by Emilie J. Calvello Hynes


Introduction and Definitions

In the last 20 years, the collective understanding of sepsis care has gone through a major transformation. The term sepsis describes a physiologic syndrome with characteristic biochemical abnormalities initiated by infection. While the mortality from sepsis in many high-income countries is decreasing, the reported incidence has found to be increasing due to aging populations as well as greater attention paid to early recognition of a potentially deadly syndrome. The true incidence of sepsis worldwide is unknown, and there is no doubt, even with the most conservative estimates, that sepsis is a leading cause of critical illness and death on the planet.

Sepsis recognition and appropriate care have a huge possible impact on human mortality, and yet the public health awareness of sepsis is quite poor. Sepsis can have many presentations making it sometimes difficult for even the most experienced physicians to detect, further emphasizing the need for clear definitions to prompt the right treatment interventions.

Prior definitions of sepsis were predicated on the inflammatory response from the host, termed the systemic inflammatory response syndrome (SIRS).

Systemic Inflammatory Response Syndrome

Two or more of the following

  • Heart rate > 90 beats/min
  • Respiratory rate > 20 cycles/min or PaCO2 <32 mm Hg
  • Temperature > 38°C or < 36°C
  • WBC > 12,000/mm3, < 6,000/mm3 or > 10% bandemia

SIRS can be caused by a large variety of inciting agents that induce host inflammatory response, such as burns, pancreatitis, a variety of infectious organisms and toxins. Sepsis, for the last two decades, has been understood to be SIRS plus an infectious source. Severe sepsis was defined as sepsis plus organ dysfunction. Whereas, septic shock was defined as hypotension induced by sepsis that persisted despite adequate fluid resuscitation. However, a recent task force has fundamentally shifted the previously understood definitions of sepsis in the following important ways. (Table 1)

Comparison of Sepsis Definition Evolution

Old Definition (pre 2016)Current Definition
Sepsis = SIRS + infectious sourceSepsis = life-threatening organ dysfunction due to a dysregulated host response to infection
• ED patients: 2 or more of the following qSOFA score may identify patients with increased mortality
• SBP less than or equal to 100 mm Hg
• RR ≥ 22
• Altered mental status (GCS <15)
Severe sepsis = sepsis + organ system dysfunctionThe term severe sepsis is NO LONGER USED.
Septic shock
Adults = persistent arterial hypotension despite adequate fluid resuscitation
Pediatrics* = tachycardia with decreased signs of perfusion
Septic Shock = subset of patients with sepsis and profound circulatory, cellular, and metabolic abnormalities

Clinical Criteria
Despite adequate volume resuscitation,
Persistent hypotension requiring vasopressors to maintain MAP ≥ 65 mm Hg
Lactate ≥ 2 mmol/L
Original by the author
Read for new definitions from - Rubulotta FM, et al. Crit Care Med. 2009;37(1): 167-170.

* Because of higher vascular tone, neonates and children may be in a shock state long before manifestation of hypotension.


SIRS criteria is not adequately sensitive or specific in identifying those who may go on to have significant morbidity and mortality from overwhelming infection. Rather, sepsis is now defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Organ dysfunction is best defined in the undifferentiated emergency department patient by the quickSOFA score (qSOFA). [SOFA = Sepsis related Organ Failure Assessment Score]

Identification of these patients should prompt further diagnostic evaluation for end-organ damage. The definition of septic shock has been simplified as a subset of sepsis in which underlying circulatory and cellular/metabolic abnormalities are profound enough to increase mortality substantially. These patients are identified by persistent hypotension and having lactate greater than 2 mmol/L after fluid resuscitation. Of note, the term severe sepsis should no longer be used as all sepsis is considered to have a high probability of being severe.

Case Presentation

74 y/o female with history of diabetes, hypertension and coronary stent placement presents with confusion and cough. She has had a cough for 2 days and saw her primary care doctor who prescribed an antibiotic. Her husband describes her as behaving normally until today 3 hours prior to presentation. She is taking Insulin, Lisinopril, Aspirin, Metoprolol, and Azithromycin. There are no allergies to medications.

On exam, the patient is spontaneously breathing with eyes closed but opens to verbal command. She is lethargic and oriented only to self. Blood pressure is 92/48mmHg, heart rate 122/min, respiratory rate 24 cycles/min, temperature is 37.5 °C and oxygen saturation is 89% on room air. She has dry mucous membranes, and her skin is cool and diaphoretic. The lung exam reveals crepitations in the left base and heart sounds are regular but tachycardic. Her abdomen is flat and non-tender, and her neurological exam reveals no focal deficits.

Critical Bedside Actions and General Approach

For the critically ill patient, you must make a rapid determination of syndromic category of their acute illness. If they meet the above definition of sepsis and there is a concern for ongoing shock, proceed to the critical bedside actions.

First 5 – 10 minutes if high suspicion for septic shock

  • Transfer to critical care room if available
  • Vital signs, primary bedside evaluation with ABC…, administer O2, attach to the cardiac monitor
  • 2 large bore IVs
  • Check glucose
  • Start 2 L IV Fluid bolus (LR or NS) for adults or 20 mL/kg for pediatrics (unless malnourished)
  • Be prepared to assist with airway patency or protection (i.e., intubation) if necessary
  • Prepare broad-spectrum antibiotics for administration within the first hour

Differential Diagnosis

Differential Diagnosis of Sepsis – non infectious etiologies

Shock states

  • Cardiogenic shock
  • Hypovolemic shock
  • Hemorrhagic shock
  • Obstructive shock
  • Distributive shock


  • Myocardial infarction
  • Congestive heart failure
  • Pulmonary embolism
  • Acute respiratory distress syndrome


  • Heat stroke
  • Burns


  • DKA
  • Adrenal crisis
  • Thyrotoxicosis
  • Pancreatitis
  • Hypoglycemia


  • Salicylate toxicity
  • Neuroleptic Malignant Syndrome
  • Serotonin syndrome
  • Sympathomimetic toxidrome
  • Delerium tremens


  • Status epilepticus
  • Cerebral hemorrhage

History and Physical Exam Hints


  • History of immunocompromise (HIV, chemotherapy, etc.), alcoholism, malignancy, liver disease, diabetes, ongoing steroid use, intravenous drug use
  • Travel history, vaccination status
  • Recent illness, sick contacts
  • History associated with source: cough, dysuria, shortness of breath, chest pain, abdominal pain, vomiting, diarrhea, back pain, decreased urine output, focal neurological deficits, rash or skin changes, change in mental status
  • Pediatric-specific: increased work of breathing, decreased PO intake, change in behavior

Physical Exam Signs

  • Vital Signs: Tachycardia, fever, low BP, tachypnea
  • Poor perfusion: hot or cool skin, altered mental status, poor urine output (<0.5 mL/kg/hr), weak pulses,
  • Pediatric-specific: skin mottling, delayed capillary refill skin, poor urine output (<1 mL/kg/hr)
  • Associated finding less likely to be non-infectious source: chest pain, evidence of DVT, evidence of ingestion (pill fragments)

Findings Associated with an Infectious Source

Finding Source
Pulmonary findingsPneumonia, empyema, parapneumonic effusion
Urine appearanceURI, pyelonephritis, infected renal calcluli
Skin findings (wounds, rash, crepitus, bullae)Cellulitis, abscess, meningococcus, viral or tick borne disease, gangrene, necrotizing fasciitis
Focal neurologic deficitCerebral abscess, epidural abscess
Bony findings (pain or asymmetry in extremities)Myositis, discitis, osteomyelitis, septic joint
Peritoneal signsIntra-abdominal abscess/inflammation, perforation, spontaneous bacterial peritonitis
Heart findings (rub, murmur)Pericarditis, endocarditis
StridorEpiglotitis, tracheitis, croup
Vaginal dischargePelvic inflammatory disease, endometritis, septic abortion, chorioamnionitis
original by the author


Emergency Diagnostic Tests and Interpretation


  • Specific derangements in sepsis: creatinine, LFTs, bilirubin, platelets, coagulation studies
  • Serial serum lactates
  • Source testing (guided by H&P): UA, CSF, pleural, intraperitoneal, synovial fluid
  • Cultures: Blood, urine
  • CSF, body fluid if indicated
  • Cultures are positive in sepsis only 30-40% of the time
  • Special tests (if indicated): malaria, dengue, viral hemorrhagic fever, etc.


  • Guided by history and physical
  • Chest x-ray for all
  • Bedside ultrasound of IVC to monitor resuscitation

Video tutorial for IVC measurement

  • Consider based on history:

Emergency Treatment Options

Mortality for sepsis and septic shock can be as high as 40-50%. Decreases in mortality are accomplished via two goals:

  1. Restore tissue perfusion
  2. Locate and treat infectious source

Restore tissue perfusion

  • Fluids
    • Resuscitation with normal saline
      • General recommendations for adults include 20-40 mL/kg in defined volumes amounts (500 mL) with reevaluation after every bolus administration.
      • Pediatrics – start with 20 mL/kg bolus
        • Significant caution in those malnourished or severely anemic
    • Hydroxyethyl starch should be avoided.
    • Albumin may be used if indication AFTER adequate crystalloid resuscitation.
    • Monitor for signs of fluid overload (increasing hypoxia, rales, hepatomegaly in children).
  • Oxygenation
    • Target saturation of > 90%
    • Intubation for respiratory failure and consider for those in refractory septic shock.
  • Vasopressors
    • Provide for those with MAP < 65 mmHg despite adequate fluid resuscitation. (MAP = [(2 x diastolic) + systolic]/ 3)
    • Initial vasopressors may be given peripherally initially, although central venous access preferred.
    • Norepinephrine (0.01-3 mcg/kg/min) the preferred choice, with the recommended second agent of epinephrine (0.1 – 1 mcg/kg/min) or vasopressin (0.03 units/min)
  • Steroids
    • Consider for those with MAP < 65 mmHg despite fluid and vasopressor therapy.
    • Hydrocortisone (adults – 200 mg, pediatric 1-2 mg/kg) or equivalent

Locate and treat infectious source

  • Location
    • Guided by history and physical
    • Source control:
      • Debride or drain any localized source of infection; surgical consult for deeper infections such as intrabdominal abscess or empyema.
      • Remove catheters and lines associated with infection.
  • Timing
    • Critically ill patients should have antibiotics given within 1 hour.
    • Do not delay antibiotics for testing!
  • Antibiotics
    • Choice of antibiotics driven by local resistance patterns, region-specific epidemiology (HIV, malaria, influenza, etc. prevalence), and availability of drugs
    • Those with septic shock should always include broad-spectrum coverage (gram positive, gram negative, anaerobes).
    • Consider antimalarials where appropriate.
    • Consider specific anti-viral therapy when appropriate (i.e., acyclovir for meningoencephalitis, oseltamivir for influenza in the immunocompromised host).

Pediatric, Geriatric, Pregnant Patient and Other Considerations


  • Neonates and immunocompromised (sickle cell, oncology, diabetic and HIV) patients are at particular risk for overwhelming infection.
  • Controversy exists regarding fluid management in developing countries with high malaria prevalence rates with fluid boluses found to increase mortality.
  • For respiratory distress and hypoxemia, make early use of high flow nasal cannula and CPAP while starting resuscitation.
  • Extracorporeal Membrane Oxygenation (ECMO) may be considered for refractory pediatric shock and respiratory failure.


  • Increased risk factors due to comorbidities, endocrine deficiencies, pre-existing malnutrition, and age-related immunosenescence.
  • Diagnosis may be more difficult as the initial inflammatory response to infection may be blunted or absent.
  • 1.5 higher mortality rates than younger patients.


  • The etiology of sepsis in pregnant women is expanded and includes septic abortion, chorioamnionitis/endometritis, group A Streptococcus infection, particular susceptibility to influenza and necrotizing vulvitis.
  • Adequate resuscitation of the mother often will improve outcomes for the fetus; however, in the critically ill patient, early delivery of the fetus should be considered with appropriate consultation.

Disposition Decisions

  • All patients with suspected sepsis should be admitted.
  • ICU level care for those who meet criteria for septic shock.

References and Further Reading

  • Gaieski DF, Edwards JM, KallanMJ, Carr BG.Benchmarking the incidence and mortality ofsevere sepsis in the United States. Crit Care Med. 2013;41(5):1167-1174.
  • Dellinger RP, Levy MM, Rhodes A, et al.; Surviving Sepsis Campaign Guidelines Committee Including the Pediatric Subgroup. Surviving Sepsis Campaign: international guidelines for management of severe sepsis and septic shock: 2012. Crit Care Med. 2013;41(2):580-637.
  • Vincent J-L, Marshall JC, Namendys-Silva SA, et al.; ICON Investigators. Assessment of the worldwide burden of critical illness: the Intensive Care Over Nations (ICON) audit. Lancet Respir Med. 2014;2(5):380-386.
  • Fleischmann C, Scherag A, Adhikari NK, et al.; International Forum of Acute Care Trialists. Assessment of global incidence and mortality of hospital-treated sepsis: current estimates and limitations. Am J Respir Crit Care Med. 2015.
  • Rubulotta FM, Ramsay G, Parker MM, Dellinger RP, Levy MM, Poeze M; Surviving Sepsis Campaign Steering Committee; European Society of Intensive Care Medicine; Society of Critical Care Medicine. An international survey: public awareness and perception of sepsis. Crit Care Med. 2009;37(1): 167-170.
  • Bone RC, Balk RA, Cerra FB, et al. American College of Chest Physicians/Society of Critical Care Medicine Consensus Conference: definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Crit Care Med. 1992;20(6):864-874.
  • Levy MM, Fink MP, Marshall JC, et al.; International Sepsis Definitions Conference. 2001 SCCM/ESICM/ACCP/ATS/SIS International Sepsis Definitions Conference. Intensive Care Med. 2003; 29(4):530-538.
  • Singer M, Deutschman, C., Seymour, C.W., et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA 2016; 315:801-10.
  • Kaukonen K-M, Bailey M, Pilcher D, Cooper DJ, Bellomo R. Systemic inflammatory response syndrome criteria in defining severe sepsis. N Engl J Med. 2015;372(17):1629-1638.
  • Gaieski DF, Mikkelsen ME, Band RA, et al. Impact of time to antibiotics on survival in patients with severe sepsis or septic shock in whom early goal directed therapy was initiated in the emergency department. Crit Care Med 2010; 38:1045.
  • Sasse KC, Nauenberg E, Long A, et al. Long term survival after intensive care unit admission with sepsis. Crit Care Med 1995; 23:1040.
  • ProCESS Investigators, Yealy DM, Kellum JA, et al. A randomized trial of protocol based care for early septic shock. N Engl J Med 2014; 370:1683.
  • ARISE Investigators, ANZICS Clinical Trials Group, Peake SL, et al. Goal directed resuscitation for patients with early septic shock. N Engl J Med 2014; 371:1496.
  • Cardenas-Garcia J, Schaub, KF, Belchikov YG, et al. Safety of Peripheral Intravenous Administration of Vasoactive Medication. J Hosp Med 2015. Sep;10(9):581-5.
  • Maitland K, Kiguili, S, Opoka RO, et al. and the FEAST Trial Group. Mortality after Fluid Bolus in African Children with Severe Infection. N Engl J Med. 2011 Jun 30;364(26):2483-95.
  • Opal SM, Girard TD, Ely EW. The immunopathogenesis of sepsis in elderly patients. Clin Infect Dis.2005;41 Suppl 7:S504–S512.
  • Castle SC, Norman DC, Yeh M, Miller D, Yoshikawa TT. Fever response in elderly nursing home residents: are the older truly colder? J Am Geriatr Soc.1991;39:853–857.
  • Nasa P, Juneja D, Singh O, Dang R, Arora V. Severe sepsis and its impact on outcome in elderly and very elderly patients admitted in intensive care unit. J Intensive Care Med. 2012 May-Jun; 27(3):179-83.
  • Angus DC, van der Poll T. Severe sepsis and septic shock. NEJM. 2013, Aug 29; 369(9):840-51.
  • Mathias B, Mira, JC, Larson, SD. Pediatric sepsis. Curr Opin Pediatr. 2016 March 15; 28: 1-8.

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