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    Sep.18.2024

    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 often includes fever, tachypnea, tachycardia, hypotension, and signs of tissue hypoperfusion
    • Diagnosis is based on history and clinical presentation, together with laboratory test 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 anatomical site of infection
    • Treatment includes immediate stabilization, fluid resuscitation, collection of blood and other relevant specimens for culture, 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 on recognition r3
    • Early lactate measurement is key to recognizing sepsis; delay is associated with increased mortality r5
    • Surviving Sepsis Campaign bundle (2021) recommends doing the following within the first hour when diagnosis is suspected: r1r4
      • Measure lactate level
      • Obtain blood specimens for culture
      • 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 r2
    • Presentation of sepsis in older adults is often different from presentation in younger people, which may delay diagnosis and treatment r6
      • Be aware of subtle signs of sepsis in older adults, including delirium, urinary incontinence, weakness, malaise, anorexia, and falls
      • Older adult 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 (Sequential Organ Failure Assessment; originally the Sepsis-Related Organ Failure Assessment) of 2 or more 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 MAP (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 r3
    • Low threshold of suspicion and early recognition of sepsis are essential for successful outcomes r3
    • Thorough and timely history focuses on symptoms, comorbidities, recent surgery, recent antibiotic use, presence of medical devices, and travel r3
    • Common generalized symptoms of sepsis include: r3
      • 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: r3
      • 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 with gastrointestinal luminal infections, such as Clostridioides 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
    • Older adults may have limited or nonspecific symptoms (eg, poor oral intake, inanition) r3c26c27

    Physical examination

    • Physical examination focuses on detecting generalized signs of sepsis and determining the source; a careful and thorough examination may uncover an unexpected site
    • Generalized evidence of sepsis is highly variable but commonly includes:
      • Fever (above 38.5 °C) or hypothermia (below 36 °C) c28
        • Fever is the most common sign of sepsis
      • Hypotension (systolic blood pressure lower than 90 mm Hg and/or MAP lower than 70 mm Hg) c29c30
        • Presenting sign in 40% of patients with sepsis r3
      • Tachycardia (heart rate greater than 90 beats per minute) c31
      • Tachypnea (respiratory rate greater 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 (longer 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
          • Surgical incisions and IV sites on currently or recently hospitalized patients c61c62
        • There may be erythema and/or edema on inspection c63c64
        • Drainage may be evident, either spontaneous or expressed c65
        • Crepitus or fluctuance 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 site 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 patients with neutropenia 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%) r3
        • Common sources of 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 species 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 patients who have received broad-spectrum antibiotics c91
            • Obstruction of urine flow 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 c98d5
            • Cholecystitis, cholangitis; biliary obstruction caused by gallstone impaction increases the risk of severe infection c99c100d6
            • Bowel infarction or perforation with peritonitis c101c102c103d7
            • Diverticulitis 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 infections are prevalent in many areas c112
                • Presentation of MRSA infection is often characterized by deep red or violaceous erythema surrounding a necrotic center, resembling a spider bite
            • Carbuncles c113
              • Usually caused by 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 and yeast are also common pathogens c120c121c122c123c124
            • Necrotizing fasciitis c125d11
              • Group A Streptococcus or synergistic polymicrobial infections are the most common cause 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
    • Older adults 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 r2c150
    • Genetic variants leading to deficiency of mannose-binding lectin are associated with increased risk of sepsis, particularly pneumococcal sepsis r2
    • Other hypotheses related to genetic predisposition to sepsis have been considered but are as yet unproven r2
    Ethnicity/race
    • Black Americans are twice as likely to develop sepsis as 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 Americans have a lower incidence of sepsis and a lower case fatality rate than Black Americans; rates among Hispanic Americans are similar to those among 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 c160c161c162
      • Cancer r19
      • Diabetes r20
      • Obesity r21
      • 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: r18c167c168c169c170
        • Immunodeficiency c171
        • Diabetes or gestational diabetes c172
        • Invasive procedures such as cesarean or forceps delivery c173c174c175
        • Prolonged rupture of membranes c176
        • Close contact with people with group A streptococcal infection
        • Continued vaginal bleeding or discharge with offensive odor c177c178

    Diagnostic Procedures

    Primary diagnostic tools

    • Diagnosis is based primarily on history and physical examination, coupled with laboratory test results providing evidence for an inflammatory process and a microbial infection c179
    • 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 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 for patients not in ICU c180
      • 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 r22
    • Initial laboratory tests for all patients include a CBC with differential; a metabolic panel; creatinine, bilirubin, and lactate levels; coagulation tests; blood gas levels; and urinalysis r3r7c181c182c183c184c185c186c187c188
      • Elements of SOFA score include platelet count, bilirubin level, creatinine level, and PaO₂ (partial pressure of oxygen) r7
      • Obtain results promptly; in particular, measure lactate level within 1 hour of presentation of patient with possible sepsis r1
    • For all patients, obtain blood and a specimen from any suspected source of infection for culture. Do this before initiation of antimicrobial therapy if it can be done without significant delay (less than 45 minutes) r23c189
    • Additional laboratory tests may provide etiologic information (eg, rapid influenza antigen testing; 1,3-β-D-glucan assay; legionella and pneumococcal antigens) r3r23c190c191c192
    • Perform imaging (eg, radiography, ultrasonography, CT, MRI) to confirm suspected anatomical site of infection; specific choice of imaging mode depends on site of suspected infection r24c193c194c195c196
    • Measurement of MAP is indicated for patients with persistent hypoperfusion after fluid challenge r23
      • May provide support for 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 in both diagnosis and management remains unclear r25r26c197c198

    Laboratory

    • CBC r24c199
      • 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 r24c200c201
      • 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 greater 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 c202
      • Elevated serum lactate level is both diagnostic and prognostic for sepsis because 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
        • Monitored serially in protocols for goal-directed therapy for sepsis
      • In adults, blood lactate level greater than 2 mmol/L is a defining criterion for septic shock r27
        • 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 are also associated with increased mortality from septic shock, but the optimal threshold has not been established r27
    • Coagulation tests r24c203
      • 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 c204c205
      • 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 r24
    • Cultures to determine pathogen and susceptibility to antibiotics
      • Blood cultures c206
        • 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) r23r27
          • Sensitivity of blood cultures is significantly reduced if done even shortly after initiation of empiric antimicrobial therapy r28
        • Draw 2 sets of blood specimens for culture, each for both aerobic and anaerobic incubation, from separate sites r23
        • If vascular access devices are present and have been in place for 48 hours or more, draw blood for culture from each device if possible and from at least 1 peripheral site r23
          • If the specimen from the peripheral site and the specimen from the vascular access device develop the same pathogen on culture, the vascular access device is likely the source of sepsis
            • Culture positivity more than 2 hours earlier in blood drawn from the device compared with 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 for 50% to 65% of patients with sepsis r3
      • Urine cultures c207
        • Performed in conjunction with urinalysis for patients with suspected sepsis if urinary tract is a possible source r24
      • Stool culture c208
        • May be performed for patients with diarrhea who have been in the hospital for less 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
        • In addition, consider tests for Clostridioides difficile toxin in patients with diarrhea and recent antibiotic use
      • Sputum culture c209
        • Performed in conjunction with Gram stain for suspected respiratory source of sepsis r24
        • 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 c210
        • Performed in conjunction with Gram stain on drainage from abscesses or surgical sites r24
        • Culture of intact skin (eg, in cellulitis) is of little value and should not be done
      • Cerebrospinal fluid cultures c211
        • 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 r29c212
    • Urine testing for legionella and pneumococcal antigens is advisable for patients with severe community-acquired pneumonia r29c213c214
    • Serum 1,3-β-D-glucan assay and mannan and antimannan antibody assays are recommended when fungal sepsis is suspected r23c215

    Imaging

    • Radiography
      • Chest radiography is used to confirm the presence of pneumonia c216
      • Abdominal radiography identifies bowel perforation by the presence of free air; it may also provide preliminary imaging clues for other causes of sepsis by showing the presence of gallstones, kidney stones, or other abnormalities that can be further explored with other tests c217
      • Plain radiographs may also be of value in showing the presence of air in soft tissues (eg, necrotizing infections) or osteomyelitis c218
    • Ultrasonography
      • Abdominal ultrasonography is used to identify abdominal infections (eg, appendicitis, cholecystitis, pancreatitis) r30c219
      • Renal ultrasonography is used to identify renal obstruction or pyelonephritis c220
      • Echocardiography is used to identify endocarditis in patients with a cardiac murmur or suspected IV drug use c221
    • CT
      • CT of chest is used to confirm pneumonia as the source infection if chest radiography is not diagnostic c222
      • CT of abdomen and pelvis is used to identify abdominal or pelvic abscesses (eg, pancreatic abscess, renal abscess) or ischemic bowel c223
      • CT may also be used to determine depth and extent of some serious soft tissue infections (eg, necrotizing fasciitis) c224
    • MRI
      • MRI of brain and/or spine is used in evaluation of meningitis, encephalitis, and epidural abscess c225c226

    Functional testing

    • SOFA score r7c227
      • Either the standard score or the quick version (qSOFA) is recommended for all patients to identify organ dysfunction, a defining feature of sepsis r4
      • Do not use qSOFA as a single screening tool for sepsis or septic shock r4
      • In the standard version (0-4 points), an increase from baseline of 2 points or more indicates presence of organ failure; if baseline is unknown, assume it to be 0. Assign 0 to 4 points for each of the following parameters:
        • PaO₂/FiO₂ ratio (partial pressure of oxygen to fraction of inspired oxygen)
          • 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
        • MAP/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
      • qSOFA score
        • Consists of 3 parameters. Presence of any 2 of the following 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) r23c228
      • MAP
        • Calculation of average pressure in 1 cardiac cycle and a measure of organ perfusion
        • MAP of less than 60 mm Hg suggests that tissue oxygen and nutrient needs are not being met

    Differential Diagnosis

    Most common r3

    • Hypovolemic or hemorrhagic shock c229c230
      • Rapid fluid loss resulting in inadequate circulating volume and hypoperfusion; most often caused by burns, trauma, gastrointestinal bleeding, or 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 that indicate source of hemorrhage or other volume loss
    • Pulmonary embolism r31c231d15
      • 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, which detects pulmonary emboli; D-dimer levels are usually elevated
    • Myocardial infarction c232d16
      • 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 ST elevation, ST depression, or T-wave inversion on ECG; cardiac troponin level is elevated
    • Acute pancreatitis r32c233d9
      • 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 r33c234d17
      • 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, and decreased serum bicarbonate level
    • Adrenal insufficiency r34c235d18
      • 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 and elevated adrenocorticotropic hormone level
    • Transfusion reaction r35c236
      • 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 that diagnosis is suspected r1
        • Begin fluid resuscitation for patients who are hypotensive or who have serum lactate levels of 4 mmol/L or higher; complete within 3 hours after presentation
        • If hypotension persists during or after fluid resuscitation, start vasopressors immediately
    • Initial antimicrobial treatment: broad-spectrum agents until 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 r36

    Recommendations for specialist referral

    • Refer to an infectious diseases specialist to identify cause and direct appropriate antimicrobial therapy
    • Consult a 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 regardless of setting r4

    • Implementation of multidisciplinary sepsis bundles that promote early identification and provide management protocols may result in improved outcomes r1r37

    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 r3
    • Invasive monitoring of hemodynamic parameters is recommended for patients with septic shock, and it can be used for 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 r38
    • Establish adequate IV access (2 large-gauge IV devices, preferably 18 gauge or larger) and begin infusing crystalloid solution immediately on 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 reduce mortality in more recent studies r23r39r40r41
      • Nevertheless, adequate fluid resuscitation is essential, and many patients require large volumes, depending on hemodynamic response
        • Normalization of lactate levels may also be used as a guide to adequate fluid resuscitation r42r43
        • 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 r38r44
      • 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 r4r45r46
      • Normal saline has typically been the primary IV fluid given; however, balanced crystalloid solutions (eg, lactated Ringer solution) are now recommended because they may have fewer adverse metabolic effects and a lower rate of complications r4r47
    • After collecting blood and other specimens for culture, but within the first hourr4r1 of recognizing septic shock or a high likelihood of sepsis, begin antimicrobial therapy r27
      • Immediate (within 1 hour) administration of antibiotics may reduce mortality by as much as 33% compared with later administration r48r49
      • Most recent Surviving Sepsis guidelines recommend antibiotic administration as soon as possible, ideally within 1 hour for adult patients with possible septic shock or a high likelihood of sepsis r4
      • For adult patients with possible sepsis without shock, the recommendation is to quickly assess for infection and administer antibiotics within 3 hours if sepsis is still suspected r4
      • International guidelines for children recommend starting antibiotic therapy as soon as possible after appropriate evaluation and: r27
        • Ideally within 1 hour of recognition for those with septic shock
        • Within 3 hours of recognition for those with sepsis-associated organ dysfunction but without shock r4
      • Initial antimicrobial therapy is empiric
        • Begin with IV anti-infective 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 r3r27
        • Current Surviving Sepsis guidelines recommend empiric combination therapy using at least 2 antibiotics from different classes for patients with septic shock r23
        • 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) r23
          • While continuous infusion has advantage of delivering constant drug levels above the minimal inhibitory concentration, a randomized trial comparing meropenem given as a continuous or intermittent infusion showed no significant difference in mortality or length of stay r50
        • Optimize antibiotic therapy once culture and sensitivity results are available; this may involve broadening or narrowing coverage, or stopping antibiotic if sepsis is excluded r51
      • For suspected pneumonia r52
        • Community-acquired pneumonia
          • Broad-spectrum β-lactam agent (cefotaxime, ceftazidime, cefepime, or piperacillin-tazobactam) plus either a respiratory fluoroquinolone (moxifloxacin or levofloxacin) or azithromycin
        • Guidelines additionally recommend corticosteroids for 5 to 7 days r53
        • Medical care–associated pneumonia
          • Antipseudomonal carbapenem (imipenem, doripenem, or meropenem) or cefepime
          • If legionella is a possibility, add azithromycin or a fluoroquinolone r23
        • For either community-acquired or medical care–associated pneumonia, add oseltamivir if influenza is suspected or confirmed; IV peramivir can be used if oral or enteric oseltamivir cannot be tolerated r29r54
      • For suspected abdominal source r52
        • 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 r52
        • 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 r52
        • 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 r52
        • Community-acquired infection
          • Vancomycin plus a carbapenem (imipenem, doripenem, meropenem, or ertapenem)
        • Medical care–associated infection
          • Vancomycin plus cefepime
      • For unknown source in children r55
        • 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 are 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 oseltamivirr54
        • An echinocandin may be added for medical care–associated cases in which yeast is a possible pathogen (eg, cases involving indwelling vascular catheters, intra-abdominal infection, or neutropenia) r52
        • Add fidaxomicin, or oral or enteral vancomycin (with or without IV metronidazole) if Clostridioides difficile infection is a possibility r56
    • Provide vasopressor agents to target MAP 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 for patients with baseline hypertension r4
      • Higher MAP target of 75 to 85 mm Hg resulted in no difference in mortality or need for renal replacement therapy in patients with shock requiring vasoactive medications; in the subgroup of patients with history of chronic hypertension, targeting a higher MAP reduced risk for renal replacement therapy r57
      • Norepinephrine is first line therapy r23r58r59
        • 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 r60
      • Epinephrine and vasopressin may be added if necessary to achieve target MAP r4r61
        • Vasopressin is the preferred second line agent r62
      • Dopamine is a third line agent used only for patients meeting specific cardiac criteria r23r63
      • Vasopressor use requires balancing the risks of hypotension against vasopressor-associated complications; some evidence suggests lower vasopressor exposure is associated with reduced mortality r64
    • Consider inotropic therapy with dobutamine as an adjunct or alternative to vasopressor therapy in selected patients with elevated cardiac filling pressures and low cardiac output suggestive of myocardial dysfunction or persistent clinical signs of hypoperfusion after adequate volume and MAP have been achieved r4
    • Consider corticosteroid therapy with IV hydrocortisone if ongoing requirement for vasopressor therapy does not restore hemodynamic stability r4
      • Critical care medicine guidelines suggest the administration of corticosteroids in adult patients with septic shock r53
        • Short duration of high-dose corticosteroids of more than 400 mg/day of hydrocortisone is not recommended
      • These same guidelines recommend against corticosteroids in adult patients with sepsis not in shockr53
      • A meta-analysis showed that systemic corticosteroids hasten resolution of shock
        • 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 r65
    • 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 r4r66
        • Evidence suggests that transfusion to higher levels does not confer an advantage in terms of mortality or ischemic events r66r67
        • Acute hemorrhage, myocardial ischemia, or severe hypoxemia may necessitate a higher transfusion threshold r4
      • Administer platelets prophylactically to patients with sepsis, 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 histamine type-2 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) r23

    • Combination therapy is recommended in some circumstances, which are as follows: r4
      • Ongoing septic shock
      • Infection with certain multidrug-resistant pathogens such as Acinetobacter and Pseudomonas species r68r69r70r71
      • 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 for 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 r72
    • Procalcitonin levels within reference range can be used to support a decision to discontinue antibiotics for these patients and those who initially appeared septic but in whom no evidence of infection has emerged
      • Procalcitonin-guided antibiotic therapy results in shorter duration of treatment and reduced long-term infection-associated adverse events (eg, Clostridioides difficile infection) but no greater risk of treatment failure r73r74
    • Antimicrobial therapy may need to be continued beyond 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 r3c237
      • Broad-spectrum penicillins c238
        • Ampicillin-sulbactam c239
          • 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 for serious infections.
          • Ampicillin Sodium, Sulbactam Sodium Solution for injection; Adults: 3 g (2 g ampicillin and 1 g sulbactam) IV every 6 hours.
        • Piperacillin-tazobactam r23c240
          • 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: 4.5 g (4 g piperacillin and 0.5 g tazobactam) IV every 6 hours.
      • Cephalosporins c241
        • Third generation r23c242
          • Ceftriaxone c243
            • Ceftriaxone Sodium Solution for injection; Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 12 hours.
            • Ceftriaxone Sodium Solution for injection; Adults: 1 to 2 g IV every 12 to 24 hours.
          • Ceftazidime c244
            • Antipseudomonal third generation cephalosporin
            • Ceftazidime Sodium Solution for injection; Infants and Children: 90 to 150 mg/kg/day (Max: 6 g/day) IV divided every 8 hours; 200 to 300 mg/kg/day (Max: 6 g/day) IV divided every 8 hours for serious P. aeruginosa 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 r23c245
          • Cefepime c246
            • Cefepime Hydrochloride Solution for injection; Infants, Children, and Adolescents: 50 mg/kg/dose (Max: 2 g/dose) IV every 8 hours.
            • Cefepime Hydrochloride Solution for injection; Adults: 2 g IV every 8 hours.
      • Carbapenems r23c247
        • Imipenem-cilastatin c248
          • Imipenem, Cilastatin Sodium Solution for injection; Infants 1 to 2 months: 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).
          • Imipenem, Cilastatin Sodium Solution for injection; Adults: 500 mg IV every 6 hours or 1 g IV every 8 hours.
        • Meropenem c249
          • Meropenem Solution for injection; Infants, Children, and Adolescents: 20 to 40 mg/kg/dose (Max: 2 g/dose) IV every 8 hours.
          • Meropenem Solution for injection; Adults: 2 g IV every 8 hours.
      • Levofloxacin r23c250
        • Levofloxacin, Dextrose Solution for injection; Adults: 750 mg IV every 24 hours.
      • Azithromycin c251
        • Azithromycin Solution for injection; Infants, Children, and Adolescents 4 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 5-day treatment course.
        • Azithromycin Solution for injection; Adults: 500 mg IV once daily for at least 5 days.
      • Aminoglycosides c252
        • Amikacin c253
          • 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 every 24 hours.
        • Gentamicin r23c254
          • 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 every 24 hours.
      • Vancomycin c255
        • Oral dosing
          • For Clostridioides difficile infection
            • For initial episode
              • Vancomycin Hydrochloride Oral solution; Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 125 mg/dose) PO 4 times daily for 10 days.
              • Vancomycin Hydrochloride Oral capsule; Adults: 125 mg PO 4 times daily for 10 days.
            • For fulminant infection
              • Vancomycin Hydrochloride Oral solution; Infants, Children, and Adolescents: 10 mg/kg/dose (Max: 500 mg/dose) PO 4 times daily for 10 days; consider adding metronidazole IV.
              • Vancomycin Hydrochloride Oral capsule; Adults: 500 mg PO or via nasogastric tube 4 times daily with IV metronidazole. If clinical improvement after 48 to 72 hours, consider decreasing the dose to 125 mg PO every 6 hours for 10 days. If an ileus is present, consider adding vancomycin as a retention enema.
        • IV dosing
          • Vancomycin Hydrochloride Solution for injection; Infants 1 to 2 months: 45 to 60 mg/kg/day IV divided every 6 to 8 hours; adjust dose based on target PK/PD parameter. Consider loading dose of 20 to 35 mg/kg IV.
          • Vancomycin Hydrochloride Solution for injection; Infants and Children 3 months to 11 years: 60 to 80 mg/kg/day IV divided every 6 hours (Usual Max: 3,000 mg/day; may require up to 3,600 mg/day); adjust dose based on target PK/PD parameter. Consider loading dose of 20 to 35 mg/kg IV.
          • Vancomycin Hydrochloride Solution for injection; Obese Infants and Children 3 months to 11 years: 20 mg/kg/dose (Max: 3,000 mg/dose) IV loading dose, followed by 60 to 80 mg/kg/day IV divided every 6 hours (Usual Max: 3,000 mg/day; may require up to 3,600 mg/day); adjust dose based on target PK/PD parameter.
          • Vancomycin Hydrochloride Solution for injection; Children and Adolescents 12 to 17 years: 60 to 70 mg/kg/day IV divided every 6 to 8 hours (Usual Max: 3,000 mg/day; may require up to 3,600 mg/day); adjust dose based on target PK/PD parameter. Consider loading dose of 20 to 35 mg/kg (Max: 3,000 mg/dose) IV.
          • Vancomycin Hydrochloride Solution for injection; Obese Children and Adolescents 12 to 17 years: 20 mg/kg/dose (Max: 3,000 mg/dose) IV loading dose, followed by 60 to 70 mg/kg/day IV divided every 6 to 8 hours (Usual Max: 3,000 mg/day; may require up to 3,600 mg/day); adjust dose based on target PK/PD parameter.
          • Vancomycin Hydrochloride Solution for injection; Adults: 20 to 35 mg/kg/dose (Max: 3,000 mg/dose) IV loading dose, followed by 15 to 20 mg/kg/dose IV every 8 to 12 hours; adjust dose based on target PK/PD parameter.
          • Vancomycin Hydrochloride Solution for injection; Obese Adults: 20 to 25 mg/kg/dose (Max: 3,000 mg/dose) IV loading dose, followed by 15 to 20 mg/kg/dose IV every 8 to 12 hours (Usual Max: 4,500 mg/day); adjust dose based on target PK/PD parameter.
      • Fidaxomicin c256
        • For Clostridioides difficile infection
          • Fidaxomicin Oral suspension; Infants 6 months and older weighing 4 to 6 kg: 80 mg PO twice daily for 10 days.
          • Fidaxomicin Oral suspension; Infants and Children 6 months and older weighing 7 to 8 kg: 120 mg PO twice daily for 10 days.
          • Fidaxomicin Oral suspension; Infants and Children 6 months and older weighing 9 to 12.4 kg: 160 mg PO twice daily for 10 days.
          • Fidaxomicin Oral suspension; Children and Adolescents weighing 12.5 kg or more: 200 mg PO twice daily for 10 days.
          • Fidaxomicin Oral tablet; Adults: 200 mg PO twice daily for 10 days.
      • Metronidazole c257
        • Oral dosing
          • For nonsevere initial Clostridioides difficile infection
            • Metronidazole Oral suspension; 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 dosing
          • For general sepsis
            • Metronidazole Solution for injection; Infants, Children, and Adolescents: 22.5 to 40 mg/kg/day (Max: 1.5 g/day) IV divided every 8 hours.
            • Metronidazole Solution for injection; Adults: 500 mg IV every 8 to 12 hours.
          • For fulminant initial Clostridioides difficile infection
            • 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 c258
        • Clindamycin Solution for injection; Infants, Children, and Adolescents 1 month to 16 years: 40 mg/kg/day (Max: 2,700 mg/day) IV divided every 6 to 8 hours.
        • Clindamycin Solution for injection; Adolescents 17 years: 600 to 900 mg IV every 8 hours; doses up to 4,800 mg/day IV have been used for life-threatening infections in adults.
        • Clindamycin Solution for injection; Adults: 600 to 900 mg IV every 8 hours; doses up to 4,800 mg/day IV have been used for life-threatening infections.
      • Antiviral agents c259
        • Oseltamivir c260
          • 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 c261
          • Peramivir Solution for injection; Infants and Children 6 months to 12 years: 12 mg/kg/dose (Max: 600 mg/dose) IV as a single dose.
          • Peramivir Solution for injection; Adolescents: 600 mg IV as a single dose.
          • Peramivir Solution for injection; Adults: 600 mg IV as a single dose.
      • Antifungal agents c262
        • Caspofungin r23c263
          • Caspofungin Solution for injection; Infants 1 to 2 months†: Very limited data available. 25 mg/m2/dose IV once daily may provide comparable exposure to usual dose in adults. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Caspofungin Solution for injection; Infants, Children, and Adolescents 3 months to 17 years: 70 mg/m2/dose (Max: 70 mg/dose) IV loading dose on day 1, followed by 50 mg/m2/dose (Max: 70 mg/dose) IV once daily. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. May increase dose to 70 mg/m2/dose (Max: 70 mg/dose) if there is an inadequate clinical response. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
          • Caspofungin Solution for injection; Adults: 70 mg IV loading dose on day 1, then 50 mg IV once daily. Treat for 2 weeks after documented clearance from the bloodstream and resolution of signs and symptoms for invasive candidiasis without metastatic complications. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.
    • Vasopressors c264
      • Norepinephrine c265
        • Norepinephrine Bitartrate Solution for injection; Infants†, Children†, and Adolescents†: 0.1 mcg/kg/minute continuous IV infusion, initially. Titrate dose as needed based on 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 dose by 0.02 mcg/kg/minute (or more in emergency cases) every 2 to 5 minutes based on clinical response. Usual dose: 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 c266
        • Epinephrine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 1 mcg/kg/minute continuous IV infusion. Titrate dose as needed based on clinical response.
        • Epinephrine Hydrochloride Solution for injection; Adults: 0.01 to 2 mcg/kg/minute continuous IV infusion. Titrate dose by 0.05 to 0.2 mcg/kg/minute every 10 to 15 minutes based on clinical response.
      • Vasopressin c267
        • Vasopressin Solution for injection; Infants†, Children†, and Adolescents†: 0.1 to 8 milliunits/kg/minute continuous IV infusion; reserve for catecholamine-resistant shock, dosage range not well established.
        • Vasopressin Solution for injection; Adults: 0.01 unit/minute continuous IV infusion, initially; titrate by 0.005 unit/minute every 10 to 15 minutes to clinical response. Max: 0.07 unit/minute.
      • Dopamine c268
        • Dopamine Hydrochloride Solution for injection; Infants†, Children†, and Adolescents†: 1 to 5 mcg/kg/minute continuous IV infusion, initially. Titrate dose by 2.5 to 5 mcg/kg/minute as needed based on clinical response. 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 dose by 5 to 10 mcg/kg/minute based on clinical response. Usual dose: 2 to 20 mcg/kg/minute. Max: 50 mcg/kg/minute.
    • Inotropes c269
      • Dobutamine c270
        • Dobutamine Hydrochloride Solution for injection; Infants, Children, and Adolescents: 0.5 to 1 mcg/kg/minute continuous IV/IO infusion. Titrate every few minutes to clinical response. Usual dose: 2 to 20 mcg/kg/minute.
        • Dobutamine Hydrochloride Solution for injection; Adults: 0.5 to 1 mcg/kg/minute continuous IV infusion. Titrate every few minutes to clinical response. Usual dose: 2 to 20 mcg/kg/minute. Max: 40 mcg/kg/minute.
    • Corticosteroids c271
      • Hydrocortisone c272
        • 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 for 7 days or until ICU discharge.

    Nondrug and supportive care

    Procedures
    • Fluid resuscitation c273
      • 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
        • Guidelines recommend use of a balanced solution (eg, lactated Ringer solution, Hartmann solution) over normal saline r4r47r75
      • 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 r75r76
      • 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) MAP (goal is 65 mm Hg for most patients, including children older than 12 yearsr38) r4
        • Such clinical monitoring may be supplemented by bedside cardiac ultrasonography if available r38r44
      • As patient's condition improves, de-escalate fluid therapy and/or adopt fluid removal strategies r63
      • May use normalization of lactate levels as a guide, in addition to hemodynamic parameters r23r42
      • After hemodynamic stabilization, a restrictive approach to IV fluid administration (prioritizing vasopressors and lower IV fluid volumes) has been associated with a reduced duration of mechanical ventilation and ICU stay when compared with a more liberal approach (prioritizing higher volumes of IV fluids before vasopressor use) r77
      • However, 90-day mortality was not significantly different between patients with sepsis-induced hypotension refractory to initial fluid resuscitation who were treated with fluid restriction and early initiation of vasopressors compared with more liberal fluid administration r78r79
    • Respiratory support
      • Give supplemental oxygen initially to all adult patients with sepsis to achieve target oxygen saturation of 94% to 98%r18c274
        • More intensive respiratory support is required if supplemental oxygen does not improve oxygenation
      • For patients with severe hypoxia, increased ventilatory support may include noninvasive ventilation or high-flow oxygen via nasal canula (preferred) r4c275
      • If necessary, use mechanical ventilation for sepsis-induced acute respiratory distress syndrome r4c276
        • 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 r62
        • Target a plateau pressure of 30 cm H₂O or less
        • Apply positive end-expiratory pressure to avoid alveolar collapse at end expiration
        • Use strategies of higher rather than lower levels of positive end-expiratory pressure 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 c277
        • Risk reduction strategies to prevent development of ventilator-associated pneumonia include: r80
          • Elevate head of bed to 30° to 45° c278
          • Selective oral and digestive decontamination c279
          • Oral care with toothbrushing (without chlorhexidine)
        • Establish weaning protocols for patients to undergo spontaneous breathing trials regularly to evaluate whether mechanical ventilation can be discontinued
      • Use caution with sedation, analgesia, and neuromuscular blockade for 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 no 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 r4r27
      • 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 c280
        • Debride infected tissue and necrotic tissue c281
        • Remove infected device c282
          • Remove intravascular catheters that are suspected to be a source as soon as alternate access is established
    • Blood product administration r4c283
      • Blood products may be required after initial management in select cases
        • Transfuse RBCs if: c284
          • 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 for patients with myocardial ischemia, hemorrhage, or severe hypoxemia
        • Administer platelets prophylactically if platelet count is: c285
          • 10,000 cells/mm³ or lower in the absence of bleeding
          • 20,000 cells/mm³ or lower with a significant risk of bleeding
          • 50,000 cells/mm³ or lower for active bleeding, surgery, or invasive procedures
    • Glycemic control r4c286
      • Target an upper blood glucose level of 180 mg/dL or less in adults and children r27
      • Begin insulin dosing when 2 consecutive blood glucose level readings are higher 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 r4c287
      • Subcutaneous low-molecular-weight heparin daily is the recommended pharmacologic therapy
      • For creatinine clearance less than 30 mL/minute, use an alternate anticoagulant with lower renal clearance (eg, unfractionated heparin) or dose-adjusted low-molecular-weight heparin r81
      • For patients with a contraindication for pharmacoprophylaxis, mechanical prophylactic treatment is recommended
      • Combination of daily pharmacologic therapy and intermittent pneumatic compression devices may be used for patients who have no contraindications for 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 have been shown to significantly decrease clinically significant stress-related mucosal bleeding compared with histamine type-2 blockers r82c288c289
    • Renal replacement therapy r4c290
      • For patients with acute kidney failure resulting from sepsis
        • Continuous renal replacement therapies and intermittent hemodialysis are equivalent for most patients
        • Use continuous therapies to facilitate management of fluid balance in hemodynamically unstable septic patients
    • Nutrition r23
      • Administer oral feedings or (if necessary) enteral feedings within the first 48 hours after diagnosis
      • Avoid mandatory full caloric feeding in the first week c291
        • 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 c292
      • Consider prokinetic agents for patients with feeding intolerance c293
      • Consider use of a postpyloric feeding tube for patients with feeding intolerance who are at risk for aspiration c294
      • Use nutrition without specific immunomodulating supplementation

    Comorbidities

    • Common comorbidities include conditions that cause immunosuppression: c295
      • HIV infection r2r16c296
      • Hematologic malignancies r2c297
      • Splenic deficiency r2c298
      • Chronic conditions requiring high-dose corticosteroids or other immunosuppressant therapy r2
      • Chronic kidney failure r16c299
      • Diabetes mellitus r16c300
      • Excessive alcohol use r16c301

    Special populations

    • Older adult patients r6
      • 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 older adult patients at higher risk for adverse events related to drug therapy; careful drug monitoring is required, and dose adjustment may be necessary
      • Increased capacitance of vasculature in older adult patients creates a narrower therapeutic range of fluid resuscitation; there is a risk for either underresuscitation or fluid overload
    • Pediatric patients r24r83r84
      • Assessment parameters are altered for pediatric patients
        • Vital signs and WBC counts are age-dependent (tables are availabler84)
        • Target MAP is generally between the 5th and 50th percentiles or higher than the 50th percentile for age r27
        • Pediatric patients who are in septic shock often have a lactate level within reference range; do not exclude sepsis based on lactate levels within reference range r24
        • May use trends in lactate level to guide resuscitation r27
      • Young children are at greater risk for respiratory collapse than older children and adults r84
        • 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 r24
          • 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 r24r27r83
      • 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 and other medications r83
          • Avoid prolonged attempts to obtain IV access if difficult and quickly move to intraosseous route, except in children weighing less than 3 kg for whom intraosseous access is contraindicated r85
          • All emergency medications can be administered via interosseous route r85
        • As soon as access is obtained, administer isotonic crystalloids (preferred) or albumin r83
          • 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 r27
          • 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 r27
          • 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 r83
        • Either epinephrine or norepinephrine is the first line agent given when hemodynamic parameters do not improve with fluids (40 to 60 mL/kg) or when signs of fluid overload preclude further fluid resuscitation
      • May consider adjunctive hydrocortisone for children with septic shock refractory to fluid and vasoactive-inotropic therapy r27
      • 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 r27
      • Hypoglycemia and hypocalcemia are common in children with sepsis; the former may be an indicator of adrenal insufficiency r83
      • 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 r24
      • Up to 50% of children with sepsis do not have an obvious source of infection r85

    Monitoring

    • Monitor blood pressure, heart rate, MAP (for patients with shock), capillary refill, and urine output continuously during fluid resuscitation c302c303c304c305
    • Monitor serum lactate levels every 6 hours to guide fluid resuscitation c306
    • Follow published recommendations for dosing and monitoring if treating with vancomycin r86
    • Serum procalcitonin, although not considered to be diagnostic for sepsis, may be monitored as a way to determine when antibiotics may be safely discontinued c307

    Complications and Prognosis

    Complications

    Prognosis

    • Mortality rate varies depending on response to treatment and severity at presentation r3r87
    • With sepsis, now defined as including organ failure (since 2016),r7 the most relevant portion of the evidence base from before 2016 is the portion reporting on categories of "severe sepsis and septic shock" (as then defined) r87r88
    • 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 r3

    Screening and Prevention

    Screening c317

    Prevention

    • Prevention of community-acquired infection
      • Vaccination
        • Annual influenza vaccine for all persons older than 6 months r89r90c318
        • Age-appropriate vaccines for children and adolescents r90c319
        • Pneumococcal vaccines for older adults r89r91c320
        • Other vaccines (eg, meningococcus, Haemophilus species) as recommended for persons with chronic conditions or immunodeficiency r89r90
      • Wound care c321
      • Personal hygiene c322
    • Prevention of medical care–associated infection r92
      • Proper hand hygiene and general infection control measures c323c324
      • Oral care and positioning to prevent hospital-acquired pneumonia and ventilator-associated pneumonia c325c326
      • Care and timely removal of indwelling devices (eg, urinary catheters, peripheral IV catheters, central venous catheters) r93c327c328
      • Wound and surgical site care c329
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