Effect of intraoperative Hartmann's versus hypotonic solution administration on FLACC pain scale scores in children: A prospective randomized controlled trial.

BACKGROUND: In healthy children, an isotonic solution containing no glucose or a small amount of glucose (1-2%) has been recommended as an intraoperative maintenance fluid due to the potential risk of hyponatremia associated with hypotonic solutions. However, a hypotonic solution with glucose is still widely used as a maintenance fluid for pediatric anesthesia. We speculated that the hypotonic solution may worsen postoperative discomfort and irritability in pediatric patients due to hyponatremia. PATIENTS AND METHODS: In the current study, we compared the post-operative Face, Legs, Activity, Cry, Consolability(FLACC) scale scores of pediatric patients aged 3-10 years who received either a 1:2 dextrose solution or Hartmann's solution during Nuss Bar removal.
RESULTS: The FLACC scale score in the post-anesthesia care unit was higher in the 1:2 dextrose solution group(HYPO) (n = 20) than in the Hartmann's solution group(ISO) (n = 20) (6.30 vs 4.70, p = 0.044, mean difference and 95% Confidence Interval(CI) was 1.6 (0.04 to 3.16)). We also compared opioid consumption at the post-anesthesia care unit. Total dose of fentanyl per body weight in the post-anesthesia care unit was also higher in the HYPO (0.59 vs 0.37 mcg/kg, p = 0.042, mean difference and 95% CI was 0.22 mcg/kg (0.030 to 0.402)).
CONCLUSIONS: Intraoperative use of the hypotonic solution in children causes increased FLACC scale scores, leading to higher opioid consumption in post-anesthesia care unit.

RCT Entities:   Population Interventions Outcomes

Introduction

In healthy children, an isotonic solution containing no glucose or a small amount of glucose (1–2%) has been recommended as an intraoperative maintenance fluid due to the potential risk of hyponatremia associated with hypotonic solutions [1]. A recent systematic review discussed, however, that the existing evidence does not suffice to conclude on the optimal intraoperative fluid for children [2]. Moreover, some current practice guidelines recommend a hypotonic solution as a pediatric intraoperative maintenance fluid [3,4]. As a result, a hypotonic solution with glucose is still widely used as a maintenance fluid for pediatric patients, including in the author’s institution [5]. It is based on a traditional recommendation by Holiday-Segar [6]. However, hypotonic solution could decrease plasma sodium level during induction of general anesthesia [7].We speculated that the hypotonic solution may worsen postoperative discomfort and irritability in pediatric patients due to hyponatremia. In this regard, we hypothesized that infusion with the hypotonic solution may increase patient discomfort in the immediate postoperative period.

Patients and methods

This study was a pragmatic, single-blind, single-center, prospective, randomized controlled trial performed in two parallel groups. It was pragmatic because we used the same infusion protocol for fluids and opioids that we use in current clinical practice. The study protocol was approved on December 16, 2015, by the institutional review board of St. Mary’s Hospital, Seoul, Korea (KC16MISI0682), and was registered with the Clinical Research Information Service (http://cris.nih.go.kr, KCT0002199). The authors confirm that all ongoing and related trials for this intervention are registered. Registering of the current study was delayed after patient enrollment of participants started because of miscommunication between authors. Written informed consent was obtained from the parents or legal guardians of the participants.

We collected data from pediatric patients who underwent a Nuss bar removal operation between February 2016 and December 2016. Patient recruitment was done between February 2016 and October 2016. Follow-up was not necessary for the current study. Inclusion criteria were age between 3 and 10 years, American Society of Anesthesiologists physical status I, and only one Nuss bar in the chest. Patients with any other comorbidities and preoperative laboratory abnormalities were excluded. We chose Nuss bar removal as the study operation because only one experienced surgeon performs it at our institution and the procedure is highly standardized, meaning that operation times, intraoperative blood loss, and the dose of anesthetic agents and infused fluid were relatively constant with minimal variability among patients.

We compared the effects of an intraoperative 1:2 dextrose solution (hypotonic dextrous solution) with Hartmann’s solution(isotonic solution) on the postoperative FLACC scale scores and the change in plasma sodium and glucose immediately prior to and following surgery.

Plasma sodium and glucose levels were assessed the day before surgery (T0; preoperative baseline values), immediately prior to the surgery (T1), and at the end of surgery before awakening the patient (T2).

As a primary outcome, we assessed the FLACC scale to evaluate irritability in the post-anesthesia care unit(PACU). The FLACC scale is simple, well-validated, and minimally affected by interpersonal variation [8]. Nurses measured the FLACC scale score at 30 min after the patient arrived at the PACU. In the PACU, 0.5 mcg/kg of fentanyl was given when the FLACC scale score was more than three. If the patient’s irritability was not ameliorated (FLACC scale score ≥ 3) after 5 min, 0.25 mcg/kg of additional fentanyl was given.

The patients were blinded, but the practitioner and observer were not. The patients were randomly assigned to either a HYPO or an ISO in a 1:1 ratio by random numbers generated with “https://www.graphpad.com/quickcalcs/randomize2/”. Group allocation was coded and concealed in opaque sealed envelopes until the statistical analyses were completed. The blinding and allocations were done by another anesthesiologist who did not participate in the trial.

All patients arrived at the preoperative waiting room under the administration of hypotonic dextrous solution. In the preoperative waiting room, the fluid was changed to isotonic solution if the patient was assigned to the ISO. Compositions of the hypotonic dextrous solution and isotonic solution are explained in Table 1.

Table 1

Composition of the study fluids.

	Isotonic solution	Hypotonic solution
Sodium; mEq/l	130	51.3
Chloride; mEq/l	109	51.3
Glucose; g/l	0	33.3
Potassium; mEq/l	4	0
Calcium; mEq/l	2.7	0
Lactate; mEq/l	28	0

As blood loss is negligible during Nuss bar removal in the author’s institution, intraoperative fluid is given as 4 mL/kg/h for bodyweight up to 10 kg, 2 mL/kg/h for 10 to 20 kg body weight, 1 mL/kg/h for body weight over 20 kg. For the first hour of surgery, the supplement dose is the total maintenance dose of the first half of the fasting period. For the rest of the surgery, the supplement dose is one-quarter of the entire fasting period (8 h) [9]. The patients were sedated with 1.5 mg/kg ketamine i.v. in the preoperative waiting room. After they were transferred to the operating room, 1 μg/kg fentanyl and 0.6 mg/kg rocuronium were administered before endotracheal intubation. Anesthesia was maintained with one minimum alveolar concentration of sevoflurane.

To minimize risks to the patient, we set the plasma sodium level limit between 125 mEq/l and 150 mEq/l, and the plasma glucose level limit between 80 mg/dL and 300 mg/dL. If any value measured at the preoperative period or after anesthetic induction exceeded these limits, the patient was to be excluded from the study and appropriate measures were to be undertaken to restore the patient’s state.

The primary outcome of this study was the FLACC scale score. The FLACC scale score of 50 pediatric patients in the PACU after Nuss bar operation in our institution was 6.7 ± 1.8. A sample size of 20 per group was required to detect a 25% difference in FLACC scale score between the two groups with a 2-sided test using α = 0.05 and β = 0.2, allowing for a 10% drop-out rate.

GraphPad Prism version 7.03 for Windows (GraphPad Software, La Jolla, CA, www.graphpad.com) was used for statistical analyses. Data are given as mean ± standard deviation, or median (range) (for non-normal distributions). A p-value < 0.05 was considered to be significant. All reported p-values are based on two-sided tests. For plasma sodium and glucose level at T0, T1, and T2, we performed a repeated measures 2-way ANOVA to determine differences between the groups and over time. For other values, between-group differences were assessed using Student’s t-test or Mann-Whitney U test, when appropriate. The correlations between the FLACC scale score and sodium level at baseline and after the anesthetic induction were analyzed using Pearson’s correlation coefficient.

Results

Of the 95 patients who underwent a Nuss bar removal during the study period, 55 were excluded (not meeting inclusion criteria, n = 38; declined to participate, n = 17). Forty patients were finally enrolled and analyzed (Fig 1). Patients’ characteristics are shown in Table 2.

Fig 1

Consort flow chart.

Table 2

Baseline characteristics of patients.

	HYPO (n = 20)	ISO (n = 20)
Age; years	6(4–10)	6(5–10)
Height; cm	117.9(104.0–136.5)	117.6(103.1–143.0)
Weight; kg	21.7(16.2–36.9)	23.3(16.7–35.1)
Sex; male	15	16
Total anesthesia time; minutes	72.5(38–110)	75(40–95)
Infused fluid per bodyweight; ml/kg	6.1(3.3–9.1)	6.3(3.4–7.9)

Values are median(Range)

There were no adverse events, and all 40 patients enrolled in the study completed the procedures. Total anesthesia time (p = 0.84) and infused fluid per bodyweight (p = 0.76) were comparable between the groups (Table 2). The minimum and maximum sodium values were 132 and 143 mEq/l, and the minimum and maximum glucose values were 86 and 204 mg/dL, respectively.

There were statistically significant differences in the FLACC scale scores in the PACU between the two groups (Fig 2). The mean score was 1.34 times higher in the HYPO. Mean ± SD was 6.30 ± 2.39 in the HYPO and 4.70 ± 2.47 in the ISO (p = 0.044). Mean difference and 95% Confidence Interval(CI) was 1.6 (0.04 to 3.16). There was a weak negative correlation between the FLACC scale score and sodium level after the induction of anaesthesia (r = -0.32, p = 0.043) and at the end of surgery (r = -0.35, p = 0.025). In the HYPO, the correlation between the FLACC scale score and sodium level was higher after anesthesia induction (r = -0.4798, p = 0.032).

Fig 2

Face, Legs, Activity, Cry and Consolability(FLACC) scale score in PACU.

Asterisk(*) represents statistically significant values between the two groups.

The total dose of fentanyl given at PACU was also statistically higher in the HYPO (Fig 3). Fentanyl was given to 17 of 20 patients in the HYPO and 13 of 20 patients in the ISO. The mean dose of fentanyl was 1.58 times higher in the HYPO. Mean ± SD was 0.59 ± 0.31 in the HYPO and 0.37 ± 0.26 in the ISO (p = 0.042). Mean difference and 95% CI was 0.22mcg/kg (0.030 to 0.402).

Fig 3

Fentanyl per body weight at PACU.

Asterisk(*) represents statistically significant values between the two groups.

Mean plasma sodium level decreased after the induction of anesthesia (T1) in both groups, and it had not recovered by the end of surgery (T2) (Fig 4). In the HYPO, plasma sodium level decreased by 6.4 mEq/l at T1 and by 6.0 mEq/l at T2. In the ISO, plasma sodium level decreased by 3.45 mEq/l at T1 and 2.85 mEq/l at T2. Mean plasma sodium level was significantly lower in the HYPO at both T1 and T2 (Table 3).

Fig 4

Plasma sodium concentration.

Solid line: HYPO. Dashed line: ISO. Asterisk(*) represents statistically significant values between the two groups.

Table 3

Mean and SD of plasma sodium and glucose level at T0, T1, and T2.

	HYPO	ISO	Mean difference	CI	P-value
Sodium_T0	141.2 ± 1.11	141.1 ± 1.41	0.10	-1.20 to 1.40	0.99
Sodium_T1	134.8±1.51	137.7 ± 2.11	-2.90	-4.15 to -1.55	<0.0001 (*)
Sodium_T2	135.2 ± 1.94	138.2 ± 1.91	-3.00	-4.35 to -1.75	<0.0001 (*)
Glucose_T0	108.5 ± 15.33	101.4 ± 11.55	7.15	-11.27 to 25.27	0.73
Glucose_T1	149.5 ± 32.23	109.0 ± 19.67	40.55	22.28 to 58.82	<0.0001 (*)
Glucose_T2	143.4 ± 38.6	102.1 ± 11.3	41.30	23.03 to 59.57	<0.0001 (*)

Mean plasma glucose level increased significantly in the HYPO after anesthesia induction (Fig 5). Plasma glucose level in the HYPO increased from 108.5 mg/dL to 149.5 mg/dL at T1. It slightly decreased at T2 but remained significantly higher than that at T0 (143.4 mg/dL vs 108.5 mg/dL). In the ISO, mean plasma glucose levels were not changed significantly after anesthesia induction or at the end of surgery. Mean plasma glucose level was significantly higher in the HYPO at both T1 and T2(Table 3).

Fig 5

Plasma glucose concentration.

Solid line: HYPO. Dashed line: ISO. Asterisk(*) represents statistically significant values between the two groups.

Discussion

Acute hyponatremia should be avoided in children because they are more vulnerable to brain swelling due to an increased brain-to-skull size ratio and smaller intracerebral volume of cerebrospinal fluid than adults, which can lead to headache, nausea, vomiting, confusion, and even death [10]. Hypotonic solutions are still prevalently used as a pediatric maintenance fluid [1,5,10-12], however, despite the fact that it can potentially induce hyponatremia.

In the present study, patients treated with a hypotonic solution showed an increased postoperative FLACC scale score compared to those treated with the Hartmann solution. Furthermore, fentanyl use was also higher in the HYPO, which highlights the clinical significance of our results. This is the first published study, to our knowledge, to have examined this issue. In this regard, our results add to the disadvantages of the intraoperative use of hypotonic solutions.

The suspected mechanism underlying the present results is that hyponatremia induced by intraoperative hypotonic solution administration may have caused patient discomfort and irritability, leading to increased FLACC scale scores, because hyponatremia may induce irritability and various types of discomfort including headache, chest/abdominal pain, and restlessness [13]. As the basis for this assumption, there was a weak correlation between plasma sodium level at T1 and FLACC scale score in the PACU. Although the FLACC scale is designed for evaluating pain [14], facial grimacing, uneasiness or leg kicking, increased activity, crying, and difficulty consoling the patient (which are the five components of the FLACC scale scoring system) that increase the FLACC score can also be caused by patient discomfort and irritability as a manifestation of hyponatremia.

In the current study, even the short-term use of hypotonic dextrous solution infused during surgery was associated with increased plasma glucose levels and decreased plasma sodium levels. Plasma sodium was abruptly reduced during the induction of anesthesia; which was in line with the findings of a recent observational study [7]. The lowest sodium value in the ISO was 135 mEq/l, suggesting that Hartmann’s solution is safer than 1:2 dextrose saline with regard to hyponatremia.

One to two dextrose saline contains 3.3% glucose. While the infusion of fluid without glucose during surgery prevents hyperglycemia [15], there is a risk of hypoglycemia and ketoacidosis. On the other hand, hyperglycemia can increase hypoxic cerebral injuries in pediatric patients and a 5% glucose solution is associated with severe hyperglycemia [16]; thus, solutions containing smaller amounts of glucose are highly preferable [17]. In the current study, the hypotonic dextrous solution increased glucose levels by approximately 37% after anesthesia induction, but they remained relatively constant in the ISO. While the HYPO did exhibit a much higher mean glucose level than the ISO, it was still within the acceptable range. Additionally, both groups exhibited slightly reduced mean glucose levels at the end of surgery.

If we had used 0.9% saline as a maintenance fluid for the control group, the difference of FLACC scale scores could have been larger in degree. However, 0.9% saline is associated with hyperchloremic metabolic acidosis and adverse postoperative outcomes, such as acute kidney injuries [18].

The current study had some limitations. First, it was single-, not double-, blinded (the practitioner and observer were not blinded). However, we did take steps to minimize bias. We used the same volume of fluid and opioid management protocol that we routinely use in our institution and the nurses who obtained the FLACC scale scores were not aware that the children were involved in a clinical trial. Second, we used ketamine to prevent patient anxiety in the preoperative waiting room, which may also have influenced agitation and pain at the PACU. The dose of ketamine, however, was the same between the groups, resulting in an equal contribution of its effect on both groups. Third, we did not measure plasma sodium levels in the PACU, which may have further elucidated the relationship between plasma sodium levels and the FLACC score.

Conclusions

Intraoperative use of hypotonic dextrous solution for children caused an increased FLACC pain score, leading to higher opioid use in the acute postoperative period. After confirming this result, we changed our standard clinical procedure. We now use Hartmann’s solution instead of hypotonic dextrose solution as the standard intraoperative maintenance fluid in children aged > 1 year.

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31 Dec 2019

PONE-D-19-19250

Effect of intraoperative Hartmann’s versus hypotonic solution administration on FLACC pain scale scores in children: a prospective randomized controlled trial

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Reviewer #1: Requires a major restructuring

This paper appears to address an important clinical question which has been carefully investigated but cannot be accepted in its current form. The main research question addresses the difference in FLACC score between the two solution groups but this is not given sufficient prominence in the main Results section. Instead, this comparison is somewhat lost among the complex description of less important items. In the Abstract however, it is correctly emphasised as the key comparison.

Points to consider

Line

General It would simplify the presentation if ‘Dextrose solution group’ and ‘Hartmann’s solution’ could be given acronyms, say DEXT and HART, which would then simplify the subsequent text.

32 Move both (n = 20) to Results section of the Abstract

34 Very important that the difference in FLACC mean scores between the groups is quoted together with the 95% CI

34 Usual to quote p-values to two significant figures only – here 0.044

36 Very important that the difference in fentanyl dose mean scores between the groups is quoted together with the 95% CI

36 Usual to quote p-values to two significant figures only – here 0.042

Table 1 Although it is not wrong here to quote mean and standard deviation, here it is usually more informative for the reader to quote mean and range here.

134 -160 Much of this would be better presented in tabular form. As it is, it makes very confusing reading.

General I have counted 18 statistical tests reported in this paper. That is one for every two patients recruited. This is far too many, testing should be confined to the main outcome measures FLACC and Fentanyl and possibly one or two more. The rest of the comparisons should be only made descriptively.

Figs 4 & 5 What is more important than the above comment is that these Figures and their associated text in the Results section should be given more prominence and moved to near the beginning of the results section. To me this is the major flaw in this otherwise good paper.

Reviewer #2: A recommendation has been published to use hypotonic solutions during operations,

rather than isotonic solutions. The authors have conducted a randomized clinical trial in

40 patients in which Group 1 was assigned to a solution that was 1:2 dextrose (hypotonic) versus

Group 2, Hartmann's solution which is 1:2 dextrose [what these ratios actually mean is not

explained.] (isotonic) The published recommendation states that isotonic solutions are

associated with hyponatremia. The primary endpoint is the FLACC scale, which reflects

levels of observed discomfort in the patient. Larger values on the scale indicate more

discomfort. The main conclusion of the paper is that the isotonic (Hartmann's) solution

is better.

The authors appear to stress that the main difference between the solutions is the dextrose

ratios. But are there other constituents of the solutions (NaCl, calcium, etc) which might

account for the observed difference. This may need to be included in the discussion.

The authors should state and describe more clearly which solutions are isotonic and

which are hypotonic, and label them as such in tables and graphs.

There are multiple other outcomes of interest. However there is no indication in the

stat methods section that there was (or wasn't) an adjustment for multiple comparisons.

Whichever it was should be stated clearly.

Reviewer #3: This is an interesting study.

Please refer to the following suggestion to make a good article.

Please list the constitution (sodium, potassium, glucose concentration, and etc) of the two infusions in new table.

Reviewer #4: This is an interesting manuscript where the authors demonstrate that a change from hypotonic to a near isotonic perioperative solution decreases hyponatremia and pain. There are areas of the manuscript that are unclear or could be better explained. Below are my comments.

In both the abstract and the manuscript, the rationale for why 1 – 2% dextrose solution was being used is poorly explained. There really is no rational for it. It is sufficient to say that it has been common practice to administer hypotonic fluids to children intraoperatively based on previous recommendation by Holiday-Segar, or something like that. It is really based on tradition and no sound physiology. Reference 5 is not listed and I doubt it exists. Reference 6 is an outlier and is not reflective of the majority of studies.

In both the abstract and the methods, the design of the study is not explicitly stated. It should explicitly state to compare an intraoperative hypotonic solution with dextrose to Hartmann’s solution to evaluate the FLACC scale score and the change in serum sodium and glucose immediately prior to and following surgery. Or something like that.

Please explain clearly what 1:2 dextrose solution is. What is the dextrose concentration of this fluid and what is the sodium and potassium concentration of this fluid.

The TO, T1 an T2 time points along with what is being measured needs to occur earlier in the methods and be more explicit.

It is not clear what the term waiting room mean. Better to say the preoperative waiting room and recovery room.

The limits of 125 – 150 are too broad. There were probably no patient with a serum sodium of between 125 – 130. The were no patients with a serum sodium < 130 with the lowest sodium in the group 132. Probably better to change this to 130 – 150. Everyone may have had a normal serum sodium at T0, so you could also say 135 -145 if it was true.

The statement about desalinization does not make any sense and should be removed. Saline is no more likely to call desalinization then a more hypotonic fluids and is not a reason not to use it.

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Reviewer #1: Yes: David Machin

Reviewer #2: No

Reviewer #3: Yes: Kentaro Ouchi

Reviewer #4: No

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11 Feb 2020

Response to Reviewers

To Editor :

As per the journal’s editorial policy, please include in the Methods section of your paper:

a) your reasons for your delay in registering this study (after enrolment of participants started);

:It was because of miscommunication between authors. We thought the trial was registered but it was not. After we found it, we registered the study at once. ( line 65-66 )

b) confirmation that all related trials are registered by stating: “The authors confirm that all ongoing and related trials for this drug/intervention are registered”.

:We added the suggested sentence. ( line 64-65 )

Please also ensure you report the date at which the ethics committee approved the study as well as the complete date range for patient recruitment and follow-up in the Methods section of your manuscript.

:We added an arrival date by the ethics committee. ( line 62 )

: We added the complete date range for patient recruitment. Follow-up of the patient was not necessary because the study was done only in the operation room and the post anesthesia care unit. We also mentioned it. ( line 69-70)

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

: We deposited the data to public repository. (DOI : http://dx.doi.org/10.17632/63mbdj7dyd.2 )

: To mask the patients’ information, We omitted the operation date and rearranged the order of data.

________________________________________

To : Reviewer #1

General It would simplify the presentation if ‘Dextrose solution group’ and ‘Hartmann’s solution’ could be given acronyms, say DEXT and HART, which would then simplify the subsequent text.

: We assign “HYPO” to 1:2 Dextrose solution group and “ISO” to Hartmann’s solution group. We think it is more appropriate to use “HYPO” instead of “DEXT” because the primary interest of the current study is sodium.

32 Move both (n = 20) to Results section of the Abstract

: We modified the manuscript as suggested by Reviewer #1 (line 34)

34 Very important that the difference in FLACC mean scores between the groups is quoted together with the 95% CI

: We add the difference in FLACC mean scores between the groups together with the 95% CI both in abstract and result section as suggested by Reviewer #1 ( line 35, line 146-147 )

34 Usual to quote p-values to two significant figures only – here 0.044

: We modified the manuscript as suggested by Reviewer #1 ( line 35 )

36 Very important that the difference in fentanyl dose mean scores between the groups is quoted together with the 95% CI

: We add the difference in fentanyl dose mean scores between the groups together with the 95% CI as suggested by Reviewer #1 ( line 38, 154 )

36 Usual to quote p-values to two significant figures only – here 0.042

: We modified the manuscript as suggested by Reviewer #1 ( line 37,154 )

Table 1 Although it is not wrong here to quote mean and standard deviation, here it is usually more informative for the reader to quote mean and range here.

: We substitute range for standard deviation as suggested by Reviewer #1. ( line 99 )

: We remove preoperative plasma sodium & glucose value. We moved them into table 3. We add Total anesthesia time and infused fluid per bodyweight into the table.

: We made a correction for note of the table. The values in the table are median, not mean.

134 -160 Much of this would be better presented in tabular form. As it is, it makes very confusing reading.

General I have counted 18 statistical tests reported in this paper. That is one for every two patients recruited. This is far too many, testing should be confined to the main outcome measures FLACC and Fentanyl and possibly one or two more. The rest of the comparisons should be only made descriptively.

: We rewrite most of the results section to follow Reviewer #1’s recommendation. We also made a table 3 for plasma sodium and glucose level. ( line 162-175 )

Figs 4 & 5 What is more important than the above comment is that these Figures and their associated text in the Results section should be given more prominence and moved to near the beginning of the results section. To me this is the major flaw in this otherwise good paper.

: We re-arrange the mentioned paragraph into the beginning of the results section as suggested by Reviewer #1. Fig 4 & 5 are now Fig 2 & 3. ( line 144-160 )

________________________________________

To : Reviewer #2

The authors appear to stress that the main difference between the solutions is the dextrose ratios. But are there other constituents of the solutions (NaCl, calcium, etc) which might account for the observed difference. This may need to be included in the discussion.

: The constitution of the two infusions is explained in the new table, Table 1.

: The main difference between the solutions is the concentration of sodium and we discuss the risk of the low sodium concentration solution in Discussion section.

The authors should state and describe more clearly which solutions are isotonic and which are hypotonic, and label them as such in tables and graphs.

: We assign “HYPO” to 1:2 Dextrose solution group and “ISO” to Hartmann’s solution group.

: Also we assign “hypotonic dexterous solution” to 1:2 Dextrous solution and “isotonic solution” to Hartmann’s solution.

: We change or add labels in tables and graphs as recommended by reviewer #2

There are multiple other outcomes of interest. However there is no indication in the stat methods section that there was (or wasn't) an adjustment for multiple comparisons.

Whichever it was should be stated clearly.

: We used repeated measure 2-way ANOVA for multiple comparisons. We re-write the paragraph for statistics and include a sentence as follow :

: “For plasma sodium and glucose level at T0, T1, and T2, we performed a repeated measures 2-way ANOVA to determine differences between the groups and over time.” ( line 121-123 )

________________________________________

To :Reviewer #3

Please list the constitution (sodium, potassium, glucose concentration, and etc) of the two infusions in new table.

: The constitution of the two infusions is explained in the new table, Table 1. ( line 99 )

________________________________________

To: Reviewer #4

In both the abstract and the manuscript, the rationale for why 1 – 2% dextrose solution was being used is poorly explained. There really is no rational for it. It is sufficient to say that it has been common practice to administer hypotonic fluids to children intraoperatively based on previous recommendation by Holiday-Segar, or something like that. It is really based on tradition and no sound physiology.

: To follow the recommendation from reviewer #4, we add sentences and references as below.

: “It is based on a traditional recommendation by Holiday-Segar[6]. However, hypotonic solution could decrease plasma sodium level during induction of general anesthesia[7].” ( line 50-52 )

Reference 5 is not listed and I doubt it exists.

: We fix the citation error. ( line 50 )

Reference 6 is an outlier and is not reflective of the majority of studies.

: We remove the reference 6 and related sentences as recommended by reviewer #4

In both the abstract and the methods, the design of the study is not explicitly stated. It should explicitly state to compare an intraoperative hypotonic solution with dextrose to Hartmann’s solution to evaluate the FLACC scale score and the change in serum sodium and glucose immediately prior to and following surgery. Or something like that.

: We add a sentence as below to follow reviewer #4’s suggestion.

: “We compared the effects of an intraoperative 1:2 dextrose solution (hypotonic dextrous solution) with Hartmann’s solution(isotonic solution) on the postoperative FLACC scale scores and the change in plasma sodium and glucose immediately prior to and following surgery.” ( line 77-79 )

Please explain clearly what 1:2 dextrose solution is. What is the dextrose concentration of this fluid and what is the sodium and potassium concentration of this fluid.

: We made a table for the composition of study fluids at Table 1 in Patients and Methods. ( line 99 )

The TO, T1 an T2 time points along with what is being measured needs to occur earlier in the methods and be more explicit.

: We re-write a related sentence and move it more front : ( line 80-82 )

: “Plasma sodium and glucose levels were assessed the day before surgery (T0; preoperative baseline values), immediately prior to the surgery (T1), and at the end of surgery before awakening the patient (T2).”

It is not clear what the term waiting room mean. Better to say the preoperative waiting room and recovery room.

: We change them “wating room” to “preoperative waiting room” as suggested by Reviewer #4. ( line 94,95, 106, 226 )

The limits of 125 – 150 are too broad. There were probably no patient with a serum sodium of between 125 – 130. The were no patients with a serum sodium < 130 with the lowest sodium in the group 132. Probably better to change this to 130 – 150. Everyone may have had a normal serum sodium at T0, so you could also say 135 -145 if it was true.

: When we conduct another clinical trial, we will narrow the range following Reviewer #4's suggestion.

The statement about desalinization does not make any sense and should be removed. Saline is no more likely to call desalinization then a more hypotonic fluids and is not a reason not to use it.

: We removed the entire sentence about salinization and the associated reference as suggested by reviewer #4.

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

26 Feb 2020

PONE-D-19-19250R1

Effect of intraoperative Hartmann’s versus hypotonic solution administration on FLACC pain scale scores in children: a prospective randomized controlled trial

PLOS ONE

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Reviewer #1: Yes

Reviewer #3: Yes

Reviewer #4: Yes

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Reviewer #1: Table 3 Title should be amended by adding: ‘Mean and SD of plasma …’

Table 3 CI for plasma quote to 2 decimal places only

Table 3 P-values to 2 decimal places: Amend to 0.99 (although strictly 1) and 0.73

Reviewer #3: Thank you for fixing.

It reflects my point.

Accept.

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27 Feb 2020

To reviewer #1:

Table 3 Title should be amended by adding: ‘Mean and SD of plasma …’

Table 3 CI for plasma quote to 2 decimal places only

Table 3 P-values to 2 decimal places: Amend to 0.99 (although strictly 1) and 0.73

-> We mended table 3 as recommended by reviewer #1. ( line 136 in Manuscript )

Submitted filename: Response to Reviewers.docx

Click here for additional data file.

4 Mar 2020

Effect of intraoperative Hartmann’s versus hypotonic solution administration on FLACC pain scale scores in children: a prospective randomized controlled trial

PONE-D-19-19250R2

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Academic Editor

PLOS ONE

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Comments to the Author

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Reviewer #1: All comments have been addressed

**********

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**********

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**********

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Reviewer #1: (No Response)

**********

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Reviewer #1: Yes: David Machin

6 Mar 2020

PONE-D-19-19250R2

Effect of intraoperative Hartmann’s versus hypotonic solution administration on FLACC pain scale scores in children: a prospective randomized controlled trial

Dear Dr. Lee:

I am pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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