#51 Sepsis 101

Written By Nick Mark

On this week's episode of Critical Care Time, Cyrus & Nick take a deep dive into the wide world of sepsis! This one has been a long time in the making so buckle up for a journey through the history of sepsis and critical care, culminating in a review of our approach to diagnosis and management in 2025 complete with some hot topics and controversies. Please give us a listen or a watch, leave us some feedback and share our show with your friends and colleagues!

Historical Context

  • Hippocrates (460-370 BCE) was one of the first to describe disease as a natural phenomenon rather than the result of supernatural forces. He introduced the concept of crisis, a turning point in the disease course, and the term sepsis, from the Greek "σήψις" meaning putrefaction.

  • The theory of miasma (bad air) dominated medical thinking for centuries; the term malaria ("bad air" in Italian) reflects this belief.

  • Understanding the role of microbes in illness

    • Antonie van Leeuwenhoek (1632–1723 CE) discovered microorganisms using his handmade microscopes but did not connect them to disease causation.

    • Ignaz Semmelweis, an obstetrician in Vienna in the 1840s, observed lower mortality rates in midwife-run wards and linked infections to contamination from cadaveric material on the hands of doctors. His handwashing intervention drastically reduced maternal mortality but was rejected by contemporaries. He was institutionalized, beaten by guards, and died of sepsis in 1865.

    • Louis Pasteur (1822–1895 CE) demonstrated that microbes cause disease, laying the groundwork for germ theory.

    • Joseph Lister (1827-1912 CE) influenced by Pasteur's work, introduced antiseptic surgical techniques using carbolic acid. His 1867 paper, "On the Antiseptic Principle in the Practice of Surgery," transformed surgical practice.

  • Building intensive care units:

    • Florence Nightingale (1820-1910 CE) arguably laid the foundation for ICU care by concentrating critically ill patients in specialized settings, instituting specialized training, and using data visualization to support her reforms.

    • During the 1952 polio epidemic in Copenhagen, Bjørn Ibsen created the first modern ICU using manual positive pressure ventilation. This is detailed in the book The Autumn Ghost by Hannah Wunsch.

  • Peforming invasive measurements:

    • Werner Forssmann (1904-1979 CE) performed the first human cardiac catheterization - on himself - in 1929, demonstrating that central venous access and invasive hemodynamic measurements were possible.

    • Swan-Ganz pulmonary artery catheters, developed in the 1970s, enabled detailed hemodynamic monitoring and influenced sepsis resuscitation strategies.

  • Rigorously defining sepsis

    • The 1991 ACCP/SCCM Consensus Conference introduced the concept of Systemic Inflammatory Response Syndrome (SIRS) with criteria including:

      • Temperature >38°C or <36°C

      • HR >90

      • RR >20 or PaCO2 <32 mmHg

      • WBC >12,000 or <4,000/µL

    • In addition to SIRS, this also introduced the widespread use of sepsis, severe sepsis, and septic shock.

  • 2001: The Rivers' Early Goal-Directed Therapy (EGDT) Era begins

    • Emmual Rivers defined a protocolized approach to sepsis resuscitaiton, begining in the ED, that used invasive measurements to guide hemodynamic interventions.

    • A single-center RCT showed that protocolized care using CVP, MAP, and ScvO2 targets reduced mortality from 46.5% to 30.5%.

    • Led to widespread adoption of EGDT and inspired the Surviving Sepsis Campaign (SSC).

  • 2014–2015: The EGDT Reconsidered

    • Three large RCTs challenged EGDT:

    • All RCTs found no mortality benefit to mandatory EGDT over usual care, which had already improved to include early antibiotics and fluids.

      • This de-emphasized the need for invasive measurements (ScvO2), transfusions, and aggressive fluid resuscitation.

      • Reminder that single center RCTs often fail to be replicated.

  • 2016: Sepsis-3 Definition

    • Singer et al., JAMA 2016

    • Sepsis defined as life-threatening organ dysfunction caused by a dysregulated host response to infection.

    • Implemented qSOFA (RR ≥22, SBP ≤100, GCS <15) proposed as a bedside risk stratification tool.

    • Retired SIRS and the term "severe sepsis."

  • 2021: Contemporary guidelines

    • Evans et al., Crit Care Med 2021

    • Start antibiotics within 1 hour for septic shock; within 3 hours for suspected sepsis without shock.

    • Fluid resuscitation: Begin with 30 mL/kg balanced crystalloids.

      • This is likely too much for many and too little for others; more personalized care likely better!

    • Start vasopressors early, even through peripheral IVs if needed.

      • Norepinephrine is first-line; add vasopressin if needed.

    • Consider hydrocortisone for refractory shock.

Balanced vs Isotonic Fluids

  • SMART Trial, NEJM 2018: Balanced crystalloids reduced death, renal replacement therapy, and persistent renal dysfunction.

  • SALT-ED Trial, NEJM 2018: Showed benefit in non-ICU ED patients.

  • Meta-analyses (Liu 2019, Dong 2022): Show consistent benefit for balanced fluids over saline.

  • FLUID trial (McIntyre et al, NEJM 2025): Underpowered but found 1% reduction in mortality (not significant) with use of LR instead of normal saline.

  • Meta-analyses suggest that balanced crystalloids likely reduce the risk of AKI, need for RRT, and mortality in people with sepsis.

Controversies and Future Directions

  • Vitamin C Cocktails: Proposed based on very flimsly evidence. 7 RCT demonstrated vitamin C cocktail was ineffective. The recent LOVIT Trial, NEJM 2022 showed harm in using IV Vitamin C in sepsis.

  • Beta-blockers (e.g., esmolol) may reduce mortality by attenuating sympathetic overdrive.

    • This is still controversial.

  • Endotoxin Adsorbers: EUPHRATES Trial, JAMA 2018 was negative.

  • Point-of-care renin testing may guide use of angiotensin II.

  • Artificial Intelligence may help with earlier recognition of sepsis.

  • Immunophenotyping may identify patients who would benefit most from specific interventions (steroids, angiotensin II, etc).

Clinical Takeaways

  1. Recognize sepsis early. Use fast bedside scores like qSOFA or NEWS.

  2. Administer antibiotics and achieve source control promptly. Each hour of delay increases mortality by ~7%.

  3. Use fluids judiciously. Start with 30 mL/kg but assess fluid responsiveness dynamically. Don’t be afraid to personalize fluid based on history and fluid responsiveness.

  4. Initiate vasopressors early, especially if MAP <65 mmHg. Norepinephrine is first-line, vasopressin second.

  5. Consider corticosteroids in refractory septic shock.

  6. Address long-term effects. Post-sepsis syndrome includes cognitive, emotional, and physical impairments.


Nick Mark
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#50 Fever in the ICU and Fever in the Returning Traveler