Assessing Toxicity of Intravenous Crystalloids in Critically Ill Patients
Authors: John A. Kellum, Andrew D. Shaw
Journal: JAMA (2015)

Intravenous administration of a specific fluidmay have very different effects comparedwith enteral administration of the same fluid. For example, pure water is well tolerated when given orally, but is highly injurious (leading to hemolysis)whenadministered intravenously. Intravenous fluids are the most common intervention prescribed for hospitalized patients and may be administered for multiple reasons, such as for rehydration (as an alternative to the enteral route), as a vehicle or carrier formedication delivery, and to produce directphysiologiceffectsoncardiacoutputandelectrolyteconcentrations (as drugs). There are important differences in the composition, volume, and rate of administration of fluids for these different uses. Over the last 25 years, the safety and efficacy of intravenous fluids have been vigorously debated. First, the composition of lactated Ringer solution was changed from a racemic mixture of lactate ions to pure L-lactate when high concentrations of the D-isomer were found to be toxic, including cardiac and neural toxicity.1 Next, the combination of several small studies examining the use of albumin for fluid resuscitation suggested an association with decreased survival.2 Even though a subsequent large trial showed no overall mortality difference between albumin vs saline for fluid resuscitation of patients in the intensive care unit (ICU), there was evidence of toxicity in 1 predefined subgroup.3 Subsequent analysis including detailed follow-up provided additional evidence that a 4% albumin solution was harmful for patients with increased intracranial pressure, probably related to its hypotonicity and the effect on intracranial pressure.4 More recently, the use of hydroxyethyl starch was found to have an adverse effect on survival among patients with sepsis, apparently related to its effect on acute kidney injury (AKI).5 A subsequent larger trial showed no significant difference between hydroxyethyl starch vs saline administration and mortality, and also demonstrated that hydroxyethyl starch was associated with a reduction in AKI but a small increase in the use of dialysis.6 Importantly, trials showing harm used much larger volumes of starch and studied higher-risk patients.7 As a result, most experts now accept that hydroxyethyl starch is at least mildly nephrotoxic, although disagreement exists as to whether the solution still has a role in the management of some patients. Isotonic0.9%sodiumchloride (saline) solution is themost commonly used intravenous fluid in much of the world, and especially in North America.8 The toxic potential of sodium chloride solutionswas known at least as early as the late 19th century and was described by Cushing9 among others. Although the sodium concentration of isotonic saline is only slightly higher than that of plasma, the higher than physiologic chloride concentration can lead tohyperchloremia and acidosis if isotonic saline is administered fast enough, and in large enough volumes.10 Bolus administration of either isotonic saline or albumin in saline was found to increase shorttermmortality in childrenwith sepsis inAfrica.11 Although the mechanism of this toxicity is unclear, increased deaths appeared to bemainly related to late cardiovascular collapse—a known consequence of experimental hyperchloremic metabolic acidosis in septic animals.12 Numerous observational studies13-15 and a sequential period trial16 have suggested a signal of potential harm when saline administration was compared with administration of fluids with more physiologic chloride concentrations, although the kinds of adverse outcomes have varied. Some studies have shown increased AKI or dialysis,13,16 whereas other reports have shown increased hospital mortality without an effect on AKI.14 This heterogeneity of effect is important because it demonstrates 2 essential aspects about toxicity—that toxicity is dose dependent and that the manifestation of toxicity depends on the susceptibility of the population exposed. A high “dose” of a low-toxicity substance will cause harm in a susceptible patient, whereas a low dose of a highly toxic substancemay be undetectable in a low-risk patient. Put more simply, if there is a hazard with saline administration, then healthier patients who receive small doses will deal with the hazard better than sicker patients who receive large doses. In this issue of JAMA, Young and colleagues17 report the 0.9% Saline vs Plasma-Lyte 148 for ICU fluid Therapy (SPLIT) trial, a multicenter study comparing 0.9% saline with a buffered electrolyte solution for fluid therapy among 2278 patients who were receiving treatment in 4 ICUs in New Zealand and required crystalloid fluid therapy. The indications for fluid were not specified, but presumably included both volume replacement as well as fluid resuscitation and other indications. The overall exposure to study fluids was small (a median of only 2 L) during the ICU stay, and most of the fluid administration occurred during the first 24 hours. The population was (at most) moderate risk (mean Acute Physiology and Chronic Health Evaluation [APACHE] II score, 14) and predominantly included postoperative patients. Overall, development of AKI within 90 days of enrollment (the primary outcome) occurred in only approximately 9%, and rates Related article page 1701 Opinion