Objective: The objective of this work was to evaluate the influence of the use of nifedipine on the outcome of renal function in patients undergoing myocardial revascularization with extracorporeal circulation. Methods: The casuistics and variables related to extracorporeal circulation were studied. Serum creatinine levels were measured preoperatively, 24, 48 hours and on 7th day postoperatively. Renal failure was defined as an increase in 30% of serum creatinine levels at 24 or 48 hours postoperatively compared to those at baseline. Patients were assigned to four groups: G1 (patients who received nifedipine preoperatively); G2 (patients who received nifedipine postoperatively); G3 (patients who received nifedipine pre and postoperatively) and G4 (patients who did not receive nifedipine). Results: The mean serum creatinine levels postoperatively presented greater rise in G4 (G4>G1=G2=G3), and G4 also presented a higher percentage of patients with acute renal failure (G4>G1 and G4>G3, P<0.05; G1=G3 and G2=G4, P>0.05). Conclusion: The evaluation of serum creatinine values and incidence of acute kidney injury postoperatively suggest a possible nefro-potective effect of nifedipine in patients undergoing myocardial revascularization with extracorporeal circulation.
OBJETIVO: Avaliar durante o período perioperatório o uso da nifedipina na incidência de lesão renal aguda dos pacientes submetidos à revascularização do miocárdio com circulação extracorpórea. MÉTODOS: Foram estudados, de modo prospectivo e sequencial, 94 pacientes submetidos à revascularização do miocárdio com circulação extracorpórea. As dosagens da creatinina sérica foram realizadas durante pré-operatório e pós-operatório de 24, 48 horas e no 7º dia. Estabeleceu-se como definição para presença de lesão renal a elevação da creatinina sérica 30% em relação ao seu valor basal nas primeiras 24 ou 48 horas de pós-operatório. Os pacientes foram divididos em quatro grupos: G1, que recebeu nifedipina no pré-operatório; G2, que recebeu nifedipina no pós-operatório; G3, que recebeu nifedipina no pré e pós-operatórios e, G4, que não recebeu nifedipina. RESULTADOS: O grupo G4 mostrou maior elevação do percentual de creatinina sérica e maior percentual de pacientes que apresentaram insuficiência renal aguda em relação aos demais grupos no pós-operatório. CONCLUSÃO: Os valores da creatinina sérica e a incidência de lesão renal aguda no pós-operatório sugerem possível efeito nefroprotetor da nifedipina em pacientes submetidos à revascularização do miocárdio com circulação extracorpórea
Cardiopulmonary bypass is identified by the system as an aggression, complex, multifactorial agent, generating also a multifactorial response . The consequences of cardiopulmonary bypass (CPB) manifest as temporary dysfunction of different organs, producing a series of reactions and changes in the physiological balance. More serious complications may still result in systemic inflammatory response syndrome (SIRS) and death . Among them, one of the most common is acute renal lesion (ARL), which causes abrupt decline of the renal function, resulting in serum retention of nitrogenized products . Its incidence in cardiovascular surgery is é variable (5% to 39%), depending on the degree of function loss, considered as a diagnostic criterion of acute renal insufficiency .
Associated diseases, aging, compromised renal function, emergency surgery and obesity are acknowledged as factors of predisposition for the occurrence of acute renal insufficiency (ARI). The non-pulsatile flow during CPB is an important factor that results in renal vasoconstriction and lesion by ischemia .
Alongside classical aspects of the ARI mechanism, molecular and cellular mechanisms, specifically calcium and other molecules, are involved in the ischemic event .
The inhibitors of calcium conduits contribute in the treatment of hypertension, coronary insufficiency and alterations in the cardiac rhythm. They were used previously and after kidney insult in the treatment of arterial coronary disease . Its action interrupts further progression of ischemia that causes cellular demise, reducing transportation of the calcium ion and its use by the mitochondrias. Although not being a routine therapeutic measure, its benefits were observed in real transplantations, in nephrotoxicity by cyclosporine and in procedures with iodide contrasts [7-9].
Considering the references in literature emphasizing the role of the calcium ion in the cellular lesion of ARL and reports about the apparent protection of the inhibitors of calcium conduits, alleviating the renal aggression, we believe it is appropriate to investigate the possible protective role of nifedipine over the renal aggression in the perioperative period of the myocardial revascularization surgery using cardiopulmonary bypass.
There were studied sequentially and prospectively, 94 patients interned in the cardiovascular surgery ward of the Hospital das Clínicas da Faculdade de Medicina de Botucatu, UNESP - Universidade Estadual Paulista from November 2003 to December 2004. The patients were divided in four groups according to the decision regarding the use and method of administration of nifedipine by the the medical team that assisted those patients:
G1, consisting of 16 patients that received nifedipine in the preparative period; G2, consisting of 29 patients that received nifedipine in the postoperative period; G3, consisting of 34 patients that received nifedipine in the preparative and postoperative periods and G4, consisting of 15 patients that did not receive nifedipine.
For the exclusion criteria were established: duration of CPB over 2 hours and 30 minutes; mean blood pressure lower than 50 mmHg over 10 minutes during CPB, age over 70 years; reoperation; another associated surgery; emergency surgery; use of counterpulsating device; chronic renal lesion.
The protocol of the study concluded that: inclusion of the patients after their consent, identification of preoperative co-morbidities; medical prescription observation; routine laboratory evaluation and serum creatinine dosage 24 hours prior to surgery. During the surgical procedure intraoperative risk factors were identified (CPB) and laboratory evaluation for CPB management performed. In the immediate postoperative (24 and 48 hours) and in the late postoperative (7th
day), laboratory evaluation with serum creatinine dosage and medical prescription observations were carried out; in the 7th
day the protocol was completed.
The protocol of perfusion used by our service concluded that: perfusate combined with sodium chloride solution at 0.9% and mannitol at 20%. After sodium heparinization at dosage of 4mg/kg and activate coagulation time (ACT) over 480 seconds, the cannulas were installed and the CPB started with arterial flow around 60ml/kg/min, maintaining mean blood pressure (MBP) at 60mmHg and body temperature between 28ºC and 30ºC. After aortic clamping, it was performed an intermittent and hypothermic anterograde myocardial protection with induction and maintenance dosage. After completing CPB and removing the cannulas, it was administered protamine hydrochloride at dosage 1:1, in order to achieve ACT equal or lower than 120 seconds.
It was established as ARI criterion the increase of serum creatinine of 30% related to its basal value in the first 24 or 48 hours of surgical procedure, excluded of pre-renal causes. This criterion is used in our Service, for it increases the sensibility of the diagnostic, contributing for an early action of the nephrologist [3,10,11]. In order to determine the serum creatinine, blood samples were collected in 4 moments: M1, preoperative; M2, 24 hours of postoperative; M3, 48 hours of postoperative and M4, 7th
day of postoperative.
The inhibitor of the calcium conduit used was Nifedipine (Adalat Retard®, Bayer), in the dosage 10 to 20 mg, every 8 hours. The medication was interrupted in the preoperative period, one day prior surgery, and it was reintroduced in the immediate postoperative period.
This work was submitted to evaluation of the Ethics and Research Committee of the Hospital das Clínicas da Faculdade de Medicina de Botucatu - UNESP, and approved on 11/03/2003.
In the statistical analysis it was used a regression model for repeated measures (proc mixed of the SAS program), in which were calculated the values of serum creatinine; being the latter the only variable with normal distribution (calculated the mean). The gama distribution was adjusted (general linear model with error assuming gama distribution) for variables that did not present normal distribution. For CPB variables it was used a general linear model (proc genmod of the SAS program) with error gama distribution and connection function log. The Fisher's exact test was used for the calculation of the percentile of patients that presented an increase in serum creatinine higher than 30% (Δ>30%). With significance level of 5% (P value
There were followed up 94 patients described in Table 1, with ages ranging from 57 to 60 years in the groups, being 67(73.3%) male patients. For each group studied, it was observed the presence of comorbidities [high blood pressure (HBP), diabetes mellitus, dyslipidemia], calculus for median serum creatinine and calculus for 30% increase in the basal value of serum creatinine characterizing ARL.
There was no statistical difference among the groups studied related to the parameters of CPB (Table 2).
In Table 3, we can observe that there was no association among the variables: gender and groups with presence or absence of comorbidities (HBP, diabetes mellitus, dyslipidemia) and the statistical analysis showed that there was no significant difference among the data acquired.
ARL was diagnosed in 28(29.7%) patients, i.e., with serum creatinine higher than 30% of its basal value in the first and second postoperative, where G4>G1 for P
=0.05 and G4>G3 for P=0.001, observed in Figure 1.
Fig. 1 - Percentile of patients with serum creatinine higher than 30% of its basal value according to groups, where G4>G1 for P=0.05; G4>G3 P=0.001 and G1=G3 and G2=G4 P>0.05
In Figure 2, the mean of serum creatinine did not present statistical difference among the groups studied (G1,G2,G3,G4), although among the groups and moments (M1,M2,M3,M4) it was observed an increase in serum creatinine specifically in group G2 (postoperative medication) at the moment M1 (preoperative) for M2 (24 hours of postoperative). Compared to the remaining groups (G1,G3,G4), there was no statistical difference compared to the moments (M1,M2,M3,M4).
Fig. 2 - Means of the values of serum creatinine according to moments and groups, where M1 to M2 with P<0.05
The means of the delta percentiles of serum creatinine were calculated (%"), and it was observed an increase in serum creatinine in G4 at the moments of 24 hours (58%) and 48 hours (50%) of postoperative, and this value decreases in the 7th day (30%), being significant (P
<0.05) when compared to the other groups studied, and G1=G2=G3 (P
>0.05). It was observed higher renal compromise in G4 (Figure 3).
Fig. 3 - Means of the values of the delta percentiles (Ä%) of serum creatinine among the moments in the groups, where G4 < 0.05.
ARL may occur in the postoperative period of any surgery and it is referred as the acute reduction of the renal function in hours or days. Despite the technological advances in monitoring and assistance of patients, its prognostic remains serious, with the possibility of death.
The diagnostic of ARL in the present study was based on the increase of serum creatinine, defined as equal or higher than 30% of its basal value in the first 24 and 48 hours of postoperative. This criterion was described by Barretti & Soares  and Balbi et al.  in works performed in our Institution, which identified as the main cause of ARL intrinsic to ischemia, being responsible for approximately 50% of the cases.
In cardiovascular surgery, several studies have been indicating that ARL is a frequent complication, being associated to high rates of mortality and prolonged stay in ICU [12-14]. Machado et al.  refer mortalities within 30 days of patients with and without acute renal lesion of 12.6% and 1.4%, respectively. Thakar et al.  attribute to ARL high risk alone for mortality compared to other types of complications in the postoperative and developed an ARL prediction score in the postoperative of cardiac surgery, incorporating all major risk factors . For Kochi et al. , the detection of contributing factors for the development of ARL after cardiac surgery makes possible adopting early procedures in order to avoid renal dysfunction and decrease mortality.
There is vast evidence that the harmful effects of CPB on the kidneys are related to the duration of perfusion and other conditions of CPB [1,3,17-20]. Stallwood et al.  reported that CPB alone is associated to the significant increase in the risk of ARI in coronariopathic patients. The renal blood flow and the glomerular filtration rhythm during CPB are reduced in 75% with partial, but not complete, recovery after the first postoperative.
The analysis of conditions of CPB in our study showed that there was no statistical difference among the groups related to the perioperative parameters of CPB.
Epstein  showed that the inhibitors of calcium conduits produce beneficial effects over the renal function. In experimental studies in kidneys of rats, applying videoscopical techniques that allowed direct visualization of efferent arteriolae, it was observed that the inhibitors of calcium conduits antagonize the glomerular vasoconstriction . In addition to it, its natriuretic effect suggests that its use may prevent or reduce the occurrence of ARL.
Bertolissi et al.  evaluated the effects of the continuous administration of nifedipine over the renal function during the CPB procedure. They observed that the continuous infusion of nifedipine during the CPB reduced the occurrence of ARL and pointed out that this may consist in an extra tool for the protection of the renal function in patients submitted to cardiac surgery with CPB, decreasing the influx of calcium in the slow conduits and producing vasodilatation of the arteries.
Stafoord-Smith  refer that although not being a routine therapeutical procedure, the benefit of the inhibitors of calcium conduits may be used for the treatment of patients that present increase in serum creatinine, in average, 48 hours after cardiac surgery with CPB, with no need for dialysis.
Our results showed in group G4 (without nifedipine) increase in the basal value of serum creatinine of, respectively, 58% and 50% in moments 24 hours (M2) and 48 hours (M3) in the postoperative, and decreasing to 30% at the 7th
day of late postoperative (M4), elevated values compared to the rest of the groups (G1, G2, G3), showing higher risk of this group.
The patients that developed ARL in group G4 was 46.66%, compared to G1 of 12.5%, G2 of 37.93% and G3 of 23.53%, reinforcing the hypothesis that nifedipine may reduce the occurrence of ARL in the postoperative of patients submitted to cardiac surgery with CPB when compared to the work performed by Bertolissi et al. .
The higher incidence of ARL in group G4 (without nifedipine) than in groups G1 (preoperative nifedipine) and G3 (preoperative and postoperative nifedipine) may be related to the protective effect of nifedipine administered in the preoperative period, following the protocol of our study.
The group G2 (postoperative nifedipine) presented an increase in the mean values of serum creatinine in moment M1 (preoperative) to moment M2 (24 hours of postoperative), but did not show difference in the means of creatinine compared to the groups G1 (preoperative) and G3 (preoperative and postoperative). Perhaps this behavior may be due to fact of the patients in this group (G2) having received nifedipine only in the postoperative period and the administration of the drug being started very closely to the time of blood collection for the creatinine dosage of 24 hours, when its effect was still small or even inexistent.
Therefore, we believe that the references about the possible nephroprotective effect of nifedipine, its frequent use by patients holding coronary insufficiency, as described by Lopes et al. , and the importance of tools for preventing renal lesion in patients submitted to myocardial revascularization with CPB, justifies the performance of new studies in this area.
In the postoperative period, the mean of the percentile of the delta means of serum creatinine were higher in group G4 (without nifedipine) compared to the other groups. The percentile of patients with values of serum creatinine higher than 30% of its basal value in the 48 hours of postoperative was also higher in the group G4 (without nifedipine) compared to the patients in groups G1 (preoperative nifedipine) and G3 (preoperative and postoperative nifedipine). The behavior of serum creatinine and the incidence of ARL in the postoperative period in different groups enforce the hypothesis of the nephroprotecting effect of nifedipine in the patients submitted to myocardial revascularization with CPB.
1. Souza MAL, Elias DO. Fundamentos da circulação extracorpórea. Rio de Janeiro:Centro Editorial Alfa Rio;1995. v.1. p.441.
2. Moura HV, Pomerantzeff PMA, Gomes WJ. Síndrome da resposta inflamatória na circulação extracorpórea: papel das interleucinas. Rev Bras Cir Cardiovasc. 2001;16(4):376-87.
3. Kochi AC, Martins AS, Balbi AL, Moraes e Silva MA, Lima MCP, Martins LC, et al. Fatores de risco pré-operatórios para o desenvolvimento de insuficiência renal aguda em cirurgia cardíaca. Rev Bras Cir Cardiovasc. 2007;22(1):33-40. [MedLine] View article
4. Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med. 1998;104(4):343-8. [MedLine]
5. Carvalho da Costa M, Burdmann EA, Yu L. Insuficiência renal aguda isquêmica. In: Homsi E, editor. Insuficiência renal aguda em UTI. São Paulo:Atheneu;1998. p.69-82.
6. Lopes NH, da Silva Paulitsch F, Pereira A, Garzillo CL, Ferreira JF, Stolf N, et al. Mild chronic kidney dysfunction and treatment strategies for stable coronary artery disease. J Thorac Cardiovasc Surg. 2008;137(6):1443-9.
7. Santos BFC, Anção MS, Korn D, Santos OFP. Insuficiência renal aguda. In: Knobel E, editor. Condutas no paciente grave. São Paulo:Atheneu;1997. p.386-98.
8. Epstein M. Calcium antagonists and renal protection. Current status and future perspectives. Arch Intern Med. 1992;152(8):1573-84. [MedLine]
9. Epstein M. Calcium antagonists and the kidney: future therapeutic perspectives. Am J Kidney Dis. 1993;21(6 Suppl 3):16-25. [MedLine]
10. Barretti P, Soares VA. Insuficiência renal aguda. J Bras Nefrol. 1997;173(4):101-6.
11. Balbi AL, Barsnate RC, Silva VS, Martin LC, Camaroni JT. Insuficiência aguda em um hospital universitário: o que mudou em 10 anos? J Bras Nefrol. 2002;24(suppl 2):159.
12. Machado MN, Miranda RC, Takakura IT, Palmegiani E, Santos CA, Oliveira MA, et al. Lesão renal aguda após revascularização do miocárdio. Arq Bras Cardiol. 2009,93(3):247-52. [MedLine]
13. Santos FO, Silveira MA, Maia RB, Monteiro MDC, Martinelli R. Insuficiência renal aguda após cirurgia de revascularização do miocárdio com circulação extracorpórea: incidência, fatores de risco e mortalidade. Arq Bras Cardiol. 2004;83:145-8.
14. Novis BK, Roizen MF, Aronson S, Thisted RA. Association of preoperative risk factors with postoperative acute renal failure. Anesth Analg. 1994;78(1):143-9. [MedLine]
15. Thakar CV, Liangos O, Yared JP, Nelson D, Piedmonte MR, Hariachar S, et al. ARF after open-heart surgery: influence of gender and race. Am J Kidney Dis. 2003;41(4):742-51. [MedLine]
16. Thakar CV, Arrigain S, Worley S, Yared JP, Paganini EP. A clinical score to predict acute renal failure after cardiac surgery. J Am Soc Nephrol. 2005;16(1):162-8. [MedLine]
17. Teixeira Filho GF. Temas atuais de circulação extracorpórea. Porto Alegre:SBCEC;1997. p.301.
18. Abu-Omar Y, Ratnatunga C. Cardiopulmonary bypass and renal injury. Perfusion. 2006;21(4):209-13. [MedLine]
19. Raja SG, Dreyfus GD. Impact of off-pump coronary artery bypass surgery on postoperative renal dysfunction: current best available evidence. Nephrology (Carlton). 2006;11(4):269-73.
20. Stallwood MI, Grayson AD, Mills K, Scawn ND. Acute renal failure in coronary artery bypass surgery: independent effect of cardiopulmorary bypass. Ann Thorac Surg. 2004;77(3):968-72. [MedLine]
21. Bertolissi M, Antonucci F, De Monte A, Padovani R, Giordano F. Effects on renal function of a continuous infusion of nifedipine during cardiopulmonary bypass. J Cardiothorac Vasc Anesth. 1996;10(2):238-42. [MedLine]
22. Stafoord-Smith M. Perioperative renal dysfunction: Implications and stratigies for protection. In: Newman MF, editor. Perioperative organ protection. Baltimore:Society of Cardiovascular Anesthesiologists;2003. p.89-124.
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