Additional Sepsis Management - References

References

Use of Norepinephrine as First-Line Vasopressor

• Avni, T. et al. Vasopressors for the treatment of septic shock: Systematic review and meta-analysis. PLoS One 2015.
• Evidence suggests a survival benefit, better hemodynamic profile and reduced adverse events rate for norepinephrine over dopamine. Norepinephrine should be regarded as the first line vasopressor in treatment of septic shock.
• De Backer, D. et al. Comparison of dopamine and norepinephrine in the treatment of shock. N Engl J Med 2010.
• The use of dopamine as first-line vasopressor agent was associated with a greater number of adverse events than the use of norepinephrine.
• Permpikul, C. et al. Early Use of Norepinephrine in Septic Shock Resuscitation(CENSER). A Randomized Trial Am J Respir Crit Care Med 2019.
• Early norepinephrine was significantly associated with increased shock control by 6 hours.

 Peripheral Use of Vasopressors

• Cardenas-Garcia, J. et al. Safety of Peripheral Intravenous Administration of Vasoactive Medication. J of Hosp Med 2015.
• Administration of norepinephrine, dopamine, or phenylephrine by peripheral intravenous access was feasible and safe in this single-center medical intensive care unit. Clinicians should not regard the use of vasoactive medication is an automatic indication for central venous access.
• Munroe, E. et al. Use and Outcomes of Peripheral Vasopressors in Early Sepsis-Induced Hypotension Across Michigan Hospitals: A Retrospective Cohort Study. CHEST 2023.
• Peripheral vasopressor initiation was common across Michigan hospitals and had practical benefits, including expedited vasopressor administration and avoidance of central line placement in one-third of patients. However, the findings of wide practice variation that was not explained by patient case mix and lower use of first-line norepinephrine with peripheral administration suggest that additional standardization may be needed.
• Associated Podcast Episode: CHEST Journal Podcast - April 2024
• Yerke, J. R. et al. Peripheral Administration of Norepinephrine: A Prospective Observational Study. CHEST 2024.
• A prospective observational cohort study assessing the use of a protocol for peripheral norepinephrine administration in medical ICU patients. The primary outcome was number of days of CVC use avoided and secondary outcome was incidence of extravasation events. The study suggests that implementing a protocol for peripheral norepinephrine administration can safely avoid 1 CVC day in the average patient and result in few extravasation events causing minimal or no tissue injury.

 Use of Adjunctive Steroids in Septic Shock

• Bosch, N. et al. Comparative Effectiveness of Fludrocortisone and Hydrocortisone vs. Hydrocortisone Alone Among Patients With Septic Shock. JAMA 2023.
• Among patients with septic shock receiving norepinephrine who initiated hydrocortisone treatment, the addition of fludrocortisone was associated with lower rates of the composite of death or discharge to hospice compared with hydrocortisone alone.
• Fang, F. et al. Association of Corticosteroid Treatment with Outcomes in Adult Patients with Sepsis: A Systematic Review and Meta-Analysis. JAMA IM 2019.
• This systematic review and meta-analysis of 37 randomized clinical trials suggests that administration of corticosteroid treatment in patients with sepsis is associated with significant improvement in health care outcomes and thus with reduced 28-day mortality.
• Rygård, S.L. et al. Low-dose corticosteroids for adult patients with septic shock: A systematic review with meta-analysis and trial sequential analysis. Intensive Care Med 2018.
• In adults with septic shock treated with low dose corticosteroids, short- and longer-term mortality are unaffected, adverse events increase, but duration of shock, mechanical ventilation and ICU stay are reduced.

Use of Balanced Solutions (e.g., Lactated Ringers) Over Other Fluids

• Bledsoe, J. et al. Order Substitutions and Education for Balanced Crystalloid Solution Use in an Integrated Health Care System and Association With Major Adverse Kidney Events JAMA Network Open 2022.
• This study evaluated a multifaceted implementation program to promote the use of lactated ringers solution over normal saline in adult patients receiving 1L or more of intravenous fluids across 22 hospitals. Among 148,423 patients, the proportion of balanced crystalloids increased significantly from 28% to 75% over the study period. The incidence of major adverse kidney events (MAKE30), showed a 2.2% absolute risk reduction, with decreases in persistent kidney dysfunction and mortality but not in dialysis. The implementation program effectively increased the use of lactated ringers solution, which was associated with improved patient outcomes in the health care system.
• Brown, R.M. et al. Balanced Crystalloids versus Saline in Sepsis. A Secondary Analysis of the SMART Clinical Trial. American Journal of Respiratory and Critical Care Medicine 2019.
• This secondary analysis of the SMART trial compared the impact of balanced crystalloids versus saline on 30-day in-hospital mortality among critically ill adults with sepsis. Of the 1,641 sepsis patients admitted to the medical ICU, those receiving balanced crystalloids had a lower 30-day in-hospital mortality rate (26.3% vs. 31.2%). Additionally, balanced crystalloids were linked to a lower incidence of major adverse kidney events within 30 days, and higher numbers of vasopressor-free and renal replacement therapy-free days. The findings suggest that balanced crystalloids improve outcomes in sepsis patients compared to saline.
• Hammond, N.E. et al. Balanced Crystalloids versus Saline in Critically Ill Adults — A Systematic Review with Meta-Analysis New England Journal of Medicine Evidence 2022. 
• This study systematically reviewed 13 randomized clinical trials comparing balanced crystalloids with saline for fluid therapy in critically ill adults, involving 35,884 participants. The risk ratio (RR) for 90-day mortality with balanced crystalloids versus saline was 0.96, indicating a high probability that balanced crystalloids reduce mortality. Secondary outcomes such as the incidence of acute kidney injury, the need for renal replacement therapy, and differences in ventilator-free and vasopressor-free days showed no significant differences between crystalloids and saline. Overall, balanced crystalloids may slightly reduce the risk of death compared to saline in these patients.
• Jackson, K.E. et al. Effect of early balanced crystalloids before ICU admission on sepsis outcomes. CHEST 2021.
• This secondary analysis of the SMART Trial examined the impact of balanced crystalloids vs saline on outcomes for septic patients, focusing on differences between early resuscitation in the emergency department (ED) and post-admission to the ICU. The study included 1,641 medical ICU patients diagnosed with sepsis. Fluid administration was controlled only in the ICU during the first 7 months and coordinated between the ED and ICU during the final 15 months. Results showed that 30-day in-hospital mortality was similar between balanced crystalloids and saline during the ICU-only period, but lower for the balanced crystalloid group during the ED and ICU period (24.9% vs 30.6%). This suggests that initiating balanced crystalloid fluid therapy in the ED, rather than waiting until ICU admission, is associated with improved mortality outcomes for sepsis patients.
• Semler, M. et al. Balanced Crystalloids versus Saline in Critically Ill Adults. New England Journal of Medicine 2018.
• This pragmatic, cluster-randomized trial involving 15,802 critically ill adults compared the use of saline versus balanced crystalloids across five ICUs. The primary outcome was the occurrence of a major adverse kidney event within 30 days, which was lower in the balanced-crystalloids group (14.3%) compared to the saline group (15.4%. Additionally, the balanced-crystalloids group showed a non-significant trend toward lower in-hospital mortality at 30 days and similar rates of new renal-replacement therapy and persistent renal dysfunction.
• Rochwerg, B. et al. Fluid Resuscitation in Sepsis: A systematic review and network meta-analysis. Annals of Internal Medicine 2014
• Demonstrates that among patients with sepsis, resuscitation with balanced crystalloids or albumin compared with other fluids seems to be associated with reduced mortality.
• Vallée, M. et al. Compatibility of Lactated Ringer’s Injection With 94 Selected Intravenous Drugs During Simulated Y-site Administration. Hospital Pharmacy 2021.
• This study tested the compatibility of IV Lactated Ringer’s solution with 94 IV medications during simulated Y-site administration. Of the 94 tested drugs, 86 were found to be compatible with LR and 8 were found to be incompatible.
• Zampieri, F.G. et al. Effect of Intravenous Fluid Treatment With a Balanced Solution vs 0.9% Saline Solution on Mortality in Critically Ill Patients: The BaSICS Randomized Clinical Trial. JAMA 2021.
• This double-blind, randomized clinical trial conducted across 75 ICUs in Brazil evaluated whether a balanced solution versus saline solution improves 90-day survival in critically ill patients. A total of 11,052 patients were randomized, with 10,520 available for analysis. Participants, who were critically ill and required fluid expansion, were assigned to receive either a balanced solution or 0.9% saline solution for all intravenous fluids. By day 90, mortality was 26.4% in the balanced solution group and 27.2% in the saline group, showing no significant difference (adjusted hazard ratio, 0.97; P = .47). No unexpected severe adverse events occurred in either group, suggesting that the use of a balanced solution does not significantly reduce 90-day mortality compared to saline.
• Zampieri, F.G. et al. Association between Type of Fluid Received Prior to Enrollment, Type of Admission, and Effect of Balanced Crystalloid in Critically Ill Adults: A Secondary Exploratory Analysis of the BaSICS Clinical Trial American Journal of Respiratory and Critical Care Medicine 2022.
• This secondary analysis of the BaSICS trial aimed to assess whether the results of a randomized controlled trial could be affected by fluid use before enrollment and admission type. The study involved 10,520 patients who were categorized according to fluid use in the 24 hours before enrollment in four groups (balanced solutions only, 0.9% saline only, a mix of both, and no fluid before enrollment) and according to admission type (planned, unplanned with sepsis, and unplanned without sepsis). Overall, there was a low probability that balanced solutions improved 90-day mortality for the entire trial population, but there was a high probability of benefit for those who had received only balanced solutions before enrollment, particularly in unplanned admissions due to sepsis and planned admissions.

Antibiotics Delivered in Recommended Sequence

• Amoah, et al. Administration of a β-Lactam Prior to Vancomycin as the First Dose of Antibiotic Therapy Improves Survival in Patients with Bloodstream Infections. Clin Infec Dis 2022.
• Prioritizing administration of a β-lactam over vancomycin may reduce early mortality, underscoring the significant impact of a relatively simple practice change on improving patient survival.
• Strich, J.R. et al. Considerations for empiric antimicrobial therapy in sepsis and septic shock in an era of antimicrobial resistance. Journ Infect Dis 2020.
• Hospitals should have a performance improvement program to reduce the time from initial patient presentation to the administration of appropriate therapy for all patients who meet the screening definition of sepsis. An essential education element for nurses is the order of administration of antibiotics for sepsis. β-lactam antibiotics should be administered first before MRSA coverage given the broader spectrum activity and shorter infusion times for initial dosing.

Lung Protective Ventilation Strategy Used

• Angus, D. et al. Caring for Patients With Acute Respiratory Distress Syndrome: Summary of the 2023 ESICM Practice Guidelines JAMA 2023.
• Summary of the 2023 ESICM Practice Guidelines.
• Neto, A.S. et al. Chapter 6 – Ventilatory Support of Patients with Sepsis or Septic Shock in Resource-Limited Settings. Sep Man Res Lim Set 2019.
• This chapter reviews recommendations on the identification of patients with ARDS, indications for mechanical ventilation, and strategies for lung-protective ventilation in resource-limited settings.
• Neto, A.S. et al. Association between use of lung-protective ventilation with lower tidal volumes and clinical outcomes among patients without acute respiratory distress syndrome: A meta-analysis. JAMA 2012.

This analysis found evidence that a ventilation strategy using lower tidal volumes is associated with a lower risk for developing ARDS. Furthermore, the strategy was associated with lower mortality, fewer pulmonary infections, and less atelectasis when compared with higher tidal volume ventilation in patients without lung injury at the onset of ventilation.

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