Local infiltration analgesia with bupivacaine and adrenaline does not reduce perioperative blood loss in total hip arthroplasty.

This study evaluates the effect of local infiltration analgesia with bupivacaine and adrenaline on perioperative blood loss in total hip arthroplasty. Patients who had primary total hip arthroplasty were retrospectively assigned to two groups. One group had 100 ml of bupivacaine/adrenaline solution injected into periarticular soft tissues at the end of the procedure. There were 55 patients in the infiltrated hip group and 44 patients in the not infiltrated group. Patients' hemoglobin level (Hb), hematocrit (HTC), red blood count (RBC), platelet count (PLT) and International Normalized Ratio (INR) as well as the need for blood transfusions were compared statistically between groups preoperatively and postoperatively. There were no significant differences between Hb, HTC or RBC levels as well as the rate and amount of blood transfusions on the 1st, 4th postoperative days or at patients' discharge between infiltrated and not infiltrated groups. This study does not support the hypothesis that the use of local infiltration analgesia with adrenaline may reduce perioperative blood loss in total hip arthroplasty.

Introduction

Hip arthroplasty is one of the most common orthopedic surgeries performed worldwide [1-3]. It is an extensive procedure with a range of associated problems, including pain and significant blood loss, among other [1, 3, 4]. Many improvements have been made in the operative technique [2, 5, 6] as well as in the perioperative management of the patient to minimize operative trauma and improve rehabilitation process [1, 4, 7].

Local infiltration analgesia (LIA) is a well-recognized method for controlling pain in the early postoperative period. In orthopedic surgery, it is most commonly used for total hip and knee arthroplasty [4, 8, 9]. A range of different solutions of regional anaglesics are used diluted in normal saline [4], with or without addition of adrenaline. Adrenaline in this solution has proven to have an additional benefit of decreasing perioperative blood loss and transfusion rates in total knee arthroplasty [10], especially when used together with tranexamic acid [11]. In total hip arthroplasty, local infiltration analgesia with adrenaline has proven to be beneficial in postoperative pain control [7, 12], but it failed to show a consistent effect on bleeding [3, 13, 14] using different solutions and application protocols as in this study.

Our hypothesis was that local infiltration analgesia with bupivacaine and adrenaline in total hip arthroplasty would significantly decrease the perioperative blood loss in patients who were infiltrated with the solution by at least 350 ml (what is approximately equal to 1 unit of transfused blood) [10], what would in turn reduce the required amount of blood transfusion. This study attempts to answer the question whether LIA with adrenaline can be administered for the purpose of limiting perioperative blood loss, what would provide additional benefit when compared to LIA without adrenaline or to local nerve blocks.

Material and methods

All patients who underwent standard total hip arthroplasty between 1. October 2009 and 30. May 2010 in the Department of Orthopedic Surgery, Medical University of Gdansk, Poland were retrospectively analysed in the study. Patients provided an informed written consent to allow their medical data to be analyzed in this study. This study was approved by the local Bioethics Committee (issued 25.11.2009, NKEBN/332/2009). Only patients with primary osteoarthritis were included. Total hip arthroplasty is a standard procedure for treatment of this disease at our institution. No modifications in patient treatment were undertaken for the purpose of this study, and the patient’s standard medical data was analysed retrospectively. All patients were prepared for surgery by a general practitioner and consulted by an anaesthesiologist to ensure that their potential comorbidities, including hypertension, diabetes mellitus, coronary heart disease or other less common diseases, were well controlled and the general risk of surgery regarding overall health status was minimized. Exclusion criteria were as follows: previous fractures of the femur or acetabulum, a history of septic arthritis, previous hip surgery, osteonecrosis, coagulopathy, or general contraindications for infiltration with local anesthetic and adrenaline.

Patients were operated by senior residents (MC, TS, MR), under the supervision of two senior orthopedic surgeons (KK, MT). In Poland, patients can choose any hospital they want to be treated in and once they choose they become assigned to the hospital’s orthopedic centre, but not to a particular surgeon in this hospital. Therefore, the patients were assigned at random to one of the senior surgeons for supervision and one of the senior residents for surgery. Once the patient has given an informed consent regarding surgery as well as accepted the operating team, the operation was performed. One of the senior surgeons (MT) required a routine use of infiltration analgesia during surgeries that he supervised for the purpose of early postoperative pain control, the other (KK) did not used it as a part of standard patients’ care. This created two groups of patients, where one group received infiltration analgesia and the other did not. This approach, based on supervising surgeon preference regarding infiltration analgesia was a standard practice at our institution until 2013, when local nerve blocks were introduced and wound infiltration with local anesthetics was no longer used for early postoperative pain control. During patients’ hospital stay, their clinical data was collected including gender, age, weight, accompanying chronic ailments, the size of prosthesis components as well as the drainage output and blood parameters measured pre and postoperatively.

Patients were operated on using standard spinal anesthesia [10]. The standard lateral Hardinge approach was used for the hip arthroplasty [15]. The local anesthetic mixture was prepared with 100 ml saline solution with 50 mg of bupivacaine and 1 mg adrenaline. This solution was prepared according to a standard developed in our institution, and is similar to the solutions used in other studies [3]. The infiltration analgesia was used after completion of the arthroplasty procedure, but before wound closure. The solution was injected into the tissues around the rim of the acetabulum including the capsule, the exposed incised gluteus medius and vastus lateralis muscles, as well as into the subcutaneous tissue. A total of 100 ml of solution was used. Two drains were inserted: one into the joint, and the other under the fascia lata after gluteus medius closure. The operative time was recorded within 5 minute intervals.

Drainage was continued for 48 hours after surgery. The drainage output was collected with Redon drains, the volume was recorded after 24 and 48 hours separately. Hemoglobin levels (Hb), hematocrit (HTC) and red blood cell count (RBC) was measured after 24 hours (Day 1) and on the 4th postoperative day (Day 4). Blood transfusion was indicated when Hb levels were below 10 g/100 ml on Day 1, or 9 g/100 ml on the Day 4. Patients were discharged home on Day 4. In patients who required blood transfusions on Day 4 as well as the patients who had Hb levels between 9 and 10 g/100 ml, the discharge was delayed for 48 hours when the blood parameters were measured once again and then they were discharged. Therefore, the Hb, HTC and RBC at discharge are a pooled data of their final levels at the end of hospital stay, where the Day 4 levels of patients who had their hospital stay prolonged were substituted for their final levels at discharge.

Patients were taught to get out of bed and walk with crutches on the first or second postoperative day, depending on their functional status, in physiotherapist’s assistance. The postoperative pain and functional status was not recorded and assessed in detail.

Patients’ gender, age, weight, body mass index (BMI), acetabulum and stem size, operative time, Hb, HTC, RBC, as well platelet count (PLT) and International Normalized Ratio (INR) to screen for bleeding disorders were compared statistically between groups. The blood volume was estimated from the preoperative Hb levels, body weight and height using the formula from Meunier et al. [10, 16] and compared as well. There were 55 patients in the infiltrated hip group (M:F = 22:33) and 44 patients in the not infiltrated group (M:F = 24:20). The data on implant size was available in 40 patients in the infiltrated group and in 37 patients in the not infiltrated group. Patients’ characteristics and comparison between groups are given in Table 1. The comparison of Hb, HTC, RBC and INR preoperatively is given in Table 2. All patients’ data is supplied in the S1 File.

Table 1

Patient characteristics.

	Infiltrated group	Not infiltrated group	Statistics
	(n = 55)	(n = 44)
Age (years)	68.07	68.05	p = 0.98
	SD = 9.3	SD = 8.9
	R: 46–86	R: 47–87
Weight (kilograms)	78.4	77.3	p = 0.69
	SD = 15.1	SD = 13.7
	R: 48–130	R: 55–109
Body mass index	26.46	25.94	p = 0.23
	SD = 3.32	SD = 2.54
	R: 20–38	R: 21–32
Acetabulum sizea (mm)	54.95	55.38	p < 0.001
	SD = 4.19	SD = 4.78
	R: 46–62	R: 44–65
Stem sizea	12.19	11.75	p = 0.63
	SD = 2.54	SD = 2.68
	R: 7.5–18	R: 7.5–17.5
Estimated blood volume (ml)	2914.63	2928.02	p = 0.76
	SD = 592.45	SD = 445.6
	R: 1770.9–4483.46	R: 2002.46–4112.78

The sample sizes for the acetabulum and the stem were n = 40 patients in the infiltrated group and n = 37 patients in the not infiltrated group.

Table 2

The comparison of preoperative blood and INR results.

	Infiltrated group	Not infiltrated group	Statistics
	(n = 55)	(n = 44)
Hb (g/dl)	13.9	13.94	p = 0.33
	SD = 1.35	SD = 1.2
	R: 11.5–16.5	R: 11.5–16.4
HTC (%)	41.4	41	p = 0.91
	SD = 3.5	SD = 2.9
	R: 35.1–49.1	R: 36–48
RBC (T/l)	4.68	4.7	p = 0.46
	SD = 0.38	SD = 0.39
	R: 4.06–5.64	R: 4.02–5.46
PLT (G/l)	253	244	p = 0.52
	SD = 77	SD = 69
	R: 153–456	R: 140–425
INR	1.03	1.03	p = 0.73
	SD = 0.09	SD = 0.1
	R: 0.85–1.25	R: 0.82–1.32

Hb, hemoglobin level; HTC, hematocrit; RBC, red blood count; PLT, platelet count; INR, International Normalized Ratio.

The sample size calculation was performed considering a 350 ml (SD = 300 ml) difference in blood loss to be significant [10] at an average total blood loss of 1200 ml. Alpha and beta levels were set at 5% and 20%, respectively. The required total sample size was 24 (12 per group). In other similar studies, a maximum total number of enrolled patients required was 70 with 100 tested [10], 12 with 49 tested [10], 20 with 121 tested [17]. Current study had a total of 99 patients (55 v/s 44 in both groups), therefore it should be considered adequately powered.

The Kolmogorov-Smirnov test was used to assess normality of distribution. The two-tail T-student test was used for comparison between results was used when normal distribution was assumed, and the Mann Whitney U test was used for comparison of results when normal distribution was not assumed. The chi-square test was used for comparison between groups when categorical variables were analysed. The Statistica PL v. 13.3 software was used for calculations.

Results

There no significant differences in the female to male ratio in both groups (2x2 chi-square test p = 0.15), as well as with regard to age, weight, BMI, estimated blood volume, Hb, HTC, RBC, PLT or INR between corresponding groups (Tables 1 and 2). The acetabular size was slightly, but significantly larger in the not infiltrated group, with no differences in stem size (Table 1).

No significant differences were found regarding operative time in both groups (p = 0.47). In the infiltrated group it was 90.81 minutes (SD– 15.06; R: 55–125), in the not infiltrated group it was 90.56 minutes (SD = 14.38, R: 60–120).

There were no significant differences between Hb, HTC or RBC levels on Day 1, Day 4 or at patients’ discharge between infiltrated and not infiltrated groups (Table 3).

Table 3

The comparison of postoperative hemoglobin levels (Hb), hematocrit (HTC) and red blood count (RBC).

Postoperative day		Infiltrated group	Not infiltrated group	Statistics
		(n = 55)	(n = 44)
Day 1	Hb (g/dl)	11.24	11.55	p = 0.92
		SD = 1.2	SD = 1.34
		R: 9–14.1	R: 7.6–14.4
	HTC (%)	33.3	34	p = 0.95
		SD = 3.43	SD = 3.8
		R: 26.3–42.4	R: 23–41
	RBC (T/l)	3.81	3.89	p = 0.80
		SD = 0.4	SD = 0.48
		R: 3.04–5.07	R: 2.51–4.89
Day 4	Hb (g/dl)	10.64	10.73	p = 0.83
		SD = 1.36	SD = 1.22
		R: 7.2–13.9	R: 8.3–13.6
	HTC (%)	31.6	32	p = 0.89
		SD = 3.86	SD = 3.4
		R: 20.4–41.8	R: 24–40
	RBC (T/l)	3.58	3.66	p = 0.96
		SD = 0.48	SD = 0.45
		R: 2.36–5.14	R: 2.65–4.89
Discharge	Hb (g/dl)	10.91	10.97	p = 0.71
		SD = 1.08	SD = 1.12
		R: 9.1–13.9	R: 9.3–13.6
	HTC (%)	32.5	33	p = 0.97
		SD = 2.9	SD = 3.1
		R: 27.4–41.8	R: 28–40
	RBC (T/l)	3.68	3.74	p = 0.99
		SD = 0.38	SD = 0.41
		R: 3.02–5.14	R: 2.97–4.89

Hb, hemoglobin level; HTC, hematocrit; RBC, red blood count.

The drain output (Table 4) was significantly greater (T-student test) in the not infiltrated group on the 2nd postoperative day, as well as the total output (the sum of the 1st and 2nd postoperative day). The differences were on average 31 ml on the 1st day, 34 ml on the 2nd and 65 ml in total.

Table 4

Drainage output volume in milliliters.

Postoperative day	Infiltrated group	Not infiltrated group	Statistics
	(n = 55)	(n = 44)
Day 1	365	396	p = 0.24
	SD = 127	SD = 134
	R: 80–600	R: 70–720
Day 2	156	190	p = 0.025
	SD = 70	SD = 78
	R: 30–360	R: 80–450
Total	521	586	p = 0.04
	SD = 150	SD = 156
	R: 190–810	R: 340–940

Since the acetabular size was significantly greater in the not infiltrated group, the results were corrected for the acetabular size according to the following simple formula developed by the authors:

Ratio = drainage output volume (ml)/acetabular size (mm)

After correction, the drainage output showed no significant differences between groups for the 1st postoperative day, 2nd postoperative day or total output (Table 5). A strong positive correlation (Pearson correlation) was found between acetabular size and bleeding (R: 0.94, p<0.001), but for the stem size there was a weak negative correlation (R: -0.3, p = 0.006).

Table 5

Drainage output volume in milliliters corrected for acetabular size in millimeters (ratio: Drainage output volume/acetabular size).

Postoperative day	Infiltrated group	Not infiltrated group	Statistics
	(n = 55)	(n = 44)
Day 1	6.76	7.21	p = 0.86
	SD = 2.23	SD = 2.04
	R: 1.66–10.64	R: 1.89–12
Day 2	2.86	3.46	p = 0.31
	SD = 1.26	SD = 1.43
	R: 0.52–6	R: 1.53–8.33
Total	9.62	10.66	p = 0.19
	SD = 2.58	SD = 2.45
	R: 4.1–15.38	R: 6.55–16.66

The infiltrated hip group required on average 1.53 blood units (SD = 1.24, R: 0–5) to be transfused and the not infiltrated group 1.61 (SD = 1.11, R: 0–4). The differences were statistically not significant (T-test p = 0.71). In the infiltrated group, 18 of 55 patients did not require transfusion, an in the not infiltrated group, 12 of 44 patients (chi-square test p = 0.39).

The blood loss was estimated according to Meunier et al. [10, 16]. The blood loss was compared in the 1st postoperative day before any blood products were transfused. Moreover, taking into account the assumption that one unit of transfused blood equates to approximately 350ml of blood, total blood loss was estimated with the previous mentioned formula using Hb levels at discharge. The estimated volume of transfused blood was added by multiplying the number of blood units by 350 ml. The 1st day and total blood loss was compared between groups, and no significant differences were found (Table 6).

Table 6

Comparison of estimated blood loss in milliliters between groups.

	Infiltrated group	Not infiltrated group	Statistics
	(n = 55)	(n = 44)
Day 1	549.41	495.32	p = 0.37
	SD = 268.28	SD = 284.97
	R: 60.94–1232.29	R: 67.22–1138.24
Total	1158.22	1191.82	p = 0.84
	SD = 425.78	SD = 367.1
	R: 525.1–2410.23	R: 544.1–2006.17

The total estimated blood loss was corrected for acetabular size in a similar fashion as the drain output shown in Table 5, using the formula:

Ratio = total blood loss (ml)/acetabular size (mm).

In the infiltrated group (n = 40) the ratio was 21.41 (SD = 7.99; R: 10.1–45.26), in the not infiltrated group (n = 37) the ratio was 21.37 (SD = 6.04; R: 11.77–34.6). The results were statistically not significant (p = 0.47).

A separate analysis in two age groups: 60–69 and 70–89 years of age was performed additionally (S2 File). The only significant difference found was regarding acetabular size in the 70–79 years old group, but the correction performed in a similar manner for drainage output and total blood loss did not show any statistically significant differences. No significant differences between the infiltrated and not infiltrated groups were found in any other evaluated parameter.

No incident of deep vein thrombosis, infection, acute cardiac arrhythmia, allergic reactions or hip dislocation occurred in either groups during hospital stay.

Discussion

This study failed to prove any significant benefit of periarticular injection of a solution of a local anesthetic and adrenaline in total hip arthroplasty. Both the infiltrated and the not infiltrated groups had a similar loss of Hb, HTC and RBC levels, a similar number of patients that required blood transfusions, as well as there was the same average number of blood unit per patient. The estimated blood loss did not differ significantly between groups. There was a slightly greater drain output in the not-infiltrated group, but when the results were corrected for acetabular size, no significant differences were found. A similar correction performed for total estimated blood loss did not show any significant differences either. A separate evaluation in age groups showed similar results as in the comparison of the whole groups.

Interestingly, there was a significant correlation found between implant size and drain output. This suggests that acetabular size, but not necessarily the femoral stem size, may be a significant predictor of perioperative bleeding. Such findings were not reported in literature before. However, since this factor proved to be significant, it should be included in similar studies in the future, as the difference in prosthesis size between groups may bias the outcome. The findings of this study are with concordance with a randomized controlled study on the effect of local infiltration analgesia on acute pain and bleeding after primary total hip arthroplasty by Villatte et al. [3], who found no differences in Hb levels or the need of blood transfusions in either groups.

A study by Yewlett et al. [14] showed that washing the surgical field with a saline solution with epinephrine does not reduce intraoperative blood loss, drainage levels or drop in haemoglobin. However, they found that the patients who had the surgical field washed with epinephrine solution required significantly less blood transfusions, what is different from our study.

This study is in contrast with the finding that a solution of bupivacaine with epinephrine similar to the one used in the current study reduce blood loss in total knee arthroplasty [18]. Generally, solutions containing adrenaline were found to reduce perioperative blood loss in total knee arthroplasty [10, 19, 20], with some exceptions [11, 17].

Several studies suggest that solutions which include tranexamic acid with adrenaline have a significant effect in controlling blood loss in total hip arthroplasty [1]. Our study, which did not include tranexamic acid, failed to prove any benefit. Those differences in findings are in concordance with the findings of Durgut et al. [11], who found that adrenaline alone does not decrease bleeding, but the tranexamic acid does.

This study does not assess pain intensity or functional status, what may be considered a limitation. Those parameters are sometimes evaluated in similar studies [3], but are not required to draw conclusions about the bleeding status [10, 11, 21]. The observation period included only the duration of hospital stay [10, 11, 21]. Longer periods of observation are required to evaluate the analgesic effect of the local infiltration analgesia [3, 9]. Another limitation is that the patients were not operated by the same surgeon, but by the same senior residents in both groups with a similar experience in performing hip arthroplasty. Operative time in both groups was similar. Therefore the surgeons’ experience and technique therefore would likely not affect the results of the study. The perioperative care was the same for both groups, as they were operated on in the same period of time in a single orthopedic clinic [10].

In conclusion, this study does not support the hypothesis that the use of local infiltration analgesia with adrenaline may reduce perioperative blood loss in total hip arthroplasty, therefore its use for the purpose of limiting blood loss or reduction of transfusion rates is unjustified. Moreover, this study found that prosthesis size, especially the acetabulum size, may be a significant predictor of blood loss. This factor should be taken into account in similar studies in the future.

Data file.

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Supplementary tables file.

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3 Jun 2021

PONE-D-21-08207

Local infiltration analgesia with bupivacaine and adrenaline does not reduce perioperative blood loss in total hip arthroplasty.

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Reviewer #1: General comments

As long as wound infiltration with local anesthetics is no longer necessary for early postoperative pain control after development of local nerve blocks (lines 70-72),\\n what is the importance of the current research?

Abstract

. Line 23: meaning of the abbreviations Hb, HTC or RBC \\nwere not previously reported

. Lines 24-25: “amount of blood transfusions on the 1st, 4th or at patients’ discharge between infiltrated and not infiltrated groups”. \\nshould be corrected to” the 1st or 4th post-operative days”

Introduction

. Introduction must highlight the importance of the current research. The authors in lines 42-44: In total hip arthroplasty, local infiltration analgesia with adrenaline has proven to be \\nbeneficial in postoperative pain control [7,12], but it failed to show a consistent effect on bleeding [3,13,14]. \\nSo, what is the clinical significance of the current research?

. Material and Methods

The 2 groups are not operated by the same surgeon and this is one of the limitations of the study, it is not a randomization and not a point of strength

Line 99: Meaning of abbreviation “BMI” was not previously mentioned.

Results

. Line 137: “There no significant differences in the female to male ratio in both groups (2x2 chi-square test “\\n

. Authors did not report use of Chi – square test in Statistical methods (lines 130-133)

. Line 169: “Ratio = drainage output volume (ml)/acetabular size (mm)” Was this equation developed by the authors? \\n

Discussion

Is too long and should be shortened

. Line 226: “The study is not a randomized controlled study, but some criteria of randomization are met”. This sentence is not true and must be deleted. \\n

Tables

Considering each table as a separate entity, meaning of all abbreviations used in each table must be reported in a footnote after each table.

Reviewer #2: The authors evaluated whether local infiltration analgesia with bupivacaine and adrenaline reduced perioperative blood loss in THA. They compared a group with the analgesia and the other without it in a retrospective manner and found that there were no significant differences between the two groups. This is an interesting study which could answer this clinical question in a straightforward manner. However, this manuscript has obvious limitations and issues to be solved.

1, To answer a certain clinical question by a retrospective analysis, one needs to have a clear hypothesis BEFORE the start of the study. What was it in this study? Please describe it clearly.

2, Then, the researcher(s) must calculate the sample size depending on the hypothesis according to previous similar reports. Please describe the calculation in this study.

3, The blood loss should be estimated not only the drainage output but also calculated by the differences between preoperative and postoperative Hb, HTC, and RBC. Moreover, the estimated blood loss can be calculated by established formulae using those values. Please show these results.

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Reviewer #1: Yes: Mohamed Abdel-Wanis

Reviewer #2: No

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6 Jul 2021

The authors wish to thank for a kind and meaningful review. We did our best to fulfill all the requirements and address comments properly. All the reviewer comments were taken into account.

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Patients provided an informed written consent to allow their medical data to be analyzed in this study. This study was approved by the local Bioethics Committee (issued 25.11.2009, NKEBN/332/2009). – This statement is included now in the Material and Methods section. I am sorry to have not included it previously as it should have been.

Reviewer #1: General comments

As long as wound infiltration with local anesthetics is no longer necessary for early postoperative pain control after development of local nerve blocks (lines 70-72),\\n what is the importance of the current research?

Thank you for this comment. The idea behind this study was whether LIA with adrenaline would provide additional benefit compared to local nerve blocks by limiting perioperative blood loss and justify returning to LIA with adrenaline, disregarding the local nerve blocks. This is stated clearly in the introduction section under the hypothesis.

Abstract

. Line 23: meaning of the abbreviations Hb, HTC or RBC \\nwere not previously reported - corrected

. Lines 24-25: “amount of blood transfusions on the 1st, 4th or at patients’ discharge between infiltrated and not infiltrated groups”. \\nshould be corrected to” the 1st or 4th post-operative days” – corrected

Introduction

. Introduction must highlight the importance of the current research. The authors in lines 42-44: In total hip arthroplasty, local infiltration analgesia with adrenaline has proven to be \\nbeneficial in postoperative pain control [7,12], but it failed to show a consistent effect on bleeding [3,13,14]. \\nSo, what is the clinical significance of the current research? – other studies used different solutions and application protocols as in this study

Material and Methods

The 2 groups are not operated by the same surgeon and this is one of the limitations of the study, it is not a randomization and not a point of strength - this expression has been removed; the discussion section explaining this matter has been updated to discuss this limitation.

Line 99: Meaning of abbreviation “BMI” was not previously mentioned. – corrected for “body mass index (BMI)”

Results

. Line 137: “There no significant differences in the female to male ratio in both groups (2x2 chi-square test “\\n

. Authors did not report use of Chi – square test in Statistical methods (lines 130-133) – the use of this test is mentioned in this section

. Line 169: “Ratio = drainage output volume (ml)/acetabular size (mm)” Was this equation developed by the authors? \\n – the formula was developed by the authors, this fact is mentioned in the text now

Discussion

Is too long and should be shortened – the discussion was updated and redundant information excluded.

. Line 226: “The study is not a randomized controlled study, but some criteria of randomization are met”. This sentence is not true and must be deleted. \\n – this section in the discussion has been updated.

Tables

Considering each table as a separate entity, meaning of all abbreviations used in each table must be reported in a footnote after each table. – the footnotes were applied where appropriate

Reviewer #2: The authors evaluated whether local infiltration analgesia with bupivacaine and adrenaline reduced perioperative blood loss in THA. They compared a group with the analgesia and the other without it in a retrospective manner and found that there were no significant differences between the two groups. This is an interesting study which could answer this clinical question in a straightforward manner. However, this manuscript has obvious limitations and issues to be solved.

1, To answer a certain clinical question by a retrospective analysis, one needs to have a clear hypothesis BEFORE the start of the study. What was it in this study? Please describe it clearly.

The hypothesis is described at the end of the introduction.

2, Then, the researcher(s) must calculate the sample size depending on the hypothesis according to previous similar reports. Please describe the calculation in this study.

The sample size was calculated according to previous reports and was considered adequately powered.

3, The blood loss should be estimated not only the drainage output but also calculated by the differences between preoperative and postoperative Hb, HTC, and RBC. Moreover, the estimated blood loss can be calculated by established formulae using those values. Please show these results.

The comparison of preoperative and postoperative values of Hb, HTC and RBC are provided in tables 2 and 3. The blood loss was estimated according to an appropriate formula by Meunier et al. (source cited in the article) and compared between groups in an additional table (Tab. 6).

Sincerely ours

Submitted filename: Response to the reviewers.docx

Click here for additional data file.

20 Jul 2021

PONE-D-21-08207R1

Local infiltration analgesia with bupivacaine and adrenaline does not reduce perioperative blood loss in total hip arthroplasty.

PLOS ONE

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Comments to the Author

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Reviewer #3: All comments have been addressed

Reviewer #4: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #3: Yes

Reviewer #4: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #3: Yes

Reviewer #4: I Don't Know

**********

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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.

Reviewer #3: Yes

Reviewer #4: Yes

**********

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Reviewer #3: Yes

Reviewer #4: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #3: • I see the senior surgeon of both groups is different. Are the bleeding control practices of both surgeons similar during the patients' operations? For example; In the hospital where I work for total hip replacement surgery, there are two kind of surgeons one does this surgery in half an hour and the other one in 2 hours. The approaches of these two surgeons to bleeding and acetabular reaming are completely different. For these and similar reasons, it would not be correct to compare the patients of these two surgeons in the same study. In my opinion, the fact that two different surgeons have two different applications does not mean that it is appropriate to compare these two different groups. As a result, this situation causes bias in the study. This is huge one of the limitations of the present study.

• Another limitation of the study is the significant difference in acetabular sizes between the two groups.

• Line 215: " ... randomized controlled study by Villatte et al. ... " The study about what?

Reviewer #4: Dear Authors

I congratulate you for your valuable study examining the effect of bupivacaine and adrenaline applied during total hip arthroplasty surgery on postoperative blood loss. I think some methodological adjustments are needed for your study to be published. My recommendations are as follows:

Keywords are not suitable for MESH. I recommend using “https://meshb.nlm.nih.gov/search” for keyword selection to increase the scannability of the article.

Comorbidity was not included in the exclusion criteria. An explanatory sentence might be appropriate in this regard.

The age range was kept very wide in the selection of the patients included in the study. Such a wide age range may make a difference in terms of susceptibility to coagulopathy. Analysis by age groups can improve the quality of the study.

Is there a difference between the two groups in terms of surgical time? No information was given about this. Extended surgical time is a factor that increases bleeding.

Is the content of the injected solution (The local anesthetic mixture was prepared with 100 ml saline solution with 50 mg of bupivacaine and 1 mg adrenaline) a standard protocol defined in the literature or is it the surgeon's preference?

“In the infiltrated group 8 patients and in the not infiltrated group 5 patients had their stay prolonged above Day 4.” The sentence should be in the results section.

BMI and blood loss can be compared. The correction calculation made for the acetabular size can also be made for the BMI.

**********

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Reviewer #3: No

Reviewer #4: Yes: Ismail Eralp Kacmaz

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10 Aug 2021

The authors wish to thank for a kind and meaningful review. We did our best to fulfill all the requirements and address comments properly. All the reviewer comments were taken into account.

Reviewer #3: • I see the senior surgeon of both groups is different. Are the bleeding control practices of both surgeons similar during the patients' operations? For example; In the hospital where I work for total hip replacement surgery, there are two kind of surgeons one does this surgery in half an hour and the other one in 2 hours. The approaches of these two surgeons to bleeding and acetabular reaming are completely different. For these and similar reasons, it would not be correct to compare the patients of these two surgeons in the same study. In my opinion, the fact that two different surgeons have two different applications does not mean that it is appropriate to compare these two different groups. As a result, this situation causes bias in the study. This is huge one of the limitations of the present study.

We agree that the fact that both groups were not operated by a single surgeon is a limitation of this study, but this limitation is difficult to overcome in a retrospective analysis such as this study. The senior surgeons, as well as the whole operating team, has similar bleeding control practices, as they learned their craft and performed surgeries in the same center all their professional careers. The surgeries were performed by senior residents, who learned their basic skills, such as surgical approaches and bleeding control, from both senior supervising surgeons (KK, MT). The senior residents operated patients in both groups, therefore the operating surgeon bias is partially avoided. None of the patients in this study were operated on the supervising surgeons personally; they were the first surgical assistants and their role was to guide the residents with their experience during surgeries. The senior residents (all of them in their 4th or 5th year of residency with several hundred different surgeries performed personally) already have their bleeding practices well established, therefore the supervising surgeons’ influence on their basic performance, including bleeding control practices, is very limited. Therefore we believe that the influence of the surgeons’ experience and bleeding control practices have very little if any influence on the results of the study.

Additionally, we compared surgical time in both groups and there were no significant differences between them. This may be considered an indirect indication of similar bleeding control practices, as significant differences in this area would result in longer operating times when a more meticulous and time consuming bleeding control was done in one of the groups.

• Another limitation of the study is the significant difference in acetabular sizes between the two groups.

This is probably the most difficult limitation to overcome in this study. We did our best to at least partially overcome this problem by correcting the total drainage output by acetabular size as seen in tab. 5. Moreover, in the revised manuscript we performed a similar correction of total estimated blood loss (the most important outcome criterion in our opinion) by acetabular size to further check its influence on the results. No significant differences were found in this regard, as seen at the end of the Results section (below Tab. 6). A short comment was added in the discussion section.

• Line 215: " ... randomized controlled study by Villatte et al. ... " The study about what? – an explanation is provided in the appropriate location

Reviewer #4: Dear Authors

I congratulate you for your valuable study examining the effect of bupivacaine and adrenaline applied during total hip arthroplasty surgery on postoperative blood loss. I think some methodological adjustments are needed for your study to be published. My recommendations are as follows:

1. Keywords are not suitable for MESH. I recommend using “https://meshb.nlm.nih.gov/search” for keyword selection to increase the scannability of the article.

The keywords were updated and checked in MESH. The terms: total hip arthroplasty, bleeding, hemostasis, local anesthesia, can be found in MESH.

2. Comorbidity was not included in the exclusion criteria. An explanatory sentence might be appropriate in this regard.

A short explanation of patients’ preparation for surgery with regard to their general health status was added to the Materials and Methods section. Patients with general contraindications for surgery were not operated on and therefore not included in the study.

3. The age range was kept very wide in the selection of the patients included in the study. Such a wide age range may make a difference in terms of susceptibility to coagulopathy. Analysis by age groups can improve the quality of the study.

An analysis in two age groups, that is between 60 and 69 years of age and 70-79 years of age, was performed separately. The number of patients above and below this age threshold was too limited for evaluation. A short remark about those results was added in the results as well as in the discussion section. Generally, the results were similar as in the general evaluation. To avoid too much specific data, the results in tables were added as supplementary material.

4. Is there a difference between the two groups in terms of surgical time? No information was given about this. Extended surgical time is a factor that increases bleeding. – The operative time was included in patient comparison, no significant differences were found between groups.

5. Is the content of the injected solution (The local anesthetic mixture was prepared with 100 ml saline solution with 50 mg of bupivacaine and 1 mg adrenaline) a standard protocol defined in the literature or is it the surgeon's preference?

This solution was prepared according to a standard developed in our institution, and is similar to the solutions used in other studies – this sentence is now included in the Material and Methods section.

6. “In the infiltrated group 8 patients and in the not infiltrated group 5 patients had their stay prolonged above Day 4.” The sentence should be in the results section. – after careful consideration we removed this sentence completely, as this information is irrelevant to the results of the study and is not discussed at any point in the manuscript.

7. BMI and blood loss can be compared. The correction calculation made for the acetabular size can also be made for the BMI.

In this study, the acetabular size was the only significant difference between groups in the patients’ characteristics. There were no differences in age, weight, BMI and stem size, all of which can theoretically influence postoperative bleeding.

The the idea behind the correction for acetabular size was to minimize the influence of the size differences between groups on the results. There were no significant differences between BMI results between groups, therefore we believe that a direct comparison of the results was enough and no correction for the BMI results was needed.

We performed the correction as requested, but taking into account all the above mentioned arguments, decided not to include it in the main body of the manuscript. It does not change the results of the study and the conclusion in any way, and the inclusion of this information would make the already complicated manuscript even more difficult to read. The calculation is done in the Suppl. 1 data file, including statistical comparison.

However, since the acetabular sizes may be of great importance in the results, we corrected the total estimated blood loss for acetabular size and included the results in the manuscript. This is the most important parameter in this study and we believe that this additional information may increase the value of the results.

Submitted filename: Response to the reviewers 2.docx

Click here for additional data file.

26 Aug 2021

Local infiltration analgesia with bupivacaine and adrenaline does not reduce perioperative blood loss in total hip arthroplasty.

PONE-D-21-08207R2

Dear Dr. Ceynowa,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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Kind regards,

Robert Jeenchen Chen, MD, MPH

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #4: All comments have been addressed

Reviewer #5: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #4: Yes

Reviewer #5: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #4: I Don't Know

Reviewer #5: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

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.

Reviewer #4: Yes

Reviewer #5: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #4: Yes

Reviewer #5: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #4: Thank you for the revisions. A study examining one of the important problems in hip arthroplasty. I think it will contribute to the literature.

Reviewer #5: Though article has been concluded against hypothesis, it would be benificial for the readers if they highlight more on the alternate methods to reduce blood loss at pre-op stage.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

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Reviewer #4: Yes: Ismail Eralp Kacmaz

Reviewer #5: No

31 Aug 2021

PONE-D-21-08207R2

Local infiltration analgesia with bupivacaine and adrenaline does not reduce perioperative blood loss in total hip arthroplasty.

Dear Dr. Ceynowa:

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