Continuing Education Activity

Crystalloid fluids are a type of intravenous solution employed in medical settings. Essential for fluid resuscitation in cases of hypovolemia, hemorrhage, sepsis, and dehydration, these solutions are indispensable for maintaining patient hemodynamic stability. Beyond resuscitation, crystalloids are used for intravenous medication delivery, provision of maintenance fluids for individuals with limited or no enteral nutrition, blood pressure management, and facilitation of increased diuresis to mitigate the risk of nephrotoxicity induced by drugs or toxins. This activity discusses the pharmacodynamics, adverse event profile, toxicity, dosing, and monitoring aspects of crystalloid fluids. Participants will be equipped with the knowledge necessary to effectively utilize crystalloid fluids in addressing hypovolemia and related indications.

Objectives:

• Differentiate between various types of crystalloid fluids, such as normal saline and balanced electrolyte solutions, to select the most suitable option.

• Implement crystalloid fluid therapy as part of resuscitation or maintenance strategies according to established protocols.

• Assess patients' response to crystalloid therapy while monitoring vital signs and laboratory parameters.

• Select the appropriate crystalloid fluid volume and rate of administration based on individual patient requirements.

Indications

Crystalloid fluids are a subset of intravenous solutions frequently used in the clinical setting. Crystalloid fluids are the first choice for fluid resuscitation in the presence of hypovolemia, hemorrhage, sepsis, and dehydration. Other clinical applications include intravenous medication delivery, delivering maintenance fluid in patients with limited or no enteral nutrition, blood pressure management, and increasing diuresis to avoid nephrotoxic drug or toxin-mediated end-organ damage.[1]

Intravenous fluids are commonly administered during resuscitation. Broadly, intravenous fluids fall into 2 separate categories: crystalloids and colloids. In most clinical settings, crystalloids are the choice for many indications for fluid resuscitation, maintenance, or as a solvent for medication delivery. While normal saline (0.9% NaCl solution) is the most frequently used crystalloid fluid, many other formulations can improve clinical outcomes in specific patient populations.

FDA-Approved Indications

Some commercially available crystalloid fluids and their indications include:

• 0.9% NaCl (normal saline): parenteral replenishment of fluid and sodium chloride as required by the patient's clinical condition.

• 0.45% NaCl (hypotonic solution; "half-normal saline"): parenteral replenishment of fluid and sodium chloride as required by the patient's clinical condition.

• Lactated Ringer/Hartman solution (lactate buffered solution): This solution is indicated as a source of water and electrolytes and serves as an alkalinizing agent.

• Acetate buffered solution: Indicated as a source of sodium to be added to large-volume intravenous fluids for the prevention or correction of hyponatremia in patients with restricted or no oral intake. These fluids also serve as an additive for preparing specific intravenous fluid formulas when the patient's needs cannot be met using standard electrolyte or nutrient solutions.

• Acetate and gluconate buffered solution: Indicated as a source of water and electrolytes or as an alkalinizing agent.

• 3% NaCl (hypertonic solution): Indicated as a source of water and electrolytes.

• 5% dextrose in water: This is indicated for parenteral replenishment of fluid and minimal carbohydrate calories as necessitated by the patient's clinical condition.

• 10% dextrose in water: Indicated as a source of water and calories.

This is not an exhaustive list of these crystalloid solution products or their indications.

Mechanism of Action

Most crystalloid solutions are administered for hydration purposes. Water is an integral component of all body tissues, accounting for approximately 70% of total body weight. Average standard adult daily requirements are between 2 and 3 L/d to cove insensible water loss from processes like urination and perspiration.

A crystalloid fluid is an aqueous solution of mineral salts and other small, water-soluble molecules. Most commercially available crystalloid solutions are isotonic to human plasma. These fluids approximate concentrations of various solutes found in plasma and do not exert an osmotic effect in vivo. Crystalloid fluids function to expand intravascular volume without disturbing ion concentration or causing significant fluid shifts between intracellular, intravascular, and interstitial spaces.

Hypertonic solutions, such as 3% or 5% saline solutions, contain higher concentrations of solutes than those found in human serum. Because of this elevated concentration, these fluids are osmotically active and will cause fluid shifts. Their primary indication is for emergent replacement of serum solutes, such as in hyponatremia with neurologic symptoms.

Buffered solutions contain molecules that metabolize in vivo to bicarbonate. These solutions were designed to sustain a normal physiologic plasma pH. The 3 commonly used molecules are lactate, acetate, and gluconate. Lactate and gluconate are hepatically metabolized to bicarbonate, while acetate is predominantly metabolized peripherally by skeletal muscle.

Some crystalloid solutions contain carbohydrates and are designed to provide calories. Dextrose may assist in minimizing glycogen depletion and exert a protein-sparing action. Solutions with electrolytes will supply those ions as needed and are even capable, in some instances, of inducing diuresis depending on the patient's clinical condition.

Administration

Available Dosage Forms

Crystalloid fluids are administered parenterally via an intravenous infusion. Infusion rates depend on the clinical presentation and indication for administration.

Adult Dosing

Fluid Resuscitation

A rapid infusion of crystalloid fluids may be indicated in an acute setting. Such cases may require a pressure apparatus to achieve a higher infusion rate. In this clinical setting, large-bore intravenous cannulas should help ensure the safe administration of high fluid volumes. Fluids should be administered via large-bore peripheral lines (18 gauge or larger) or central access, which may also be used to deliver blood products if required.

In 2012, the Surviving Sepsis Campaign guidelines recommended Early Goal-directed Therapy (EGDT) as the standard of care for managing septic shock patients. These guidelines previously required that patients receive empirically dosed rapid volume resuscitation. Patients should receive a fluid challenge of 20 mL/kg over the first 30 minutes of treatment. Subsequent volume dosing should depend on the severity of hypovolemia and should be adjusted in increments of 500 mL, aiming for an ultimate central venous pressure of 8 to 12 mm Hg.[2] However, revised guidelines in 2018 have called into question the efficacy of EGDT. The revised guidelines now state that fluid provision should be in a 1-hour bundle by administering 30 mL/kg crystalloid for hypotension or lactate 4 mmol/L. This guideline has a "strong recommendation" rating.

Maintenance Fluids

The fluid requirements of patients were previously determined to be related to a patient's caloric demand by Drs. Holliday and Segar in 1957.[3] Since then, their initial formula has been modified to provide clinicians with guidelines for administering maintenance crystalloid fluids. The mass-based formula uses what is known as the "4-2-1" rule:

• 0 to 10 kg: +4 mL/kg/h
• 10 to 20 kg: +2 mL/kg/h
• >20 kg: +1 mL/kg/h

Example: 100 kg patient: 20 kg (40 + 20 mL/h) + 80 kg (80 mL/h) = 140 mL/h

Additional formulas for fluid administration have been developed for specific clinical scenarios (eg, the Parkland Formula for fluid maintenance in burn patients).[4]

Special Patient Population

Pregnancy considerations: There is not much evidence for many of these solutions regarding use in pregnancy. In general, caution is advised during pregnancy, and clinicians should consult the package insert for the particular fluid they are considering. Normal saline, Ringer's lactate, sodium acetate, 5% dextrose, and hypertonic sodium chloride are all rated pregnancy category C due to lack of evidence.

Breastfeeding considerations: There is also minimal to no data on how these fluids affect infants or milk production. Again, clinicians are advised to use caution and consult the package insert for the particular fluid they are considering.

Pediatric patients: Little to no data exists regarding the use of these solutions in pediatric patients.

Older patients: Data on older patients is lacking. However, it stands to reason that older patients will generally have reduced renal function, so care is necessary in dose selection/infusion rate.

Adverse Effects

Volume expansion with crystalloid fluids may cause iatrogenic fluid overload.[5] The risk of this complication is elevated in patients with impaired kidney function (eg, acute kidney injury, chronic kidney disease). Therefore, these patients should receive treatment with judicious use of intravenous fluids. Patients with congestive heart failure are at elevated risk for serious adverse effects of crystalloid fluid administration. Fluid overload can cause life-threatening pulmonary edema and the worsening of diastolic or systolic heart failure, leading to end-organ damage or even death. The clinician must monitor these patients carefully and administer the minimum required volume to maintain volume homeostasis. 

The Solutions and Major Adverse Renal Events (SMART) Trial compares normal saline with balanced crystalloid solutions in critically ill patients.[6] The study suggested that using balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause. However, in the BaSICS trial, the primary outcome did not differ significantly between the balanced crystalloid and normal saline groups (hazard ratio = 0.97; 95% confidence interval, 0.9 to 1.05). This trial revealed a 90-day mortality of 26.4% versus 27.2%, respectively.[7] However, the fluid choice in the initial resuscitation of patients who are critically ill significantly impacts patient outcomes.[8] Patients who receive balanced crystalloid solutions during the initial resuscitation are far better than patients who receive normal saline.

Normal Saline (0.9% Saline)

Normal saline has a higher concentration of chloride ions (154 mmol/L) than human serum (98 to 106 mmol/L). With the administration of large volumes of normal saline, hyperchloremia occurs.[9] While there is still some debate on the exact mechanism of this pH disturbance, the thinking is that the increase in chloride concentration adjusts the substantial ion difference in plasma, resulting in more free water in the intravascular space. As a result, the hydrogen ion concentration in the serum would increase to maintain electrochemical neutrality. Excessive renal bicarbonate excretion can occur, resulting in metabolic acidosis.[10] The dilution of serum bicarbonate through non-buffered crystalloids (eg, normal saline) may also contribute to acidosis. Besides metabolic acidosis, clinical research has shown that high volumes of normal saline can cause hyperchloremia-induced renal afferent arteriole constriction, which can cause a decrease in the glomerular filtration rate.[11][9] Hypertonic sodium chloride solutions can cause vein damage.

Acetate-buffered crystalloid solutions have been the subject of much debate in the medical literature. Studies performed on dogs have shown that even small volumes of acetate-containing crystalloids can significantly increase the serum concentration of acetate up to 40 times the physiologic level. Some suggest that acetate may potentiate hemodynamic instability by decreasing myocardial contractility and blood pressure.[12] 

Unlike acetate-buffered solutions, lactated crystalloid fluids have the potential to induce hyperglycemia. Lactate is a metabolically active compound utilized during gluconeogenesis to produce glucose. Hence, excessive administration of lactated crystalloids may be of concern in patients with diabetes.[12]

Contraindications

Contraindications of crystalloid fluids are listed below. 

• Patients who are fluid overloaded should not receive crystalloid fluids. Special care is important when administering fluids to patients with congestive heart failure or those with significant renal impairment (eg, patients on dialysis).[13][14]

• Hypertonic saline is contraindicated in all clinical settings except in patients with severe hyponatremia and neurologic sequelae. Rapid correction of hyponatremia may cause central pontine myelinolysis, a devastating neurologic condition.[15]

• Hypotonic solutions are also contraindicated in patients with or at risk of developing cerebral edema.

• Five percent dextrose injection without electrolytes should not be administered simultaneously with blood through the same infusion set because of the potential for pseudo-agglutination of red cells.

• Crystalloids containing potassium (eg, Lactate Ringer's solution, Hartman's solution) are contraindicated in patients with hyperkalemia since these may exacerbate their condition, which can lead to ventricular dysrhythmias.

• Clinicians should avoid using crystalloids containing dextrose (D5W, D10W, D5, 0.45% NS, etc) in patients with hyperglycemia.

• Ringer's lactate solution contains calcium ions. Calcium can induce coagulation of the blood products in the IV tubing, inhibiting their effective delivery. In patients who require a blood transfusion, blood products should utilize a separate IV setup. Ringer's lactate is also contraindicated in patients with hypercalcemia, calcium renal calculi, or a history of the same.

• Ringer's lactate is contraindicated in neonates aged 28 days and younger receiving ceftriaxone therapy, even if separate infusion lines are used, due to the risk of fatal ceftriaxone-calcium salt precipitation in the infant's bloodstream. Ringer's lactate is contraindicated in patients older than 28 days, including adults, receiving concomitant ceftriaxone treatment through the same infusion line (eg, a Y-connector). If the same line is used for sequential infusions, it must be thoroughly flushed between administrations with a compatible fluid.

• Sodium acetate injection is contraindicated in patients with fluid retention or hypernatremia.

Monitoring

Patients should undergo an assessment for signs and symptoms of dehydration and fluid overload. Elevated lactate and creatinine concentrations in the absence of an alternate cause indicate that a patient may receive inadequate volume. Urine output also requires monitoring. An ideal urine output target of 0.5 mL/kg/h indicates adequate hydration but may not be helpful in assessing volume status in patients with renal impairment.

Patients at high risk of developing this complication should receive frequent revaluations to monitor for fluid overload. Providers should assess for new or worsening crackles. These sounds may indicate pulmonary edema secondary to volume overload. Any new or worsening peripheral edema in the extremities is also a potential indication of excessive crystalloid fluid administration.

Frequent neurologic checks are necessary to assess clinical improvement in patients receiving hypertonic saline for severe hyponatremia with neurologic sequelae. Such monitoring can also help identify worsening neurologic function as a potential indicator of cerebral edema or central pontine myelinolysis.

Patients receiving large volumes of crystalloid fluids should be monitored for electrolyte imbalances caused by crystalloid fluid administration.[9]

Toxicity

Crystalloid fluids are generally safe and well-tolerated, but there are some toxic concerns. One example is when Ringer's lactate was modified from a racemic mixture of lactate ions to pure L-lactate after researchers determined that high concentrations of the D-isomer were toxic, including cardiac and neural toxicity.[16] Toxicity can result from too-rapid infusion, especially in solutions containing sodium ions.[17] Toxicity studies such as the SPLIT, CHEST, and SAFE trials have shown these agents to be generally safe, although more research is necessary.[18][19][20] In fluid overload, clinicians should follow facility-specific guidelines for addressing the situation.

Enhancing Healthcare Team Outcomes

The 2018 sepsis guidelines from the Surviving Sepsis Campaign have suggested initiating treatment with crystalloid fluids. However, they do not recommend which fluid is the best choice. According to their recommendations, fluids should be aggressively administered at 30 mL/kg in the first hour in a setting of hypotension or a lactate concentration greater than 4 mmol/L.[21][15] 

Established guidelines for crystalloid fluid under various clinical conditions are not yet extant. The SMART and SMART-SURG trials demonstrated a decreased rate of AKI but not overall survival among critically ill patients who received Ringer's lactate, a balanced, lactate-buffered crystalloid over normal saline.[6]

Given the lack of established guidelines for these fluids, the interprofessional team must utilize extensive collaboration and open communication between all physicians, specialists, advanced practice practitioners, nursing staff, and pharmacists. Even though these fluids are safe and well-tolerated, making the optimal therapeutic choice requires collaborative decision-making and monitoring to avoid adverse events. The interprofessional team must be well-informed regarding institutional protocols for fluid resuscitation and consult them for guidance for use, particularly to address any developing adverse events or unique situations.