Fluid resuscitation is the cornerstone of resuscitation for hypovolemia and shock, and intravenous fluids are among the most commonly used therapies worldwide.(1,2) Yet there remains uncertainty as to the most appropriate fluid type to restore effective blood volume and optimize organ perfusion. In the absence of a clear role for the early use of colloids, administration of crystalloid fluids is generally preferred (except in cases of hemorrhage).(3,4) Crystalloid fluids are inexpensive, stable at room temperature, and safe to rapidly administer to most patients, making them useful in a wide variety of care settings.
Crystalloid fluids can be categorized as either non-buffered or balanced. Non-buffered crystalloids are salt solutions, of which isotonic 0.9% normal saline (NS) is the most relevant for shock resuscitation. Hypotonic saline solutions, such as 0.45% saline, should not be used for large-volume fluid resuscitation; hypertonic saline solutions, such as 3% saline, do not have proven benefit for resuscitation.(5-7) Several balanced solutions are available, including lactated Ringer’s (LR) solution, Hartmann solution, and Plasma-Lyte (Baxter Healthcare International, Inc.). Unlike NS, which consists of only sodium and chloride in a 1:1 ratio, balanced fluids have an electrolyte composition closer to human blood plasma, though formulations vary (Table 1). NS contains a supraphysiologic concentration of chloride (1.5 times that of plasma) and a strong ion difference (SID) of zero, but is isotonic compared to extracellular fluid. Balanced solutions have less chloride, small amounts of additional electrolytes, and a higher SID due to the presence of an anion buffer. Although NS is the preferential crystalloid used for resuscitation in 80% to 90% of pediatric and adult patients,(8-11) recent data have called into question the relative safety of NS compared to more balanced solutions.
Infusion of saline to restore circulating blood volume was first attempted during the cholera outbreak of the 1830s. In a letter to The Lancet published on June 2, 1832, Thomas Latta noted that, with intravenous saline, “improvement in the pulse and countenance is almost simultaneous, the cadaverous expression gradually gives place to appearances of returning animation, the livid hue disappears, the warmth of the body returns.”(12) Fluids of various composition were subsequently described, with the first reference to a solution similar to that of NS in the 1880s. Hartog Jakob Hamburger recognized that erythrocytes did not lyse when placed in NS and concluded that “the blood of man was isotonic with a NaCl solution of 0.9%”.(13) Although these observations conceivably led to the “normal” moniker for 0.9% NS (nobody knows for sure), human plasma is actually closer to 0.6% sodium chloride. Subsequent events leading to the widespread adoption of NS into clinical practice remain unclear. LR was also born in the 1880s when Sydney Ringer added calcium and potassium to saline after observing that inorganic constituents of pipe water better preserved frog heart muscle ex vivo than just salt dissolved in distilled water.(14) In 1932, the pediatrician Alexis Hartmann modified Ringer’s original formula in order to reduce the acidosis observed in infants with diarrhea.(13) More recently, Plasma-Lyte was developed to address the slight hypotonicity and presence of calcium (leading to some drug incompatibilities) in LR and Hartmann solutions.
The high chloride content and low SID of NS have been associated with acute kidney injury (AKI), acidemia, hyperkalemia, vascular permeability, inflammation, coagulopathy, fluid overload, and death.(15) For example, infusion of NS reduced renal blood flow and glomerular filtration rate in a dog model to a greater extent than more balanced fluids.(16) In healthy human volunteers, infusion of NS also led to more abdominal discomfort, drowsiness, and impaired cognition than balanced fluids.(17) Other studies have demonstrated that large volumes of NS induce a hyperchloremic metabolic acidosis due to the dilution of plasma bicarbonate within a constant CO2 environment in the absence of an alternative buffer.(18) In blood with normal protein levels, the SID (abbreviated Na + K – Cl) is approximately +40. Infusion of NS with a SID of 0 (154 Na + 0 K – 154 Cl) produces an acidemia.(19) Although the clinical importance of NS-induced acidemia is uncertain,(20) hyperchloremic metabolic acidosis is proinflammatory in cell culture experiments(21) and has been associated with mortality following noncardiac surgery.22 Moreover, since acidemia is often attributed to tissue hypoperfusion in shock, a low blood pH following NS resuscitation may propagate a feed-forward cycle of excessive fluid administration and volume overload.
Several recent clinical studies have compared the effects of NS and buffered crystalloids on patient outcomes. In a sequential period study of critically ill adults, the use of chloride-restrictive fluids (mostly Hartmann solution) reduced the odds of AKI by almost 50%.(23) However, the SPLIT randomized double-crossover trial of Plasma-Lyte and NS in 2,278 critically ill adults found no differences in AKI or mortality.(24) Similarly, in the CRISTAL open-label randomized trial of adult ICU patients with hypovolemic shock, 31% of 72 patients who received LR died, compared to 27% of 1,035 who received NS (p = 0.49).(25) In contrast, a propensity-matched observational study of 6,730 adults with vasopressor-dependent septic shock found that receipt of at least some balanced fluids was associated with a 14% relative reduction in hospital mortality.(26) In a meta-analysis, adult septic patients who received balanced fluids had a trend toward lower mortality more than those who received NS (OR 0.78, 95% CI, 0.58–1.05) though no trial was included that directly compared NS to balanced fluids.(27) In a randomized trial of 65 adults with trauma, resuscitation with balanced fluids resulted in improved acid-base status and less hyperchloremia at 24 hours.(28) Finally, in adult patients undergoing abdominal surgery, use of balanced fluids on the day of surgery was associated with fewer postoperative infections.(29)
Despite these data, none of the proprietary balanced solutions are truly physiologic, and each has potential disadvantages. LR and Hartmann solution are both slightly hypotonic and have been shown to lower blood osmolality, increase brain water content, and transiently raise intracranial pressure.(30,31) Infants with a disproportionally large brain and patients with an injured blood-brain barrier may be at particularly high risk of cerebral edema with hypotonic balanced solutions. The presence of calcium may also lead to microvascular thromboses and, in some patients, an inability to clear lactate may lead to a lactic acidosis. Moreover, in a randomized trial of four fluid regimens in children with dengue fever, patients receiving LR were slower to recover from shock compared to those receiving NS.(32) Even Plasma-Lyte, which is the most physiologically balanced solution and avoids compatibility issues with calcium, is limited by a cost that is several times that of other crystalloid fluids.(1)
So what are we left to do at the bedside? Data from the Surviving Sepsis Campaign demonstrate that early crystalloid fluid resuscitation saves lives(33) (though the FEAST study calls into question this routine practice in resource-limited areas(34)), regardless of the precise composition. But whether there is a benefit for either NS or a more balanced fluid strategy remains unknown. Because crystalloid fluids are so commonly used, even a small relative benefit of one fluid resuscitation strategy could provide a substantial public health impact. Ongoing studies will shed some additional light on this question (PLUS study, ClinicalTrials.gov NCT02721654; SaLt-ED study, ClinicalTrials.gov NCT02614040), but more data are needed. Given that both types of fluids are inexpensive, stable at room temperature, commonly used, have identical storage and dosing volumes, and are of proven clinical benefit, crystalloids fluids provide the ideal scenario for a large pragmatic comparative effectiveness trial. Such studies should differentiate between patients requiring fluids for shock versus mild dehydration or maintenance fluids, select for patients requiring large-volume fluid resuscitation (since type of crystalloid probably matters less for patients who need only one or two fluid boluses), and enroll patients early on in their resuscitation. For this last point, trial designs incorporating delayed or exception from informed consent should be considered. After 180 years, our patients deserve to know that we are prescribing the best fluid, whether it is “normal” or balanced.
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