The use of intravenous fluids is a cornerstone of medical therapy in many settings. In recent years, much debate has ensued attempting to determine the ideal type of crystalloid solution, and a growing body of evidence has accumulated describing the effects of 0.9% sodium chloride, or normal saline (NS), on acid/base balance. At many institutions, house officers are taught to favor “balanced” crystalloid solutions, and the use of such fluids, like Ringer’s lactate (LR), is becoming the favored and default management strategy for many. However, in our opinion, careful clinical reasoning rather than algorithmic assessment is needed to determine the optimal fluid to utilize, and we will here offer a defense for the use of normal saline in certain clinical settings.
The desired outcome with use of crystalloid fluids is to expand the intravascular compartment without disturbing the metabolic indices of homeostasis. The concern with NS has been its effect on promoting hyperchloremic metabolic acidosis, a finding well described in past studies. Although we will not review this literature here, the SALT-ED and SMART trials, which randomized patients to use of NS or balanced fluid, are important to note (1,2). The former found no difference in the primary outcome of hospital-free days, and the latter reported a lower rate in the primary composite outcome of major adverse kidney events with the use of balanced fluids, but both trials had methodological limitations. The recently published landmark BaSICS trial randomized more than 10,000 patients to use of NS or balanced fluid and found that the use of balanced solutions over NS was associated with no survival benefit. In the subgroup of patients with traumatic brain injury treated with balanced solutions, a higher mortality rate was observed (3).
In this context, we suggest several clinical scenarios to consider where there may be benefit from NS over LR. While each clinical encounter is unique, the following scenarios highlight physiologic principles underlying the benefits of using NS, understanding that there are downsides to all forms of crystalloid therapy.
First, patients with kidney impairment and concomitant hyperkalemia warrant consideration for the use of NS. LR contains a relatively small amount of potassium, about 4 mEq/L (4), which by definition is a concentration less than the serum potassium of hyperkalemic patients. The standard teaching to avoid LR in hyperkalemia has recently been called into question by several trials showing favorable outcomes when using LR in hyperkalemic patients (5), leading to the misunderstanding that this applies in all clinical scenarios. These trials randomized patients to receive NS or LR and noted that hyperkalemia (and hyperchloremic metabolic acidosis) was more common in the NS group than in the LR group. Critically, however, the trials were performed in patients undergoing kidney transplantation, in whom large volumes of fluid were used (in excess of 5–6 L), as is customary in the immediate post–kidney transplant phase—a practice not standard in other clinical scenarios outside of this specialized care. The suspected mechanism of hyperkalemia in patients treated with NS in this manner is secondary to extracellular shifting of potassium as a result of hyperchloremia associated with the large volume NS infusion.
Physiologically, one must consider not only the effects of intercellular shift, but more importantly, the urinary excretion of potassium, which is directly related to sodium delivery to the distal tubule. In a patient with robust (especially osmotic) urine output with high degrees of distal sodium delivery, urinary potassium excretion will be increased and the development of hyperkalemia is less likely (ignoring the shift mechanism in the setting of high volumes of crystalloid stated above). In contrast, in an oliguric patient who is highly dependent on distal sodium delivery to maximize urinary potassium excretion in the face of hyperkalemia, administering a relatively hypotonic fluid like LR will result in less delivery of sodium to the distal tubule and subsequently less urinary potassium excretion. The physiologic principle at play here has been misunderstood to mean avoiding the input of 4 mEq/L of potassium in LR, rather than understanding that the true governing physiologic principle is optimization of distal sodium delivery and net potassium excretion—a far more important metric than intercellular shift. Therefore, we would suggest that patients with hyperkalemia with kidney impairment (and especially oliguric kidney impairment) are likely to benefit more from treatment with isotonic NS than LR, with the express purpose of maximizing distal sodium delivery and subsequent potassium excretion.
Second, for the management of cerebral edema when regulating serum tonicity is key, patients are more likely to benefit more from the isotonicity of NS than the hypotonicity of LR. The osmolality of NS is about 286 mOsm/kg H2O, which is isotonic to plasma’s osmolality of 288 mOsm/kg H2O and significantly higher than LR’s osmolality of 256 mOsm/kg H2O (6). A delta in osmolality drives water down its osmotic gradient and therefore from the extracellular to the intracellular compartments. Animal studies have demonstrated an increase in cerebral edema associated with administration of hypotonic fluids like LR, which decrease the plasma’s osmolality relative to that of the central nervous system, thereby promoting water movement across the blood-brain barrier (7). Human volunteer studies examining the variable effects on osmolality between NS and LR have confirmed a reduction in serum osmolality with LR but not with NS, a finding consistent with the results of both the SAFE and the BaSICS trials (3), leading to recommendations to avoid hypotonic fluids in patients with brain injury. Therefore, in patients suffering from intracranial pathology and in whom maintenance of serum tonicity to prevent increased cerebral edema is critical, use of isotonic NS is physiologically preferred to use of hypotonic LR.
Third, patients with cirrhosis may benefit from NS rather than LR. One of LR’s unique attributes, even relative to other balanced solutions, is its use of lactate as an alternate anion to chloride. LR contains 28 mmol/L of lactate (4), and the effects of using a lactate-containing fluid must be carefully considered in cirrhotic patients. Lactate undergoes metabolism into bicarbonate, predominantly in the liver and to a lesser extent in the kidneys. Cirrhotic patients have reduced capacity to metabolize administered lactate, and administration of LR in these patients has been shown to result in elevated levels of lactate in the blood (8). Of course, endogenous lactate production and lactate administration through crystalloid fluid are physiologically distinct. Given the potential adverse biochemical and clinical effects of elevated serum lactate levels, caution is warranted before administering a lactate-containing fluid to cirrhotic patients.
For example, elevated lactate levels can block ATP production, an effect that may be exacerbated in the state of insulin resistance often seen in critical illness as insulin resistance can impair lactate metabolism (9). Further, elevations in serum lactate as a result of administration of LR causes uncertainty in the prognostic interpretation of this value as a marker for resuscitation. Such misinterpretation of serum lactate levels could potentially lead to inadvertent over-resuscitation; each 1-L bag of NS and LR contains 9 and 6 g of sodium, respectively, and excessive volume loading in goal-directed resuscitation on the basis of serum lactate values could potentially lead to adverse effects. To our knowledge, no robust data exist in the literature examining this question, and it is an area that would benefit from further investigation.
An additional area of uncertainty is the optimal fluid of choice to utilize in managing toxic ingestions. In our experience, we have observed the increasing use of LR in cases such as lithium overdose where nondialytic management is used. Although this may be effective, no specific data exist to support the use of LR in this context. In contrast, there is a substantial body of evidence on the use of forced saline diuresis for water soluble intoxications like lithium, theophylline, and ethylene glycol (among other alcohols), in cases where kidney replacement therapy is not indicated (10). This is another area that would benefit from further investigation.
In conclusion, we have offered a commentary in defense of normal saline. The arguments that have been made in the literature regarding the potential downsides of NS, namely development of a hyperchloremic metabolic acidosis, are well taken and should be thoughtfully considered. However, we disagree that this provides sufficient basis to minimize NS use in preference to balanced solutions like LR in all circumstances, understanding that all forms of crystalloid therapy have both pros and cons and that additional investigation is needed. In the case of NS, we have suggested three distinct clinical scenarios—hyperkalemia with kidney impairment, cerebral edema, and advanced liver disease—each of which has a physiology most aptly treated with NS rather than LR. Each clinical scenario presents its own physiology, and we submit that the decision of which crystalloid fluid to use is nuanced and requires thoughtful, individualized clinical reasoning to determine the fluid choice that most optimally addresses the pathophysiologic demand.
A.Z. Fenves reports royalties from UpToDate, honoraria from Advance Medical for Teledoc expert opinion, consultancy agreements with Teladoc, and expert review of records from law firm Shook, Hardy and Bacon. B. Mikhael reports employment by Somatus, Inc. D.J.R. Steele reports consultancy agreements with Blackstone LifeSciences and other interests/relationships regarding FMC Medical Directorship.
The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s).
A.Z. Fenves and B. Mikhael were responsible for the conceptualization, investigation, and methodology; A.Z Fenves and D.J.R. Steele were responsible for the supervision and validation; B. Mikhael wrote the original draft of the manuscript; and all authors reviewed and edited the manuscript.
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