Author: Emily Stock, BS, PharmD Candidate 2023 – St. Louis College of Pharmacy at UHSP
Mentor: Paul Juang, PharmD, BCPS, BCCCP, FASHP, FCCM – Barnes-Jewish Hospital 

 

Of all hospitalizations ending in death, sepsis is present in 30 to 50%. In the US, sepsis accounts for 250,000 deaths annually.¹ According to the 2021 Surviving Sepsis Campaign International Guidelines for the Management of Sepsis, sepsis and septic shock are medical emergencies that necessitate immediate resuscitation and treatment.² While many factors can be optimized in the treatment of sepsis, like use of antibiotics and appropriate monitoring parameters, the best choice of fluids for initial resuscitation has been debated. The 2021 Surviving Sepsis Campaign Guidelines provides an update to the 2016 recommendations on the choice of fluids in resuscitation.² 

The Guideline again recommends crystalloid over colloid as the initial fluid of choice.² Examples of crystalloids include normal saline, lactated ringers, and Plasma-Lyte. Examples of colloid fluids are albumin and, not widely used, hetastarch. Crystalloids are inexpensive and widely available which supports their use in sepsis. In addition, studies have shown there is no clear benefit of colloids over crystalloids.³In 2016, the guideline recommended either saline or balanced salt solutions for choice of crystalloid fluid for initial resuscitation in septic shock. The 2021 update now recommends balanced salt solutions instead of normal saline.² Balanced salt solutions, like lactated ringers, have electrolytes in concentrations more similar to the serum and the extracellular fluid. This potentially reduces adverse effects related to the disruption of acid-base balance that can be associated with normal saline.⁴ Potential adverse effects of normal saline include hyperchloremic metabolic acidosis, renal vasoconstriction, increased cytokine secretion, and concern for acute kidney injury (AKI).⁵In a study evaluating fluid choice in a rat model of sepsis, volume resuscitation with the normal saline resulted in higher rates of kidney injury and acidosis compared to volume resuscitation with Plasma-Lyte.⁶ 

The scientific basis of the adverse effects associated with normal saline is related to its chemical makeup. There is 10% more sodium and 50% more chloride in normal saline compared to normal extracellular fluid (see Table 1).⁵ Based on this higher concentration of chloride, potassium can shift out of the cell in response to the hyperchloremic acidosis. Hyperchloremic acidosis can also increase inflammation via increase in inflammatory mediators. Hyperchloremia can result in renal vasoconstriction and reduced glomerular filtration rate. The acidosis and hyperkalemia that can be induced by normal saline can potentiate existing kidney issues in septic shock patients. 

Besides the scientific argument for balanced crystalloids, there is some clinical evidence suggesting the benefit of lactated ringers over normal salinein regards to renal function and possibly mortality. The SMART trial in 2018 showed a lower incidence of major adverse kidney event within 30 days (MAKE30) with balanced crystalloids when compared to saline in critically ill adults. MAKE30 is a composite endpoint of death, new renal replacement therapy, or persistent renal dysfunction.⁷ Likewise, the SALT-ED trial showed a difference in the secondary outcome of MAKE30 with a statistically significant reduction in the balanced crystalloid group.⁸ However, the SPLIT trial in 2015 showed no difference in the primary outcome of AKI within 90 days.⁹ The SMART, SALT-ED, and PLUS trials showed statistically significant lower concentrations of chloride and higher pH levels in patients treated with balanced crystalloids compared to normal saline.^{7, 8, 10} The most recent trial, the PLUS trial, found no statistically significant difference in the primary outcome of death from any cause.¹⁰ The table below (Table 2) highlights pertinent studies comparing balanced crystalloids to saline. In the trials listed, rate and volume of fluid administered was chosen at the discretion of the treating physician. The 2022 New England Journal of Medicine meta-analysis estimates the effect of using balanced crystalloids versus normal saline ranges from 9% reduction to 1% relative increase in death, concluding there is a high probability that balanced crystalloids reduce mortality.¹¹ 

In regards to fluid choices for initial resuscitation in sepsis, the change to recommend balanced salt solutions over normal saline is weak with a low quality of evidence. This change, in addition to the weakening of the recommendation for 30 mL/kg of fluids to be given, is aimed to improve the care of patients with sepsis.² While more data are needed to strengthen fluid recommendations, current guidelines and clinical data can guide decision making in the setting of fluid resuscitation in sepsis.  

References 

1. Rhee C, Jones TM, Hamad Y, et al. Prevalence, underlying causes, and preventability of sepsis-associated mortality in US acute care hospitals. JAMA Netw Open. 2019;2(2):e187571. doi:10.1001/jamanetworkopen.2018.7571 
2. Evans L, Rhodes A, Alhazzani W, et al. Surviving sepsis campaign: international guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021;47(11):1181-1247. doi:10.1007/s00134-021-06506-y 
3. Lewis SR, Pritchard MW, Evans DJ, et al. Colloids versus crystalloids for fluid resuscitation in critically ill people. Cochrane Database Syst Rev. 2018;8(8):CD000567. Published 2018 Aug 3. doi:10.1002/14651858.CD000567.pub7 
4. Semler MW, Kellum JA. Balanced crystalloid solutions. Am J Respir Crit Care Med. 2019;199(8):952-960. doi:10.1164/rccm.201809-1677CI 
5. Li H, Sun SR, Yap JQ, Chen JH, Qian Q. 0.9% saline is neither normal nor physiological. J Zhejiang Univ Sci B. 2016;17(3):181-187. doi:10.1631/jzus.B1500201 
6. Zhou F, Peng ZY, Bishop JV, Cove ME, Singbartl K, Kellum JA. Effects of fluid resuscitation with 0.9% saline versus a balanced electrolyte solution on acute kidney injury in a rat model of sepsis. Crit Care Med. 2014;42(4):e270-e278. doi:10.1097/CCM.0000000000000145 
7. Semler MW, Self WH, Wanderer JP, et al; SMART investigators and the Pragmatic Critical Care Research Group: Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018; 378:829–839 
8. Self WH, Semler MW, Wanderer JP, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med. 2018;378(9):819-828. doi:10.1056/NEJMoa1711586 
9. Young P, Bailey M, Beasley R, et al. Effect of a buffered crystalloid solution vs saline on acute kidney injury among patients in the intensive care unit: The SPLIT randomized clinical trial. JAMA. 2015;314(16):1701–1710. doi:10.1001/jama.2015.12334 
10. Finfer S, Micallef S, Hammond N, et al. Balanced multielectrolyte solution versus saline in critically ill adults. N Engl J Med. 2022;386(9):815-826. doi:10.1056/NEJMoa2114464 
11. Hammond NE, Zampieri FG, Di Tanna GL, et al. Balanced crystalloids versus saline in critically ill adults – a systemic review with meta-analysis. NEJM Evid. 2022;1(2). doi.org/10.1056/EVIDoa2100010 
12. Zampieri FG, Machado FR, Biondi RS, 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;326(9):818–829. doi:10.1001/jama.2021.11684