      • Within 1 hour of recognition in those with septic shock
      • Within 3 hours of recognition in those with sepsis-associated organ dysfunction but without shock
    • Initial antimicrobial therapy is empiric
      • Begin with IV antiinfective agents that are active against all likely pathogens (ie, bacterial, viral, fungal)
      • Choice of specific agent or agents for empiric antimicrobial therapy depends on suspected source of infection, clinical situation, recent antibiotic use, and local resistance patterns r2r23
      • Current Surviving Sepsis guideline recommends empiric combination therapy using at least 2 antibiotics from different classes for patients with septic shock r4
      • Consult a clinical pharmacist if possible to optimize dosing and administration according to pharmacokinetic and pharmacodynamic principles (eg, continuous versus intermittent infusion of β-lactam agents) r4
      • Optimize antibiotic therapy once culture and sensitivity results are available; this may involve broadening or narrowing coverage, or stopping antibiotic if sepsis is excluded r47
    • For suspected pneumonia r48
      • Community-acquired pneumonia
        • Broad-spectrum β-lactam agent (cefotaxime, ceftazidime, cefepime, or piperacillin-tazobactam) plus either a respiratory fluoroquinolone (moxifloxacin or levofloxacin) or azithromycin
      • Medical care–associated pneumonia
        • Antipseudomonal carbapenem (imipenem, doripenem, or meropenem) or cefepime
        • If legionella is a possibility, add azithromycin or a fluoroquinolone r4
      • For either community-acquired or medical care–associated pneumonia, add oseltamivir if suspected or confirmed influenza; IV peramivir can be used if oral or enteric oseltamivir cannot be tolerated r25r49
    • For suspected abdominal source r48
      • Community-acquired infection
        • Carbapenem (imipenem, doripenem, or meropenem) or piperacillin-tazobactam with or without an aminoglycoside
        • For suspected biliary tract infection, piperacillin-tazobactam or ampicillin-sulbactam or ceftriaxone plus metronidazole
      • Medical care–associated infection
        • Antipseudomonal carbapenem (imipenem or meropenem) with or without an aminoglycoside
    • For suspected urinary source r48
      • Community-acquired infection
        • Antipseudomonal fluoroquinolone (ciprofloxacin or levofloxacin)
          • If urine Gram stain shows gram-positive cocci, use either ampicillin or vancomycin, with or without an aminoglycoside
      • Medical care–associated infection
        • Vancomycin plus either imipenem or meropenem or cefepime
    • For suspected skin and soft tissue infection r48
      • Community-acquired infection
        • Vancomycin or daptomycin plus either imipenem or meropenem or piperacillin-tazobactam
      • Medical care–associated infection
        • Vancomycin or daptomycin plus either imipenem or meropenem or cefepime
      • For either community-acquired or medical care–associated infection
        • Add clindamycin if toxin-producing organism is suspected (eg, Streptococcus pyogenes, Staphylococcus aureus)
    • For unknown source in adults r48
      • Community-acquired infection
        • Vancomycin plus a carbapenem (imipenem, doripenem, meropenem, or ertapenem)
      • Medical care–associated infection
        • Vancomycin plus cefepime
    • For unknown source in children r50
      • Community-acquired infection
        • Third-generation cephalosporin (ceftriaxone or cefotaxime) plus vancomycin
      • Medical care–associated infection
        • Vancomycin plus either piperacillin-tazobactam, ceftazidime, cefepime, or a carbapenem (imipenem or meropenem)
    • Other considerations
      • Add oseltamivir if influenza is likely
        • There is insufficient data about efficacy of zanamivir, IV peramivir, and oral baloxavir in hospitalized patients with influenza; however, can use IV peramivir if patient cannot tolerate oral or enteric oseltamivirr51r51
      • An echinocandin may be added in medical care–associated cases in which yeast is a possible pathogen (eg, cases involving indwelling vascular catheters, intra-abdominal infection, or neutropenia) r48
      • Add fidaxomicin, or oral or enteral vancomycin (with or without IV metronidazole) if Clostridium difficile infection is a possibility r52
  • Provide vasopressor agents to target a mean arterial pressure of at least 65 mm Hg, if initial fluid resuscitation has not achieved that goal; a higher target (eg, 75 mm Hg or more) may be appropriate in patients with baseline hypertension r4
    • Norepinephrine is first line therapy r4r53r54
      • There is some evidence that early administration (within 2 hours of shock onset) of norepinephrine improves outcomes, and that every hour of delay results in an incremental increase in mortality r55
    • Epinephrine and vasopressin may be added if necessary to achieve target mean arterial pressure r4r56
    • Dopamine is a third line agent used only in patients meeting specific cardiac criteria r4r57
  • Consider inotropic therapy with dobutamine as an adjunct or alternative to vasopressor therapy in select cases with elevated cardiac filling pressures and low cardiac output suggestive of myocardial dysfunction or persistent clinical signs of hypoperfusion after adequate volume and mean arterial pressure have been achieved r4
  • Consider corticosteroid therapy with IV hydrocortisone if fluid resuscitation and vasopressor therapy do not restore hemodynamic stability r4
    • Use of steroids may be reasonable, even though evidence for efficacy is not conclusive r57r58r59r60
    • A Cochrane review indicates treatment with corticosteroids results in large reductions in length of hospitalization and probably reduces mortality among adults and children with sepsis r61
  • Source control within the first 12 hours if possible (eg, drainage of abscess, debridement of necrotic tissue, relief of ureteral obstruction, removal of infected device) r4

Additional treatment required after initial management in select cases of sepsis

  • Blood product administration
    • RBC transfusion if hemoglobin level is less than 7 g/dL after tissue hypoperfusion has been treated adequately r4r62
      • Evidence suggests that transfusion to higher levels does not confer an advantage in mortality or ischemic events r62r63
      • Acute hemorrhage, myocardial ischemia, or severe hypoxemia may necessitate a higher transfusion threshold r4
    • Administer platelets prophylactically in septic patients with thrombocytopenia and increased risk for bleeding r4
      • Less than 10,000 cells/mm³
      • Less than 20,000 cells/mm³ if there is a significant risk of bleeding
      • Less than 50,000 cells/mm³ for active bleeding, invasive procedure
  • Glycemic control targeting an upper blood glucose level of 180 mg/dL or less r4
    • Evidence suggests that there is no benefit in tighter control and that adverse events are more frequent
  • Deep vein thrombosis prophylaxis using a combination of daily pharmacologic therapy and intermittent pneumatic compression devices r4
  • Stress ulcer prophylaxis with a proton pump inhibitor or H₂ blocker is recommended for patients with sepsis or septic shock who are at risk for gastrointestinal bleeding r4
  • Continuous renal replacement therapy or intermittent hemodialysis is recommended for acute kidney injury r4
  • Oral nutrition or (if necessary) enteral nutrition within the first 48 hours after diagnosis, with low-dose feeding as tolerated r4
    • If enteral feeding is not possible initially, a 7-day trial of IV glucose and advancement of enteral feeding is recommended over early parenteral nutrition

Once the causative pathogen is identified, de-escalate antimicrobial treatment, based on culture and sensitivity results, and continue for a duration appropriate to the diagnosis (7-10 days in most cases) r4

  • Combination therapy is recommended in some circumstances: r4
    • Ongoing septic shock
    • Multidrug-resistant pathogens such as Acinetobacter and Pseudomonas species
    • Bacteremic infections caused by Streptococcus pneumoniae (eg, β-lactam agent plus a macrolide)
    • Group A streptococcal toxic shock (penicillin and clindamycin)
  • Shorter courses may be appropriate in patients with urinary tract or intra-abdominal infections and rapid clinical response to prompt source control r4
  • De-escalation may be associated with improved survival r64
  • Procalcitonin levels within reference range can be used to support a decision to discontinue antibiotics in these patients and in those who initially appeared septic but in whom no evidence for infection has emerged
    • Procalcitonin-guided antibiotic therapy results in shorter duration of treatment but no greater risk of treatment failure. r65
  • Antimicrobial therapy may need to be continued past 7 to 10 days in certain clinical situations: r4
    • Endocarditis
    • Immunologic deficiencies (eg, neutropenia)
    • Slow clinical response to antimicrobial therapy
    • Undrainable foci of infection
    • Bacteremia with Staphylococcus aureus
    • Select fungal and viral infections

Drug therapy

  • Antimicrobial agents r2c226
    • Broad-spectrum penicillins c227
      • Ampicillin-sulbactam c228
        • Ampicillin Sodium, Sulbactam Sodium Solution for injection; Infants†, Children†, and Adolescents†: 100 to 200 mg/kg/day ampicillin component (150 to 300 mg/kg/day ampicillin; sulbactam) IV divided every 6 hours (Max: 8 g/day ampicillin [12 g/day ampicillin; sulbactam]); doses up to 400 mg/kg/day ampicillin component (600 mg/kg/day ampicillin; sulbactam) have been reported rarely for serious infections.
        • Ampicillin Sodium, Sulbactam Sodium Solution for injection; Adults: 1.5 g (1 g ampicillin and 0.5 g sulbactam) or 3 g (2 g ampicillin and 1 g sulbactam) IV/IM every 6 hours.
      • Piperacillin-tazobactam r4c229
        • Piperacillin Sodium, Tazobactam Sodium Solution for injection; Infants, Children, and Adolescents: 80 mg/kg/dose piperacillin component (90 mg/kg/dose piperacillin; tazobactam) IV every 6 hours (Max: 4 g/dose piperacillin [4.5 g/dose piperacillin; tazobactam]).
        • Piperacillin Sodium, Tazobactam Sodium Solution for injection; Adults: 3.375 g (3 g piperacillin and 0.375 g tazobactam) IV every 6 hours or 4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 6 to 8 hours for 7 to 10 days as part of combination therapy.
    • Cephalosporins c230
      • Third generation r4c231
        • Ceftriaxone c232
          • Ceftriaxone Sodium Solution for injection; Infants, Children, and Adolescents: 50 to 100 mg/kg/day IV/IM divided every 12 to 24 hours (Max: 4 g/day).
          • Ceftriaxone Sodium Solution for injection; Adults: 1 to 2 g IV/IM every 12 to 24 hours (Max: 4 g/day).
        • Ceftazidime c233
          • Antipseudomonal cephalosporin
          • Ceftazidime Sodium Solution for injection; Infants and Children: 30 to 50 mg/kg/dose IV every 8 hours (Max: 2 g/dose); use higher doses (e.g., 50 mg/kg/dose IV every 8 hours) for immunocompromised patients. 200 to 300 mg/kg/day IV divided every 8 hours (Max: 12 g/day) recommended by AAP for serious Pseudomonas infections.
          • Ceftazidime Sodium Solution for injection; Adolescents: 2 g IV every 8 hours.
          • Ceftazidime Sodium Solution for injection; Adults: 2 g IV every 8 hours.
      • Fourth generation r4c234
        • Cefepime c235
          • Cefepime Hydrochloride Solution for injection; Infants, Children, and Adolescents: 50 mg/kg/dose IV every 8 hours (Max: 2 g/dose).
          • Cefepime Hydrochloride Solution for injection; Adults: 1 to 2 g IV every 8 to 12 hours.
    • Carbapenems r4c236
      • Imipenem-cilastatin c237
        • Imipenem, Cilastatin Sodium Solution for injection; Infants 1 to 2 months weighing 1.5 kg or more: 25 mg/kg/dose IV every 6 hours.
        • Imipenem, Cilastatin Sodium Solution for injection; Infants, Children, and Adolescents 3 months to 17 years: 15 to 25 mg/kg/dose IV every 6 hours (Max: 2 g/day for fully susceptible organisms; 4 g/day for moderately susceptible organisms).
        • Imipenem, Cilastatin Sodium Solution for injection; Adults: 500 mg IV every 6 hours or 1 g IV every 8 hours for fully susceptible organisms and 1 g IV every 6 hours for organisms with intermediate susceptibility.
      • Meropenem c238
        • Meropenem Solution for injection; Infants, Children, and Adolescents: 20 to 40 mg/kg/dose IV every 8 hours (Max: 2 g/dose).
        • Meropenem Solution for injection; Adults: 1 g IV every 8 hours or 500 mg IV every 6 hours.
    • Levofloxacin r4c239
      • Provides coverage of respiratory pathogens and gram-negative aerobic bacteria, including Pseudomonas aeruginosa
      • Levofloxacin Solution for injection; Adults: 750 mg IV every 24 hours for at least 7 days.
    • Azithromycin c240
      • Azithromycin Solution for injection; Infants, Children, and Adolescents 3 months to 15 years†: 10 mg/kg/dose (Max: 500 mg/dose) IV once daily for 2 days, followed by oral therapy to complete a 5-day treatment course.
      • Azithromycin Solution for injection; Adolescents 16 to 17 years: 500 mg IV once daily for at least 2 days, followed by oral therapy to complete a 7- to 10-day treatment course
      • Azithromycin Solution for injection; Adults: 500 mg IV once daily for at least 5 days.
    • Aminoglycosides c241
      • Gentamicin (extended-interval dosing) r4c242
        • Gentamicin Sulfate Solution for injection; Infants, Children, and Adolescents: 5 to 7.5 mg/kg/dose IV/IM every 24 hours.
        • Gentamicin Sulfate Solution for injection; Adults: 5 to 7 mg/kg/dose IV/IM. Dosing interval often determined via nomogram and adjusted based on a random concentration drawn 8 to 12 hours after the first dose; dosing intervals of 24, 36, and, in some cases, 48 to 72 hours, may be necessary.
      • Amikacin (extended-interval dosing) c243
        • Enhanced antipseudomonal activity
        • Amikacin Sulfate Solution for injection; Infants, Children, and Adolescents: 15 to 22.5 mg/kg/dose IV/IM every 24 hours.
        • Amikacin Sulfate Solution for injection; Adults: 15 to 20 mg/kg/dose IV/IM. Initial dose intervals are often determined using a nomogram, then adjusted based on random concentration drawn 8 to 12 hours after first dose; dosing intervals of 24, 36, and, in some cases, 48 to 72 hours, may be necessary.
    • Vancomycin c244
      • Vancomycin Hydrochloride Solution for injection; Infants, Children, and Adolescents: 40 to 60 mg/kg/day IV divided every 6 hours; a loading dose of 20 to 25 mg/kg IV may be considered for seriously ill patients. Adjust dosage based on serum concentrations. For MRSA, treat at least 2 weeks for uncomplicated bacteremia and 4 to 6 weeks for complicated bacteremia.
      • Vancomycin Hydrochloride Solution for injection; Adults: 25 to 30 mg/kg (actual body weight) IV loading dose, then 15 to 20 mg/kg/dose (actual body weight) IV every 8 to 12 hours per guidelines. Adjust dose based on serum concentrations. FDA-approved dosage is 500 mg IV every 6 hours or 1 g IV every 12 hours. For MRSA, treat at least 2 weeks for uncomplicated bacteremia and 4 to 6 weeks for complicated bacteremia.
      • Oral vancomycin for Clostridium difficile infections: r52
        • Vancomycin Hydrochloride Oral solution; Infants, Children, and Adolescents: 40 mg/kg/day (Max: 2 g/day) PO in 3 to 4 divided doses for 7 to 10 days is FDA-approved dosage. Clinical guidelines recommend 10 mg/kg/dose (Max: 125 mg/dose) PO 4 times daily for 10 days as first line option for nonsevere initial cases or for first recurrence. For severe/fulminant cases, 10 mg/kg/dose (Max: 500 mg/dose) PO 4 times daily for 10 days; consider adding IV metronidazole. For second/subsequent episodes, treat with vancomycin using a tapered and/or pulse regimen: 10 mg/kg/dose (Max: 125 mg/dose) PO 4 times daily for 10 to 14 days, then 10 mg/kg/dose (Max: 125 mg/dose) PO 2 times daily for 1 week, then 10 mg/kg/dose (Max: 125 mg/dose) PO once daily for 1 week, then 10 mg/kg/dose (Max: 125 mg/dose) PO every 2 to 3 days for 2 to 8 weeks. Additional option for second/subsequent episodes is 10 mg/kg/dose (Max: 500 mg/dose) PO 4 times daily for 10 days and then rifaximin for 20 days.
        • Vancomycin Hydrochloride Oral capsule; Adults: 125 mg PO 4 times daily for 10 days as first line option for nonsevere/severe initial cases and for first recurrence after metronidazole therapy. For fulminant cases, 500 mg PO or nasogastric tube 4 times daily with IV metronidazole; consider vancomycin retention enema for ileus. For first recurrence in patients initially treated with vancomycin or in second/subsequent episodes, treat with vancomycin using a tapered and/or pulse regimen: 125 mg PO 4 times daily for 10 to 14 days, then 125 mg PO 2 times daily for 1 week, then 125 mg PO once daily for 1 week, then 125 mg PO every 2 to 3 days for 2 to 8 weeks. Additional option for second/subsequent episodes is vancomycin 125 mg PO 4 times daily for 10 days followed by rifaximin for 20 days.
    • Fidaxomicin c245
      • For Clostridium difficile infection:
        • Fidaxomicin Oral tablet; Children and Adolescents weighing at least 12.5 kg and able to swallow tablets: 200 mg PO twice daily for 10 days.
        • Fidaxomicin Oral tablet; Adults: 200 mg PO twice daily for 10 days.
    • Metronidazole c246
      • Metronidazole Solution for injection; Infants†, Children†, and Adolescents†: 22.5 to 40 mg/kg/day IV divided every 6 to 8 hours (Usual Max: 500 mg/dose; up to 4 g/day rarely for severe infections).
      • Metronidazole Solution for injection; Adults: 15 mg/kg IV loading dose, then 7.5 mg/kg/dose IV every 6 hours (Max: 4 g/day).
      • For Clostridium difficile infection:
        • Oral
          • Metronidazole benzoate Oral powder; Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) PO every 6 to 8 hours for 10 days.
          • Metronidazole Oral tablet; Adults: 500 mg PO 3 times daily for 10 days.
        • IV
          • Metronidazole Solution for injection; Infants, Children, and Adolescents: 7.5 mg/kg/dose (Max: 500 mg/dose) IV every 6 to 8 hours for 10 days plus vancomycin.
          • Metronidazole Solution for injection; Adults: 500 mg IV every 8 hours plus vancomycin.
    • Clindamycin c247
      • Clindamycin Phosphate Solution for injection; Infants, Children, and Adolescents 13 to 16 years: 40 mg/kg/day IV/IM divided every 6 to 8 hours (Max: 2,700 mg/day).
      • Clindamycin Phosphate Solution for injection; Adolescents 17 years: 600 mg IV/IM every 6 to 12 hours to 900 mg IV every 8 to 12 hours; every 6 to 8 hour intervals most commonly used in pediatric practice.
      • Clindamycin Phosphate Solution for injection; Adults: 600 mg IV/IM every 6 to 12 hours to 900 mg IV every 8 to 12 hours.
    • Antiviral agents c248
      • Oseltamivir c249
        • Oseltamivir Phosphate Oral suspension; Infants 1 to 8 months: 3 mg/kg/dose PO twice daily for 5 days.
        • Oseltamivir Phosphate Oral suspension; Infants 9 to 11 months: 3.5 mg/kg/dose PO twice daily for 5 days.
        • Oseltamivir Phosphate Oral suspension; Children weighing 15 kg or less: 30 mg PO twice daily for 5 days.
        • Oseltamivir Phosphate Oral suspension; Children weighing 16 to 23 kg: 45 mg PO twice daily for 5 days.
        • Oseltamivir Phosphate Oral suspension; Children weighing 24 to 40 kg: 60 mg PO twice daily for 5 days.
        • Oseltamivir Phosphate Oral suspension; Children and Adolescents weighing more than 40 kg: 75 mg PO twice daily for 5 days.
        • Oseltamivir Phosphate Oral capsule; Adults: 75 mg PO twice daily for 5 days.
      • Peramivir c250
        • Peramivir Solution for injection; Infants 30 to 90 days: 8 mg/kg/dose IV once daily for 5 days as alternative in patients who are unable to tolerate or absorb oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
        • Peramivir Solution for injection; Infants 91 to 180 days: 10 mg/kg/dose IV once daily for 5 days as alternative in patients who are unable to tolerate or absorb oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
        • Peramivir Solution for injection; Infants older than 180 days and Children 1 to 5 years: 10 to 12 mg/kg/dose IV once daily for 5 days as alternative in patients who are unable to tolerate or absorb oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
        • Peramivir Solution for injection; Children and Adolescents 6 to 17 years: 10 mg/kg/dose IV once daily (Max: 600 mg/dose) for 5 days as alternative in patients who are unable to tolerate or absorb oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
        • Peramivir Solution for injection; Adults: 600 mg IV once daily for 5 days as alternative in patients who are unable to tolerate or absorb oseltamivir. Consider longer courses (e.g., 10 days) for severely ill hospitalized patients or immunosuppressed patients.
    • Antifungal agents c251
      • Caspofungin r4c252
        • Caspofungin Solution for injection; Neonates† and Infants 1 to 2 months†: Very limited data available; other agents preferred (i.e., amphotericin B, fluconazole). 25 mg/m2/dose IV every 24 hours may provide comparable exposure to usual dose in adults. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treat for 2 weeks after documented clearance from bloodstream and resolution of symptoms. For invasive candidiasis with metastatic focus, therapy will be longer and response-dependent.
        • Caspofungin Solution for injection; Infants 3 months and older, Children, and Adolescents: 70 mg/m2 IV (Max: 70 mg/dose) loading dose on day 1, followed by 50 mg/m2/dose IV (Max: 70 mg/dose) once daily; if response inadequate, may increase to 70 mg/m2/day (Max: 70 mg/dose). Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treat for 2 weeks after documented clearance from bloodstream and resolution of symptoms. For invasive candidiasis with metastatic focus, therapy will be longer and response-dependent.
        • Caspofungin Solution for injection; Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. Treat for 2 weeks after documented clearance from bloodstream and resolution of symptoms. For invasive candidiasis with metastatic focus, therapy will be longer and response-dependent.
  • Vasopressors c253
    • Norepinephrine c254
      • First line therapy r4
      • Norepinephrine Bitartrate Solution for injection; Infants†, Children†, and Adolescents†: 0.1 mcg/kg/minute continuous IV infusion; titrate to clinical response (Usual Max: 2 mcg/kg/minute).
      • Norepinephrine Bitartrate Solution for injection; Adults: 0.1 mcg/kg/minute (weight-based) or 8 to 12 mcg/minute (flat-dose) continuous IV infusion, initially. Titrate by 0.02 mcg/kg/minute (or more in emergency cases) to clinical response. Usual dosage range: 0.05 to 0.4 mcg/kg/minute (weight-based) or 2 to 4 mcg/minute (flat-dose). Infusion rates up to 3.3 mcg/kg/minute have been used.
    • Epinephrine c255
      • First or second line therapy; may be added or used as an alternative to norepinephrine r4
      • Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion; titrate to clinical response. Doses up to 5 mcg/kg/minute may be necessary.
      • Epinephrine Hydrochloride Solution for injection; Adults: 0.05 to 2 mcg/kg/minute continuous IV infusion; titrate by 0.05 to 0.2 mcg/kg/minute every 10 to 15 minutes to clinical response.
    • Vasopressin c256
      • Second or third line therapy; may be added to norepinephrine if necessary or used as salvage therapy r4
      • Vasopressin Solution for injection; Adults: 0.01 unit/minute continuous IV infusion; titrate by 0.005 unit/minute every 10 to 15 minutes to clinical response. Max: 0.07 unit/minute.
    • Dopamine c257
      • Third line agent used only in patients with bradycardia and/or a low risk of tachyarrhythmias r4
      • Dopamine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 1 to 5 mcg/kg/minute continuous IV infusion, initially. Titrate by 2.5 to 5 mcg/kg/minute until desired hemodynamic response is attained. Usual Max: 15 to 20 mcg/kg/minute.
      • Dopamine Hydrochloride Solution for injection; Adults: 2 to 5 mcg/kg/minute continuous IV infusion, initially. Titrate by 5 to 10 mcg/kg/minute until desired hemodynamic and/or renal response is attained. Usual dosage: 2 to 20 mcg/kg/minute. Max: 50 mcg/kg/minute
  • Inotropes c258
    • Dobutamine c259
      • May be considered as an adjunct or alternative to vasopressor therapy in select cases r4
        • Elevated cardiac filling pressures and low cardiac output suggestive of myocardial dysfunction
        • Persistent clinical signs of hypoperfusion after adequate volume and mean arterial pressure have been achieved
      • Dobutamine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 0.5 to 1 mcg/kg/minute continuous IV infusion; titrate to clinical response. Usual dosage range: 2 to 20 mcg/kg/minute.
      • Dobutamine Hydrochloride Solution for injection; Adults: 0.5 to 1 mcg/kg/minute continuous IV infusion; titrate to clinical response. Usual dosage range: 2 to 20 mcg/kg/minute. Max: 40 mcg/kg/minute.
  • Corticosteroids c260
    • Hydrocortisone c261
      • Continuous IV hydrocortisone if fluid resuscitation and vasopressor therapy do not restore hemodynamic stability r4
      • Hydrocortisone Sodium Succinate Solution for injection; Infants and Children 1 month to 2 years: 2 mg/kg [weight-based], 25 mg [flat-dose], or 100 mg/m2 [BSA-based] IV bolus, followed by 1 to 2 mg/kg/day [weight-based] or 50 to 100 mg/m2/day [BSA-based] IV in divided doses at 6-hour intervals or as a continuous IV infusion.
      • Hydrocortisone Sodium Succinate Solution for injection; Children 3 to 12 years: 2 mg/kg (Max: 100 mg) [weight-based], 50 mg [flat-dose], or 100 mg/m2 [BSA-based] IV bolus, followed by 1 to 2 mg/kg/day [weight-based] or 50 to 100 mg/m2/day [BSA-based] IV in divided doses at 6-hour intervals or as a continuous IV infusion.
      • Hydrocortisone Sodium Succinate Solution for injection; Adolescents: 2 mg/kg (Max: 100 mg) [weight-based], 100 mg [flat-dose], or 100 mg/m2 [BSA-based] IV bolus, followed by 1 to 2 mg/kg/day [weight-based] or 50 to 100 mg/m2/day [BSA-based] IV in divided doses at 6-hour intervals or as a continuous IV infusion.
      • Hydrocortisone Sodium Succinate Solution for injection; Adults: 50 mg IV every 6 hours or 200 mg/day continuous IV infusion. Taper dose once vasopressors are no longer required.

Nondrug and supportive care

Procedures
  • Fluid resuscitation c262
    • Begin fluid resuscitation with an infusion of isotonic crystalloid solution within the first hourr1 to patients with hypotension or a lactate level of 4 mmol/L; the recommended goal is 30 mL/kg within 3 hoursr1r4
      • Some experts favor use of a balanced solution (eg, lactated Ringer solution, Hartmann solution) over normal saline when large volumes are needed r43r66
    • Albumin may be needed in patients requiring large volumes of crystalloids r4
    • Take care not to administer too much fluid, especially if there is little hemodynamic response to initial fluids r66r67
    • Titrate initial and continued fluid administration based on physiologic parameters such as heart rate, blood pressure, respiratory rate, oxygen saturation, urine output, and (if invasive monitoring has been started) mean arterial pressure (goal is 65 mm Hg for most patients, including children older than 12 yearsr34) r4
      • Such clinical monitoring may be supplemented by bedside cardiac ultrasonography if available r34r40
    • As patient condition improves, de-escalate fluid therapy and/or adopt fluid removal strategies r57
    • May use normalization of lactate levels as a guide, in addition to hemodynamic parameters r4r38
    • After hemodynamic stabilization, a restrictive approach to IV fluid administration is associated with a reduced duration of mechanical ventilation and ICU stay when compared with a more liberal approach r68
  • Respiratory support
    • Give supplemental oxygen initially to all patients with sepsis to achieve target oxygen saturation of 94% to 98% in adultsr18c263
      • More intensive respiratory support is required if supplemental oxygen does not improve oxygenation
    • If necessary, use mechanical ventilation for sepsis-induced acute respiratory distress syndrome r4c264
      • May be needed to improve oxygenation, protect airway, or prevent imminent respiratory failure
      • Target a tidal volume of 6 mL/kg of predicted body weight
      • Target a plateau pressure of 30 cm H₂O or less
      • Apply PEEP to avoid alveolar collapse at end expiration
      • Use strategies of higher rather than lower levels of PEEP with moderate to severe acute respiratory distress syndrome
      • Implement recruitment maneuvers with severe refractory hypoxemia (eg, CPAP) if needed
      • Consider prone positioning in patients with a PaO₂/FiO₂ ratio of 100 mm Hg or less c265
      • Risk reduction strategies to prevent development of ventilator-associated pneumonia include: r69
        • Elevate head of bed to 30° to 45° c266
        • Selective oral and digestive decontamination c267
        • Oropharyngeal decontamination with oral chlorhexidine gluconate
      • Establish weaning protocols for patients to undergo spontaneous breathing trials regularly to evaluate whether mechanical ventilation can be discontinued
    • If possible, use noninvasive mask ventilation as an alternative to mechanical ventilation c268
    • Use caution with sedation, analgesia, and neuromuscular blockade in mechanically ventilated patients r4
      • Minimize continuous or intermittent sedation in mechanically ventilated patients
      • Avoid neuromuscular blockade in patients without sepsis-induced acute respiratory distress syndrome
      • Use a short course of neuromuscular blockade of not longer than 48 hours for patients with early sepsis-induced acute respiratory distress syndrome and a PaO₂/FiO₂ ratio less than 150 mm Hg
  • Source control r4r23
    • Determine source of infection as quickly as possible, and begin intervention within 12 hours if possible
    • Use the least invasive but adequately effective strategy for source control (eg, percutaneous versus open surgical technique)
    • Depending on the source, strategies may include the following:
      • Drain abscess c269
      • Debride infected tissue and necrotic tissue c270
      • Remove infected device c271
        • Remove intravascular catheters that are suspected to be a source as soon as an alternate access is established
  • Blood product administration r4c272
    • Blood products may be required after initial management in select cases
      • Transfuse RBCs if: c273
        • Hemoglobin level is less than 7 g/dL after tissue hypoperfusion has been treated adequately
          • Target hemoglobin level after transfusion is 7 to 9 g/dL for adults
          • Transfusion may be indicated at higher thresholds in patients with myocardial ischemia, hemorrhage, or severe hypoxemia
      • Administer platelets prophylactically if platelet count is: c274
        • 10,000 cells/mm³ or fewer in the absence of bleeding
        • 20,000 cells/mm³ or fewer with a significant risk of bleeding
        • 50,000 cells/mm³ or fewer for active bleeding, surgery, or invasive procedures
  • Glycemic control r4c275
    • Target an upper blood glucose level of 180 mg/dL or less in adults and children r23
    • Begin insulin dosing when 2 consecutive blood glucose level readings are greater than 180 mg/dL
    • Adjust insulin dose based on repeated blood glucose level measurements every 1 to 2 hours until glucose values and insulin rates are stable, then monitor every 4 hours and adjust insulin dose as needed
  • Deep vein thrombosis prophylaxis r4c276
    • Subcutaneous low-molecular-weight heparin daily is the recommended pharmacologic therapy
    • For creatinine clearance less than 30 mL/minute, use dalteparin or unfractionated heparin
    • For those with a contraindication to pharmacoprophylaxis, mechanical prophylactic treatment is recommended
    • Combination of daily pharmacologic therapy and intermittent pneumatic compression devices may be used in patients who have no contraindications to either measure
  • Stress ulcer prophylaxis r4
    • Recommended for patients at risk for bleeding, such as those with the following:
      • Thrombocytopenia
      • Multiorgan failure
      • Mechanical ventilation
    • Proton pump inhibitors rather than H₂ blockers are preferred c277c278
  • Renal replacement therapy r4c279
    • For patients with acute renal failure resulting from sepsis
      • Continuous renal replacement therapies and intermittent hemodialysis are equivalent in most patients
      • Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients
  • Nutrition r4
    • Administer oral feedings or (if necessary) enteral feedings within the first 48 hours after diagnosis
    • Avoid mandatory full caloric feeding in the first week c280
      • Advance low-dose feeding only as tolerated
    • Avoid parenteral nutrition in the first week, even if enteral feeding is not possible initially; use IV glucose and attempt to advance enteral feeding c281
    • Consider prokinetic agents in patients with feeding intolerance c282
    • Consider a postpyloric feeding tube in patients with feeding intolerance who are at risk for aspiration c283
    • Use nutrition without specific immunomodulating supplementation

Comorbidities

  • Common comorbidities include conditions that cause immunosuppression: c284
    • HIV infection r3r16c285
    • Hematologic malignancies r3c286
    • Splenic deficiency r3c287
    • Chronic conditions requiring high-dose corticosteroids or other immunosuppressant therapy r3
    • Chronic renal failure r16c288
    • Diabetes mellitus r16c289
    • Excessive alcohol use r16c290

Special populations

  • Elderly people r6
    • Elderly people are more likely to have repeated antimicrobial exposure owing to chronic illness and medical intervention, resulting in multidrug-resistant microbial flora; very-broad-spectrum empirical antimicrobial therapy is required
    • Age-related renal and hepatic impairment put elderly people at higher risk for adverse events related to drug therapy; careful drug monitoring is necessary, and dose adjustment may be necessary
    • Increased capacitance of vasculature in elderly people creates a narrower therapeutic range of fluid resuscitation; there is a risk for either underresuscitation or fluid overload
  • Pediatric patients r20r70r71
    • Assessment parameters are altered for pediatric patients
      • Vital signs and WBC counts are age dependent (tables are availabler70)
      • Target mean arterial pressure is generally between the 5th and 50th percentile or greater than 50th percentile for age r23
      • Pediatric patients who are in septic shock often have a lactate level within normal range; do not exclude sepsis based on lactate levels within normal range r20
      • May use trends in lactate level to guide resuscitation r23
    • Young children are at greater risk for respiratory collapse than older children and adults r70
      • Begin high-flow oxygen within the first few minutes
      • Avoid mechanical ventilation if less invasive means of respiratory support are adequate, owing to associated increased intrathoracic pressure, which can reduce venous return and worsen shock r20
        • If mechanical ventilation is necessary, institute lung-protective strategies (eg, high-frequency oscillatory ventilation)
      • Extracorporeal membrane oxygenation is suggested for pediatric patients with refractory respiratory failure related to septic shock and/or refractory septic shock r20r23r71
    • Vascular access is more difficult in pediatric patients but may be aided by use of ultrasonography
      • Intraosseous route is an option for fluid resuscitation and delivery of antibiotics (preferably within 1 hour) and other medications r71
      • As soon as access is obtained, administer isotonic crystalloids (preferred) or albumin r71
        • Balanced/buffered crystalloids (eg, lactated Ringer solution) are preferred over 0.9% saline unless there is a specific indication for an alternative type of fluid r23
        • Give bolus of 10 to 20 mL/kg over 5 to 10 minutes and repeat as needed, to a total of 40 to 60 mL/kg, aiming to restore age-appropriate blood pressure and heart rate, capillary refill (2 seconds or less), strong peripheral pulses, urine output (more than 1 mL/kg/hour), and mentation r23
        • A pump may be required to deliver such volume at the necessary rate
    • Vasopressors and inotropic agents may be required earlier in pediatric patients owing to limited ability to increase heart rate beyond higher baseline rates typical in children r71
      • Either epinephrine or norepinephrine is the first line agent given when hemodynamic parameters do not improve with 40 to 60 mL/kg fluids, or if signs of fluid overload preclude further fluid resuscitation
    • May consider adjunctive hydrocortisone for children with septic shock that is refractory to fluid and vasoactive-inotropic therapy r23
    • Give stress doses of hydrocortisone to children with acute or chronic corticosteroid exposure, hypothalamic-pituitary-adrenal axis disorders, congenital adrenal hyperplasia, or recent treatment with ketoconazole or etomidate r23
    • Hypoglycemia and hypocalcemia are common in children with sepsis; the former may be an indicator of adrenal insufficiency r71
    • Pediatric patients are at increased risk for toxic shock; clindamycin (in addition to primary antistaphylococcal or antistreptococcal therapy) and antitoxin therapy (eg, IV immunoglobulin) are recommended for toxic shock syndrome with refractory hypotension r20

Monitoring

  • Monitor blood pressure, heart rate, mean arterial pressure (for patients with shock), and urine output continuously during fluid resuscitation c291c292c293c294
  • Monitor serum lactate levels every 2 hours to guide fluid resuscitation c295
  • Follow published recommendations for dosing and monitoring if treating with vancomycin r72
  • Serum procalcitonin, although not considered to be diagnostic for sepsis, may be followed as a way to determine when antibiotics may be safely discontinued c296

Complications and Prognosis

Complications

Prognosis

  • Mortality rate varies depending on response to treatment and severity at presentation r2r73
  • With sepsis now defined as including organ failure (since 2016),r7 the portion of the evidence base from before 2016 that is most relevant is the portion reporting on the categories of "severe sepsis and septic shock" (as then defined) r73r74
  • Under those definitions, some representative reports gave mortality ranges as follows:
    • Severe sepsis: 25% to 30% r2r3
    • Septic shock: 40% to 70% r2r3
      • In septic shock, mortality increases by 7.6% for every hour that appropriate antimicrobial medications are delayed r8
  • Patients who survive sepsis have a higher mortality rate after discharge as well as higher incidences of persistent pulmonary dysfunction, physical disability, cognitive dysfunction, and posttraumatic stress disorder r2

Screening and Prevention

Screening c306

Prevention

  • Prevention of community-acquired infection
    • Vaccination
      • Annual influenza vaccine for all persons older than 6 months r75r76c307
      • Age-appropriate vaccines for children and adolescents r76c308
      • Pneumococcal vaccines for older adults (23-valent pneumococcal polysaccharide vaccine for everyone aged 65 years or older; it may be preceded by 13-valent pneumococcal conjugate vaccine as individualized by shared decision making) r75r77c309
      • Other vaccines (eg, meningococcus, Haemophilus species) as recommended for chronic conditions or immunodeficiency r75r76
    • Wound care c310
    • Personal hygiene c311
  • Prevention of medical care–associated infection r78
    • Proper hand hygiene and general infection control measures c312c313
    • Oral care and positioning to prevent hospital-acquired pneumonia and ventilator-associated pneumonia c314c315
    • Care and timely removal of indwelling devices (eg, urinary catheters, IV access) c316c317
    • Wound and surgical site care c318
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