• 1.

    Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983; 71:726735. doi: 10.1172/jci110820

  • 2.

    Kellum JA. Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: Improved short-term survival and acid-base balance with Hextend compared with saline. Crit Care Med 2002; 30:300305. doi: 10.1097/00003246-200202000-00006

    • Search Google Scholar
    • Export Citation
  • 3.

    Chowdhury AH, et al. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and Plasma-Lyte 148® on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012; 256:1824. doi: 10.1097/SLA.0b013e318256be72

    • Search Google Scholar
    • Export Citation
  • 4.

    Yunos NM, et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308:15661572. doi: 10.1001/jama.2012.13356

    • Search Google Scholar
    • Export Citation
  • 5.

    Young P, 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; 314:17011710. doi: 10.1001/jama.2015.12334

    • Search Google Scholar
    • Export Citation
  • 6.

    Semler MW, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018; 378:829839. doi: 10.1056/NEJMoa1711584

  • 7.

    Self WH, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med 2018; 378:819828. doi: 10.1056/NEJMoa1711586

    • Search Google Scholar
    • Export Citation
  • 8.

    Zampieri FG, 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; 326:112. doi: 10.1001/jama.2021.11684

    • Search Google Scholar
    • Export Citation
  • 9.

    Finfer S, et al. Balanced multielectrolyte solution versus saline in critically ill adults. N Engl J Med 2022; 386:815826. doi: 10.1056/NEJMoa2114464

    • Search Google Scholar
    • Export Citation
  • 10.

    Hammond NE, et al. Balanced crystalloids versus saline in critically ill adults—a systematic review with meta-analysis. NEJM Evid 2022; 1:112. https://evidence.nejm.org/doi/10.1056/EVIDoa2100010

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Balanced Salt Solutions: Are We Crystal Clear or Still Murky?

Aniketh PrabhakarAniketh Prabhakar, MD, DNB, is a nephrologist consultant with Sigma Hospital, Mysore, India. Vinant Bhargava, DNB, FASN, FRCP (Edin), is a senior consultant with the Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.

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Vinant BhargavaAniketh Prabhakar, MD, DNB, is a nephrologist consultant with Sigma Hospital, Mysore, India. Vinant Bhargava, DNB, FASN, FRCP (Edin), is a senior consultant with the Department of Nephrology, Sir Ganga Ram Hospital, New Delhi, India.

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… only in recent years has normal saline been under the spotlight with several studies questioning whether this is the best solution to use.

Intravenous fluids are ubiquitously given to hospitalized patients, both critically and non-critically ill. The most widely used intravenous fluid remains 0.9% sodium chloride (normal saline). Although both balanced crystalloids and saline have been available for clinical use and scientific scrutiny for more than 100 years, only in recent years has normal saline been under the spotlight with several studies questioning whether this is the best solution to use.

Animal studies have shown unfavorable effects of normal saline by demonstrating that it causes acidosis because of a supranormal chloride concentration leading to detrimental vasodilation in the critically ill. This acidosis also leads to an increase in inflammation. In isolated dog kidneys and septic rats infused with saline, renal vasoconstriction was noticed, which was attributed to increased tubular chloride reabsorption. Furthermore, in healthy human volunteers, studies have demonstrated that intravenous normal saline administration leads to reduced kidney blood flow and decreased cortical tissue perfusion (13).

The alternative—i.e., balanced crystalloids (with a composition resembling plasma in both chloride and sodium concentrations)—may prevent the decrease in cortical perfusion and alleviate the increase in tubuloglomerular feedback because of their lower chloride content. So, what is the evidence?

Initial trials

Yunos et al. (4), in collaboration with Australian colleagues, published the Chloride High Level of Resuscitation Infusion Delivered Evaluation (CHLORIDE) trial, the first study, to our knowledge, demonstrating that balanced salt solutions might reduce incident acute kidney injury (AKI). This was a prospective, open-label study in which saline and balanced solutions (Hartmann’s solution, Plasma-Lyte 148 and chloride-poor 20% albumin) were introduced sequentially to 760 patients in an intensive care unit (ICU) setting after a 6-month washout period. The results showed significantly less AKI with the use of balanced solutions. The 0.9% Saline vs. Plasma-Lyte 148 for Intensive Care Fluid Therapy (SPLIT) trial was published 3 years later in 2015 by Young et al. (5) in an ICU setting. This was the first blind randomized clinical trial (RCT), to our knowledge, and did not report any significant difference in the incidence of AKI, kidney replacement therapy (KRT) use, and in-hospital mortality between balanced and saline solutions in the ICU setting.

Large, pragmatic trials

The Isotonic Solutions and Major Adverse Renal Events Trial (SMART) (6) was a single-center, cluster-randomized, multiple cross-over, pragmatic study conducted in an ICU setting in which over 15,000 adults either received 0.9% saline or balanced crystalloids during their stay in the ICU. Major adverse kidney events within 30 days (MAKE-30; i.e., a composite of death, need for new KRT, and persistent kidney dysfunction at 30 days) were assessed in both groups. An absolute difference of 1.1% in MAKE-30 (14.3% in the balanced group versus 15.4% in the saline group) was obtained between the groups, which was statistically significant (p = 0.04)

The Saline against Lactated Ringers or Plasmalyte in the Emergency Department (SALT-ED) trial (7) included more than 13,000 non-critically ill patients from the same single center as SMART. Although the primary outcome of hospital-free days did not differ between the groups receiving 0.9% saline or balanced crystalloids, the secondary outcome of MAKE-30 was significantly less (p = 0.01) in the balanced crystalloid group. Furthermore, the difference in MAKE-30 appeared to be highest in patients with hyperchloremia or an elevated plasma creatinine value at presentation.

The limitations of SMART and the SALT-ED trial included the open-label nature, involvement of only a single center, and the decision to start KRT based on individual clinician preference, which had implications in the final outcomes.

New entries into the debate

The Balanced Solution Versus Saline in Intensive Care Study (BaSICS) trial, published in 2021 by Zampieri et al. (8) was a multi-center, double-blind RCT conducted in 75 ICUs in Brazil and randomized approximately 11,000 patients to balanced crystalloids or saline groups. The researchers found that at 90 days, there was no difference in death with either strategy. The secondary outcomes, such as incidence of AKI and need for KRT, were also not statistically different. This lack of difference was despite achieving significantly less chloride levels in the balanced crystalloids group.

The Plasma-Lyte 148® Versus Saline Study (PLUS) trial of 2022 (9) is the latest publication, to our knowledge, to address this debate about use of balanced crystalloids or saline. More than 5000 people were randomized to receive balanced crystalloids versus saline in multiple centers as a part of this double-blind RCT. In this study, 90 days’ mortality, start of KRT, and increased creatinine were similar between both groups. Despite achieving lower chloride levels, the balanced crystalloid group did not demonstrate less mortality or reduced kidney injury.

The limitations of the BaSICS and PLUS trials included the use of non-study fluids for drugs and infusion, which may have led to some degree of contamination. Fluids were administered before randomization, and many participants in both the balanced crystalloids and saline groups were elective surgical patients, which may have reduced overall mortality.

A meta-analysis by Hammond et al. in 2022 (10) used data from the BaSICS and PLUS trials and 11 other RCTs. This analysis showed that with a low risk of bias among these studies, there was a reduction in relative risk of both mortality and AKI in a heterogenous group receiving balanced solutions.

Conclusions

Today, we have two more multi-centric RCTs (8, 9) that do not reiterate the findings of their predecessors and have gone on to demonstrate no such benefit when balanced salt solutions are used. However, a meta-analysis and systemic review (10) of 13 previously published RCTs in this field did show risk reduction with use of balanced solutions. So, where do we stand now with all of this evidence?

Some common points across these trials are that the use of balanced salt solutions was detrimental in patients with traumatic brain injury and caused higher mortality. Saline also remains an intuitive choice in cases of hypovolemic hyponatremia or hypochloremic metabolic alkalosis. Furthermore, the compatibility of balanced solutions with various drugs is not clear, and saline may be preferred for these purposes. The cost also needs to be recognized, considering the massive quantities of all fluids (especially plasmalyte) used.

Considering recent and past studies, we may be able to conclude that in patients without any baseline or impending kidney dysfunction, choice of fluid may not affect kidney outcomes. However, in patients with increased creatinine, acidosis, and hyperchloremia or with impending kidney injury, moving to a balanced solution strategy may be justified to reduce adverse kidney-related events.

References

  • 1.

    Wilcox CS. Regulation of renal blood flow by plasma chloride. J Clin Invest 1983; 71:726735. doi: 10.1172/jci110820

  • 2.

    Kellum JA. Fluid resuscitation and hyperchloremic acidosis in experimental sepsis: Improved short-term survival and acid-base balance with Hextend compared with saline. Crit Care Med 2002; 30:300305. doi: 10.1097/00003246-200202000-00006

    • Search Google Scholar
    • Export Citation
  • 3.

    Chowdhury AH, et al. A randomized, controlled, double-blind crossover study on the effects of 2-L infusions of 0.9% saline and Plasma-Lyte 148® on renal blood flow velocity and renal cortical tissue perfusion in healthy volunteers. Ann Surg 2012; 256:1824. doi: 10.1097/SLA.0b013e318256be72

    • Search Google Scholar
    • Export Citation
  • 4.

    Yunos NM, et al. Association between a chloride-liberal vs chloride-restrictive intravenous fluid administration strategy and kidney injury in critically ill adults. JAMA 2012; 308:15661572. doi: 10.1001/jama.2012.13356

    • Search Google Scholar
    • Export Citation
  • 5.

    Young P, 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; 314:17011710. doi: 10.1001/jama.2015.12334

    • Search Google Scholar
    • Export Citation
  • 6.

    Semler MW, et al. Balanced crystalloids versus saline in critically ill adults. N Engl J Med 2018; 378:829839. doi: 10.1056/NEJMoa1711584

  • 7.

    Self WH, et al. Balanced crystalloids versus saline in noncritically ill adults. N Engl J Med 2018; 378:819828. doi: 10.1056/NEJMoa1711586

    • Search Google Scholar
    • Export Citation
  • 8.

    Zampieri FG, 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; 326:112. doi: 10.1001/jama.2021.11684

    • Search Google Scholar
    • Export Citation
  • 9.

    Finfer S, et al. Balanced multielectrolyte solution versus saline in critically ill adults. N Engl J Med 2022; 386:815826. doi: 10.1056/NEJMoa2114464

    • Search Google Scholar
    • Export Citation
  • 10.

    Hammond NE, et al. Balanced crystalloids versus saline in critically ill adults—a systematic review with meta-analysis. NEJM Evid 2022; 1:112. https://evidence.nejm.org/doi/10.1056/EVIDoa2100010

    • Search Google Scholar
    • Export Citation
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