The Clinical and Metabolic Derangements after Using 0.9% Normal Saline as Maintenance Intravenous Fluid in Children

Abstract

Background:

Isotonic fluids like 0.9% normal saline (NS) are recommended for maintenance intravenous fluid (mIVF) therapy in children. However, concerns exist regarding hyperchloremia and its associated complications, particularly in younger children.

Objective:

The objective of the study was to evaluate the clinical and metabolic effects of 0.9% NS as mIVF in noncritically ill pediatric patients.

Materials and Methods:

This longitudinal study included 80 children aged 1 month to 13 years admitted to a tertiary care center, who received 0.9% NS as mIVF for at least 50% of a 24-h period. Baseline and 48-h clinical and biochemical parameters were recorded and compared.

Results:

After 48 h, there was a significant decrease in heart rate, respiratory rate, blood urea, and serum creatinine, and a significant increase in blood pressure, serum sodium, potassium, and chloride (P < 0.05). Hyperchloremia was observed in 7.5% of children, all aged <5 years.

Conclusion:

0.9% NS may lead to significant clinical and metabolic changes, particularly hyperchloremia in younger children.

INTRODUCTION

Hypotonic solutions were widely accepted as the maintenance intravenous fluid (mIVF) of choice during the last 50 years, until more recent evidence demonstrated a clear association between the use of hypotonic fluids and iatrogenic hyponatremia-related morbidity and mortality.[,2,3,4] Consequently, isotonic solutions are now recommended by a number of practice guidelines as a safer and more appropriate empiric mIVF of choice in children.[,6,7,8,9,10,11,12,13]

Although hospital acquired hyponatremia may be reduced by isotonic fluids,[14,15] there is a growing concern about iatrogenic hyperchloremia. There is emerging evidence in both adult and pediatric populations that hyperchloremia is increasingly common following use of isotonic solutions as mIVF and may be associated with adverse outcomes. Hyperchloremia has been reportedly associated with acute kidney injury, coagulopathy, gastrointestinal dysfunction, and even increased mortality in critically ill adults and children.[,17,18,19,20] There is a scarcity of literature that has looked into this issue, especially in young children. Literature regarding the addition of maintenance potassium chloride to the intravenous infusion of 0.9% normal saline (NS) is also scarce. In this study, our objective was to determine the clinical and metabolic derangements after using 0.9% NS as an isotonic mIVF in pediatric patients.

MATERIALS AND METHODS

This longitudinal study was undertaken at a semi-urban tertiary care hospital for a period of 18 months. The study was approved by the institutional ethics committee, and informed consent from parents was taken before enrollment. Consecutive noncritically ill children between age groups 1 month to 13 years admitted to the pediatric ward whose treatment necessitated the use of 0.9% NS as m IVF and who had at least 50% of their calculated maintenance fluid for 24 h as IVF, were include in the study. The total amount of total daily fluid (oral + intravenous) administered was based on Holliday Segar formula, based on body weight.

Exclusion criteria were children with acute diarrheal disease with dehydration, nephrotic syndrome, on various drugs such as furosemide, hydrochlorothiazide, vasopressin or desmopressin, congestive cardiac failure, diabetes mellitus, acute or chronic liver failure, abnormal baseline serum sodium or metabolic acidosis (as per standard lab values), and those children whose treatment necessitated a shift to Pediatric Intensive Care Unit (PICU). The study used to calculate sample size was Malviya et al.[21] Assuming a power of 80% and 5% significance level, the sample size was calculated as 80. To allow for a potential recruitment failure rate, 560 children were assessed for eligibility for enrollment in the study. A pro forma containing socio-demographic variables, relevant history, and examination findings was filled. Baseline clinical variables like blood pressure (BP), heart rate (HR), and respiratory rate (RR) were noted, and blood was collected for metabolic variables such as serum sodium, potassium, chloride, blood urea, serum creatinine, and venous blood gas (VBG). Serum electrolytes were analyzed with direct potentiometry and VBG by blood gas analyzer. Children received 0.9% NS with potassium chloride (KCL) at the standard infusion rate for weight (20 meq of potassium/L). Repeat blood samples were taken 48 h after the intravenous infusion. Baseline BP, HR, RR, serum sodium, chloride and bicarbonate, blood urea, creatinine, pH, and lactate levels and changes in these variables 48 h after starting m IVF were documented. Standard normal lab values and those for hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypochloremia, hyperchloremia, acidosis, and alkalosis were defined. The range for each parameter was calculated as between ± 2 standard deviation (SD) from the mean baseline value. The value which fell beyond this range at 48 h after mIVF was considered abnormal.

The anonymity of the patient was maintained, privacy was ensured, and confidentiality of data was assured. An informed written consent, in a language that is familiar to them, was procured from the parents of the participants of the study. The study was commenced following approval from the Institutional Ethics Committee.

Statistical analysis

Categorical and quantitative variables were expressed as frequency (percentage) and mean ± SD, respectively, the normality of distributed data was tested using histogram and parametric test done. The paired t-test was used to compare paired samples for the continuous variables. Statistical analyses were performed using a statistical software package SPSS Statistics Version 23 (IBM Corp., Armonk, NY, USA). For all statistical interpretations, P < 0.05 was considered the threshold for statistical significance.

RESULTS

A total of 560 patients were assessed for eligibility in the study, of whom 408 were not eligible as they did not receive IVF (flow chart study plan). A total of 152 children fitting the inclusion criteria were enrolled in the study. Out of these, 72 were excluded based on exclusion criteria. A total of 80 children were finally included in the study [Figure 1]. The baseline clinical characteristics with the mean and SD for the clinical and metabolic variables are presented in Table 1. The etiological diagnosis of the study subjects included in the study is presented in Table 2. The proportion of patients with abnormal values was seen more in the <5-year age group compared to older children (5–13 years of age). The abnormal values with the highest proportion were for serum potassium, followed by diastolic BP (DBP), serum chloride, and serum sodium as presented in Table 3. The clinical and metabolic parameters after 48 h of mIVF showed a statistically significant difference from the baseline value so far as HR, RR, systolic BP (SBP), DBP, serum sodium, potassium, chloride, creatinine, and blood urea were concerned as detailed in Table 4. After 48 h of 0.9% NS as mIVF in noncritically ill pediatric patients; there was a statistically significant (P < 0.05) decrease in HR, RR, blood urea, and serum creatinine values from baseline. There was also a statistically significant (P < 0.05) increase in SBP and DBP, serum sodium, serum potassium, and serum chloride values from the baseline. Serum chloride in 6 (7.5%) study subjects was in the hyperchloremia range [Table 5]. None of the other values fell into the hyponatremia, hypernatremia, hypokalemia, hyperkalemia, hypochloremia, acidosis, and alkalosis range.

Figure 1.

Flow chart of the study plan

Table 1.

Baseline clinical characteristics

Characteristic	n=80, n (%)
Age
1 month–5 years	54 (67.5)
5 years–13 years	26 (32.5)
Sex
Male	40 (50)
Female	40 (50)
Clinical and metabolic parameters (mean±SD)
HR/min	118.2±25.9
RR/min	41.6±14.51
Systolic BP (mmHg)	93.80±7.792
Diastolic BP (mmHg)	55.05±7.073
Sodium (mEq/L)	137.3±2.69
Potassium (mEq/L)	4.169±0.590
Chloride (mEq/L)	103.2±2.707
Urea (mg/dL)	19.65±7.718
Creatinine (mg/dL)	0.351±0.118
PH	7.374±0.047
Bicarbonate (mEq/L)	21.29±3.745
PCO2 (mmHg)	38.16±7.747
Lactate (mmol/L)	1.664±0.630

SD=Standard deviation, BP=Blood pressure, HR=Heart rate, RR=Respiratory rate

Table 2.

Etiological diagnosis of the study subjects

Diagnosis	n (%)
Pneumonia/LRTI	37 (46.25)
Viral fever	11 (13.75)
Upper respiratory infection	9 (11.25)
HFMD/oral ulcers	8 (10.00)
Acute wheeze	5 (6.25)
Acute bronchiolitis	5 (6.25)
Dengue fever	2 (2.50)
Migraine	1 (1.25)
UTI	1 (1.25)
Meningitis	1 (1.25)

LRTI=Lower respiratory tract infection, HFMD=Hand, foot and mouth disease, UTI=Urinary tract infection

Table 3.

Clinical and metabolic parameters values in abnormal range (>2 SD) after 48 h

Clinical and metabolic parameters	Mean±2 SD (range)	Abnormal values, n (%)	Age 1 month–5 years, n (%)	Age 5–13 years, n (%)	Direction of change
HR/min	66.3–170.1	-	-	-
RR/min	12.58–70.6	-	-	-
Systolic BP (mmHg)	78.2–109.4	7 (8.75)	4 (57.14)	3 (42.86)	Increase
Diastolic BP (mmHg)	40.9–69.2	3 (3.75)	1 (33.3)	2 (66.6)	Increase
Sodium (mEq/L)	131.9–142.7	5 (6.2)	4 (80)	1 (20)	Increase
Potassium (mEq/L)	3.58–4.76	19 (23.7)	16 (84.0)	3 (15.8)	Increase
Chloride (mEq/L)	97.78–108.61	6 (7.5)	6 (100)	-	Increase
Urea (mg/dL)	4.21–35.08	1 (1.25)	1 (100)	-	Decrease
Creatinine (mg/dL)	0.115–0.587	1 (1.25)	-	1 (100)	Decrease
PH	7.28–7.468	-	-	-	-
Bicarbonate (mEq/L)	13.8–28.78	3 (3.75)	2 (66.6)	1 (33.3)	Decrease
PCO2 (mmHg)	23.21–53.11	3 (3.75)	1 (33.3)	2 (66.6)	Decrease
Lactate (mmol/L)	0.404–2.924	4 (5)	3 (75)	1 (25)	Increase

SD=Standard deviation, BP=Blood pressure, HR=Heart rate, RR=Respiratory rate

Table 4.

P value of clinical and metabolic parameters values baseline and after 48 h

Clinical and metabolic parameters	Baseline, mean±SD	After 48 h, mean±SD	P
HR/min	118.2±25.95	105.5±16.82	0.000
RR/min	41.6±14.51	33.94±8.475	0.000
Systolic BP (mmHg)	93.80±7.792	96.78±7.594	0.000
Diastolic BP (mmHg)	55.05±7.073	57.7±6.147	0.000
Sodium (mEq/L)	137.3±2.689	139±2.152	0.000
Potassium (mEq/L)	4.169±0.590	4.31±0.537	0.046
Chloride (mEq/L)	103.2±2.707	104.1±3.532	0.017
Urea (mg/dL)	19.65±7.718	16.43±6.838	0.000
Creatinine (mg/dL)	0.351±0.118	0.30±0.110	0.001
PH	7.374±0.047	7.283±0.825	0.333
Bicarbonate (mEq/L)	21.29±3.745	22.12±4.122	0.116
PCO2 (mmHg)	38.16±7.474	38.53±7.647	0.732
Lactate (mmol/L)	1.664±0.630	1.661±0.881	0.981

SD=Standard deviation, BP=Blood pressure, HR=Heart rate, RR=Respiratory rate

Table 5.

Incidence of hyperchloremia at 48 h

Serum chloride (mEq/L)	108–109	≥110	Total (n=5), n (%)
n=80	2	4	6 (7.5)

DISCUSSION

The study included children between 1 month to 13 years with an equal number of males and females. 47.5% (38 out of 80) participants were between 1 month and 5 years old, with more females than males in this age group. Pneumonia was the most common diagnosis (46.25%), followed by viral fever (13.75%) and upper respiratory tract infection (11.25%) [Table 4].

This study found a statistically significant change in HR and RR after 48 h of 0.9% IVF therapy. The HR decreased significantly from 118.2 ± 25.95 before IVF to 105.5 ± 16.82 after IVF. Similarly, the RR decreased significantly from 41.63 ± 14.51 before IVF to 33.94 ± 8.47 after IVF. However, neither the HR nor the RR showed a change >2 SD from baseline.

In this study 8.75% of patients, there is elevation in SBP >2 SD, and 3.75% patients, there is an increase in DBP >2 SD. Increase in the SBP is more pronounced in females than in males and is nearly the same in both age groups under 5 years and over 5 years. Increase in the DBP is higher in females and >5 years old compared to <5 years. Both increases in SBP and DBP are statistically significant. SBP significantly increases after IVF administration (96.78 ± 7.59) compared to before IVF administration (93.80 ± 7.79). DBP also significantly increases after IVF administration (57.70 ± 6.14) compared to before (55.05 ± 7.07). Earlier research has revealed variable effects on BP, with some studies not reporting an increase in BP like Malviya et al.[21] When compared to isotonic fluids, Choong et al. found that 1.54% of children receiving hypotonic fluids developed new-onset hypertension.[22]

In this study, 6.2% of patients exhibited a >2 SD increase in serum sodium levels after 48 h of mIVF, mostly in males under 5 years old. Sodium levels increased after IVF administration (139.0 ± 2.15) compared to before (137.3 ± 2.68), which was statistically significant. There were no occurrences of notable hypo- or hypernatremia in this study. In the study by Malviya et al., the increase in serum sodium from baseline to 48 h (P = 0.017) was significant like in our study.[21] Choong et al.[22] and Kannan et al.[8] studies have revealed a negligible risk of hypernatremia and a decreased risk of hyponatremia after 0.9% NS as isotonic mIVF. Studies of Sen et al.[23] noted significant changes in serum sodium after isotonic saline administration, particularly in critically ill patients. In the majority of research, isotonic and hypotonic fluids have been compared.[,9,10,11,12,13] Saba et al. randomized 16 children to receive 0.9% NS and 21 children to receive 0.45% NS as maintenance IVFs, monitoring the alteration in serum sodium as the main outcome. Serum sodium was assessed at baseline and 12 h later. Results indicated an increase in serum sodium in 0.9% NS group compared to the 0.45% NS group. The difference between the two groups was not found to be statistically significant.[24] In a related study, Bagri et al.[25] discovered that children receiving 0.9% NS had higher serum sodium levels at 24 h compared to those receiving 0.45%NS (P < 0.01). But at 48 h, there was no significant difference in serum sodium between the two groups, nor were there any cases of symptomatic hypo-or hypernatremia. Likewise, Kumar et al.[26] documented notable alterations in serum sodium levels at 12 and 24 h compared to baseline in the group receiving isotonic solution (12 h: P =0.005; 24 h: P < 0.001). However, there were no occurrences of notable hypo- or hypernatremia, like in our study.

In this study, 17.5% of children had a >2 SD increase in serum potassium levels after 48 h of IVF infusion. Potassium levels increased after IVF administration (4.31 ± 0.53) compared to before (4.169 ± 0.590), which is statistically significant. Most of these children were under 5 years old, with a majority under 1 year and a predominance of males but there were no cases of hyperkalemia. A possible reason for this increase could be the addition of KCL to the maintenance IVF at our hospital. No other study has analyzed the changes in potassium. We postulated that the increase could be secondary to extracellular shifting of potassium as a result of hyperchloremia.

In the present study, 7.5% of patients had a >2 SD increase in chloride after 48 h of IVF administration (104.1 ± 3.53) compared to before (103.2 ± 2.70), which is statistically significant and comparable to the study by Malviya et al.[21] All of these patients in our study were children under 5 years old, with most being males, and 4 (5%) had serum chloride ≥110 meq/L and 6 had serum chloride ≥108 meq/L. Previous reports have documented significant hyperchloremia following 0.9% NS in adults,[,18,19,20,23] but there are limited data about pediatric cases. Lima et al.[27] conducted a comparison between 0.9% NS and balanced crystalloid in 49 pediatric patients undergoing neurosurgery. There was a marked increase in serum chloride levels compared to the initial measurement in the 0.9% saline group (P < 0.01). Furthermore, the occurrence of hyperchloremic metabolic acidosis was more prevalent in the saline-treated group following surgery (P = 0.02). Bulfon et al.[28] conducted a retrospective study with 543 PICU patients who received minimum 50% of total maintenance fluid intravenously, as 0.9% NS, during the first 24 h. It found that the occurrence of hyperchloremia was 94.9%, and the incidence of hyperchloremic metabolic acidosis was 38.9% at 72 h of admission. Evidence suggests that using 0.9% NS for resuscitation increases the likelihood of hyperchloremia and hyperchloremic metabolic acidosis, which supports the use of balanced solutions in the adult population.[17,19,20,29] Earlier research has shown notable mortality and morbidity associated with hyperchloremia, mainly because of its impact on kidneys.[,18,19,20,23,28,29,30] Hyperchloremia might impair the reabsorption of chloride in PCT, enhancing chloride transport to the distal nephron. This leads to a negative feedback mechanism causing vasoconstriction of afferent renal vessels, which reduces renal perfusion and can result in kidney injury and failure.[30]

Blood urea levels decreased after IVF administration (16.43 ± 6.83) compared to before IVF (19.65 ± 7.71). Similarly, serum creatinine levels decreased after IVF administration (0.30 ± 0.11) compared to before IVF (0.35 ± 0.11). The change in both urea and creatinine levels was statistically significant.

The change in VBG pH after IVF administration was not statistically significant. The pH after IVF administration (7.28 ± 0.82) was almost the same as before IVF administration (7.37 ± 0.04). The bicarbonate level was nearly unchanged after IVF administration (22.12 ± 4.122) compared to before (21.29 ± 3.745). Similarly, carbon dioxide levels also showed minimal change after IVF administration (38.53 ± 7.647) compared to before (38.16 ± 7.47). In other words, there was no statistically significant difference in HCO₃ and CO₂ in VBG after IVF administration. There was no statistically significant change in lactate levels after IVF administration (1.66 ± 0.88) compared to before (1.66 ± 0.63).

One of the limitations of the study was the study design; a randomized controlled trial would have had more significance. Furthermore, there is the risk of unaccounted confounding associated with the observational design of the study. While we powered our study adequately, we acknowledge the potential for imprecision given the relatively small number of patients. We did not address the quantitative relevance of fluids administered as drug diluents and to guarantee catheter patency, the so-called fluid creep. There was an unexpectedly low volume of crystalloids, as mIVF is usually deescalated to oral as soon as child improves. However, we ensured that a minimum of 50% of mIVF was given to all study subjects. Finally, our findings are limited to one center and hence may not be generalizable. The strengths of the study were that there were well-defined inclusion and exclusion criteria which were strictly adhered [Figure 1]. There was a uniform fluid strategy based on weight, and none of the children received fluid bolus as part of fluid resuscitation. We did a sequential evaluation of the variables, which may provide more relevant information than an isolated measurement.

Based on results, hyperchloremia could be a major electrolyte abnormality following 0.9% NS as mIVF in noncritically ill patients. In addition, 0.9%NS as mIVF does lead to statistically significant alterations in clinical parameters and certain metabolic parameters like serum sodium, chloride, potassium, urea, and creatinine. Hyperchloremia was seen in younger children. While providing a high level of evidence, this study does not give a definitive answer. The most appropriate mIVF type in children is still debatable. Although the most recommended and widely used isotonic mIVF fluid has been 0.9% NS, increased incidence of adverse effects like hyperchloremic metabolic acidosis cannot be ignored more so in centers with a large number of patients requiring mIVF with resource limited settings of patient monitoring.

CONCLUSION

Use of 0.9% normal saline can lead to notable clinical and metabolic disturbances, with younger children being particularly prone to developing hyperchloremia.

Conflicts of interest

There are no conflicts of interest.

Funding Statement

Nil.