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).
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.
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.
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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© 2016 International Anesthesia Research Society
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