Intravenous fluid therapy is one of the most fundamental interventions in modern medicine and is administered daily to millions of patients worldwide for volume replacement, hemodynamic optimization, and medication delivery.^{( 1 )}

In neurosurgery, where the maintenance of cerebral homeostasis is critical, appropriate crystalloid selection is particularly important, influencing not only acid-base and electrolyte balance but also intracranial pressure, cerebral perfusion, and neurological outcomes.^{( 2 - 4 )} Despite this universal relevance, the choice between balanced crystalloids and 0.9% saline remains one of the most debated issues in contemporary anesthesiology and perioperative medicine, with profound implications for patient outcomes across diverse clinical settings.^{( 5 - 7 )}

Over the past two decades, scientific evidence regarding crystalloids has evolved substantially. The pioneering study by Yunos et al. first demonstrated that a chloride-restrictive strategy significantly reduced the incidence of acute kidney injury by 40% (8.4% versus 14%, p<0.001) in 1,533 critically ill patients.^{( 8 )} This finding was subsequently validated on a much larger scale by the Isotonic Solutions and Major Adverse Renal Events Trial (SMART) and Saline against Lactated Ringer’s or Plasma-Lyte in the Emergency Department (SALT-ED) studies (2018), which demonstrated consistent renal protection with balanced crystalloids in more than 29,000 patients. The SMART study, involving 15,802 critically ill patients, showed a significant reduction in major adverse kidney events (14.3% versus 15.4%, p=0.04), whereas the SALT-ED study, involving 13,347 non-critically ill patients, confirmed similar renal protection (4.7% versus 5.6%, p=0.01).^{( 9 , 10 )}

However, more recent high-impact studies have refined this body of evidence and challenged the long-held assumption that balanced crystalloids are universally superior to 0.9% saline. The Balanced Solution versus Saline in Intensive Care Study (BaSICS; 2021), involving 10,520 critically ill patients, found no significant difference in mortality (26.4% versus 27.2%, p=0.47), raising specific concerns about balanced crystalloids in traumatic brain injury.^{( 11 )} This concern was amplified by recent meta-analyses, including the study by Diz et al., which demonstrated increased 90-day mortality with balanced crystalloids in patients with traumatic brain injury (odds ratio [OR] 1.31, 95% confidence interval [95%CI] 1.03-1.65, p=0.03).^{( 12 )} The Plasma-Lyte 148 versus Saline (PLUS) study (2022), one of the most recent and rigorous double-blind clinical trials involving 5,037 critically ill patients, confirmed this equipoise by demonstrating no significant difference in mortality (21.8% versus 22.0%, p=0.90) or renal function between Plasma-Lyte 148 and saline.^{( 13 )}

Despite the extensive literature in general critical populations, a substantial knowledge gap persists in the context of elective neurosurgery.^{( 14 , 15 )} Unlike traumatic brain injury, where primary brain injury, edema, intracranial hypertension, and hemodynamic instability create a complex pathophysiological context, elective neurosurgery occurs under controlled conditions in stable patients with an intact blood-brain barrier.^{( 16 , 17 )} This distinction is crucial, as the proposed mechanisms explaining the adverse effects of balanced crystalloids in traumatic brain injury, including cerebral edema, intracranial pressure alterations, and blood-brain barrier dysfunction, may not apply to the elective context.^{( 18 , 19 )}

The few specific studies in elective neurosurgery have consistently demonstrated the metabolic advantages of balanced crystalloids. In a study of 80 patients undergoing elective craniotomy, Shrivastava et al. found that Plasma-Lyte was associated with a significantly higher pH (7.42 versus 7.38, p<0.001) and a lower incidence of metabolic acidosis.^{( 20 )} Similarly, Dey et al. found identical results in 44 patients, with superior arterial pH (7.41 versus 7.36, p<0.001) and a better electrolyte profile with Plasma-Lyte.^{( 21 )} Kang et al., in a study involving 586 patients undergoing aneurysm clipping, demonstrated not only metabolic advantages but also superior clinical outcomes, including earlier extubation (122 versus 250 min, p=0.016) and shorter intensive care unit (ICU) stay (1.12 versus 1.37 days, p=0.001) with balanced crystalloids.^{( 22 )}

The physiological basis for these metabolic advantages is well-established. A 0.9% saline solution with a chloride concentration of 154mEq/L (substantially higher than plasma’s 103mEq/L) induces hyperchloremic acidosis through reduction of the strong ion difference, as described by Stewart’s approach.^{( 23 , 24 )} In contrast, balanced crystalloids, such as Plasma-Lyte 148, with a chloride concentration of 98 mEq/L and presence of metabolic buffers (acetate and gluconate), maintain acid-base balance closer to physiological conditions.^{( 25 )} Recent experimental studies, including work by Bessa et al. involving an animal model of ischemic stroke, have demonstrated that different sodium concentrations in fluids considerably affect brain, lung, and kidney injury, suggesting that an optimized electrolyte composition may have neuroprotective implications.^{( 26 )}

Considering this gap in the literature and the growing importance of individualized fluid therapy based on clinical context, we conducted this randomized, double-blind controlled trial to directly compare the effects of Plasma-Lyte 148 and 0.9% saline on acid-base balance, electrolyte profile, and perioperative outcomes in patients undergoing elective neurosurgery. Our primary hypothesis was that Plasma-Lyte 148, owing to its more physiological composition, would offer superior acid-base homeostasis compared to 0.9% saline, as measured by arterial pH at the end of surgery. By providing meaningful metabolic advantages without compromising safety, Plasma-Lyte 148 could help refine current evidence in the elective neurosurgical setting. In this context, balanced crystalloids may deliver benefits under controlled conditions while maintaining comparable safety, thereby informing clinical practice and guiding future guidelines in this specialized field.

To evaluate the effects of Plasma-Lyte 148 and 0.9% saline on acid-base balance, electrolyte profile, and perioperative outcomes in patients undergoing elective neurosurgery, with arterial pH at the end of surgery as the primary endpoint.

Study reporting adhered to the CONSORT 2010 guidelines for randomized controlled trials.^{( 67 )} Methodological quality was assessed using contemporary risk of bias evaluation tools, ensuring transparency and reproducibility of findings.^{( 27 , 49 , 68 )}

A total of 68 patients completed the study and were included in the per-protocol analysis: 35 patients in the 0.9% saline group and 33 in the Plasmalyte 148 group ( Figure 1 ). The results presented represent the outcomes of patients who reached the end of the study according to their initial allocation (per protocol).

Figure 1

Baseline demographic and clinical characteristics were similar between groups, including age, sex distribution, weight, height, ASA classification, and surgical indication. Baseline acid-base and electrolyte values were also similar between groups ( Table 1 ).

Table 1

Variable	0.9% Saline Group (n=35)	Plasma-Lyte Group (n=33)
Demographic
Age (years)*	50.6±15.6	48.3±14.1
Gender (Male/Female)† - %	15/20 (42.9/57.1)	13/20 (39.4/60.6)
Weight (kg)*	73.5±14.5	74.8±13.6
Height (cm)*	1.67±0.10	1.65±0.12
ASA (I/II/III/IV)†	0/17/16/2	2/11/18/2
Surgical indication (Tumor/Aneurysm)† - %	24/11 (68.6/31.4)	24/9 (72.7/27.3)
Changes in ECG* - %	2 (5.7)	3 (9.1)
Changes in X-ray* - %	2 (5.7)	1 (3.0)
Baseline values
pH*	7.37±0.05	7.40±0.04
HCO3- (mmol/L)#	22.9±2.5	23.6±2.7
Base Excess*	-1.2±2.7	-0.4±2.6
Sodium (mmol/L)#	139.2±2.8	138.9±3.2
Potassium (mmol/L)#	3.9±0.3	3.9±0.3
Calcium (mmol/L)#	1.18±0.04	1.16±0.04
Chlorine (mmol/L)#	109.1±3.1	108.8±2.7
Lactate (mmol/L)§	1.0 (0.8/1.4)	1.0 (0.7/1.4)
Blood Glucose (mg/dL)§	107 (100.0/132.0)	102 (92.0/114.0)

^* Values are expressed as mean±standard deviation and were analyzed using the Student’s t-test; ^† Values are expressed as absolute and relative frequencies and were analyzed using the Chi-square and Fisher exact tests; ^§ Values are expressed as mean±standard deviation; ^¶ Values are expressed as median with quartiles.

Intraoperative data are presented in table 2 . No significant differences were observed between groups in intraoperative management, including total crystalloid volume administered. There were no significant differences in pRBC transfusion (6 versus 4 patients, p=0.735) or the number of patients requiring norepinephrine (18 versus 14 patients, p=0.457). Diuresis was similar in the Plasma-Lyte 148 and 0.9% saline groups (900 mL [380/1,750] versus 925mL [457/1,450], p=0.846).

Table 2

Variable	0.9% Saline Group (n=35)	Plasma-Lyte Group (n=33)	Difference between groups (95% CI)	p value
Surgery duration (min)*	360 (220/440)	270 (227/330)	+75 (0.0 to +135.0)	0.058
Anesthesia duration (min)*	480 (360/570)	370 (300/465)	+70 (0.0 to 140.0)	0.053
Crystalloid volume (mL)*	3000 (2000/4000)	2227 (1416/3000)	+515 (-100.0 to +1160.0)	0.107
Urine output (mL)*	900 (380/1750)	925 (457/1450)	+50 (-325.0 to +400.0)	0.846
Fluid balance (mL)*	+1785 (850/2570)	+1200 (634/1950)	+400 (-250.0 to +999.0)	0.216
Transfusion of red blood cells† - %	6 (17.1)	4 (12.1)	+5 (-14.7 to +24.0)	0.735
Plasma transfusion†	0	1 (3)	-3 (-9.6 to +17.5)	0.485
Ephedrine dose (mg)*	0.0 (0.0/0.0)	0.0 (0.0/10.0)	0.0 (0.0 to 0.0)	0.052
Metaraminol dose (mg)*	1.0 (0.0/2.3)	0.0 (0.0/1.0)	0.0 (0.0 to 1.0)	0.075
Use of norepinephrine† - %	18 (5.4)	14 (42.4)	+10 (-15.9 to +32.5)	0.457

^* Values are expressed as the median with the first and third quartiles and were analyzed using the Mann-Whitney U test; ^† Values are expressed as absolute and relative frequencies and were analyzed using the Chi-square and Fisher exact tests.

At the end of surgery, the Plasma-Lyte group had significantly higher arterial pH than the saline group (7.39±0.04 versus 7.35±0.05, p<0.001). Secondary outcomes showed that the Plasma-Lyte group had higher bicarbonate levels (22.5±1.8 versus 20.6±2.2mmol/L, p<0.001), less negative base excess (-1.6±2.3 versus -3.9±2.6, p<0.001), and lower chloride levels (109.1±6.6 versus 113.9±4.5 mmol/L, p=0.001).

The saline group had higher glucose levels (133 versus 119mg/dL, p=0.030) and slightly higher calcium levels (1.17±0.05 versus 1.14±0.04mmol/L, p=0.040). Sodium and potassium levels were similar between groups ( Table 3 ).

Table 3

Variable	0.9% Saline Group (n=35)	Plasma-Lyte Group (n=33)	Difference between groups (95% CI)	P value
Primary outcome
pH*	7.35±0.05	7.39±0.04	-0.04 (from -0.06 to -0.02)	<0.001
Secondary outcomes
HCO3- (mmol/L)*	20.6±2.2	22.5±1.8	-1.83 (from -2.82 to -0.83)	<0.001
Base Excess*	-3.9±2.6	-1.6±2.3	-2.36 (from -3.57 to -1.16)	<0.001
Sodium (mmol/L)*	140.9±3.6	139.8±3.7	+1.03 (from -0.76 to +2.82)	0.255
Potassium (mmol/L)*	4.1±0.3	4.1±0.2	+0.05 (from -0.10 to +0.21)	0.480
Calcium (mmol/L)*	1.17±0.05	1.14±0.04	+0.02 (from +0.00 to +0.51)	0.040
Chlorine (mmol/L)*	113.9±4.5	109.1±6.6	+4.83 (from +2.09 to +7.58)	0.001
Lactate (mmol/L)†	1.4 (1.0/2.0)	1.3 (1.0/1.9)	0.9 (from -0.23 to +0.40)	0.595
Blood Glucose (mg/dL)†	133 (118.0/162.0)	119 (109.0/140.2)	+15.0 (from +1.00 to +28.0)	0.030

^* Values are expressed as mean and standard deviation and were analyzed using the Student’s t-test; ^† Values are expressed as median and quartiles and were analyzed using the Mann-Whitney U test and Hodges-Lehmann estimate of the median difference.

We did not observe differences between groups regarding sodium, potassium, and lactate values.

There were no differences between groups regarding extubation performed in the operating room, length of hospital stay, length of ICU stay, new neurological deficit, or mortality (p>0.05) (Table 2S, Supplementary Material ).

No patient in either group received mannitol or hypertonic saline.

This double-blind randomized controlled study demonstrated that Plasma-Lyte 148 provided significant metabolic advantages over 0.9% saline in patients undergoing elective neurosurgery, consistent with patterns reported in the international literature. With Plasma-Lyte, we observed superior arterial pH (7.39±0.04 versus 7.35±0.05, p<0.001), higher bicarbonate levels (22.5±1.8 versus 20.6±2.2mmol/L, p<0.001), less negative base excess (-1.6±2.3 versus -3.9±2.6, p<0.001), and lower chloride concentrations (109.1±6.6 versus 113.9±4.5mmol/L, p<0.001). These findings are virtually identical to those reported by Shrivastava et al., with similar methodology,^{( 20 )} as well as Dey et al. in elective craniotomies,^{( 21 )} and Sundaram et al. in aneurysm clipping,^{( 69 )} establishing a robust pattern of specific evidence for neurosurgery.

The remarkable consistency of these metabolic findings across multiple neurosurgical studies reflects a universal pattern observed in more than 50,000 patients in the general literature. The meta-analysis by Huang et al., involving 871 patients undergoing non-renal surgery, demonstrated similar differences: lower postoperative pH (mean difference 0.05, p<0.001) and lower base excess (mean difference 2.04, p<0.001) with saline.^{( 65 )} This pattern has been confirmed in diverse contexts, from the landmark study by Yunos et al. in critically ill patients^{( 8 )} to studies on renal transplantation^{( 70 )} and abdominal surgery,^{( 71 )} demonstrating that the metabolic advantages of balanced crystalloids extend across specific populations and clinical contexts.

In our study, no patient required mannitol or hypertonic saline. Administration of these agents to relieve intracranial pressure and cerebral edema could have resulted in hemodynamic and electrolyte changes that could not be attributed solely to the randomized solution.^{( 72 )}

Our findings should be interpreted within the context of the evolving evidence regarding crystalloids. Although previous studies, such as SMART and SALT-ED, demonstrated not only metabolic advantages but also significant renal protection in more than 29,000 patients,^{( 9 , 10 )} more recent studies, such as BaSICS (2021) and PLUS (2022), revealed substantial equipoise, particularly in general critical populations.^{( 11 , 13 )} The PLUS study, which included 5,037 patients, demonstrated that despite expected metabolic advantages, there were no significant differences in mortality (21.8% versus 22.0%) or renal function between Plasma-Lyte 148 and saline.^{( 13 )} This evolution in evidence emphasizes the importance of contextualization and individualization of fluid therapy.

Elective neurosurgery represents a clinical context that is distinct from that of the general critical population studied in large clinical trials. Unlike traumatic brain injury, for which recent meta-analyses have raised concerns about balanced crystalloids,^{( 12 )} elective neurosurgery occurs in stable patients with intact blood-brain barrier and without the confounding factors typical of trauma, such as primary brain injury, edema, and hemodynamic instability.^{( 16 , 17 )} Our findings, which demonstrate metabolic advantages without compromising safety, align with this pathophysiological distinction and suggest that the benefits of balanced crystalloids can be obtained with equivalent safety in an elective neurosurgical setting.

The observed metabolic advantages have a solid physiological basis and potentially important clinical implications. Hyperchloremic acidosis induced by saline through a reduction in the strong ion difference, according to Stewart’s approach,^{( 23 , 24 )} can affect multiple organ systems. Sen et al. demonstrated that each 100 mEq increase in chloride load was associated with a 5.5% increase in death risk at 1 year, even after controlling for total fluid volume.^{( 73 )} In neurosurgery, where cerebrovascular acid-base regulation is critical for maintaining adequate cerebral perfusion,^{( 74 , 75 )} preservation of physiological acid-base balance may have neuroprotective implications, as suggested by recent experimental studies.^{( 26 )}

In our study, serum ionic calcium levels were lower in the Plasma-Lyte 148 group than in the 0.9% saline group, although mean values in both groups were within the normal range. This may have occurred because of calcium chelation by plasma gluconate accumulation and the absence of calcium in Plasma-Lyte 148, similar to findings from previous studies,^{( 19 , 21 , 76 )} suggesting that serum calcium should be monitored in patients receiving Plasma-Lyte 148.

We found no significant differences in plasma concentrations of lactate, sodium, or potassium in both groups, consistent with findings from previous studies.^{( 7 , 77 , 78 )} Plasma lactate has been used as a marker of tissue perfusion in critically ill patients.^{( 79 )} The absence of differences in lactate levels between groups in our study indicated that the fluid management was equivalent and adequate to maintain optimum tissue perfusion, independent of the solution infused. Moreover, despite the different sodium concentrations between the two fluids studied (Plasma-Lyte 148, 140mEq/L; 0.9% saline, 154mEq/L), the sodium levels at the end of the procedure did not differ between groups, consistent with findings from other studies using similar methodology.^{( 21 )}

O’Malley et al.^{( 80 )} compared Ringer’s lactate and 0.9% saline during kidney transplantation and found higher potassium levels in the 0.9% saline group (19% versus 0%), possibly as a result of hyperchloremic metabolic acidosis. Our study excluded patients with chronic kidney injury, pre-existing abnormalities of acid-base or electrolyte balance, or diuretic use, which are commonly encountered in renal transplant surgery and increase susceptibility to acidosis and hyperkalemia. This may explain why no difference in potassium levels was observed between groups.

We observed an increase in diuresis in the Plasma-Lyte 148 group, possibly due to the diuretic effect of gluconate, although this was not statistically significant. Similar findings have been reported by Roquilly et al.,^{( 81 )} who compared 0.9% saline with balanced solutions in patients with traumatic brain injury, and Chaussard et al.^{( 76 )} who compared Ringer’s Lactate with Plasma-Lyte 148 in patients with burns in intensive care.

Our findings contribute to the current refinement of fluid therapy, which has evolved from a “one-size-fits-all” approach to individualized strategies based on specific clinical contexts. Recent international consensus statements and guidelines, including European Society of Intensive Care Medicine (ESICM) 2024^{( 5 )} and PeriOperative Quality Initiative (POQI) 2024,^{( 3 )} emphasize the importance of this individualization. In elective neurosurgery, where controlled conditions fundamentally differ from general critical contexts, our findings suggest that the metabolic advantages of balanced crystalloids can be achieved safely, offering an optimized therapeutic strategy for this specific population.

Despite the exploratory nature of secondary outcomes, we observed no differences between groups in hospital or ICU length of stay, new neurological deficit, or mortality. Prior neurosurgical studies using a methodology similar to ours did not evaluate these parameters.^{( 21 , 78 )} We acknowledge that our sample size was calculated focusing solely on the primary outcome. Nevertheless, our study makes a novel contribution by evaluating these outcomes, serving as a foundation for future studies.

Although a significant difference in blood glucose levels was observed between groups, values remained within the normal range and did not require clinical intervention. Additionally, multiple univariate analyses increase the risk of family-wise error rate. Therefore, this difference may be random without clinical relevance. In a similar study, Abhiruchi et al. did not find differences in glucose levels between groups.^{( 78 )}

This study has several strengths. As a double-blind, randomized controlled trial, it demonstrated high methodological quality, with low risk of bias across all evaluated domains. A comprehensive assessment using both the modified Jadad scale and the National Heart, Lung, and Blood Institute (NHLBI) Quality Assessment Tool confirmed the internal validity and reliability of our findings. The maximum scores achieved in both assessment tools indicate that our study meets the highest standards for clinical trial methodology and provides robust evidence for clinical decision-making.^{( 82 , 83 )}

Nevertheless, certain limitations should be acknowledged. Although the sample size was sufficient to detect metabolic differences, it may be insufficient to evaluate rare clinical outcomes. The study population, restricted to elective neurosurgery, limits the generalizability of the findings to other neurosurgical contexts. Future studies with larger sample sizes and long-term follow-ups are needed to assess whether the observed metabolic advantages translate into sustained clinical benefits. Additionally, evaluation of specific biomarkers of brain injury and renal function could provide valuable mechanistic insights into the effects of different crystalloids in the neurosurgical context.

In conclusion, this study demonstrated that Plasma-Lyte 148 provides substantial metabolic advantages over 0.9% saline in elective neurosurgery, confirming the universal pattern observed in the international literature. These findings, obtained in a controlled context that fundamentally differs from the general critical population, contribute to the growing body of evidence supporting individualization of fluid therapy based on clinical context. In elective neurosurgery, where metabolic advantages of balanced crystalloids can be obtained with an equivalent safety profile, our findings offer valuable evidence for informed and personalized clinical decision-making. Future studies should focus on large, multicenter trials powered to detect clinical outcomes, investigation of long-term neurological effects, and exploration of optimal fluid management strategies across different neurosurgical populations. Additionally, the integration of goal-directed fluid therapy protocols with balanced crystalloids presents a promising avenue for optimizing perioperative care in patients undergoing neurosurgery.^{( 51 , 84 )} Our study provides the foundational evidence necessary to inform future investigations and contributes essential data to guide evidence-based crystalloid selection in contemporary neurosurgical practice.

This randomized controlled trial demonstrated that Plasma-Lyte 148 provides superior acid-base homeostasis compared to 0.9% saline in elective neurosurgery, with statistically significant improvements in pH, bicarbonate, base excess, and chloride levels, while maintaining an equivalent safety profile. These findings support the use of balanced crystalloids in elective neurosurgical patients—a clinical context distinct from traumatic brain injury, where balanced solutions have shown concerning outcomes—and contribute essential evidence to support individualized perioperative fluid management.