Early Sepsis Identification and Treatment - References

References

Consensus Guidelines for Diagnosis and Treatment of Sepsis

  • Evans, L et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Critical Care Medicine 2021.
    • International consensus guidelines from the Surviving Sepsis Campaign outlining recommendations for best practices in sepsis diagnosis and treatment, updated in 2021.
  • Singer, M. et al. The Third International Consensus Definitions for Sepsis and Septic Shock(Sepsis-3). JAMA, 2016.
    • The updated definitions and clinical criteria for sepsis and septic shock. The new definitions address the limitations of previous criteria, focusing too heavily on inflammation and using inadequately specific and sensitive systemic inflammatory response syndrome (SIRS) criteria. The new definition describes sepsis as life-threatening organ dysfunction due to a dysregulated host response to infection, operationalized by an increase in the SOFA score by 2 or more points. Septic shock is defined as a subset of sepsis with heightened mortality risks, identified by a vasopressor requirement to maintain mean arterial pressure ≥65 mm Hg and serum lactate >2 mmol/L. The qSOFA score, including criteria like a respiratory rate ≥22/min, altered mentation, or systolic blood pressure ≤100 mm Hg, is recommended for rapid identification of potentially poor outcomes.

Early Identification and Diagnosis of Sepsis

Implementation of Sepsis Bundles / Protocolized Care:

  • Ferrer, R. et al. Improvement in Process of Care and Outcome After a Multicenter Severe Sepsis Educational Program in Spain. JAMA 2008.
    • This study evaluated the impact of a national educational program, based on the Surviving Sepsis Campaign guidelines, trained staff in the recognition and treatment of severe sepsis and septic shock in 59 ICUs across Spain. Patients were monitored before the intervention (854), immediately after (1465), and one year later in a subset of ICUs (247). The educational program led to improved compliance with care processes and a significant reduction in hospital mortality (from 44.0% to 39.7%). Compliance with the sepsis resuscitation bundle and management bundle also improved post-intervention. However, the compliance with the resuscitation bundle declined to baseline levels within a year, though mortality and management bundle compliance remained stable.
  • Kahn, et al. Association Between State-Mandated Protocolized Sepsis Care and In-hospital Mortality Among Adults With Sepsis. JAMA 2019.
    • In 2013, New York State mandated hospitals to implement evidence-based sepsis management protocols and report adherence and outcomes. This study evaluated the impact of these regulations using a retrospective cohort approach, comparing outcomes in New York with those in control states. The results showed that New York's regulations were associated with a significant reduction in 30-day in-hospital mortality for sepsis patients compared to control states. Other findings included no significant changes in ICU admission rates, a relative decrease in hospital length of stay and C. difficile infection rates, and increased central venous catheter use. The study concludes that mandated sepsis protocols in New York improved sepsis outcomes, though generalizability to other states remains uncertain due to differing baseline mortality rates.
  • Levy, M. et al.The Surviving Sepsis Campaign: results of an international guideline-based performance improvement program targeting severe sepsis. Intensive Care Medicine 2010.
    • This study examined the impact of the Surviving Sepsis Campaign (SSC) guidelines on clinical behavior and patient outcomes for severe sepsis and septic shock across multiple healthcare settings in the US, Europe, and South America. A total of 15,022 patients from 165 sites were included, with interventions based on resuscitation and management bundles to be completed within 6 and 24 hours, respectively. Over two years, compliance with the resuscitation bundle increased from 10.9% to 31.3% and with the management bundle from 18.4% to 36.1%. Hospital mortality decreased from 37% to 30.8%.
  • Levy, M. et al. Mortality Changes Associated with Mandated Public Reporting for Sepsis. The Results of the New York State Initiative. American Journal of Respiratory and Critical Care Medicine 2018.
    • This study assessed the impact of the New York State Department of Health's 2013 initiative to improve early recognition and treatment of severe sepsis and septic shock. The analysis included data from 91,357 hospitalizations across 183 hospitals between April 1, 2014, and June 30, 2016. Hospitals were required to implement evidence-based protocols including 3-hour and 6-hour sepsis bundles. Compliance with the 3-hour bundle increased from 53.4% to 64.7%, and the 6-hour bundle increased from 23.9% to 30.8%. The initiation of sepsis protocols was associated with a decrease in risk-adjusted mortality from 28.8% to 24.4%. Higher compliance with sepsis bundles correlated with reduced hospital length of stay and lower adjusted mortality rates. The study demonstrates that statewide initiatives can improve compliance with sepsis management protocols and reduce mortality.
  • Mouncey, P. et al. Trial of Early, Goal-Directed Resuscitation for Septic Shock (The PROMISE Trial). New England Journal of Medicine 2016.
    • This study examined the effectiveness of Early, Goal-Directed Therapy (EGDT) for patients with early septic shock. In a randomized trial involving 56 hospitals in England, patients were assigned either to EGDT or usual care. The results showed no significant difference in 90-day mortality or other secondary outcomes between the two groups, although EGDT led to increased treatment intensity and higher costs. The study concludes that EGDT did not improve outcomes compared to usual care in patients who received early identification and initial management for septic shock.
  • Rivers, E. et.al. Early Goal-Directed Therapy in the Treatment of Severe Sepsis and Septic Shock. New England Journal of Medicine 2001.
    • This randomized study evaluated the efficacy of early goal-directed therapy (EGDT) compared to standard therapy in patients with severe sepsis or septic shock before ICU admission. Results showed that in-hospital mortality was significantly lower in the EGDT group (30.5%) compared to the standard therapy group (46.5%). Additionally, patients in the EGDT group had better resuscitation outcomes, including higher central venous oxygen saturation, lower lactate concentration, lower base deficit, higher pH, and lower APACHE II scores, indicating less severe organ dysfunction.
  • The ARISE Investigators and the ANZICS Clinical Trials Group. Goal-Directed Resuscitation for Patients with Early Septic Shock. New England Journal of Medicine 2014.
    • This study evaluated the effectiveness of Early Goal-Directed Therapy (EGDT) compared to usual care in patients with early septic shock at 51 centers in Australia and New Zealand. Among 1600 patients randomized, the EGDT group received higher volumes of intravenous fluids, vasopressor infusions, red-cell transfusions, and dobutamine within the first 6 hours than the usual care group. At 90 days, mortality rates were similar between the EGDT group (18.6%) and the usual care group (18.8%), with no significant differences in survival time, in-hospital mortality, duration of organ support, or hospital stay. The study concluded that EGDT did not reduce all-cause mortality at 90 days for these patients.
  • The PRISM Investigators. Early, Goal-Directed Therapy for Septic Shock — A Patient-Level Meta-Analysis. New England Journal of Medicine 2017.
    • This meta-analysis examined the effectiveness of early, goal-directed therapy (EGDT) for septic shock by combining data from three multicenter trials (ProCESS, ARISE, and ProMISe). The results showed that 90-day mortality was similar between the EGDT group (24.9%) and the usual care group (25.4%), with no significant difference in primary or most secondary outcomes. EGDT was associated with greater use of intensive care and cardiovascular support and higher hospitalization costs compared to usual care. Subgroup analyses did not reveal any specific patient or hospital characteristics that benefited more from EGDT.
  • The PROCESS Investigators. A Randomized Trial of Protocol-Based Care for Early Septic Shock, New England Journal of Medicine 2014.
    • This multicenter trial evaluated the effectiveness of protocol-based resuscitation strategies, including early goal-directed therapy (EGDT), for patients with septic shock in emergency departments. Patients were randomly assigned to three groups: protocol-based EGDT, protocol-based standard therapy (without central venous catheters, inotropes, or blood transfusions), or usual care. The primary endpoint was 60-day in-hospital mortality. Among 1341 enrolled patients, no significant differences in mortality were observed: 21.0% for the EGDT group, 18.2% for the standard-therapy group, and 18.9% for the usual-care group. Additionally, there were no significant differences in 90-day or 1-year mortality or the need for organ support. The study concluded that protocol-based resuscitation, including EGDT, did not improve outcomes compared to usual care for patients with septic shock.
  • Van Zanten, et al. Guideline Bundles Adherence and Mortality in Severe Sepsis and Septic Shock.  Critical Care Medicine 2014.
    • This study aimed to evaluate the impact of implementing a national program to screen patients for severe sepsis and septic shock and implement Surviving Sepsis Campaign bundles across 82 ICUs in the Netherlands. By comparing 52 ICUs that participated in a national sepsis program with 30 that did not, researchers assessed bundle adherence and case-mix adjusted mortality rates. They found that increased duration of participation in the program improved bundle adherence and reduced in-hospital mortality rates significantly in participating ICUs.

Antimicrobial Timing in Sepsis

  • Ballester, L. et al. Differences in Hypotensive vs. Non-Hypotensive Sepsis Management in the Emergency Department: Door-to-Antibiotic Time Impact on Sepsis Survival.  Med Sci (Basel) 2018.
    • Initial management of patients with community-onset severe sepsis differed according to their clinical presentation. Initial hypotension was associated with early hemodynamic management and less ICU requirement. A non-significant delay was observed in the administration of antibiotics to initially non-hypotensive patients. The time of door-to-antibiotic administration was related to mortality.
  • Bisarya, R. et al. Antibiotic Timing and Progression to Septic Shock Among Patients in the ED with Suspected Infection. CHEST 2022.
    • This retrospective cohort study investigated whether the time to administer antibiotics in the emergency department is linked to the progression to septic shock in patients with suspected infection but without initial shock. Analyzing over 74,000 patient encounters, the study found that 7.4% progressed to septic shock, with an increased risk correlating with each hour of delay in antibiotic administration. The quick Sequential Organ Failure Assessment (qSOFA) score was a better predictor of septic shock than the Systemic Inflammatory Response Syndrome (SIRS) score, despite earlier administration of antibiotics, indicating a more specific but worse outcome. Overall, delaying antibiotics heightens the risk of septic shock in these patients.
  • Hechtman, R et al. Heterogeneity of Benefit from Earlier Time-to-Antibiotics for Sepsis. American Journal of Respiratory and Critical Care Medicine 2024.
    • This observational cohort study of patients hospitalized with community-onset sepsis across found that a shorter time-to-antibiotics (within 3 hours) is associated with a greater reduction in 30-day mortality, particularly for patients with metastatic cancer, shock, or multiple acute organ dysfunctions. The findings emphasize that timely administration of antibiotics is especially crucial for patients with certain high-risk characteristics.
  • Hooper, G. et al. Concordance Between Initial Presumptive and Final Adjudicated Diagnoses of Infection Among Patients Meeting Sepsis-3 Criteria in the Emergency Department. Clinical Infectious Diseases 2023.
    • This retrospective cohort study evaluated the incidence and drivers of false-positive infection not to have an infection and 18.0% had a different source of infection on final assessment compared to the initial ED diagnosis. Factors associated with false-positive diagnoses included hypothermia, altered mental status, high comorbidity burden, and an "unknown infection source" in the ED. Importantly, false-positive infection diagnoses were not linked to increased 30-day mortality.
  • Klouwenberg, P et al. Likelihood of infection in patients with presumed sepsis at the time of intensive care unit admission: a cohort study. Critical Care 2015.
    • This study assessed the accuracy of diagnosing sepsis in ICU patients by evaluating the likelihood of infection post-hoc among patients admitted with suspected sepsis across two Dutch ICUs. 13% of these patients had no infection and 30% had only a possible infection upon further assessment. Despite differing infection likelihoods by site, the results largely indicated that a higher likelihood of initial infection was associated with increased length of stay and complications. Importantly, in multivariable analyses, patients with an unlikely infection had a higher mortality rate compared to those with a definite infection.
  • Liu, V.X. et al. The Timing of Early Antibiotics and Hospital Mortality in Sepsis. American Journal of Respiratory and Critical Care Medicine 2017.
    • This retrospective study evaluated the relationship between the timing of antibiotic administration and mortality among 35,000 sepsis patients treated in 21 emergency departments in Northern California from 2010 to 2013. Antibiotics were given within 6 hours of emergency department registration, with a median administration time of 2.1 hours. Each hour of delay in antibiotic administration after registration was associated with a 9% increase in the odds of hospital mortality. The increase in absolute mortality was 0.3% for sepsis, 0.4% for severe sepsis, and 1.8% for septic shock per hour of delay. The study concluded that even within the 6-hour window, quicker administration of antibiotics significantly reduces mortality risk, especially in patients with septic shock.
  • Miller, R and Clemmer, T. et al. Multicenter Implementation of a Severe Sepsis and Septic Shock Treatment Bundle. American Journal of Respiratory and Critical Care Medicine, 2013.
    • This multicenter observational study evaluates the impact of adhering to severe sepsis and septic shock bundles on hospital mortality. Conducted across 18 ICUs in Utah and Idaho, it found that in-hospital mortality significantly decreased from 21.2% in 2004 to 8.7% in 2010 as compliance with the full sepsis management bundle improved from 4.9% to 73.4%. Regression analyses revealed that adherence to specific interventions, such as inotropes, red cell transfusions, glucocorticoids, and lung-protective ventilation, was associated with lower mortality rates. Early resuscitation compliance was particularly effective, reducing the need for subsequent interventions by lowering the severity of illness.
  • Pak, T et al. Risk of Misleading Conclusions in Observational Studies of Time-to-Antibiotics and Mortality in Suspected Sepsis. Clinical Infectious Diseases 2023.
    • This study retrospectively analyzed adults admitted with suspected infection to evaluate the impact of antibiotic timing on in-hospital mortality. Modeling each hour separately confirmed that every hour of delay was associated with increased mortality for septic shock, but only delays >6 hours were associated with higher mortality for sepsis without shock. The authors note that these associations are highly sensitive to analytic choices.
  • Peltan, I.D. et al. ED Door-to-Antibiotic Time and Long-Term Mortality in Sepsis. CHEST 2019.
    • This retrospective cohort study examined the association between door-to-antibiotic time and long-term mortality in ED patients with sepsis. Each additional hour delay in antibiotic administration was associated with a 10% increase in 1-year mortality. This linear association was consistent across various time intervals and mortality outcomes (hospital, 30-day, and 90-day mortality). Notably, mortality was significantly higher when antibiotics were administered more than 3 hours after ED arrival compared to within 3 hours.
  • Prescott, H.C. et al. Temporal trends in antimicrobial prescribing during hospitalization for potential infection and sepsis. JAMA IM 2022.
    • In this multihospital cohort study, the time to first antimicrobial for sepsis decreased over time, but this trend was not associated with increasing antimicrobial use, days of therapy, or broadness of antimicrobial coverage, which suggests that shortening the time to antibiotics for sepsis is feasible without leading to indiscriminate antimicrobial use.
  • Seymour, C.W. et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis.  New England Journal of Medicine 2017.
    • This study analyzed data from New York State hospitals between April 2014 and June 2016 to assess the impact of the speed of sepsis treatment on patient outcomes. Among 49,331 patients with sepsis or septic shock, 82.5% had a 3-hour bundle of care (blood cultures, broad-spectrum antibiotics, and lactate measurement) completed within the recommended time. The median times to complete the bundle, administer antibiotics, and provide a fluid bolus were 1.30, 0.95, and 2.56 hours, respectively. Faster completion of the 3-hour bundle and quicker administration of antibiotics were associated with significantly lower risk-adjusted in-hospital mortality, whereas the speed of the fluid bolus administration was not. The findings support rapid implementation of sepsis care protocols to improve patient outcomes.
  • Taylor, S.P. et al. First-to-second antibiotic delay and hospital mortality among emergency department patients with suspected sepsis Am J Emerg Med 2021.
      • This study investigated the impact of delays between the first and second antibiotic administration on hospital mortality in suspected sepsis cases. Conducted across twelve hospitals in the Southeastern United States, the study involved 25,717 adult patients who received at least two antibiotics within 12 hours. Results showed that a delay of more than one hour between antibiotics was linked to a higher risk of hospital death in patients with septic shock but not in those without shock or the overall cohort. The findings suggest that reducing antibiotic delays could be particularly beneficial for patients with septic shock.
  • Taylor, S.P. et. al. Real-World Implications of Updated Surviving Sepsis Campaign Antibiotic Timing Recommendations. Critical Care Medicine 2024.
    • A retrospective cohort study of 12 hospitals between 2017 and 202, this study assessed the real-world impact of the updated Surviving Sepsis Campaign recommendations regarding antibiotic timing for suspected serious infections. The study involved 166,559 adult patients treated in emergency departments. The findings indicated that 30% of patients classified as having a possible infection without shock typically received antibiotics within a median of 5.5 hours and had low mortality rates; whereas, those with probable infections received antibiotics more quickly, especially if shock was present, but had higher mortality. The study supports aligning antibiotic timing with risk and probability of infection, suggesting that a 1-hour target is unnecessary for patients without shock and with only possible sepsis.
  • Whiles, B and Simpson, S. et al. Increased Time to Initial Antimicrobial Administration is Associated with Progression to Septic Shock in Severe Sepsis Patients. Critical Care Medicine, 2017.
    • This retrospective cohort study of 3,929 patients in a single academic medical center investigates whether the timing of initial antimicrobial administration affects the progression of severe sepsis to septic shock in emergency department patients. It found that the median time to receive antimicrobials was longer in patients who progressed to septic shock compared to those who did not, with each additional hour increasing the risk of progression by 8%. Factors such as male sex, higher Charlson Comorbidity Index, and the number of infections were also associated with progression to septic shock. The findings highlight the critical importance of early, broad-spectrum antimicrobial administration to reduce progression to septic shock and in-hospital mortality.

Prolonged versus Intermittent infusions of Beta Lactam Antibiotics

Initial 30ml/kg Fluid Resuscitation in Sepsis

  • Acharya, P. et al. Fluid resuscitation and outcomes in heart failure patients with severe sepsis or septic shock: A retrospective case-control study. PLoS One 2021.
    • The use of ≥30 mL/kg fluid bolus appears to confer protection against in-hospital mortality and is not associated with increased chances of mechanical ventilation in heart failure patients presenting with severe sepsis or septic shock.
  • Kuttab, HI. et al. Evaluation and predictors of fluid resuscitation in patients with severe sepsis and septic shock. Critical Care Medicine 2019.
    • This retrospective cohort study aimed to evaluate the predictors and outcomes of achieving a 30 mL/kg crystalloid bolus within 3 hours of sepsis onset (30by3) in patients with severe sepsis or septic shock at an urban tertiary care center. Among 1032 patients, 49.3% received 30by3. The study found that elderly patients, males, obese individuals, those with end-stage renal disease, heart failure, or documented volume overload were less likely to achieve 30by3. Those who did not meet 30by3 had increased odds of mortality (17.1% overall, 20.4% in the shock group), delayed hypotension, and longer ICU stays. Higher fluid volumes within the first 3 hours correlated with decreased mortality, with a plateau effect observed between 35 and 45 mL/kg. The study concludes that failure to achieve 30by3 is associated with worse outcomes, and identifying predictors of inadequate resuscitation could inform interventions to improve survival, although future validation is needed.
  • Liu, V.X. et al. Multicenter Implementation of a Treatment Bundle for Patients with Sepsis and Intermediate Lactate Values. American Journal of Respiratory and Critical Care Medicine 2016.
    • This study evaluates the impact of implementing a treatment bundle for hemodynamically stable sepsis patients with intermediate lactate values (2-4 mmol/L) in the emergency department across multiple centers. The study compared data before and after the bundle's implementation, which included measures like timely antibiotics, repeat lactate testing, and fluid administration. Among 18,122 patients identified, compliance with the treatment bundle rose from 32.2% in 2011 to 44.9% post-implementation, while hospital mortality decreased from 9.3% in 2012 to 7.9% in 2013.  The most significant mortality reduction was observed in patients with a history of heart failure and/or chronic kidney disease, likely due to adjusted fluid resuscitation practices in these patients. The study concludes that the implementation of a targeted treatment bundle for sepsis patients with intermediate lactate values improved compliance and was linked to lower hospital mortality, especially in patients with a history of heart failure or kidney disease.
  • Wang, H-L. et al. Initial fluid resuscitation(30 mL/kg) in patients with septic shock: More or less? The American Journal of Emergency Medicine, 2021.
    • This multicenter prospective observational study aimed to evaluate the impact of different initial fluid resuscitation doses on mortality in adult patients with septic shock. The study categorized 302 patients into three groups based on their initial fluid dose: low-volume (<20 mL/kg), medium-volume (20-30 mL/kg), and high-volume (>30 mL/kg). The 28-day mortality rate was lowest in the medium-volume group (26.3%) and highest in the high-volume group (48.3%). Patients receiving 30 mL/kg within the first 1-2 hours showed the lowest mortality (22.8%). The study concludes that an initial fluid resuscitation of 20-30 mL/kg in the first hour may improve 28-day survival in septic shock patients, though further randomized controlled trials are necessary to confirm these findings.
  • Zampieri, F.G. et al. Fluid Therapy for Critically Ill Adults with Sepsis. JAMA 2023.
    • Fluids are an important component of treating patients who are critically ill with sepsis. Although optimal fluid management in these patients remains uncertain, clinicians should consider the risks and benefits of fluid administration in each phase of critical illness and facilitate fluid removal for patients recovering from acute respiratory distress syndrome.

Restrictive versus Liberal Fluid Resuscitation (What to do in cases of continued hypotension after patient has received initial 30ml/kg fluid bolus)

  • Chen, C. and Kollef, M. Targeted Fluid Minimization Following Initial Resuscitation in Septic Shock A Pilot Study. CHEST, 2015.
    • This study explored the effectiveness and safety of targeted fluid minimization (TFM) in patients with septic shock. Conducted with 82 participants at Barnes-Jewish Hospital, patients undergoing TFM, guided by daily fluid responsiveness assessments, were compared to those receiving usual care. Results showed that the TFM group had a lower median net fluid balance by days 3 and 5, though not significantly. Clinical outcomes such as in-hospital mortality, ventilator days, renal replacement therapy, and vasopressor days were similar between the groups, indicating that TFM is likely safe. The study concludes that larger trials are needed to further evaluate TFM in septic shock management.
  • Corl, K. et al. The Restrictive IV Fluid Trial in Severe Sepsis and Septic Shock(RIFTS): A Randomized Pilot Study. Critical Care Medicine. 2019.
    • This pilot study aimed to compare the outcomes of low-volume versus high-volume IV fluid resuscitation in patients with severe sepsis and septic shock. Conducted at two hospitals within a single academic system, 109 patients were randomly assigned to either a restrictive resuscitation strategy or usual care for the first 72 hours. The restrictive group received significantly less fluid than the usual care group (47.1 vs 61.1 mL/kg). By 30 days, mortality rates and the incidence of new organ failure, hospital or ICU length of stay, and serious adverse events were similar between the groups. The study supports that a restrictive fluid strategy can be safely implemented and merits further investigation in a larger multicenter trial.
  • Douglas, I. et al. Fluid Response Evaluation in Sepsis Hypotension and Shock (The FRESH Trial). CHEST 2020.
    • This prospective, multicenter, randomized clinical trial investigated the efficacy of using dynamic measures, specifically stroke volume change during passive leg raises, to guide fluid and vasopressor management in septic shock patients. The intervention group was assessed for fluid responsiveness before administering fluid boluses or increasing vasopressors, while the control group received usual care. The intervention group exhibited a significantly lower positive fluid balance at 72 hours or ICU discharge and required less renal replacement therapy (5.1% vs 17.5%) and mechanical ventilation (17.7% vs 34.1%) compared to the usual care group.
  • Hjortrup, P. et al. Restricting volumes of resuscitation fluids in adults with septic shock after initial management: the CLASSIC randomized parallel-group, multicentre feasibility trial. Intensive Care Medicine 2016.
    • This randomized study assessed the effects of a fluid restriction protocol compared to standard care in ICU patients with septic shock after initial resuscitation. The fluid restriction group received less resuscitation fluid at day 5 and during the ICU stay compared to the standard care group, with mean differences of -1.2 L and -1.4 L respectively. No significant differences were found in total fluid input, balance, or serious adverse reactions. The fluid restriction group experienced fewer ischemic events and less worsening of acute kidney injury, although only the latter was statistically significant. Additionally, there was a non-significant trend toward lower 90-day mortality in the fluid restriction group.
  • MacDonald, et al. REstricted Fluid REsuscitation in Sepsis-associated Hypotension(REFRESH): study protocol for a pilot randomised controlled trial. Intensive Care Medicine 2018.
    • This study aimed to assess the feasibility of using a restricted fluids and early vasopressor regimen compared to usual care for initial resuscitation of hypotensive patients with suspected sepsis. In the randomized, open-label clinical trial, 99 emergency department patients were analyzed, where the restricted volume group received significantly less fluid within 6 hours compared to the usual care group. The study found no significant difference in 90-day mortality between the two groups, with low overall mortality rates and similar rates of serious adverse events. The results suggest that this resuscitation approach is feasible, but further trials are needed to evaluate its impact on clinical outcomes in high-risk patients.
  • Meyhoff, T.S. et al. Restriction of Intravenous Fluid in ICU Patients with Septic Shock (The CLASSIC Trial). New England Journal of Medicine 2022.
    • This international, randomized trial investigated the effects of restricted versus standard IV fluid therapy in adult patients with septic shock in the ICU. A total of 1554 patients were enrolled, with 770 in the restrictive-fluid group and 784 in the standard-fluid group. Patients in the restrictive-fluid group received a median of 1798 ml of IV fluids, compared to 3811 ml in the standard-fluid group. At 90 days, mortality rates were similar between the two groups: 42.3% in the restrictive-fluid group and 42.1% in the standard-fluid group, with no significant difference. Additionally, the incidence of serious adverse events in the ICU and the number of days alive without life support or hospitalization were comparable. The study concluded that fluid restriction did not reduce 90-day mortality compared to standard fluid therapy in septic shock patients in the ICU.
  • Semler, M. et al. Conservative Fluid Management After Sepsis Resuscitation: A Pilot Randomized Trial. Journal Intensive Care Medicine, 2020.
    • This study investigated the impact of conservative fluid management on fluid balance and ICU-free days in sepsis patients. Conducted as a single-center, phase II/III randomized trial, it included adults with suspected infection and either shock or respiratory insufficiency, who were assigned to either usual care or a conservative fluid management protocol. The protocol aimed to limit intravenous fluids and maintain equal fluid input and output through diuretics. The trial was stopped at phase II as the difference in mean daily fluid balance between groups did not meet the predefined threshold of −500 mL. Ultimately, the conservative fluid management did not result in significant reductions in daily fluid balance compared to usual care, and hemodynamic, respiratory, and renal functions were similar between groups.
  • Shapiro, N. et al. Early Restrictive or Liberal Fluid Management for Sepsis-Induced Hypotension(The CLOVERS Trial). New England Journal of Medicine 2023.
    • This unblinded superiority trial conducted at 60 U.S. centers compared restrictive and liberal fluid strategies in patient with sepsis-induced hypotension. Patients who did not respond to initial treatment with 1 to 3 liters of intravenous fluid were randomized into either a restrictive fluid group or a liberal fluid group within 4 hours. The results indicated no significant difference in 90-day mortality between the restrictive fluid group (14.0%) and the liberal fluid group (14.9%). Both groups had similar rates of serious adverse events.

 

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