Background Diabetic ketoacidosis (DKA) is a common and serious complication of diabetes, often requiring hospitalization and intensive care. Fluid resuscitation is a cornerstone of DKA management, with traditional guidelines recommending isotonic normal saline (NS) for initial volume replacement. Recent studies, however, suggest that large volumes of NS may lead to undesirable outcomes such as hyperchloremic metabolic acidosis. This study investigates the effects of large-volume NS resuscitation on clinical outcomes in DKA management, comparing it to other fluids, such as lactated Ringers (LR). Objective To evaluate whether large-volume resuscitation with isotonic normal saline (NS) is associated with prolonged ICU length of stay (LOS), increased time on insulin infusion, and higher rates of non-anion gap metabolic acidosis in patients with DKA. Materials and methods This was a single-center, retrospective, observational study conducted at Naples Comprehensive Healthcare System. We reviewed electronic medical records of patients diagnosed with DKA, defined by pH <
7.3, bicarbonate <
18, and anion gap >
12. The primary outcome was ICU LOS, and secondary outcomes included overall length of stay, insulin infusion duration after DKA resolution, and incidence of non-anion gap metabolic acidosis after DKA resolution. Patients were grouped by the amount of NS received during resuscitation: 0L, 1L, 2L, and ≥3L. Statistical analyses included analysis of variance (ANOVA), t-tests, and chi-square tests to compare outcomes between groups. Results A total of 109 patients were included in the study. The mean age was 51.34 years, and the cohort consisted of 43.1% females and 56.9% males. There was no significant difference in ICU LOS between patients who received 0L and 1L of NS. However, patients who received 2L (p=0.0249) and ≥3L (p=0.00065) had significantly longer ICU LOS compared to those who received 0L of NS. No significant difference in overall LOS was also observed across all groups (p=0.894). Patients who received ≥3L of NS had a significantly longer duration of insulin infusion compared to those who received 0L (p=0.0101) after DKA anion gap closure while a significant increase in the incidence of non-anion gap acidosis after DKA resolution was observed in patients receiving ≥2L of NS (p=0.0000). Conclusion This study suggests that large-volume resuscitation with isotonic NS in DKA patients is associated with increased ICU length of stay, prolonged insulin infusion, and a higher incidence of non-anion gap metabolic acidosis. These findings support the use of balanced crystalloids, such as lactated Ringers, for initial resuscitation in DKA patients, as they may reduce the risk of complications related to hyperchloremia and improve clinical outcomes. Further prospective studies are needed to confirm these findings and guide fluid management protocols in DKA.