Prevention of contrast‐induced nephropathy by adequate hydration combined with isosorbide dinitrate for patients with renal insufficiency and congestive heart failure

Adequate hydration remains the mainstay of contrast‐induced nephropathy prevention, and nitrates could reduce cardiac preload.


| Study protocol
Patients were randomly assigned to isosorbide dinitrate with adequate hydration or standard hydration protocol with sealed envelopes that contained a computer-generated randomization sequence. The control group received a continuous intravenous infusion of isotonic saline at a rate of 0.5 mL/kg/h 6 hours before and 12 hours after the operation. The experiment group received continuous intravenous infusion of isosorbide dinitrate at a rate of 2 mg/h combined with intravenous infusion of isotonic saline at a rate of 1 mL/kg/h 6 hours before and 12 hours after the operation. Blood urea nitrogen, serum creatinine (Scr), serum electrolytes and cardiac enzymes were evaluated at baseline, the day of coronary angiography, each day for the following 3 days and at hospital discharge. All patients had an electrocardiogram on baseline, immediately after procedure. Acute heart failure (AHF) was observed during perioperative period, and we followed up these high-risk patients by routine clinical visit and recorded any main adverse cardiac events from hospitalization to 90 days after the procedure, medications were changed as required by the clinical situation.

| Study end points
The primary end point was incidence of CIN, which was defined as a 25% or 0.5 mg/dL rise in SCr over baseline during the first 72 hours post-procedure. 1 Secondary end points were major post-procedure adverse clinical events including AHF, myocardial infarction, all-cause death and CIN requiring renal replacement therapy. AHF was defined as a symptom of heart failure (paroxysmal nocturnal dyspnea or orthopnea with rales in both lungs) with objective examination (hypoxemia in blood gas analysis and pulmonary edema in X-ray).
Non-Q-wave myocardial infarction was defined as a creatine kinasemyocardial band enzyme elevation three times the upper normal value without new Q-waves on the electrocardiogram. Q-wave myocardial infarction was defined as presence of new pathologic Q-waves on an electrocardiogram in conjunction with an elevation in creatine kinasemyocardial band enzyme elevation three times the upper normal value. All adverse clinical events, as well as study end points, were monitored and adjudicated by the independent event committee.

| Statistical analysis
Continuous variables are presented as mean AE SD and were compared using the t test for independent samples. Variables not normally distributed are presented as median and interquartile range, and compared with the Wilcoxon rank sum test. Categorical data are presented as percentages and were compared using the χ 2 test or the   Table 1. The mean age of the cohort was 66 years, and 34% were female. The two groups were comparable regarding gender, type of procedure (diagnostic angiography or PCI) and baseline SCr, while the ejection fraction was 38% AE 8% in the adequate hydration group and 37% AE 8% in the control group (P = 0.271). Prevalence of diabetes was also no significant difference between the two groups (adequate hydration group, 49.5%; control group, 53.0%; P = 0.545). Mean contrast volume delivered during the entire procedure was not significantly different between groups (adequate hydration group, 172 AE 88 mL; control group, 179 AE 82 mL; P = 0.400).

| Incidence of AHF and major adverse cardiovascular events
The incidence of AHF after procedure did not differ between the two groups (8 [4.08%] vs 6[3.03%]; P = 0.599), and the dose of needed to treat with diuretic during the perioperative period is similar between the two groups. Figure 3 showed the occurrence of hospitalization for AHF and other major adverse cardiovascular events in the both groups during the 90-day follow-up. A total of four patients died during follow-up, and two in adequate hydration group, two in control group. Less occurrences of cumulative major adverse events were observed in the adequate hydration group compared with the control group (P for log-rank = 0.002). Myocardial infarction and stroke developed in 18 patients and was more frequently observed in the control group than in the adequate group (11 vs 7 events, P = 0.346).

| DISCUSSION
The main finding of our study is that in patients with CKD and CHF undergoing coronary angiography, a prophylactic nitrates with matched adequate hydration is an effective and safe strategy for the prevention of CIN in this patients.
Hydration of high-risk patients for CIN before contrast administration is a universally accepted measure to prevent CIN. It expands the volume, suppresses the renin-angiotensin-aldosterone system, reduces tubuloglomerular feedback and dilutes contrast media. 1,11,12 However, hydration could further increase cardiac pre-load and induce pulmonary edema. Patients with CKD or CHF did not receive routine adequate hydration because of fear of pulmonary edema. 13,14 CHF or CKD itself is independent risk factor for CIN. 3 trial found that furosemide with hydration induced high urine output significantly reduces the risk of CIN and may be associated with improved in-hospital outcome. 18 Our previous study also reported that CVP-guided fluid administration could safely and effectively FIGURE 1 Flow diagram reduce the risk of CIN in patients with CKD and CHF. 19 There has been a retrospective study demonstrated that the use of nitrates, particularly intravenous nitroglycerin prior to and during PCI may be associated with a decreased incidence of CIN. 20 Previous studies have shown that intravenous isosorbide dinitrate treatment of CHF patients was significantly more effective than nitroglycerin group, and had less adverse effects. 21 In our study, we applied isosorbide dinitrate instead of nitroglycerin to prevent CIN, and made similar conclusions.
It should be emphasized that although hydration could prevent CIN, 22 adequate hydration also could increase the incidence of pulmonary edema for CHF patients. In our study, we applied nitrates to ensure safety of adequate hydration, and we monitored the blood pressure, oxygen saturation and other signs of AHF during perioperative period. Incidence of AHF didn't differ between two groups. The incidence of CIN was significantly lower in the nitrates group than in the control group (12.8% vs 21.2%; P = 0.018). We hypothesized nitrates could formed of nitric oxide, which could act to protect renal medulla from regional hypoxia and oxidative stress. 23,24

| Limitation
First, this study is a single-center study. Incidence of AHF in two groups had no significant difference, but we cannot ensure the safety of adequate hydration because of the limited cases. Therefore, our conclusion needs further validation in large-scale prospective multicenter studies. Finally, the physicians in the hydration procedure are not blind, which may affect our results. Abbreviations: ACEI/ARB, angiotensin converting enzyme inhibitors or angiotensin receptor blockers; DBP, diastolic blood pressure; eGFR, evaluated glomerular filtration rate; HR, heart rate; LDL-c, low density lipoprotein cholesterol; NSTEMI, non-ST elevated myocardial infarction; NT-proBNP, N terminal-pro brain natriuretic peptide; PCI, percutaneous coronary intervention; SBP, systolic blood pressure; TC, total cholesterol. a Wilcoxon rank sum tests.