The Effect on Serum Electrolytes in Patients Undergoing Elective Craniotomy for Supratentorial Brain Tumors Using PlasmaLyte A and Normal Saline as Intravenous Replacement Fluid

Background and aim The type of fluid which is administered to patients is very crucial and important. In this study normal saline is compared with PlasmaLyte A in patients undergoing craniotomy for supratentorial brain tumors. Generally normal saline is used in neurosurgical patients; it is seen to be associated with hyperchloremic acidosis. A balanced crystalloid, e.g. PlasmaLyte A, maintains a better metabolic status than normal saline. This study was planned to study the metabolic effects of using PlasmaLyte A as compared with normal saline as intravenous fluids in patients undergoing supratentorial brain tumour surgeries. Methods This is a prospective, randomized, double-blinded study in patients undergoing craniotomy for supratentorial brain tumors. Written informed consent was taken from patients and they were divided into two groups, Group A and B of 40 patients each by computer-generated random numbers. Group A received PlasmaLyte A and Group B received normal saline intra-operatively as maintenance fluid. Heart rate, mean arterial pressure, total fluid administered, serum sodium, serum potassium, chloride, lactate, pH, serum urea, serum creatinine, osmolarity, and urine output were assessed at different time intervals in both groups. Blood urea and creatinine were assessed to see acute kidney injury. Results There was no difference in mean values of serum sodium, potassium, lactate, serum urea, creatinine and serum osmolarity in both groups throughout the study period. However there was a rise in serum chloride and a low pH was noted in Group B. The urine output was also similar in both groups. The metabolic status of patients receiving PlasmaLyte was better than those receiving normal saline. Conclusion Normal saline may cause hyperchloremic metabolic acidosis which may be avoided by using balanced crystalloids. The use of balanced crystalloids should be preferred to normal saline in neurosurgical patients to ensure a better metabolic status and good clinical outcome.


Introduction
Intravenous fluids should be given the same consideration as other pharmacologically active agents. Ringer's lactate and normal saline are the most common fluids used in neurosurgery. The osmolarity of Ringer's lactate is 278 mosm/l which is less than plasma osmolarity and can thus result in cerebral edema [1,2]. A large volume of normal saline infusion is known to cause hyperchloremic acidosis, which can lead to acute kidney injury. Hyperchloremic acidosis causes afferent arteriolar vasoconstriction, reduced glomerular filtration rate and delayed micturition following surgery [3][4][5][6]. It may have fatal consequences because it can cause coagulation abnormality, decrease myocardial contractility, alter the immune system, and harm the renal system [7]. PlasmaLyte A is a balanced crystalloid and its composition is nearly similar to plasma. Its osmolarity is 295 mosm/l. It may aid in avoiding the issues of metabolic disturbances associated with normal saline. There is very limited research comparing normal saline with PlasmaLyte in neurosurgical patients.

Materials And Methods
This is a prospective, randomized, double-blinded trial and was conducted after getting approval from the Institutional Ethics Committee. The article is written as per consort guidelines. This trial is registered in the Clinical Trials Registry, India, CTRI/2022/05/042837.

Inclusion criteria
Patients between 18 to 60 years of age and American Society of Anesthesiologist Physical status grade lll undergoing surgery for supra tentorial brain tumor were included.

Exclusion criteria
Patients with renal dysfunction, hemoglobin <10gm/dl, electrolyte imbalance, hypersensitivity to PlasmaLyte A, surgery involving blood loss >1.5l, surgeries of more than five hours duration, and cases requiring intra-operative vasopressors were excluded.

Method
Pre-anesthetic checkup was done one day prior to surgery. Written informed consent was taken. All the patients received injection ranitidine 150mg and injection metoclopramide 10mg as premedication. Patients were divided into two groups on the basis of computer-generated random numbers. Group A received PlasmaLyte A intra-operatively and Group B received normal saline intra-operatively as maintenance fluids. Allocation concealment was done by using sequentially numbered opaque sealed envelopes. Both the intravenous fluid bottles were completely covered with dark-coloured opaque paper. PlasmaLyte A was labelled as 'A' and normal saline was labelled as 'B'. Patients were taken to the operation table and all the essential monitors were attached. The sensors for bi-spectral index were applied before pre-oxygenation. Bispectral index was maintained at 40 to 60 throughout surgery. Pre-oxygenation was done with 100% O2 for three minutes and patients were induced with injection fentanyl 2 mcg/kg, injection propofol 1.5-2.0 mg/kg in slow incremental bolus doses titrated to the loss of vocal responsiveness. After ascertaining proper bag and mask ventilation, injection atracurium 0.5 mg/kg was given. After ventilating for three to four minutes, the trachea was intubated with the proper size endotracheal tube. End tidal carbon dioxide was monitored throughout surgery. Right subclavian vein was cannulated using the Seldinger technique. Left radial artery was cannulated for invasive blood pressure monitoring and regular acid base gas analysis. Anesthesia was maintained with N2O, O2, isoflurane and top-up doses of atracurium. The rate of infusion of either fluid was maintained at a range of 8-10 ml/kg/hour in both groups. Analysis of arterial blood gas was done at baseline (T1), at the time of dura opening (T2), one hour after dura opening (T3), at skin closure (T4), one hour postoperatively (T5), 24 hours postoperatively (T6), and 48 hours postoperatively (T7). The parameters that were observed during these time intervals were heart rate (HR), mean arterial pressure (MAP), serum sodium, serum potassium, serum chloride, lactate, pH, serum urea, serum creatinine, osmolarity, and urine output.

Statistics
Considering a 95% confidence interval, power of 80% and precision of 5% assuming standard deviation (σ)=18 and effect size of 10, and considering attrition of 10%, the final sample size came out to be 40 in each group [8].
Data were analysed by SPSS software version 22 (IBM Corp., Armonk, NY, USA). Continuous variables are presented as mean±standard deviation. The categorical variables are presented as absolute numbers and percentages. The comparison of normally distributed continuous variables between the groups was performed using the student's t-test. Nominal categorical data between the groups were compared using the chi-square test or Fisher's exact test as appropriate. P<0.05 was considered significant.

Demographic characteristics of patients
It was observed that there was no significant difference in mean age (p=0.801), mean weight (p=0.672) or gender distribution (p=0.348) between both groups ( Table 1).

Comparison of heart rate and mean arterial pressure
There was no significant difference in mean heart rate or mean arterial pressure at different time intervals in both groups (

Comparison of serum sodium and potassium
There was no significant change in the mean values of serum sodium and potassium at all time intervals in both groups ( Table 3).

Comparison of serum chloride, lactate and pH
The mean value of serum chloride was insignificant when compared at T1 and T2 time intervals. However there was a significant rise in mean chloride levels at T3, T4, T5, T6 and T7 time intervals ( Table 4). The serum lactate showed no significant difference in both the groups throughout the study period ( Table 4). There was no difference in the mean values of pH at T1, T2 and T3 time intervals. However the mean difference for change in pH was found statistically significant after the T4 time interval (Table 4).

Comparison of fluid administered and serum osmolarity
There was no difference in the mean values of the amount of fluid administered at T1 time (baseline) as both the groups received 500 ml of fluid respectively. Both groups received a comparable volume of intraoperative fluid at all time intervals ( Table 5). The serum osmolarity of both groups showed no significant difference over the study period (

Comparison of serum urea and creatinine
There was no significant difference in the mean values of serum urea and creatinine at T1, T6 and T7 time intervals in both groups ( Table 6).

Mean±SD P value
Urea (mg/kg)

Discussion
The cornerstone of anesthetic management in supratentorial craniotomy is to provide optimal conditions for adequate resection of the tumour. The choice of peri-operative intravenous fluid plays a vital role in the metabolic status of the patients. The intravenous fluids with a near-normal plasma osmolarity tend to remain in the intravascular compartment reducing the likelihood of development of brain edema and raised intracranial pressure.
The most commonly used iso-osmolar fluid in neurosurgery is 0.9% normal saline (308 mOsm/L), which is easily available and has a decent safety record as long-term fluid therapy. However administration of 0.9% normal saline in large quantities is known to produce normal anion gap hyperchloremic metabolic acidosis [9]. PlasmaLyte A is an iso-osmolar balanced salt solution (295 mOsm/L) that contains organic acid buffers like acetate and gluconate and is physiologically very similar to plasma [10].
In our study, which is a double-blinded randomized study, we compared the effects of two near-normal isoosmolar fluids, PlasmaLyte A and 0.9% normal saline on the changes in metabolic status over a period of time. All the other possible factors affecting acid base balance such as hypoxia, hypercarbia, and MAP were continuously monitored. The patients in the study group were adequately ventilated maintaining a partial pressure of carbon dioxide (PaCO2) between 35 -45 mm Hg. In our study, we observed that the changes in electrolytes and pH were initially comparable in both PlasmaLyte A and 0.9% normal saline group. However, with the progression of time, significant acidosis was observed in Group B. There was also a significant increase in the serum chloride levels starting from T3 time interval to the T7 time.
A study done by Dey et al. found that the metabolic profile was better maintained with PlasmaLyte A when compared to 0.9% normal saline [11]. The brain relaxation score was well comparable in both their study groups. The authors used neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker that helps in early detection of acute kidney injury as early as six hours of clinical insult. They observed a significant rise in serum NGAL levels in the normal saline group and a significant difference in the urea and creatinine levels in both the groups on the fifth postoperative day though the values were within the normal physiological range in both their study groups. In our study we used serum urea, creatinine and urine output as clinical and biochemical parameters to assess acute kidney injury. We, however, did not find any significant difference in the serum urea and creatinine levels in both groups. It may be attributable to the fact that creatinine starts to rise 24 to 72 hours after the injury has occurred [12].
A study done by Roquilly et al. on brain-injured patients found that use of balanced solutions reduces the incidence of hyperchloremic metabolic acidosis [13].
Several other non-neurological studies have been done comparing the benefits and drawbacks of normal saline and PlasmaLyte A. Shaw et al. in their study compared the effect of 0.9% normal saline and PlasmaLyte A on postoperative morbidity after open abdominal surgeries. They concluded that the use of calcium-free balanced crystalloid solution for replacement of fluid losses was associated with less postoperative morbidity compared to 0.9% normal saline [14].
Semlar et al. compared the clinical effects of a balanced crystalloid solution and 0.9% normal saline in both critically ill and non-critically ill patients. They found that the use of a balanced crystalloid solution resulted in a lower rate of the composite outcome of death from any cause such as new renal replacement therapy or persistent renal dysfunction [15]. They also did a similar study in non-critically ill patients and concluded that balanced crystalloids resulted in a lower incidence of major adverse renal events within 30 days of hospital stay [16].
Yunos et al. in their study compared the effects of chloride liberal vs chloride restricted intravenous fluid administration in critically ill adults. They concluded that the implementation of chloride restrictive strategy in the ICU was associated with a significant decrease in the incidence of acute kidney injury and renal replacement therapy [17].
The available literature so far suggests that balanced crystalloid solutions are better than 0.9% normal saline. Hyperchloremia has also been found to cause coagulation abnormalities which have been studied by thromboelastography and platelet aggregometry [18]. It has also been shown that it influences renal function in the postoperative period by causing renal vasoconstriction and altering tubular chloride reabsorption [19]. Acidosis following hyperchloremia is also known to increase inflammatory markers in serum [19]. A study in elderly surgical patients showed that hyperchloremic acidosis may also impair splanchnic circulation [20].
Serum osmolarity was similar in both groups A and B. Maintaining serum osmolarity is a major concern in neurosurgical patients as hypo-osmolarity causes development of brain edema and thus a rise in intracranial pressure. The mean values in serum potassium also did not show any significant difference.
The major benefit while using PlasmaLyte A as an intravenous replacement fluid is its positive effect on acid base equilibrium particularly on serum chloride levels. However, the available literature so far has very little and inconclusive evidence, as far as association between acidosis and postoperative outcome is concerned. The disadvantage of PlasmaLyte A is that it is available at a higher cost compared to normal saline.
It was observed that the MAP, HR, and oxygen saturation (SpO2) readings were comparable in both groups. Serum chloride levels began to rise at the T3 time frame in Group B and remained significant throughout the study time frame. The pH also showed similar trends and began to decrease after the T2 time frame in Group B and remained below the normal level (7.35) throughout the end of the time frame. The rest of the biological parameters were comparable in both the study groups at all time intervals. There was a slight decrease in urine output in Group B at the T6 time frame. However, at the T7 time frame, the urine output was comparable in both the study groups. Urea and creatinine levels were comparable in both study groups at all time frames.
One of the major limitations of the present study is that we have taken creatinine to be a marker of acute kidney injury. It takes about 24 to 72 hours for creatine to rise in acute kidney injury. The study duration is 48 hours so there are chances that cases of acute kidney injury might have been missed. The most common biochemical marker for acute kidney injury is NGAL. NGAL detects acute kidney injury in as early as six hours. In the present study if NGAL had been used instead of creatinine, then early detection of acute kidney injury would have been possible [12].

Conclusions
Normal saline 0.9% when used as a sole intravenous fluid in supratentorial brain tumour surgeries has a higher probability to cause hyperchloremic metabolic acidosis when compared to PlasmaLyte A. The metabolic parameters are better maintained with PlasmaLyte A than normal saline.

Additional Information Disclosures
Human subjects: Consent was obtained or waived by all participants in this study. Institutional Ethics Committee, Rajendra Institute of Medical Sciences, Ranchi, Jharkhand issued approval Memo no. 249. Animal subjects: All authors have confirmed that this study did not involve animal subjects or tissue.

Conflicts of interest:
In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work.