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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 hour^r1), 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% ^r2^r3
- Septic shock has a mortality rate of 40% to 70% ^r2^r3

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: ^r1^r4
- 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 ^r7^r9
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 ^r7^r9

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 ^c1^c2^c3
- Confusion, anxiety ^c4^c5
- Fatigue, malaise ^c6^c7
- Myalgia ^c8
- Dyspnea ^c9
- Nausea and vomiting ^c10^c11
- Decreased urination ^c12
Localizing symptoms may include: ^r3
- Headache and stiff neck when meningitis is the cause of sepsis ^c13^c14
- Cough and pleuritic chest pain with pneumonia ^c15^c16
- 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 ^c19^c20
- Bone or joint pain with osteomyelitis or septic arthritis ^c21^c22
- Skin or soft tissue pain with abscesses, wounds, or other soft tissue infections ^c23^c24^c25
Older adults may have limited or nonspecific symptoms (eg, poor oral intake, inanition) ^r3^c26^c27

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) ^c29^c30
  - 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 ^c34^c35^c36
- Increased capillary refill time (longer than 3 seconds) ^c37
- Mottled skin on inspection; petechiae may be seen with severe thrombocytopenia or meningococcemia ^c38^c39
- Diaphoresis; clammy skin ^c40^c41
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 ^c42^c43
  - 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 ^c50^c51^c52
    - Localization of tenderness may indicate source (eg, right upper quadrant for liver or gallbladder infection) ^c53
- Genitourinary
  - Costovertebral tenderness and suprapubic pain on palpation ^c54^c55
  - Vaginal discharge or bleeding ^c56^c57
- Skin and soft tissue
  - Wounds, ulcerations, furuncles, or carbuncles on inspection ^c58^c59^c60
    - Surgical incisions and IV sites on currently or recently hospitalized patients ^c61^c62
  - There may be erythema and/or edema on inspection ^c63^c64
  - 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 ^c66^c67
  - Lymphadenopathy may be detected proximal to infection site ^c68
- Other less common findings may include:
  - Meningismus, Kernig sign, or Brudzinski sign in meningitis ^c69^c70^c71
  - 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 ^c73^c74
  - 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 ^c77^c78
    - 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) ^r10^c81
      - Community-acquired pneumonia ^d1
        Streptococcus pneumoniae and Staphylococcus aureus are commonly implicated in sepsis caused by pneumonia ^c82^c83
        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) ^r10^c85^d3
      - Usually gram-negative or enterococcal species ^c86^c87
        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 ^c92^c93
    - Gastrointestinal tract infections (account for 11% of sepsis cases): often polymicrobial, involving enteric gram-negative bacilli, streptococcal species, and anaerobes ^r10^c94^c95^c96^c97
      - Appendicitis ^c98^d5
      - Cholecystitis, cholangitis; biliary obstruction caused by gallstone impaction increases the risk of severe infection ^c99^c100^d6
      - Bowel infarction or perforation with peritonitis ^c101^c102^c103^d7
      - Diverticulitis ^c104^c105^d8
      - Pancreatitis may cause sepsis due to infection or may cause an inflammatory response that mimics sepsis ^c106^d9
    - Skin and soft tissue infections (account for 11%^r10 of sepsis cases) ^c107^c108
      - Cellulitis ^c109^d10
        Usually caused by Staphylococcus aureus or streptococci ^c110^c111
        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 aureus^c114
      - Wounds (traumatic or surgical) ^c115^c116
        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 ^c120^c121^c122^c123^c124
      - Necrotizing fasciitis ^c125^d11
        Group A Streptococcus or synergistic polymicrobial infections are the most common cause of this unusual life-threatening condition ^c126^c127^c128
    - Less common but important sources of sepsis include:
      - Bone and joint infections
        Osteomyelitis ^c129^d12
        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 ^c131^c132
      - Central nervous system infections ^c133
        Meningitis ^c134^d13
        Typical pathogens vary by age range; Streptococcus pneumoniae and Neisseria meningitidis are the most common ^c135^c136
        Encephalitis ^c137^d14
        Usually viral; HSV and West Nile virus have been associated with sepsis ^c138^c139
        Epidural abscess ^c140
        Uncommon; spinal epidural abscesses are usually secondary to bacteremia, with Staphylococcus aureus as the most frequent pathogen ^r11^c141

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 ^r13^c142
  - Aged 65 years or older: about 120 per 10,000 population ^r13^c143
  - Aged 85 years or older: about 270 per 10,000 population ^r13^c144
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) ^r15^c145
- Associated with prematurity, low birth weight, and maternal group B streptococcal infection ^r14^c146

Sex

Males are 25% to 30% more likely to develop sepsis than females ^r16^c147
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 ^r16^c148^c149

Genetics

Interleukin 1β-511 homozygosity is associated with increased risk of mortality from sepsis ^r2^c150
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 ^r16^r17^c151
- Likely caused by interaction between differences in incidence of chronic comorbidities, socioeconomic factors, and genetics ^r16^r17
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 ^r2^r3^r16^r18
- Recent surgery or hospitalization ^c152^c153
- Indwelling urinary catheters ^c154
- Intravascular access devices ^c155
- Endotracheal tubes ^c156
- Malnutrition ^c157
- Burns and/or trauma ^c158^c159
- Chronic illness ^c160^c161^c162
- Cancer ^r19
- Diabetes ^r20
- Obesity ^r21
- Immunosuppression (eg, immunosuppressive medical therapy, HIV infection) ^c163^c164^c165
- IV drug use ^r18^c166
- Pregnancy or recent childbirth, miscarriage, or pregnancy termination—particularly if the following are present: ^r18^c167^c168^c169^c170
  - Immunodeficiency ^c171
  - Diabetes or gestational diabetes ^c172
  - Invasive procedures such as cesarean or forceps delivery ^c173^c174^c175
  - Prolonged rupture of membranes ^c176
  - Close contact with people with group A streptococcal infection
  - Continued vaginal bleeding or discharge with offensive odor ^c177^c178

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 ^r3^r7^c181^c182^c183^c184^c185^c186^c187^c188
- 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) ^r23^c189
Additional laboratory tests may provide etiologic information (eg, rapid influenza antigen testing; 1,3-β-D-glucan assay; legionella and pneumococcal antigens) ^r3^r23^c190^c191^c192
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 ^r24^c193^c194^c195^c196
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 ^r25^r26^c197^c198

Laboratory

CBC ^r24^c199
- 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 ^r24^c200^c201
- 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 ^r24^c203
- 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 ^c204^c205
- 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) ^r23^r27
    - 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 ^r29^c212
Urine testing for legionella and pneumococcal antigens is advisable for patients with severe community-acquired pneumonia ^r29^c213^c214
Serum 1,3-β-D-glucan assay and mannan and antimannan antibody assays are recommended when fungal sepsis is suspected ^r23^c215

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) ^r30^c219
- 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 ^c225^c226

Functional testing

SOFA score ^r7^c227
- 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) ^r23^c228
- 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 ^c229^c230
- 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 ^r31^c231^d15
- 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 ^c232^d16
- 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 ^r32^c233^d9
- 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 ^r33^c234^d17
- 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 ^r34^c235^d18
- 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 ^r35^c236
- 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 ^r1^r37

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 ^r1^r4
- Early goal-directed therapy, a core component of previous sepsis guidelines, has not been shown to reduce mortality in more recent studies ^r23^r39^r40^r41
- 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 ^r42^r43
  - 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 ^r38^r44
- 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 ^r4^r45^r46
- 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 ^r4^r47
After collecting blood and other specimens for culture, but within the first hour^r4^r1 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 ^r48^r49
- 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 ^r3^r27
  - 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 ^r29^r54
- 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 oseltamivir^r54
  - 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 ^r23^r58^r59
  - 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 ^r4^r61
  - Vasopressin is the preferred second line agent ^r62
- Dopamine is a third line agent used only for patients meeting specific cardiac criteria ^r23^r63
- 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 shock^r53
- 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 ^r4^r66
  - Evidence suggests that transfusion to higher levels does not confer an advantage in terms of mortality or ischemic events ^r66^r67
  - 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 ^r68^r69^r70^r71
- 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 ^r73^r74
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 ^r3^c237
- 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 ^r23^c240
    - 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 ^r23^c242
    - 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 ^r23^c245
    - 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 ^r23^c247
  - 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 ^r23^c250
  - 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 ^r23^c254
    - 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 ^r23^c263
    - 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 hour^r1 to patients with hypotension or a lactate level of 4 mmol/L; the recommended goal is 30 mL/kg within 3 hours^r1^r4
  - Guidelines recommend use of a balanced solution (eg, lactated Ringer solution, Hartmann solution) over normal saline ^r4^r47^r75
- 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 ^r75^r76
- 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 years^r38) ^r4
  - Such clinical monitoring may be supplemented by bedside cardiac ultrasonography if available ^r38^r44
- 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 ^r23^r42
- 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 ^r78^r79
Respiratory support
- Give supplemental oxygen initially to all adult patients with sepsis to achieve target oxygen saturation of 94% to 98%^r18^c274
  - 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) ^r4^c275
- If necessary, use mechanical ventilation for sepsis-induced acute respiratory distress syndrome ^r4^c276
  - 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 ^r4^r27
- 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 ^r4^c283
- 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 ^r4^c286
- 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 ^r4^c287
- 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 ^r82^c288^c289
Renal replacement therapy ^r4^c290
- 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 ^r2^r16^c296
- Hematologic malignancies ^r2^c297
- Splenic deficiency ^r2^c298
- Chronic conditions requiring high-dose corticosteroids or other immunosuppressant therapy ^r2
- Chronic kidney failure ^r16^c299
- Diabetes mellitus ^r16^c300
- Excessive alcohol use ^r16^c301

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 ^r24^r83^r84
- Assessment parameters are altered for pediatric patients
  - Vital signs and WBC counts are age-dependent (tables are available^r84)
  - 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 ^r24^r27^r83
- 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 ^c302^c303^c304^c305
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

Ventilator-associated pneumonia ^r23^c308^d2
End-organ dysfunction (eg, renal, pulmonary) ^r24^c309^c310^c311
Deep vein thrombosis ^r23^c312^d19
Stress ulcer ^r23^c313
Physical, cognitive, and emotional disabilities ^r3^c314^c315^c316

Prognosis

Mortality rate varies depending on response to treatment and severity at presentation ^r3^r87
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) ^r87^r88
Under those definitions, some representative reports gave mortality ranges as follows:
- Severe sepsis: 25% to 30% ^r2^r3
- Septic shock: 40% to 70% ^r2^r3
  - 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 ^r89^r90^c318
  - Age-appropriate vaccines for children and adolescents ^r90^c319
  - Pneumococcal vaccines for older adults ^r89^r91^c320
  - Other vaccines (eg, meningococcus, Haemophilus species) as recommended for persons with chronic conditions or immunodeficiency ^r89^r90
- Wound care ^c321
- Personal hygiene ^c322
Prevention of medical care–associated infection ^r92
- Proper hand hygiene and general infection control measures ^c323^c324
- Oral care and positioning to prevent hospital-acquired pneumonia and ventilator-associated pneumonia ^c325^c326
- Care and timely removal of indwelling devices (eg, urinary catheters, peripheral IV catheters, central venous catheters) ^r93^c327^c328
- Wound and surgical site care ^c329

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