Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2025 Apr 22;15(1):54.
doi: 10.1186/s13613-025-01473-9.

Stewart's theory and acid-base changes induced by crystalloid infusion in humans: a randomized physiological trial

Antonio Maria Dell'Anna  1 , Domenico Luca Grieco  2 , Cristina Dominedò  1 , Marta Cicetti  1 , Irene Cisterna  1 , Rossano Festa  1 , Rosa Lamacchia  1 , Giuseppina Giannì  1 , Nicoletta Filetici  1 , Teresa Michi  1 , Cristina Rossi  3 , Francesca Danila Alcaro  3 , Alessandro Mele  1 , Aurora Rocchi  1 , Demetrio Del Prete  1 , Maria Concetta Meluzio  4 , Francesco Ciro Tamburrelli  4 , Marco Rossi  1 , Massimo Antonelli  1
Affiliations

Stewart's theory and acid-base changes induced by crystalloid infusion in humans: a randomized physiological trial

Antonio Maria Dell'Anna et al. Ann Intensive Care. .

Abstract

Background: Stewart's acid-base theory states that, under isocapnic conditions, crystalloid infusion affects plasma pH due to changes in strong ion difference and total weak acid concentration: a comprehensive study also assessing renal response and hemodilution effects has not been conducted in humans. We aimed to evaluate Stewart's approach during crystalloid infusion in humans.

Methods: In this randomized trial, patients undergoing surgery with minimal blood losses were randomized to receive to normal saline (chloride content 154 mEq/L, strong ion difference 0 mEq/L), lactated Ringer's (chloride content 112 mEq/L, strong ion difference 29 mEq/L) or Crystalsol (chloride content 98 mEq/L, strong ion difference 50 mEq/L): patients received 10 ml/kg immediately after intubation, and 20 ml/kg after 2 h. Plasma/urinary acid-base and electrolytes were measured before study start and then at prespecified timepoints. The primary endpoint was pH one hour after the second fluid bolus: secondary outcomes included urinary/plasmatic electrolyte concentrations and strong ion difference during the study.

Results: Forty-five patients were enrolled (15 in each group). The extent of hemodilution achieved with the first (median [Interquartile range]: saline 9% [6-15], Ringer's 7% [4-9], Crystalsol 8% [5-12]) and the second fluid bolus (saline 13% [5-17], Ringer's 12% [9-15], Crystalsol 15% [10-20]) was not different between groups (p = 0.39 and p = 0.19, respectively). Patients in saline group received more chloride (449 mEq [383-495]) vs. Ringer's (358 mEq [297-419]) and Crystalsol groups (318 mEq [240-366]) (p = 0.001). One hour after the second bolus, pH was lower in saline group (7.34 [7.32-7.36]) vs. Ringer's (7.40 [7.35-7.43) and Crystalsol groups (7.42 [7.38-7.44]) (both p < 0.01), since plasma chloride increased significantly over time in saline group but not in Ringer's and Crystalsol groups. Overall chloride urinary excretion was not different between study groups (saline 36 mEq [28-64], Ringer's 42 mEq [29-68], Crystalsol 44 mEq [27-56], p = 0.60) but, at the end of experiments, urinary chloride concentration was higher and diuresis was lower in saline group vs. Ringer's and Crystalsol groups (p = 0.01, p = 0.04, respectively).

Conclusions: Consistent with Stewart's approach, crystalloid solutions with high chloride content lower pH due to reduced strong ion difference, progressive hemodilutional acidosis and limited renal response to chloride load.

Trial registration: Registered on clinicaltrials.gov (NCT03507062) on April, 24th 2018.

Keywords: Acid–base balance; Chloride; Crystalloids; Stewart; Strong ion difference.

PubMed Disclaimer

Conflict of interest statement

Declarations. Ethics approval and consent to participate: The study was approved by local Ethics Committee and informed consent was obtained by enrolled patients according to committee recommendations. Consent for publication: Not applicable. Competing interests: The authors declare that they have no conflicts of interests for the material discussed in the manuscript.

Figures

Fig. 1
Fig. 1
Consort diagram
Fig. 2
Fig. 2
pH changes in NS, LR and CR group throughout study period. Data are presented as median and interquartile range. NS = normal saline, LR = lactated Ringer’s, CR = Crystalsol. *NS vs LR, p = 0.04; NS vs CR, p = 0.03. §NS vs LR, p = 0.001; NS vs CR, p < 0.001. # NS vs LR, p = 0.008; NS vs CR, p < 0.001
Fig. 3
Fig. 3
Changes in SIDa, Atot and pCO2 among the three groups. Green circles: normal saline (NS); red squares: lactated Ringer’s (LR); sky blue triangles: crystalsol (CR). A *NS vs CR, p = 0.018; LR vs CR, p = 0.024. §NS vs CR, p = 0.003; LR vs CR, p < 0.001. # NS vs LR, p = 0.04; NS vs CR, p = 0.002. B. All comparisons had p > 0.05. C *NS vs CR, p = 0.04; LR vs CR, p = 0.024. §NS vs CR, p < 0.001; LR vs CR, p = 0.02. # NS vs LR, p = 0.02; NS vs CR, p = 0.003
Fig. 4
Fig. 4
Total amount of infused sodium, chloride and potassium. Sodium infused: NS 459 (383–505), LR 422 (365–494), CR 440 (328–508) mEq. Chloride infused: NS 449 (383–495), LR 360 (297–419), CR 318 (240–366) mEq. Potassium infused: NS 2.5 (2.5–2.5), LR 15.5 (11–19), CR 16 (12–18) mEq; p < 0.001. *p < 0.001; #p < 0.001
Fig. 5
Fig. 5
Urinary concentration of sodium, chloride and potassium and SID. A All inter-group differences were non significant. B *NS 86 (46–146) CR 30 (18–85) mEq/L, p = 0.01. C All inter-group differences were non significant. D CR 102 (55–112) vs NS 23 (11–33) vs LR 14 (4–51) mEq/L; #p = 0.006; *p < 0.001
Fig. 6
Fig. 6
Total chloride elimination among groups and diuresis across time point. A Total Cl urinary elimination NS 36 (28.4–63.7), LR 42.1 (28.8–68.3), CR 43.9 (26.7–55.7) mEq. B *NS 0 (0–0.14) LR 0.4 (0–2) CR 1.3 (0.3–1.7) p = 0.002 (p = 0.001); # NS 1.1 (0.6–2.5) LR 2.9 (1.3–4.6) CR 2.1 (1.5–3.9) p = 0.04
See this image and copyright information in PMC

References

    1. Glassford NJ, Bellomo R. The complexities of intravenous fluid research: questions of scale, volume, and accumulation. Korean J Crit Care Med. 2016;31:276–99.
    1. Awad S, Allison SP, Lobo DN. The history of 0.9% saline. Clin Nutr. 2008;27:179–88. - PubMed
    1. Finfer S, Myburgh J, Bellomo R. Intravenous fluid therapy in critically ill adults. Nat Rev Nephrol. 2018;14:541–57. - PubMed
    1. Messina A, Robba C, Calabrò L, Zambelli D, Iannuzzi F, Molinari E, et al. Association between perioperative fluid administration and postoperative outcomes: a 20-year systematic review and a meta-analysis of randomized goal-directed trials in major visceral/noncardiac surgery. Crit Care. 2021;25:43. - PMC - PubMed
    1. Van Regenmortel N, Verbrugghe W, Roelant E, Van den Wyngaert T, Jorens PG. Maintenance fluid therapy and fluid creep impose more significant fluid, sodium, and chloride burdens than resuscitation fluids in critically ill patients: a retrospective study in a tertiary mixed ICU population. Intensive Care Med. 2018;44:409–17. - PMC - PubMed

Associated data

LinkOut - more resources