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The Risk of Acute Kidney Injury from Fluid Restriction and Hydroxyethyl Starch in Thoracic Surgery

Ahn, Hyun Joo MD, PhD*; Kim, Jie Ae MD, PhD*; Lee, Ae Ryung MD; Yang, Mikyung MD, PhD*; Jung, Hyun Joo MD*; Heo, Burnyoung MD*

doi: 10.1213/ANE.0000000000000974
Critical Care, Trauma, and Resuscitation: Research Report

BACKGROUND: Fluid is restricted in thoracic surgery to reduce acute lung injury, and hydroxyethyl starches (HES) are often administered to reduce fluid amount. This strategy may contribute to the development of acute kidney injury (AKI). We evaluated the incidence, risk factors, and prognosis of AKI in thoracic surgery. We especially focused on whether fluid restriction/HES administration increased AKI.

METHODS: This is a retrospective study of patients undergoing thoracic surgery in a tertiary care academic center. Postoperative AKI was diagnosed within 72 hours after surgery based on the Acute Kidney Injury Network criteria. Demographic, intraoperative, and postoperative data were compared between non-AKI and AKI groups. Logistic regression was used to model the association between risk factors and AKI.

RESULTS: Final analysis included 1442 patients. Of these, 74 patients developed AKI (5.1%). Crystalloid restriction (≤3 mL·kg−1·h−1) was unrelated to AKI, regardless of preoperative renal functions (odds ratio [OR], 0.5; 95% confidence interval [CI] 0.2–1.4). AKI occurred more often when HES were administered to the patients with decreased renal function (OR, 7.6; 95% CI, 1.5–58.1) or having >2 risk factors with normal renal function (OR, 7.2; 95% CI, 3.6–14.1). Multivariate analysis revealed several risk factors: angiotensin-converting enzyme inhibitor/angiotensin receptor blockers, open thoracotomy, pneumonectomy/esophagectomy, diabetes mellitus, cerebrovascular disease, low albumin level, and decreased renal function.

CONCLUSIONS: Fluid restriction neither increased nor was a risk factor for AKI. HES should be administered with caution in high-risk patients undergoing thoracic surgery.

Published ahead of print September 28, 2015

From the *Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea; and Department of Anesthesiology and Pain Medicine, Jeju National University School of Medicine, Jeju, South Korea.

Accepted for publication July 24, 2015.

Published ahead of print September 28, 2015

Funding: None.

The authors declare no conflicts of interest.

Reprints will not be available from the authors.

Address correspondence to Jie Ae Kim, MD, PhD, Department of Anesthesiology and Pain Medicine, Samsung Medical Center, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, South Korea. Address e-mail to

Acute lung injury is related to the amount of fluid administered during thoracic operations.1,2 One study suggested that for every 500-mL increase in perioperative fluids, the odds ratio (OR) of developing acute lung injury after lung resection was 1.17.2 Concern that IV fluids may exacerbate, or even cause, pulmonary complications has led to the widespread adoption of perioperative restriction of fluids for thoracic surgical patients. However, restricting fluids also incurs risks, such as a hypovolemic state with impaired tissue perfusion, which may result in organ dysfunction and postoperative acute kidney injury (AKI).

Hydroxyethyl starches (HES) are often administered to reduce the overall fluid amount given in thoracic surgery. However, HES have also been associated with increased risk of renal impairment, especially in sepsis and cardiac surgery.3,4

AKI is a major postoperative complication in thoracic surgery, occurring in approximately 6% of patients, and correlated with a prolonged duration of hospital stay and poor overall prognosis.5,6 The pathophysiology of AKI after thoracic surgery is considered distinct from that in other types of surgeries and has a considerable inflammatory component. Several authors have postulated “lung biotrauma,” whereby lung injury provokes renal epithelial apoptosis7 and elevates inflammatory markers in kidney tissue.8 The routine practice of perioperative fluid restriction and the use of HES may put patients at a higher risk of AKI in thoracic surgery.

Several publications have addressed risk factors for AKI in patients after cardiac surgery9,10 and noncardiac surgeries.11,12 However, little is known about the effect of fluid management on postoperative AKI in thoracic surgery.

In this retrospective study, we identified risk factors for and prognosis of AKI in patients undergoing thoracic surgery. We focused especially on whether fluid restriction and HES administration were related to AKI when the confounding factors were adjusted for.

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Study Population

We retrospectively studied patients who underwent thoracic surgery in a tertiary care academic center. This study was approved by our IRB, and the need for informed consent was waived. We investigated all patients who underwent thoracic surgery between January 2012 and December 2012. Patients who received preoperative hemodialysis were excluded. Patients who died intraoperatively or within 24 hours postoperatively were excluded because a meaningful diagnosis of postoperative AKI could not be made in these patients.

AKI was defined according to the classification of Acute Kidney Injury Network (AKIN) based on changes in serum creatinine (sCr) level. The time frame for the changes from baseline was limited to 72 hours postoperatively to ensure that the occurrence of AKI was related to the index procedure. All available sCr values and the estimated glomerular filtration rate (eGFR) within postoperative 72 hours were reviewed. sCr and eGFR were measured at 8 AM every day for 3 days. The latest sCr before operation and the highest sCr level within postoperative 72 hours were used to confirm a diagnosis of AKI.

All electronic medical records were reviewed, and the following baseline information was gathered: age, sex, the body mass index, ASA physical status, comorbidities, medications, and preoperative laboratory data.

Intraoperative data included operation type, anesthetic duration, surgeons, vasopressor use, positive end-expiratory pressure, the lowest value of peripheral oxygen saturation (SpO2), body temperature, administered fluid type/volume, and urine output. Intra- and postoperative transfusions of red blood cells, fresh frozen plasma, or platelets were also recorded.

Outcome variables other than AKI included postoperative occurrence of atrial fibrillation, tracheal reintubation, acute respiratory distress syndrome, or pneumonia; the duration of postoperative mechanical ventilation, length of intensive care unit and hospital stay; and in-hospital mortality. Postoperative mechanical ventilation was defined as any extension of ventilator support outside the operating room, whether as a continuation of intraoperative care or as a support for postoperative respiratory failure. The length of hospital stay was the period between the day of surgery and the day of discharge or in-hospital death.

In our hospital, patients undergoing thoracic surgery were ventilated with the same protocol. Thoracoscopic cases converted to open thoracotomy were recorded as open cases. In those patients who had >1 thoracic surgery during the study period, only the data related to the first operation were included. HES solutions used during the study period were Voluven® (6% HES 130/0.4 saline based; Fresenius Kabi, Bad Homburg, Germany), Volulyte® (6% HES 130/0.4 balanced salt based, Fresenius Kabi), and Hextend® (6% HES 650/0.75 balanced salt based; Biotime, Berkeley, CA). Maintenance crystalloid solution was lactated Ringer’s solution.

The primary end point was renal outcome, considered to be the incidence of AKI defined by AKIN criteria within 72 hours after thoracic surgery. We also performed subdivision analysis according to patients’ preoperative renal function (decreased renal function: sCr >1.2 mg·dL−1 or eGFR <60 mL·min−1·(1.73 m2)−1 versus normal renal function).

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Statistical Analysis

We compared the baseline, intraoperative, and postoperative variables between patients who developed AKI (AKI group) and patients who did not (non-AKI group). Categorical variables were presented as number of patients (%) and compared using the χ2 or Fisher exact test as appropriate. Continuous variables with normal distribution were presented as mean (SD), and variables without normal distributions were presented as median (interquartile range). Continuous variables were compared using either the independent t test or the Mann-Whitney U test as appropriate.

A stepwise multivariate logistic regression analysis (total patients and patients with normal renal function) or exact logistic regression (patients with decreased renal function) was used to determine independent risk factors for AKI. To determine predictive accuracy, discriminative power was analyzed by calculating the area under receiver operating curves (ROCs). The mortality analysis was performed using product-limit survival estimates (Kaplan-Meier method and the log-rank test). A P value <0.05 was considered statistically significant for all tests. Data were analyzed by the software program SAS 9.4 software (SAS Institute Inc., Cary, NC). Package “pROC” in R version 3.1.2 (Vienna, Austria; and 10,000 stratified bootstrap method were used for area under the curve calculation and 95% confidence interval (CI), respectively.

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We reviewed 1444 cases of lung resection or esophageal surgery occurring between January 2012 and December 2012. Of these, 2 patients on dialysis before surgery were excluded and 1442 patients were entered into the study. Seventy-four patients developed AKI (5.1%) within the first 72 hours postoperatively. All cases were AKIN stage 1 (n = 39), stage 2 (n = 2), or stage 3 (n = 33). Two patients required renal replacement therapy (0.1%). The incidence of AKI was 4.5% in patients with normal preoperative renal function and 14.0% in patients with decreased renal function (sCr >1.2 mg·dL−1 or eGFR <60 mL·min−1·(1.73 m2)−1).

Demographic characteristics, medical history, and preoperative laboratory findings are summarized in Table 1. Most patients were ASA physical status II (74%) or I (19%).

Table 1

Table 1

The most common procedure was lobectomy (n = 771), followed by wedge resection/segmentectomy (n = 462), esophageal resection (n = 172), and pneumonectomy (n = 37). The thoracoscopic approach was used in 595 patients (41%). The incidence of AKI based on procedure type was 13% in esophageal resection, 11% in pneumonectomy, 5% in lobectomy, and 2% in wedge resection/segmentectomy (Table 2).

Table 2

Table 2

We assessed whether fluid restriction increased AKI. Crystalloid of ≤3 mL·kg−1·h−1 did not significantly increase AKI incidence (fluid restriction: 2.9%, nonrestriction: 5.4%, P = 0.17; Fig. 1). It was true with a lesser cutoff value (≤2 mL·kg−1·h−1 and >2 mL·kg−1·h−1: 6.9% and 5.1%, P = 0.99). Between the non-AKI and AKI groups, mean crystalloid volume (non-AKI: 4.8 ± 1.8 mL·kg−1·h−1 versus AKI: 4.8 ± 2.0 mL·kg−1·h−1) and the number of patients who received ≤3 mL·kg−1·h−1 were not different (non-AKI: 12.2% versus AKI: 6.8%, P = 0.22; Table 2). The occurrence of AKI was not affected by the restriction of crystalloid infusion, even in the patients with abnormal renal function (fluid restriction versus nonrestriction: OR, 0.5; 95% CI, 0.2–1.4; P = 0.20 in total patients; OR, 0.6; 95% CI, 0.2–1.7; P = 0.30 in patients with normal renal function; OR, 0.3; 95% CI, 0.0–2.9; P = 0.50 in patients with abnormal renal function; Table 3).

Table 3

Table 3

Figure 1

Figure 1

We also determined whether the use of HES increased AKI incidence. AKI incidence was significantly increased when HES was administered in all patients (HES (+) versus HES (−): 7.5% vs 3.1%; P = 0.0002; OR, 2.6; CI, 1.6–4.2) and in patients with normal renal function (HES (+) versus HES (−): 6.4% vs 2.9%; P = 0.0023; OR, 2.3; CI, 1.3–4.0). AKI incidence may have been also significantly increased in patients with abnormal renal function (HES (+) versus HES (−): 24.4% vs 5.8%; P = 0.0171; OR, 5.3; CI, 1.3–20.7). The mean volume was 526 ± 219 mL among patients who received HES, and each 500-mL aliquot increased the odds of AKI 1.75-fold (r = 0.0015; P < 0.0001; Table 2). However, multivariate analysis indicated HES as a risk factor only in patients with abnormal renal function (total patients OR, 1.2; 95% CI, 0.7–2.2; patients with normal renal function OR, 0.9; 95% CI, 0.5–1.7; patients with abnormal renal function OR, 7.6; 95% CI, 1.5–58.1; Table 3).

The type of HES, such as low- versus high-molecular-weight HES or balanced salt versus normal saline-based HES, did not affect AKI occurrence (AKI incidence: Voluven 4.7% among 106 patients, Hextend 6.8% among 161 patients, Volulyte 8.6% among 396 patients, P = 0.38; normal saline based 4.7% versus balanced salt based 8.1%, P = 0.32; high molecular weight 6.8% versus low molecular weight 7.8%, P = 0.83).

Several preoperative predictors were identified by multivariate analysis: use of angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB), open thoracotomy, pneumonectomy/esophagectomy, low albumin level, diabetes mellitus, cerebrovascular disease, and decreased renal function (sCr <1.2 mg·dL−1 or eGFR <60 mL·min−1·(1.73 m2)−1). In patients with normal renal function, low sCr and male sex were additional risk factors. In patients with decreased renal function, use of ACEI/ARB and HES administration were risk factors (Table 3). Odd ratios and power for each risk factor are shown in Figure 2. We evaluated whether administration of HES increases AKI to the patients with normal preoperative renal function (n = 1349) but with multiple risk factors. An ROC curve was constructed with the number of risk factors (from 0 to 6, excluding decreased renal function). Having >2 risk factors was found to be a cutoff. The incidence of AKI was 18% vs 3% between the patients with >2 risk factors and fewer risk factors when HES was administered (P < 0.0001; OR, 7.2; 95% CI, 3.6–14.1; χ2 test).

Figure 2

Figure 2

Postoperative AKI was associated with a significantly increased rate of tracheal reintubation (2% vs 11%, P = 0.0001), acute respiratory distress syndrome/pneumonia (5% vs 14%, P = 0.0001), increased duration of mechanical ventilation (8.6 ± 58.50 vs 34.0 ± 117.1 hours, P = 0.0007), intensive care unit stay (32.6 ± 84.9 vs 79.4 ± 151.5 hours, P = 0.0001), and hospital stay (9.2 ± 9.7 vs 16.1 ± 13.6 days, P = 0.0001). In-hospital mortality may also have been higher in the AKI group (0.8% vs 4%, P = 0.03; Table 4; Fig. 3).

Table 4

Table 4

Figure 3

Figure 3

Table 5

Table 5

Table 6

Table 6

Figure 4

Figure 4

To improve clinical usability, 7 risk factors were used to create an unweighted risk factor scale (RFS) for each patient (Table 5). The RFS was defined as the number of risk factors a patient has. Before creating the RFS, we conducted an ROC analysis for albumin, a continuous risk factor, to search for its cutoff. An optimal sensitivity and specificity were achieved at 4.3 g·dL−1. An ROC curve was constructed across different values of RFS, and the area under ROC curve was 0.79 (95% CI, 0.73–0.84; Fig. 4). The positive predictive value for developing AKI increased from 6.6% to 8.9%, 14.9%, 24.7%, 38.5%, and 100% (lower confidence limits) as RFS increased (Table 6).

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Our study showed that fluid restriction neither increased AKI nor was a risk factor for AKI development in thoracic surgery. We also found that HES administration was a risk factor for AKI in patients already at high risk for AKI.

Previous studies of restrictive fluid regimens for perioperative care have defined “restrictive” as a background rate of 4 mL·kg−1·h−1.13 In our study, <3 mL·kg−1·h−1 was not associated with AKI in univariate or multivariate analysis.14 Our result supports the current recommendation of fluid restriction in thoracic surgery. One report has even recommended 1 to 2 mL·kg−1·h−1 for intra- and postoperative maintenance fluid in lung resection surgery.15 We also tested 2 mL·kg−1·h−1 criteria in our study, and <2 mL·kg−1·h−1 did not increase AKI risk either. However, only 1.9% of patients received this amount of fluid. It is beyond the scope of this study to discuss to what extent fluid can be restricted without AKI risk, and thus further studies may be required on this matter.

We also found that, in high-risk patients, HES administration is associated with AKI after thoracic surgery. The proposed mechanism includes ischemic injury from osmotic nephrosis, where glomerular filtration rate (GFR) is decreased secondary to a reduction in the filtration fraction.16 Cases of AKI associated with the use of HES have been evaluated in multiple studies with conflicting results. A large randomized controlled trial by Brunkhorst et al.3 demonstrated an increased risk of acute renal failure in a dose-dependent manner with pentastarch 10% (HES 200/0.5) compared with Ringer’s lactate solution in patients with severe sepsis. Similarly, pentastarch 10% was associated with increased risk of AKI in a retrospective cohort of patients undergoing cardiac surgery.4 In contrast, Magder et al.17 did not observe a relationship between pentastarch 10% and AKI in their randomized controlled trial of 200 patients after cardiac surgery. Van Der Linden et al.18 suggested that, in their systemic review (39 trials, 3389 patients), there were no indications that the use of tetrastarches during surgery induces adverse renal effects.

The reasons for these diverse outcomes are unclear but may be because of a combination of different factors, such as different patient populations, different surgeries, and different types and volume of HES. We used Voluven, Volulyte, or Hextend, and the mean administration volume was 526 ± 219 mL. Neither the amount nor the type of HES administration alone increased AKI incidence by multivariable analysis. However, in patients with decreased renal function or >2 risk factors, HES administration increased the risk of AKI. In such patients, 500 mL of HES increased AKI, regardless of their molecular weights and based solution.

Until now, only 1 study5 has demonstrated an association between HES and AKI after lung resection surgery. In that retrospective, single-center study on 1129 patients who underwent lung resection surgery, multivariate analysis demonstrated an independent association between postoperative AKI and HES use (OR, 1.5; 95% CI, 1.1–2.1) and open procedures. However, only 7% of patients received HES.5 In our study, 46% of patients received HES, making our results potentially more suited for assessing the effect of HES administration on AKI occurrence in thoracic surgery.

In our study, multivariate analysis revealed 7 independent risk factors: ACEI/ARB, open thoracotomy, pneumonectomy/esophagectomy, diabetes mellitus, cerebrovascular disease, low albumin level, and decreased renal function. Our data are consistent with Ishikawa et al.,5 who found an association between ACEI/ARB and AKI in lung resection surgery (OR, 2.2; 95% CI, 1.1–4.4) and Arora et al.19 who showed a similar relationship between ACEI/ARB and AKI in cardiovascular surgery (OR, 1.41; 95% CI, 1.1–1.8). Preoperative use of ACEI/ARB decreases angiotensin II activity, aldosterone and antidiuretic hormone secretion, and sympathetic nervous system activity. In addition, ACEI/ARB diminishes the ability of the efferent arteriole to constrict, impairing renal autoregulation.20 The patient receiving chronic ACEI/ARB treatment may thus develop a significant decrease in perfusion pressure with decreased urine production. Furthermore, because the lungs are major sites of angiotensin-converting enzyme expression and angiotensin II production, thoracic surgery may exacerbate the effect of ACEI/ARB by further decreasing angiotensin-converting enzyme and angiotensin II production.21 Although current evidence does not support stopping ACEI/ARB use before thoracic surgery, preoperative discontinuation of these medications may be reasonable to protect kidney function.

In our study, decreased preoperative renal function (sCr >1.2 mg·dL−1 or GFR <60 mL·min−1·(1.73 m2)−1) predicted an increased risk of postoperative AKI, a result also shown in other study.22 Higher sCr, however, correlated with a reduced risk of AKI in patients with normal renal function (OR, 0.0; 95% CI, 0.0–0.2). One possible explanation is that sCr is related to body muscle mass, especially in patients with normal renal function. Elderly patients with depleted body muscle mass may have a lower baseline sCr, indicating reduced physical reserve and increased risk of postoperative AKI.23 We also found that low albumin level was a risk factor for AKI. Low albumin concentration has been used as a marker of protein malnutrition.24 Albumin also functions as an antioxidant25 and as a negative acute-phase protein that decreases with ongoing inflammation.26 Albumin may have a role in preventing lung biotrauma.

In the Society of Thoracic Surgeons’ database, AKI occurred in only 1.4% of cases.27 This low rate is because research on AKI after thoracic surgery has defined AKI as either a doubling of sCr or a requirement for renal replacement therapy. End points such as renal replacement therapy underestimate the clinical impact of reduced GFR. Postoperative sCr increases as small as 0 to 0.5 mg·dL−1 are associated with an approximately 3-fold increase in mortality after cardiac surgery.28 In addition, increased sCr after operations correlates with decreased long-term survival, even after full recovery of renal function.29 Our study used the AKIN criteria, in which AKI was defined as an abrupt (occurring within a 48-hour period) reduction in kidney function with an absolute increase in sCr of 0.3 mg·dL−1 as a diagnostic criterion for stage 1 disease. In our study, postoperative AKI diagnosed by increased sCr was associated with a significantly increased morbidity, mortality, and resource utilization in accordance with other studies.30

The limitations of the present study include the following: first, the study may be subject to bias from unmeasured risk factors because of its retrospective observational nature. Although we attempted to control for selection bias with multivariate regression analysis and risk adjustment for these factors, we could not completely eliminate the potential for residual confounding. However, in the absence of a comparable prospective database of AKI, a retrospective study with compensatory statistical methods would be a reasonable approach. Second, our time frame for observation and analysis of events was 72 hours postoperatively to limit analysis to preoperative and perioperative factors associated with AKI. This may have resulted in missing some cases of delayed AKI. Third, perioperative care practice may be different in other institutions, potentially accounting for the differences in outcomes. Fourth, we considered vasopressor use a surrogate measure of intraoperative hypotension. However, this approach may have included cases with vasopressor use for other reasons. Last, HES and ACEI/ARB have wide CIs that could make the conclusions less precise. Further prospective studies are required to evaluate the effect of current volume restriction strategy, use of HES, and ACEI/ARB on AKI.

In conclusion, restrictive fluid management was not related to AKI, but HES should be used with caution in patients with decreased renal function or with >2 risk factors for perioperative renal failure.

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Name: Hyun Joo Ahn, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and write the manuscript.

Attestation: Hyun Joo Ahn has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Jie Ae Kim, MD, PhD.

Contribution: This author helped design the study, conduct the study, analyze the data, and prepare the manuscript.

Attestation: Jie Ae Kim has seen the original study data, reviewed the analysis of the data, approved the final manuscript, and is the author responsible for archiving the study files.

Name: Ae Ryung Lee, MD.

Contribution: This author helped conduct the study and analyze the data.

Attestation: Ae Ryung Lee has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Mikyung Yang, MD, PhD.

Contribution: This author helped analyze the data and prepare the submitted manuscript.

Attestation: Mikyung Yang has seen the original study data and approved the final manuscript.

Name: Hyun Joo Jung, MD.

Contribution: This author helped analyze the data and prepare the manuscript.

Attestation: Hyun Joo Jung has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

Name: Burnyoung Heo, MD.

Contribution: This author helped analyze the data and prepare the manuscript.

Attestation: Burnyoung Heo has seen the original study data, reviewed the analysis of the data, and approved the final manuscript.

This manuscript was handled by: Avery Tung, MD.

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We gratefully acknowledge the assistance of statistician, Kyunga Kim, PhD, and Juna Goo, MS, from Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, for the statistical analysis.

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