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ORIGINAL ARTICLE |
Department of Cardiovascular and Thoracic Surgery, Showa University Tokyo, Japan
Masahiro Ohno, MD, Tel: +81 3 3784 8588, Fax: +81 3 3784 8307, Email: m.ohno21{at}med.showa-u.ac.jp, Department of Cardiovascular and Thoracic Surgery, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
ABSTRACT
Moderate hypothermic circulatory arrest with selective cerebral perfusion has been developed for cerebral protection during thoracic aortic surgery. However, visceral organs, particularly the kidneys, suffer greater tissue damage under moderate hypothermic circulatory arrest, and acute renal failure after hypothermic circulatory arrest is an independent risk factor for early and late mortality. This study investigated whether atrial natriuretic peptide could prevent the reduction in renal perfusion and protect renal function after moderate hypothermic circulatory arrest. Twelve pigs cooled to 30°C during cardiopulmonary bypass were randomly assigned to a peptide-treated group of 6 and a control group of 6. Moderate hypothermic circulatory arrest was induced for 60 min. Systemic arterial mean pressure and renal artery flow did not differ between groups during the study. However, renal medullary blood flow increased significantly in the peptide-treated group after hypothermic circulatory arrest. Myeloperoxidase activity was significantly reduced in the medulla of the peptide-treated group. Renal medullary ischemia after hypothermic circulatory arrest was ameliorated by atrial natriuretic peptide which increased medullary blood flow and reduced sodium reabsorption in the medulla. Atrial natriuretic peptide also reduced the release of an inflammatory marker after ischemia in renal tissue.
Key Words: Atrial Natriuretic Factor • Heart Arrest • Induced • Hypothermia • Induced • Renal Circulation
INTRODUCTION
Hypothermic circulatory arrest (HCA) has been developed to avoid cerebral injury during thoracic aortic surgery, and cerebral perfusion during HCA has been maintained by antegrade selective or retrograde cerebral perfusion (RCP). Body temperature during HCA using RCP has been cooled to approximately 20°C (deep HCA). In contrast, selective cerebral perfusion can maintain adequate cerebral flow, allowing maintenance of a higher body temperature (moderate HCA) than deep HCA.1–3 Moderate HCA is associated with shorter cardiopulmonary bypass (CPB) times, reduced incidence of coagulation disorders, and inhibition of inflammatory parameters. Moderate HCA using selective cerebral perfusion decreases the rates of both transient and permanent neurological complications (5.1%–12.6% and 1%–5.1%, respectively) and operative mortality (7.9%–12.7%).1–3 However, visceral organs, especially the kidneys, can be more severely damaged by moderate than deep HCA. Postoperative renal failure remains a serious complication and an independent risk factor for early and late mortality after cardiac surgery, including thoracic aortic surgery.2,4 Renal insufficiency associated with HCA is caused by reduced renal blood flow, loss of pulsatile flow, atheroembolisms, and inflammatory responses induced by ischemia-reperfusion (I/R) injury. Recent studies have indicated that abnormal regional renal circulation, particularly in the medulla, is an important factor in acute renal dysfunction.5–7
Atrial natriuretic peptide (ANP) is a circulating hormone of cardiac origin with diuretic activity and vasodilatory effects elicited by increasing intracellular cyclic guano-sine monophosphate (cGMP). Recombinant ANP is frequently administered to patients with congestive heart failure. Furthermore, a clinical study has shown that ANP helps to prevent renal dysfunction after CPB by inhibiting the renin-angiotensin-aldosterone system and improving renal perfusion.8 However, the effects of ANP during and after HCA remain unknown. We postulated that ANP helps to increase renal perfusion and inhibit renal tissue damage caused by I/R injury following HCA. The effects of ANP on renal function during and after moderate HCA were studied in a porcine model. Regional renal flow was measured using laser-Doppler flowmetry, and myeloperoxidase (MPO) activity in renal tissue was examined as an indicator of I/R injury.
MATERIALS AND METHODS
Twelve female pigs weighing 33.8–40.2 kg (mean, 36.7 ± 1.7 kg) were randomly divided into control (n =6) and ANP (n =6) groups. Mean body weight did not differ significantly between the 2 groups. All animals received humane care in compliance with the "Guide for the Care and Use of Laboratory Animals" published by the National Institute of Health (NIH publication 85-23, revised 1985).
The pigs were anesthetized with sodium pentobarbital 20 mg kg–1 and ketamine hydrochloride 10 mg kg–1 by intramuscular administration, and maintained with a continuous infusion of ketamine hydrochloride 1 mg kg–1 h–1. They were intubated and ventilated using a respirator (ACE-3000, Acoma Co., Tokyo, Japan), with percutaneous oxygen saturation maintained at 95%–100%. An arterial line was inserted into the right femoral artery, and a central venous line was placed in the right external jugular vein for infusion and to monitor central venous pressure. Limb lead electrocardiograms were also monitored. All animals underwent a laparotomy, and the left kidney was prepared for measurement of renal blood flow. Left renal artery flow was continuously monitored using an ultrasonic blood probe (T101, Transonic Systems, Inc., NY, USA). Regional microcirculatory changes in the kidneys were measured using 2 needle-type laser-Doppler flowmetry leads (ALF21R, Advance, Inc., Tokyo, Japan) inserted into the cortex and medulla to respective depths of 5 and 10 mm from the kidney surface, in a manner similar to that described by Stern and colleagues.9 After a median sternotomy, the pericardium was opened. A perfusion cannula (D II FEM II 018A, Edwards Life Science Co., Tokyo, Japan) was inserted into the ascending aorta, and a drainage cannula (CV-4881, Terumo Co., Tokyo, Japan) was inserted into the right atrium after heparinization (300 IU kg–1). Another cannula (CV-164665; Terumo Co.) was inserted into the aortic root for venting and perfusion with cardioplegic solution. CPB was instituted using a pump (CX-SP45, Terumo Co.) and an oxygenator (CX-RX15RE, Terumo Co.). Nonpulsatile CPB was initiated at a flow rate adjusted to maintain a mean arterial pressure of 50–70 mm Hg. A heat exchanger (DCH, Terumo Co.; HHC-51, Mera Co., Tokyo, Japan) provided core cooling, and the surface was cooled with a cooling blanket. The CPB circuit was primed with 1,000 mL of Ringer’s acetate solution. The pH was maintained at 7.40 using the alpha-stat principle with an arterial PCO2 of 35 to 40 mm Hg (uncorrected for temperature). The hematocrit was maintained between 23% and 28% using pooled whole blood. At a rectal temperature of 30°C, the CPB pump was turned off and cold St. Thomas’ Hospital crystalloid cardioplegic solution was infused (15–20 mL kg–1) via the cannula inserted into the aortic root, to achieve cardioplegic arrest. Circulatory arrest was maintained for 60 min, after which the pump was restarted, and reperfusion and rewarming commenced. The core and surface were rewarmed until the rectal temperature reached 36°C. A difference >10°C between the perfusate and the core temperature was scrupulously avoided. The 6 pigs in the ANP group were continuously infused with recombinant ANP 0.05 µg kg–1 min–1 from the start of CPB. Femoral arterial pressure, regional renal blood flow in the cortex and medulla, and renal arterial blood flow were continuously monitored in all animals, and measurements of creatinine and sodium were taken at various time points, as shown in Figure 1
. After a physiological examination, the right kidney was removed for histopathology and measurements of myeloperoxidase (MPO) activity.
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All values are expressed as mean ± standard deviation. The 2 groups were compared using the Mann-Whitney test, with p < 0.05 being considered statistically significant.
RESULTS
Table 1 shows the results of systemic and renal hemodynamic parameters. Femoral arterial pressure did not differ significantly between the control and ANP groups during CPB. After CPB, femoral arterial pressure was similar in both groups. Renal arterial flow in both groups was significantly and similarly decreased by HCA in both groups. After HCA, renal arterial flow gradually and similarly increased in both groups, with no significant difference. Cortical and medullary blood flow decreased in both groups during HCA. After rewarming, both cortical and medullary blood flow rates gradually increased. Cortical flow did not significantly differ between the 2 groups. However, medullary flow increased significantly in the ANP group after HCA. After starting CPB, urinary flow rates increased in both groups to the same extent (Table 1). Urine flow decreased in both groups immediately after HCA, and gradually increased thereafter. After CPB, urine flow was significantly increased in the ANP group (1.6 ± 1.4 vs. 3.4 ± 1.1 mL min–1; p =0.03). Creatinine clearance (CCr) increased after starting CPB, and HCA caused CCr to decrease in both groups, with no significant difference between groups (Figure 2). However, the recovery rate of CCr after CPB was faster in the ANP group than the control group, but the difference did not reach significance (33.3% ± 35.7% vs. 69.2% ± 33.3%, p>0.05). Sodium clearance was calculated from plasma and urinary sodium concentrations, as well from as urine flow. Fractional excretion of sodium (FENa) was calculated using sodium clearance and CCr. Sodium clearance was obviously decreased by HCA in both groups, but not significantly different between groups; however, it gradually and significantly increased in the ANP group compared with the control group after HCA (0.4 ± 0.4 vs. 2.2 ± 1.3; p =0.02). The FENa value was markedly increased by HCA in both groups, with no significant differences between them. The FENa gradually decreased in the control group after HCA. However, FENa did not decrease in the ANP group after HCA, with a significant difference between the 2 groups (1.7 ± 1.5 vs. 4.9 ± 4.9; p =0.02; Figure 2). The activity of MPO in the medulla of the ANP group was significantly reduced compared to the control group (0.057 ± 0.035 vs. 0.026 ± 0.019 U mg–1; p =0.03; Figure 3), while the activity of MPO in the cortex was also lower in the ANP group, but the difference did not reach significance (0.038 ± 0.015 vs. 0.021 ± 0.012 U mg–1, p>0.05).
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These results show that ANP ameliorated renal medullary ischemia after HCA and reduced an inflammatory marker after ischemia in renal tissue. ANP stimulates synthesis of the intracellular second messenger, cGMP, which results in vasodilation. The natriuretic effect of ANP is derived from the regulation of tubular sodium transport controlled by cGMP and angiotensin II activity.11 Furthermore, nitric oxide synthesis is also enhanced by ANP, which is associated with increased cGMP and phosphokinase C.12 Previous studies have indicated that the effects of ANP in the kidney are dose-dependent. High doses of ANP induce natriuresis and renal artery vasodilation, whereas low doses increase natriuresis without renal artery vasodilation. Maack and colleagues13 reported that ANP administered intravenously in a dose of 1.0 µg kg–1 with constant infusion of 0.1 µg kg–1 min–1 increases natriuresis without increasing renal blood flow or systemic blood pressure. Banks and colleagues14 and Salazar and colleagues15 also reported that natriuresis induced by a low dose of ANP is associated with redistribution of renal blood flow, and that GFR is not necessarily increased. We demonstrated that a low dose (0.05 µg kg–1 min–1) of ANP did not induce significant changes in mean systemic pressure and renal arterial flow, and exerted natriuretic activity without significant changes in GFR.
Abnormal regional renal perfusion, especially in the renal medulla, causes acute renal failure after HCA. Renal medullary hypoxia is thought to be an important factor in the pathogenesis of acute tubular necrosis.5–7 Renal blood flow is mostly directed to the renal cortex. The estimated medullary blood flow per unit of tissue weight is <50% of that in the cortex. Additionally, the medulla receives 
10% of the total renal blood flow, because the medulla comprises <30% of total kidney volume.15,16 Renal blood flow to the cortex is regulated to optimize GFR, and blood flow to the medulla is regulated to preserve osmotic gradients and enhance urinary concentrations. The medulla requires a large amount of oxygen to generate osmotic gradients through active sodium reabsorption, especially in the medullary thick ascending limb.5 Figure 4 outlines the abnormal circulatory regulation in the medulla that arises following HCA. The process begins with a reduction of medullary blood flow, which causes a reduction in medullary oxygen supply. Augmented GFR after HCA ultimately increases reabsorption work, which increases oxygen demand in the medulla. An imbalance between oxygen supply and demand results in medullary ischemia, which subsequently depresses the ability to regulate the preservation of osmotic gradients and enhances urine concentration. A medullary oxygen insufficiency results in cortical vasoconstriction and decreasing GFR mediated by tubuloglomerular feedback, and these cause acute renal failure. Smith and colleagues7 found that CPB significantly reduced medullary PO2. Oxygen demand during reabsorptive work is associated with natriuretic activity and GFR. Natriuresis increases urine volume and sodium excretion, which together lead to increasing sodium clearance and FENa, as well as decreasing oxygen demand. In this abnormal circulatory situation, increased GFR conversely causes increased medullary oxygen demand, which results in medullary hypoxia. ANP reduces the oxygen demand-supply imbalance after HCA primarily by increasing medullary blood flow, and reduces medullary oxygen demand by decreasing sodium reabsorption work without a significant increase of GFR, thereby eliminating medullary ischemia.
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This study has some limitations. Firstly, we measured MPO activity in renal tissue to assess whether ANP prevents I/R injury. This study could not provide any other data to substantiate the hypothesis that ANP reduces renal tissue injury induced by I/R injury, and we did not measure the duration of renal ischemia. Secondly, CPB maintained a systemic mean pressure of 50 to 70 mm Hg, which might result in slightly higher CPB flow in the ANP group than in the control group due to the vasodilatory effect of ANP. However, renal arterial flow did not significantly differ between the 2 groups throughout the study. Although CPB flow was higher in the ANP group, ANP specifically ameliorated medullary flow. Thirdly, the results of this study might depend on the dose of ANP and the severity of HCA. The low dose of ANP used (0.05 µg kg–1 min–1) was the same as that usually applied clinically to treat renal insufficiency after CPB. We assessed renal function after HCA with low-dose ANP, but we could not identify the optimal dose required for renal protection. This study was undertaken at 30°C, and not at any lower temperatures. Further studies are required to elucidate the effects of ANP under HCA.
It was concluded that ANP administered continuously before HCA prevents medullary ischemia and postischemic renal dysfunction. This protection is mediated by improved medullary perfusion, inhibition of reabsorption work, and the prevention of polymorphonuclear cell-mediated renal tissue injury. Our data suggest that ANP confers important clinical advantages for preventing the postoperative renal failure that can occur after thoracic aortic surgery requiring HCA
Presented at the 16th Annual Meeting of the Asia Society for Cardiovascular & Thoracic Surgery, Singapore, March 13–16, 2008, where it received the Young Investigator’s Award.
ACKNOWLEDGMENTS
This study was supported in part by a Grant-in-Aid for Young Investigator’s Research from the Japan Heart Foundation, and by a Grant-in-Aid for Young Researchers from Showa University.
REFERENCES
Asian Cardiovasc Thorac Ann 2009;
17:401-407
© 2009 by SAGE Publications
DOI: 10.1177/0218492309341712
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