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{{AdultPage|Sepsis (peds)}}
==Background==
*Sepsis should be defined as life-threatening organ dysfunction caused by a dysregulated host response to infection<ref name="sepsis3">Singer, Mervyn et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287</ref>
*The infection is most commonly by [[bacteria]], but can also be by [[fungi]], [[viruses]], or [[parasites]]<ref>Jui, Jonathan (2011). "Ch. 146: Septic Shock". In Tintinalli, Judith E.; Stapczynski, J. Stephan; Ma, O. John; Cline, David M. et al. Tintinalli's Emergency Medicine: A Comprehensive Study Guide (7th ed.). New York: McGraw-Hill. pp. 1003–14. </ref> 
*The most common primary sources of infection resulting in sepsis are the [[pneumonia|lungs]], the abdomen, and the [[UTI|urinary tract]]<ref>Munford, Robert S.; Suffredini, Anthony F. (2014). "Ch. 75: Sepsis, Severe Sepsis and Septic Shock". In Bennett, John E.; Dolin, Raphael; Blaser, Martin J.. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases (8th ed.). Philadelphia: Elsevier Health Sciences. pp. 914–34.</ref>
*Sepsis and septic shock are major healthcare problems, killing between one in three and one in six of those affected<ref name="SSC2021">Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49(11):e1063-e1143.</ref>
*In-hospital mortality for septic shock is approximately 30-40%<ref name="SSC2021"/>
*Positive cultures are not obligatory in the diagnosis of sepsis
*[[Pneumonia]], intra-abdominal infections, and [[pyelonephritis]] are the most common primary causes

===Sepsis-3 Definitions (2016)===
''In 2016 new definitions were adopted for the evaluation and diagnosis of Sepsis and Septic Shock<ref name="seymour">Seymour C. Assessment of Clinical Criteria for Sepsis For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):762-774. doi:10.1001/jama.2016.0288.</ref>''
{| {{table}}
| align="center" style="background:#f0f0f0;"|
| align="center" style="background:#f0f0f0;"|'''Old Definition'''
| align="center" style="background:#f0f0f0;"|'''Sepsis-3 Definition (2016)'''
|-
| '''Sepsis'''||2 [[SIRS]] criteria + suspected infection||Life-threatening organ dysfunction caused by a dysregulated host response to infection, operationalized as:
*Suspected/documented infection '''PLUS'''
*Increase in [[SOFA]] score by ≥2 points
|-
| '''Severe Sepsis'''||Sepsis + organ dysfunction:
*SBP <90, or
*MAP <65, or
*Lactate >2, or
*INR >1.5, or
*Bili >2, or
*Urine output <0.5 mL/kg/hr, or
*Creatinine >2.0, or
*Platelets <100, or
*SpO₂ <90%
||'''No longer a category''' (subsumed into "sepsis," which now requires organ dysfunction by definition)
|-
| '''Septic Shock'''||Sepsis + hypotension after adequate fluid resuscitation||Sepsis '''PLUS''':
*Vasopressors needed to maintain MAP ≥65 '''AND'''
*Lactate >2 mmol/L (>18 mg/dL) despite adequate volume resuscitation
|}

===qSOFA (Bedside Screening Tool)===
''The [[qSOFA]] was proposed as a bedside screening tool to identify patients outside the ICU who may have sepsis. It is not the definition of sepsis.''<ref name="seymour"/>

SSC 2021 recommends against using qSOFA as a single screening tool for sepsis or septic shock, as it has poor sensitivity; however, it may prompt further workup when positive.<ref name="SSC2021"/>

{{QSOFA Score}}

*qSOFA ≥2 should prompt:
**Consideration of possible sepsis
**Initiation of workup (cultures, lactate, imaging)
**Assessment for organ dysfunction (formal [[SOFA]] score)
*A qSOFA <2 does not rule out sepsis

===[[SOFA]] Score===
*The [[SOFA]] score is the formal tool for identifying organ dysfunction in sepsis (increase of ≥2 points = sepsis)<ref name="sepsis3"/>
*Generally used in the ICU; can stratify mortality based on initial score and subsequent changes
*Baseline SOFA score assumed to be 0 in patients without known pre-existing organ dysfunction

===MEDS Score===
*The Mortality in Emergency Department Sepsis (MEDS) prediction rule is a proposed method to risk stratify ED patients with sepsis
*Has not gained widespread clinical adoption

===NEWS 2 Score===
*National Early Warning Score (NEWS) 2 determines degree of illness in non-pregnant patients ≥16 years old<ref>Royal College of Physicians. National Early Warning Score (NEWS) 2: Standardising the assessment of acute-illness severity in the NHS. Updated report of a working party. London: RCP, 2017.</ref>
*Used by the UK NHS to identify acutely ill patients, including those with sepsis
*Not reliable in spinal cord injury patients due to disturbance of autonomic responses
*Combination of:
**Respiratory rate
**Presence of hypercapnic respiratory failure
**Presence of supplemental O₂
**Temperature
**SBP
**Pulse rate
**Consciousness (AVPU scale)
*See below for MDCalc link

{{SIRS Score}}

==Clinical Features==
===Sepsis===
''Life-threatening organ dysfunction caused by a dysregulated host response to infection.''<ref name="sepsis3"/>
*Suspected infection with evidence of new organ dysfunction ([[SOFA]] increase ≥2), which may manifest as:
**[[Hypotension]]
**[[Altered mental status]]
**[[Tachypnea]]
**[[Acute kidney injury|Oliguria]]
**Coagulopathy
**Elevated [[lactate]]
**[[Hypoxia]]
**Ileus

===[[Septic shock]]===
Patients with sepsis and both of the following despite adequate volume resuscitation:<ref name="sepsis3"/>
#[[Vasopressors|Vasopressor]] requirement to maintain a mean arterial pressure ≥65 mm Hg AND
#Serum [[lactate]] level >2 mmol/L (>18 mg/dL)

==Differential Diagnosis==
*[[Adrenal Insufficiency]]
*[[Salicylate Toxicity]] 
*[[Anticholinergic Toxicity]]
*[[Neuroleptic Malignant Syndrome]]
*[[Malignant Hyperthermia]]
*[[Thyrotoxicosis]]

{{Shock DDX}}
{{Adrenal crisis ddx}}

==Evaluation==
===Work-Up===
*CBC
*[[Urinalysis]]/Urine culture
*[[Blood culture]] (at least 2 sets, ideally before antibiotics but should not delay antibiotic administration)
*[[CXR]]
*Chem (BMP)
*[[LFTs]]
*Lipase
*[[VBG]] or [[ABG]]
*[[Lactate]] (re-measure within 2-4 hours if initially elevated)<ref name="SSC2021"/>
*Coags
*Consider:
**[[Procalcitonin]] (may help guide de-escalation of antibiotics; should not be used to withhold initial empiric antibiotics)
**[[DIC]] panel (fibrinogen, [[D-dimer]], FDP)
**T&S
**[[CT head]] and/or [[LP]]
**TSH ([[thyroid storm]])
**Cosyntropin stim vs. random cortisol ([[adrenal insufficiency]])
**Pelvic exam ([[toxic shock syndrome]], tampon) 
**[[Influenza]] and respiratory viral testing
**CT Abd/Pelvis (abscess, other intra-abdominal source)
**Spine imaging ([[epidural abscess]], other)

==Management==
===Hour-1 Bundle===
''Time zero is the time of triage in the emergency department or the earliest documentation of sepsis-consistent elements. Sepsis and septic shock are medical emergencies; treatment and resuscitation should begin immediately.''<ref name="SSC2021"/>

The Hour-1 Bundle should be viewed as a quality improvement target. Ideally all interventions begin in the first hour, though they may not all be completed within that time:
#Measure [[lactate]] level (re-measure within 2-4 hours if initial lactate >2 mmol/L)
#'''Obtain [[blood cultures]]''' prior to administration of antibiotics (but do not delay antibiotics to obtain cultures)
#Administer broad-spectrum [[antibiotics]] (see timing below)
#Begin rapid administration of 30 mL/kg crystalloid for hypotension or lactate ≥4 mmol/L
#Apply [[vasopressors]] if patient is hypotensive during or after fluid resuscitation to maintain MAP ≥65 mmHg

===Antibiotic Timing (SSC 2021)===
''Timing is stratified by presence of shock and likelihood of infection:''<ref name="SSC2021"/>
{| {{table}}
| align="center" style="background:#f0f0f0;"|'''Clinical Scenario'''
| align="center" style="background:#f0f0f0;"|'''Antibiotic Timing'''
|-
| '''Septic shock''' or '''high likelihood of sepsis'''||'''Immediately, ideally within 1 hour''' of recognition (strong recommendation)
|-
| '''Possible sepsis without shock'''||Rapid assessment of infectious vs. non-infectious causes; '''within 3 hours''' if concern for infection persists (weak recommendation)
|-
| '''Alternative non-infectious diagnosis identified'''||Reassess; '''discontinue empiric antibiotics''' if infection is not confirmed<ref name="SSC2021"/>
|}

*See [[Initial Antibiotics in Sepsis (Main)]] for regimen selection
*Initial choice dependent on suspected source, local antibiogram, and severity of illness
*Prolonged (extended/continuous) infusions of beta-lactam antibiotics are suggested for maintenance therapy over conventional bolus infusions<ref name="SSC2021"/>
*Perform daily reassessment for antimicrobial de-escalation<ref name="SSC2021"/>

===Source Control===
*Identify and control the source of infection as soon as medically and logistically practical, ideally within 6-12 hours<ref name="SSC2021"/>
*Remove any infected lines or devices
*Drain [[abscesses]]
*Consult surgery or other specialists if indicated (e.g. for [[appendicitis]], [[cholangitis]], [[necrotizing fasciitis]], etc.)
*Prolonged efforts at medical stabilization should not delay source control in severely ill patients

==Circulation Management==
===[[IVF]]===
*SSC 2021 suggests (downgraded from ''recommends'' in 2016) initial 30 mL/kg crystalloid for sepsis-induced hypoperfusion or septic shock, to be given within the first 3 hours<ref name="SSC2021"/>
**This is a starting point; some patients will need more, some less
**'''Reassess after each bolus''' — do not reflexively give the full 30 mL/kg without clinical reassessment
*Balanced crystalloids (e.g. [[Lactated Ringer's]]) are suggested over 0.9% [[normal saline]] (weak recommendation)<ref name="SSC2021"/>
*Use '''dynamic measures''' to guide ongoing fluid resuscitation (suggested over physical exam or static parameters alone):<ref name="SSC2021"/>
**Passive leg raise with assessment of stroke volume/cardiac output
**Fluid challenge with reassessment of hemodynamic response
**Stroke volume variation, pulse pressure variation
**Bedside [[Ultrasound: In Shock and Hypotension|cardiovascular ultrasound]] ([[IVC ultrasound]])
*Capillary refill time can be used to guide resuscitation as an adjunct to other measures<ref name="SSC2021"/>
*Lactate-guided resuscitation: Suggest targeting a decrease in lactate (re-measure q2-4h) as a marker of tissue perfusion<ref name="SSC2021"/>
*Increasing evidence that excessive fluid resuscitation can be harmful:
**Positive fluid balance on day 3 of hospital admission independently associated with increasing mortality<ref>Sakr Y et al. Higher Fluid Balance Increases the Risk of Death From Sepsis: Results From a Large International Audit. Critical care medicine. 45(3):386-394, Mar 2017.</ref>
**Protocolized fluid administration (i.e. traditional Early Goal Directed Therapy) has no mortality benefit over usual care<ref>Yealy DM, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370:1683-93. DOI: 10.1056/NEJMoa1401602</ref><ref>Mouncey PR, et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock. N Engl J Med 2015;372:1301-11. DOI: 10.1056/NEJMoa1500896</ref>
**High volume (5+ L) resuscitation associated with increased mortality<ref>Marik PE, et al. Fluid administration in severe sepsis and septic shock, patterns and outcomes: an analysis of a large national database. Intensive Care Med (2017) 43:625–632 DOI 10.1007/s00134-016-4675-y</ref>
*Consider assessing [[diastolic dysfunction]] via echo in [[CHF]] patients in whom IVC [[ultrasound]] is not reliable
*'''CVP targets (>8 cmH₂O non-intubated, >12 cmH₂O intubated) are no longer recommended''' as resuscitation endpoints<ref name="SSC2021"/>

''A central line and measurement of ScvO₂ is not required and does not impact mortality''<ref>ProCESS Investigators, Yealy DM, Kellum JA, Juang DT, et al. A randomized trial of protocol-based care for early septic shock. N Engl J Med 2014;370(18):1683-1693. [[EBQ:ProCESS_Trial|Full Text]]</ref><ref>The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-directed resuscitation for patients with early septic shock. N Engl J Med 2014; 371:1496-1506.</ref><ref>Mouncey PR, Osborn TM, Power GS, et al for the ProMISe trial investigators. Trial of early, goal-directed resuscitation for septic shock. N Engl J Med 2015:DOI: 10.1056/NEJMoa1500896.</ref>

===[[Pressors]]===
*Indicated if MAP <65 despite initial fluid resuscitation, or if fluid resuscitation is contraindicated/unlikely to be sufficient
*'''Vasopressors may be started peripherally''' while central access is being obtained — do not delay initiation to place a central line<ref name="SSC2021"/>
*Target MAP ≥65 mmHg (SSC 2021 recommends an initial target of 65 mmHg over higher MAP targets)<ref name="SSC2021"/>

Options:
*{{MedicationDose|drug=Norepinephrine|dose=0.1-1 mcg/kg/min (typical start 5-20 mcg/min)|route=IV drip|context=1st line vasopressor|indication=Sepsis (main)|population=Adult}} <ref>[[EBQ:SOAP II Trial]]</ref><ref name="SSC2021"/>
*{{MedicationDose|drug=Vasopressin|dose=0.03 units/min (fixed dose)|route=IV drip|context=2nd line vasopressor, added to norepinephrine|indication=Sepsis (main)|population=Adult}}<ref name="SSC2021"/>
**SSC 2021 suggests adding vasopressin before epinephrine
**May reduce the risk of atrial fibrillation compared to catecholamine-only regimens<ref>McIntyre WF, Um KJ, Alhazzani W, et al. Association of Vasopressin Plus Catecholamine Vasopressors vs Catecholamines Alone With Atrial Fibrillation in Patients With Distributive Shock. JAMA. 2018;319(18):1889.</ref>
*{{MedicationDose|drug=Epinephrine|dose=1-20 mcg/min|route=IV drip|context=3rd line vasopressor|indication=Sepsis (main)|population=Adult}}<ref name="SSC2021"/>
*[[Dopamine]] — should be used hesitantly and only in highly selected patients (e.g. patients with low risk of tachyarrhythmias and absolute or relative bradycardia)
**Do not use low-dose dopamine for renal protection
**Dopamine may have increased mortality rates compared to other vasopressors, especially in the pediatric septic patient<ref>Ventura AM, Shieh HH, Bousso A, et al. Double-Blind Prospective Randomized Controlled Trial of Dopamine Versus Epinephrine as First-Line Vasoactive Drugs in Pediatric Septic Shock. Crit Care Med 2015;43:2292-302.</ref> 
*[[Phenylephrine]] — should not be used for treating septic shock except if:
**Norepinephrine is associated with serious arrhythmias
**Cardiac output is known to be high and blood pressure persistently low
**As salvage therapy when combined inotrope/vasopressor drugs and low-dose vasopressin have failed to achieve MAP target
*[[Methylene blue]] — consideration for septic shock refractory to catecholaminergic pressors (limited evidence)

===[[Vasopressors|Inotropes]]===
*{{MedicationDose|drug=Dobutamine|dose=2-20 mcg/kg/min|route=IV drip|context=Inotrope for sepsis-related myocardial dysfunction|indication=Sepsis (main)|population=Adult}} may be added if:
**Myocardial dysfunction as suggested by elevated cardiac filling pressures and low cardiac output
**Ongoing signs of hypoperfusion despite achieving adequate intravascular volume and adequate MAP
**Note: Beta-2 agonism causes vasodilation; therefore needs to be used in conjunction with vasopressors

===[[Steroids]]===
*SSC 2021 suggests IV corticosteroids for adults with septic shock and an ongoing requirement for vasopressor therapy (weak recommendation)<ref name="SSC2021"/>
*The 2024 SCCM Focused Update further clarifies:<ref name="SCCM2024">Chaudhuri D, Nei AM, Rochwerg B, et al. 2024 Focused Update: Guidelines on Use of Corticosteroids in Sepsis, Acute Respiratory Distress Syndrome, and Community-Acquired Pneumonia. Crit Care Med. 2024;52(5):e219-e233.</ref>
**Suggests corticosteroids for adults with septic shock (conditional recommendation, low certainty)
**Recommends against high-dose/short-duration corticosteroids (>400 mg/day hydrocortisone equivalent for <3 days) (strong recommendation, moderate certainty)
*Dosing: {{MedicationDose|drug=Hydrocortisone|dose=50 mg IV q6h (200 mg/day)|route=IV|context=Stress dose steroids for septic shock|indication=Sepsis (main)|population=Adult}}
*Do not administer steroids for treatment of sepsis in the absence of shock
*Stress dose steroids are associated with faster time to shock resolution and faster ICU discharge<ref>Venkatesh B, Finfer S, Cohen J, et al; ADRENAL Trial Investigators. Adjunctive Glucocorticoid Therapy in Patients with Septic Shock. N Engl J Med. 2018;378(9):797-808.</ref>
*While stress dose steroids shorten recovery time, they have not been consistently shown to decrease overall mortality (though meta-analyses suggest a possible small benefit)<ref name="SCCM2024"/>
*Newer meta-analyses do not show an increased incidence of superinfections related to initiation of stress dose steroids<ref>Sligl WI, Milner DA Jr, Sundar S, Mphatswe W, Majumdar SR. Safety and efficacy of corticosteroids for the treatment of septic shock: A systematic review and meta-analysis. Clin Infect Dis. 2009 Jul 1;49(1):93-101.</ref>
*Addition of fludrocortisone likely unnecessary as hydrocortisone has both glucocorticoid and mineralocorticoid effects
*ACTH cosyntropin testing is likely unreliable in critically ill patients and should not guide the decision to give steroids
*Steroids are associated with adverse effects including hyperglycemia, hypernatremia, and neuromuscular weakness; weigh risks and benefits<ref>Pitre T, Drover K, Chaudhuri D, et al. Corticosteroids in Sepsis and Septic Shock: A Systematic Review, Pairwise, and Dose-Response Meta-Analysis. Crit Care Explor. 2024;6(1):e1000.</ref>

===[[Esmolol]]===
*One open-label, single-center RCT showing ~40% reduction in mortality when [[esmolol]] paired with [[norepinephrine]] infusion, with goal HR 80-95 BPM<ref>Andrea Morelli et al. Effect of Heart Rate Control With Esmolol on Hemodynamic and Clinical Outcomes in Patients With Septic Shock: A Randomized Clinical Trial. JAMA. 2013;310(16):1683-1691.</ref>
*All patients were fluid resuscitated, intubated, given hydrocortisone 300 mg/day
*Not standard of care — will require further multi-center RCTs to confirm findings; this result has not been replicated

==[[Blood Products]]==
===[[RBCs]]===
*Only transfuse RBCs when hemoglobin decreases to <7.0 g/dL (target 7.0–9.0 g/dL in adults)<ref name="SSC2021"/>
===Erythropoietin===
*Do not use erythropoietin as a specific treatment of anemia associated with severe sepsis 
===[[Platelets]]===
*In severe sepsis, administer platelets prophylactically when counts are <10,000/mm³ (10 × 10⁹/L) in the absence of apparent bleeding
*If <20,000/mm³ (20 × 10⁹/L) and significant risk of bleeding, then administer platelets
*<50,000/mm³ (50 × 10⁹/L) if there is active bleeding, planned surgery, or other procedures

==Disposition==
*Admit, likely to step-down or ICU
*SSC 2021 suggests admitting patients with sepsis or septic shock who require ICU care within 6 hours of identification<ref name="SSC2021"/>

== Calculators ==
{{QSOFA_Calculator}}

{{SIRS_Calculator}}

{{SOFA_Calculator}}

==External Links==
*[http://www.mdcalc.com/sirs-sepsis-and-septic-shock-criteria/ MDCalc - SIRS, Sepsis, and Septic Shock Criteria]
*[http://www.mdcalc.com/qsofa-quick-sofa-score-for-sepsis-identification/ MDCalc - qSOFA Score]
*[https://www.mdcalc.com/national-early-warning-score-news-2#evidence MDCalc - NEWS 2]
*[http://emcrit.org/podcasts/sepsis-3/ EMCrit Sepsis 3.0]
*[https://journals.lww.com/ccmjournal/fulltext/2021/11000/surviving_sepsis_campaign__international.21.aspx SSC 2021 Guidelines (Full Text)]

==See Also==
*[[Initial Antibiotics in Sepsis (Main)]]
*[[Sepsis (Peds)]]
*[[EBQ:ProCESS Trial]]
*[[Quick Sequential (Sepsis Related) Organ Failure Assessment Score (qSOFA)]]
*[[Pneumonia (main)]]

==References==
{{reflist|2}}

[[Category:ID]]
[[Category:Critical Care]]