Sepsis and Septic Shock (Clinical)

Organ dysfunction resulting from a dysregulated systemic host response to

infection separates sepsis from uncomplicated infection. The etiology is mainly
bacterial and pneumonia is the most common known source. Patients
commonly present with fever, tachycardia, tachypnea, hypotension, and/or
altered mentation. Septic shock is diagnosed during treatment when
vasopressors are necessary to control hypotension. Sepsis and septic shock
are medical emergencies, and antibiotics are given within an hour of diagnosis.

Last updated: August 28, 2023

CONTENTS

Overview
Etiology and Pathophysiology
Clinical Presentation
Diagnosis
Management
References

Overview
Definitions
 Sepsis: a potentially life-threatening organ dysfunction caused by a
dysregulated host response to infection
Septic shock: sepsis with a substantial increase in mortality risk due to
circulatory and cellular/metabolic abnormalities

Epidemiology[2,5]
Mortality ranges from 20%–50% (higher in septic shock)
More common in survivors:
Hospital readmission (about 40% within 3 months)
Early death
Physical and neurocognitive dysfunction
Mood disorders
Low quality of life
Leading cause of death in hospitalized patients
Nearly 20% of all global deaths
Higher incidence in extremes of age, men, and Black people
Septic shock follows in 30% of sepsis cases.

Risk factors[2,5,14]
Chronic diseases (e.g., chronic obstructive pulmonary disease, HIV
infection, and cancer)
Immunosuppression
Prior organ dysfunction
Recent invasive procedure or surgery
Breach of skin integrity
IV drug use
Indwelling catheters

Etiology and Pathophysiology

Etiology[2,5]
 May be community- or hospital-acquired
Source of infection:
Identified in ⅓ of patients
Most commonly pneumonia, followed by intra-abdominal and
genitourinary infections
Cultures:
Blood cultures: positive in ⅓ of patients
Negative cultures from all sites are common
Most common gram-positive pathogens:
Staphylococcus aureus
Streptococcus pneumonia
Most common gram-negative pathogens:
Escherichia coli
Klebsiella spp.
Pseudomonas aeruginosa
Fungi: reported in about 20% of cases
Viruses: reported in only 1% of cases

Pathophysiology[2,5]
Pathogen load and virulence + host genetic composition and comorbidities
result in a complex, exaggerated, and prolonged host response to infection
that evolves over time.
1. Recognition of pathogen-associated molecular patterns (PAMPs) by
pathogen recognition receptors on innate immune cells → inflammatory
response (e.g., release of tumor necrosis factor) → tissue damage and
necrotic cell death → release of damage-associated molecular patterns
(DAMPs) → further activation of leukocytes → microvascular changes
(endothelial cell dysfunction + coagulation and complement activation)
2. Macrovascular changes: vasodilation and hypotension
3. Microvascular changes + macrovascular changes → vascular leak, edema,
intravascular volume depletion → impaired tissue oxygenation, cellular
alterations such as greater glycolysis (lactate production), mitochondrial
injury, and release of oxygen species → increasing organ damage
Clinical Presentation
Skin and peripheral pulses:[2,5]
Early septic shock with low volume status: cold extremities and
narrow pulse pressure reflecting increased systemic vascular
resistance (SVR) and reduced cardiac output (CO)
With progression of shock: relatively warm extremities and widening
of pulse pressure reflecting reduced SVR and increased CO
Respiratory failure:
Symptoms of acute respiratory distress syndrome (ARDS) including:
Tachypnea
Shallow breathing
Use of accessory muscles
Respiratory fatigue with paradoxical abdominal movement
Bilateral rales (crackles)
Hypoxia
Bilateral pulmonary infiltrates not explained by heart failure
Cardiac failure:
Hypotension
Tachycardia
Tachypnea
Pulmonary rales subsequent to pulmonary edema
Acute kidney injury (AKI):
Decreased urinary output (oliguria)
Azotemia/uremia
Neurologic presentation and complications:
Altered mental status:
Delirium
Coma
No focal lesions on imaging
Global encephalopathy on electroencephalography
Critical-illness polyneuropathy and myopathy if especially prolonged
intensive care unit (ICU) stay
Chronic moderate-to-severe cognitive impairment
Other clinical/laboratory features and complications:
Ileus
Elevated liver enzymes
Disseminated intravascular coagulation
Adrenal failure
Sick euthyroid syndrome
Diagnosis
General approach[2,3,6,9,13,14,16]
1. Suspect sepsis in any individual presenting with any of the following:
Infection without apparent organ dysfunction
New-onset and unexplained organ dysfunction without apparent
infection
Abnormal vital signs such as fever, tachypnea, tachycardia, or low
blood pressure
Altered mental status
2. Administer screening tools: serve as early identification tools and/or risk
stratification tools:
 Surviving Sepsis Campaign recommends against using qSOFA as a
single screening tool for sepsis because of its low sensitivity
compared to NEWS or MEWS.
NEWS (National Early Warning Score):
Strongest level of evidence exists for the NEWS score
Sensitive ED screening tool, predicts sepsis-related outcomes
MEWS (Modified Early Warning Score): similar to NEWS, but
supplemental O2 use is not factored into scoring.
SOFA (Sequential Organ Failure Assessment):
Predicts mortality risk in individuals with sepsis
Designed to evaluate mortality in populations, but not as useful
in determining individual risk
UK: National Institute for Health and Care Excellence (NICE) risk
stratification tool
qSOFA (quick Sequential Organ Failure Assessment):
No longer recommended as a solitary screening tool for sepsis
Useful in predicting poor outcomes (prolonged ICU course and
death)
SIRS (Systemic Inflammatory Response Syndrome) criteria:
No longer recommended as a solitary screening tool for sepsis
Relies on laboratory results, which delays diagnosis (unsuitable
for triage)
Criteria may be met in conditions unrelated to infection
TREWS (Targeted Real-Time Early Warning System):[11]
Bedside tool using artificial intelligence to screen and alert for
risk of sepsis
Still under investigation
3. Sepsis standard operating procedures: Initiate early interventions in
individuals at moderate-to-high risk of sepsis based on screening tools
(formerly known as early goal directed therapy)
4. Initiate hour-1 bundle: Closely monitor for response to interventions and
criteria of septic shock.

Diagnostic criteria
Criteria for sepsis:[9]
Suspected (or documented) infection
Increase in ≥ 2 SOFA points

Criteria for septic shock:[9]

 Suspected (or documented) infection
Vasopressor therapy necessary to maintain mean arterial pressure (MAP)
≥ 65 mm Hg despite adequate IV crystalloid administration
Serum lactate > 2.0 mmol/L despite adequate IV crystalloid administration

SOFA score:[6,9]
Calculator
Organizes and classifies organ dysfunction related to sepsis
Evaluates 6 organ systems:
Respiratory
Coagulation
Hepatic
Cardiovascular
CNS
Renal
Total score:
0: no dysfunction
24: severe dysfunction

Table: SOFA score[1,6,9]

Organ/system SOFA Indication

score

Respiratory system: 0 ≥ 400

PaO2/FiO2 (mm
Hg) +1 300–399

+2 200–299

+3 100–199 + mechanically
ventilated

+4 < 100 + mechanically ventilated

Nervous system: 0 15
Glasgow coma
scale
+1 13–14
 +2 10–12

+3 6–9

+4 <6

Cardiovascular 0 MAP ≥ 70 mm Hg
system: MAP OR
need for
+1 MAP < 70 mm Hg
vasopressors

+2 Dopamine ≤ 5 μg/kg/min or
dobutamine (any dose)

+3 Dopamine > 5 μg/kg/min OR

epinephrine ≤ 0.1 μg/kg/min OR
norepinephrine ≤ 0.1 μg/kg/min

+4 Dopamine > 15 μg/kg/min OR

epinephrine > 0.1 μg/kg/min OR
norepinephrine > 0.1 μg/kg/min

Liver: bilirubin 0 < 1.2

(mg/dL)

+1 1.2–1.9

+2 2–5.9

+3 6–11.9

+4 ≥ 12

Coagulation: 0 ≥ 150
platelets × 1000/μL

+1 100–149

+2 50–99
 +3 20–49

+4 < 20

Kidneys: creatinine 0 < 1.2

(mg/dL) or urine
output
+1 1.2–1.9

+2 2–3.4

+3 3.4–4.9 or < 500 mL/day

+4 > 5.0 or < 200 mL/day

The SOFA score quantifies the number and severity of organ failure.
It assesses 6 organ systems. Each organ system is given 0–4 points
based on severity of involvement. The overall SOFA score ranges
from 0 (no organ failure) to 24 (most severe) points.
SOFA: sequential organ failure assessment
MAP: mean arterial pressure

National Early Warning Score (NEWS):[6,8]

Calculator
Assesses severity and likelihood for ICU care
Score is based on rapid bedside assessment of:
Respiration rate
O2 saturation
Need for supplemental O2
Temperature
Systolic blood pressure
Heart rate
Level of consciousness
Scoring:
0–4: low clinical risk
5–6: medium clinical risk → urgent assessment and next steps
based on clinician’s judgment
≥ 7: high clinical risk → emergent assessment and critical care
recommended
NEWS2 score is an updated version of NEWS endorsed in UK
Table: NEWS[8]

Clinical parameter Result Score

Respiratory rate ≤ 8 breaths/minute 3

9–11 breaths/minute 1

12–20 breaths/minute 0

21–24 breaths/minute 2

≥ 25 breaths/minute 3

Oxygen saturations ≤ 91% 3

92%–93% 2

94%–95% 1

≥ 96% 0

Use of supplemental oxygen No 0

Yes 2

Temperature ≤ 35℃ 3

35.1–36℃ 1

36.1–38℃ 0

38.1–39℃ 1

≥ 39℃ 2
Systolic blood pressure ≤ 90 mm Hg 3

91–100 mm Hg 2

101–110 mm Hg 1

111–219 mm Hgg 0

≥ 220 mm H 3

Heart rate ≤ 40/min 3

41–50/min 1

51–90 bpm 0

91–110/min 1

111–130/min 2

≥ 131/min 3

AVPU score Alert 0

Voice 3

Pain 3

Unresponsive 3
 Score: 0–4: low clinical risk
Score 5–6: medium clinical risk
Score ≥ 7: high clinical risk
Note: A score ≥ 3 for any individual clinical parameter requires
urgent review by a clinician.
NEWS: National Early Warning Score
AVPU: alert, voice, pain, unresponsive

Supporting evaluation[6,9,14,16]
The following are often ordered in the evaluation of sepsis and
septic shock. Workup should be guided by the clinical presentation.
Clinical:
Scrutinize the patient’s history (e.g., recent infection exposures,
procedures, foreign body placement)
Evaluate suggestive symptoms
Perform a thorough physical examination (including full skin
evaluation)
Identify any indwelling catheters or tubes
Laboratory studies:
 CBC → evaluate for:
Leukocytosis or leukopenia
Thrombocytopenia
Anemia
Comprehensive metabolic panel → evaluate for:
Renal dysfunction
Electrolyte derangement
Evidence of metabolic acidosis
Elevated liver enzymes
Procalcitonin:
May be elevated
A normal value should not prevent administration of antibiotics
Lactate:
Elevated levels signal hypoperfusion
Used to guide fluid resuscitation efforts
Infectious workup (list is not exhaustive):
Blood cultures
Urinalysis and culture
Obtain cultures from any indwelling lines or tubes
Viral panels (e.g., COVID-19, influenza)
Stool cultures and NAAT, including for C. difficile (if diarrhea
present)
Fungal cultures (if risk factors present)
Coagulation studies → evaluate for DIC
Imaging/procedures:
Chest X-ray → pulmonary infections
Lumbar puncture → if clinical signs of meningitis
Other imaging based on signs, symptoms, and relevant history

Management
Sepsis and septic shock are medical emergencies and treatment should
begin immediately!

Initial management[4,6,9,13,14,16]
Ideally, the following steps should begin within the 1st hour after the
diagnosis of sepsis.
 1. Draw and monitor serum lactate level (remeasure if > 2 mmol/L).
2. Obtain 2 sets of blood cultures (positive in only 30% of patients with
presumed sepsis) from separate sites before initiating antibiotics.
3. Initiate broad-spectrum antibiotics within 1 hour of recognition.
4. Intravenous (IV) crystalloids:
Rapidly administer (30 mL/kg) if hypotensive (mean arterial pressure
< 65 mm Hg) and/or lactate ≥ 4 mmol/L.
Balanced crystalloids are preferred over normal saline (when
available).
Albumin should be used after large volumes of crystalloid have been
administered.
Starches are not recommended.
5. Vasopressors:
Administer if hypotensive during or after resuscitation with IV
crystalloids.
Goal: MAP ≥ 65 mm Hg
Options:
Norepinephrine (1st choice)
Add vasopressin to reduce norepinephrine use
Add epinephrine if MAP inadequate with norepinephrine +
vasopressin
Add dobutamine to norepinephrine (or use epinephrine alone)
if there is evidence of cardiac dysfunction
Vasopressors can be started peripherally and should not be delayed
while awaiting central venous access.

Respiratory support[2,3,6,9]
 Goal: arterial oxygen saturation of 92%–95%
Indications for endotracheal intubation and mechanical ventilatory
support:
Significant hypoxemia (PaO2 < 60 mm Hg or oxygen saturation <
90%)
Hypoventilation (rising PCO2)
Significantly altered level of consciousness
Inability to protect airways with risk of aspiration
Persistent metabolic acidosis with pH < 7.20
Ventilation strategies for sepsis-induced
acute respiratory distress syndrome (ARDS):
Target low tidal volumes (around 6 mL/kg).
Use higher PEEP values.
Upper limit of plateau pressure: 30 cm H2O
Use prone ventilation for > 12 hours a day.
If use is required, use intermittent boluses of neuromuscular
blocking agents rather than a continuous infusion.

Antibiotics[2,3,6,7,9,14]
Initial coverage:
Cover all likely pathogens (including fungi, if suspected) while
determining source of infection.
If there is a high likelihood of multidrug-resistant (MDR) organisms,
use double gram-negative coverage.
Include methicillin-resistant Staphylococcus aureus (MRSA)
coverage for high-risk patients.
De-escalate therapy once cultures and sensitivities identify the
responsible pathogens.
Procalcitonin:
Should not be used in the decision to start antibiotic therapy
Can be used in conjunction with the clinical evaluation when
deciding to discontinue antibiotic therapy (when the optimal duration
of treatment is unclear)
Opt for the shortest duration of therapy necessary to adequately treat the
infection (avoid unnecessarily long antibiotic courses).

Table: Choice of empirical antibiotic therapy in adult patients

with sepsis (all antibiotics administered intravenously)

Patient’s immune Choice of antibiotic

status
 Immunocompetent Any of the following:
Piperacillin-tazobactam
Cefepime
Meropenem or imipenem-cilastatin
Aztreonam, ciprofloxacin, or
levofloxacin if allergic to beta-
lactam antibiotics
PLUS:
Vancomycin (or linezolid) if risk of
MRSA is high or if in septic shock

Neutropenic (< 500 Any of the following:

neutrophils/μL) Piperacillin-tazobactam
Cefepime
Meropenem or imipenem-cilastatin
PLUS:
Vancomycin (or linezolid), tobramycin,
and caspofungin

Splenectomy Any of the following:

Ceftriaxone
Levofloxacin or moxifloxacin if
allergic to beta-lactams
PLUS:
Vancomycin (or linezolid)

Associated with Refer to the treatment of community-

pneumonia and ventilator-acquired pneumonia.

Associated with severe Any of the following:

intra-abdominal Piperacillin-tazobactam
infections Cefepime or ceftazidime
Meropenem or imipenem-cilastatin
Ciprofloxacin or levofloxacin
PLUS:
Metronidazole

Hemodynamic treatment and monitoring[2,6,9]

 Advanced monitoring options:
Arterial line:
Preferred device to monitor MAP when vasopressors are
required; should be obtained as soon as practical
Noninvasive blood pressure measurements can be inaccurate
Central venous pressure (CVP)
Arterial pulse contour analysis
Focused echocardiography (cardiac output, beat-to-beat
stroke volume, and pulse pressure variation)
Passive leg-raise maneuver
Inferior vena cava collapsibility on ultrasound
Alternative monitoring options:
Can be used when advanced monitoring is not available
Includes:
Extremity temperature
Skin mottling
Capillary refill time
Fluid management:
Continued IV fluid is generally required after the initial bolus.
There is no consensus on optimal fluid therapy.
Some recommend repeated small boluses (in contrast to a
continuous infusion).
Must balance correction of volume depletion with the potential for
volume overload.
The following may help guide fluid administration:
Improvement in lactate levels (keep in mind, normal levels may
not be achievable in some patients)
Vasopressor requirements
Urine output
Vitals and CVP
Advanced (or alternative) monitoring findings
Respiratory support requirements (e.g., increasing
requirements may signal pulmonary edema)
Vasopressor therapy:
Goal: MAP ≥ 65 mm Hg
Continuously attempt to wean and reassess the need for
vasopressors.

Glucocorticoids[4,6,9,15]
 Should not be used routinely
Dexamethasone has been shown to reduce mortality in patients with
coronavirus disease 2019 (COVID-19) who are receiving respiratory
support.
Weak recommendation:
Initiate IV hydrocortisone if septic shock does not respond to fluids
and vasopressors
Consider if norepinephrine (or epinephrine) dose is ≥ 0.25 µg/kg/min
≥ 4 hours after initiation
Dose: 50 mg IV every 6 hours (200 mg/day) → can also be given as
a continuous infusion
Wean steroids if vasopressors are no longer needed.

Additional measures[4,6]
Red blood cell transfusion:
Only recommended if hemoglobin is < 7 g/dL
Restrictive transfusion strategy is preferred (over liberal).
Insulin therapy: A blood glucose target of 144–180 mg/dL (8–10 mmol/L) is
recommended.
Prophylaxis:
For stress ulcers in patients at risk for gastrointestinal bleeding
For deep venous thrombosis:
If no contraindications (active bleeding or significant
thrombocytopenia)
Low-molecular-weight heparin (LMWH) is preferred over
unfractionated heparin.
Close monitoring and treatment of electrolyte abnormalities
Bicarbonate:
Recommended for severe metabolic acidemia (pH ≤ 7.2) and
acute kidney injury
Not recommended to improve hemodynamics or reduce
vasopressor requirements
Nutritional support:
Enteral route is preferred.
Should be initiated within 72 hours, when possible
Effectively communicate sepsis status during hand-offs.

References
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https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4968574/

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https://emedicine.medscape.com/article/168402-overview

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