Normal saline is one of the most widely used intravenous fluids in clinical medicine. It is often the first-line choice for fluid resuscitation, perioperative hydration, and treatment of hypovolemia. Despite its name, however, it is not physiologically “normal.” Its composition differs significantly from human plasma, and repeated or large-volume administration of normal saline can contribute to metabolic derangements—most notably, a form of hyperchloremic metabolic acidosis. Understanding the biochemical basis and clinical implications of this risk is essential for safe fluid management.
Normal saline is a solution of sodium and chloride in water, with an osmolarity slightly above that of plasma. While the sodium content is relatively close to what is found in blood, the chloride content is disproportionately higher than typical plasma levels. This relative excess of chloride is the main reason why normal saline can contribute to disturbances in acid–base balance 1.
Large volumes of normal saline raise plasma chloride disproportionately, producing hyperchloremic metabolic acidosis. First, infusion dilutes plasma bicarbonate. Second, the chloride rise narrows the gap between fully dissociated cations and anions, lowering pH. Third, excess chloride reduces renal bicarbonate reabsorption and increases its excretion, further decreasing plasma bicarbonate. The net effect of too much normal saline is a non-anion gap (hyperchloremic) metabolic acidosis, distinct from lactic acidosis or ketoacidosis 2,3.
Many clinical and experimental studies have confirmed this phenomenon. Healthy volunteers given large infusions of normal saline develop reductions in serum bicarbonate and pH. In critically ill patients, especially those requiring aggressive resuscitation, the use of normal saline has been associated with metabolic acidosis, biochemical changes linked to renal vasoconstriction, and in some trials modestly higher risks of kidney injury compared to balanced crystalloids such as lactated Ringer’s or Plasma-Lyte 1,4,5.
For most patients receiving small volumes of normal saline (for example, as a carrier fluid for medications), the risk of acidosis is minimal. However, in settings requiring aggressive fluid therapy, such as trauma, sepsis, or major surgery, the risk becomes clinically relevant. Hyperchloremic acidosis may contribute to hemodynamic instability and has the potential to reduce catecholamine efficacy, impair cardiac function, alter vascular tone, and affect immune responses, although direct outcome data in humans remain limited 6,7.
Balanced crystalloids such as lactated Ringer’s or Plasma-Lyte have electrolyte compositions closer to plasma and contain buffers that are metabolized to bicarbonate, thereby minimizing the risk of acidosis. Many recent guidelines now recommend balanced crystalloids as first-line resuscitation fluids in most settings, reserving normal saline for specific indications, such as correcting hypochloremic metabolic alkalosis and hyponatremia or in situations where potassium-containing fluids should be avoided 8–10.
Normal saline remains a valuable and readily available intravenous fluid. However, its use is not without risk. Large-volume administration can cause hyperchloremic metabolic acidosis, a complication that may affect patient outcomes, particularly in critically ill populations. Clinicians should be aware of these risks and consider balanced crystalloids as safer alternatives for resuscitation, tailoring fluid choice to the clinical scenario.
References
1. Patel, P., Tonog, P. & Lakhkar, A. D. Normal Saline. in StatPearls (StatPearls Publishing, Treasure Island (FL), 2025).
2. Metabolic Acidosis: Causes, Symptoms, Diagnosis & Treatment. Cleveland Clinic https://my.clevelandclinic.org/health/diseases/24492-metabolic-acidosis.
3. Miller, L. R., Waters, J. H. & Provost, C. Mechanism of hyperchloremic metabolic acidosis. Anesthesiology 84, 482–483 (1996). DOI: 10.1097/00000542-199602000-00044
4. Waters, J. Saline-Based Fluids Can Cause a Significant Acidosis That May Be Clinically Relevant. Critical Care Medicine 28, 3376 (2000).
5. Tabuchi, M., Morozumi, K., Maki, Y., Toyoda, D. & Kotake, Y. Hyperchloremic metabolic acidosis due to saline absorption during laser enucleation of the prostate: a case report. JA Clinical Reports 8, 20 (2022). DOI: 10.1186/s40981-022-00499-3
6. Eisenhut, M. Causes and effects of hyperchloremic acidosis. Crit Care 10, 413 (2006). DOI: 10.1186/cc4963
7. Hyperchloremic Acidosis Clinical Presentation: History, Physical Examination. https://emedicine.medscape.com/article/240809-clinical?form=fpf.
8. Prescott, H. C. & Ostermann, M. What is new and different in the 2021 Surviving Sepsis Campaign guidelines. Med Klin Intensivmed Notfmed 1–5 (2023) doi:10.1007/s00063-023-01028-5. DOI: 10.1007/s00063-023-01028-5
9. Corrêa, T. D., Cavalcanti, A. B. & de Assunção, M. S. C. Balanced crystalloids for septic shock resuscitation. Rev Bras Ter Intensiva 28, 463–471 (2016). DOI: 10.5935/0103-507X.20160079
10. Song, B., Fu, K., Zheng, X. & Liu, C. Fluid resuscitation in adults with severe infection and sepsis: a systematic review and network meta-analysis. Front. Med. 12, (2025). DOI: 10.3389/fmed.2025.1543586