Redefining the Standard: A Review of the SMART and SALT-ED Trials

Eileen Friery, Doctor of Pharmacy Candidate 2019, Wilkes University Nesbitt School of Pharmacy

Amanda Holyk, PharmD, BCCCP, Mount Nittany Medical Center

Background

It is common practice for patients admitted to the hospital to necessitate intravenous (IV) fluids. Historically, 0.9% sodium chloride (normal saline (NS)) has been the fluid of choice among many providers. However, NS is neither normal nor physiological (Table 1). Balanced crystalloids better reflect physiological levels of sodium, potassium, and chloride; as such, appear a more intuitive choice for IV fluids. Conflicting evidence exists on whether balanced crystalloids improve outcomes with less risk to the patient compared to NS.^1-3 Recent evidence shows that acidosis secondary to NS induced hyperchloremia can result in acute kidney injury and mortality, with a more profound effect in critically ill patients.^4-6 

Given the prevalence of IV fluids in both critically ill and noncritically ill patients, the SMART and SALT-ED trials aimed to clarify the impact of fluid type on patient outcomes.

All values are in mEq/L, expect for osmolarity, which is in mOsm/L.  Sodium Chloride Injection, USP; lactated Ringer’s Injection, USP; Plasma-Lyte A®, USP; all from Baxter Healthcare Corporation in Deerfield, IL, USA were used.

Methods

Two pragmatic, single-centered, multiple-crossover trials compared balanced crystalloids (lactated Ringer's (LR) or Plasma-Lyte A®) versus NS, with the IV fluid alternating monthly. The SMART trial measured outcomes for patients across five intensive care units (ICU) in a single-center for the primary outcome of MAKE 30 (major adverse kidney events; the composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction within 30 days) over the course of 22 months. Patients under the age of 18 were excluded from the study.⁴

The SALT-ED trial evaluated adult patients hospitalized outside of the ICU over 16 months for the primary outcome of hospital-free days and a secondary outcome of MAKE 30. Similarly, this study excluded patients under the age of 18. ⁵

Results

SMART enrolled 15,802 patients, with no significant differences between the two groups at baseline.  There was a significant reduction in the composite outcome of MAKE 30 in the group receiving balanced fluids vs. NS (14.3 vs. 15.4, p = 0.04; number needed to treat (NNT) = 94). However, no individual component of MAKE 30 was statistically significant. Overall significance of MAKE 30 was driven by significance in subgroup analyses, where a reduction in the primary outcome was seen among patients with sepsis (p = 0.01, NNT = 20), patients admitted to the medical ICU (p = 0.04, NNT = 42) or neurologic ICU (p = 0.04, NNT = 48), and patients who previously received renal replacement therapy (p = 0.01, NNT = 17). There was a dose-response relationship between larger volumes of fluids administered and improved outcomes. Lactated Ringer's accounted for 95% of balanced crystalloids administered in the study.⁴

SALT-ED found that with 13,347 patients there was no difference in hospital-free days between the balanced crystalloid and NS groups (p = 0.41). Statistical significance for reducing major adverse kidney events, death from any cause, or new renal replacement therapy was observed, favoring the balanced crystalloid group (4.7% vs. 5.6%, p = 0.01).⁵

Discussion

NS and balanced crystalloids are both reasonable options for IV fluids. However, emerging evidence, including the SMART and SALT-ED trials, may shift practice in favor of balanced crystalloids, namely Lactated Ringer’s, due to the potential benefits on mortality and renal function.

Study Strengths

Results are bolstered due to some patients receiving both types of crystalloid and the ability of providers to override the fluid as clinically needed. Despite crossover between study arms, a statistical significance was found. Additionally, the use of intention-to-treat analysis should minimize effects of crossover and bias. Pragmatic study design and expansive inclusion criteria improves external validity due to patient population generalizability.^4,5

Study Limitations

Single-center design leaves uncertainty regarding reproducibility. Additionally, small median volumes of fluid were given; in SMART only 1000 mL for the balanced crystalloid group and 1020 mL in the NS group. Relatively few patients, especially critically ill patients, would receive such small volumes. Patients presenting with shock, diabetic ketoacidosis, or sepsis typically necessitate significantly larger volumes of intravenous fluids, making the generalizability of these studies is rather limited with regard these populations. Furthermore, significance was found for a composite outcome, which increases the likelihood of obtaining statistically significant results that are not clinically significant.^4,5

Clinical Impact

In light of this new evidence, increased use of balanced solutions will likely be a process change for many institutions. Furthermore, medication y- site compatibility with balanced crystalloids is not as established compared with NS. Most IV medications are diluted in NS or D5W with little to no data to support dilution with normosol-R. ICU patients often require multiple infusions and have limited line access; sparse compatibility data may prove a logistical challenge in this patient population. In addition, infusion of these medications can account for administration of a significant volume of IV fluids, especially in the setting of antibiotic use.

Lactated Ringer's is very similar to NS in terms of cost and both are readily available. Any increased cost associated with use of balanced electrolyte solutions would be offset compared to $1,795 increase in cost due to acute kidney injury (AKI) in hospitalized patients.⁷  

Balanced crystalloids demonstrated a reduction in mortality and adverse renal events.⁴ Given the frequency of IV fluid administration in the critically ill population, the clinical impact of these results is significant. Interestingly, patients who present with sepsis or those with previous renal-replacement therapy appear to experience the most benefit.⁴

One of the reasons that NS may have fared so poorly could be due to its link with hyperchloremic metabolic acidosis due to a significant reduction in the strong ion gap.^8,9  In fact, even in healthy volunteers who received 2000 mL of NS, hyperchloremic acidosis has been shown to occurr.¹⁰ Data supporting this claim has been studied with growing frequency and is associated with worse outcomes.^6,11,12 In animal models, hyperchloremia has been linked to acidosis^5,13, hemodynamic instability¹³,  AKI¹⁴, and renal vasoconstriction.¹⁴  Additionally, data in human studies show that hyperchloremia is associated with AKI¹⁵ and higher rates of hospital mortality.¹⁶ Likewise, in the SMART trial, significantly fewer patients in the balanced crystalloid group experienced a plasma chloride level greater than 110 mmol/L than those in the NS group (1945 vs. 2796, p < 0.001).

While results of this study favor balanced crystalloids, there is no consensus regarding superiority. In these studies, 95% of the patients treated with balanced crystalloids received LR; as such, no clinical difference between balanced fluids can be definitively discerned. Nevertheless, there are some attributes specific to LR and other balanced crystalloids that give physicians pause. Sodium lactate, a component of LR, has raised concern due to possible effects on serum lactate levels. This has historically been reported as minimal with no clinically significant effects.¹⁷ Furthermore, the SMART trial shows that septic patients actually experienced reduced mortality, despite a potential serum lactate elevation. Clinicians have also expressed concern administering potassium containing fluids in patients with poor kidney function. While both LR, normosol-R, and Plasma-Lyte A® contain potassium, the amount is minimal, ≤ 5 mmol/L.¹⁸ Furthermore, NS induced hyperchloremic acidosis may be just as likely to contribute to hyperkalemia.^19,20 Another common provider concern is administering LR in patients with hyponatremia, given the comparatively low sodium content. The clinical impact of this on various neurosurgical disorders such as traumatic brain injury has yet to be determined as the comparative hypotonicity may poorly affect intracranial pressure. 

Bottom Line

In light of new evidence, use of balanced crystalloid fluids should be considered based on population.  For patients with sepsis, previous renal-replacement therapy, or admitted to the medical or neurological ICUs, serious consideration should be given to the use of balanced crystalloids over NS. In all other patients and those with traumatic brain injury or compatibility issues, NS may still be considered as the crystalloid of choice. Future studies should aim to identify if there is a difference between balanced crystalloids, which populations would derive the most benefit, and how total volume administered affects potential benefit.

References

1. Raghunathan K, Shaw A, Nathanson B, Stürmer T, Brookhart A, Stefan M et al. Association Between the Choice of IV Crystalloid and In-Hospital Mortality Among Critically Ill Adults With Sepsis. Crit Care Med. 2014;42(7):1585-1591.
2. Rochwerg B, Alhazzani W, Sindi A, Heels-Ansdell D, Thabane L, Fox-Robichaud A et al. Fluid Resuscitation in Sepsis. Ann of Intern Med. 2014;161(5):347.
3. Krajewski M, Raghunathan K, Paluszkiewicz S, Schermer C, Shaw A. Meta-analysis of high-versus low-chloride content in perioperative and critical care fluid resuscitation. Br J Surg. 2014;102(1):24-36.
4. Semler M, Self W, Wanderer J, Ehrenfeld J, Wang L, Byrne D et al. Balanced Crystalloids versus Saline in Critically Ill Adults. N Engl J Med. 2018;378(9):829-839.
5. Self W, Semler M, Wanderer J, Wang L, Byrne D, Collins S et al. Balanced Crystalloids versus Saline in Noncritically Ill Adults. N Engl J Med. 2018;378(9):819-828.
6. Honore P, Jacobs R, Spapen H. Normal saline as resuscitation fluid in critically ill patients: not dead yet! Ann of Intensive Care. 2016;6(1).
7. Silver S, Long J, Zheng Y, Chertow G. Cost of acute kidney injury in hospitalized patients. J Hosp Med. 2017;12(2):70-76.
8. Martini W, Cortez D, Dubick M. Comparisons of normal saline and lactated Ringer’s resuscitation on hemodynamics, metabolic responses, and coagulation in pigs after severe hemorrhagic shock. Scand J Trauma Resusc Emerg Med. 2013;21(1):86.
9. Burdett E, Roche A, Mythen M. Hyperchloremic Acidosis: Pathophysiology and Clinical Impact. Transfus Altern Transfus Med. 2003;5(4):424-430.
10. Chowdhury A, Cox E, Francis S, Lobo D. 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(1):18-24.
11. Skellett S. Chasing the base deficit: hyperchloraemic acidosis following 0.9% saline fluid resuscitation. Arch Dis Child. 2000;83(6):514-516.
12. Handy J, Soni N. Physiological effects of hyperchloraemia and acidosis. Br J Anaesth. 2008;101(2):141-150.
13. Orbegozo D, Su F, Santacruz C, He X, Hosokawa K, Creteur J et al. Effects of Different Crystalloid Solutions on Hemodynamics, Peripheral Perfusion, and the Microcirculation in Experimental Abdominal Sepsis. Anesthesiology. 2016;125(4):744-754.
14. Zhou F, Peng Z, Bishop J, Cove M, Singbartl K, Kellum J. 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.
15. Suetrong B, Pisitsak C, Boyd J, Russell J, Walley K. Hyperchloremia and moderate increase in serum chloride are associated with acute kidney injury in severe sepsis and septic shock patients. Crit Care. 2016;20(1).
16. Neyra J, Canepa-Escaro F, Li X, Manllo J, Adams-Huet B, Yee J et al. Association of Hyperchloremia With Hospital Mortality in Critically Ill Septic Patients. Crit Care Med. 2015;43(9):1938-1944.
17. Ichai C, Orban J, Fontaine E. Sodium lactate for fluid resuscitation: the preferred solution for the coming decades? Crit Care. 2014;18(4):163.
18. Aboujamous H, Walton T, Doran JJ (2016) Evaluation of the Change in Serum Potassium Levels after Potassium Administration. J Clin Nephrol Ren Care. 2:013.
19. Scheingraber S, Rehm M, Sehmisch C, Finsterer U. Rapid saline infusion produces hyperchloremic acidosis in patients undergoing gynecologic surgery. Anesthesiology 1999;90 (5):1265-1270.
20. Prough DS, Bidani A. Hyperchloremic metabolic acidosis is a predictable consequence of intraoperative infusion of 0.9% saline. Anesthesiology. 1999;90(5):1247-1249.