Balanced Crystalloids versus Saline in Critically and Noncritically Ill Adults


 2018 Mar 1;378(9):829-839. doi: 10.1056/NEJMoa1711584. Epub 2018 Feb 27.

Balanced Crystalloids versus Saline in Critically Ill Adults.

Semler MW1, Self WH1, Wanderer JP1, Ehrenfeld JM1, Wang L1, Byrne DW1, Stollings JL1, Kumar AB1, Hughes CG1, Hernandez A1, Guillamondegui OD1, May AK1, Weavind L1, Casey JD1, Siew ED1, Shaw AD1, Bernard GR1, Rice TW1; SMART Investigators and the Pragmatic Critical Care Research Group.

Abstract

BACKGROUND

Both balanced crystalloids and saline are used for intravenous fluid administration in critically ill adults, but it is not known which results in better clinical outcomes.

METHODS

In a pragmatic, cluster-randomized, multiple-crossover trial conducted in five intensive care units at an academic center, we assigned 15,802 adults to receive saline (0.9% sodium chloride) or balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) according to the randomization of the unit to which they were admitted. The primary outcome was a major adverse kidney event within 30 days - a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) - all censored at hospital discharge or 30 days, whichever occurred first.

RESULTS

Among the 7942 patients in the balanced-crystalloids group, 1139 (14.3%) had a major adverse kidney event, as compared with 1211 of 7860 patients (15.4%) in the saline group (marginal odds ratio, 0.91; 95% confidence interval [CI], 0.84 to 0.99; conditional odds ratio, 0.90; 95% CI, 0.82 to 0.99; P=0.04). In-hospital mortality at 30 days was 10.3% in the balanced-crystalloids group and 11.1% in the salinegroup (P=0.06). The incidence of new renal-replacement therapy was 2.5% and 2.9%, respectively (P=0.08), and the incidence of persistent renal dysfunction was 6.4% and 6.6%, respectively (P=0.60).

CONCLUSIONS

Among critically ill adults, the use of balanced crystalloids for intravenous fluid administration resulted in a lower rate of the composite outcome of death from any cause, new renal-replacement therapy, or persistent renal dysfunction than the use of saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SMART-MED and SMART-SURG ClinicalTrials.gov numbers, NCT02444988 and NCT02547779 .).

 

Balanced Crystalloids versus Saline in Noncritically Ill Adults.

Self WHSemler MWWanderer JPWang LByrne DWCollins SPSlovis CMLindsell CJEhrenfeld JMSiew EDShaw ADBernard GRRice TWSALT-ED Investigators

N Engl J Med. 2018 Mar 01; 378(9):819-828

Background Comparative clinical effects of balanced crystalloids and saline are uncertain, particularly in noncritically ill patients cared for outside an intensive care unit (ICU). Methods We conducted a single-center, pragmatic, multiple-crossover trial comparing balanced crystalloids (lactated Ringer's solution or Plasma-Lyte A) with saline among adults who were treated with intravenous crystalloids in the emergency department and were subsequently hospitalized outside an ICU. The type of crystalloid that was administered in the emergency department was assigned to each patient on the basis of calendar month, with the entire emergency department crossing over between balanced crystalloids and saline monthly during the 16-month trial. The primary outcome was hospital-free days (days alive after discharge before day 28). Secondary outcomes included major adverse kidney events within 30 days - a composite of death from any cause, new renal-replacement therapy, or persistent renal dysfunction (defined as an elevation of the creatinine level to ≥200% of baseline) - all censored at hospital discharge or 30 days, whichever occurred first. Results A total of 13,347 patients were enrolled, with a median crystalloid volume administered in the emergency department of 1079 ml and 88.3% of the patients exclusively receiving the assigned crystalloid. The number of hospital-free days did not differ between the balanced-crystalloids and saline groups (median, 25 days in each group; adjusted odds ratio with balanced crystalloids, 0.98; 95% confidence interval [CI], 0.92 to 1.04; P=0.41). Balanced crystalloids resulted in a lower incidence of major adverse kidney events within 30 days than saline (4.7% vs. 5.6%; adjusted odds ratio, 0.82; 95% CI, 0.70 to 0.95; P=0.01). Conclusions Among noncritically ill adults treated with intravenous fluids in the emergency department, there was no difference in hospital-free days between treatment with balanced crystalloids and treatment with saline. (Funded by the Vanderbilt Institute for Clinical and Translational Research and others; SALT-ED ClinicalTrials.gov number, NCT02614040 .).

 

COMMENTARY

Solutions such as Plasma-Lyte A or Ringer's lactate appear preferable for all label indications in preference to 0.9% saline based upon the existing literature and these new studies from Vanderbilt. Saline infusions is associated in these randomized trials with increased renal injury in emergency department patients and renal failure and mortality in critically ill patients.  There is a substantial an animal model, in vitro mechanism and observational data linking saline to abdominal pain, metabolic acidosis, renal injury, mortality, toxicity to endothelial cells and other tissues, etc.  

While the AABB only recommends saline as the preferred solution for blood component administration and cell washing, we believe the evidence now strongly supports abandoning saline for these indications, and substitution with Plasma-Lyte A or other solution approved for use with blood components.  We have a paper in press at the American Journal of Clinical Pathology (M. Refaai et al.) demonstrating increased hemolysis with normal saline in vitro.  This is a reasonable mechanism for the renal injury seen in patients, at least hypothetically.  Mark Gladwin and his group and the Vanderbilt group led by Lorraine Ware have provided ample evidence that low level hemolysis can have devastating effects on morbidity and mortality, both in animal models and patients.

Our group has been interested in the toxicity of normal saline to red cells (and platelets), for a variety of reasons. The short version is that short-term (4-24 hours) in vitro exposure to normal saline causes strikingly more hemolysis than do other solutions, such as Plasma-Lyte A. These data should be in the literature soon. Whether hemolysis occurs in vivo with saline and red cell transfusion, or with saline alone is not known. However, hemolysis could potentially explain the association of saline with renal injury. For those interested in a transfusion/hematology oriented review of the literature, we have one in press {1}.

Bottom line, I personally would not prefer saline for any indication I can think of if a buffered solution like Plasmalyte-A (FDA label approved for use with blood components) were available, if I were the ordering physician. Since I'm not a bedside physician at this point in my career, I don't have to make that choice, but that's my advice to those who are.

References

1. 0.9% NaCl (Normal Saline) - Perhaps not so normal after all? Blumberg N, Cholette JM, Pietropaoli AP, Phipps R, Spinelli SL, Eaton MP, Noronha SA, Seghatchian J, Heal JM, Refaai MA. Transfus Apher Sci. 2018 Feb 21;

PMID: 29523397 DOI: 10.1016/j.transci.2018.02.021