Eur J Cardiothorac Surg 2008;33:691-694. doi:10.1016/j.ejcts.2008.01.006
Copyright © 2008, European Association for Cardio-thoracic Surgery. Published by Elsevier. All rights reserved.
Intraoperative skeletal muscle ischemia contributes to risk of renal dysfunction following thoracoabdominal aortic repair
Charles C. Miller, III*,
Martin A. Villa,
Paul Achouh,
Anthony L. Estrera,
Ali Azizzadeh,
Sheila M. Coogan,
Eyal E. Porat,
Hazim J. Safi
Department of Cardiothoracic and Vascular Surgery, The University of Texas Medical School at Houston, Houston, TX, USA
* Corresponding author. Address: Department of Cardiothoracic and Vascular Surgery, The University of Texas Medical School at Houston, 6410 Fannin Street, Suite 450, Houston, TX 77030, USA. Tel.: +1 713 500 5420; fax: +1 713 500 0656. (Email: Charles.C.Miller{at}uth.tmc.edu).
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Abstract
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Objective: Renal dysfunction is among the most commonly occurring morbidities following descending thoracic and thoracoabdominal aortic repair. We hypothesized that myoglobin nephrotoxicity might arise from leg ischemia caused by femoral artery cannulation, which is required for distal aortic perfusion. Lacking complete historical laboratory data on myoglobinemia, we studied somatosensory evoked potential (SSEP) changes in the leg (a functional marker of leg ischemia), as a surrogate predictor of acute postoperative renal failure. Methods: Intraoperative leg SSEP function and preoperative glomerular filtration rate (GFR – an essential covariate) were available for 299 patients. Change in SSEP was defined as 10% increase in latency or 50% decrease in amplitude. Postoperative renal dysfunction was 1 mg/dl/day increase in creatinine for 2 days, clinical diagnosis of ARF or need for dialysis postoperatively. Results: Change in SSEP in the cannulated leg occurred in 108/299 (36%) of cases intraoperatively. All recovered normal SSEP function at decannulation. Patients with SSEP changes had 41/108 (38%) postoperative renal failure compared to 49/191 (26%) without (odds ratio 1.8, p
< 0.03). Modeled with GFR, aneurysm extent, and chronic obstructive pulmonary disease (COPD), SSEP changes had an adjusted odds ratio of 1.9, p
< 0.03. Pre-op GFR was also a highly significant predictor of postoperative renal failure (OR 0.98/ml; p
< 0.0001). Conclusion: This is the first study to show a relationship between intraoperative leg ischemia and postoperative renal failure. It provides epidemiological evidence that the ischemic leg may be an important contributor to rhabdomyolysis-like renal morbidity after thoracoabdominal aortic surgery.
Key Words: Thoracoabdominal aortic surgery • Renal dysfunction • Rhabdomyolysis
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1. Introduction
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Renal dysfunction is among the most commonly occurring morbidities following descending thoracic and thoracoabdominal aortic (TAAA) repair. While no standard definition of post-TAAA renal dysfunction has become established in the literature, studies that define it in terms of increasing postoperative creatinine report rates of 10–40%, [1–6] while those that define it as requirement for new dialysis report rates in the 2–15% range [3,4,6–8]. The only large multicenter report in the literature to date describes renal failure rates submitted by hospitals to Medicare as part of their billing data. These data are derived from hospital ICD-9 coding; the study authors estimate the rate of acute renal failure to be 14%. [9]. Whatever the definition, postoperative renal dysfunction has been unequivocally linked to poor long-term survival [5,6,10]. Therefore, meaningful reduction of the occurrence of this problem is of great clinical importance.
Despite over a decade of varied attempts to protect the kidneys intraoperatively, our group has yet to find a technique that produces clear and consistent improvement in the rates of postoperative renal dysfunction when applied to large numbers of patients, and this has led us to question whether we might be overlooking some important element in the causal pathway. When a colleague of ours recently pulled out of a 160 km endurance running race with exertional rhabdomyolysis, it occurred to us that intraoperative muscular hypoperfusion might create similar consequences in patients undergoing TAAA repair. The ideal way to look at this would be to examine changes in serum creatine phosphokinase (CPK) and myoglobin between pre- and postoperative conditions, but we have not collected these laboratory markers routinely in the past. We have, however, monitored somatosensory evoked potentials (SSEP) for the last few years, and have noted that the reference signal in the leg cannulated for distal aortic perfusion commonly disappears for a time before returning upon decannulation. We reasoned that ischemic changes in the large muscles of the leg that are detectable by SSEP might be linked to release of nephrotoxic muscular proteins.
The purpose of this study was to examine the relationship between loss of SSEP in the cannulated leg and postoperative renal dysfunction, as part of a hypothesis-generating epidemiological study to investigate the potential role of rhabdomyolysis as a contributor to renal dysfunction following TAAA repair.
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2. Methods
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We reviewed 299 TAAA cases that met criteria for the study from our database which was approved by the institutional review board. Patients who experienced spinal or bilateral peripheral somatosensory evoked potential (SSEP) changes were excluded from the cohort because of the difficulty of interpreting the extent of ischemia in such patients. Only patients who experienced isolated cannulated-leg signal disruption or who had completely normal SSEPs throughout the procedure were included. Intraoperative deaths were also excluded due to the inability to ascertain postoperative renal function in such patients.
The procedures were conducted between 1992 and 2007, but only six were done in the time period prior to 2000. These six were retained in the cohort for completeness. Median age of the study group was 68 (range 25–87), and 193/299 (64.5%) were male. All patients were treated using our standard TAAA operative protocol, which has been described in detail previously [11]. Briefly, a thoracoabdominal incision is used, beginning in the abdomen and continuing over the sixth rib before curving cephalad just posterior to the tip of the scapula. The lung is deflated, and the sixth rib is excised. This incision is completed by dividing the costal cartilage with heavy scissors. The diaphragm is partially incised to improve exposure and to avoid traction injury to the phrenic nerve. A self-retaining retractor is then inserted, and the aorta is inspected. The pericardium is opened posterior to the phrenic nerve, and the patient is given 1 mg (90 IU) per kg body weight of sodium heparin. The left atrium is cannulated through the left pulmonary vein or the left atrial appendage. A BioMedicus (Minneapolis, MN) pump with an inline heat exchanger is attached to this cannula, and the arterial inflow is established through the left femoral artery or the descending thoracic aorta. All patients were treated with distal aortic perfusion and cerebrospinal fluid drainage.
SSEP and EEG monitoring: An eight-channel EEG monitoring system was used during the surgical procedure (Fig. 1
). SSEP stimulatory electrodes were placed bilaterally at the level of the malleolus. Recording electrodes were bilaterally placed at 3 levels: popliteal fossa, 5th cervical vertebral body and cortex. Evoked potentials were induced using a Digitimer generator/stimulator (Letchworth Garden City, UK). The right and left posterior tibial nerves (PTN) were alternatively stimulated at the ankle (rate= 4.7Hz; stimulus duration = 0.05–0.7 s; stimulus intensity = 0.3 A) in order to get a sustained waveform. SSEP were bilaterally recorded on three channels: popliteal, cervical and cortical. A baseline SSEP tracing was obtained before the beginning of the procedure. All the following SSEP tracings were superposed and compared to the baseline tracing. SSEP abnormalities were defined as either a 10% increase in latency or a 50% reduction in amplitude. The simultaneous interpretation of the three channels enabled us to distinguish SSEP changes related to spinal cord injury from those related to peripheral nerve ischemia or cerebral injury. Peripheral nerve ischemia (secondary to cannulation of the femoral artery or interruption of distal aortic perfusion) would result in a change or loss of SSEP signals in all three channels. Spinal cord injury or dysfunction would result in a change or loss of SSEP signals in the cervical and cortical channels, with normal popliteal signals. A cerebral injury would translate into a change or loss of SSEP signals in the cortical channel as well as in the EEG recording, with normal popliteal and cervical SSEP signals. Although intraoperative maneuvers to reduce critical spinal ischemia are employed in response to changes in spinal SSEP signals, this was not true for loss of leg SSEP during the period of the study. Patients with spinal signal changes were not eligible for inclusion in this study, so any intraoperative maneuvers made in response to spinal signal changes were excluded from the present cohort by design.
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Fig. 1. SSEP technique. Stimulus is administered at the ankle (A), and read at popliteal fossa (B), cervical spine (C) and cortical electrode (D). Signal lost at the popliteal fossa in the cannulated leg, but not at any other site on the opposite side, is considered lost by our definition here. Patients with any spinal or cortical losses were excluded from the study. All remaining patients had normal tracings throughout.
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Preoperative glomerular filtration rate was estimated using the prediction equation of Cockcroft and Gault [12]. Postoperative renal dysfunction was defined as any of the following: (a) increase of 1 mg/dl/day in serum creatinine for two consecutive days above the preoperative value; (b) a clinical diagnosis of renal failure by an independent nephrologist; or (c) requirement of postoperative hemodialysis.
Univariate measures of association between risk factors and renal dysfunction were computed using contingency table methods, and adjusted analyses were conducted by multiple logistic regression. All computations were performed using SAS software version 9.1.3 service pack 4 (SAS Institute, Inc., Cary, NC). The null hypothesis of no association was rejected at a nominal alpha of p
< 0.05.
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3. Results
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Ninety cases of postoperative renal dysfunction were observed in 299 patients (30.1%). Median estimated preoperative glomerular filtration rate was 66 (ml/min/1.73 m2), while the 75th percentile was 98 (ml/min/1.73 m2), indicating that nearly 75% of the population had abnormal renal function preoperatively and roughly half the population had significant (moderate or greater according to US National Kidney Foundation) dysfunction [13].
Univariate associations between selected risk factors and postoperative renal dysfunction are shown in Table 1
. Significant univariate predictors were age >75, preoperative GFR <67 (ml/min/1.73 m2), aneurysm extent involving the visceral circulation (TAAA II, III or IV), chronic obstructive pulmonary disease, hypertension, aortic cross-clamp time >45 min, and distal aortic perfusion time >60 min. Loss of signal in the cannulated leg was significantly associated with increased renal dysfunction (odds ratio 1.77, p
< 0.03).
Adjusted analyses are shown in Table 2
. In multivariable analysis, GFR, aortic cross-clamp time, Crawford Extents II, III and IV aneurysms (aneurysms involving the visceral circulation), and COPD remained statistically significant predictors. Isolated leg ischemia also remained significant, with an adjusted odds ratio of 1.94, p
< 0.03. Age >75, hypertension, aortic cross-clamp time, and distal aortic perfusion time all dropped from the multivariable model. We did not find any association between SSEP loss and history of diabetes or peripheral vascular disease. Although we do not routinely do peripheral vascular studies on aneurysm patients in the absence of indications, all patients do receive history and physical exam at clinic and upon admission, and these findings are entered into the record.
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4. Discussion
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This is the first report in the literature to document an association between functional peripheral muscle ischemia and renal dysfunction following thoracoabdominal aortic surgery. We conducted thorough multivariable analyses to isolate the effects of other likely confounding variables such as ischemic time, pump time, peripheral vascular disease, and hypertension (associated with both renovascular disease and occult peripheral vascular disease), as these bear on the relationship between leg ischemia and renal dysfunction.
The association also persists despite adjustment for numerous risk factors known to be strong predictors of postoperative renal dysfunction, including preoperative renal function, COPD, and aneurysm extent. While some possibility exists that signal loss arises from poor collateralization due to peripheral vascular disease (which would also likely be associated with renal dysfunction) we were not able to identify any association between documented peripheral vascular disease or hypertension in adjusted analysis.
The persistence of leg ischemia as a risk factor despite statistical adjustment supports the hypothesis that non-physiologic circulation may be associated with renal dysfunction through a pathway other than the direct end-renal ischemia mechanism that has long been assumed to be primary.
Lack of a clear definition of postoperative renal dysfunction in the literature makes generalization of these findings troublesome. Ranges of reported renal dysfunction are highly variable, ranging in large series from 10% to 40%. This wide range makes the effect of any newly identified mechanism hard to estimate. Our definition is broadly inclusive and captures cases that many other centers would not classify as renal dysfunction. According to the RIFLE criteria, which are seeing increased adoption in the multispecialty literature, our patients would fall in the range of ‘R’ to ‘I’ and above, which captures renal risk and injury and not clinical renal failure only [14].
In our population, renal outcome is highly dependent on preoperative renal function and aneurysm involvement of the visceral circulation. In the thoracoabdominal patients, over half have visceral involvement. Similarly, approximately half our population had moderate or greater preoperative renal insufficiency according to American Kidney Foundation guidelines. Clearly, management of aneurysms in patients with poor preoperative renal function is a significant challenge, and a better understanding of the pathophysiology of postoperative renal dysfunction is of great clinical importance.
Further studies are required to make direct measures of the muscular proteins CPK and myoglobin, to determine how these relate to leg ischemia, and ultimately to determine whether increased values of these muscle proteins are causally associated with postoperative renal dysfunction.
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Appendix A
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Conference discussion
Dr M. Turina (Zurich, Switzerland): The most surprising result is that COPD emerges as a factor for something which should be a peripheral phenomenon. We know that COPD is a very strong predictive factor for rupture from the work in Dr Griepp's laboratory, but how do you explain the COPD as a predictor?
Dr Miller: We think the statistical relationship between COPD and renal failure stems from the subset of renal failure that occurs in the multi-organ failure cascade. So when you have one thing going, you likely have the others going as well. When renal dysfunction occurs in the context of multi-organ failure, often respiratory failure and other organ systems are involved.
Dr Turina: Further questions? Randy, you might comment on that study.
Dr R. Griepp (New York, NY): I think it's very interesting, and I think you may be right. But you’re probably now using side grafts to avoid this problem.
And I also might suggest that in most of these cases, the artery can be cannulated with a Seldinger technique without interrupting distal flow.
We have also seen this unilateral loss, and we usually think it's just because our cannulation isn’t perfect. But with the Seldinger technique and not putting a tourniquet on the artery, it's relatively unusual.
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Acknowledgments
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The research reported in this article was supported by a grant from the National Heart Lung Blood Institute 5 P50 HL083794-02 (TAAD-SCCOR). The opinions contained herein are solely those of the authors.
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Footnotes
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Presented at the 21st Annual Meeting of the European Association for Cardio-thoracic Surgery, Geneva, Switzerland, September 16–19, 2007.
The research reported in this article was supported by a grant from the National Heart Lung Blood Institute 5 P50 HL083794-02 (TAAD-SCCOR). The opinions contained herein are solely those of the authors.
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Abstract
1. Introduction
