Lactated Ringer Preferred Over Normal Saline in SCD Vaso-Occlusive Episodes

Findings from a retrospective target-trial emulation study published in JAMA Internal Medicine demonstrate that balanced fluids such as lactated Ringer’s (LR) solution may promote better outcomes compared with normal saline (NS) during fluid resuscitation for vaso-occlusive episodes in sickle cell disease (SCD).¹

Whereas NS (0.9%; isotonic) provides only sodium and chlorine electrolytes with no added buffers, isotonic balanced fluids such as LR contain comparatively less chlorine and additional buffers such as lactate, potassium, and calcium, better approximating the composition of human plasma.

Nicholas A. Bosch, MD, MSc, an assistant professor at Boston University and the final author on the study, pointed out that in the past, NS was used almost universally for hospitalized (non-SCD) patients requiring volume replacement. However, this has recently changed, as several randomized trials in multiple care settings have shown small but statistically significant benefits for patients receiving balanced fluids such as LR, including reduced risk of hyperchloremic metabolic acidosis and death.^2,3

Many patients with SCD experiencing vaso-occlusive episodes require fluid replacement, and hypovolemia exacerbates sickling of erythrocytes. Metabolic acidosis, which can be worsened by hypovolemia, can also worsen sickling. Moreover, earlier data have suggested that on a microvascular level, NS may increase risk of erythrocyte sickling.⁴

However, most patients with SCD who are given fluids during vaso-occlusive episodes still receive NS. Dr. Bosch explained that he and his colleagues began this study to explore this discrepancy, as current guidelines from the American Society of Hematology do not make specific recommendations about fluids, and clinical support tools such as UpToDate endorse the use of NS.⁵

Dr. Bosch and colleagues used a target trial emulation model and a multicenter administrative database to design their retrospective study. This kind of trial design mimics a hypothetical randomized clinical trial to help properly develop inclusion and exclusion criteria and avoid common pitfalls of observationally designed studies, such as time biases.⁶ Using their selection criteria, they included more than 55,500 vaso-occlusive episodes in patients with SCD in which NS or LR had been given at the clinician’s discretion (n=52,079 and n=3,495, respectively).¹

The study’s primary endpoint was hospital-free days by day 30. At day 30, patients who had received LR had more hospital-free days compared with those who received NS (marginal mean difference 0.4 days). Additionally, these patients had a lower risk of 30-day readmission (marginal risk difference -5.8). Differences between the groups were stronger in those who received larger amounts of fluids.

Dr. Bosch acknowledged one potential limitation of the study, in addition to those inherent in retrospective designs, is that this difference in hospital-free days, although statistically significant, was small, consistent with other studies in patients without SCD; consequently, some might argue that this finding is not clinically meaningful. However, from his perspective, even a half day less in the hospital can positively affect patients’ quality of life. Additionally, because the costs and availability of LR and NS are similar, the potential drawbacks of switching to LR seem minimal.

Dr. Bosch noted that given the number of patients required and other factors, it’s unlikely that a randomized controlled trial on this topic would ever be performed. “We think this is practice changing,” he said. “This builds upon earlier evidence that we already had, which suggested we should have been using LR, but it’s nice to see that our results support that.”

This study couldn’t address the ideal amount of fluid needed in vaso-occlusive crises. Although it’s important to correct hypovolemia, giving too much fluid is also undesired, as some patients with SCD have some degree of undiagnosed heart failure. Dr. Bosch and his team are hoping to explore such questions in future studies, as well as gather data on the role of continuous hypotonic saline (e.g., 0.45% “half normal” saline), which may have additional benefits in decreasing sickling.

Any conflicts of interest declared by the authors can be found in the original article.

References

1. Alwang AK, Law AC, Klings ES, et al. Lactated Ringer vs normal saline solution during sickle cell vaso-occlusive episodes [published online ahead of print, 2024 September 9]. JAMA Intern Med. doi: 10.1001/jamainternmed.2024.4428.
2. Hammond DA, Lam SW, Rech MA, et al. Balanced crystalloids versus saline in critically ill adults: a systematic review and meta-analysis. Ann Pharmacother. 2020;54(1):5-13.
3. Yunos NM, Kim IB, Bellomo R, et al. The biochemical effects of restricting chloride-rich fluids in intensive care. Crit Care Med. 2011;39(11):2419-2424.
4. Carden MA, Fay ME, Lu X, et al. Extracellular fluid tonicity impacts sickle red blood cell deformability and adhesion. Blood. 2017;130(24):2654-2663.
5. Brandow AM, Carroll CP, Creary S, et al. American Society of Hematology 2020 guidelines for sickle cell disease: management of acute and chronic pain. Blood Adv. 2020;4(12):2656-2701.
6. Ruhl AP, Hsieh MM, Stuart EA. Charting the waters of sickle cell disease with target trial emulation [published online ahead of print, 2024 September 9]. JAMA Intern Med. doi: 10.1001/jamainternmed.2024.4435.