Lactated Ringers versus Normal Saline: Myths and Pearls in the ED

Authors: Gabrielle Leonard, MD (EM Resident Physician, Vanderbilt University Medical Center) and Aaron Lacy, MD (@AaronLacyMD, EM Attending Physician, Vanderbilt University Medical Center) // Reviewed by: Alex Koyfman, MD (@EMHighA); Brit Long, MD (@long_brit)

Case:

A 70-year-old-female is brought to the ED for altered mental status. The patient has had decreased PO intake over the last 3-4 days and fever and confusion that worsened in the last 24 hours. Her past medical history is significant for hypertension and coronary artery disease.

Vitals are notable for a blood pressure of 82/44, HR of 118, temperature of 39.1C, RR of 14, and 96% on RA. The patient appears confused and dehydrated. Evaluation reveals a WBC of 24,000, lactate of 6.0, K of 5.8, and UTI on urinalysis. You have identified that the patient is in septic shock and requires fluid resuscitation.

What fluid will you use to resuscitate your patient? What evidence will support that decision? Does the patients’ elevated lactic acid and potassium play a role in your choice of fluid?

Background

Fluids are a standard treatment for various disease processes that present to the ED. Thought to increase intravascular and intracellular volume, fluids are critical in treatment of multiple disease processes that cause dehydration and loss of circulating fluid, leading to hypoperfusion and hypotension.¹  Historically, normal saline (NS) has been the fluid of choice for resuscitation with more than 200 million liters given annually.² There has been recent debate about which fluids are preferable based on composition, and multiple clinical trials have evaluated whether balanced crystalloids, such as lactated ringers (LR) or plasma-lyte, have less harmful associated reactions and are superior in treatment of various illnesses.

Fluid Composition

Table 1. Fluid composition of human plasma compared to 0.9% saline, LR, and plasma-lyte. Used with permission from Self et al.³

NS 0.9% has markedly more sodium and chloride than human plasma.^3,4 There is concern the high concentration of chloride in NS may lead to hyperchloremic metabolic acidosis, delaying recovery in some disease processes and contributing to worsening renal function during treatment.^{2, 5} It is theorized that elevated chloride causes renal vasoconstriction and may decrease renal perfusion via this mechanism.⁵ Balanced crystalloids such as LR and plasma-lyte more closely resemble the physiologic makeup of human plasma.^2,6 Decreasing risk of acidosis when compared to NS, as well as similar physiologic makeup more similar to human plasma, have led to studies investigating adverse reactions and patient outcomes in different presenting illnesses.

Two randomized clinical trials conducted in 2016 at a single center large academic hospital sought to compare NS and balanced crystalloids in both non-critically ill (SALT-ED trial) and critically ill (SMART) patients.^2,5 The SALT-ED trial randomized patients to either saline or balanced crystalloids and monitored the course of their hospitalization (if admitted to a unit outside of the intensive care areas). This trial evaluated hospital-free days as well as major adverse kidney events within 30 days (composite of death from any cause, new renal replacement therapy, persistent renal dysfunction with creatinine >200% from baseline) and found that while the primary outcome of hospital-free days did not have a significant difference between NS and crystalloid groups, there was a significantly lower rate of adverse major kidney events in 30 days (4.7% vs. 5.6%). Additionally, patients in the balanced crystalloid arm showed lower chloride and higher bicarbonate concentrations persisting for several days into hospitalization. Patients with underlying renal dysfunction or hypochloremia at presentation appeared to have the largest benefit from the crystalloid therapy by having reduced incidents of major adverse kidney events in 30 days.² The SMART trial randomized patients to receive NS or balanced crystalloids and monitored the course of their hospitalization if admitted to an intensive care unit, with the majority of patients continuing to receive the fluids they were initially randomized to in the ED. This trial showed a significant decrease in major adverse kidney events within 30 days for balanced crystalloids vs NS (14.3%% vs 15.4%, p=0.04). There was also an insignificant decrease in in-hospital mortality at 30 days for the balanced crystalloid vs. NS group (10.3% vs 11.1%, p=0.06). Similarly, the balanced crystalloid group showed lower incidence of hyperchloremia defined as Cl > 110 mmol/L (24.5% VS 35.6%) and lower incidence of plasma bicarbonate concentration < 20 mmol/L (35.2% vs. 42.1%) when compared to NS. Importantly, patients with a diagnosis of sepsis had lower incidence of 30-day mortality in the balanced crystalloid vs. NS groups (25.2% vs 29.4%, p=0.02). This is also important because fluids are a key treatment in sepsis and volume of fluid resuscitation is often higher. Based on these results, 1 patient in every 94 admitted to the ICU and treated with balanced crystalloid instead of NS may prevent the need for new renal replacement therapy, persistent renal dysfunction, or death when compared to NS.⁵

These two RCTs were groundbreaking and practice changing, leading many emergency departments and intensive care units to transition to more regularly using balanced crystalloids over NS. While conclusions of the trials often point to LR being superior to NS, it can also be reassuring that NS was given to so many patients without substantial harm.

More recently in August of 2021 a robust RCT, BaSICS was published. This was a double-blind, randomized clinical trial in 75 ICUs in Brazil with over 10,000 patients participating. The two intervention arms were looking at both fluid type (plasma-lyte vs NS) and fluid infusion speed (333ml/hr and 999ml/hr).  Of note, LR was not the balanced fluid evaluated in this study. Ultimately, 90-day mortality rate was 26.4% in the plasma-lyte group and 27.2% in the NS group (aHR 0.97, CI 0.90-1.05, P=.47),⁷ and 26.6% in the slower infusion rate vs 27.0% in the faster infusion rate group (aHR, 1.03; 95% CI, 0.96-1.11; P=.46).⁸ A secondary outcome from the BaSICS trial showed no significant difference in need for renal replacement therapy or doubled creatinine in balanced crystalloid group (27.8%) versus NS group (28.9%) (95% CI, 0.86-1.04). This study also sought to answer another important question about the volume and rate or volume given to patients during resuscitation. The idea of “you have to swell to get well” is no longer the standard of care, and permissive hypotension is preferred in several disease states.⁹ Currently a RCT, CLOVERS, comparing early transition from fluids to vasopressors in patients with septic shock is underway and set to finish sometime in 2021, which will add further data in this domain.¹⁰

Given the recent publication of BaSICS it becomes clear that there is not one fluid that is the end all, and certain populations and diseases will benefit from selected fluid choice.  We will discuss myths surrounding LR along with specific disease processes for choosing balanced crystalloids versus NS.

Pearls:  Two RCTs show that both non-critically ill and critically ill patients who received balanced crystalloids were less likely to have renal injury leading to need for renal replacement therapy or to have persistent renal dysfunction, but an additional large ICU based RCT did not show statistical difference in balanced crystalloid versus NS. Fluid therapy should be targeted to specific patient populations and presenting disease. 

One of the most significant issues from these studies is that the amount of IV fluid administered is likely more important that the specific type of fluid (i.e., worse outcomes with excess IV fluid).

Myths surrounding lactated ringers 

Despite these studies, there are still several concerns regarding the use of LR in the ED. Which of these concerns are myths, truths, or something in between?

Hyperkalemia

Myth – “Lactated Ringers should not be used in hyperkalemia because it contains potassium and may make the problem worse.”

Of all electrolyte abnormalities, hyperkalemia is the most likely to quickly kill a patient. Major causes of hyperkalemia include renal failure, acidosis, drug-effect (NSAIDs, Ace-I, TMP-SMX), rhabdomyolysis, or cell death.¹¹ If hyperkalemia is suspected, the K level should be repeated and an EKG obtained immediately.  The question then arises, knowing that LR and plasma-lyte contain a higher concentration of potassium (4-5mEq/L) when compared to NS (0 mEq/L), should these balanced crystalloids be avoided in patients with known or suspected hyperkalemia?

The potassium composition of LR is physiologically closest to human serum and is typically slightly lower.³ Due to this, there is negligible effect on overall serum potassium level as a result of LR infusion. Potassium’s volume of distribution is greater in extracellular fluid causing little to no change on the overall serum potassium level. It would take a significant amount of fluid to have any effect on raising overall serum potassium level since the potassium equilibrates between intracellular and extracellular fluid spaces. Additionally, the hyperchloremic metabolic acidosis which can result from NS infusion will increase cellular shifting and worsen extracellular potassium levels when compared to lactated ringers which has no effect on the K+/H+ gradient. In fact, the alkalinization that occurs as a result of lactated ringer infusion due to the 28 mEq/L of bicarbonate may even further drive potassium into the cell, lowering the overall serum potassium level.¹²

One subgroup analysis from the SALT-ED trial evaluated critically ill adults with hyperkalemia who received balanced crystalloids LR or plasma-lyte vs. NS. Overall, eight (8.5%) of the patients in the balanced crystalloid group vs. 13 (14.0%) patients in the NS group developed severe hyperkalemia (p=0.24). While this is not statistically significant, it does show that the higher level of potassium that is administered from LR or plasma-lyte (4-5) vs. NS (0) is closer to physiologic plasma and does not lead to worsening hyperkalemia.¹³

Pearl: LR is a safe fluid to use in resuscitation of patients with elevated potassium levels. The potassium/hydrogen shifts that occur as result of the acidic environment from normal saline infusion may worsen serum potassium levels.

Lactic Acidosis

Myth – “Lactated Ringers causes lactic acidosis, and therefore should be avoided.”

Lactic acidosis is a result of failed oxidative metabolism, leading to an anion-gap metabolic acidosis. This can be secondary to decreased metabolism of naturally generated lactate in the body (such as in liver disease) or increased production of lactate when there is decreased oxygen available for aerobic metabolism. The most common etiologies of lactic acidosis in the ED are from sepsis, trauma, and dehydration.¹⁴ While less common, there can also be iatrogenic causes of type B lactic acidosis secondary to beta agonist administration, such as epinephrine¹⁵ or albuterol.¹⁶

There is speculation that the lactate concentration in LR (28 mEq/L) compared to NS (0 mEq/L) and human plasma (1-2 mEq/L) may worsen lactic acidosis. In reality, this lactate is in the form of sodium lactate which our bodies metabolize to products that prevent cellular death. It is not the same lactate that is generated during anaerobic metabolism, which causes metabolic acidosis.⁶

One double-blind RCT evaluated the change in lactate between LR and NS groups while also looking at the overall change in pH, bicarbonate, sodium, and chloride levels. This study found that after an infusion of 30mL/kg IV LR, lactate increased by 0.93 mmol/L compared to 0.37 mmol/L in the NS group (p-0.2), but the NS group saw a larger decline in overall pH (0.06 vs. 0.03) and bicarbonate level (2.35 vs. 0.36).¹⁴ In an additional RCT published in 1997, 24 healthy adults received 1L infusions of LR, NS, dextrose, or D5W and showed no difference in lactate levels post-infusion.¹⁷

It is theorized that the lactate infused in the LR group may be metabolized under ischemic conditions and decrease overall cell death and is less likely to worsen an acidosis when compared to the hyperchloremic acidosis that results from NS.⁶

Pearl: Though LR contains sodium lactate, this is generally metabolized by the body and does not contribute to worsening lactic acidosis. In fact, the acidosis associated with NS likely has more clinically harmful effects.

Medication Reactions

Some Truth – “Because lactated ringers can have calcium precipitation with so many medications, it is easier and safer to use normal saline.”

Which fluids can be administered concomitantly with medications such as antibiotics or blood transfusions? The FDA warns against using LR with ceftriaxone in infants <28 days due to the risk of ceftriaxone-calcium salt precipitation which has previously been linked to death.¹⁸ In patients older than 28 days, a separate infusion line must be used for calcium-containing solutions such as LR and ceftriaxone to avoid precipitation. The precipitates were noted as early as 1999 when infusions of ceftriaxone were mixed with varying doses of LR in the IV lines. It was postulated that the sodium concentration within ceftriaxone contributes to the formation of calcium precipitates and therefore the mixture of these solutions in the same line should be avoided.¹⁹ It is safe to use LR in fluid resuscitation when infused through a separate line.

An additional study evaluated compatibility of LR with 94 medications by in vitro visual observation, particle counting testing, and light obscuration particle count testing. Eight drugs were considered incompatible with lactated ringers including ciprofloxacin, cyclosporine, diazepam, ketamine, lorazepam, nitroglycerin, phenytoin, and propofol and are recommended against administering through the same IV line as lactated ringers.²⁰

Two separate studies were performed to evaluate the incidence of clot formation when LR was transfused with pRBCs and Whole Blood. In both studies, there was on statistically significant difference in clot formation when NS or LR was infused or used as a diluent in emergent transfusions.^{21, 22} There is theoretical risk of coagulation when LR is administered together with preserved blood (with citrate anticoagulant) via the same infusion set. In order to avoid this, a separate line should be considered or alternative fluid should be chosen if limited access is available.⁶

Pearl: Though theoretical risk of clotting exists, LR can be administered simultaneously in patients >28 days with ceftriaxone, blood products and other calcium-containing medications. If possible, a separate line should be used to avoid potential precipitation.

Specific Indications

Diabetic Ketoacidosis (DKA)

In patients with DKA, the body responds to low insulin levels by burning fatty acids and producing ketone bodies, leading to an anion-gap metabolic acidosis. Often overall body potassium is low; however, it may appear to be falsely elevated due to hydrogen ions shifting intracellularly and potassium moving extracellularly. Fluids, in addition to insulin and potassium, are the main treatment for this disease process.¹

One subgroup analysis from the SALT-ED and SMART trial compared patients with a clinical diagnosis of DKA to look at time to resolution (glucose <200 mg/dL and 2 of the following: bicarb > 15, venous pH >7.3, anion gap < or equal to 12) as well as time to discontinuation of insulin infusion. Given the sheer volume of fluid required to treat this disease process, (on average, 4.5 liters) differences in fluid composition can be a key factor in recovery. This study found a significant decrease in both time to resolution of DKA (13 hours vs 16.9 hours) in the balanced crystalloid group as well as time to insulin discontinuation (9.8 hours vs 13.4 hours).¹ This equates to an absolute reduction of 4 hours and relative reduction of 20-30% in time to DKA resolution and discontinuation of insulin infusion, possibly decreasing overall hospital stay and associated morbidity. This is hypothesized to be due to the concentrations of sodium lactate in LR and acetate in plasma-lyte which metabolize into bicarbonate helping to close the anion gap metabolic acidosis.²³ Additionally, fewer patients in the balanced crystalloid group exhibited hypokalemia (K<3) compared with the NS group. However, this study was in contrast to prior work on the subject which failed to show any significant difference.^{3, 24-27}

Dehydration

In patients with dehydration (defined as dry mucous membranes, SBP <90, HR >100 or PO intolerance), one randomized controlled trial comparing normal saline balanced crystalloids showed significantly lower pH levels in patients who received NS (7.40 7.37 7.36) as well as a drop in bicarbonate levels (23.1, 22.2, 21.5) compared to an increase in the plasma-lyte group (23.4, 23.9, 24.4).²³ A similar study conducted in pediatric patients with acute diarrhea and severe dehydration showed no significant difference in pH between NS and LR, but the LR group required less fluids (310 vs 530mL) and had a shorter median hospital stay (38 vs 51).²⁸

Pancreatitis

One RCT compared LR with NS in patients with acute pancreatitis and found a significant reduction in SIRS after 24 hours in the LR group (84% vs 0%, p=0.035). There was also a reduction in CRP in the LR group (51.5 vs 104, p=0.02), a marker of systemic inflammation.²⁹ An additional study by Lee et al showed that there was a significantly shorter hospital length of stay and fewer ICU admissions in patients diagnosed with acute pancreatitis who were treated with aggressive fluid resuscitation via LR compared to NS.³⁰ Though the exact mechanism is unknown, there are animal studies showing decrease in enzymes involved in pancreatitis such as zymogen.³¹

Pearl: Several studies balanced crystalloids are associated with improved outcomes in patients with DKA, dehydration, and pancreatitis.

Considerations for Alternative Fluid to LR

Traumatic Brain Injury

It is theorized that due to hyperosmolarity of the solution and ability to decrease cerebral edema, NS is the preferred resuscitation fluid in patients with Traumatic Brain Injuries (TBI) when compared with LR. Additionally, LR is thought to increase neutrophil and inflammatory responses. One study comparing outcomes of patients with TBI who were treated with LR vs NS prior to hospital arrival found LR was associated with higher 30-day mortality than NS (HR = 1.78, CI 1.04 – 3.04).³² Subgroup analysis on this topic with the best RCT to date, BaSICS, showed that a balanced crystalloid (plasma-lyte) had higher 90-day mortality rate (31.3%) versus NS (21.1%) (HR 1.48, 95% CI 1.03-2.12, P=0.02).⁷

Hyponatremia

LR contains 130 mEq/L Na compared to 135-145mEq/L Na in plasma.¹ Because of this, there is concern that resuscitation with LR may worsen or lead to hyponatremia. There is limited data around LR causing hyponatremia or the use of LR in treating acute hypovolemic hyponatremia in the Emergency Department setting. One study evaluated post-operative hyponatremia and cited quantity of fluid resuscitation as the cause of hyponatremia versus use of LR itself. The theory is that increased extracellular volume leads to ADH release and worsens hyponatremia.³³ There is opportunity for further investigation into the use of LR for hypovolemic hyponatremia as well as the potential for LR to cause hyponatremia after ED resuscitation.

Burns

In acute burns, there is concern for both dehydration and electrolyte imbalances such as hyponatremia and hypoglycemia secondary to evaporative losses and changes in cellular permeability. One RCT evaluated the use of LR alone in burn resuscitation when compared to use of LR and dextrose NS in an attempt to correct electrolyte abnormalities. This study showed that due to low sodium (130mEq/L) and potassium (4mEq/L) levels in LR when compared to human plasma, dextrose containing NS should be used as an adjunct to assist in replenishing electrolytes. Burn patients treated with LR and DNS had statistically significant less evidence of hyponatremia and hypoglycemia.³⁴

Pearl: In patients presenting with hyponatremia and acute burns, LR is not necessarily the sole fluid choice for resuscitation, and NS is preferred in patients with concern for TBI.

Case Conclusion:

The 70-year-old female is febrile with signs of dehydration and hypotension in the setting of sepsis due to a urinary tract infection. She also has a lactic acidosis and hyperkalemia on her initial workup. Based on the data above, lactated ringers are a safe and appropriate approach to fluid resuscitation in combination with antibiotics. Broad spectrum antibiotics were started and the patient was admitted to the medical intensive care unit for further workup and care.

Pearls:

• LR composition is more similar to human plasma than NS.
• LR is preferred to NS in select ED presentations, such as DKA.
• LR will not worsen hyperkalemia and the acidosis from NS may in fact be more detrimental.
• LR does contain sodium lactate but will not contribute to clinically significant worsening lactic acidosis.
• NS is preferred to plasma-lyte in patients with TBI.
• Consider NS when mixed with certain medications such as ceftriaxone or blood transfusions to avoid precipitation when only a single IV access site it available.

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