- Email: [email protected]
Effects of Levosimendan on Renal Function in Patients Undergoing Coronary Artery Surgery
Effects of Levosimendan on Renal Function in Patients Undergoing Coronary Artery Surgery Anne Ristikankare, MD,* Reino Pöyhiä, MD, PhD,* Heidi Eriksson, MD, PhD,* Mika Valtonen, MD, PhD,† Kari Leino, MD, PhD,† and Markku Salmenperä, MD, PhD* Objectives: To evaluate the effect of levosimendan on postoperative renal function in patients with compromised heart function undergoing on-pump coronary artery bypass graft surgery. Design: A prospective, randomized, placebo-controlled, double-blind substudy. Setting: Cardiothoracic surgery, anesthesiology, and intensive care units at 2 university hospitals. Participants: Sixty patients with left ventricular ejection fraction <50% were randomized into 2 parallel treatment groups. Interventions: Levosimendan or placebo was started after the induction of anesthesia with a 12-g/kg bolus in 10 minutes followed by the infusion of 0.2 g/kg/min for the next 23 hours and 50 minutes. Measurements and Results: Serum cystatin C and plasma creatinine were measured at baseline; at 6 and 24 hours
after declamping the aorta; and on the 1st, 2nd, and 5th postoperative days. Urine N-acetyl--glucosaminidase (UNAG) was measured at baseline and at 6 and 24 hours after declamping of the aorta. Renal function was estimated with calculated glomerular filtration rate (eGFR). The changes in plasma creatinine, serum cystatin C, and urine NAG were not significant among the placebo and the levosimendan groups at any of the measuring points. Conclusions: After coronary artery surgery, levosimendan did not have a significant influence on the kidney function measured with these specific kidney markers. © 2012 Elsevier Inc. All rights reserved.
A
In the primary study, levosimendan facilitated weaning from CPB in patients with a decreased ejection fraction of the left ventricle.13 The aim of this substudy was to evaluate the renal effect of levosimendan and its safety in coronary artery surgery patients with compromised heart function using creatinine, cystatin C, and a tubular sensitive biomarker (ie, N-acetyl-bglucosaminidase [NAG]) as renal markers. Renal function also was estimated with the calculated GFR.
CUTE KIDNEY INJURY (AKI) is a severe complication of cardiac surgery, occurring in up to 30% of patients depending on the definition of AKI.1 Even mild and reversible changes in kidney function have been shown to increase both short- and long-term mortality2,3; therefore, any means to reduce the incidence of AKI should be sought. The underlying cause of AKI is multifactorial, and both patient- and procedurerelated factors have been identified. Patients’ age, previous renal insufficiency, left ventricular dysfunction, the use of an intra-aortic balloon pump (IABP), anemia, emergency surgery, the use of perioperative red blood cell transfusions, prolonged cardiopulmonary bypass (CPB), and surgical re-exploration are associated with AKI.4 Furthermore, preoperative left ventricular dysfunction and postoperative renal dysfunction have been shown to have an additive effect on long-term mortality.5 Levosimendan is an inotrope that improves cardiac contractility by sensitizing myofilaments to calcium. It also induces vasodilatation by opening adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in vascular smooth muscle and reduces preload and afterload.6 In experimental studies, levosimendan has been shown to have an anti-ischemic effect that may be complemented by the opening of cardiac mitochondrial ATP-sensitive K⫹ channels.7 In cardiac surgery and in critically ill patients, levosimendan has reduced mortality, probably because of its cardioprotective properties.8,9 The elimination of levosimendan is prolonged in severe renal failure, and, according to the safety profile of this medication, it should be used cautiously for patients with severe renal failure.10 However, the renal function estimated by the glomerular filtration rate (GFR) improved after levosimendan but not after dobutamine treatment in patients suffering from decompensated heart failure although both drugs improved left ventricular failure similarly.11 In a rat study with experimental endotoxemic acute renal failure, levosimendan as a KATP agonist had no effect on the tubular function but seemed to protect the kidneys, probably by augmenting renal perfusion.12 The results of these studies cannot be extrapolated to the setting of cardiac surgery, and studies assessing the effects of perioperative use of levosimendan on renal function are lacking.
KEY WORDS: acute kidney injury, coronary artery surgery, levosimendan
METHODS This prospective, randomized, placebo-controlled, and double-blind study was performed on the same patients as in the previous study assessing levosimendan for weaning patients from CPB.13 Sixty patients undergoing on-pump coronary artery bypass graft surgery were enrolled in 2 university centers. The ethics committees of the hospitals approved this study, and all patients provided a written informed consent before screening. All the included patients had coronary artery disease with an impaired left ventricular ejection fraction (ⱕ0.50), signs of acute ischemic congestive heart failure, or both. Patients with a previous administration of levosimendan within the preceding 30 days and predialysis or end-stage chronic renal failure were excluded. The power of the primary study was calculated to evaluate levosimendan’s effect on advancing weaning from CPB in patients with impaired left ventricular function.13 Anesthesia was conducted with intravenous agents (ie, propofol, sufentanil, and rocuronium) using the standardized protocol. A mean arterial pressure of 60 mmHg or higher was maintained throughout the surgery. Hypotension was treated with an ephedrine bolus during the induction of anesthesia followed by phenylephrine boluses or vaso-
From the *Department of Anaesthesiology and Intensive Care, Helsinki University Central Hospital, Helsinki, Finland; and †Department of Anaesthesiology, Turku University Hospital, Turku, Finland. Address reprint requests to Anne Ristikankare, MD, Department of Anaesthesiology and Intensive Care, Helsinki University Central Hospital, PO Box 340, 00029 Helsinki, Finland. E-mail: anne. [email protected] © 2012 Elsevier Inc. All rights reserved. 1053-0770/2604-0010$36.00/0 http://dx.doi.org/10.1053/j.jvca.2012.01.035
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pressin during the surgery; after being weaned from CPB, they were converted to norepinephrine if needed. Ringer’s solution was administered at 40 to 60 mL/h, the filling pressure of the left ventricle was maintained at the baseline value or at a pulmonary capillary wedge pressure of 10 to 12 mmHg, and additional fluid was infused accordingly. The blood glucose level was sustained between 4 and 8 mmol/L with short-acting insulin. After the insertion of the pulmonary arterial catheter, hemodynamic values were measured, and levosimendan or a corresponding placebo infusion was started. A bolus dose of 12 g/kg of levosimendan was administrated in 10 minutes and it was followed by a continuous infusion of 0.2 g/kg/min for a total infusion period of 24 hours. CPB was performed using a nonpulsatile flow of 2.4 L/min/m2 or more, a hollow-fiber membrane oxygenator, and an arterial filter. The perfusion circuit was primed with Ringer’s solution and 100 mL of 15% mannitol. During the perfusion, the mean arterial pressure was maintained between 60 and 80 mmHg, the hematocrit above 22%, and mixed venous saturation above 70%. Myocardial protection was attained with cold blood cardioplegia. Patients were allowed to cool passively to 32°C to 33°C and were actively rewarmed to 36°C before removing the aortic cross-clamp. The weaning was successful when the cardiac index was 2.2 L/m2/min or higher and the mixed venous saturation was 70% or higher with adequate filling pressures. If these requirements were not met, first epinephrine and, if needed, an IABP and later milrinone were administered when necessary. Fluid balance and hemodynamic parameters were assessed during the first 24 hours. Plasma creatinine and serum cystatin C samples were obtained at the baseline just before surgery, at 6 and 24 hours after declamping of the aorta, and on the 2nd and 5th postoperative days. Urine NAG was measured at the baseline and at 6 hours and 24 hours after declamping of the aorta. The estimated GFR (eGFR) was calculated with the Modification of Diet Renal Disease equation as follows: GFR ⫽ 186 ⫻ plasma creatinine level (mg/dL)⫺1.154 ⫻ age⫺0.203 ⫻ 0.742 (if female); the GFR is measured in mL/min/1.73 m2. Preoperative renal dysfunction was considered to exist if the eGFR was ⬍60 mL/min/1.73 m2. Renal risk was defined when the eGFR decreased more than 25%, renal injury when the eGFR decreased ⬎50%, and renal failure when the eGFR decreased ⬎75%.14 Plasma and urine creatinine were analyzed with the enzymatic assay method (Roche Diagnostics GmgH, Mannheim, Germany), and serum cystatin C samples were analyzed with the particle-enhanced immunoturbidimetric assay (Dako Cytomation, Clostrup, Denmark A/S). The reference values above normal limits were 95 mol/L for creatinine and 1.2 mg/L for serum cystatin C. Urine NAG was measured using the colorimetric assay (Roche Diagnostics GmgH). The groups were compared using the 2-group t test and the Fisher exact test for continuous and categoric variables, respectively. The continuous variables were compared using a repeated-measures analysis of variance model with effects for treatment, time point, and treatment-time point interaction. They also were evaluated separately at each time point by treatment using analysis of variance. RESULTS
This study was performed in 2 centers. Thirty patients received levosimendan (21 in center 1 and 9 in center 2), and 30 patients received placebo (21 in center 1 and 9 in center 2). There were no statistically significant differences in the demographic and procedure characteristics between the groups (Table 1). According to the laboratory measurements collected before the induction of anesthesia, 0 in the levosimendan group and 2 in the placebo group had renal dysfunction; 1 of these patients had a risk for kidney injury postoperatively. There were no significant differences between the groups with creat-
Table 1. Demographic and Intraoperative Data of the Patients Levosimendan (n ⫽ 30)
Male (n) Age (y) BMI (kg/m2) Diabetes (n) Hypertension LVEF (%) Medication -blocker ACE inhibitor Statins Preoperative laboratory values P-creatinine (mol/L) S-cystatin C (mg/L) Procedure CPB time (min)
Placebo (n ⫽ 30)
p Value
28 64 ⫾ 10 29 ⫾ 5 13 18 36 ⫾ 8
26 64 ⫾ 10 27 ⫾ 4 10 22 36 ⫾ 8
0.389 0.851 0.289 0.596 0.412 0.838
28 16 26
28 17 25
1.000 1.000 1.000
72.9 ⫾ 15.9 0.9 ⫾ 0.2
71.8 ⫾ 23.9 ⬎0.05 0.9 ⫾ 0.4 ⬎0.05
116 ⫾ 33
125 ⫾ 27
0.412
NOTE. Results are presented as mean ⫾ SD or as counts. Analysis of variance was performed for continuous variables and the chisquare test for categoric variables. Abbreviations: ACE, angiotensin-converting enzyme; BMI, body mass index; LVEF, left ventricular ejection fraction.
inine, cystatin C, and urine NAG values at any measurement points during the study period (Fig 1). In the levosimendan group, 5 patients developed a risk for renal injury, 1 developed a renal injury, and 2 developed renal failure. In the placebo group, 10 patients developed a risk for renal injury, 3 patients developed a renal injury, and none developed renal failure during the 5-day period. None of the patients had renal replacement therapy. Altogether 8 (26.6%) of the patients in the levosimendan group and 13 (43.3%) of the patients in the placebo group had a renal incident. There was not a significant difference between the groups (p ⫽ 0.167). In the levosimendan group, the baseline value of creatinine was 72.9 mol/L (standard deviation [SD] ⫽ 15.9 mol/L), and in the placebo group it was 71.8 mol/L (SD ⫽ 23.9 mol/L) (p ⫽ 1.086). The eGFR values were 103 mL/min/1.73 m2 (SD ⫽ 26 mL/ min/1.73 m2) and 109 mL/min/1.73 m2 (SD ⫽ 36) (p ⫽ 0.479). The peak values of creatinine and eGFR were on day 2; creatinine in the levosimendan group was 96 (SD ⫽ 46) mol/L and in the placebo group it was 86 (SD ⫽ 39) mol/L (p ⫽ 0.317), and the eGFR was 84 (SD ⫽ 31) mL/min/1.73 m2 and 92 (SD 32) mL/min/1.73 m2 (p ⫽ 0.312), respectively. The fluid balance after 24 hours from the beginning of the surgery was 7,760 mL (SD ⫽ 4,140) and 6,490 mL (SD ⫽ 5,640) in the levosimendan and placebo groups, respectively. The increase of cardiac index was higher in the levosimendan group at the end of surgery; otherwise, there were no differences between the groups in hemodynamic variables during the surgery and 4 hours after declamping the aorta (Table 2).13 During the surgery, hypotension was treated with phenylephrine and converted to norepinephrine after the perfusion. In the levosimendan group, the cumulative doses of phenylephrine were significantly higher (median ⫽ 14 mg [interquartile range, 10-20) than in the placebo group (median ⫽ 5 mg [interquartile range, 1-13]). Postoperatively, 27 patients in the levosimendan group and 22 patients in the placebo group required norepi-
EFFECTS OF LEVOSIMENDAN ON RENAL FUNCTION
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dose was 64 mg (SD ⫽ 52) and 56 mg (SD ⫽ 54), respectively. Four patients, all in the placebo group, received an IABP when they were weaned from CPB. During the hospital stay, 2 patients in the placebo group died: 1 of ventricular fibrillation and 1 of multiorgan failure.
Mean change in creatinine
A 35 30
µmol/l
25 20
Levosimendan
15
Placebo
10 5 0 -5 6 h after 24 h DA after DA
Day 2
Day 5
Time point
B
Mean change in cystatin C 0,3
0,25 0,2
mg/ml
0,15 0,1
Levosimendan
0,05
Placebo
0 -0,05 -0,1 -0,15
6 h after 24 h after Day 2 DA DA Time point
Day 5
Mean change in U-NAG
C
5
4
U/L
3
Levosimendan
2
Placebo
1
0 6h after DA
24 after DA
-1
Fig 1. (A-C) The mean changes and standard errors in plasma creatinine, serum cystatin C and urine NAG in every time point (p > 0.05).
nephrine for hypotension, but there was not a significant difference among the cumulative doses; the medians were 12 mg (range, 8-25 mg) and 13 mg (range, 8-21 mg) (p ⫽ 0.755, Mann-Whitney U test). After weaning from the CPB and during intensive care unit stay, 19 (63.3%) patients in the levosimendan group and 26 (86.7%) patients in the placebo group received inotropic medication. The mean dose of epinephrine was 11 mg (SD ⫽ 15) and 9 mg (SD ⫽ 8), and the milrinone
DISCUSSION
The authors studied the renal effects of levosimendan during cardiac surgery in a placebo-controlled manner using conventional, novel, and sensitive biomarkers of renal function. Although these markers increased similarly in these groups, only 26.6% of the patients in the levosimendan group compared with 43.3% in the placebo group suffered from mild-to-more severe renal insufficiency as detected by the eGFR. In addition to measuring the renal function with creatinine and cystatin C, the authors also detected tubular damage with urine NAG levels. In cardiac surgery, cystatin C, a novel marker of renal dysfunction, displayed more sensitivity than creatinine in discovering early AKI15; yet, cystatin C might be more accurate in chronic kidney injury than in AKI.16 No significant differences in any of these kidney biomarkers between the groups were observed. However, using the AKI criterion of ⬎25% decrease in eGFR, in the levosimendan group 8 patients had mild-to-more severe renal injury, whereas in the placebo group 13 patients suffered a similar injury. Even though a significant difference was not detected with the biomarkers or with the AKI criteria, this result suggests that levosimendan is safe to kidneys in patients with impaired cardiac function undergoing coronary artery surgery. Although the systemic hemodynamics of the patients were controlled carefully and manipulated with inotropes and vasopressors to meet the target values in both study groups,13 the renal blood flow was not measured. Jakob et al17 showed that regional blood flow distribution and oxygen uptake can be dissimilar with different inotropes. The effects of levosimendan on blood flow distribution have not been tested on humans yet, but in healthy dogs levosimendan has indeed increased renal blood flow.18 In addition, the mechanisms of renal failure are relevant to the renal effects of levosimendan. One of the main intraoperative pathogenesis of AKIs is systemic inflammatory response syndrome provoked by CPB. A similar process is found in sepsis. Both can alter renal blood flow; CPB might have an even greater effect because of nonpulsatile flow. There is a lack of studies on levosimendan’s effect on blood flow to kidneys in CPB, but because of the similarities between sepsis and CPB, some speculations can be drawn. There is a growing bulk of evidence to support that KATP channels are opened in septic shock and that KATP channel antagonists have provided renal protection in tubular ischemic and hypoxemic injury.19,20 Levosimendan, as a known KATP channel opener, might putatively affect renal perfusion adversely in septic shock or in related situations, such as in the vasoplegic state after CPB.21 In experimental studies with endotoxemic animals, levosimendan showed either no effect in renal blood flow or some renal protection determined by levosimendan’s ability to reverse the renal vasoconstriction induced by sepsis.22,23 By contrast, septic shock induces renal vasoconstriction,
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Table 2. Mean Changes of the Mean Arterial Pressure (mmHg), Pulmonary Capillary Wedge Pressure (mmHg), Confidence Interval (L/min/ m2), and Systemic Vascular Resistance Index (mmHg/[L/min]/m2) Levosimendan (n ⫽ 30)
MAP
PCWP
CI
SVRI
Placebo (n ⫽ 30)
Time Point
Mean
Mean Change (SD)
Mean
Mean Change (SD)
p
Baseline End of surgery 4 h after DA Baseline End of surgery 4 h after DA Baseline End of surgery 4 h after DA Baseline End of surgery 4 h after DA
74 65 68 11 12 11 1.8 2.4 2.9 10.8 7.3 6.3
— ⫺8.5 (18.3) ⫺6.4 (15.5) — 0.9 (3.4) 1.5 (3.8) — 0.6 (0.5) 1.1 (0.7) — ⫺3.7 (3.7) ⫺4.6 (4.3)
77 73 78 11 13 12 1.9 2.2 2.7 11.4 9.4 8.1
— ⫺3.7 (16.5) 0.8 (17.4) — 2.0 (3.4) 0.2 (5.0) — 0.3 0.8 (0.7) — ⫺2.0 (4.5) ⫺3.5 (3.9)
— 0.295 0.098 0.251 0.887 — 0.013 0.123 — 0.133 0.336
NOTE. Statistics were performed using repeated-measures analysis of variance. Abbreviations: MAP, mean arterial pressure; DA, declamping of the aorta; PCWP, pulmonary capillary wedge pressure; CI, confidence interval; SVRI, systemic vascular resistance index.
which is mediated at least partly by angiotensin-2, and levosimendan could alleviate this by inducing mesangial cell relaxation.12 Another possible renoprotective mechanism of levosimendan could be its anti-inflammatory action; but, at least in experimentally induced septic shock, levosimendan failed to reduce the levels of inflammatory biomarkers.12 In a study with septic patients, levosimendan showed a signif-
icant increase in creatinine clearance, but, unfortunately, renal blood flow was not measured.24 In this pilot study, levosimendan did not show a significant effect on renal function measured by multiple biomarkers, but it did show some capacity to preserve kidneys in coronary artery surgery. More clinical studies are needed to confirm this finding.
REFERENCES 1. Rosner MH, Okusa MD: Acute kidney injury associated with cardiac surgery. Clin J Am Soc Nephrol 1:19-32, 2006 2. Lassnigg A, Schmidlin D, Mouhieddine M, et al: Minimal changes of serum creatinine predict prognosis in patients after cardiothoracic surgery: A prospective cohort study. J Am Soc Nephrol 15:1597-1605, 2004 3. Loef BG, Epema AH, Smilde TD, et al: Immediate postoperative renal function deterioration in cardiac surgical patients predicts inhospital mortality and long-term survival. J Am Soc Nephrol 16:195200, 2005 4. Karkouti K, Wijeysundera DN, Yau TM, et al: Acute kidney injury after cardiac surgery: Focus on modifiable risk factors. Circulation 119:495-502, 2009 5. Loef BG, Epema AH, Navis G, et al: Postoperative renal dysfunction and preoperative left ventricular dysfunction predispose patients to increased long-term mortality after coronary artery bypass graft surgery. Br J Anaesth 102:749-755, 2009 6. Lilleberg J, Nieminen MS, Akkila J, et al: Effects of a new calcium sensitizer, levosimendan, on haemodynamics, coronary blood flow and myocardial substrate utilization early after coronary artery bypass grafting. Eur Heart J 19:660-668, 1998 7. Kersten JR, Montgomery MW, Pagel PS, et al: Levosimendan, a new positive inotropic drug, decreases myocardial infarct size via activation of K(ATP) channels. Anesth Analg 90:5-11, 2000 8. Landoni G, Mizzi A, Biondi-Zoccai G, et al: Levosimendan reduces mortality in critically ill patients. A meta-analysis of randomized controlled studies. Minerva Anestesiol 76:276-286, 2010 9. Landoni G, Mizzi A, Biondi-Zoccai G, et al: Reducing mortality in cardiac surgery with levosimendan: a meta-analysis of randomized controlled trials. J Cardiothorac Vasc Anesth 24: 51-57, 2010
10. Puttonen J, Kantele S, Kivikko M, et al: Effect of severe renal failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites. Clin Pharmacokinet 46:235-246, 2007 11. Yilmaz MB, Yalta K, Yontar C, et al: Levosimendan improves renal function in patients with acute decompensated heart failure: Comparison with dobutamine. Cardiovasc Drugs Ther 21:431-435, 2007 12. Zager RA, Johnson AC, Lund S, et al: Levosimendan protects against experimental endotoxemic acute renal failure. Am J Physiol Ren Physiol 290:F1453-F1462, 2006 13. Eriksson HI, Jalonen JR, Heikkinen LO, et al: Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function. Ann Thorac Surg 87:448-454, 2009 14. Bellomo R, Ronco C, Kellum JA, et al: Acute renal failure— Definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204-R212, 2004 15. Haase-Fielitz A, Bellomo R, Devarajan P, et al: Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery—A prospective cohort study. Crit Care Med 37:553-560, 2009 16. Haase M, Bellomo R, Devarajan P, et al: Novel biomarkers early predict the severity of acute kidney injury after cardiac surgery in adults. Ann Thorac Surg 88:124-130, 2009 17. Jakob SM, Ruokonen E, Takala J: Effects of dopamine on systemic and regional blood flow and metabolism in septic and cardiac surgery patients. Shock 18:8-13, 2002 18. Pagel PS, Hettrick DA, Warltier DC: Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs. Br J Pharmacol 119:609-615, 1996 19. Buckley JF, Singer M, Clapp LH: Role of KATP channels in sepsis. Cardiovasc Res 72:220-230, 2006
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20. Pompermayer K, Souza DG, Lara GG, et al: The ATP-sensitive potassium channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats. Kidney Int 67:1785-1796, 2005 21. Salmenperä M, Eriksson H: Levosimendan in perioperative and critical care patients. Curr Opin Anaesthesiol 22:496-501, 2009 22. Faivre V, Kaskos H, Callebert J, et al: Cardiac and renal effects of levosimendan, arginine vasopressin, and norepinephrine
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in lipopolysaccharide-treated rabbits. Anesthesiology 103:514-521, 2005 23. Oldner A, Konrad D, Weitzberg E, et al: Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med 29:2185-2193, 2001 24. Morelli A, De Castro S, Teboul JL, et al: Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med 31:638-644, 2005
after declamping the aorta; and on the 1st, 2nd, and 5th postoperative days. Urine N-acetyl--glucosaminidase (UNAG) was measured at baseline and at 6 and 24 hours after declamping of the aorta. Renal function was estimated with calculated glomerular filtration rate (eGFR). The changes in plasma creatinine, serum cystatin C, and urine NAG were not significant among the placebo and the levosimendan groups at any of the measuring points. Conclusions: After coronary artery surgery, levosimendan did not have a significant influence on the kidney function measured with these specific kidney markers. © 2012 Elsevier Inc. All rights reserved.
A
In the primary study, levosimendan facilitated weaning from CPB in patients with a decreased ejection fraction of the left ventricle.13 The aim of this substudy was to evaluate the renal effect of levosimendan and its safety in coronary artery surgery patients with compromised heart function using creatinine, cystatin C, and a tubular sensitive biomarker (ie, N-acetyl-bglucosaminidase [NAG]) as renal markers. Renal function also was estimated with the calculated GFR.
CUTE KIDNEY INJURY (AKI) is a severe complication of cardiac surgery, occurring in up to 30% of patients depending on the definition of AKI.1 Even mild and reversible changes in kidney function have been shown to increase both short- and long-term mortality2,3; therefore, any means to reduce the incidence of AKI should be sought. The underlying cause of AKI is multifactorial, and both patient- and procedurerelated factors have been identified. Patients’ age, previous renal insufficiency, left ventricular dysfunction, the use of an intra-aortic balloon pump (IABP), anemia, emergency surgery, the use of perioperative red blood cell transfusions, prolonged cardiopulmonary bypass (CPB), and surgical re-exploration are associated with AKI.4 Furthermore, preoperative left ventricular dysfunction and postoperative renal dysfunction have been shown to have an additive effect on long-term mortality.5 Levosimendan is an inotrope that improves cardiac contractility by sensitizing myofilaments to calcium. It also induces vasodilatation by opening adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in vascular smooth muscle and reduces preload and afterload.6 In experimental studies, levosimendan has been shown to have an anti-ischemic effect that may be complemented by the opening of cardiac mitochondrial ATP-sensitive K⫹ channels.7 In cardiac surgery and in critically ill patients, levosimendan has reduced mortality, probably because of its cardioprotective properties.8,9 The elimination of levosimendan is prolonged in severe renal failure, and, according to the safety profile of this medication, it should be used cautiously for patients with severe renal failure.10 However, the renal function estimated by the glomerular filtration rate (GFR) improved after levosimendan but not after dobutamine treatment in patients suffering from decompensated heart failure although both drugs improved left ventricular failure similarly.11 In a rat study with experimental endotoxemic acute renal failure, levosimendan as a KATP agonist had no effect on the tubular function but seemed to protect the kidneys, probably by augmenting renal perfusion.12 The results of these studies cannot be extrapolated to the setting of cardiac surgery, and studies assessing the effects of perioperative use of levosimendan on renal function are lacking.
KEY WORDS: acute kidney injury, coronary artery surgery, levosimendan
METHODS This prospective, randomized, placebo-controlled, and double-blind study was performed on the same patients as in the previous study assessing levosimendan for weaning patients from CPB.13 Sixty patients undergoing on-pump coronary artery bypass graft surgery were enrolled in 2 university centers. The ethics committees of the hospitals approved this study, and all patients provided a written informed consent before screening. All the included patients had coronary artery disease with an impaired left ventricular ejection fraction (ⱕ0.50), signs of acute ischemic congestive heart failure, or both. Patients with a previous administration of levosimendan within the preceding 30 days and predialysis or end-stage chronic renal failure were excluded. The power of the primary study was calculated to evaluate levosimendan’s effect on advancing weaning from CPB in patients with impaired left ventricular function.13 Anesthesia was conducted with intravenous agents (ie, propofol, sufentanil, and rocuronium) using the standardized protocol. A mean arterial pressure of 60 mmHg or higher was maintained throughout the surgery. Hypotension was treated with an ephedrine bolus during the induction of anesthesia followed by phenylephrine boluses or vaso-
From the *Department of Anaesthesiology and Intensive Care, Helsinki University Central Hospital, Helsinki, Finland; and †Department of Anaesthesiology, Turku University Hospital, Turku, Finland. Address reprint requests to Anne Ristikankare, MD, Department of Anaesthesiology and Intensive Care, Helsinki University Central Hospital, PO Box 340, 00029 Helsinki, Finland. E-mail: anne. [email protected] © 2012 Elsevier Inc. All rights reserved. 1053-0770/2604-0010$36.00/0 http://dx.doi.org/10.1053/j.jvca.2012.01.035
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pressin during the surgery; after being weaned from CPB, they were converted to norepinephrine if needed. Ringer’s solution was administered at 40 to 60 mL/h, the filling pressure of the left ventricle was maintained at the baseline value or at a pulmonary capillary wedge pressure of 10 to 12 mmHg, and additional fluid was infused accordingly. The blood glucose level was sustained between 4 and 8 mmol/L with short-acting insulin. After the insertion of the pulmonary arterial catheter, hemodynamic values were measured, and levosimendan or a corresponding placebo infusion was started. A bolus dose of 12 g/kg of levosimendan was administrated in 10 minutes and it was followed by a continuous infusion of 0.2 g/kg/min for a total infusion period of 24 hours. CPB was performed using a nonpulsatile flow of 2.4 L/min/m2 or more, a hollow-fiber membrane oxygenator, and an arterial filter. The perfusion circuit was primed with Ringer’s solution and 100 mL of 15% mannitol. During the perfusion, the mean arterial pressure was maintained between 60 and 80 mmHg, the hematocrit above 22%, and mixed venous saturation above 70%. Myocardial protection was attained with cold blood cardioplegia. Patients were allowed to cool passively to 32°C to 33°C and were actively rewarmed to 36°C before removing the aortic cross-clamp. The weaning was successful when the cardiac index was 2.2 L/m2/min or higher and the mixed venous saturation was 70% or higher with adequate filling pressures. If these requirements were not met, first epinephrine and, if needed, an IABP and later milrinone were administered when necessary. Fluid balance and hemodynamic parameters were assessed during the first 24 hours. Plasma creatinine and serum cystatin C samples were obtained at the baseline just before surgery, at 6 and 24 hours after declamping of the aorta, and on the 2nd and 5th postoperative days. Urine NAG was measured at the baseline and at 6 hours and 24 hours after declamping of the aorta. The estimated GFR (eGFR) was calculated with the Modification of Diet Renal Disease equation as follows: GFR ⫽ 186 ⫻ plasma creatinine level (mg/dL)⫺1.154 ⫻ age⫺0.203 ⫻ 0.742 (if female); the GFR is measured in mL/min/1.73 m2. Preoperative renal dysfunction was considered to exist if the eGFR was ⬍60 mL/min/1.73 m2. Renal risk was defined when the eGFR decreased more than 25%, renal injury when the eGFR decreased ⬎50%, and renal failure when the eGFR decreased ⬎75%.14 Plasma and urine creatinine were analyzed with the enzymatic assay method (Roche Diagnostics GmgH, Mannheim, Germany), and serum cystatin C samples were analyzed with the particle-enhanced immunoturbidimetric assay (Dako Cytomation, Clostrup, Denmark A/S). The reference values above normal limits were 95 mol/L for creatinine and 1.2 mg/L for serum cystatin C. Urine NAG was measured using the colorimetric assay (Roche Diagnostics GmgH). The groups were compared using the 2-group t test and the Fisher exact test for continuous and categoric variables, respectively. The continuous variables were compared using a repeated-measures analysis of variance model with effects for treatment, time point, and treatment-time point interaction. They also were evaluated separately at each time point by treatment using analysis of variance. RESULTS
This study was performed in 2 centers. Thirty patients received levosimendan (21 in center 1 and 9 in center 2), and 30 patients received placebo (21 in center 1 and 9 in center 2). There were no statistically significant differences in the demographic and procedure characteristics between the groups (Table 1). According to the laboratory measurements collected before the induction of anesthesia, 0 in the levosimendan group and 2 in the placebo group had renal dysfunction; 1 of these patients had a risk for kidney injury postoperatively. There were no significant differences between the groups with creat-
Table 1. Demographic and Intraoperative Data of the Patients Levosimendan (n ⫽ 30)
Male (n) Age (y) BMI (kg/m2) Diabetes (n) Hypertension LVEF (%) Medication -blocker ACE inhibitor Statins Preoperative laboratory values P-creatinine (mol/L) S-cystatin C (mg/L) Procedure CPB time (min)
Placebo (n ⫽ 30)
p Value
28 64 ⫾ 10 29 ⫾ 5 13 18 36 ⫾ 8
26 64 ⫾ 10 27 ⫾ 4 10 22 36 ⫾ 8
0.389 0.851 0.289 0.596 0.412 0.838
28 16 26
28 17 25
1.000 1.000 1.000
72.9 ⫾ 15.9 0.9 ⫾ 0.2
71.8 ⫾ 23.9 ⬎0.05 0.9 ⫾ 0.4 ⬎0.05
116 ⫾ 33
125 ⫾ 27
0.412
NOTE. Results are presented as mean ⫾ SD or as counts. Analysis of variance was performed for continuous variables and the chisquare test for categoric variables. Abbreviations: ACE, angiotensin-converting enzyme; BMI, body mass index; LVEF, left ventricular ejection fraction.
inine, cystatin C, and urine NAG values at any measurement points during the study period (Fig 1). In the levosimendan group, 5 patients developed a risk for renal injury, 1 developed a renal injury, and 2 developed renal failure. In the placebo group, 10 patients developed a risk for renal injury, 3 patients developed a renal injury, and none developed renal failure during the 5-day period. None of the patients had renal replacement therapy. Altogether 8 (26.6%) of the patients in the levosimendan group and 13 (43.3%) of the patients in the placebo group had a renal incident. There was not a significant difference between the groups (p ⫽ 0.167). In the levosimendan group, the baseline value of creatinine was 72.9 mol/L (standard deviation [SD] ⫽ 15.9 mol/L), and in the placebo group it was 71.8 mol/L (SD ⫽ 23.9 mol/L) (p ⫽ 1.086). The eGFR values were 103 mL/min/1.73 m2 (SD ⫽ 26 mL/ min/1.73 m2) and 109 mL/min/1.73 m2 (SD ⫽ 36) (p ⫽ 0.479). The peak values of creatinine and eGFR were on day 2; creatinine in the levosimendan group was 96 (SD ⫽ 46) mol/L and in the placebo group it was 86 (SD ⫽ 39) mol/L (p ⫽ 0.317), and the eGFR was 84 (SD ⫽ 31) mL/min/1.73 m2 and 92 (SD 32) mL/min/1.73 m2 (p ⫽ 0.312), respectively. The fluid balance after 24 hours from the beginning of the surgery was 7,760 mL (SD ⫽ 4,140) and 6,490 mL (SD ⫽ 5,640) in the levosimendan and placebo groups, respectively. The increase of cardiac index was higher in the levosimendan group at the end of surgery; otherwise, there were no differences between the groups in hemodynamic variables during the surgery and 4 hours after declamping the aorta (Table 2).13 During the surgery, hypotension was treated with phenylephrine and converted to norepinephrine after the perfusion. In the levosimendan group, the cumulative doses of phenylephrine were significantly higher (median ⫽ 14 mg [interquartile range, 10-20) than in the placebo group (median ⫽ 5 mg [interquartile range, 1-13]). Postoperatively, 27 patients in the levosimendan group and 22 patients in the placebo group required norepi-
EFFECTS OF LEVOSIMENDAN ON RENAL FUNCTION
593
dose was 64 mg (SD ⫽ 52) and 56 mg (SD ⫽ 54), respectively. Four patients, all in the placebo group, received an IABP when they were weaned from CPB. During the hospital stay, 2 patients in the placebo group died: 1 of ventricular fibrillation and 1 of multiorgan failure.
Mean change in creatinine
A 35 30
µmol/l
25 20
Levosimendan
15
Placebo
10 5 0 -5 6 h after 24 h DA after DA
Day 2
Day 5
Time point
B
Mean change in cystatin C 0,3
0,25 0,2
mg/ml
0,15 0,1
Levosimendan
0,05
Placebo
0 -0,05 -0,1 -0,15
6 h after 24 h after Day 2 DA DA Time point
Day 5
Mean change in U-NAG
C
5
4
U/L
3
Levosimendan
2
Placebo
1
0 6h after DA
24 after DA
-1
Fig 1. (A-C) The mean changes and standard errors in plasma creatinine, serum cystatin C and urine NAG in every time point (p > 0.05).
nephrine for hypotension, but there was not a significant difference among the cumulative doses; the medians were 12 mg (range, 8-25 mg) and 13 mg (range, 8-21 mg) (p ⫽ 0.755, Mann-Whitney U test). After weaning from the CPB and during intensive care unit stay, 19 (63.3%) patients in the levosimendan group and 26 (86.7%) patients in the placebo group received inotropic medication. The mean dose of epinephrine was 11 mg (SD ⫽ 15) and 9 mg (SD ⫽ 8), and the milrinone
DISCUSSION
The authors studied the renal effects of levosimendan during cardiac surgery in a placebo-controlled manner using conventional, novel, and sensitive biomarkers of renal function. Although these markers increased similarly in these groups, only 26.6% of the patients in the levosimendan group compared with 43.3% in the placebo group suffered from mild-to-more severe renal insufficiency as detected by the eGFR. In addition to measuring the renal function with creatinine and cystatin C, the authors also detected tubular damage with urine NAG levels. In cardiac surgery, cystatin C, a novel marker of renal dysfunction, displayed more sensitivity than creatinine in discovering early AKI15; yet, cystatin C might be more accurate in chronic kidney injury than in AKI.16 No significant differences in any of these kidney biomarkers between the groups were observed. However, using the AKI criterion of ⬎25% decrease in eGFR, in the levosimendan group 8 patients had mild-to-more severe renal injury, whereas in the placebo group 13 patients suffered a similar injury. Even though a significant difference was not detected with the biomarkers or with the AKI criteria, this result suggests that levosimendan is safe to kidneys in patients with impaired cardiac function undergoing coronary artery surgery. Although the systemic hemodynamics of the patients were controlled carefully and manipulated with inotropes and vasopressors to meet the target values in both study groups,13 the renal blood flow was not measured. Jakob et al17 showed that regional blood flow distribution and oxygen uptake can be dissimilar with different inotropes. The effects of levosimendan on blood flow distribution have not been tested on humans yet, but in healthy dogs levosimendan has indeed increased renal blood flow.18 In addition, the mechanisms of renal failure are relevant to the renal effects of levosimendan. One of the main intraoperative pathogenesis of AKIs is systemic inflammatory response syndrome provoked by CPB. A similar process is found in sepsis. Both can alter renal blood flow; CPB might have an even greater effect because of nonpulsatile flow. There is a lack of studies on levosimendan’s effect on blood flow to kidneys in CPB, but because of the similarities between sepsis and CPB, some speculations can be drawn. There is a growing bulk of evidence to support that KATP channels are opened in septic shock and that KATP channel antagonists have provided renal protection in tubular ischemic and hypoxemic injury.19,20 Levosimendan, as a known KATP channel opener, might putatively affect renal perfusion adversely in septic shock or in related situations, such as in the vasoplegic state after CPB.21 In experimental studies with endotoxemic animals, levosimendan showed either no effect in renal blood flow or some renal protection determined by levosimendan’s ability to reverse the renal vasoconstriction induced by sepsis.22,23 By contrast, septic shock induces renal vasoconstriction,
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Table 2. Mean Changes of the Mean Arterial Pressure (mmHg), Pulmonary Capillary Wedge Pressure (mmHg), Confidence Interval (L/min/ m2), and Systemic Vascular Resistance Index (mmHg/[L/min]/m2) Levosimendan (n ⫽ 30)
MAP
PCWP
CI
SVRI
Placebo (n ⫽ 30)
Time Point
Mean
Mean Change (SD)
Mean
Mean Change (SD)
p
Baseline End of surgery 4 h after DA Baseline End of surgery 4 h after DA Baseline End of surgery 4 h after DA Baseline End of surgery 4 h after DA
74 65 68 11 12 11 1.8 2.4 2.9 10.8 7.3 6.3
— ⫺8.5 (18.3) ⫺6.4 (15.5) — 0.9 (3.4) 1.5 (3.8) — 0.6 (0.5) 1.1 (0.7) — ⫺3.7 (3.7) ⫺4.6 (4.3)
77 73 78 11 13 12 1.9 2.2 2.7 11.4 9.4 8.1
— ⫺3.7 (16.5) 0.8 (17.4) — 2.0 (3.4) 0.2 (5.0) — 0.3 0.8 (0.7) — ⫺2.0 (4.5) ⫺3.5 (3.9)
— 0.295 0.098 0.251 0.887 — 0.013 0.123 — 0.133 0.336
NOTE. Statistics were performed using repeated-measures analysis of variance. Abbreviations: MAP, mean arterial pressure; DA, declamping of the aorta; PCWP, pulmonary capillary wedge pressure; CI, confidence interval; SVRI, systemic vascular resistance index.
which is mediated at least partly by angiotensin-2, and levosimendan could alleviate this by inducing mesangial cell relaxation.12 Another possible renoprotective mechanism of levosimendan could be its anti-inflammatory action; but, at least in experimentally induced septic shock, levosimendan failed to reduce the levels of inflammatory biomarkers.12 In a study with septic patients, levosimendan showed a signif-
icant increase in creatinine clearance, but, unfortunately, renal blood flow was not measured.24 In this pilot study, levosimendan did not show a significant effect on renal function measured by multiple biomarkers, but it did show some capacity to preserve kidneys in coronary artery surgery. More clinical studies are needed to confirm this finding.
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10. Puttonen J, Kantele S, Kivikko M, et al: Effect of severe renal failure and haemodialysis on the pharmacokinetics of levosimendan and its metabolites. Clin Pharmacokinet 46:235-246, 2007 11. Yilmaz MB, Yalta K, Yontar C, et al: Levosimendan improves renal function in patients with acute decompensated heart failure: Comparison with dobutamine. Cardiovasc Drugs Ther 21:431-435, 2007 12. Zager RA, Johnson AC, Lund S, et al: Levosimendan protects against experimental endotoxemic acute renal failure. Am J Physiol Ren Physiol 290:F1453-F1462, 2006 13. Eriksson HI, Jalonen JR, Heikkinen LO, et al: Levosimendan facilitates weaning from cardiopulmonary bypass in patients undergoing coronary artery bypass grafting with impaired left ventricular function. Ann Thorac Surg 87:448-454, 2009 14. Bellomo R, Ronco C, Kellum JA, et al: Acute renal failure— Definition, outcome measures, animal models, fluid therapy and information technology needs: The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) Group. Crit Care 8:R204-R212, 2004 15. Haase-Fielitz A, Bellomo R, Devarajan P, et al: Novel and conventional serum biomarkers predicting acute kidney injury in adult cardiac surgery—A prospective cohort study. Crit Care Med 37:553-560, 2009 16. Haase M, Bellomo R, Devarajan P, et al: Novel biomarkers early predict the severity of acute kidney injury after cardiac surgery in adults. Ann Thorac Surg 88:124-130, 2009 17. Jakob SM, Ruokonen E, Takala J: Effects of dopamine on systemic and regional blood flow and metabolism in septic and cardiac surgery patients. Shock 18:8-13, 2002 18. Pagel PS, Hettrick DA, Warltier DC: Influence of levosimendan, pimobendan, and milrinone on the regional distribution of cardiac output in anaesthetized dogs. Br J Pharmacol 119:609-615, 1996 19. Buckley JF, Singer M, Clapp LH: Role of KATP channels in sepsis. Cardiovasc Res 72:220-230, 2006
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20. Pompermayer K, Souza DG, Lara GG, et al: The ATP-sensitive potassium channel blocker glibenclamide prevents renal ischemia/reperfusion injury in rats. Kidney Int 67:1785-1796, 2005 21. Salmenperä M, Eriksson H: Levosimendan in perioperative and critical care patients. Curr Opin Anaesthesiol 22:496-501, 2009 22. Faivre V, Kaskos H, Callebert J, et al: Cardiac and renal effects of levosimendan, arginine vasopressin, and norepinephrine
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in lipopolysaccharide-treated rabbits. Anesthesiology 103:514-521, 2005 23. Oldner A, Konrad D, Weitzberg E, et al: Effects of levosimendan, a novel inotropic calcium-sensitizing drug, in experimental septic shock. Crit Care Med 29:2185-2193, 2001 24. Morelli A, De Castro S, Teboul JL, et al: Effects of levosimendan on systemic and regional hemodynamics in septic myocardial depression. Intensive Care Med 31:638-644, 2005