Proper hydration in contrast-induced nephropathy among patients with acute myocardial infarction and cardiac insuciency

Backgrounds The recommended strategy to prevent contrast-induced nephropathy (CIN) among acute myocardial infarction (AMI) patients is adequate hydration. However, it is still controversial whether adequate hydration should be used to prevent CIN in AMI patients with Killip class>I. Methods In this prospective, observational registry study, 407 acute myocardial infarction (AMI) patients with Killip class>I undergoing percutaneous coronary intervention (PCI) were analyzed. The recommended hydration rate is haved before or after the procedure(0.5 mL/kg/h for Killip class >I). The endpoint was CIN(an absolute increase in serum creatinine of ≥ 0.5 mg/dL or a relative increase of ≥ 25% within 48-72 hours).Patients were divided into 2 groups by approximate median hydration volumn(HV)750ml. Multivariable logistic regression analysis was carried out to clarify the independent predictors of CIN and worsening heart failure(WHF). Univariate analysis and multivariate logistic regression models involving stepwise selection

The incidence of CIN is often higher in patients with acute myocardial infarction AMI due to the frequent hemodynamic compromise and the lack of su cient time for adequate hydration therapy [4][5][6][7]. Some studies showed that compared with patients without CIN, CIN increased the risk of adverse cardiovascular events and mortality after PCI with even relatively stable hemodynamics after a 1-year follow-up [8][9][10]. Recommended strategies to prevent CIN include adequate hydration,usage of low osemolar contrast media and a high-dose statin. Hydration speed should be halved 0.5ml/kg/h if left ventricular ejection fraction LVEF <35% or Killip class>I [11].
But the agents, timing, quantity of hydration have not been investigated in patients with cardiac insu ciency,especially in AMI patients with Killip class>I. In addition, the e cacy of adequate hydration in preventing CIN and avoiding worsening heart failure was lacking in convinced evidence. The purpose of this study was to evaluate the relationship between adequate hydration and incidence of CIN and WHF among AMI patients with Killip class >I.

Study Population
This prospective observational study was conducted at Guangdong Provincial People's Hospital between April 2009 to December 2013. We enrolled all consecutive patients with AMI aged more than 18 years old.Eligible participants should be assigned to Killip class>I by physicians. According to our institute protocol, exclusion criteria included malignancy, cardiovascular surgery or endovascular repair, end-stage renal disease or renal replacement and pregnant. The Ethics Committee of Guangdong Provincial People's Hospital approved the study, and all patients gave written informed consent.

PCI Procedure
Cardiac catheterization was performed according to standard clinical practice. Contrast volumn was left to the discretion of the interventional cardiologist. Patients would receive isotonic saline intravenously at a rate of 0.5 mL/kg 12h before or 12-24h after the contrast exposure due to Killip class>I. The standard post-PCI therapy consisted of lipid-lowering agents, β-blockers, angiotensin-converting enzyme inhibitors, aspirin, and clopidogrel, based on interventional guidelines.

Data Collection and de nition
Serum creatinine measurement at admission before coronary angiography and a subsequent measurement within 7 days after the procedure were required.
Creatinine clearance was calculated by the Modi cation of Diet in Renal Disease formula MDRD . The primary endpoint was the occurrence of CIN, which was de ned as an increase in serum creatinine of ≥0.5 mg/dL or ≥25% from baseline within 48 h of contrast exposure. The second endpoint was WHF, which was diagnosed by at least one clinical evidence of heart failure,including the increasing need for intravenous therapy inotrope or vasodilator or mechanical support, new radiologic evidence of pulmonary edema during the index hospitalization by clinicians. A baseline eGFR 90 mL/min/1.73m2 was de ned as chronic kidney disease CKD . Killip grading was evaluated by phycians.

Statistical Analysis
Patients were divided into 2 groups by 750ml due to the median of hydration volumn 700ml and consideration of the general liquid package 250ml .Continuous variables were presented as mean ± standard deviation and independent sample t-tests were performed for normally distributed data. The Wilcoxon rank-sum test was used for 2 groups that did not satisfy a normal distribution. Fisher's exact test or Pearson's chi-square test were used for categorical data, which were expressed as percentages and frequencies. Univariate analysis and multivariate logistic regression models involving stepwise selection and backward elimination were used to identify the predictors of CIN and WHF. A 2-sided p-value <0.05 was considered signi cant for all analyses. All data analyses were performed using SAS version 9.4 SAS Institute, Cary, NC, USA .
The patients in the HV > 750 mL group were signi cantly older, had poorer renal function and higher Nterminal pro-brain natriuretic peptide (NT-proBNP) levels. They were more likely to had more hypotensive status and higher Mehran risk scores, and more frequently required diuretics (Table 1). In addition, contrast volume-to-estimated glomerular ltration rate(CV/eGFR) was statistically signi cant difference.
However, contrast volumn was not signi cantly different in two groups(129.4±51.13 vs 136.7±58.05,P = 0.22). There were no statistically signi cant differences in diabetes mellitus and anemia.

Associations Between Hydration Volumn and In-Hospital Outcomes
There was statistically signi cant difference between hydration volumn and CIN in two hydration groups (HV >750 mL vs. HV = <750mL: 28.46% vs. 18.18%,P = 0.020), the same tendency was found in the WHF (16.2% vs 5.19%, P = 0.001). The patients in the higher HV group showed higher rate of in-hospital death than the lower HV group (6.72% vs1.95%, P = 0.031). However, dialysis rates were similar between the two groups. (Table 2).

Logistic regression analysis for association between HV > 750ml and CIN and WHF
Multivariate logistic regression analysis demonstrated that after adjusting 7 confounders including age>75,diabetes,hypotension,anemia eGFR<60 LVEF<40% and female, multivariate analysis showed that higher HV was signi cantly associated with CIN (adjusted OR = 1.83, 95% CI 1.05-3.20,P = 0.034) Figure  1 . Female was also an independent risk factor for CIN( adjusted OR = 1.84,95%CI:1.009-3.371,P = 0.047). Similarly, age>75 and LVEF<40% was also independent risk factors in the multivariate model. In the other multivariate model for WHF, after adjusting 7 confounders, multivariate logistic regression analysis revealed that the higher HV>750ml was associated with an increased risk of WHF risk (adjusted OR = 2.59, 95% CI:1.10-6.06,p = 0.029) Figure 2 Discussion The present study explored the effective and safe hydration volume for the prevention of CIN after CAG or PCI among AMI patients with cardiac insu ciency. Multivariate logistic regression showed that in AMI patients with Killip class>I, hydration volume >750ml at routine speed was not statistically associated with reducing the incidence of CIN, but an independent risk factor for WHF.
Several previous studies have explored the optimal hydration strategy [15][16][17], but the guidelines for patients with cardiac insu ciency still don't have speci c hydration strategy recommendation, especially in patients with cardiac insu ciency [18]. The recommended prevention for CIN was routine hydration 12 hour before and 6-24 hour after the procedure with saline at regular speed(1 ml/kg/h or 0.5ml/kg/h for patients with NYHA>II or LVEF<35%). Hydration strategy was used to be normalized by weight. However, most patients with primary PCI were not likely to obtain their weight and monitor their creatine before the contrast exposure. Fluid overload plays an important role in the pathogenesis of WHF and leads to prolonged hospitalization [19,20]. Therefore, AMI patients with Killip>I should get a targeted treatment to prevent CIN and to avoid uid overload.
The incidence of CIN was much higher in our study when compared with other clinical trials of patients with acute coronary syndrome [9,21,22]. The mehran score in two groups were both recognised as the middle risk. But their cardiac function have contributed to the high incidence of CIN and WHF. Maioli et al [17] assigned 450 STEMI patients to receive preprocedural and postprocedural hydration of isotonic saline or sodium bicarbonate. Their study suggested that adequate hydration may prevent CIN in patients undergoing primary PCI and hydration volume <960 mL was one of the independent predictors of CIN. The result was contrary to ours. The hydration agents in the 2 groups were sodium bicarbonate and saline. Meanwhile the propotion of patients with Killip>I was less than 25% in 3 groups. Many studies have demonstrated that furosemide with matched hydration by the RenalGuard System seems to reduce the incidence of CIN [4,[23][24][25]. The hydration volume was 3,995±1,401 ml and 1,742±290 ml in the Renalguard and control group, respectively. The RenalGuard system matching with furosemide could maintain a high urine output [>300 ml/h] during the procedure and improve simultaneously renal medulla perfusion. However, All patients with symptoms of acute heart failure were excluded. And the device was so expensive and inconvenient that the clinical application was not feasible. Some expert opinion of prevention of AKI suggested that hydration volumes above 11 ml/kg were associated with continuously increased rates of AKI in patients with chronic kidney disease (CKD) [26]. Study by Chen et al illustrated that hydration volumes greater than 15 ml/kg at routine speed may be associated with risk of CIN in patients with advanced congestive heart failure undergoing PCI [27], consistent with our understanding of the hydration volume in cardiac insu ciency.
Fluid overload could increase intraventricular pressure, myocardial stretching, and neurohormonal activation. Excessive hydration may or may not lead to an increase in renal interstitial pressure and oedema, reduction of renal blood ow and local oxygen exchange, and diffuse metabolic dysfunction at the same time [28,29]. This may explain that adequate hydration may not reduce CIN.
Most of the patients in our study might represent a special subtype of Type 1 acute cardiorenal syndrome (CRS), which is de ned as acute kidney injury complicating acute heart failure resulting from acute coronary syndrome. The latest statement about CRS [30] from the American Heart Association has mentioned some optimal methods to assess uid status, such as RenalGuard System, Bioimpedance vector analysis (BIVA), measurement of intra-abdominal pressures (IAP), relative blood volume monitoring devices and so on hopefully. However, whether the non-invasive devices will affect clinical outcomes in patients with HF still remains unknown.
Our studies suggested that the maximum volume was 750ml regardless of the weight of patients in AMI patients with Killip>I. Another clinical implication in our study is that in patients with Killip >I, monitoring urinary output and uid status might be helpful in earlier detection of renal function.
This study has several limitations. First of all, this single-center study might have been subject to bias although we have adjusted for confounders.
The evidence may not be as strong for its small simple size. Large size of prospective multicenter for hydration strategy in patients with HF are needed. Second, oral hydration volume was lacking. There must be some bias in the nal hydration volume.
This study has several limitations. First of all, this single-center study might have been subject to bias althought we have adjusted for confounders. The evidence may not be as strong for its small simple size.
Large size of prospective multicenter and randomized controlled studies are needed. Second, oral hydration volumn were lacking. There must be some bias in the nal hydration volume. Third, variation in the measurement times may have led to the missing of postprocedural peak levels of creatinine.Further multicenter, randomized, controlled clinical trials are needed to explore the optimal hydration strategy to prevent CIN.
In conclusion, adequate hydration volume with normal saline at a routine speed may associated with higher risk of CIN and WHF among AMI patients with Killip>I. Device-assisted hydration strgeties are expected to evaluate the uid status and receive individualized hydration

Declarations
Availability of data and materials The dataset used in the analyses reported here are not publicly available. Access to these data was provided by Yong Liu MD under a limited agreement. Requests to access these de-identi ed data can  Figure 1 Multivariate logistic regression analysis for the association between CIN and HV >750ml Figure 2