Current Controversies in Sepsis Management

Stephanie R. Moss, MD; Hallie C. Prescott, MD, MSc


Semin Respir Crit Care Med. 2019;40(5):594-603. 

In This Article

"Normal" Saline Versus Balanced Crystalloids for Resuscitation

IV crystalloid solutions are ubiquitous in the hospital setting, and play an integral role in resuscitation of the septic patient. 0.9% sodium chloride (so-called "normal" saline) has long been the most common crystalloid solution used for fluid resuscitation, although practice varies by region and treating specialty.[76] However, balanced crystalloid solutions (including Ringer's lactate and PlasmaLyte) more closely approximate the composition of extracellular fluid (Table 2). In particular, the concentration of chloride in normal saline far exceeds the concentration in extracellular fluid. The popularity of normal saline was examined in a historical review by Awad et al, in which the composition of numerous early crystalloid solutions was examined.[77] 0.9% sodium chloride was first described by a Dutch chemist, Hartog Hamburger, in the late 19th century based on in vitro experiments. They postulate that its subsequent popularity despite no in vivo evidence may have stemmed from its low cost and ready availability.[77]

Despite (or perhaps because of) its widespread use, there has been increasing concern about adverse effects from normal saline, including hyperchloremic metabolic acidosis[78] and acute kidney injury.[79] A systematic review of 14 studies of 18,916 patients found a possible survival advantage with balanced crystalloids versus normal saline (90-day mortality, odds ratio [OR]: 0.78; 95% CI: 0.58–1.05) although the results were not statistically significant.[80] However, a subsequent RCT of 974 patients randomized to balanced crystalloids versus normal saline did not demonstrate any differences in mortality or adverse kidney events.[81]

In 2018, the SMART trial—the largest study of normal saline versus balanced crystalloid solutions for resuscitation of critically ill patients (n = 15,802)—was published.[82] This was a pragmatic, single-center, multiple-crossover, unblinded trial in which ICUs at a single institution were randomized to either normal saline or a balanced crystalloid on a monthly basis. The primary endpoint was a composite outcome of mortality, new renal replacement, or persistent renal dysfunction at 30 days. Patients in the balanced crystalloid group had a lower rate of the composite outcome (14.3 vs. 15.4%, p = 0.04). Likewise, 30-day in-hospital mortality was 10.3 versus 11.1%, p = 0.06.[82]

The trial included all ICU patients, but also examined prespecified subgroups by diagnosis. The effect size was greatest in patients with sepsis (OR: 0.80; 95% CI: 0.67–0.94; p = 0.01, for the development of the primary composite outcome in patients who received a balanced crystalloid).[82] Likewise, 30-day in-hospital mortality was also lower in the balanced crystalloid group (25.2 vs. 29.4%, p = 0.02).[82] Although the SMART trial had a large study population size, it was a single-center study, so needs to be validated in a multicenter trial.

Several large-scale multicenter clinical trials are currently randomizing patients to balanced crystalloids versus 0.9% sodium chloride. The BASICS trial led by the Brazilian Research in Intensive Care Network has recruited more than 7,000 of a planned 10,000 patients from 100 sites (NCT # 02875873) as of April 1, 2019.[83] The PLUS trial led by the Australian and New Zealand Intensive Care Society is also underway and has recruited 880 of a planned 8,800 patients from 50 sites (NCT #02721654).[84] Both BASICS and PLUS will have the advantage of being blinded with respect to fluid type. While we await these study results, we favor balanced solutions for the resuscitation of septic shock patients.