Skip to main content
PLOS ONE logoLink to PLOS ONE
. 2021 Feb 24;16(2):e0241114. doi: 10.1371/journal.pone.0241114

Intraoperative blood loss may be associated with myocardial injury after non-cardiac surgery

Jungchan Park 1,#, Ji-hye Kwon 1,#, Seung-Hwa Lee 2,*, Jong Hwan Lee 1, Jeong Jin Min 1, Jihoon Kim 2, Ah Ran Oh 1, Wonho Seo 1, Cheol Won Hyeon 2, Kwangmo Yang 3, Jin-ho Choi 2,4, Sang-Chol Lee 2, Kyunga Kim 5,6, Joonghyun Ahn 5, Hyeon‐Cheol Gwon 2
Editor: Wen-Chih Hank Wu7
PMCID: PMC7904206  PMID: 33626048

Abstract

Background

This study aimed to evaluate the association between intraoperative blood loss and myocardial injury after non-cardiac surgery (MINS), which is a severe and common postoperative complication.

Methods

We compared the incidence of MINS based on significant intraoperative bleeding, defined as an absolute hemoglobin level < 7 g/dL, a relative hemoglobin level less than 50% of the preoperative measurement, or need for packed red cell transfusion. We also estimated a threshold for intraoperative hemoglobin level associated with MINS.

Results

We stratified a total of 15,926 non-cardiac surgical patients with intraoperative hemoglobin and postoperative cardiac troponin (cTn) measurements according to the occurrence of significant intraoperative bleeding; 13,416 (84.2%) had no significant bleeding while 2,510 (15.8%) did have significant bleeding. After an adjustment with inverse probability weighting, the incidence of MINS was higher in the significant bleeding group (35.2% vs. 16.4%; odds ratio, 1.58; 95% confidence interval, 1.43–1.75; p < 0.001). The threshold of intraoperative hemoglobin associated with MINS was estimated to be 9.9 g/dL with an area under the curve of 0.643.

Conclusion

Intraoperative blood loss appeared to be associated with MINS. Further studies are needed to confirm these findings.

Clinical registration

The cohort was registered before patient enrollment at https://cris.nih.go.kr (KCT0004244).

Introduction

Myocardial injury after non-cardiac surgery (MINS) has recently arisen as a strong predictor of postoperative mortality [1]. Occurring in an estimated 8 million cases out of more than 200 million non-cardiac surgery patients every year, MINS has become the most common postoperative state related to mortality [2]. Massive blood loss is frequently encountered during surgical procedures and can lead to decreased hemoglobin levels. Oxygen supply/demand mismatch is a proposed as one of the mechanism for MINS [3]. Therefore, the compromised balance between oxygen supply/demand due to decreased hemoglobin levels and oxygen content is likely to be related to MINS [4], but the association between intraoperative blood loss and the occurrence of MINS has never been investigated.

Intraoperative blood loss and decreased hemoglobin levels are independently associated with perioperative mortality and serious morbidity such as myocardial infarction, stroke, and renal failure [57]. Furthermore, blood replacement by packed red blood cell (RBC) transfusion may lead to other severe side effects, complicating the perioperative clinical situation when the risks of anemia and transfusion needs to be balanced [4, 6, 8, 9]. Indeed, increased need for transfusion is one of the mechanisms of perioperative morbidity in anemic patients, and it is difficult to specify whether the morbidity originates from anemia or transfusion. Therefore, in this study, we evaluated whether intraoperative blood loss is associated with MINS. We also separately selected patients with actual hemoglobin decreases and those who required transfusion of packed RBCs using a de-identified real-world cohort.

Materials and methods

Because this registry was generated in a de-identified format, the Institutional Review Board at Samsung Medical Center waived the need for approval for this study and the requirement for written informed consent for access to the registry (SMC 2019-08-048). The cohort was registered before patient enrollment at https://cris.nih.go.kr (KCT0004244).

Study population and data collection

Our institution operates a paperless electronic medical record system that contains data from more than 4 million patients with more than 2 million surgeries, 900 million laboratory findings, and 200 million prescriptions. We developed “Clinical Data Warehouse Darwin-C,” an electronic system designed for investigators to search and retrieve de-identified medical records from our electronic archive system. Using these systems, we generated the SMC-TINCO registry (Samsung Medical Center Troponin in Non-cardiac Operation), a large single-center cohort containing data from 43,019 consecutive patients who had cTn I levels measured before or within 30 days after non-cardiac surgery between January 2010 and June 2019.

Our exclusion criteria for this study were: 1) patients who were younger than 18 at the time of surgery, 2) patients without postoperative cTn I measurements, 3) patients who had cardiac massage before the diagnosis of MINS, and 4) patients without intraoperative hemoglobin level measurements. Patients were divided according to significant intraoperative bleeding. Significant intraoperative bleeding was defined as an intraoperative lowest hemoglobin level < 7 g/dL, an intraoperative lowest hemoglobin level less than 50% of the preoperative measurement, or need for intraoperative packed RBC transfusion [1013].

Study outcomes and definitions

The primary outcome was MINS, which was defined as a peak cTn I level above the 99th percentile of the upper reference limit within 30 days after surgery. Elevations of cTn from non-ischemic etiology such as sepsis, pulmonary embolus, atrial fibrillation, cardioversion, or chronic elevation were excluded [3, 14]. Among 3,193 patients with postoperative cTn elevation, 110 patients were diagnosed with a non-ischemic cause, and 3,083 (19.4%) patients were diagnosed with MINS. Preoperative anemia was defined as a last preoperative hemoglobin level < 13 g/dL in men and < 12 g/dL in women [15]. Active cancer was defined as a histologic diagnosis of cancer within the 6 months prior to surgery [16]. High-risk surgery was defined as procedures with reported mortality risk >5% according to the 2014 European Society of Cardiology/Anesthesiology guidelines [17].

Perioperative cTn I measurement and blood management

Perioperative cTn I was measured for patients with moderate or high cardiovascular risk based on current guidelines [17], but it was also measured in patients with mild risk at the discretion or request of an attending clinician. An automated analyzer (Advia Centaur XP, Siemens Healthcare Diagnostics, Erlangen, Germany) was used. The lowest limit of detection was 6 ng/L, and the 99th percentile upper reference limit provided by the manufacturer was 40 ng/L [18]. Patients with elevated cTn levels were referred to cardiologists for further evaluation and management.

Preoperative hemoglobin measurement was included in routine preoperative blood tests, and packed RBCs were preoperatively transfused in anemic patients at the discretion of an attending clinician or at the request of an anesthesiologist. During the intraoperative period, hemoglobin measurement was not a routine procedure, but was selectively performed in patients suspected to have massive bleeding. Our indication for intraoperative transfusion of packed RBCs changed during the study period. Following the current guidelines at the time, the threshold of hemoglobin level for RBC transfusion was changed from 10 g/dL to 7 g/dL in January 2017 [1012]. Intraoperative transfusion was also performed at the discretion of the attending anesthesiologist or surgeon in patients with higher cardiovascular risk or anticipated massive bleeding.

Statistical analysis

For continuous variables, differences were compared by the t-test or the Mann-Whitney test and presented as the mean ± standard deviation or median with interquartile range. Categorical data are presented as number (%) and compared by using the chi-square or Fisher’s exact test, as applicable. The incidence of MINS was compared using a stratified logistic regression model and was reported as an adjusted odds ratio (OR) with 95% confidence interval (CI). Mortalities were compared with Cox regression analysis and reported as the hazard ratio (HR) with 95% CI. To retain a large sample size and maximize the study power while maintaining a balance in covariates between the two groups, we conducted rigorous adjustment for differences in baseline patient characteristics using weighted regression models with inverse probability weighting (IPW) [19]. According to this technique, weights for patients without significant bleeding were the inverse of the propensity score and weights for patients with significant bleeding were the inverse of 1 –the propensity score. For sensitivity analysis, we evaluated whether the observed association was significant in patients with chronic kidney disease and heart failure; we also tested whether this was significant after January 2017, when the threshold of hemoglobin for intraoperative transfusion was lowered to 7 g/dL. We also estimated the potential impact of unmeasured confounders by calculating the change in OR and CI according to associations of unmeasured confounders with significant bleeding and MINS, using an assumed unmeasured confounder with a prevalence of 40% [20]. To assess the efficacy of intraoperative hemoglobin level in predicting MINS, Pearson’s correlation coefficient and receiver-operating characteristic (ROC) plots were constructed to estimate the threshold for intraoperative hemoglobin level and compute the specificity and sensitivity. Statistical analyses were performed with R 3.6.1 (Vienna, Austria; http://www.R-project.org/). All tests were 2-tailed and p < 0.05 was considered statistically significant.

Results

Out of 43,019 patients in the registry, we excluded 1,154 patients who were younger than 18 at the time of surgery, 6,596 patients without postoperative cTn I measurements, 46 patients who had cardiac massage before the diagnosis of MINS, and 19,297 patients who did not have intraoperative hemoglobin levels. We included 15,926 patients in the final analysis (Fig 1).

Fig 1. Patient flowchart.

Fig 1

Patients were divided into two groups based on the presence of significant intraoperative bleeding: 13,416 (84.2%) patients had no significant bleeding, while 2,510 (15.8%) patients did have significant intraoperative bleeding (Table 1). After adjustment with multivariable analysis, the risk for MINS was significantly increased in the significant bleeding group (35.2% vs. 16.4%; OR, 1.80; 95% CI, 1.61–2.00; p < 0.001) (Table 2). After IPW adjustment, there was still an increased risk for MINS in the significant bleeding group (OR, 1.58; 95% CI, 1.43–1.75; p < 0.001) (Table 2). Subgroup analysis demonstrated that the association between significant bleeding and MINS was confounded by emergency surgery. The risk of MINS was significantly increased in patients with significant bleeding when undergoing elective surgery, but not when undergoing emergency surgery (Fig 2). In our sensitivity analysis, this association was consistently significant in patients with chronic kidney disease and heart failure, and after the hemoglobin threshold for intraoperative transfusion was lowered in 2017 (S1 Table). Significant bleeding was associated with MINS, even if the assumed unmeasured confounders were present in one of our groups with a prevalence up to 40%. (S2 Table).

Table 1. Baseline characteristics according to significant intraoperative bleeding.

Entire population IPW
No significant bleeding (N = 13416) Significant bleeding (N = 2510) ASD No significant bleeding (N = 13370.5) Significant bleeding (N = 2644.5) ASD
Male sex 8133 (60.6) 1562 (62.2) 3.3 8145.0 (60.9) 1658.9 (62.7) 3.7
Age (years) 61.7 (±13.5) 60.0 (±13.5) 12.4 61.5 (±13.6) 62.2 (±13.3) 5.0
Preoperative anemia 4949 (36.9) 1646 (65.6) 59.9 5497.0 (41.1) 1064.8 (40.3) 1.7
Diabetes 7890 (58.8) 1748 (69.6) 22.7 8019.3 (60.0) 1446.4 (54.7) 10.7
Hypertension 7290 (54.3) 1424 (56.7) 4.8 7331.9 (54.8) 1436.0 (54.3) 1.1
Current smoking 1362 (10.2) 236 (9.4) 2.5 1337.6 (10.0) 282.8 (10.7) 2.3
Current alcohol 2798 (20.9) 360 (14.3) 17.2 2639.6 (19.7) 556.3 (21.0) 3.2
Chronic kidney disease 680 (5.1) 332 (13.2) 28.6 850.8 (6.4) 166.3 (6.3) 0.3
History of ischemic heart disease 1913 (14.3) 365 (14.5) 0.8 1939.1 (14.5) 395.5 (15.0) 1.3
History of heart failure 282 (2.1) 45 (1.8) 2.2 277.8 (2.1) 51.3 (1.9) 1.0
History of stroke 938 (7.0) 161 (6.4) 2.3 926.8 (6.9) 176.3 (6.7) 1.1
History of arrhythmia 882 (6.6) 161 (6.4) 0.6 875.4 (6.5) 179.4 (6.8) 0.9
History of heart valve disease 149 (1.1) 21 (0.8) 2.8 143.2 (1.1) 25.9 (1.0) 0.9
Active cancer 7422 (55.3) 1112 (44.3) 22.2 7216.2 (54.0) 1555.1 (58.8) 9.8
Preoperative care
    RBC transfusion 608 (4.5) 151 (6.0) 6.6 638.0 (4.8) 123.2 (4.7) 0.5
    Intensive care unit 424 (3.2) 278 (11.1) 31.2 574.7 (4.3) 111.4 (4.2) 0.4
    ECMO 0 1 (0.0) 2.8 0 0.2 (0.0) 1.1
    Continuous renal replacement therapy 18 (0.1) 54 (2.2) 19.1 54.7 (0.4) 11.3 (0.4) 0.3
    Ventilator 67 (0.5) 56 (2.2) 15.0 101.2 (0.8) 18.9 (0.7) 0.5
Operative variables
    ESC/ESA surgical high risk 3997 (29.8) 1258 (50.1) 42.4 4306.0 (32.2) 748.8 (28.3) 8.5
    Emergency operation 1521 (11.3) 549 (21.9) 28.6 1745.6 (13.1) 354.4 (13.4) 1.0
    General anesthesia 13305 (99.2) 2500 (99.6) 5.5 13267.8 (99.2) 2610.5 (98.7) 5.2
    Operation duration, hours 3.94 (±2.14) 5.57 (±2.86) 64.4 4.20(±2.51 4.16±2.20) 1.7
    Continuous infusion of inotropes 4592 (34.2) 1278 (50.9) 34.2 4855.3 (36.3) 798.6 (30.2) 13.0
Types of surgery >0.99
    Vascular 981 (7.3) 169 (6.7)
    Orthopediatric 667 (5.0) 146 (5.8)
    Neuro 3317 (24.7) 166 (6.6)
    Breast or Endo 148 (1.1) 22 (0.9)
    Plastic or otolaryngeal or eye 279 (2.1) 53 (2.1)
    Transplantation 300 (2.2) 768 (30.6)
    Gynecology or urology 823 (6.1) 258 (10.3)
    Gastrointestinal 4559 (34.0) 741 (29.5)
    Noncardiac thoracic 2328 (17.4) 184 (7.3)
    Other 14 (0.1) 3 (0.1)

Data are presented as n (%) or mean (±standard deviation).

IPW, inverse probability weighting; ASD, absolute standardized mean difference; RBC, red blood cell; ECMO, extracorporeal membranous oxygenation; RAAS, renin-angiotensin-aldosterone system; ESC, European Society of Cardiology; ESA, European Society of Anesthesiology.

Table 2. The incidence of myocardial injury after noncardiac surgery and mortality.

Univariable analysis Multivariable analysis IPW analysis
No significant bleeding (N = 13416) Significant bleeding (N = 2510) Unadjusted OR/HR (95% CI) p value Adjusted OR/HR (95% CI) p value Adjusted OR/HR (95% CI) p value
MINS 2200 (16.4) 883 (35.2) 2.77 (2.52–3.04) < 0.001 1.80 (1.61–2.00) < 0.001 1.58 (1.43–1.75) < 0.001
30-day mortality 173 (1.3) 112 (4.5) 3.52 (2.77–4.46) < 0.001 2.04 (1.55–2.67) < 0.001 2.51 (1.91–3.28) < 0.001
Cardiovascular 50 (0.4) 28 (1.1) 3.04 (1.91–4.82) < 0.001 1.92 (1.13–3.27) 0.02 1.90 (1.10–3.29) < 0.001
Noncardiovascular 123 (0.9) 84 (3.3) 3.71 (2.81–4.90) < 0.001 2.10 (1.53–2.88) < 0.001 2.76 (2.02–3.76) < 0.001

Data are presented as n (%).

MINS was presented with OR, and mortalities were presented as HRs.

IPW, inverse probability weighting; MINS, myocardial injury after noncardiac surgery; OR, odds ratio; HR, hazard ratio; CI, confidence interval.

Fig 2. Forest plot for subgroup analysis.

Fig 2

Patients were also stratified into four groups to account for both hemoglobin decrease and the use of intraoperative RBC transfusion. There were 13,416 (84.2%) patients who had no hemoglobin decrease and no transfusion, 1,937 (12.2%) who had no hemoglobin decrease with transfusion, 275 (1.7%) who had a hemoglobin decrease without transfusion, and 298 (1.9%) who had hemoglobin decrease with transfusion (S3 Table). Compared to patients who had no hemoglobin decrease and no transfusion, the risk for MINS increased according to both hemoglobin decrease and receipt of RBC transfusion (OR, 2.04; 95% CI, 1.83–2.27; p < 0.001 for no hemoglobin decrease with transfusion; OR, 6.13; 95% CI, 4.81–7.82; p < 0.001 for hemoglobin decrease without transfusion; and OR, 8.66; 95% CI, 6.77–10.96; p < 0.001 for hemoglobin decrease with transfusion) (Table 3). When the patients were solely divided according to hemoglobin decrease without considering RBC transfusion, 15,353 (96.4%) patients had no hemoglobin decrease whereas 573 (3.6%) patients did have decreased hemoglobin (S4 Table). The incidence of MINS was substantially increased in the decreased hemoglobin group (58.3% vs. 17.9%; OR, 3.28; 95% CI, 2.70–4.00; p < 0.001) (S5 and S6 Tables).

Table 3. The incidence of myocardial after noncardiac surgery and mortality according to intraoperative hemoglobin decrease and transfusion.

No hemoglobin decrease without transfusion (N = 13416) No hemoglobin decrease with transfusion (N = 1937) Hemoglobin decrease without transfusion (N = 275) Hemoglobin decrease with transfusion (N = 298)
MINS, No (%) 2200 (16.4) 549 (28.3) 147 (53.5) 187 (62.8)
    Unadjusted OR (95% CI) 1 [reference] 2.02 (1.81–2.24) 5.85 (4.60–7.46) 8.59 (6.77–10.94)
    p value < 0.001 < 0.001 < 0.001
30-day mortality, No (%) 173 (1.3) 61 (3.1) 26 (9.5) 25 (8.4)
    Unadjusted HR (95% CI) 2.46 (1.84–3.30) 7.75 (5.14–11.71) 6.76 (4.45–10.29)
    p value < 0.001 < 0.001 < 0.001
Cardiovascular mortality, No (%) 50 (0.4) 17 (0.9) 9 (3.3) 2 (0.7)
    Unadjusted HR (95% CI) 2.37 (1.37–4.11) 9.23 (4.54–18.78) 1.87 (0.45–7.67)
    p value < 0.001 < 0.001 0.39
Non-cardiovascular mortality, No (%) 123 (0.9) 44 (2.3) 17 (6.2) 23 (7.7)
    Unadjusted HR (95% CI) 2.50 (1.77–3.52) 7.14 (4.30–11.86) 8.76 (5.61–13.67)
    p value < 0.001 < 0.001 < 0.001

Data are presented as n (%).

MINS was presented with OR, and mortalities were presented as HRs.

MINS, myocardial injury after noncardiac surgery; OR, odds ratio; HR, hazard ratio; CI, confidence interval.

The threshold for intraoperative hemoglobin level associated with MINS was estimated to be 9.9 g/dL in ROC analysis, and the area under the ROC curve was 0.643. Using this value, the sensitivity and specificity were 45.2 and 76.8%, respectively (Fig 3).

Fig 3. Receiver-operating characteristic curves for intraoperative hemoglobin level associated with myocardial injury after non-cardiac surgery.

Fig 3

Discussion

The main finding of this study was that the incidence of MINS was associated with intraoperative blood loss. The calculated threshold for intraoperative hemoglobin level associated with MINS was 9.9 g/dL. Our findings suggest that maintaining an adequate intraoperative hemoglobin level may be helpful for preventing MINS.

Intraoperative blood loss is a well-established risk factor for postoperative mortality and morbidity [6, 7]. Despite various possible causes, the most frequently proposed mechanism for MINS is oxygen supply/demand mismatch, and our previous study also showed that preoperative anemia was associated with MINS [21]. In this follow-up study, we demonstrated that blood loss during surgical procedures could also increase MINS. So, our results on the association between intraoperative hemoglobin decrease and the increased incidence of MINS can be explained by reduced oxygen-carrying capacity compromising the myocardial oxygen supply while simultaneously requiring higher cardiac output to maintain adequate systemic circulation [22]. Moreover, the cardiac effects of oxygen supply/demand mismatch can be aggravated in a high cardiac output state such as the perioperative period [14]. In this study, we demonstrated an association between blood loss and MINS, reinforcing the importance of avoiding intraoperative anemia. However, there are issues that require discussion.

First, definitive criteria for intraoperative blood loss have not been established, and the definitions of bleeding vary between studies on surgical patients. In this study, we selected patients whose intraoperative hemoglobin level decreased below 7 g/dL, which is generally assumed to be the level that most patients can tolerate [1012, 23]. However, by selecting patients only according to absolute hemoglobin level, the amount of bleeding in patients with a high baseline hemoglobin may be underestimated, or the degree of intraoperative anemia that can be safely tolerated in chronically anemic patients may be overlooked. Therefore, we also applied a relative hemoglobin threshold of less than 50% from baseline to define significant bleeding, which has previously been associated with adverse outcomes [13]. Our primary analysis based on these composite criteria demonstrated a significant association between intraoperative bleeding and MINS. However, in this setting, it was uncertain whether the increased incidence of MINS was caused by the low hemoglobin level or receipt of transfusion, the side effects of which could also elevate cardiac troponin [24]. Therefore, we further conducted an analysis by separately considering RBC transfusion during the surgery and the actual decrease in hemoglobin.

The four-group comparison according to hemoglobin reduction and receipt of RBC transfusion showed that groups with decreased hemoglobin had increased MINS risk regardless of transfusion status. In addition, MINS risk was greater for patients with actual hemoglobin reduction regardless of transfusion status. Together, these results suggest that maintaining an adequate hemoglobin level may be more effective in preventing MINS than minimizing RBC transfusion. Previous studies also showed that intraoperatively transfused RBCs could not improve oxygenation, which is critical for MINS prevention [25, 26]. In addition, in patients with a hemoglobin decrease, the incidence of MINS was increased by RBC transfusion, suggesting that transfusion side effects might also contribute to the occurrence of MINS [4, 6, 9]. Despite the current guidelines advocating restrictive use of blood transfusion during surgical procedures, our findings suggest that the hemoglobin threshold for intraoperative transfusion may be higher than 7g/dL in order to prevent MINS [1012, 17]. However, the net effect of intraoperative transfusion has long been controversial and inconclusive [8].

The observed association between intraoperative bleeding was significant in most of subgroups with risk factors for MINS. However, it was not significant in patients undergoing emergency surgery. This may be because patients requiring emergency surgery include those with preoperative hemodynamic instability or massive bleeding, which could be strongly associated with cTn elevation. These events causing a large fluctuation of hemoglobin levels from the preoperative period might have diluted the effect of intraoperative blood loss. In addition, the observed association between intraoperative blood loss and MINS was significant before and after lowering the institutional threshold for intraoperative RBC transfusion from 10 g/dL to 7 g/dL at January 2017.

The threshold of intraoperative hemoglobin level associated with MINS was estimated to be 9.9 g/dL in this study, higher than the currently suggested guidelines [1012]. Instead, this estimated level is in line with the levels recommended for patients with high cardiovascular risks such as anemia, bleeding, and ischemic disease [10, 27]. Indeed, this study was conducted among 15,926 patients who needed intraoperative hemoglobin measurements; a larger number of patients (19,297) who did not need intraoperative hemoglobin measurement were excluded. Moreover, the entire registry inherently contains patients with some level of cardiovascular risk who were selected for perioperative cTn measurements. Another limitation of this estimate is that the area under the ROC curve was 0.643, reflecting a relatively low predictive value. This may be due to multifactorial nature of MINS and suggests that factors other than blood loss and receipt of transfusion need to be considered to predict MINS.

Our study has several limitations. First, this is a single-center, observational study; the possibility of selection bias or unmeasured confounding factors exists. In addition, our data may not be generalizable to populations in other countries considering ethnic differences in blood management. In addition, this study contains all types of noncardiac surgery, and the result might be different in particular types of surgery. Second, perioperative cTn I measurement was not included as a routine clinical practice at our institution. Although the measurement followed the institutional protocol, it was usually performed in patients with a high cardiovascular risk; therefore, our results may have been exaggerated by selection bias. Third, a detailed protocol for perioperative blood management was absent, and intraoperative hemoglobin measurement was selectively performed. In addition, RBC transfusion was treated as a binary variable in the analyses; the number of transfused packed RBC units was not considered. Despite these limitations, this is the first study to evaluate the occurrence of MINS according to intraoperative blood loss, suggesting the need for further studies on this subject.

Conclusion

Intraoperative blood loss appeared to be associated with MINS, and further studies are needed.

Supporting information

S1 Table. Sensitivity analysis of the observed association between significant bleeding and myocardial injury after noncardiac surgery.

(DOCX)

S2 Table. Sensitivity analysis of the effect of an unmeasured confounder on odds ratio of significant bleeding for myocardial injury after noncardiac surgery.

(DOCX)

S3 Table. Baseline characteristics according to the actual hemoglobin decrease and intraoperative transfusion.

(DOCX)

S4 Table. Baseline characteristics according to the actual hemoglobin decrease without regarding intraoperative transfusion.

(DOCX)

S5 Table. The incidence of myocardial injury after noncardiac surgery and mortality according to the actual hemoglobin decrease without regarding intraoperative transfusion.

(DOCX)

S6 Table. Sensitivity analysis of the effect of an unmeasured confounder on odds ratio of hemoglobin decrease for myocardial injury after noncardiac surgery.

(DOCX)

Data Availability

The data we used for this study was curated using Clinical Data Warehouse (CDW) which psuedonomynize the data from our institutional electronic medical records. So, our data is deidentified by eliminating all identifiable variables such as name, social security number, hospital number, and etc. However, it is illegal to open this data to the public without restriction. Regarding the availability of our data, please contact jong-hwan.park@samsung.com, the head of our institutional data security department.

Funding Statement

Unfunded studies.

References

  • 1.Sessler DI, Khanna AK. Perioperative myocardial injury and the contribution of hypotension. Intensive Care Med. 2018; 44:811–22. 10.1007/s00134-018-5224-7 [DOI] [PubMed] [Google Scholar]
  • 2.Weiser TG, Regenbogen SE, Thompson KD, Haynes AB, Lipsitz SR, Berry WR, et al. An estimation of the global volume of surgery: a modelling strategy based on available data. Lancet. 2008; 372:139–44. 10.1016/S0140-6736(08)60878-8 [DOI] [PubMed] [Google Scholar]
  • 3.Devereaux PJ, Szczeklik W. Myocardial injury after non-cardiac surgery: diagnosis and management. Eur Heart J. 2019. 10.1093/eurheartj/ehz301 [DOI] [PubMed] [Google Scholar]
  • 4.Docherty AB, O’Donnell R, Brunskill S, Trivella M, Doree C, Holst L, et al. Effect of restrictive versus liberal transfusion strategies on outcomes in patients with cardiovascular disease in a non-cardiac surgery setting: systematic review and meta-analysis. BMJ. 2016; 352:i1351 10.1136/bmj.i1351 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Musallam KM, Tamim HM, Richards T, Spahn DR, Rosendaal FR, Habbal A, et al. Preoperative anaemia and postoperative outcomes in non-cardiac surgery: a retrospective cohort study. Lancet. 2011; 378:1396–407. 10.1016/S0140-6736(11)61381-0 [DOI] [PubMed] [Google Scholar]
  • 6.Wu WC, Smith TS, Henderson WG, Eaton CB, Poses RM, Uttley G, et al. Operative blood loss, blood transfusion, and 30-day mortality in older patients after major noncardiac surgery. Ann Surg. 2010; 252:11–7. 10.1097/SLA.0b013e3181e3e43f [DOI] [PubMed] [Google Scholar]
  • 7.Wolters U, Wolf T, Stutzer H, Schroder T. ASA classification and perioperative variables as predictors of postoperative outcome. Br J Anaesth. 1996; 77:217–22. 10.1093/bja/77.2.217 [DOI] [PubMed] [Google Scholar]
  • 8.Shander A, Javidroozi M, Ozawa S, Hare GM. What is really dangerous: anaemia or transfusion? Br J Anaesth. 2011; 107 Suppl 1:i41–59. 10.1093/bja/aer350 [DOI] [PubMed] [Google Scholar]
  • 9.Association of Anaesthetists of Great Britain and Ireland, Thomas D, Wee M, Clyburn P, Walker I, Brohi K, et al. Blood transfusion and the anaesthetist: management of massive haemorrhage. Anaesthesia. 2010; 65:1153–61. 10.1111/j.1365-2044.2010.06538.x [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Carson JL, Grossman BJ, Kleinman S, Tinmouth AT, Marques MB, Fung MK, et al. Red blood cell transfusion: a clinical practice guideline from the AABB*. Ann Intern Med. 2012; 157:49–58. 10.7326/0003-4819-157-1-201206190-00429 [DOI] [PubMed] [Google Scholar]
  • 11.Retter A, Wyncoll D, Pearse R, Carson D, McKechnie S, Stanworth S, et al. Guidelines on the management of anaemia and red cell transfusion in adult critically ill patients. Br J Haematol. 2013; 160:445–64. 10.1111/bjh.12143 [DOI] [PubMed] [Google Scholar]
  • 12.Murphy MF, Wallington TB, Kelsey P, Boulton F, Bruce M, Cohen H, et al. Guidelines for the clinical use of red cell transfusions. Br J Haematol. 2001; 113:24–31. 10.1046/j.1365-2141.2001.02701.x [DOI] [PubMed] [Google Scholar]
  • 13.Hogervorst E, Rosseel P, van der Bom J, Bentala M, Brand A, van der Meer N, et al. Tolerance of intraoperative hemoglobin decrease during cardiac surgery. Transfusion. 2014; 54:2696–704. 10.1111/trf.12654 [DOI] [PubMed] [Google Scholar]
  • 14.Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, et al. Fourth universal definition of myocardial infarction (2018). Eur Heart J. 2019; 40:237–69. 10.1093/eurheartj/ehy462 [DOI] [PubMed] [Google Scholar]
  • 15.Lundström U. Iron deficiency anaemia: Assessment, prevention, and control. Gut. 2001 [Google Scholar]
  • 16.Lee AYY, Kamphuisen PW, Meyer G, Bauersachs R, Janas MS, Jarner MF, et al. Tinzaparin vs Warfarin for Treatment of Acute Venous Thromboembolism in Patients With Active Cancer: A Randomized Clinical Trial. JAMA. 2015; 314:677–86. 10.1001/jama.2015.9243 [DOI] [PubMed] [Google Scholar]
  • 17.Kristensen SD, Knuuti J. New ESC/ESA Guidelines on non-cardiac surgery: cardiovascular assessment and management. Eur Heart J. 2014; 35:2344–5. 10.1093/eurheartj/ehu285 [DOI] [PubMed] [Google Scholar]
  • 18.Mahajan VS, Jarolim P. How to interpret elevated cardiac troponin levels. Circulation. 2011; 124:2350–4. 10.1161/CIRCULATIONAHA.111.023697 [DOI] [PubMed] [Google Scholar]
  • 19.Austin PC, Stuart EA. Moving towards best practice when using inverse probability of treatment weighting (IPTW) using the propensity score to estimate causal treatment effects in observational studies. Stat Med. 2015; 34:3661–79. 10.1002/sim.6607 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20.Groenwold RH, Nelson DB, Nichol KL, Hoes AW, Hak E. Sensitivity analyses to estimate the potential impact of unmeasured confounding in causal research. Int J Epidemiol. 2010; 39:107–17. 10.1093/ije/dyp332 [DOI] [PubMed] [Google Scholar]
  • 21.Kwon JH, Park J, Lee SH, Lee JH, Min JJ, Kim J, et al. Pre-operative anaemia and myocardial injury after noncardiac surgery: A retrospective study. Eur J Anaesth. 2021; 37:1–9. 10.1097/EJA.0000000000001421 [DOI] [PubMed] [Google Scholar]
  • 22.Sabatine MS, Morrow DA, Giugliano RP, Burton PB, Murphy SA, McCabe CH, et al. Association of hemoglobin levels with clinical outcomes in acute coronary syndromes. Circulation. 2005; 111:2042–9. 10.1161/01.CIR.0000162477.70955.5F [DOI] [PubMed] [Google Scholar]
  • 23.Karkouti K, Wijeysundera DN, Yau TM, McCluskey SA, van Rensburg A, Beattie WS. The influence of baseline hemoglobin concentration on tolerance of anemia in cardiac surgery. Transfusion. 2008; 48:666–72. 10.1111/j.1537-2995.2007.01590.x [DOI] [PubMed] [Google Scholar]
  • 24.Agewall S, Giannitsis E, Jernberg T, Katus H. Troponin elevation in coronary vs. non-coronary disease. Eur Heart J. 2011; 32:404–11. 10.1093/eurheartj/ehq456 [DOI] [PubMed] [Google Scholar]
  • 25.Zimmerman R, Tsai AG, Salazar Vazquez BY, Cabrales P, Hofmann A, Meier J, et al. Posttransfusion Increase of Hematocrit per se Does Not Improve Circulatory Oxygen Delivery due to Increased Blood Viscosity. Anesth Analg. 2017; 124:1547–54. 10.1213/ANE.0000000000002008 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Roberson RS, Bennett-Guerrero E. Impact of red blood cell transfusion on global and regional measures of oxygenation. Mt Sinai J Med. 2012; 79:66–74. 10.1002/msj.21284 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Ding YY, Kader B, Christiansen CL, Berlowitz DR. Hemoglobin Level and Hospital Mortality Among ICU Patients With Cardiac Disease Who Received Transfusions. J Am Coll Cardiol. 2015; 66:2510–8. 10.1016/j.jacc.2015.09.057 [DOI] [PubMed] [Google Scholar]

Decision Letter 0

Wen-Chih Hank Wu

24 Jun 2020

PONE-D-20-14264

Intraoperative blood loss may be associated with myocardial injury after non-cardiac surgery

PLOS ONE

Dear Dr. Lee,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Specifically, strongly consider the suggestions of reviewer one by minimizing exclusion criteria for the overall analysis and conduct sensitivity analyses based on the specific exclusions.

Please submit your revised manuscript by Aug 08 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Wen-Chih Wu, MD, MPH

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. Please include captions for your Supporting Information files at the end of your manuscript, and update any in-text citations to match accordingly. Please see our Supporting Information guidelines for more information: http://journals.plos.org/plosone/s/supporting-information

3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. 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 #1: Partly

Reviewer #2: Partly

**********

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

**********

3. 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 #1: No

Reviewer #2: Yes

**********

4. 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 #1: Yes

Reviewer #2: Yes

**********

5. 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 #1: I have uploaded an attachment as a word file xxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxxx

Reviewer #2: Overall well written paper confirming pre-existing literature.

Database/registry study with many limitations, most of which were addressed in the text of the paper. They acknowledged that more studies (more rigorously conducted studies to be specific) need to be conducted to support their conclusions and essentially this study is mostly hypothesis generating.

Large population included in study and overall well conducted (given limitations of registry) so does add some controversy to literature that is worth considering (changing transfusion 'triggers' in high risk populations to avoid MINS).

There were significant differences in baseline characteristics in patients who had blood loss versus those that didn't therefore there were many confounding factors that could influence reasons for these patients to have more MINS besides just blood loss, not sure all of this was accounted for by the statistics or fully explained/justified.

Few errors in supplemental tables that need to be corrected - Supplemental Table 1 has a category of surgery "Orthopediatric" since all patients were above age 18 I can only assume this should be 'Orthopedic'. Supplemental Table 3 says "ionotropics" should read 'ionotropes'.

**********

6. 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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

Attachment

Submitted filename: PONE-D-20-14264.docx

PLoS One. 2021 Feb 24;16(2):e0241114. doi: 10.1371/journal.pone.0241114.r002

Author response to Decision Letter 0


17 Jul 2020

July, 2020

Dr. Wen Chih-Wu

Academic Editor

PLOS ONE

Revision of the manuscript

PONE-D-20-14264

“Intraoperative blood loss may be associated with myocardial injury after non-cardiac surgery”

Dear Editor,

Thank you for your letter dated June 24th, regarding our submitted manuscript. We appreciate the opportunity to resubmit our revised manuscript entitled “Intraoperative blood loss may be associated with myocardial injury after non-cardiac surgery”. We thank you for your constructive criticisms and suggestions for revision, which improved the presentation of our paper significantly. In this revision, we did our best to fully accommodate the comments and questions.

The specific revisions and corrections made in point-by-point response to the editor and reviewers are presented in the following response letter.

All authors have read and approved its submission to the PLOS ONE and have contributed significantly to this work. The whole manuscript or part of it, neither has been published and is not being considered for publication elsewhere in any language except as an abstract. None of the authors have any financial relationships with any company or any other bias or conflict of interest.

We hope that the revised version is now acceptable for publication in PLOS ONE.

.

Sincerely,

Seung-Hwa Lee, MD, Division of Cardiology, Department of Medicine, Heart Vascular Stroke Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul, Korea.

Tel: +82-2-3410-3214; Fax: +82-2-3410-3849

E-mail address: shuaaa.lee@samsung.com

Response to the Reviewers

Reviewer #1.

Major comments

Introduction: our current understanding of MINS is not, as the authors state, principally myocardial oxygen supply/demand imbalance (which more accurately describes Type 2 myocardial infarction according to the 4th universal definition as published by the American College of Cardiology) but is pathophysiologically undefined. Exact causation has not been established but it is likely a heterogenous syndrome of cardiac myocyte necrosis secondary to ischemia, inflammation, immunological stress reaction (mostly through circulating cytokines such as TNF-alpha), and neuroendocrine dysregulation, and as such has a large number of potential clinical correlates. MINS is therefore more accurately a biomarker for increased postoperative morbidity and mortality from a range of sources.

>> Response: We thank you for your kind comments. Following your recommendation, we changed the Introduction section as below.

“During surgical procedures, massive blood loss can be frequently encountered and can lead to decreased hemoglobin level, and oxygen supply/demand mismatch has been proposed as one of mechanisms for the occurrence of MINS [3].” (Line 78)

The authors have excluded patients with conditions that cause raised troponin elevation (such as renal impairment, heart failure, sepsis, atrial fibrillation, pulmonary embolism etc.) as these are regarded as artefactual troponin rises. This is can be a legitimate decision, but requires justification. These conditions are often co-morbid with MINS as they share a common pathology (inflammatory response to tissue trauma), so true MINS incidence may be missed. This could be screened for using a sensitivity analysis, as was done for renal impairment and heart failure in the original VISION paper (1), where the MINS concept was first popularised.

>> Response: We agree with reviewer that other conditions related to troponin elevation should have been more carefully analysed, so we added the sensitivity analysis as below.

“For sensitivity analysis, we evaluated whether the observed association was significant in patients with chronic kidney disease and heart failure and after January 2017 when the threshold of hemoglobin for intraoperative transfusion was lowered to 7 g/dL.” (Line 166)

“In the sensitivity analysis, this association was consistently found to be significant in patients with chronic kidney disease and heart failure and after lowering the threshold of hemoglobin for intraoperative transfusion in 2017 (S1 Table).” (Line 197)

“The observed association between intraoperative bleeding was shown to be significant in most of subgroups with risk factor for MINS.” (Line 287)

Supplemental table 1. Sensitivity Analysis of the Observed Association between Significant Bleeding and Myocardial Injury after Noncardiac Surgery

  OR (95% CI) P-value

Patients with heart failure (n=327) 4.63 (2.42-9.05) <0.001

Patients with chronic kidney disease (n=1012) 1.17 (0.86-1.59) <0.001

Surgeries after 2017 with the threshold of

hemoglobin level < 7 g/dL for intraoperative transfusion 2.20 (1.94-2.50) <0.001

OR, odds ratio; CI, confidence interval; RBC, red blood cell

There is a significant clinical and statistical difference in baseline characteristics between the bleeding and non-bleeding cohorts, with regard to anemia, alcohol use, chronic kidney disease, active cancer, being in ICU, continuous renal replacement therapy, ventilation, surgical risk, emergency operation status and requirement for continuous inotropic support. All of these affect the risk of MINS, and therefore confound the effect of bleeding on the incidence of MINS. This is a major limitation.

>> Response: We fully agree with the reviewer that there is a large difference in baseline characteristics of the two groups. So, we conducted inverse probability weighting for statistical adjustment for the difference. The result was not changed after mor rigrous statistical adjustment. Addistionally for clarification, we added in the limitation section that it could stll be biased by unmaseured confounders despite statistical adjustment.

” To retain a large sample size and maximize the study power while maintaining a balance in covariates between the two groups, we conducted rigorous adjustment for differences in baseline characteristics of patients using the weighted regression models with the inverse probability weighting (IPW) [19]. According to this technique, weights for patients without significant bleeding were the inverse of the propensity score and weights for patients with significant bleeding were the inverse of 1 – the propensity score.” (Line 160)

“First, this is a single-center, observational study; the possibility of selection bias or unmeasured confounding factors exists. Also, our data may not be generalized to populations in other countries considering ethnic differences in blood management.” (Line 307)

Table 1. Baseline characteristics according to significant intraoperative bleeding.

Entire population IPW

  No significant bleeding

(N = 13416) Significant bleeding

(N = 2510) ASD No significant bleeding

(N = 13370.5) Significant bleeding

(N = 2644.5) ASD

Male 8133 (60.6) 1562 (62.2) 3.3 8145.0 (60.9) 1658.9 (62.7) 3.7

Age 61.7 (±13.5) 60.0 (±13.5) 12.4 61.5 (±13.6) 62.2 (±13.3) 5.0

Preoperative anemia 4949 (36.9) 1646 (65.6) 59.9 5497.0 (41.1) 1064.8 (40.3) 1.7

Diabetes 7890 (58.8) 1748 (69.6) 22.7 8019.3 (60.0) 1446.4 (54.7) 10.7

Hypertension 7290 (54.3) 1424 (56.7) 4.8 7331.9 (54.8) 1436.0 (54.3) 1.1

Current smoking 1362 (10.2) 236 (9.4) 2.5 1337.6 (10.0) 282.8 (10.7) 2.3

Current alcohol 2798 (20.9) 360 (14.3) 17.2 2639.6 (19.7) 556.3 (21.0) 3.2

Chronic kidney disease 680 (5.1) 332 (13.2) 28.6 850.8 (6.4) 166.3 (6.3) 0.3

History of ischemic heart disease 1913 (14.3) 365 (14.5) 0.8 1939.1 (14.5) 395.5 (15.0) 1.3

History of heart failure 282 (2.1) 45 (1.8) 2.2 277.8 (2.1) 51.3 (1.9) 1.0

History of stroke 938 (7.0) 161 (6.4) 2.3 926.8 (6.9) 176.3 (6.7) 1.1

History of arrhythmia 882 (6.6) 161 (6.4) 0.6 875.4 (6.5) 179.4 (6.8) 0.9

History of heart valve disease 149 (1.1) 21 (0.8) 2.8 143.2 (1.1) 25.9 (1.0) 0.9

Active cancer 7422 (55.3) 1112 (44.3) 22.2 7216.2 (54.0) 1555.1 (58.8) 9.8

Preoperative care

RBC transfusion 608 (4.5) 151 (6.0) 6.6 638.0 (4.8) 123.2 (4.7) 0.5

Intensive care unit 424 (3.2) 278 (11.1) 31.2 574.7 (4.3) 111.4 (4.2) 0.4

ECMO 0 1 (0.0) 2.8 0 0.2 (0.0) 1.1

Continuous renal replacement therapy 18 (0.1) 54 (2.2) 19.1 54.7 (0.4) 11.3 (0.4) 0.3

Ventilator 67 (0.5) 56 (2.2) 15.0 101.2 (0.8) 18.9 (0.7) 0.5

Operative variables

ESC/ESA surgical high risk 3997 (29.8) 1258 (50.1) 42.4 4306.0 (32.2) 748.8 (28.3) 8.5

Emergency operation 1521 (11.3) 549 (21.9) 28.6 1745.6 (13.1) 354.4 (13.4) 1.0

General anesthesia 13305 (99.2) 2500 (99.6) 5.5 13267.8 (99.2) 2610.5 (98.7) 5.2

Operation duration, hours 3.94 (±2.14) 5.57 (±2.86) 64.4 4.20(±2.51 4.16±2.20) 1.7

Continuous infusion of inotropes 4592 (34.2) 1278 (50.9) 34.2 4855.3 (36.3) 798.6 (30.2) 13.0

Types of surgery >0.99

Vascular 981 (7.3) 169 (6.7)

Orthopedic 667 (5.0) 146 (5.8)

Neuro 3317 (24.7) 166 (6.6)

Breast or Endo 148 (1.1) 22 (0.9)

Plastic or Otolaryngeal or Eye 279 (2.1) 53 (2.1)

Transplantation 300 (2.2) 768 (30.6)

Gynecology or Urology 823 (6.1) 258 (10.3)

Gastrointestinal 4559 (34.0) 741 (29.5)

Noncardiac thoracic 2328 (17.4) 184 (7.3)

Others 14 (0.1) 3 (0.1)

Data are presented as n (%) or mean (±standard deviation)

IPW, inverse probability weighting; ASD, absolute standardized mean difference; RBC, red blood cell; ECMO, extracorporeal membranous oxygenation; RAAS, renin-angiotensin-aldosterone system; ESC, European Society of Cardiology; ESA, European Society of Anaesthesiology

The authors state that they have made an estimate of the effect of potential unmeasured confounders (presumably with a sensitivity analysis with a null variable although this is not explicitly stated). This technique requires more explanation, particularly in view of the very disparate and potentially powerfully confounding medical statuses of the two groups in the cohort. Sensitivity analysis is usually used in epidemiology to model the potential effect of a variable which is known or postulated from prior experience or research, but unmeasured in the study at hand. For example, “I think having X increases risk of MINS by OR 2, what effect would it have on my results if it 20% of my MINS group had X? What about 40%? Etc.” This enables you to make a statement such as “Even if X were present in one of my groups with prevalence up to 40%, it would not have changed the result”. How it was used in this study requires more explanation in the text. This technique does not compensate for the confounding caused by the major differences in medical status and operation type mentioned already.

>> Response: We agree that the statistical method and results of our sensitivity analysis needs more explanation. So, we added as below to the Method and Result sections.

“We also estimated the potential impact of unmeasured confounders by calculating the change of OR and CI according to the associations of unmeasured confounders with significant bleeding and MINS with an assumed unmeasured confounder with prevalence of 40% [20].” (Line 168)

“Significant bleeding was associated with MINS, even if the assumed unmeasured confounders were present in one of our groups with prevalence up to 40%. (S2 Table)” (Line 199)

The authors analyse their data with two different definitions of significant blood loss (including and excluding whether transfusion was required). This is confusing. They could consider picking one definition of bleeding and analysing that as the primary outcome, and then if they wanted to explore the interaction of transfusion they could do that as a secondary analysis (perhaps using matched pairs controlled for hemoglobin drop or some similar technique). Alternatively, they could divide the groups into a two-by-two table (hemoglobin decrease/transfusion) and just make this the primary reported result (as they did in table s5), skipping the intermediate steps. This would be an important result, as transfusion has it’s own risks that may be associated with MINS, and disentangling it from the effect of the bleeding event itself, and anemia, is important.

>> Response: We agree that presenting two analyses might be confusing for ther readers. Following your recommendation, we only used definition of significant blood loss as our primary analysis. We conducted for group comparison according to bleeding and intraoperative transfusion and the analysis according to the actual decrease of hemoglobin was presented as a supplemental table.

“The patients for this study were divided according to significant intraoperative bleeding. Significant intraoperative bleeding was defined as an absolute value of intraoperative lowest hemoglobin level < 7 g/dL, relative value intraoperative lowest hemoglobin level less than 50% of preoperative measurement, or need for intraoperative packed RBC transfusion [10-13].” (Line 116)

“After an adjustment with multivariable analysis, the risk for MINS was found to be significantly increased for the significant bleeding group (35.2% vs. 16.4%; OR, 1.80; 95% CI, 1.61–2.00; p < 0.001) (Table 2). The result after IPW adjustment also showed an increased risk for MINS for the significant bleeding group (OR, 1.58; 95% CI, 1.43–1.75; p < 0.001) (Table 2).” (Line 189)

“Compared with the no hemoglobin decrease without transfusion group, the risk for MINS increased according to both hemoglobin decrease and receipt of RBC transfusion (OR, 2.04; 95% CI, 1.83–2.27; p < 0.001 for no hemoglobin decrease with transfusion; OR, 6.13; 95% CI, 4.81–7.82; p < 0.001 for hemoglobin decrease without transfusion; and OR, 8.66; 95% CI, 6.77–10.96; p < 0.001 for hemoglobin decrease with transfusion) (Table 3). When the patients solely divided according to hemoglobin decrease without considering RBC transfusion, 15,353 (96.4%) patients were in the no hemoglobin decrease group and 573 (3.6%) patients were in the hemoglobin decrease group (S4 Table), the incidence of MINS was substantially increased in the hemoglobin decrease group (58.3% vs. 17.9%; OR, 3.28; 95% CI, 2.70–4.00; p < 0.001) (S5 and S6 Tables).” (Line 209)

Table 2. The incidence of myocardial injury after noncardiac surgery and mortality.

Univariable analysis Multivariable analysis IPW analysis

 

  No significant bleeding

(N = 13416) Significant bleeding

(N = 2510) Unadjusted OR/HR (95% CI) p value Adjusted OR/HR (95% CI) p value Adjusted OR/HR (95% CI) p value

MINS 2200 (16.4) 883 (35.2) 2.77 (2.52-3.04) < 0.001 1.80 (1.61-2.00) < 0.001 1.58 (1.43-1.75) < 0.001

30-day mortality 173 (1.3) 112 (4.5) 3.52 (2.77-4.46) < 0.001 2.04 (1.55-2.67) < 0.001 2.51 (1.91-3.28) < 0.001

Cardiovascular 50 (0.4) 28 (1.1) 3.04 (1.91-4.82) < 0.001 1.92 (1.13-3.27) 0.02 1.90 (1.10-3.29) < 0.001

Noncardiovascular 123 (0.9) 84 (3.3) 3.71 (2.81-4.90) < 0.001 2.10 (1.53-2.88) < 0.001 2.76 (2.02-3.76) < 0.001

Data are presented as n (%)

MINS was presented with OR, and mortalities were presented as HR

IPW, inverse probability weighting; MINS, myocardial injury after noncardiac surgery; OR, odds ratio; HR, hazard ratio; CI, confidence interval

Table 3. The incidence of myocardial after noncardiac surgery and mortality according to intraoperative hemoglobin decrease and transfusion.

  No hemoglobin decrease without transfusion

(N = 13416) No hemoglobin decrease with transfusion

(N = 1937) Hemoglobin decrease without transfusion

(N = 275) Hemoglobin decrease with transfusion

(N = 298)

 

MINS, No (%) 2200 (16.4) 549 (28.3) 147 (53.5) 187 (62.8)

Unadjusted OR (95% CI) 1 [reference] 2.02 (1.81-2.24) 5.85 (4.60-7.46) 8.59 (6.77-10.94)

p value < 0.001 < 0.001 < 0.001

30-day mortality, No (%) 173 (1.3) 61 (3.1) 26 (9.5) 25 (8.4)

Unadjusted HR (95% CI) 2.46 (1.84-3.30) 7.75 (5.14-11.71) 6.76 (4.45-10.29)

p value < 0.001 < 0.001 < 0.001

Cardiovascular mortality, No (%) 50 (0.4) 17 (0.9) 9 (3.3) 2 (0.7)

Unadjusted HR (95% CI) 2.37 (1.37-4.11) 9.23 (4.54-18.78) 1.87 (0.45-7.67)

p value < 0.001 < 0.001 0.39

Non-cardiovascular mortality, No (%) 123 (0.9) 44 (2.3) 17 (6.2) 23 (7.7)

Unadjusted HR (95% CI) 2.50 (1.77-3.52) 7.14 (4.30-11.86) 8.76 (5.61-13.67)

p value < 0.001 < 0.001 < 0.001

Data are presented as n (%)

MINS was presented with OR, and mortalities were presented as HR

MINS, myocardial injury after noncardiac surgery; OR, odds ratio; HR, hazard ratio; CI, confidence interval

Supplemental table 4. Baseline Characteristics According to the Actual Hemoglobin Decrease without Regarding Intraoperative Transfusion

  No hemoglobin decrease Hemoglobin decrease P Value

(N = 15353) (N = 573)

Male 9387 (61.1) 308 (53.8) <0.001

Age 61.6 (±13.5) 55.8 (±13.5) <0.001

Preoperative anemia 6119 (39.9) 476 (83.1) <0.001

Diabetes 9219 (60.0) 419 (73.1) <0.001

Hypertension 8401 (54.7) 313 (54.6) 0.99

Current smoking 1527 (9.9) 71 (12.1) 0.07

Current alcohol 3063 (20.0) 95 (16.6) 0.05

Chronic kidney disease 907 (5.9) 105 (18.3) <0.001

History of ischemic heart disease 2212 (14.4) 66 (11.5) 0.06

History of heart failure 322 (2.1) 5 (0.9) 0.06

History of stroke 1062 (6.9) 37 (6.5) 0.73

History of arrhythmia 1021 (6.7) 22 (3.8) 0.01

History of heart valve disease 165 (1.1) 5 (0.9) 0.8

Active cancer 8372 (54.5) 162 (28.3) <0.001

Preoperative care

RBC transfusion 695 (4.5) 64 (11.2) <0.001

Intensive care unit 570 (3.7) 132 (23.0) <0.001

ECMO 1 (0.0) 0 >0.99

Continuous renal replacement therapy 37 (0.2) 35 (6.1) <0.001

Ventilator 90 (0.6) 33 (5.8) <0.001

Operative variables

ESC/ESA surgical high risk 4905 (31.9) 350 (61.1) <0.001

Emergency operation 1854 (12.1) 216 (37.7) <0.001

General anesthesia 15235 (99.2) 570 (99.5) 0.68

Operation duration, hours 4.09 (±2.24) 6.95 (±3.26) <0.001

Continuous infusion of inotropes 5483 (35.7) 387 (67.5) <0.001

Types of surgery

Vascular 1090 (7.1) 31 (5.4)

Orthopedic 800 (5.2) 28 (4.9)

Neuro 3449 (22.5) 36 (6.3)

Breast or Endo 165 (1.1) 5 (0.9)

Plastic or Otolaryngeal or Eye 318 (2.1) 15 (2.6)

Transplantation 773 (5.0) 295 (51.5)

Gynecology or Urology 1062 (6.9) 38 (6.6)

Gastrointestinal 5176 (33.7) 112 (19.5)

Noncardiac thoracic 2494 (16.2) 13 (2.3)

Others 26 (0.2) 0

Data are presented as n (%) or mean (±standard deviation)

RBC, red blood cell; ECMO, extracorporeal membranous oxygenation; RAAS, renin-angiotensin-aldosterone system; ESC, European Society of Cardiology; ESA, European Society of Anaesthesiology

Supplemental table 5. The Incidence of Myocardial Injury after Noncardiac Surgery and Mortality According to the Actual Hemoglobin Decrease without Regarding Intraoperative Transfusion

 

  No hemoglobin decrease

(N = 15353) Hemoglobin decrease

(N = 573) Unadjusted OR/HR (95% CI) p value Adjusted OR/HR (95% CI) p value

MINS 2749 (17.9) 334 (58.3) 6.41 (5.40-7.61) < 0.001 3.28 (2.70-4.00) < 0.001

30-day mortality 234 (1.5) 51 (8.9) 6.11 (4.52-8.27) < 0.001 2.52 (1.75-3.63) < 0.001

Cardiovascular 67 (0.4) 11 (1.9) 4.58 (2.42-8.66) < 0.001 2.01 (0.94-4.32) 0.07

Noncardiovascular 167 (1.1) 40 (7.0) 6.73 (4.76-9.50) < 0.001 2.73 (1.80-4.13) < 0.001

Minor comments

Line 135 – I assume “high risk” here refers to operative mortality risk >5% in table 3 of the ESC/ESA guidelines 2014 (2)? This could be made absolutely clear.

>> Response: Following your recommendation, we clarified the definition.

“High-risk surgery was defined as procedures with mortality risk >5% according to the 2014 European Society of Cardiology/Anesthesiology guidelines [17].” (Line 131)

Line 65 and elsewhere – the authors give their main result as “16.4% vs. 35.2%; odds ratio, 1.80; 95% confidence interval, 1.61–2.00; p < 0.001” This should read “35.2% vs 16.4%; odds ratio 1.80; 95% confidence interval 1.61-2.00; p<0.001”. This is true for all the odds ratios in the text.

>> Response: Following your recommendation, we changed the orders throughout the Abstract and Results sections.

“After an adjustment with inverse probability weighting, the incidence of MINS was higher in the significant bleeding group (35.2% vs. 16.4%; odds ratio, 1.58; 95% confidence interval, 1.43–1.75; p < 0.001).” (Line 65)

“After an adjustment with multivariable analysis, the risk for MINS was found to be significantly increased for the significant bleeding group (35.2% vs. 16.4%; OR, 1.80; 95% CI, 1.61–2.00; p < 0.001) (Table 2).” (Line 189)

“When the patients solely divided according to hemoglobin decrease without considering RBC transfusion, 15,353 (96.4%) patients were in the no hemoglobin decrease group and 573 (3.6%) patients were in the hemoglobin decrease group (S4 Table), the incidence of MINS was substantially increased in the hemoglobin decrease group (58.3% vs. 17.9%; OR, 3.28; 95% CI, 2.70–4.00; p < 0.001) (S5 and S6 Tables).” (Line 214)

While the authors tell us that these are patients having high risk surgery, they do not include a breakdown of the types of surgery performed in the table 1 (Baseline Characteristics). This is important enough to be in the main text, as it affects the applicability of these findings to our individual practice settings. In addition, some surgical populations (vascular surgery in particular) are at very high risk of MINS, and a different incidence between groups may confound the data. This should be moved up into the main text from the supplement (from table S1 into table 1). P values should also be provided.

>> Response: We agree that this needs to be included in the main table. Following your recommendation, we included the types of surgery in the Table 1. However, including the types of surgery as an adjustment variable would be a double adjustment with the risk of surgery. Moreover, it is true that the risk of MINS is reported to be higher for some types of surgery, but it is also likely that the surgeries with different risks are classified within the same type of surgery. For clarification, we also added that our results could be different according to the types of surgery.

“In In addition, this study contains all types of noncaridac surgery, and the result might be different in particular types of surgery.” (Line 310)

Line 130 – the exclusion criteria of factors that artefactually increase MINS should be moved up into the methods section for clarity.

>> Response: Following your recommendation, we moved this section to the Method section.

“Among 3,193 patients with postoperative cTn elevation, 110 patients were diagnosed with non-ischemic cause, and 3083 (19.4%) patients were diagnosed with MINS.” (Line 126)

General – this dataset spans a relatively long period of time, beginning in 2010, during which our understanding of the hazards of transfusion has evolved and trigger levels of hemoglobin for transfusion have dropped from 10 to 7 g/dl. Were there changes to the author’s institutional policy or consensus in practice on transfusion triggers during this time? Did the authors consider a temporal analysis either on lowest hemoglobin before transfusion, or numbers of transfusions?

>> Response: We agree that including the change of the institutional protocol into an analysis would be helpful for readers. So, we added as below to the Method, Result, and Discussion sections as a sensitivity analysis.

““For sensitivity analysis, we evaluated whether the observed association was significant in patients with chronic kidney disease and heart failure and after January 2017 when the threshold of hemoglobin for intraoperative transfusion was lowered to 7 g/dL.” (Line 166)

“In the sensitivity analysis, this association was consistently found to be significant in patients with chronic kidney disease and heart failure and after lowering the threshold of hemoglobin for intraoperative transfusion in 2017 (S1 Table).” (Line 197)

“The observed association between intraoperative bleeding was shown to be significant in most of subgroups with risk factor for MINS.” (Line 287)

Supplemental table 1. Sensitivity Analysis of the Observed Association between Significant Bleeding and Myocardial Injury after Noncardiac Surgery

  OR (95% CI) P-value

Patients with heart failure (n=327) 4.63 (2.42-9.05) <0.001

Patients with chronic kidney disease (n=1012) 1.17 (0.86-1.59) <0.001

Surgeries after 2017 with the threshold of

hemoglobin level < 7 g/dL for intraoperative transfusion 2.20 (1.94-2.50) <0.001

OR, odds ratio; CI, confidence interval; RBC, red blood cell

Details of the power analysis outside of prospective studies are not required, even though they can be calculated, p values are sufficient. Medical readers without a research or statistics background may be confused.

>> Response: Following your recommendation, we removed the power analysis.

Reviewer #2.

Database/registry study with many limitations, most of which were addressed in the text of the paper. They acknowledged that more studies (more rigorously conducted studies to be specific) need to be conducted to support their conclusions and essentially this study is mostly hypothesis generating.

Large population included in study and overall well conducted (given limitations of registry) so does add some controversy to literature that is worth considering (changing transfusion 'triggers' in high risk populations to avoid MINS).

>> Response: We thank you for your kind comments.

There were significant differences in baseline characteristics in patients who had blood loss versus those that didn't therefore there were many confounding factors that could influence reasons for these patients to have more MINS besides just blood loss, not sure all of this was accounted for by the statistics or fully explained/justified.

>> Response: We fully agree with the reviewer that there is a large difference in baseline characteristics of the two groups. So, we conducted inverse probability weighting for statistical adjustment for the difference. The result was not changed after mor rigrous statistical adjustment.

” To retain a large sample size and maximize the study power while maintaining a balance in covariates between the two groups, we conducted rigorous adjustment for differences in baseline characteristics of patients using the weighted regression models with the inverse probability weighting (IPW) [19]. According to this technique, weights for patients without significant bleeding were the inverse of the propensity score and weights for patients with significant bleeding were the inverse of 1 – the propensity score.” (Line 160)

For clarification, we added in the limitation section that it could stll be biased by unmaseured confounders despite statistical adjustment.

“First, this is a single-center, observational study; the possibility of selection bias or unmeasured confounding factors exists. Also, our data may not be generalized to populations in other countries considering ethnic differences in blood management.” (Line 307)

Table 1. Baseline characteristics according to significant intraoperative bleeding.

Entire population IPW

  No significant bleeding

(N = 13416) Significant bleeding

(N = 2510) ASD No significant bleeding

(N = 13370.5) Significant bleeding

(N = 2644.5) ASD

Male 8133 (60.6) 1562 (62.2) 3.3 8145.0 (60.9) 1658.9 (62.7) 3.7

Age 61.7 (±13.5) 60.0 (±13.5) 12.4 61.5 (±13.6) 62.2 (±13.3) 5.0

Preoperative anemia 4949 (36.9) 1646 (65.6) 59.9 5497.0 (41.1) 1064.8 (40.3) 1.7

Diabetes 7890 (58.8) 1748 (69.6) 22.7 8019.3 (60.0) 1446.4 (54.7) 10.7

Hypertension 7290 (54.3) 1424 (56.7) 4.8 7331.9 (54.8) 1436.0 (54.3) 1.1

Current smoking 1362 (10.2) 236 (9.4) 2.5 1337.6 (10.0) 282.8 (10.7) 2.3

Current alcohol 2798 (20.9) 360 (14.3) 17.2 2639.6 (19.7) 556.3 (21.0) 3.2

Chronic kidney disease 680 (5.1) 332 (13.2) 28.6 850.8 (6.4) 166.3 (6.3) 0.3

History of ischemic heart disease 1913 (14.3) 365 (14.5) 0.8 1939.1 (14.5) 395.5 (15.0) 1.3

History of heart failure 282 (2.1) 45 (1.8) 2.2 277.8 (2.1) 51.3 (1.9) 1.0

History of stroke 938 (7.0) 161 (6.4) 2.3 926.8 (6.9) 176.3 (6.7) 1.1

History of arrhythmia 882 (6.6) 161 (6.4) 0.6 875.4 (6.5) 179.4 (6.8) 0.9

History of heart valve disease 149 (1.1) 21 (0.8) 2.8 143.2 (1.1) 25.9 (1.0) 0.9

Active cancer 7422 (55.3) 1112 (44.3) 22.2 7216.2 (54.0) 1555.1 (58.8) 9.8

Preoperative care

RBC transfusion 608 (4.5) 151 (6.0) 6.6 638.0 (4.8) 123.2 (4.7) 0.5

Intensive care unit 424 (3.2) 278 (11.1) 31.2 574.7 (4.3) 111.4 (4.2) 0.4

ECMO 0 1 (0.0) 2.8 0 0.2 (0.0) 1.1

Continuous renal replacement therapy 18 (0.1) 54 (2.2) 19.1 54.7 (0.4) 11.3 (0.4) 0.3

Ventilator 67 (0.5) 56 (2.2) 15.0 101.2 (0.8) 18.9 (0.7) 0.5

Operative variables

ESC/ESA surgical high risk 3997 (29.8) 1258 (50.1) 42.4 4306.0 (32.2) 748.8 (28.3) 8.5

Emergency operation 1521 (11.3) 549 (21.9) 28.6 1745.6 (13.1) 354.4 (13.4) 1.0

General anesthesia 13305 (99.2) 2500 (99.6) 5.5 13267.8 (99.2) 2610.5 (98.7) 5.2

Operation duration, hours 3.94 (±2.14) 5.57 (±2.86) 64.4 4.20(±2.51 4.16±2.20) 1.7

Continuous infusion of inotropes 4592 (34.2) 1278 (50.9) 34.2 4855.3 (36.3) 798.6 (30.2) 13.0

Types of surgery >0.99

Vascular 981 (7.3) 169 (6.7)

Orthopedic 667 (5.0) 146 (5.8)

Neuro 3317 (24.7) 166 (6.6)

Breast or Endo 148 (1.1) 22 (0.9)

Plastic or Otolaryngeal or Eye 279 (2.1) 53 (2.1)

Transplantation 300 (2.2) 768 (30.6)

Gynecology or Urology 823 (6.1) 258 (10.3)

Gastrointestinal 4559 (34.0) 741 (29.5)

Noncardiac thoracic 2328 (17.4) 184 (7.3)

Others 14 (0.1) 3 (0.1)

Data are presented as n (%) or mean (±standard deviation)

IPW, inverse probability weighting; ASD, absolute standardized mean difference; RBC, red blood cell; ECMO, extracorporeal membranous oxygenation; RAAS, renin-angiotensin-aldosterone system; ESC, European Society of Cardiology; ESA, European Society of Anaesthesiology

Few errors in supplemental tables that need to be corrected - Supplemental Table 1 has a category of surgery "Orthopediatric" since all patients were above age 18 I can only assume this should be 'Orthopedic'. Supplemental Table 3 says "ionotropics" should read 'ionotropes'

>> Response: These points were clearly our mistake. We changed “Orthopediatric” to “Orthopedic”, and “inotropics” to “inotropes”

Attachment

Submitted filename: response to reviewers - PONE-D-20-14264R1.docx

Decision Letter 1

Wen-Chih Hank Wu

11 Aug 2020

PONE-D-20-14264R1

Intraoperative blood loss may be associated with myocardial injury after non-cardiac surgery

PLOS ONE

Dear Dr. Lee,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

Would like the authors to:

A. Please address the comments from reviewer 2 and review the manuscript in its entirety to avoid further grammar mistakes.

B. Please clarify in your response letter the potential overlap between this manuscript and the one submitted to the European Journal of Anaesthesiology on a similar topic. Please delineate the items that are similar and the ones which are unique to this contribution to avoid duplication.

==============================

Please submit your revised manuscript by Sep 25 2020 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:

  • A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

  • A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

  • An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: http://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols

We look forward to receiving your revised manuscript.

Kind regards,

Wen-Chih Wu, MD, MPH

Academic Editor

PLOS ONE

1. It has come to our attention that a similar manuscript from your group "Association between preoperative anemia and myocardial injury after noncardiac surgery" by Dr Seung-Hwa Lee is at revision at the European Journal of Anaesthesiology. In oder to assess the distinction between these manuscripts, please provide us with a copy of the current version of your manuscript under review at the European Journal of Anaesthesiology and provide us with a discussion of how this work differs from the work in your current manuscript at PLOS ONE. This information will be used for internal purposes only, and will not be published if your paper is accepted at our journal. Please also let us know if your manuscript is to be published at the European Journal of Anaesthesiology, in which case you would need to include a discussion in this manuscript of how the works differ. Please feel free to email shepp@plos.org with any questions.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

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 #2: Partly

**********

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

Reviewer #2: I Don't Know

**********

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 #2: 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 #2: 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 #2: Many areas have been clarified and statistical analysis has improved from previous submission.

There are still some grammatical errors and confusion in the revised submission.

Line 55 - should read: which is 'a' severe and common postoperative complication.

Line 79 - should read: one of 'the' mechanisms

Line 193 - does not make sense grammatically (the word interacted), do you mean "the subgroup analysis demonstrated....was 'confounded' by emergency surgery?

Line 259 - additional reference (although done in cardiac surgery, would still support your statements) Transfusion, Jan 10, 2008. The influence of baseline hemoglobin on tolerance of anemia in cardiac surgery. Karkouti et. al.

Line 293 - should read: When the patients 'were' solely divided....

Line 284 - Although your conclusions are more or less consistent with the idea of restrictive transfusion, they do not completely support the current transfusion thresholds, your results from this study would suggest that the lower trigger limit should perhaps be higher than 7g/dL (although you do mention this point later)

Line 288 - the explanation for lack of correlation of emergency surgery with MINS makes no sense, one would expect that unstable bleeding patients would experience a greater propensity for MINS (since more supply/demand mismatch due to increased work on the heart and increased cardiac output in these situations with an increase in cytokines/inflammatory markers)

**********

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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2021 Feb 24;16(2):e0241114. doi: 10.1371/journal.pone.0241114.r004

Author response to Decision Letter 1


13 Sep 2020

Response to the Editor

A. Please address the comments from reviewer 2 and review the manuscript in its entirety to avoid further grammar mistakes.

>> Response: We thank you for your kind comments. Following your recommendation, we had the whole script proofread by a professional editor.

B. Please clarify in your response letter the potential overlap between this manuscript and the one submitted to the European Journal of Anaesthesiology on a similar topic. Please delineate the items that are similar and the ones which are unique to this contribution to avoid duplication.

>> Response: Regarding this, the reviwer and we have exchanged the letters. We explained to the reviewer as below.

“These two studies share the entire cohort, but the enrolled study populations of the two studies differ as well as their conclusions and the clinical implications.

Using the entire cohort, we first analzed the effect of "preoperative anemia' after enrolling all patients with preoeprative hemoglobin level. However, we also felt the need for further analysis on the effect of intraoperative hemoglobin level, because the recent concept of patient blood management covers maintaining an adequate hemoglobin level during pre-, intra, and postoperative periods. Owing to the retrospective nature of our cohort, not every patients with preoperative hemoglobin level had an intraoperartive measurement. So, for intraoperative hemoglobin level, we had to conduct a separate analysis after exculding those without an intraoperative measurement. The study on "preoperative anemia" was conducted among 35,170 patients, and this study on "intraoperative hemoglobin level" exluded 19,2297 patients without intraoperative hemoglobin level and was conducted in 15,926 patients.

These two studies highlight the importance on maintaining an adequate hemoglobin level to decrease MINS, but during the different period by using different study populations.

I would like to clarify that we had no intention to duplicate or hide our former analysis, but it was an inevitable decision for us to conduct separate analyses for pre- and intraopearive hemoglobin level.”

Now that the reviwer understands that those two studies are distinct. We also mentioned the result of our analysis on preoperative anemia as below.

“Despite various possible causes, the most frequently proposed mechanism for MINS is oxygen supply/demand mismatch, and our previous study also showed that preoperative anemia was associated with MINS [21]. In this follow-up study, we demonstrated that blood loss during surgical procedures could also increase MINS. So, our results on the association between intraoperative hemoglobin decrease and the increased incidence of MINS can be explained by reduced oxygen-carrying capacity compromising the myocardial oxygen supply while simultaneously requiring higher cardiac output to maintain adequate systemic circulation [22].”

Response to the Reviewers

Reviewer #1.

1. It has come to our attention that a similar manuscript from your group "Association between preoperative anemia and myocardial injury after noncardiac surgery" by Dr Seung-Hwa Lee is at revision at the European Journal of Anaesthesiology. In oder to assess the distinction between these manuscripts, please provide us with a copy of the current version of your manuscript under review at the European Journal of Anaesthesiology and provide us with a discussion of how this work differs from the work in your current manuscript at PLOS ONE. This information will be used for internal purposes only, and will not be published if your paper is accepted at our journal. Please also let us know if your manuscript is to be published at the European Journal of Anaesthesiology, in which case you would need to include a discussion in this manuscript of how the works differ. Please feel free to email shepp@plos.org with any questions.

>> Response: We thank you for your kind comments. As we dicussed on e-mails, the results of the analysis on preoperative anemia is mentioned in the script as below with a citation that needs to be confirmed after the publication of the former study.

“Despite various possible causes, the most frequently proposed mechanism for MINS is oxygen supply/demand mismatch, and our previous study also showed that preoperative anemia was associated with MINS [21]. In this follow-up study, we demonstrated that blood loss during surgical procedures could also increase MINS. So, our results on the association between intraoperative hemoglobin decrease and the increased incidence of MINS can be explained by reduced oxygen-carrying capacity compromising the myocardial oxygen supply while simultaneously requiring higher cardiac output to maintain adequate systemic circulation [22].”

When our previous work is ready to be cited , we will add it as reference 21.

Reviewer #2.

Line 55 - should read: which is 'a' severe and common postoperative complication.

>> Response: We thank you for your kind comments. We changed all the montioned parts as below and had the whole script proofread by professional editor.

“This study aimed to evaluate the association between intraoperative blood loss and myocardial injury after non-cardiac surgery (MINS), which is a severe and common postoperative complication.”

Line 79 - should read: one of 'the' mechanisms

>> Response: We changed it as below.

“Massive blood loss is frequently encountered during surgical procedures and can lead to decreased hemoglobin levels. Oxygen supply/demand mismatch is a proposed as one of the mechanism for MINS [3].”

Line 193 - does not make sense grammatically (the word interacted), do you mean "the subgroup analysis demonstrated....was 'confounded' by emergency surgery?

>> Response: We changed it as below.

“Subgroup analysis demonstrated that the association between significant bleeding and MINS was confounded by emergency surgery.”

Line 259 - additional reference (although done in cardiac surgery, would still support your statements) Transfusion, Jan 10, 2008. The influence of baseline hemoglobin on tolerance of anemia in cardiac surgery. Karkouti et. al.

>> Response: Following your recommendation, we added the reference.

“In this study, we selected patients whose intraoperative hemoglobin level decreased below 7 g/dL, which is generally assumed to be the level that most patients can tolerate [10-12,23].”

Line 213 - should read: When the patients 'were' solely divided....

>> Response: We changed it as below.

“When the patients were solely divided according to hemoglobin decrease without considering RBC transfusion, 15,353 (96.4%) patients had no hemoglobin decrease whereas 573 (3.6%) patients did have decreased hemoglobin (S4 Table). The incidence of MINS was substantially increased in the decreased hemoglobin group (58.3% vs. 17.9%; OR, 3.28; 95% CI, 2.70–4.00; p < 0.001) (S5 and S6 Tables).”

Line 284 - Although your conclusions are more or less consistent with the idea of restrictive transfusion, they do not completely support the current transfusion thresholds, your results from this study would suggest that the lower trigger limit should perhaps be higher than 7g/dL (although you do mention this point later)

>> Response: Following your recommendation, we changed it as below.

“Despite the current guidelines advocating restrictive use of blood transfusion during surgical procedures, our findings suggest that the hemoglobin threshold for intraoperative transfusion may be higher than 7g/dL in order to prevent MINS [10-12,17].”

Line 288 - the explanation for lack of correlation of emergency surgery with MINS makes no sense, one would expect that unstable bleeding patients would experience a greater propensity for MINS (since more supply/demand mismatch due to increased work on the heart and increased cardiac output in these situations with an increase in cytokines/inflammatory markers)

>> Response: This sentence needed more explanation. We agree that unstable bleeding events act as a cause of MINS. What we meant was that these preoperative events might have already caused enough metabolic stress for MINS and diluted the direct effect of intraoperative blood loss. For clarification, we added as below to the script.

“This may be because patients requiring emergency surgery include those with preoperative hemodynamic instability or massive bleeding, which could be strongly associated with cTn elevation. These events causing a large fluctuation of hemoglobin levels from the preoperative period might have diluted the effect of intraoperative blood loss.”

Attachment

Submitted filename: responseletter_20816.docx

Decision Letter 2

Wen-Chih Hank Wu

9 Oct 2020

Intraoperative blood loss may be associated with myocardial injury after non-cardiac surgery

PONE-D-20-14264R2

Dear Dr. Lee,

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.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Wen-Chih Hank Wu, 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 #2: 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 #2: Partly

**********

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

Reviewer #2: I Don't Know

**********

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 #2: 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 #2: 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 #2: Have not referenced previous work that is based on the same cohort of patients, perhaps it is not yet published? Still have one grammatical error on line 79, "Oxygen supply/demand mismatch is a proposed as one of the mechanism for MINS [3]" remove "a"

**********

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.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #2: No

Acceptance letter

Wen-Chih Hank Wu

8 Feb 2021

PONE-D-20-14264R2

Intraoperative blood loss may be associated with myocardial injury after non-cardiac surgery

Dear Dr. Lee:

I'm 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.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Wen-Chih Hank Wu

Academic Editor

PLOS ONE

Associated Data

    This section collects any data citations, data availability statements, or supplementary materials included in this article.

    Supplementary Materials

    S1 Table. Sensitivity analysis of the observed association between significant bleeding and myocardial injury after noncardiac surgery.

    (DOCX)

    S2 Table. Sensitivity analysis of the effect of an unmeasured confounder on odds ratio of significant bleeding for myocardial injury after noncardiac surgery.

    (DOCX)

    S3 Table. Baseline characteristics according to the actual hemoglobin decrease and intraoperative transfusion.

    (DOCX)

    S4 Table. Baseline characteristics according to the actual hemoglobin decrease without regarding intraoperative transfusion.

    (DOCX)

    S5 Table. The incidence of myocardial injury after noncardiac surgery and mortality according to the actual hemoglobin decrease without regarding intraoperative transfusion.

    (DOCX)

    S6 Table. Sensitivity analysis of the effect of an unmeasured confounder on odds ratio of hemoglobin decrease for myocardial injury after noncardiac surgery.

    (DOCX)

    Attachment

    Submitted filename: PONE-D-20-14264.docx

    Attachment

    Submitted filename: response to reviewers - PONE-D-20-14264R1.docx

    Attachment

    Submitted filename: responseletter_20816.docx

    Data Availability Statement

    The data we used for this study was curated using Clinical Data Warehouse (CDW) which psuedonomynize the data from our institutional electronic medical records. So, our data is deidentified by eliminating all identifiable variables such as name, social security number, hospital number, and etc. However, it is illegal to open this data to the public without restriction. Regarding the availability of our data, please contact jong-hwan.park@samsung.com, the head of our institutional data security department.


    Articles from PLoS ONE are provided here courtesy of PLOS

    RESOURCES