Effect of geography on the use of ultrafiltration during cardiac surgery with cardiopulmonary bypass

Abstract

Background

Ultrafiltration (UF) is a common practice during cardiopulmonary bypass (CPB) where it is used as a blood management strategy to reduce red blood cell (RBC) transfusion, minimize adverse effects of hemodilution, and reduce proinflammatory mediators. However, its clinical utilization has been shown to vary throughout the continents.

Purpose

The purpose of this investigation was to assess the distribution of UF use across the United States.

Data Collection

Data on UF use during cardiac surgery was obtained from a national (United States) perfusion database for adult cardiac procedures performed from January 2016 through December 2018.

Study Sample

Four geographical regions were established: Northeast (NE), South (SO), Midwest (MW) and West (WE). The primary endpoint was the use of UF with secondary endpoints UF volume, CPB and anesthesia asanguineous volumes, intraoperative allogeneic RBC transfusion, nadir hematocrit and urine output (UO). 92,859 adult cardiac cases from 191 hospitals were reviewed.

Results

The NE and the WE had similar usages of UF (59.9% and 59.7% respectively), which were higher than the MW and the SO (38.6% and 34.9%, p < .001). When UF was utilized, the median [IQR] volume removed was highest in the NE (1900 [1200-2800]mL), and similar in all other regions (WE 1500 [850-2400 mL, MW 1500 [900-2300]mL and SO 1500 [950-2200]mL, p < .001. Median total UO was lowest in the NE 400 [210,650]mL vs all other regions (p < .001), and remained so when indexed by patient weight and operative time (NE-0.8 [0.5, 1.3]mL/kg/hour, MW-1.1 [0.7, 1.8] mL/kg/hour, SO-1.3 [0.8, 2.0]mL/kg/hour, WE-1.1 [0.7, 1.3]mL/kg/hour, p < .001. Intraoperative RBC transfusion rate was highest in the SO (21.3%) and WE (20.5%), while similar rates seen in the NE (16.2%) and MW (17.6%), p < .001.

Conclusions

Across the United States there is geographic variation on the use of UF. Further research is warranted to investigate why these practice variations exist and to better understand and determine their reasons for use.

Keywords

ultrafiltration cardiopulmonary bypass blood management

Introduction

In the United States, there are between 275,000 and 300,000 annual cardiac surgical procedures,¹ with greater than 85% performed using cardiopulmonary bypass (CPB).² The conduct of CPB necessitates that fluid-filled circuits be utilized with concomitant hemodilution.^3–5 While an ideal prime volume has yet to be identified for adult CPB,⁶ excessive hemodilution can result in a number of deleterious effects that include a reduction in plasma colloid oncotic pressure, reduced hemoglobin (Hgb) levels, decreased oxygen delivery, and coagulation disturbances all of which may contribute to renal dysfunction, myocardial as well as cerebral ischemia, interstitial edema, and increased mortality.⁷

Many well-documented blood conservation techniques exist in cardiac surgery that can reduce allogeneic red blood cell (RBC) transfusion,⁸ with some purported to decrease inflammation and improve hemostasis.^9,10 Techniques that have been shown to reduce the likelihood for allogenic transfusion include acute normovolemic hemodilution (ANH), intraoperative autotransfusion (IAT), antegrade/retrograde autologous priming (AP) and ultrafiltration (UF).^11,12 There is significant variation in the geographical use of ultrafiltrators during CPB, which ranges from 1.4% use in Australia and New Zealand to 41.8% in the United States.^13,14 The purpose of this study was to determine if the use of UF varies by geography across the United States.

Methods

Consecutive cardiac surgical procedures where CPB was required on patients over 18-years of age were evaluated from a multi-institutional United States database¹ that has been previously reported.^5,8 The time period of the study was between January 2016 and December 2018 with data abstracted from 191 hospitals. The human subject’s research protocol for this study was reviewed and approved by an independent Institutional Review Board. Institutional Review Board approval and waiver of the need for consent were obtained (SpecialtyCare Protocol # 012017, ADVARRA, Center for IRB Intelligence, 6940 Columbia Gateway Drive, Suite 110, Columbia, MD 21046).

Study design

The hospital distribution across the United States was determined as a factor of operational function and not by federal census determination. There were four operational regions: Northeast (NE), South (SO), Midwest (MW) and West (WE), and states with no hospitals identified (Figure 1). National policies and procedures on UF were established by the SpecialtyCare Medical Department using published clinical practice guidelines and peer-reviewed literature, and distributed to all hospitals.¹¹ There were no changes to the policies and procedures throughout the study period. The following variables were recorded: Patient demographics, intraoperative fluid volumes that included prime, cardiopulmonary and crystalloid cardioplegia volumes, anesthesia volumes, urine output, UF volume, zero-balance ultrafiltration (ZBUF) volume, post-CPB residual blood processing technique and volume of allogenic RBC transfusion.

Data was obtained from the following procedures where CPB was utilized: Aortic surgery, isolated coronary artery bypass grafting (CABG), isolated aortic valve (AV) surgery, isolated mitral valve (MV) repair/replacement surgery, combined AV and CABG surgery, combined MV and CABG surgery, and other cardiac surgical procedures that included combination surgeries not listed, ventricular assist device insertions and heart transplants. Non-elective cases were those that were either classified as urgent, emergent, or emergent salvage procedures. Patients were not excluded if they were having a reoperative procedure.¹

Endpoints

The primary endpoint was of UF, with secondary endpoints of UF volume, CPB and anesthesia asanguineous volumes, intraoperative RBC transfusion, nadir hematocrit and urine output.

Statistical analysis

Patient demographics and operative data were summarized by geographic group using median and inter-quartile range or count and percentage, with the Kruskal-Wallis rank sum test or Chi-square test respectively, as appropriate. Mixed effects logistic regression was used to assess possible differences in the likelihood of receiving UF across geographic regions correcting for patient age, BMI, sex, first hematocrit upon entry to the OR, procedure type, whether or not an autologous ECC priming method was used, and duration of the procedure, with random intercept terms to account for possible variation in ultrafiltration use patterns by surgeon and by perfusionist. A second model (using the linear mixed effects method) was estimated in order to assess possible difference by geographic region in the total volume removed using ultrafiltration indexed by patient body weight and duration of the procedure (ml/kg/hour). This second model included all control variables described above and additionally included total urine output, patient estimated total blood volume using the Nadler formula, total volume of crystalloid cardioplegia, volume of other asanguineous fluids added intraoperatively, and packed RBC transfusion added during the intraoperative period. Post-hoc pairwise contrasts of region-specific model estimates were completed using the Tukey HSD method. Ultrafiltration survey responses were summarized as count with percent. All analyses were carried out within the R statistical computing environment (version 3.6.1) using the ‘compareGroups’, ‘lme4’, and ‘multcomp’ analysis packages.^15–18

Results

A total of 92,859 adult cardiac cases from 191 hospitals were reviewed with the number of patients in each group ranging from 17,898 in the NE to 28,705 in the MW. Patient characteristics and the distribution of surgical procedure types are shown in Table 1. While there were statistical differences found across the four geographical regions, the magnitudes of these differences were negligible. The NE had the lowest percentage of non-elective cases as well as the shortest CPB times of all regions.

Table 1.

Descriptive Statistics: patient and operative characteristics.

	Northeast region	South region	Midwest region	West region	p value
N	17,898	23,347	28,705	22,909
Weight (kg) (median [IQR])	86 [74,100]	86 [74,100]	88 [76,102]	84 [71,97]	<0.001
Height (meters) (median [IQR])	1.72 [1.65,1.78]	1.73 [1.65,1.80]	1.73 [1.65,1.80]	1.70 [1.63,1.78]	<0.001
Female (yes) (count (%))	5125 (28.6)	70,19 (30.1)	8576 (29.9)	6596 (28.8)	=0.001
Age (years) (median [IQR])	67 [59,74]	66 [58,73]	66 [59,73]	66 [58,73]	<0.001
Procedure type					<0.001
Aortic surgery (count (%))	564 (3.2)	546 (2.3)	979 (3.4)	886 (3.9)
AV surgery + CABG (count (%))	1251 (7.0)	1362 (5.8)	2143 (7.5)	1448 (6.3)
CABG reoperation (count (%))	140 (0.8)	247 (1.1)	375 (1.3)	196 (0.9)
Combined AV/MV surgery (count (%))	353 (2.0)	278 (1.2)	390 (1.4)	429 (1.9)
Isolated AV surgery (count (%))	2047 (11.5)	1973 (8.5)	2960 (10.3)	2488 (10.9)
Isolated CABG (count (%))	9914 (55.5)	15,742 (67.5)	16,895 (58.9)	12,770 (55.8)
Isolated MV surgery (count (%))	1246 (7.0)	1064 (4.6)	1621 (5.7)	1406 (6.1)
MV surgery + CABG (count (%))	415 (2.3)	483 (2.1)	742 (2.6)	586 (2.6)
Other (count (%))	1947 (10.9)	1628 (7.0)	2579 (9.0)	2673 (11.7)
Non-elective cases (count (%))	2596 (14.5)	5647 (24.2)	5828 (20.3)	6393 (27.9)	<0.001
Total CPB time (minutes) (median [IQR])	93 [68,128]	101 [75,135]	104 [80,139]	106 [79,145]	<0.001

AV: aortic valve; CABG: coronary artery bypass graft; CPB: cardiopulmonary bypass; IQR: interquartile range; MV: mitral valve.

The highest usage of UF was seen in the NE (59.9%) and WE (59.7%), while the SO (34.9%) and MW (38.6%) had the lowest (p < .001) (Table 2). When UF was utilized, the total volume removed also followed a similar trend with the highest volumes removed in the NE. The technique of ZBUF was used infrequently with the lowest in the SO (2.7%) and the highest in the NE (7.6%), with the highest indexed volumes by weight and CPB time found in the NE and WE. Total intraoperative urine output was lowest in the NE region. The NE had the lowest use of autologous prime (65.1%), while use of autologous prime was similar in the SO (87.8%), MW (93.5%) and WE (88.5%), p < .001. While there was a significant difference in both the lowest hematocrit on CPB and intraoperatively, the median values were not clinically different. The intraoperative RBC transfusion rate was lowest in the NE and MW, while the SO and WE had higher rates, p < .001 (Figure 2).

Table 2.

Intraoperative volumetrics.

	Northeast region	South region	Midwest region	West region	p Value
N	17,898	23,347	28,705	22,909
Ultrafiltration used (yes) (count (%))	10,715 (59.9)	8149 (34.9)	11,068 (38.6)	13,666 (59.7)	<0.001
Ultrafiltration vol. (mL) (median [IQR])	1,900 [1,200, 2800]	1500 [950, 2200]	1500 [900, 2300]	1500 [850, 2400]	<0.001
Ultrafiltration vol. (mL/kg/hr) (median [IQR])	3.8 [2.35, 6.02]	2.7 [1.65, 4.44]	3.0 [1.75, 4.71]	3.0 [1.68, 4.89]	<0.001
ZBUF used (yes) (count (%))	1084 (7.6)	444 (2.7)	831 (3.9)	922 (5.9)	<0.001
ZBUF volume (mL) (median [IQR])	2,000 [1,000, 2300]	1,400 [1,000, 2425]	1,050[1,000,2,000]	2000[1,000,3,000]	<0.001
ZBUF volume indexed (mL/kg/hr) (median [IQR])	3.2 [2.0, 5.0]	2.7 [1.8, 4.5]	2.6 [1.9, 4.1]	3.8 [2.1, 6.7]	<0.001
Urine output on CPB (mL) (median [IQR])	200 [100, 350]	250 [125, 425]	208 [111, 375]	230 [140, 400]	<0.001
Urine output on CPB (mL/kg/hr CPB time) (median [IQR])	1.5 [0.9, 2.6]	1.7 [0.90, 2.98]	1.4 [0.75, 2.43]	1.6 [0.90, 2.65]	<0.001
Intraoperative total urine output (mL) (median [IQR])	400 [210, 650]	600[400, 1000]	550 [350, 845]	550 [350, 800]	<0.001
Intraoperative urine output (mL/kg/hr OR time) (median [IQR])	0.8 [0.5, 1.3]	1.3 [0.8, 2.0]	1.1 [0.7, 1.8]	1.1 [0.7, 1.7]	<0.001
Autologous prime used (yes) (count (%))	9805 (65.1)	15,324 (87.8)	21,072 (93.5)	14,439 (88.5)	<0.001
Nadler estimated blood vol.* (L) (median [IQR]) 1.1 [0.7,1.8], SO 1.3 [0.8,2.0], WE 1.1 [0.7,1.7], p < .001.	5.2 [4.5, 5.8]	5.2 [4.5, 5.8]	5.3 [4.6, 5.9]	5.1 [4.4, 5.7]	<0.001
Net CPB prime vol. (mL) (median [IQR])	780 [655, 952]	780 [630, 900]	710 [582, 850]	677 [560, 835]	<0.001
Crystalloid cardioplegia vol. (mL) (median [IQR])	435 [68, 800]	320 [45, 530]	420 [200, 716]	87 [43, 683]	<0.001
Anesthesia asanguineous vol. (mL) (median [IQR])	1,000 [1,000,1,500]	1,500[1,100, 2000]	1,600[1,200, 2000]	1,200 [1,000,1,700]	<0.001
Asanguineous vol. Added during CPB (mL) (median [IQR])	210 [55, 601]	305 [89, 730]	310 [108, 730]	300 [100, 750]	<0.001
Lowest hematocrit on CPB (%) (median [IQR])	26.0 [23.0, 29.0]	25.0 [22.0, 29.0]	26.0 [22.0, 29.0]	26.0 [23.0, 29.0]	<0.001
Lowest hematocrit in operating room (%) (median [IQR])	25.1 [22.0, 28.0]	25.0 [22.0, 28.0]	25.0 [21.2, 28.0]	25.0 [22.0, 29.0]	<0.001
Intraoperative RBC transfusion (yes) (count (%))	2892 (16.2)	4982 (21.3)	5048 (17.6)	4691 (20.5)	<0.001

CPB: cardiopulmonary bypass; IQR: interquartile range; RBC: Red Blood Cell; Vol.: Volume; ZBUF: zero balanced ultrafiltration.

*The Nadler estimated blood volume was calculated from Sharma R, Sharma S. Physiology, Blood Volume. 2022 Apr 14. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2022. PMID: 30252333.

The model-adjusted percent of patients receiving ultrafiltration confirmed that the highest usage occurred in both the NE and WE regions (Figure 2). Rates of ultrafiltration use were statistically indistinguishable between the NE and WE and similarly between the MW and SO, however both NE and WE had higher adjusted ultrafiltration use compared to either/both the MW and/or SO (p < .001). Model-adjusted estimates of volume of UF removed adjusted for CPB time are given in Figure 3; the NE had greater volume removed than both SO and MW (both p < .01), and the WE region had greater volume removed than the SO region (p < .05). All other pairwise comparisons of model estimated volume removed by ultrafiltration were statistically unreliable (Figure 4).

Similar findings were also found in the volume of UF removed adjusted for CPB time (Figure 3).

Discussion

The use of CPB for patients undergoing cardiac surgical procedures is a life-saving technology; however, its use has been known to cause many adverse physiological changes such as hematological alterations, neurological sequela, systemic inflammatory response syndrome and the negative effects of excessive hemodilution. Hemodilution occurs by interventions of both the anesthesia and perfusion teams when asanguineous solutions are added to maintain hemodynamic stability. During CPB, both circuit priming and the administration of asanguineous solutions alter the concentration of the formed elements of blood; hemodilution is often further exacerbated by the use of crystalloid-based cardioplegia solutions.¹⁹ There are many blood conservation strategies that have been shown to reverse or minimize the extent of hemodilution; all are performed with the goals of maintaining red blood cell mass and coagulation factors, and reducing the potential for allogeneic blood transfusions. During and after CPB UF has been shown to be a helpful modality to achieve these goals.²⁰

The use of UF in cardiac surgery evolved from renal dialysis as a means to remove excess plasma water through the use of a semipermeable membrane and hydrostatic forces. This process maintains the formed elements of blood along with proteins and coagulation factors.^21,22 Additionally, low-molecular-weight molecules such as inflammatory mediators are also removed by UF, which has been shown to improve both pulmonary and renal function.^20,23–25

According to the recent patient blood management guidelines from The Task Force on Patient Blood Management for Adult Cardiac Surgery of the European Association for Cardio-Thoracic Surgery and the European Association of Cardiothoracic Anaesthesiology, there is a consensus that most studies have demonstrated the beneficial effect of UF on postoperative transfusion requirements, especially in the presence of preoperative anemia.²⁶ In a large randomized controlled trial the rate of respiratory, neurological and gastrointestinal complications, as well as requirements for blood transfusion, were all lower in patients who had UF compared to patients in whom an UF was not used.²⁷ An older meta-analysis by Boodhwani et al reported on 10 randomized UF trials showing that the combination of modified UF and conventional UF resulted in lower units of postoperative blood transfusion (−0.73 [1.16, −0.31], p = .001).¹⁹ More recently a mixed analysis of various types of UF has reported small but significant differences in intensive care unit length of stay, ventilation time and incidence of pneumonia when UF was used.²⁸

It is well documented that various medical practices and strategies have been found to have significant geographic variations with economic challenges being a major driving force.²⁹ This maldistribution implies that individuals may be receiving suboptimal care or that there is a misuse of health care resources.³⁰ O’Connor and colleagues investigated geographic variation in treatment of acute myocardial infarction (AMI) using a large cohort involving over 185,000 patients with confirmed acute myocardial infarction.³¹ They were able to demonstrate that geographic variations existed and that there were gaps between knowledge and practice, which translated to negative consequences.

Over the last several decades, there has been an increase in published literature aiming to demonstrate the significant disadvantages of blood transfusion on cardiac surgical patients.^4,12 Cardiac surgery is one of the highest consumers of blood products using up to 15% of the blood supply, despite such use having been shown to increase morbidity and mortality in patients who receive allogeneic transfusions.³² While it would be beneficial to have the Hgb of all cardiac surgical patients optimized prior to surgery, this is often not achievable, with many patients, even with various blood conservation strategies applied, susceptible to both anemia and allogenic transfusion.^2,3

While the use of UF has shown to be beneficial in reducing hemodilution, its effects on kidney function have not been extensively studied. In recent years, there has been an increased awareness on the influence of UF on intraoperative and postoperative urine output, and if the impact of UF has any implications on postoperative renal function.^5,20,33 In a prospective randomized study of CUF in adult cardiac surgical patients, Kuntz and associates found no differences in CPB or operative urine volumes, but non-CUF patients had significantly higher 24-h urine than CUF patients.²⁰ Paugh and colleagues demonstrated in an observational study that patients exposed to UF had a higher adjusted risk of postoperative acute kidney injury (AKI).³⁴ The risk of AKI is impacted by renal perfusion and removal of excessive UF volume can lead to renal hypoperfusion. Urine output is well documented as surrogate for adequate perfusion during CPB and a possible indicator for determining renal injury.³⁵ Our study examined urine output and its association with UF volume removed. An inverse relationship was noted; however, no inferences on causality can be made. The direct impact of UF use on postoperative renal function needs further study to determine if such a relationship exists. Over the years numerous studies have been done to compare methods of blood conservation and volume management in terms of safety, patient outcomes, and cost effectiveness, often with equivocal or contradictory results.¹⁹ An understanding of the existence of variation during CPB is imperative, and consistent with efforts to reduce unwarranted practices, and use the best available evidence, to standardize the conduct of extracorporeal circulation as a facet of optimizing care.³⁶

Our analysis demonstrated that UF use varies by geography with the highest usage in the Northeast and West and less use in the Midwest and Southern regions (Figure 2). This variation was also shown on RBC transfusion rates and total urine output, where an inverse relationship was noted between UF volume removed and both RBC transfusion rates and total urine output less than one quarter (69.6%) of cases.

While the present study was not powered to address additional factors that affect the geographical variation in UF use across the United States, there may be topographical and demographic factors that are influential. Residents at higher altitudes have been shown to have increased erythropoiesis and higher hemoglobin levels resulting in populations with less anemia and lower levels of erythropoiesis-stimulating drugs.³⁷ There exists wide geographic variation in body surface size across the United States, with increased rates of both obesity (body mass index of 30 kg/m² or above, and severe obesity (body mass index of 35 kg/m² or above) shown in the southern and Midwest states, with lower levels in western and northeastern states.³⁸ Another factor that may influence UF use is the distribution of AKI requiring dialysis treatment. Sibbel and colleagues have shown that the highest use of dialysis dependent AKI occurred in the South and Midwest regions of the United States with similar distributions in the occurrence of end stage renal disease.³⁷

Limitations

Several limitations are evident in this large multi-institutional study. The analysis was completed using retrospective data from a database used primarily for quality improvement and benchmarking of performance. The study does not demonstrate any cause and effect relationship, but does demonstrate interesting descriptive observations regarding a possible preferential utilization of UF during CPB that varies by region. As shown in Figure 1 there are a number of states where data was unavailable, which was a result of out-sourced perfusion services not provided and hence, no data collected for analysis. Protocols and logistics for UF were specific to each individual hospital, and no effort was made to standardize these protocols across facilities; therefore, differences in practice patterns involving the utility of UF varied across all hospitals.

Conclusions

Although the use of UF during CPB is common, substantial geographical variation exists in its use across the United States, with the highest usage seen in the Northeast and West regions. Greater UF utilization was concomitant with higher ultrafiltrate volumes removed. Further research is warranted to investigate why these practice variations exist, and if these variations have an impact on other variables associated with cardiopulmonary bypass and especially outcomes.

Footnotes

Acknowledgements

The authors wish to express their sincere gratitude to the perfusion associates of SpecialtyCare who participate daily in the quality improvement process that is dedicated to improving patient outcomes.

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Alfred H Stammers

Note

References

Bowdish

D'Agostino

Thourani

, et al. The society of thoracic surgeons adult cardiac surgery database: 2020 update on outcomes and research. Ann Thorac Surg 2020; 109: 1646–1655.

Deo

Elgudin

Shroyer

ALW

, et al. Off-pump coronary artery bypass grafting: department of veteran affairs' use and outcomes. J Am Heart Assoc 2022; 11: e023514.

Loor

Rajeswaran

, et al.

The least of 3 evils: exposure to red blood cell transfusion, anemia, or both?

J Thorac Cardiovasc Surg 2013; 146: 1480–1487.

Kilic

Whitman

GJR

. Blood transfusions in cardiac surgery: indications, risks, and conservation strategies. Ann Thorac Surg 2014; 97: 726–734.

Mongero

Stammers

Tesdahl

, et al. The effect of ultrafiltration on end-cardiopulmonary bypass hematocrit during cardiac surgery. Perfusion 2018; 33: 367–374.

Sun

Dickinson

Tesdahl

, et al. The unintended consequences of over-reducing cardiopulmonary bypass circuit prime volume. Ann Thorac Surg 2017; 103: 1842–1848.

Elliott

. Recent advances in paediatric cardiopulmonary bypass. Perfusion 1999; 14: 237–246.

Stammers

Tesdahl

Mongero

, et al. The effect of various blood management strategies on intraoperative red blood cell transfusion in first-time coronary artery bypass graft patients. Perfusion 2020; 35: 217–226.

Guan

Wan

Wang

, et al. Balanced ultrafiltration: inflammatory mediator removal capacity. Artif Organs 2012; 36: 894–900.

10.

Low

Gao

Sin

KYK

, et al. Modified ultrafiltration reduces postoperative blood loss and transfusions in adult cardiac surgery: a meta-analysis of randomized controlled trials. Interact Cardiovasc Thorac Surg 2021; 32: 671–682.

11.

Tibi

McClure

Huang

, et al. STS/SCA/AmSECT/SABM update to the clinical practice guidelines on patient blood management. Ann Thorac Surg 2021; 112: 981–1004.

12.

Stammers

Mongero

Tesdahl

, et al. The effectiveness of acute normovolemic hemodilution and autologous prime on intraoperative blood management during cardiac surgery. Perfusion 2017; 32: 454–465.

13.

Likosky

Baker

Newland

, et al.

Is conventional bypass for coronary artery bypass graft surgery a misnomer?

J ExtraCorp Technol 2018; 50: 225–230.

14.

Mongero

Tesdahl

Stammers

, et al. The influence of ultrafiltration on red blood cell transfusion during cardiopulmonary bypass. Perfusion 2019; 34: 303–309.

15.

R Core Team. R . A language and environment for statistical computing. Vienna, Austria: R Foundation for Statistical Computing, 2019, https://www.R-project.org/.

16.

Subirana

Sanz

Vila

. Building bivariate tables: the ‘compareGroups’ package for R. J Stat Software 2014; 57: 1–16, https://www.jstatsoft.org/v57/i12/

17.

Bates

Maechler

Bolker

, et al. Fitting linear mixed-effects models using lme4. J Stat Software 2015; 67: 1–48.

18.

Hothorn

Bretz

Westfall

. Simultaneous inference in general parametric models. Biom J 2008; 50: 346–363.

19.

Boodhwani

William

Babaev

, et al. Ultrafiltration reduces blood transfusions following cardiac surgery: a meta-analysis. Eur J Cardio Thorac Surg 2006; 30: 892–897.

20.

Kuntz

Holt

Turner

, et al. Effects of conventional ultrafiltration on renal performance during adult cardiopulmonary bypass procedures. J ExtraCorp Technol 2006; 38: 144–153.

21.

Gunaydin

Gourlay

. Novel ultrafiltration technique for blood conservation in cardiac operations. Ann Thorac Surg 2013; 95: 2148–2151.

22.

Schneditz

Putz-Bankuti

Ribitsch

, et al. Correction of plasma concentrations for effects of hemoconcentration or hemodilution. Am Soc Artif Intern Organs J 2012; 58: 160–162.

23.

Huang

Yao

Wang

, et al. Continuous ultrafiltration attenuates the pulmonary injury that follows open heart surgery with cardiopulmonary bypass. Ann Thorac Surg 2003; 76: 136–140.

24.

Johnson

Morgan

Utley

, et al. Comparative analysis of recovery of cardiopulmonary bypass residual blood: cell saver vs. hemoconcentrator. J ExtraCorp Technol 1994; 26: 194–199.

25.

Mauermann

Nuttall

Cook

, et al. Hemofiltration during cardiopulmonary bypass does not decrease the incidence of atrial fibrillation after cardiac surgery. Anesth Analg 2010; 110: 329–334.

26.

Pagano

Milojevic

Meesters

, et al. 2017 EACTS/EACTA Guidelines on patient blood management for adult cardiac surgery. Eur J Cardio Thorac Surg 2018; 53: 79-111.

27.

Luciani

Menon

Vecchi

, et al. Modified ultrafiltration reduces morbidity after adult cardiac operations: a prospective, randomized clinical trial. Circulation 2001; 104: 253.

28.

Bierer

Horne

Stanzel

, et al. Continuous ultrafiltration enhances recovery after adult cardiac surgery with cardiopulmonary bypass: a systematic Review and meta-analysis. CJC Open 2023; 5: 494–507.

29.

Hanson

Brikci

Erlangga

, et al. The Lancet Global Health Commission on financing primary health care: putting people at the centre. Lancet Glob Health 2022; 10: e715–e772.

30.

Mercuri

Gafni

. Medical practice variations: what the literature tells us (or does not) about what are warranted and unwarranted variations. J Eval Clin Pract 2011; 17: 671–677.

31.

O' Connor

Quinton

Traven

, et al. Geographic variation in the treatment of acute myocardial infarction: the cooperative cardiovascular project. JAMA 1999; 281: 627–633.

32.

Vonk

ABA

Meesters

van Dijk

, et al. Ten-year patterns in blood product utilization during cardiothoracic surgery with cardiopulmonary bypass in a tertiary hospital. Transfusion 2014; 54: 2608–2616.

33.

Stammers

Tesdahl

Mongero

, et al.

Does the use of zero-balance ultrafiltration during cardiopulmonary bypass affect urine output?

J ExtraCorp Technol 2021; 53: 27–37.

34.

Paugh

Dickinson

Martin

, et al. Impact of ultrafiltration on kidney injury after cardiac surgery: the Michigan experience. Ann Thorac Surg 2015; 100: 1683–1688.

35.

Song

Kim

Kwak

, et al. Urine output during cardiopulmonary bypass predicts acute kidney injury after cardiac surgery: a single-center retrospective analysis. Medicine 2016; 95: e3757.

36.

Stammers

Trowbridge

Pezzuto

, et al. Perfusion quality improvement and the reduction of clinical variability. J Extra Corpor Technol 2009; 42: 48–58.

37.

Sibbel

Maroni

Brunelli

. The effect of altitude on erythropoiesis-stimulating agent dose, hemoglobin level, and mortality in hemodialysis patients. J Nephrol 2017; 30: 821–829.

38.

Clark

Chandler

Zhou

, et al. Geographic variation in obesity at the state level in the all of Us Research Program. Prev Chronic Dis 2021; 18: E104.