Advertisement

Renal perfusion with histidine-tryptophan-ketoglutarate compared with Ringer's solution in patients undergoing thoracoabdominal aortic open repair

      Abstract

      Objective

      The objective of this study was to compare the efficacy of renal perfusion with Custodiol (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) versus enriched Ringer's solution for renal protection in patients undergoing open thoracoabdominal aortic aneurysm (TAAA) repair.

      Methods

      Ninety consecutive patients scheduled for elective open TAAA repair were enrolled between 2015 and 2017 in a single-center, phase IV, prospective, parallel, randomized, double-blind trial (the CUstodiol versus RInger: whaT Is the Best Agent [CURITIBA] trial), and randomized to renal arteries perfusion with 4°C Custodiol (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany; n = 45) or 4°C lactated Ringer's solution (n = 45). The incidence of acute kidney injury (AKI) in patients undergoing TAAA open surgery using Custodiol renal perfusion versus an enriched Ringer's solution was the primary end point.

      Results

      Ninety patients completed the study (45 patients in each group). The incidence of postoperative AKI was significantly lower in the Custodiol group (48.9% vs 75.6%; P = .02). In the multivariable model, only the use of Custodiol solution resulted as protective from the occurrence of any AKI (odds ratio, 0.230; 95% confidence interval, 0.086-0.614; P = .003), whereas TAAA type II extent was associated with the development of severe AKI (odds ratio, 4.277; 95% confidence interval, 1.239-14.762; P = .02). At 1-year follow-up, serum creatinine was not significantly different from the preoperative values in both groups.

      Conclusions

      The use of Custodiol during open TAAA repair was safe and resulted in significantly lower rates of postoperative AKI compared with Ringer's solution. These findings support safety and efficacy of Custodiol in this specific setting, which is currently off-label.

      Graphical abstract

      Key Words

      Abbreviations and Acronyms:

      AKI (acute kidney injury), AKIN (Acute Kidney Injury Network), CI (confidence interval), CKD (chronic kidney disease), CURITIBA (CUstodiol versus RInger: whaT Is the Best Agent), GFR (glomerular filtration rate), IQR (interquartile range), LR (likelihood ratio), OR (odds ratio), TAAA (thoracoabdominal aortic aneurysm)
      Figure thumbnail fx2
      Intraoperative image detailing visceral vessels perfusion during open thoracoabdominal aortic aneurysm repair. On the right side of the image two 9F Pruitt occlusion-perfusion balloon catheters were inserted directly into the celiac axis and superior mesenteric artery for continuous infusion of oxygenated isothermic blood via the LHBP circuit for TAAA. Two other 9F Pruitt balloon occlusion-perfusion catheters were then inserted directly into the renal arteries for continuous infusion of 4°C crystalloid solution from a separate pressure line perfusion system.
      Renal perfusion with histidine-tryptophan-ketoglutarate solution (Custodiol; Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) during open TAAA repair is safe and allows reducing postoperative acute kidney injury compared with Ringer's solution.
      The results of this trial support the use of cold Custodiol solution (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) for perfusion of the renal arteries during open TAAA repair, thanks to its ability to reduce the risk of postoperative renal dysfunction. In the future, its use will be possibly extended to juxtarenal and pararenal aneurysm repair, or in further cases of renal surgery.
      See Commentaries on pages 580, 582, and 584.
      Thoracoabdominal aortic aneurysm (TAAA) is a life-threatening disease with a 5-year survival rate ranging at approximately 10% to 20% if left untreated.
      • Griepp R.B.
      • Ergin M.A.
      • Galla J.D.
      • Lansman S.L.
      • McCullough J.N.
      • Nguyen K.H.
      • et al.
      Natural history of descending thoracic and thoracoabdominal aneurysms.
      Open surgical repair has proven to be effective in changing the natural history of this disease,
      • Goodney P.P.
      • Travis L.
      • Lucas F.L.
      • Fillinger M.F.
      • Goodman D.C.
      • Cronenwett J.L.
      • et al.
      Survival after open versus endovascular thoracic aortic aneurysm repair in an observational study of the Medicare population.
      however, it is still burdened with considerable perioperative morbidity and mortality rates.
      • Coselli J.S.
      • LeMaire S.A.
      • Preventza O.
      • de la Cruz K.I.
      • Cooley D.A.
      • Price M.D.
      • et al.
      Outcomes of 3309 thoracoabdominal aortic aneurysm repairs.
      ,
      • Moulakakis K.C.
      • Karaolanis G.
      • Antonoupoulos C.N.
      • Kakisis J.
      • Klonaris C.
      • Preventza O.
      • et al.
      Open repair of thoracoabdominal aortic aneurysms in experienced centers.
      Acute kidney injury (AKI) after vascular surgery in general is associated with an increased risk of cardiovascular events and all-cause mortality.
      • LeMaire S.A.
      • Price M.D.
      • Green S.Y.
      • Zarda S.
      • Coselli J.S.
      Results of open thoracoabdominal aortic aneurysm repair.
      Renal function is even more closely related to poorer long-term survival and increased postoperative mortality after TAAA open repair.
      • Kulik A.
      • Castner C.F.
      • Kouchoukos N.T.
      Outcomes after thoracoabdominal aortic aneurysm repair with hypothermic circulatory arrest.
      • Svensson L.G.
      • Crawford E.S.
      • Hess K.R.
      • Coselli J.S.
      • Safi H.J.
      Experience with 1509 patients undergoing thoracoabdominal aortic operations.
      • Shepens M.A.
      • Heijmen R.H.
      • Ranschaert W.
      • Sonker U.
      • Morshius W.J.
      Thoracoabdominal aortic aneurysm repair: results of conventional open surgery.
      • Crawford E.S.
      • Crawford J.L.
      • Safi H.J.
      • Coselli J.S.
      • Hess K.R.
      • Brooks B.
      • et al.
      Thoracoabdominal aortic aneurysms: preoperative and intraoperative factors determining immediate and long-term results of operations in 605 patients.
      • Pieri M.
      • Nardelli P.
      • De Luca M.
      • Landoni G.
      • Frassoni S.
      • Melissano G.
      • et al.
      Predicting the need for intra-operative large volume blood transfusions during thoraco-abdominal aortic aneurysm repair.
      • Wong D.R.
      • Parenti J.L.
      • Green S.Y.
      • Chowdhary V.
      • Liao J.M.
      • Zarda S.
      • et al.
      Open repair of thoracoabdominal aortic aneurysm in the modern surgical era: contemporary outcomes in 509 patients.
      Different definitions for kidney injury have been used, and different renal protection methods have been used, which account for large differences in incidence data all over the world.
      • Godet G.
      • Fleron M.H.
      • Vicaut E.
      • Zubicki A.
      • Bertrand M.
      • Riou B.
      • et al.
      Risk factors for acute postoperative renal failure in thoracic or thoracoabdominal aortic surgery: a prospective study.
      • Wynn M.M.
      • Acher C.
      • Marks E.
      • Engelbert T.
      • Acher C.W.
      Postoperative renal failure in thoracoabdominal aortic aneurysm repair with simple cross-clamp technique and 4°C renal perfusion.
      • Bashir M.
      • Harky A.
      • Adams B.
      • Wong K.
      • Di Salvo C.
      • Oo A.
      Renal protection in thoracoabdominal aortic aneurysm surgery.
      In the intraoperative setting, permissive or active hypothermia lowering the patient body temperature down to 32°C might be applied to prevent abdominal organ ischemia.
      • Crawford E.S.
      • Crawford J.L.
      • Safi H.J.
      • Coselli J.S.
      • Hess K.R.
      • Brooks B.
      • et al.
      Thoracoabdominal aortic aneurysms: preoperative and intraoperative factors determining immediate and long-term results of operations in 605 patients.
      Previous studies suggested to selectively perfuse kidneys with a cold crystalloid solution (4°C), and reported a significant reduction in the incidence of AKI.
      • Ko¨ksoy C.
      • LeMaire S.A.
      • Curling P.E.
      • Raskin S.A.
      • Schmittling Z.C.
      • Conklin L.D.
      • et al.
      Renal perfusion during thoracoabdominal aortic operations: cold crystalloid is superior to normothermic blood.
      • LeMaire S.A.
      • Jones M.M.
      • Conklin L.D.
      • Carter S.A.
      • Criddell M.D.
      • Wang X.L.
      • et al.
      Randomized comparison of cold blood and cold crystalloid renal perfusion for renal protection during thoracoabdominal aneurysm repair.
      • Tshomba Y.
      • Kahlberg A.
      • Melissano G.
      • Coppi G.
      • Marone E.
      • Ferrari D.
      • et al.
      Comparison of renal perfusion solutions during thoracoabdominal aortic aneurysm repair.
      Histidine-tryptophan-ketoglutarate, or Custodiol HTK solution (Custodiol; Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) is a low-potassium preservation solution used for organ transplantation and cardioplegia (Table 1). Previous observational studies suggested that renal perfusion with cold Custodiol solutions might prevent AKI during suprarenal aortic cross-clamping however, because no randomized scientific evidence on Custodiol renal perfusion actually exists, we conducted a double-blind, controlled, randomized trial to determine whether Custodiol significantly reduces the incidence of postoperative AKI after thoracoabdominal aortic repair surgery.
      Table 1Characteristics of Custodiol solution and Lactated Ringer's solution
      Custodiol (mmol/L)Ringer's (mmol/L)
      Sodium chloride15.0130.0
      Magnesium chloride N6 H2O4.00.0
      Potassium chloride9.04.0
      Potassium hydrogen 2-ketoglutarate1.00.0
      Histidine hydrochloride N H2O18.00.0
      Histidine180.00.0
      Mannitol30.00.0
      Tryptophan2.00.0
      Sodium lactate0.028.0
      Calcium chloride N2 H2O0.0152.7
      Custodiol solution is from Essential Pharmaceuticals, LLC (Durham, NC).

      Methods

      Trial Design and Eligibility Criteria

      “CUstodiol Versus RInger: whaT Is the Best Agent? A Randomized Double Blind Trial” (CURITIBA) study is a prospective, single-center, randomized, double-blind, controlled, parallel trial on AKI in patients undergoing TAAA open repair using Custodiol renal perfusion versus an enriched Ringer's solution. The trial protocol (version 4.0, dated March 4, 2015) follows the Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT) 2013 Statement for protocols of clinical trials.
      The study was approved by San Raffaele Scientific Institute Ethical Committee in October 2014, Italian Medicine Agency (EudraCT 2014-003818-92) and was registered on ClinicalTrials.gov as NCT02327611 (https://clinicaltrials.gov/ct2/show/NCT02327611). Patient recruitment started in February 2015 and ended in January 2017. The study enrolled 90 patients who were to undergo TAAA open repair surgery requiring renal perfusion (Figure 1). Each treatment group included 45 patients. All participants were adults of both sexes and able to provide written informed consent. Exclusion criteria were the following: patients who have participated in experimental trials during the previous 3 months, intervention under emergency/urgency, patient uncooperative and/or affected by mental disease, allergy/intolerance to the study drug, patient receiving chronic dialysis before surgery, and pregnant or breastfeeding women.
      Figure thumbnail gr1
      Figure 1Consolidated Standards of Reporting Trials (CONSORT) diagram of thoracoabdominal aortic repairs enrolled in the CURITIBA trial. In the study 90 patients were enrolled who were to undergo TAAA open repair surgery requiring renal perfusion. Each treatment group included 45 patients (intention-to-treat). In 2 cases (1 for each group) the assigned perfusion was not administered due to intraoperative clinical reasons, leaving 88 randomized cases (44 vs 44; per-protocol-analysis). CURITIBA, CUstodiol Versus RInger: whaT Is the Best Agent?; OR, operating room.

      Randomization and Blinding

      A computer-generated permuted block (up to a size of 10 and a 1:1 allocation) randomization sequence was used. Treatment allocation was prepared by an independent operator not otherwise involved in the trial and was concealed by opaque, sequentially numbered sealed envelopes. On the day of surgery, the patient was randomized upon operative room arrival by a CURITIBA trial staff member who prepared the blinded treatment and was not in any way involved in the clinical management of the patient. Quadruple blinding was applied (participant, care provider, investigator, outcomes assessor).

      Surgical Technique

      The surgical procedures depended on the extent of the aneurysm according to the TAAA Crawford Criteria, as reported
      • Tshomba Y.
      • Kahlberg A.
      • Melissano G.
      • Coppi G.
      • Marone E.
      • Ferrari D.
      • et al.
      Comparison of renal perfusion solutions during thoracoabdominal aortic aneurysm repair.
      (Figure 2 and Video 1). Cerebrospinal fluid drainage was routinely instituted and to monitor cerebrospinal fluid pressure we exploited an automatic system (LiquoGuard; Möller Medical GmbH & Co KG, Fulda, Germany). A left heart bypass including an inline centrifugal pump was used for distal aortic perfusion. The circuit was primed with 400 mL of lactated Ringer's solution, or in the case of anemia, with the patient's autologous blood. Mild hypothermia (34°C-35°C) was routinely allowed. After sequential clamping was performed, the aorta was then opened between the clamps.
      Figure thumbnail gr2
      Figure 2Drawing illustrating the modified Crawford classification of the extent of thoracoabdominal aortic aneurysm repair.
      Reproduced with permission from Frankel WC, Song HK, Milewski RK, Shalhub S, Pugh NL, Eagle KA, et al. Open thoracoabdominal aortic repair in patients with heritable aortic disease in the GenTAC Registry. Ann Thorac Surg. 2020;109:1378-84.
      Two 9-French (F) Pruitt occlusion-perfusion balloon catheters (LeMaitre Vascular, Inc, Burlington, Mass) were inserted directly into the celiac axis and superior mesenteric artery for continued infusion of oxygenated isothermic blood via the left heart bypass circuit (average flow of 500 mL/min). Two other 9F Pruitt balloon occlusion-perfusion catheters were then inserted directly into the renal arteries for continued infusion from a separate pressure line perfusion system. The right kidney was the first to be perfused. Patients randomized in the Custodiol arm received, upon renal artery clamping, a renal perfusion with cold (4°C) Custodiol. During renal ischemic time, a total of 1.5 mL of Custodiol per gram of estimated kidney weight were administered, thus implying an average of 400 mL of Custodiol for a 70-kg patient.
      • Molina D.K.
      • DiMaio V.
      Normal organ weights in men: part II-the brain, lungs, liver, spleen, and kidneys.
      Patients randomized in the enriched Ringer's lactate arm received a renal perfusion with cold (4°C) Ringer's lactate solution enriched with 125 mg per liter of methylprednisolone and 12.5 g per liter of mannitol.
      The solution's perfusion pressure is regulated by means of a drip chamber. Initially a rapid drop perfusion is performed, and then perfusion dosage is liberal, such as not to exceed the maximum dose calculated on the estimated kidney weight.
      Both solutions are colorless, thus impossible to distinguish. Visceral and renal arteries were managed and reattached to the graft. Intravenous methylene blue was administered after unclamping as an additional tool for intraoperative monitoring of renal function, allowing verification of the resumption of the diuresis immediately after unclamping and excluding inadvertent injuries to the urinary tract during the initial preparation phase. In the immediate postoperative period, all patients were moved to the intensive care unit for at least the first postoperative 12 hours. The trial did not affect any other aspect of patient treatment, which was left to standard clinical practice.

      Data Collection and Outcome Measures

      The CURITIBA trial primary objective was to evaluate the incidence of AKI in patients undergoing TAAA open surgery using Custodiol renal perfusion versus enriched Ringer's lactate solution. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) clinical practice guidelines as any of the following: increase in serum creatinine by ≥0.3 mg/dL (≥26.5 µmol/L) within 48 hours; or increase in serum creatinine to ≥1.5 times baseline, which is known or presumed to have occurred within the previous 7 days; or urine volume ≤0.5 mL/kg/h for 6 hours.
      • Lopes J.A.
      • Jorge S.
      The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review.
      Moreover, AKI was classified according to the Acute Kidney Injury Network (AKIN) grading system (Table 2).
      • Lopes J.A.
      • Jorge S.
      The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review.
      AKI and AKIN stages were assessed by using the highest measured postoperative value of creatinine compared with preoperative (baseline) value. Secondary outcomes included: need (temporary or permanent) of postoperative hemodialysis and/or continuous veno-venous hemofiltration, identification of independent predictors of “any AKI” (including AKIN stage 1, 2, and 3) and of “severe AKI” (including AKIN stage 2 and 3), intensive care unit length of stay, hospital length of stay, major adverse cardiac events including myocardial infarction and arrhythmia, in-hospital mortality, 30-day mortality, and 1-year mortality.
      Table 2AKIN criteria
      AKIN stageSerum creatinine criteriaUrine volume
      1Increase in serum creatinine by ≥0.3 mg/dL (≥26.5 µmol/L) or increase in serum creatinine to ≥1.5 times baselineUrine volume ≤0.5 mL/kg/h for 6 h
      2Increase in serum creatinine to 2-3 times baselineUrine volume ≤0.5 mL/kg/h for 12 h
      3Increase in serum creatinine to >3 times baseline or increase in serum creatinine by ≥0.3 mg/dL (≥44.2 µmol/L) if baseline serum creatinine was ≥4 mg/dL (≥353.6 μmol/L)Urine volume ≤0.3 mL/kg/h for 24 h or anuria
      AKIN Stage 3 also includes patients requiring renal replacement therapy independent of the previous stage. AKIN, Acute Kidney Injury Network.
      Data were collected until hospital discharge by trained observers who did not participate in patient care, and were blinded to the administered drug. Where possible, data were extracted from clinical charts independently by 2 investigators, and conflicts resolved by a third investigator who again reviewed the clinical charts. Preoperative data, intraoperative and postoperative management were anonymously collected. Serum creatinine was measured daily throughout the study period with the same enzymatic method (kinetic method with alkaline picrate) and the same biochemical analyzer (Advia 2400 Chemistry System WKC/MET085; Siemens Healthcare Diagnostics, Erlangen, Germany).
      Intraoperative data including time of surgery, time of aortic clamp, time of renal ischemia and perfusion, time of visceral ischemia and perfusion, time of 1-lung ventilation, time of left-heart bypass pump, hemodynamics, and arterial blood gases at selected surgical time points, fluid balance including blood products administration, diuresis, and use of diuretics, use of kidney and spinal cord protection strategies including administration of intravenous fenoldopam, mannitol, glucocorticoids, cerebrospinal fluid drainage, and reimplantation of renal arteries, use of inotropic or vasoactive drugs were obtained from anesthesia records. Hemoglobin, creatinine and glomerular filtration rate (GFR) values, total diuresis, and minimum hourly diuresis were recorded daily from postoperative day 1 to 6, when possible. The clinical follow-up was performed in-hospital. A telephone follow-up was performed at 30 days and 1 year after the randomization, collection of data about mortality, further hospital admissions, last serum creatinine level available, and eventual need for renal replacement treatment.

      Statistical Analysis

      On the basis of a previous observational study,
      • Tshomba Y.
      • Kahlberg A.
      • Melissano G.
      • Coppi G.
      • Marone E.
      • Ferrari D.
      • et al.
      Comparison of renal perfusion solutions during thoracoabdominal aortic aneurysm repair.
      we expected an incidence of AKI of 90% in the Ringer's group and of 61% in the patients who received Custodiol. The sample size calculation was on the basis of a 2-side α error of 0.05% and 80% power (α = 0.0500; power = 0.8000; Δ = 0.0500; r1 = 0.9300; r2 = 0.9800; diff = 0.0500). With an expected dropout due to perioperative mortality of 5%, we calculated that a sample of 45 patients per group was required.
      Continuous variables are presented as mean and standard deviation when normally distributed, and as median and interquartile range (IQR) when non-normally distributed, whereas discrete variables are reported as number (and proportion) of patients. Continuous measurements were compared using a 2-tailed paired Student t test or Wilcoxon test, as appropriate. Ordinal variables (eg, AKIN stages) were compared using a 2-tailed Mann–Whitney U test. Categorical variables were compared using a 2-tailed χ2 test or Fisher exact test, as appropriate.
      AKIN score, creatinine, and GFR trend were analyzed in the 2 groups using longitudinal mixed effect models, using the mixed effects logistic regression model (Wald test), and the random effects analysis (likelihood ratio [LR] test vs logistic model). Univariate analysis was performed to identify preoperative or intraoperative variables that could have a possible effect on the development of any AKI or of severe AKI. Multivariable analysis was then performed, using a logistic regression model, to identify independent predictors of any AKI or severe AKI. Variables that showed an association (cutoff value P < .05) with the outcomes in univariate analysis were entered in the multivariable model (Custodiol/Ringer's group, TAAA type II and III, active smoker, chronic obstructive pulmonary disease, and chronic kidney disease [CKD] stage III).
      • Hosmer Jr., D.W.
      • Lemeshow S.
      • Sturdivant R.X.
      Applied Logistic Regression.
      For multivariable analysis, the results are presented as the odds ratio (OR) with 95% confidence interval (CI). Linear correlation between preoperative CKD stage and development of postoperative AKI (“any AKI” and “severe AKI”) was measured using the Pearson correlation coefficient.
      Actuarial survival, up to 1 year, was reported using the Kaplan–Meier method, and comparison between the 2 perfusion groups was conducted using the log rank test (Mantel Cox). All of the analyses were conducted using the Stata/IC version 14.2 for Mac (64-bit Intel) software package (revision 29; Stata Corp, College Station, Tex).

      Results

      In the study period, 113 patients were admitted at the Department of Vascular Surgery of San Raffaele Scientific Institute with a diagnosis of thoraco-abdominal aortic aneurysm, with indication to open surgical repair; 96 patients were considered eligible for enrollment in the CURITIBA trial after review of inclusion/exclusion criteria. Among these, 6 refused to sign or withdrew informed consent from the trial. Finally, 90 patients underwent randomization for intention-to-treat analysis (45 Custodiol vs 45 Ringer's). In 2 cases (1 for each group) the assigned perfusion was not administered because of intraoperative clinical reasons, leaving 88 randomized cases (44 vs 44) for postoperative per-protocol analysis (included in Table E1, Table E2, Table E3).
      There were no significant differences in demographic characteristics, main comorbidities, preoperative risk factors, and TAAA Crawford's extent (Table 3). Also, the 2 groups were similar with regard to preoperative renal function, stratified in CKD stages (Table 3). Intraoperative variables also were similar in the 2 groups (Table 4), in particular the total perfusate delivered (400 mL [IQR, 350-487.2] vs 438 mL [IQR, 350-550]; P = .54), aortic clamping time (54 minutes [IQR, 42.5-70] vs 56 minutes [IQR, 43-72]; P = .22), blood loss (4850 mL [IQR, 3200-6424] vs 5000 mL [IQR, 3225-7450]; P = .46), and urinary output (4070 mL [IQR, 2070-5050] vs 3971 mL [IQR, 1941-5170]; P = .79).
      Table 3Preoperative clinical characteristics of 90 patients included in the randomization (intention-to-treat analysis)
      CharacteristicCustodiol Pts, n = 45Ringer Pts, n = 45Total Pts, n = 90
      Men33 (73.3)29 (64.4)62 (68.9)
      Women12 (26.7)16 (35.6)28 (31.1)
      Age, y63.7 ± 9.8266.4 ± 9.2165.09 ± 9.56
      TAAA type I5 (11.1)5 (11.1)10 (11.1)
      TAAA type II17 (37.7)16 (35.5)33 (36.7)
      TAAA type III15 (33.3)10 (22.2)25 (27.8)
      TAAA type IV9 (20)13 (28.8)22 (24.4)
      TAAA type V000
      Maximum aortic diameter, mm66.9 ± 15.464.7 ± 13.465.89 ± 14.46
      Chronic dissection11 (24.4)7 (15.5)18 (20)
      Connective tissue disease5 (11.1)4 (8.8)9 (10)
      Symptoms7 (15.5)7 (15.5)14 (15.6)
      Hypertension45 (100)45 (100)90 (100)
      Active smoker16 (35.6)16 (35.6)32 (35.6)
      Nonsmoker9 (20)9 (20)18 (20)
      Past smoker20 (44.4)20 (44.4)40 (44.4)
      Diabetes4 (8.9)3 (6.7)7 (7.8)
      Coronary artery disease10 (22.2)8 (17.8)18 (20)
      Peripheral arteriopathy1 (2.2)5 (11.1)6 (6.7)
      COPD7 (15.6)6 (13.3)13 (14.4)
      GOLD stage ≥116 (35.6)20 (44.4)36 (40)
      Cerebrovascular disease2 (4.4)1 (2.2)3 (3.3)
      Antiplatelet26 (57.8)28 (62.2)54 (60)
      Anticoagulant03 (6.7)3 (3.3)
      Antiplatelet with anticoagulant01 (2.2)1 (1.1)
      NYHA ≥24 (8.9)4 (8.9)8 (8.9)
      Past aortic surgery13 (28.9)16 (35.6)29 (32.2)
      Past EVAR/TEVAR8 (17.8)8 (17.8)16 (17.8)
      CKD stage I17 (37.7)14 (31.1)31 (34.4)
      CKD stage II17 (37.7)15 (33.3)32 (35.6)
      CKD stage III11 (24.4)16 (35.5)27 (30)
      CKD stage IV-V000
      Data are presented as n (%) or mean (± standard deviation). Custodiol solution is from Essential Pharmaceuticals, LLC (Durham, NC). Pts, patients; TAAA, thoracoabdominal aortic aneurysm; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; NYHA, New York Heart Association; EVAR, endovascular aortic repair; TEVAR, thoracic endovascular aortic repair; CKD, chronic kidney disease.
      Table 4Intraoperative details of 90 patients included in the randomization (intention-to-treat analysis)
      Custodiol Pts, n = 45Ringer Pts, n = 45Total Pts, n = 90P value
      LHBP38 (84.4)40 (88.9)78 (86.6).76
      CSF drainage32 (71.1)33 (73.3)65 (72.2)1.00
      Renal perfusion44 (97.8)44 (97.8)88 (97.8)1.00
      Total perfusate delivered, mL500 (400-600)400 (350-487.2)438 (350-550).54
      Aortic clamping time minutes58 (43.5-76)54 (42.5-70)56 (43-72).22
      Renal ischemia time minutes41 (20-64)36 (22-58)39 (21-62).46
      Renal stenting4 (8.9)3 (6.7)7 (7.8)1.00
      Renal endoarterectomy000-
      Intraoperative diuresis, mL3514 (1899-5200)4070 (2070-5050)3971 (1941-5170).79
      Intraoperative blood loss, mL5400 (3600-8000)4850 (3200-6425)5000 (3225-7450).46
      Data are presented as n (%) or median (25-75 percentile). Pts, Patients; LHBP, left heart bypass; CSF, cerebrospinal fluid.
      Global renal ischemic time was similar in the 2 groups (42.4 ± 21.6 minutes vs 38.1 ± 21.8 minutes; P = .40). Mean right renal perfusion time was 28.3 ± 20.6 minutes for the Custodiol group and 25.3 ± 18.4 minutes for the Ringer's group, whereas mean left renal perfusion time was and 39.1 ± 18.7 minutes for the Custodiol group and 36.1 ± 19.4 minutes for the Ringer's group. No perioperative adverse reactions related to the renal perfusion solution used were observed.

      Early Results

      Intention-to-treat analysis was performed on 90 patients; early results are summarized in Table 5. Measured creatinine and GFR values in the 2 perfusion groups, from preoperative value up to postoperative day 6, are reported as Spaghetti plots (Figure E1, Figure E2, Figure E3, Figure E4). Any AKI occurred overall in 56 patients of 90 (62.2%), with prevalence of AKIN stage 1 (32.9%) in both perfusion groups. Of the 56 patients who developed any AKI postoperatively, 60% belonged to the Ringer's group and 40% to the Custodiol group (34 vs 22; P = .01). Any AKI occurred significantly more in the Ringer's group (Custodiol group 22/45 patients [48.9%] vs Ringer's group 34/45 patients [75.6%]; P = .02). Severe AKI, even if more frequently observed in the Ringer's group, was not statistically different (Custodiol group 11/45 patients [24.4%] vs Ringer's group 16/45 patients [35.6%]; P = .36).
      Table 5Short-term results of 90 patients included in the randomization (intention-to-treat analysis)
      Custodiol Pts, n = 45Ringer Pts, n = 45Total Pts, n = 90P value
      Any AKI (AKIN 1 + 2 + 3)22 (48.9)34 (75.6)56 (62.2).02
      AKIN stage 023 (51.1)11 (24.4)34 (37.8)
      AKIN stage 111 (24.4)18 (40)29 (32.2)
      AKIN stage 27 (15.6)7 (15.6)14 (15.6).88
      Mann-Whitney U test for comparison of ordinal variables.
      AKIN stage 34 (8.9)9 (20)13 (14.4)
      Severe AKI (AKIN 2 + 3)11 (24.4)16 (35.6)27 (30).36
      Temporary CVVH/HD1 (2.2)6 (13.3)7 (7.8).11
      HD discharge01 (2.2)1 (1.1)1.00
      Respiratory failure2 (4.4)5 (11.1)7 (7.8).24
      Paraparesis/paraplegia2 (4.4)4 (8.9)6 (6.7).68
      Bowel ischemia1 (2.2)1 (2.2)2 (2.2)1.00
      Stroke1 (2.2)01 (1.1)1.00
      Major adverse cardiac events
      Major adverse cardiac events included myocardial infarction and arrhythmia.
      5 (11.1)4 (8.9)9 (10).72
      Reintervention1 (2.2)1 (2.2)2 (2.2)1.00
      ICU stay, d
      Non-normal distribution.
      1 (1-2)1 (1-3)1 (1-2).51
      LOS, d
      Non-normal distribution.
      15 (13-20)15 (13-18)15 (13-19).58
      30-Day mortality3 (6.7)6 (13.3)9 (10).23
      In-hospital mortality4 (8.9)6 (13.3)10 (11.1).49
      Data are presented as n (%) or median (25-75 percentile). Pts, Patients; AKI, acute kidney injury; AKIN, Acute Kidney Injury Network; CVVH, continuous veno-venous hemofiltration; HD, hemodialysis; ICU, intensive care unit; LOS, length of stay.
      Mann-Whitney U test for comparison of ordinal variables.
      Major adverse cardiac events included myocardial infarction and arrhythmia.
      Non-normal distribution.
      The mixed effects logistic regression model (Wald test) did not identify significant differences between the 2 groups (χ2 = 0.01; P = 1.0) for GFR and creatinine. The random effects analysis identified an effects estimate for creatinine of 40.7 (95% CI, 5.1-322.4), and an LR test versus logistic model of 84.8 (P < .001). Similarly, for GFR the effects estimate was 39.8 (95% CI, 4.9-323.9), and an LR test versus logistic model of 66.0 (P < .001).
      The need for temporary continuous veno-venous hemofiltration or hemodialysis was higher in Ringer's group patients, but this difference did not reach statistical significance (Custodiol group 1/45 patients [2.2%] vs Ringer's group 6/45 patients [13.3%]; P = .10). Other short-term outcomes, including postoperative complications, intensive care unit stay, and length of hospital stay, were not statistically different between the study groups (Table 5).
      In-hospital mortality (11.1%) was observed in 10 patents (6 in the Ringer's group and 4 in the Custodiol group; P = .49). Among these, 2 patients (both in Custodiol group) died intraoperatively; the other 8 patients (Custodiol n = 2; Ringer's n = 6; P = .97) who subsequently died developed AKI type 3 in association with a multiple organ failure scenario.
      Univariate analysis of AKI predictors (Table 6) showed the use of Ringer's solution (P = .01) and type II TAAA extension (P = .05) to be associated with the development of any AKI. In the multivariable model, only the use of Custodiol solution resulted independently protective from the occurrence of any AKI (OR, 0.23; 95% CI, 0.09-0.61; P = .003). With regard to possible predictors of severe AKI, univariate analysis identified the following: active smoking (P = .03), chronic obstructive pulmonary disease (P = .04), preoperative CKD stage III (P = .05), type II TAAA extension (P < .001), and type III TAAA extension (P = .03). In the multivariable model, only type II TAAA extension (OR, 4.28; 95% CI, 1.24-14.76; P = .02) remained independently associated with the occurrence of severe AKI.
      Table 6Univariate and multivariable analysis results, showing significant predictors of AKI, any AKI, and severe AKI (2-3) of patients included in the analysis
      OutcomeUnivariable analysisMultivariable analysis
      Risk factorP valueOR95% CIP value
      Any AKI
      Sex.51
      Age, y.51
      Custodiol/Ringer's group.0070.230.09-0.61.003
      Hypertension.30
      Active smoker.35
      Nonsmoker.91
      Past smoker.41
      Diabetes.60
      Coronary artery disease.33
      Peripheral arteriopathy.82
      COPD.24
      GOLD stage ≥1.65
      Cerebrovascular disease.87
      NYHA ≥2.98
      Past aortic surgery.08
      CKD stage I.30
      CKD stage II.62
      CKD stage III.57
      TAAA type I.39
      TAAA type II.042.750.99-7.68.05
      TAAA type III.46
      TAAA type IV.38
      Chronic dissection.67
      Connective tissue disorders.67
      Symptomatic aneurism.46
      Maximum aortic diameter, mm.62
      Severe AKI
      Sex.20
      Age, y.64
      Custodiol/Ringer's group.25
      Hypertension.38
      Active smoker.032.240.72-6.60.14
      Nonsmoker.17
      Past smoker.36
      Diabetes.35
      Coronary artery disease.73
      Peripheral arteriopathy.47
      COPD.042.850.69-11.80.14
      GOLD stage ≥1.63
      Cerebrovascular disease.25
      NYHA ≥2.65
      Past aortic surgery.38
      CKD stage I.53
      CKD stage II.21
      CKD stage III.051.670.52-5.30.38
      TAAA type I.49
      TAAA type II.0004.281.24-14.76.02
      TAAA type III.020.760.15-3.75.73
      TAAA type IV.18
      Chronic dissection.36
      Connective tissue disorders.82
      Symptomatic aneurism.59
      Maximum aortic diameter, mm.80
      Custodiol solution is from Essential Pharmaceuticals, LLC (Durham, NC). Significant P values are shown in bold. OR, Odds ratio; CI, confidence interval; AKI, acute kidney injury; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; NYHA, New York Heart Association; CKD, chronic kidney disease; TAAA, thoracoabdominal aortic aneurysm.
      When a possible correlation between postoperative development of AKI and pre-existing CKD was tested, only CKD stage III showed a mild correlation with the occurrence of severe AKI (Pearson r = 0.206; P = .05). No preoperative CKD stage showed significant correlation with the development of any AKI.

      Late Results

      The 1-year survival rate was 91.1% (95% CI, 0.04-0.83) in the Custodiol group, and 84.4% (95% CI, 0.05-0.74) in the Ringer's group. One late death was recorded, due to lung cancer. No significant difference in survival was found between groups (P = .37; Figure 3). In 45 of 79 survivors, a recent creatinine test result was available; no patient presented late worsening of renal function requiring dialysis. Mean creatinine values at 1 year were 1.24 ± 0.46 mg/dL in the Custodiol group, and 1.18 ± 0.37 mg/dL in the Ringer's group.
      Figure thumbnail gr3
      Figure 3Kaplan–Meier survival curves with 95% confidence intervals (CIs) for the Custodiol group (95% CI, 00.83-0.99), and Ringer's group (95% CI, 0.74-0.95), at 1 year of follow-up. No statistical differences were recorded between the 2 groups (P = .37). The in-hospital mortality rate was 11.1% (6 patients in the Ringer's group and 4 patients in the Custodiol group). Custodiol is from Essential Pharmaceuticals, LLC (Durham, NC).

      Discussion

      Renal injury is a well known serious complication of TAAA surgical repair. Patients who present with renal dysfunction, especially when hemodialysis or hemofiltration is required, are at high risk for the development of additional perioperative complications, including respiratory failure, cardiac events, hemodynamic instability, and spinal cord ischemia.
      • Safi H.J.
      • Miller III, C.C.
      • Huynh T.T.
      • Estrera A.L.
      • Porat E.E.
      • Winnerkvist A.N.
      • et al.
      Distal aortic perfusion and cerebrospinal fluid drainage for thoracoabdominal and descending thoracic aortic repair: ten years of organ protection.
      Many techniques have been proposed with the aim to improve intraoperative organ protection, including different methods of renal perfusion. Current consensus practice guidelines recommend either cold crystalloid or blood perfusion for intraoperative kidney protection (class IIb, level of evidence B).
      • Hiratzka L.F.
      • Bakris G.L.
      • Beckman J.A.
      • Bersin R.M.
      • Carr V.F.
      • Casey Jr., D.E.
      • et al.
      ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine.
      However, a randomized trial published in 2009 showed that perfusion with cold blood does not provide any advantage over cold crystalloid perfusion in prevention of renal injury, whereas patients receiving blood perfusion show a trend of increased risk of spinal cord ischemia.
      • LeMaire S.A.
      • Jones M.M.
      • Conklin L.D.
      • Carter S.A.
      • Criddell M.D.
      • Wang X.L.
      • et al.
      Randomized comparison of cold blood and cold crystalloid renal perfusion for renal protection during thoracoabdominal aneurysm repair.
      Consequently, most high-volume centers that perform open TAAA repair report routine use of cold perfusion with crystalloids, namely Ringer's solution, and this method for renal protection can be considered as the benchmark for comparison studies with other solutions.
      Custodiol solution is a buffered crystalloid solution produced by Dr Franz-Kohler Chemie GmbH, Bensheim, Germany. It was originally developed as a cardioplegic agent by the German surgical research pioneer H. J. Bretschneider in 1964, with histidine added in 1975. Custodiol solution was developed with aim of protecting the heart by inactivation of organ function by withdrawal of extracellular sodium and calcium.
      Compared with extracellular solutions, organ perfusion with Custodiol should reduce the cellular swelling, toxicity, and damage caused by the ischemic insults. Custodiol solution contains a high hydrogen ion buffer level that reduces acidosis associated with ongoing anaerobic metabolism. Custodiol solution is also enriched with 3 main factors: histidine/histidine hydrochloride (an amino acid buffering agent), tryptophan, and α-ketoglutarate, which enhances the buffering and protecting capacity of the solution during the ischemic-induced acidosis.
      As soon as the effectiveness of Custodiol as a cardioplegic agent was confirmed, the solution has been routinely and successfully used worldwide for many years.
      • Viana F.F.
      • Shi W.Y.
      • Hayward P.A.
      • Larobina M.E.
      • Liskaser F.
      • Matalanis G.
      Custodiol versus blood cardioplegia in complex cardiac operations: an Australian experience.
      Afterward, Custodiol was reported to have the potential to exert its protective effect not only in the heart, becoming a widely used preservation solution of several organs in transplantation procedures, including liver, pancreas, and—above all—kidney. O'Callaghan and colleagues conducted a meta-analysis including 3584 kidney allografts, which showed a minor incidence of delayed graft function with Custodiol compared with other solutions.
      • O’Callaghan J.M.
      • Knight S.R.
      • Morgan R.D.
      • Morris P.J.
      Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis.
      In a retrospective study,
      • Tshomba Y.
      • Kahlberg A.
      • Melissano G.
      • Coppi G.
      • Marone E.
      • Ferrari D.
      • et al.
      Comparison of renal perfusion solutions during thoracoabdominal aortic aneurysm repair.
      we reported that the use of Custodiol for renal perfusion during open TAAA repair was safe, and provided better results in terms of postoperative renal function compared with Ringer's solution. Thus, we conducted a prospective, randomized trial (CURITIBA) to determine whether perfusion with Custodiol could result as more effective than Ringer's solution in improving intraoperative renal protection and reducing postoperative renal failure in patients undergoing open TAAA repair.
      The results of this trial confirm that Custodiol use is safe, and is not associated with adverse events. Excluding 2 intraoperative deaths, all deceased patients presented severe renal impairment in a multiple organ failure scenario. This finding, consistent with the recent literature,
      • Chatterjee S.
      • LeMaire S.A.
      • Amarasekara H.S.
      • Green S.Y.
      • Price M.D.
      • Yanoff M.T.
      • et al.
      Early-stage acute kidney injury adversely affects thoracoabdominal aortic aneurysm repair outcomes.
      suggests that renal protection strategies are of paramount importance to reduce postoperative mortality.
      This study showed that patients who received Custodiol developed AKI at significantly lower rates compared with patients who received Ringer's solution (Figure 4). The protective effect was more evident against mild to moderate grades of renal impairment, and less significant against severe AKI. The use of Custodiol, also, resulted in a stand-alone predictor of better renal outcome in multivariable analysis: our data showed that using Ringer's lactate was associated with an increased risk of developing postoperative AKI (Figure 4). Type II extension of thoracoabdominal aortic disease was the only other independent predictor of AKI (particularly of severe AKI). Preoperative CKD is known to be a possible predictor of adverse events and of permanent renal failure after open surgery for TAAA and thoracic endovascular aortic repair.
      • Coselli J.S.
      • LeMaire S.A.
      • Preventza O.
      • de la Cruz K.I.
      • Cooley D.A.
      • Price M.D.
      • et al.
      Outcomes of 3309 thoracoabdominal aortic aneurysm repairs.
      ,
      • Marrocco-Trischitta M.M.
      • Melissano G.
      • Kahlberg A.
      • Calori G.
      • Setacci F.
      • Chiesa R.
      Chronic kidney disease classification stratifies mortality risk after elective stent graft repair of the thoracic aorta.
      However, in the current series preoperative CKD was not strongly associated with the development of postoperative AKI. Only CKD stage III was associated with occurrence of severe AKI, but this effect was lost when included in the multivariable model, suggesting that renal protection with intraoperative perfusion of Custodiol was more important that the pre-existing renal status.
      Figure thumbnail gr4
      Figure 4Results of a single-center, prospective, randomized study comparing the efficacy of Custodiol (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) renal perfusion on perioperative acute kidney injury (AKI) in patients undergoing thoracoabdominal aortic open repair. This image summarizes outcomes of renal perfusion with Custodiol compared with lactated Ringer's solution for renal protection in patients undergoing open thoracoabdominal aortic aneurysm repair. What emerged from this trial was that patients in the Custodiol group showed significantly less AKI than those in the Ringer's group (49% vs 76%; P = .02) and that the use of Custodiol resulted as protective from the occurrence of any AKI in multivariable analysis (P = .003). OR, Odds ratio; TAAA, thoracoabdominal aortic aneurysm.

      Study Limitation

      We acknowledge some limitations of this study, mainly related to its single-center nature and the relatively small sample size. This might account for a reduced statistical power in finding significant associations with the outcomes. Also, criticism might be made with regard to the high number of patients with preoperative renal dysfunction that might represent a bias in the analysis of acute postoperative renal impairment. However, preoperative renal disease, which is typical of most TAAA patients, was similarly represented in the 2 perfusion groups, and was also included in the multivariable model to eliminate its possible confounding effect when identifying AKI predictors.

      Conclusions

      The results of this trial support the use of cold Custodiol solution for perfusion of the renal arteries during open TAAA repair. It showed safety and efficacy in reducing postoperative renal dysfunction compared with standard crystalloid solutions. These findings corroborate the use of Custodiol not only in TAAA patients, but also in other cases that require suprarenal clamping, including juxtarenal and pararenal aneurysms, or in further cases of renal surgery.

      Conflict of Interest Statement

      The authors reported no conflicts of interest.
      The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest.

      Supplementary Data

      • Video 1

        Brief description of the aims and of the main results of the study, with a detailed intraoperative example of thoracoabdominal aortic aneurysm open repair with renal cold perfusion. Video available at: https://www.jtcvs.org/article/S0022-5223(21)00408-6/fulltext.

      Appendix E1

      Table E1Preoperative clinical characteristics of 88 patients included in the randomization (per-protocol analysis)
      Custodiol (n = 44)Ringer's (n = 44)Total (n = 88)
      Men33 (75)29 (65.9)62 (70.4)
      Women11 (25)15 (34.1)26 (29.5)
      Age, y63.4 ± 9.7166.8 ± 9.065.1 ± 9.46
      TAAA type I4 (9.1)5 (11.3)9 (10.2)
      TAAA type II17 (38.6)16 (36.3)33 (37.5)
      TAAA type III14 (31.8)10 (22.7)24 (27.2)
      TAAA type IV9 (20.4)12 (27.2)21 (23.8)
      TAAA type V000
      Maximum aortic diameter, mm64.25 ± 13.266.65 ± 15.565.49 ± 14.4
      Chronic dissection10 (22.7)6 (13.6)16 (18.1)
      Connective tissue disease5 (11.3)4 (9.1)9 (10.2)
      Symptoms7 (15.9)7 (15.9)14 (15.9)
      Hypertension44 (100)44 (100)88 (100)
      Active smoker16 (36.3)16 (36.3)32 (36.3)
      Nonsmoker9 (20.4)8 (18.1)17 (19.3)
      Past smoker19 (43.1)20 (45.4)39 (44.3)
      Diabetes3 (6.8)3 (6.8)6 (6.8)
      Coronary artery disease10 (22.7)8 (18.1)18 (20.4)
      Peripheral arteriopathy1 (2.2)5 (11.3)6 (13.6)
      COPD7 (15.9)6 (13.6)13 (14.7)
      GOLD stage ≥116 (36.3)20 (45.4)36 (40.9)
      Cerebrovascular disease2 (4.5)1 (2.2)3 (3.4)
      Antiplatelet26 (59.1)28 (63.6)54 (61.3)
      Anticoagulant03 (6.8)3 (3.4)
      Antiplatelet with anticoagulant01 (2.2)1 (1.1)
      NYHA ≥24 (9.1)4 (9.1)8 (9.1)
      Past aortic surgery13 (29.5)16 (36.3)29 (32.9)
      Past EVAR/TEVAR8 (18.1)8 (18.1)16 (18.1)
      CKD stage I16 (36.6)13 (29.5)29 (32.9)
      CKD stage II17 (38.6)15 (34.1)32 (36.3)
      CKD stage III11 (25)16 (36.6)27 (30.7)
      CKD stage IV-V000
      Data are presented as n (%) or mean (± standard deviation). Custodiol is from Essential Pharmaceuticals, LLC (Durham, NC). TAAA, Thoracoabdominal aortic aneurysm; COPD, chronic obstructive pulmonary disease; GOLD, Global Initiative for Chronic Obstructive Lung Disease; NYHA, New York Heart Association; EVAR, endovascular aortic repair; TEVAR, thoracic endovascular aortic repair; CKD, chronic kidney disease.
      Table E2Intraoperative details of 88 patients included in the randomization (per-protocol analysis)
      Custodiol (n = 44)Ringer's (n = 44)Total (n = 88)P value
      LHBP39 (88.6)37 (84.1)76 (86.3)1.00
      CSF drainage31 (70.4)32 (72.7)63 (71.5)1.00
      Renal perfusion444488
      Total perfusate delivered, mL500 (400-600)400 (350-487.2)438 (350-550).54
      Aortic clamping time, minutes58 (43.5-76)54 (42.5-70)56 (43-72).22
      Renal ischemia time, minutes41 (20-64)36 (22-58)39 (21-62).46
      Renal stenting4 (9)3 (6.8)7 (7.9).69
      Renal endoarterectomy000
      Intraoperative diuresis, mL3514 (1899-5200)4070 (2070-5050)3971 (1941-5170).78
      Intraoperative blood loss, mL5400 (3600-8000)4850 (3200-6425)5000 (3225-7450).45
      Data are presented as n (%) or or median (25-75 percentile). Custodiol is from Essential Pharmaceuticals, LLC (Durham, NC). LHBP, Left heart bypass; CSF, cerebrospinal fluid.
      Table E3Early results of 88 patients included in the study (per-protocol analysis)
      Custodiol (n = 44)Ringer's (n = 44)Total (n = 88)P value
      Any AKI (AKIN 1 + 2 + 3)21 (47.7)33 (75.0)54 (61.4).01
      AKI stage 110 (22.7)17 (38.6)27 (30.7)
      AKI stage 27 (15.9)7 (15.9)14 (15.9).95
      Mann–Whitney U test for comparison of ordinal variables.
      AKI stage 34 (9)9 (20.4)13 (14.7)
      Severe AKI (AKIN 2 + 3)11 (24.4)16 (35.5)27 (30.0).36
      Temporary CVVH/HD1 (2.3)6 (13.6)7 (7.9).11
      HD discharge01 (2.3)1 (1.1).32
      Respiratory failure1 (2.3)5 (11.4)6 (7.9).09
      Paraparesis/paraplegia2 (4.5)4 (11.3)6 (6.8).40
      Bowel ischemia1 (2.3)1 (2.3)2 (2.3)1.00
      Stroke1 (2.3)01 (1.1).32
      Cardiac complications4 (9)4 (9)8 (9)1.00
      Reintervention1 (2.3)1 (2.3)2 (2.3)1.00
      ICU stay, d1 (1-2)1 (1-3)1 (1-2).50
      LOS, d15 (13-20)15 (13-18)15 (13-19).60
      30-Day mortality3 (6.8)6 (13.6)9 (10.2).29
      In-hospital mortality4 (9)6 (13.6)10 (11.3).5
      Data are presented as n (%) or median (25-75 percentile). Custodiol is from Essential Pharmaceuticals, LLC (Durham, NC). Significant P values are shown in bold. AKI, Acute kidney injury; AKIN, Acute Kidney Injury Network; CVVH, continuous veno-venous hemofiltration; HD, hemodialysis; ICU, intensive care unit; LOS, length of stay.
      Mann–Whitney U test for comparison of ordinal variables.
      Figure thumbnail fx4
      Figure E1Spaghetti plot showing measured serum creatinine values in the Ringer's group patients. Pre-op, Preoperative; POD, postoperative day.
      Figure thumbnail fx5
      Figure E2Spaghetti plot showing measured serum creatinine values in the Custodiol (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) group patients. Pre-op, Preoperative; POD, postoperative day.
      Figure thumbnail fx6
      Figure E3Spaghetti plot showing measured glomerular filtration rate values in the Ringer's group patients. Pre-op, Preoperative; POD, postoperative day.
      Figure thumbnail fx7
      Figure E4Spaghetti plot showing measured glomerular filtration rate values in the Custodiol (Dr Franz-Kohler Chemie GmbH, Bensheim, Germany) group patients. Pre-op, Preoperative; POD, postoperative day.

      References

        • Griepp R.B.
        • Ergin M.A.
        • Galla J.D.
        • Lansman S.L.
        • McCullough J.N.
        • Nguyen K.H.
        • et al.
        Natural history of descending thoracic and thoracoabdominal aneurysms.
        Ann Thorac Surg. 1999; 67: 1927-1930
        • Goodney P.P.
        • Travis L.
        • Lucas F.L.
        • Fillinger M.F.
        • Goodman D.C.
        • Cronenwett J.L.
        • et al.
        Survival after open versus endovascular thoracic aortic aneurysm repair in an observational study of the Medicare population.
        Circulation. 2011; 124: 2661-2669
        • Coselli J.S.
        • LeMaire S.A.
        • Preventza O.
        • de la Cruz K.I.
        • Cooley D.A.
        • Price M.D.
        • et al.
        Outcomes of 3309 thoracoabdominal aortic aneurysm repairs.
        J Thorac Cardiovasc Surg. 2016; 151: 1323-1338
        • Moulakakis K.C.
        • Karaolanis G.
        • Antonoupoulos C.N.
        • Kakisis J.
        • Klonaris C.
        • Preventza O.
        • et al.
        Open repair of thoracoabdominal aortic aneurysms in experienced centers.
        J Vasc Surg. 2018; 68: 634-645
        • LeMaire S.A.
        • Price M.D.
        • Green S.Y.
        • Zarda S.
        • Coselli J.S.
        Results of open thoracoabdominal aortic aneurysm repair.
        Ann Cardiothorac Surg. 2012; 1: 286-292
        • Kulik A.
        • Castner C.F.
        • Kouchoukos N.T.
        Outcomes after thoracoabdominal aortic aneurysm repair with hypothermic circulatory arrest.
        J Thorac Cardiovasc Surg. 2011; 141: 953-960
        • Svensson L.G.
        • Crawford E.S.
        • Hess K.R.
        • Coselli J.S.
        • Safi H.J.
        Experience with 1509 patients undergoing thoracoabdominal aortic operations.
        J Vasc Surg. 1993; 17: 357-370
        • Shepens M.A.
        • Heijmen R.H.
        • Ranschaert W.
        • Sonker U.
        • Morshius W.J.
        Thoracoabdominal aortic aneurysm repair: results of conventional open surgery.
        Eur J Vasc Endovasc Surg. 2009; 37: 640-645
        • Crawford E.S.
        • Crawford J.L.
        • Safi H.J.
        • Coselli J.S.
        • Hess K.R.
        • Brooks B.
        • et al.
        Thoracoabdominal aortic aneurysms: preoperative and intraoperative factors determining immediate and long-term results of operations in 605 patients.
        J Vasc Surg. 1986; 3: 389-404
        • Pieri M.
        • Nardelli P.
        • De Luca M.
        • Landoni G.
        • Frassoni S.
        • Melissano G.
        • et al.
        Predicting the need for intra-operative large volume blood transfusions during thoraco-abdominal aortic aneurysm repair.
        Eur J Vasc Endovasc Surg. 2017; 53: 347-353
        • Wong D.R.
        • Parenti J.L.
        • Green S.Y.
        • Chowdhary V.
        • Liao J.M.
        • Zarda S.
        • et al.
        Open repair of thoracoabdominal aortic aneurysm in the modern surgical era: contemporary outcomes in 509 patients.
        J Am Coll Surg. 2011; 212: 569-581
        • Godet G.
        • Fleron M.H.
        • Vicaut E.
        • Zubicki A.
        • Bertrand M.
        • Riou B.
        • et al.
        Risk factors for acute postoperative renal failure in thoracic or thoracoabdominal aortic surgery: a prospective study.
        Anesth Analg. 1997; 85: 1227-1232
        • Wynn M.M.
        • Acher C.
        • Marks E.
        • Engelbert T.
        • Acher C.W.
        Postoperative renal failure in thoracoabdominal aortic aneurysm repair with simple cross-clamp technique and 4°C renal perfusion.
        J Vasc Surg. 2015; 61: 611-622
        • Bashir M.
        • Harky A.
        • Adams B.
        • Wong K.
        • Di Salvo C.
        • Oo A.
        Renal protection in thoracoabdominal aortic aneurysm surgery.
        Gen Thorac Cardiovasc Surg. 2019; 67: 192-195
        • Ko¨ksoy C.
        • LeMaire S.A.
        • Curling P.E.
        • Raskin S.A.
        • Schmittling Z.C.
        • Conklin L.D.
        • et al.
        Renal perfusion during thoracoabdominal aortic operations: cold crystalloid is superior to normothermic blood.
        Ann Thorac Surg. 2002; 73: 730-738
        • LeMaire S.A.
        • Jones M.M.
        • Conklin L.D.
        • Carter S.A.
        • Criddell M.D.
        • Wang X.L.
        • et al.
        Randomized comparison of cold blood and cold crystalloid renal perfusion for renal protection during thoracoabdominal aneurysm repair.
        J Vasc Surg. 2009; 49: 11-19
        • Tshomba Y.
        • Kahlberg A.
        • Melissano G.
        • Coppi G.
        • Marone E.
        • Ferrari D.
        • et al.
        Comparison of renal perfusion solutions during thoracoabdominal aortic aneurysm repair.
        J Vasc Surg. 2014; 59: 623-633
        • Molina D.K.
        • DiMaio V.
        Normal organ weights in men: part II-the brain, lungs, liver, spleen, and kidneys.
        Am J Forensic Med Pathol. 2012; 33: 368-372
        • Lopes J.A.
        • Jorge S.
        The RIFLE and AKIN classifications for acute kidney injury: a critical and comprehensive review.
        Clin Kidney J. 2013; 6: 8-14
        • Hosmer Jr., D.W.
        • Lemeshow S.
        • Sturdivant R.X.
        Applied Logistic Regression.
        John Wiley & Sons, Inc, Hoboken, NJ2013
        • Safi H.J.
        • Miller III, C.C.
        • Huynh T.T.
        • Estrera A.L.
        • Porat E.E.
        • Winnerkvist A.N.
        • et al.
        Distal aortic perfusion and cerebrospinal fluid drainage for thoracoabdominal and descending thoracic aortic repair: ten years of organ protection.
        Ann Surg. 2003; 238 (discussion: 380-1): 372-380
        • Hiratzka L.F.
        • Bakris G.L.
        • Beckman J.A.
        • Bersin R.M.
        • Carr V.F.
        • Casey Jr., D.E.
        • et al.
        ACCF/AHA/AATS/ACR/ASA/SCA/SCAI/SIR/STS/SVM guidelines for the diagnosis and management of patients with thoracic aortic disease: a report of the American College of Cardiology Foundation/American Heart Association task force on practice guidelines, American Association for Thoracic Surgery, American College of Radiology, American Stroke Association, Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, Society of Interventional Radiology, Society of Thoracic Surgeons, and Society for Vascular Medicine.
        Circulation. 2010; 121: e266-e369
        • Viana F.F.
        • Shi W.Y.
        • Hayward P.A.
        • Larobina M.E.
        • Liskaser F.
        • Matalanis G.
        Custodiol versus blood cardioplegia in complex cardiac operations: an Australian experience.
        Eur J Cardiothorac Surg. 2013; 43: 826-831
        • O’Callaghan J.M.
        • Knight S.R.
        • Morgan R.D.
        • Morris P.J.
        Preservation solutions for static cold storage of kidney allografts: a systematic review and meta-analysis.
        Am J Transplant. 2012; 12: 896-906
        • Chatterjee S.
        • LeMaire S.A.
        • Amarasekara H.S.
        • Green S.Y.
        • Price M.D.
        • Yanoff M.T.
        • et al.
        Early-stage acute kidney injury adversely affects thoracoabdominal aortic aneurysm repair outcomes.
        Ann Thorac Surg. 2019; 107: 1720-1726
        • Marrocco-Trischitta M.M.
        • Melissano G.
        • Kahlberg A.
        • Calori G.
        • Setacci F.
        • Chiesa R.
        Chronic kidney disease classification stratifies mortality risk after elective stent graft repair of the thoracic aorta.
        J Vasc Surg. 2009; 49: 296-301

      Linked Article

      • Commentary: Using the right tools for the job: Revisiting renal preservation during open thoracoabdominal aortic aneurysm repair
        The Journal of Thoracic and Cardiovascular SurgeryVol. 165Issue 2
        • Preview
          Surgical repair of thoracoabdominal aortic aneurysms (TAAAs) is one of the most complex and high-risk procedures performed today. Despite contemporary techniques in cardiovascular surgery, up to 30% of elective patients suffer serious complications, including death, stroke, paraplegia, and dialysis-dependent renal failure.1 In particular, surgical replacement of the juxtarenal aorta necessitates a period of renal ischemia and results in approximately 10% of these patients requiring postoperative renal-replacement therapy (RRT).
        • Full-Text
        • PDF
      • Commentary: Renal perfusion strategy during thoracoabdominal aortic repair—is Custodiol the answer?
        The Journal of Thoracic and Cardiovascular SurgeryVol. 165Issue 2
        • Preview
          Despite advances in surgical techniques and organ-protection strategies, open repair of thoracoabdominal aneurysms (TAAA) is still associated with substantial morbidity and mortality.1,2 In a recent systematic review, Moulakakis and colleagues1 summarized the surgical outcomes of 9963 patients and demonstrated a pooled in-hospital mortality rate of 11.3% (range 2.3%-32.7%) after extent I-IV TAAA repair.1 Although a decreased mortality is debated for high-volume centers and the modern surgical era, the perioperative rate of major adverse events still remains considerable.
        • Full-Text
        • PDF
      • Commentary: Advances in the pursuit of renal protection in TAAA operations
        The Journal of Thoracic and Cardiovascular SurgeryVol. 165Issue 2
        • Preview
          Thoracoabdominal resection remains a challenging and complex operation. Protection of the spinal cord and abdominal organs, especially the kidneys, is critical to optimize short- and long-term results. In this issue of the Journal, Kahlberg and colleagues1 compare the efficacy of renal perfusion with Custodiol solution versus enriched Ringer's solution for renal protection in patients undergoing open thoracoabdominal aortic aneurysm (TAAA) repair.
        • Full-Text
        • PDF