Effect of nicardipine on renal function following robot-assisted laparoscopic radical prostatectomy in patients with pre-existing renal insufficiency

Abstract

Objective

To investigate the renoprotective effect of nicardipine in patients with pre-existing renal insufficiency undergoing robot-assisted laparoscopic radical prostatectomy (RALRP).

Methods

Men with preoperative renal insufficiency (estimated glomerular filtration rate [eGFR] <60 ml/min per 1.73 m²) were enrolled and randomized to receive either 0.5 µg/kg per min nicardipine continuous infusion (nicardipine group) or normal saline (control group) during RALRP. Renal function was determined by eGFR and serum creatinine concentration.

Results

Serum creatinine levels on postoperative days (POD) 1 and 3 were significantly lower than baseline values in the nicardipine group (n = 50). In the control group (n = 50), eGFR was significantly higher on POD 3 than baseline, and was significantly higher than baseline on POD 1 and 3 in the nicardipine group. The change in eGFR from baseline to POD 1 was significantly higher in the nicardipine group than the control group.

Conclusion

Continuous infusion of nicardipine during RALRP improved postoperative renal function on POD 1 in patients with pre-existing renal insufficiency.

Keywords

Nicardipine renal insufficiency robot-assisted surgery

Introduction

The minimally invasive nature of robot-assisted laparoscopic radical prostatectomy (RALRP) limits blood loss, reduces fluid shift, decreases cardiac workload, lowers the frequency of complications, and shortens hospital stay compared with conventional open surgical methods.¹ These features make RALRP an ideal treatment option with low risks of morbidity and mortality in patients with comorbid diseases, including renal insufficiency.²

Pneumoperitoneum (essential for visualization during RALRP) has several side effects, including reductions in urine output, creatinine clearance, glomerular filtration rate (GFR) and renal blood flow, leading to the aggravation of renal dysfunction during or immediately after laparoscopic surgery.^3,4 Rats with impaired kidney function have been shown to exhibit increased sensitivity to the deleterious renal effects of pneumoperitoneum compared with normal animals.⁵ The 30° head-down tilt required for adequate visualization also results in a pronounced increase in central venous pressure and may further compromise renal perfusion and renal function.⁶ The calcium channel blocker nicardipine preferentially dilates renal arterioles and increases GFR,^7,8 and we have shown that continuous infusion of low dose nicardipine during RALRP attenuates the development of renal insufficiency in the immediate postoperative period.⁹ Patients with preoperative renal insufficiency were excluded from that study, however.

The aim of this prospective, randomized, controlled study was to use estimated GFR (eGFR) to investigate the renoprotective effect of nicardipine in patients with renal insufficiency undergoing RALRP.

Patients and methods

Study population

The study enrolled male patients with preoperative renal insufficiency (eGFR <60 ml/min per 1.73 m²) who were scheduled to undergo RALRP between June 2011 and January 2012 at Yonsei University Severance Hospital, Seoul, Republic of Korea. Patients with eGFR ≥60 ml/min per 1.73 m² were excluded from the study. The institutional review board of Yonsei University Medical Center approved the study and all subjects provided written informed consent prior to enrolment.

Study design

Patients were randomly allocated to either the control or nicardipine groups using a computer generated randomization method. According to the double-blind methodology, the patients, anaesthesia provider and the anaesthetist collecting the data were blinded to the composition of the study groups. An independent researcher prepared the syringes containing the study drug.

Anaesthesia and surgery

On the patient’s arrival at the operating theatre, standard monitoring devices were applied and a 20 G catheter was inserted into the radial artery under local anaesthesia to enable arterial pressure monitoring and blood sampling. Anaesthesia was induced using 2 mg/kg propofol i.v. and tracheal intubation was facilitated using 0.6 mg/kg rocuronium i.v. The patient’s lungs were mechanically ventilated with 50% oxygen in air at a tidal volume of 8–10 ml/kg and a respiratory rate of 8–12 breaths/min to maintain an end-tidal carbon dioxide of 30–37 mmHg throughout surgery.

After induction of anaesthesia, patients in the nicardipine group received 0.5 µg/kg per min nicardipine continuous intravenous infusion, and those in the control group received the same volume of normal saline throughout the duration of surgery (until anaesthesia was reversed). Infusions were carried out using an Orchestra® infusion device (Fresenius Kabi, Bad Homburg, Germany). Anaesthesia was maintained with 0.1–0.2 mg/kg per min remifentanil continuous intravenous infusion and 1–3% sevoflurane. Ringer’s lactate solution and normal saline were infused at a rate of 10 ml/kg per h throughout surgery.

Pneumoperitoneum was induced by carbon dioxide insufflation (12–15 mmHg) and patients were positioned in a 30° head-down tilt. The robotic system (da Vinci® Surgical System, Intuitive Surgical Inc., Mountain View, CA, USA) was controlled via telemanipulation by a surgeon at the master console. Pneumoperitoneum was released after the removal of the prostate.

Data collection

Intra-abdominal pressure and the duration of pneumoperitoneum and anaesthesia were recorded. Mean arterial pressure, heart rate and central venous pressure were recorded and arterial blood gas analyses were performed at three time points: prepneumoperitoneum (10 min after intubation, before surgical incision and with the patient in the neutral position); pneumoperitoneum (1 h after the induction of pneumoperitoneum, with the patient in the 30° head-down tilt position); and postpneumoperitoneum (20 min after the release of pneumoperitoneum).

Serum creatinine and haemoglobin were quantified every day at 06:00 hours, and the corresponding eGFRs were calculated 1 day before surgery (baseline) and on postoperative days (POD) 1 and 3. The highest serum creatinine concentration during the postoperative hospital stay was recorded. Postoperative urine output was recorded for 3 days. Ringer’s lactate solution was infused at 1–2 ml/kg per h during the postoperative period. Postoperative data were analysed by an investigator (H.H.) who was blinded to the composition of the study groups.

Statistical analyses

Data were expressed as mean ± SD or n. Sample size was calculated based on eGFR SDs from an earlier study.¹⁰ It was determined that 49 patients were required in each group to give a power of 80% to detect an eGFR of 10 ml/min per 1.73 m² and an α-level of 0.05, using the independent t-test. Between-group comparisons were made using χ² test, Fisher’s exact test, Student’s t-test, or Mann–Whitney U test, as appropriate. Within-group changes in serum creatinine concentration and eGFR were made using Student’s t-test and Bonferroni correction. Statistical analyses were performed with SPSS® version 16.0 (SPSS Inc, Chicago, IL, USA) for Windows®. P-values <0.05 were considered statistically significant.

Results

The study enrolled 100 male patients (mean age 69 ± 6 years; age range 49–81 years) who were randomly allocated between the control and nicardipine groups (n = 50 per group). Demographic and preoperative clinical data are shown in Table 1 and intra-operative data are shown in Table 2. There were no statistically significant between-group differences in demographic, or pre- and intra-operative data.

Table 1.

Demographic and clinical data of patients with renal insufficiency undergoing robot-assisted laparascopic radical prostatectomy included in a study to investigate the renoprotective effect of nicocardipine during pneuomoperitoneum.

Characteristic	Control group n = 50	Nicardipine group n = 50
Age, years	68 ± 6	68 ± 6
Body weight, kg	70 ± 9	69 ± 7
Height, cm	169 ± 5	168 ± 5
Baseline haemoglobin, g/dl	13.9 ± 1.7	14.0 ± 1.7
Underlying disease
Diabetes	5	11
Hypertension	29	37
Ischaemic heart disease	6	3
Preoperative medication
Calcium antagonists	15	17
ACEI	3	5
AIIRB	11	10
Diuretics	9	2
β-Blockers	7	6

Data are mean ± SD or n.

No statistically significant between-group differences (P ≥ 0.05; Student’s t-test or χ² test).

ACEI, angiotensin-converting enzyme inhibitor; AIIRB, angiotensin II receptor blocker.

Table 2.

Intra-operative data of patients with renal insufficiency undergoing robot-assisted laparascopic radical prostatectomy, with or without 0.5 µg/kg per min nicardipine continuous intravenous infusion.

Parameter	Control group n = 50	Nicardipine group n = 50
Duration of pneumoperitoneum, min	133 ± 29	134 ± 38
Duration of anaesthesia, min	236 ± 31	222 ± 42
Intra-abdominal pressure, mmHg	13 ± 2	13 ± 2
Intravenous fluids, ml	2255 ± 604	2063 ± 601
Mean arterial pressure, mmHg
Prepneumoperitoneum	96 ± 12	96 ± 8
Pneumoperitoneum	78 ± 3	76 ± 7
Postpneumoperitoneum	93 ± 17	88 ± 9
Heart rate, beats/min
Prepneumoperitoneum	67 ± 12	70 ± 11
Pneumoperitoneum	65 ± 11	68 ± 11
Postpneumoperitoneum	71 ± 11	74 ± 11
Central venous pressure, mmHg
Prepneumoperitoneum	9 ± 3	9 ± 2
Pneumoperitoneum	22 ± 5	18 ± 5
Postpneumoperitoneum	9 ± 4	8 ± 2
Arterial PaCO₂, mmHg
Prepneumoperitoneum	32.7 ± 7.9	35.6 ± 6.7
Pneumoperitoneum	39.6 ± 10.1	40.6 ± 8.6
Postpneumoperitoneum	39.7 ± 7.2	39.7 ± 7.0
Arterial pH
Prepneumoperitoneum	7.42 ± 0.004	7.41 ± 0.05
Pneumoperitoneum	7.35 ± 0.06	7.34 ± 0.06
Postpneumoperitoneum	7.34 ± 0.05	7.04 ± 0.06

Data are mean ± SD.

No statistically significant between-group differences (P ≥ 0.05; Student’s t-test).

Postoperative data are shown in Table 3. In the nicardipine group, serum creatinine concentrations were significantly lower than baseline at POD 1 and POD 3 (P < 0.05 for both comparisons), but there were no significant postoperative changes in the control group. There were no significant between-group differences in serum creatinine concentrations at any timepoint, highest serum creatinine concentration, or the number of patients with postoperative serum creatinine >1.4 mg/ml (Table 3).

Table 3.

Baseline (1 day preoperative) and postoperative data of patients with renal insufficiency undergoing robot-assisted laparascopic radical prostatectomy, with or without 0.5 µg/kg per min nicardipine continuous intravenous infusion.

Parameter	Control group n = 50	Nicardipine group n = 50
Serum creatinine, mg/dl
Baseline	1.35 ± 0.18	1.40 ± 0.26
POD 1	1.35 ± 0.32	1.27 ± 0.29^a
POD 3	1.33 ± 0.35	1.31 ± 0.29^a
Highest serum creatinine, mg/dl	1.41 ± 0.34	1.37 ± 0.30
Serum creatinine >1.4 mg/dl
POD 1	20 (40.0)	16 (32.0)
POD 3	16 (32.0)	15 (30.0)
eGFR, ml/min per 1.73 m²
Baseline	56.9 ± 6.7	54.9 ± 8.1
POD 1	59.1 ± 12.3	62.9 ± 13.8^a
POD 3	60.2 ± 12.7^a	61.0 ± 13.7^a
Change in eGFR, ml/min per 1.73 m²
POD 1 – Baseline	2.3 ± 10.4	8.0 ± 9.8^b
POD 3 – Baseline	3.9 ± 9.7	5.3 ± 11.3
Urine output, ml
POD 1	2587 ± 996	2498 ± 1133
POD 3	2629 ± 1092	2403 ± 902
Haemoglobin, g/dl
Baseline	13.9 ± 1.7	14.0 ± 1.7
Change in haemoglobin, g/dl
POD 1 – Baseline	−2.1 ± 1.1	−2.6 ± 2.4
POD 3 – Baseline	−3.6 ± 3.5	−3.7 ± 3.6
Length of hospital stay, days	7 ± 2	8 ± 2

Data are mean ± SD or n (%).

P < 0.05 versus baseline; ^bP < 0.05 versus control group at same time point (Student’s t-test).

POD, postoperative day; eGFR, estimated glomerular filtration rate.

At POD 1 and POD 3, eGFR was significantly higher than baseline in the nicardipine group (P < 0.05 for both comparisons; Table 3). In addition, eGFR was significantly higher on POD 3 compared with baseline in the control group (P < 0.05; Table 3). There were no significant between-group differences in eGFR at any timepoint, however. The change in eGFR from baseline to POD 1 was significantly higher in the nicardipine group than the control group (P < 0.05).

There were no significant between-group differences in urine output or change in haemoglobin concentration (Table 3).

No major postoperative complications requiring repeat surgery or postoperative intensive care occurred in either group.

Discussion

Continuous infusion of nicardipine during RALRP increased postoperative eGFR in the present study of patients with renal insufficiency. This increase in eGFR was significantly different from the control group at postoperative day 1. Low-dose nicardipine (0.5 µg/kg per min) appears to attenuate the deleterious effects of pneumoperitoneum and the marked head-down tilt in the immediate postoperative period after RALRP.

There is a strong correlation between eGFR <60 ml/min per 1.73 m² and postoperative morbidity and mortality.¹¹ Following open surgical procedures, the morbidity and mortality of patients with renal failure reach almost 50% and 4%, respectively.¹² In addition, the immunocompromised status of patients with renal failure increases their risk of wound infections.¹³ Minimally invasive surgery is rapidly replacing open procedures in many areas of surgery owing to the advantages it offers (reduced blood loss, lower incidence of complications, and shorter hospital stay¹), and the risks of morbidity, mortality and wound complications decrease significantly in patients with renal failure who are treated with RALRP rather than open surgery.¹³

In spite of the advantages of RALRP, deleterious effects are associated with the increase in abdominal pressure that is secondary to pneumoperitoneum. Pneumoperitoneum and the marked head-down tilt are essential for greater surgical visualization in RALRP,^6,14 but pneumoperitoneum induces renovascular, caval and renal parenchymal compression,^15–18 and reduces renal blood flow and urine output in animal models.^15,16,19 A worsening of renal function in association with pneumoperitoneum has also been reported in humans following laparoscopic procedures.^3,4,20,21 Extreme head-down tilting markedly increases central venous pressure and compromises renal perfusion during laparoscopic procedures.^22,23

There is a lack of consensus regarding the renoprotective effects of drugs. Low-dose dopamine has been shown to have a renoprotective effect during laparoscopic surgery,⁴ but others report that dopamine and mannitol do not prevent renal dysfunction during laparoscopic surgery.^24,25 Nicardipine has been shown to act predominantly on the renal afferent arterioles, decreasing total renal vascular resistance and increasing renal blood flow and GFR.²⁶ During pneumoperitoneum, renal vasoconstriction increases afferent and efferent arteriolar resistance, thereby decreasing renal blood flow.²⁷ In patients without renal insufficiency, continuous infusion of nicardipine (0.5 µg/kg per min) during RALRP was found to preserve eGFR and attenuate the development of renal insufficiency in the immediate postoperative period.⁹

Diminished renal blood flow during pneumoperitoneum and its return to normal flow after deflation have been shown to lead to ischaemia–reperfusion injury.^28–30 Such ischaemia–reperfusion injury has been associated with increased levels of reactive oxygen species in the kidney,³¹ where glomeruli are considerably more sensitive to oxidative injuries than any other segments of the nephron.³² Elevated calcium ion levels are a key factor in apoptosis and necrosis.³³ L-type calcium channel blockers have been shown to inhibit the calcium ion influx induced by anoxia, resulting in the inhibition of ischemia–reperfusion-induced apoptosis.³⁴ Clinically, L-type calcium channel blockers prevent acute tubular necrosis and delay the onset of renal failure.³⁵ Nicardipine, an L-type calcium channel blocker, reduces calcium ion levels and protects tubular cells from apoptosis and necrosis.^34,36,37

In the present study, we used the lowest possible dose of nicardipine (0.5 µg/kg per min³⁸) in order to avoid possible hypotension and subsequent renal hypoperfusion. Although this dose of nicardipine was found to have beneficial effects in this and our previous study,⁹ further investigation of the optimal nicardipine dosage that maximizes renoprotection while retaining stable haemodynamics is required. In addition, the cryoprotective mechanism of nicardipine remains to be elucidated.

In conclusion, we found that a continuous infusion of nicardipine at a dose of 0.5 µg/kg per min led to significantly better postoperative renal function on postoperative day 1 than control in patients with pre-existing renal insufficiency. Nicardipine may prevent the aggravation of renal dysfunction immediately after RALRP.

Footnotes

Declaration of conflicting interest

The authors declare that there are no conflict of interests.

Funding

This research was supported by the Industrial Strategic Technology Program of the Ministry of Knowledge Economy (10041120).

References

Ficarra

. Open radical nephrectomy versus open partial nephrectomy: is it still an issue? Eur Urol 2007; 51: 593–595.

Heldt

Jellison

Yuen

. Patients with end-stage renal disease are candidates for robot-assisted laparoscopic radical prostatectomy. J Endourol 2011; 25: 1175–1180.

Miki

Iwase

Kamiike

. Laparoscopic cholecystectomy and time-course changes in renal function. The effect of the retraction method on renal function. Surg Endosc 1997; 11: 838–841.

Pérez

Taurá

Rueda

. Role of dopamine in renal dysfunction during laparoscopic surgery. Surg Endosc 2002; 16: 1297–1301.

Bishara

Abu-Saleh

Awad

. Pneumoperitoneum aggravates renal function in cases of decompensated but not compensated experimental congestive heart failure: role of nitric oxide. J Urol 2011; 186: 310–317.

Parikh

Shah

Modi

. Anaesthesia for laparoscopic kidney transplantation: influence of Trendelenburg position and CO₂ pneumoperitoneum on cardiovascular, respiratory and renal function. Indian J Anaesth 2013; 57: 253–258.

Abe

Komori

Miura

. Effects of the calcium antagonist nicardipine on renal function and renin release in dogs. J Cardiovasc Pharmacol 1983; 5: 254–259.

Hashimoto

Nomura

Nakano

. Pharmacological intervention for renal protection during cardiopulmonary bypass. Heart Vessels 1993; 8: 203–210.

Cho

Shim

Chang

. Effect of nicardipine on renal function after robot-assisted laparoscopic radical prostatectomy. Urology 2009; 73: 1056–1060.

10.

Curtis

Jou

Ali

. A randomized controlled trial of sucrose and/or pacifier as analgesia for infants receiving venipuncture in a pediatric emergency department. BMC Pediatr 2007; 7: 27–27.

11.

Mooney

Ranasinghe

Chow

. Preoperative estimates of glomerular filtration rate as predictors of outcome after surgery: a systematic review and meta-analysis. Anesthesiology 2013; 118: 809–824.

12.

Kellerman

. Perioperative care of the renal patient. Arch Intern Med 1994; 154: 1674–1688.

13.

Heldt

Jellison

Yuen

. Patients with end-stage renal disease are candidates for robot-assisted laparoscopic radical prostatectomy. J Endourol 2011; 25: 1175–1180.

14.

Kalmar

Foubert

Hendrickx

. Influence of steep Trendelenburg position and CO₂ pneumoperitoneum on cardiovascular, cerebrovascular, and respiratory homeostasis during robotic prostatectomy. Br J Anaesth 2010; 104: 433–439.

15.

McDougall

Monk

Wolf

JS Jr

. The effect of prolonged pneumoperitoneum on renal function in an animal model. J Am Coll Surg 1996; 182: 317–328.

16.

Richards

Scovill

Shin

. Acute renal failure associated with increased intra-abdominal pressure. Ann Surg 1983; 197: 183–187.

17.

Joris

Noirot

Legrand

. Hemodynamic changes during laparoscopic cholecystectomy. Anesth Analg 1993; 76: 1067–1071.

18.

O’Leary

Hubbard

Tormey

. Laparoscopic cholecystectomy: haemodynamic and neuroendocrine responses after pneumoperitoneum and changes in position. Br J Anaesth 1996; 76: 640–644.

19.

Horvath

Whelan

Lier

. The effects of elevated intraabdominal pressure, hypercarbia, and positioning on the hemodynamic responses to laparoscopic colectomy in pigs. Surg Endosc 1998; 12: 107–114.

20.

Koivusalo

Kellokumpu

Ristkari

. Splanchnic and renal deterioration during and after laparoscopic cholecystectomy: a comparison of the carbon dioxide pneumoperitoneum and the abdominal wall lift method. Anesth Analg 1997; 85: 886–891.

21.

Nishio

Takeda

Yokoyama

. Changes in urinary output during laparoscopic adrenalectomy. BJU Int 1999; 83: 944–947.

22.

Hirvonen

Nuutinen

Kauko

. Hemodynamic changes due to Trendelenburg positioning and pneumoperitoneum during laparoscopic hysterectomy. Acta Anaesthesiol Scand 1995; 39: 949–955.

23.

Koivusalo

Pere

Valjus

. Laparoscopic cholecystectomy with carbon dioxide pneumoperitoneum is safe even for high-risk patients. Surg Endosc 2008; 22: 61–67.

24.

Bolte

Chin

Moon

. Maintaining urine production and early allograft function during laparoscopic donor nephrectomy. Urology 2006; 68: 747–750.

25.

O’Dair

Evans

Rigg

. Routine use of renal-dose dopamine during living donor nephrectomy has no beneficial effect to either donor or recipient. Transplant Proc 2005; 37: 637–639.

26.

Baba

Ishizaki

Ido

. Renal effects of nicardipine, a calcium entry blocker, in hypertensive type II diabetic patients with nephropathy. Diabetes 1986; 35: 1206–1214.

27.

Mikami

Kawakita

Fujise

. Catecholamine release caused by carbon dioxide insufflation during laparoscopic surgery. J Urol 1996; 155: 1368–1371.

28.

Glantzounis

Tselepis

Tambaki

. Laparoscopic surgery-induced changes in oxidative stress markers in human plasma. Surg Endosc 2001; 15: 1315–1319.

29.

Bickel

Drobot

Aviram

. Validation and reduction of the oxidative stress following laparoscopic operations: a prospective randomized controlled study. Ann Surg 2007; 246: 31–35.

30.

Arioz

Polat

Tokyol

. What should be the ideal time for ischemic preconditioning in a laparoscopic rat model? J Laparoendosc Adv Surg Tech A 2009; 19: 141–147.

31.

Akbulut

Polat

Aktepe

. The oxidative effect of prolonged CO₂ pneumoperitoneum on renal tissue of rats. Surg Endosc 2004; 18: 1384–1388.

32.

Klahr

. Oxygen radicals and renal diseases. Miner Electrolyte Metab 1997; 23: 140–143.

33.

Rizzuto

Pinton

Ferrari

. Calcium and apoptosis: facts and hypotheses. Oncogene 2003; 22: 8619–8627.

34.

Tanaka

Nangaku

Miyata

. Blockade of calcium influx through L-type calcium channels attenuates mitochondrial injury and apoptosis in hypoxic renal tubular cells. J Am Soc Nephrol 2004; 15: 2320–2333.

35.

van Riemsdijk

Mulder

de Fijter

. Addition of isradipine (Lomir) results in a better renal function after kidney transplantation: a double-blind, randomized, placebo-controlled, multi-center study. Transplantation 2000; 70: 122–126.

36.

Chen

Ding

. Ischemia/reperfusion induce renal tubule apoptosis by inositol 1,4,5-trisphosphate receptor and L-type Ca₂ + channel opening. Am J Nephrol 2008; 28: 487–499.

37.

Yao

Sato

Ina

. Benidipine inhibits apoptosis during ischaemic acute renal failure in rats. J Pharm Pharmacol 2000; 52: 561–568.

38.

Qureshi

Harris-Lane

Kirmani

. Treatment of acute hypertension in patients with intracerebral hemorrhage using American Heart Association guidelines. Crit Care Med 2006; 34: 1975–1980.