Ivana Marana

Contrast volume during primary percutaneous coronary intervention and subsequent contrast-induced nephropathy and mortality

Context Contrast-induced nephropathy (CIN) can complicate percutaneous coronary intervention (PCI). A better understanding of the relationship among contrast volume, patient characteristics, and CIN could help to reduce this complication. Contribution Of 561 patients who underwent primary PCI in the setting of ST-segment elevation myocardial infarction, 20% developed CIN, and those with CIN were more likely than those without CIN to die in hospital. Higher contrast volume and contrast ratio (volume administered/volume calculated) were associated with CIN and in-hospital death. Caution It is unclear whether the worse outcomes were due to the contrast or whether unmeasured aspects of disease severity led to both the need for more contrast and the worse outcomes. The Editors Primary percutaneous coronary intervention (PCI), defined as intervention in the culprit vessel within 12 hours after the onset of chest pain without previous thrombolytic or other clot-dissolving therapy, is the best available strategy for treatment of ST-segment elevation acute myocardial infarction (STEMI) (1). Patients having primary PCI, however, are at higher risk for contrast-induced nephropathy (CIN), although most of them do not have preprocedural renal dysfunction (2). Contrast-induced nephropathy is associated with a marked increase in in-hospital morbidity and mortality rates, which may partially thwart the survival benefit of primary PCI in patients who develop this serious renal complication (2, 3). Effective CIN prevention may further improve the clinical outcome of patients with STEMI who receive primary PCI. Potential preventive strategies include protecting the kidney from contrast- or ischemic-induced injury and limiting the amount of contrast administered. Studies of the antioxidant agent N-acetylcysteine (4) have yielded promising results for kidney protection. N-acetylcysteine has been shown to be effective in reducing CIN incidence and in improving clinical outcomes after emergency or primary PCI, particularly when administered as a high-dose intravenous bolus or with sodium bicarbonate (4, 5). Conversely, because few previous studies have reported the amount of contrast used, data on the effect of contrast volume limitation during primary PCI are lacking. Moreover, investigators disagree on the relation between the volume of contrast administered during interventional procedures and the risk for CIN. Some studies have reported no relationship, whereas others have suggested an independent correlation (614). ST-segment elevation myocardial infarction further complicates the issue. Patients with STEMI who are not undergoing primary PCI may also have acute worsening of renal function with the same prognostic implications as for CIN (15), which suggests that acute kidney injury may result from hemodynamic compromise rather than from CIN per se. In addition, primary PCI success, a major determinant of clinical outcome in patients with STEMI (1618), may require larger amounts of contrast. Thus, an optimal procedural result should be carefully weighed against risk for CIN. The association of contrast volume, as an absolute and a weight- and creatinine-adjusted value (19); CIN incidence; and clinical outcome in the setting of primary PCI remains unknown. As a result, evidence-based recommendations to guide best procedural strategies during primary PCI are still lacking. We sought to prospectively assess the possible association between contrast volume and CIN incidence and in-hospital clinical outcome in patients with STEMI who undergo primary PCI. Methods Study Population We conducted our prospective observational study at the Centro Cardiologico Monzino, University of Milan, between 1 January 2002 and 30 September 2007. We enrolled all consecutive patients with STEMI who were undergoing primary PCI. According to our institute protocol, we included patients who presented within 12 hours (18 hours for STEMI complicated by cardiogenic shock) of the onset of symptoms (characteristic pain lasting for at least 30 minutes, not responsive to nitrates, with electrocardiographic ST-segment elevation of at least 0.2 mV in 2 or more contiguous leads, or left bundle-branch block). We excluded patients receiving long-term peritoneal or hemodialysis treatment. We also excluded patients if they had cardiac surgery for emergency coronary revascularization or STEMI-related mechanical complications, died during PCI, or had been treated with an intravenous bolus of N-acetylcysteine before PCI. The Ethics Committee of the Centro Cardiologico Monzino approved the study, and all patients gave written, informed consent. PCI Procedure A 24-hour on-call interventional team performed primary PCI according to standard clinical practice by using standard guide catheters (6 French), guide wires, and balloon catheters via the femoral approach. Patients received a 5000-U bolus of heparin, followed by additional boluses during the procedure to maintain an activated clotting time longer than 300 seconds (between 200 and 250 seconds when abciximab was used). Coronary stenting was performed with standard technique. Contrast dose was left to the discretion of the interventional cardiologist. All patients received nonionic, low-osmolar contrast agents (iomeprol or iohexol). After contrast exposure, patients received isotonic (0.9%) saline intravenously at a rate of 1 mL/kg per hour for 12 hours. In patients with a left ventricular ejection fraction (LVEF) lower than 40% or overt heart failure, the hydration rate was reduced to 0.5 mL/kg per hour. Poststenting antithrombotic treatment consisted of aspirin and either clopidogrel or ticlopidine at standard dosages. Data Collection We measured serum creatinine concentration in all patients at hospital admission (before primary PCI), every day for the following 3 days, at discharge from the coronary care unit, and at hospital discharge. We estimated creatinine clearance by applying the CockcroftGault formula to the serum creatinine concentration (20). We defined preprocedural renal insufficiency as a creatinine clearance less than 1 mL/s (60 mL/min) (21). We calculated the maximum contrast dose (MCD) for each patient by using the formula proposed by Cigarroa and colleagues (19): MCD (mL) = (5body weight [kg]) divided by serum creatinine (mg/dL). From this contrast limit, we determined the contrast ratio by dividing the administered contrast amount by the calculated MCD. We left the use of -adrenergic blocking agents, angiotensin-converting enzyme inhibitors, platelet glycoprotein IIb/IIIa receptor inhibitors (abciximab), diuretics, intra-aortic balloon pump, or inotropic drug support to the discretion of the interventional and coronary care unit cardiologists, on the basis of the current standards of care recommended by published guidelines (22). During hospitalization, medications were changed as needed at the discretion of the cardiologist responsible for the patient. The primary end point of the study was the occurrence of CIN, defined as a greater than 25% increase in creatinine concentration from the baseline value in the 72 hours after primary PCI (23). In-hospital mortality rate and other major adverse clinical events were also evaluated as secondary end points. Statistical Analysis On the basis of our previous study (2), we calculated a sample size of 550 patients, assuming a 30% incidence of patients exceeding the MCD and a 10% incidence of CIN in patients with a contrast ratio less than 1. This sample size allowed 84% statistical power to assess a significantly higher ( error of 0.05) CIN incidence of 20% (odds ratio, 2) in the group with a contrast ratio greater than 1. We present continuous variables as means (SDs); we compared them by using the t test for independent samples or one-way analysis of variance, as appropriate. We compared categorical data by using the chi-square test or the Fisher exact test, as appropriate. The P values reported in Table 1 were not adjusted for multiple comparisons. Table 1. Patient and Procedure Characteristics We explored the relationship between contrast ratio and maximum percentage increase in creatinine concentration after primary PCI by using linear regression analysis. Both variables were log-transformed before analysis. We estimated predicted probabilities of CIN and mortality from the logistic models with the covariates set to the population average values. We assessed the association among contrast volume, contrast ratio, and clinical outcomes (CIN and in-hospital mortality) through logistic regression analysis. First, we included only contrast volume or contrast ratio (model 1). To adjust for potential confounders selected among recognized clinical predictors of the 2 outcomes (age, body weight, infarct location, LVEF, time to reperfusion, and baseline creatinine level), we developed 2 multivariable logistic regression models: model 2, which adjusted for the 2 major predictors (LVEF and creatinine level), and model 3, which adjusted for the 6 considered variables. Because contrast ratio is a calculated variable that includes both body weight and creatinine, we did not include those 2 variables in the models when we tested the association with contrast ratio. Thus, model 2 included LVEF and time to reperfusion, whereas model 3 included age, infarction location, LVEF, and time to reperfusion. Because of the relatively small number of events, we only considered mortality models with 2 or fewer covariates. To assess whether the effect of contrast volume on CIN differed in patients with renal insufficiency, we stratified our sample according to creatinine clearance (1 or <1 mL/s [60 or <60 mL/min]) and tested the appropriate interaction terms by using logistic regression, adjusting with model 2. All tests were 2-sided. We performed all calculations by using SAS, version 9.13 (SAS Institute, Cary, North Carolina). Role of the Funding Source The Centro Cardiologico Monz

Prevention of contrast nephropathy by furosemide with matched hydration: The MYTHOS (induced diuresis with matched hydration compared to standard hydration for contrast induced nephropathy prevention) trial

OBJECTIVES This study investigated the effect of furosemide-forced diuresis and intravenous saline infusion matched with urine output, using a novel dedicated device designed for contrast-induced nephropathy (CIN) prevention. BACKGROUND CIN is a frequent cause of acute kidney injury associated with increased morbidity and mortality. METHODS A total of 170 consecutive patients with chronic kidney disease (CKD) undergoing coronary procedures were randomized to either furosemide with matched hydration (FMH group, n = 87) or to standard intravenous isotonic saline hydration (control group; n = 83). The FMH group received an initial 250-ml intravenous bolus of normal saline over 30 min followed by an intravenous bolus (0.5 mg/kg) of furosemide. Hydration infusion rate was automatically adjusted to precisely replace the patients urine output. When a urine output rate >300 ml/h was obtained, patients underwent the coronary procedure. Matched fluid replacement was maintained during the procedure and for 4 h post-treatment. The definition of CIN was a ≥25% or ≥0.5 mg/dl rise in serum creatinine over baseline. RESULTS In the FMH group, no device- or therapy-related complications were observed. Four (4.6%) patients in the FMH group developed CIN versus 15 (18%) controls (p = 0.005). A lower incidence of cumulative in-hospital clinical complications was also observed in FMH-treated patients than in controls (8% vs. 18%; p = 0.052). CONCLUSIONS In patients with CKD undergoing coronary procedures, furosemide-induced high urine output with matched hydration significantly reduces the risk of CIN and may be associated with improved in-hospital outcome. (Induced Diuresis With Matched Hydration Compared to Standard Hydration for Contrast Induced Nephropathy Prevention [MYTHOS]; NCT00702728).

Acute kidney injury in ST-segment elevation acute myocardial infarction complicated by cardiogenic shock at admission

Objective: To evaluate the clinical and prognostic relevance of acute kidney injury (AKI) in the setting of ST-elevation acute myocardial infarction (STEMI) complicated by cardiogenic shock (CS). Design: Prospective study. Setting: Single-center study, 13-bed intensive cardiac care unit at a University Cardiological Center. Patients: Ninety-seven consecutive STEMI patients with CS at admission, undergoing intra-aortic balloon pump (IABP) support and primary percutaneous coronary intervention (PCI). Interventions: None. Measurements and Main Results: We measured serum creatinine at baseline and each day for the following 3 days. Acute kidney injury was defined as a rise in creatinine >25% from baseline. Overall, AKI occurred in 52 (55%) patients, and in 12 of these patients, a renal replacement therapy was required. In multivariate analysis, age >75 yrs (p = .005), left ventricular ejection fraction ≤40% (p = .009), and use of mechanical ventilation (p = .01) were independent predictors of AKI. Patients developing AKI had a longer hospital stay, a more complicated clinical course, and significantly higher mortality rate (50% vs. 2.2%; p <.001) than patients without AKI. In our population, AKI was the strongest independent predictor of in-hospital mortality (relative risk 12.3, 95% confidence intervals 1.78 to 84.9; p <.001). Conclusions: In patients with STEMI complicated by CS, AKI represents a frequent clinical complication associated with a poor prognosis.

Acute hyperglycemia and contrast-induced nephropathy in primary percutaneous coronary intervention

BACKGROUND Acute hyperglycemia and contrast-induced nephropathy (CIN) are frequently observed in ST-elevation acute myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PCI), and both are associated with an increased mortality rate. We investigated the possible association between acute hyperglycemia and CIN in patients undergoing primary PCI. METHODS We prospectively enrolled 780 STEMI patients undergoing primary PCI. For each patient, plasma glucose levels were assessed at hospital admission. Acute hyperglycemia was defined as glucose levels>198 mg/dL (11 mmol/L). Contrast-induced nephropathy was defined as an increase in serum creatinine>25% from baseline in the first 72 hours. RESULTS Overall, 148 (19%) patients had acute hyperglycemia; and 113 (14.5%) patients developed CIN. Patients with acute hyperglycemia had a 2-fold higher incidence of CIN than those without acute hyperglycemia (27% vs 12%, P<.001). In-hospital mortality was higher in patients with acute hyperglycemia than in those without acute hyperglycemia (12% vs 3%, P<.001). Mortality rate was also higher in patients developing CIN than in those without this renal complication (27% vs 0.9%, P<.001). Patients with acute hyperglycemia that developed CIN had the highest mortality rate (38%). Acute hyperglycemia was an independent predictor of CIN and in-hospital mortality. CONCLUSIONS In STEMI patients undergoing primary PCI, acute hyperglycemia is associated with an increased risk for CIN and with increased in-hospital mortality.

Sodium chloride vs. sodium bicarbonate for the prevention of contrast medium-induced nephropathy: A randomized controlled trial

AIMS The most effective regimen for the prevention of contrast-induced nephropathy (CIN) remains uncertain. Our purpose was to compare two regimens of sodium bicarbonate with 24 h sodium chloride 0.9% infusion in the prevention of CIN. METHODS AND RESULTS We performed a prospective, randomized trial between March 2005 and December 2009, including 258 consecutive patients with renal insufficiency undergoing intravascular contrast procedures. Patients were randomized to receive intravenous volume supplementation with either (A) sodium chloride 0.9% 1 mL/kg/h for at least 12h prior and after the procedure or (B) sodium bicarbonate (166 mEq/L) 3 mL/kg for 1 h before and 1 mL/kg/h for 6 h after the procedure or (C) sodium bicarbonate (166 mEq/L) 3 mL/kg over 20 min before the procedure plus sodium bicarbonate orally (500 mg per 10 kg). The primary endpoint was the change in estimated glomerular filtration rate (eGFR) within 48 h after contrast. Secondary endpoints included the development of CIN. The maximum change in eGFR was significantly greater in Group B compared with Group A {mean difference -3.9 [95% confidence interval (CI), -6.8 to -1] mL/min/1.73 m2, P = 0.009} and similar between groups C and B [mean difference 1.3 (95% CI, -1.7-4.3) mL/min/1.73 m(2), P = 0.39]. The incidence of CIN was significantly lower in Group A (1%) vs. Group B (9%, P = 0.02) and similar between Groups B and C (10%, P = 0.9). CONCLUSION Volume supplementation with 24 h sodium chloride 0.9% is superior to sodium bicarbonate for the prevention of CIN. A short-term regimen with sodium bicarbonate is non-inferior to a 7 h regimen. ClinicalTrials.gov Identifier: NCT00130598.

Angioplasty of atherosclerotic and fibromuscular renal artery stenosis: Time course and predicting factors of the effects on renal function

The effects of percutaneous transluminal renal angioplasty (PTRA) on the renal function of stenotic kidneys are usually assessed by evaluating the changes in serum creatinine, which is quite a rough indicator of glomerular filtration rate (GFR). In 27 hypertensive patients with 19 atherosclerotic and 11 fibromuscular significant renal artery stenoses, we investigated with renal scintigraphy the short-term (5 days) and long-term (10 months) effects of a technically successful PTRA (in seven cases combined with a stent implantation) on GFR of the stenotic and contralateral kidneys; these measurements were combined with those of plasma renin activity (PRA) and of angiotensin II (AII). We found that in short-term studies after PTRA GFR rose from 29.7 +/- 3.5 to 34.6 +/- 3.1 mL/min and from 36.9 +/- 4.0 to 45.1 +/- 4.3 mL/min, respectively, in atherosclerotic and fibromuscular poststenotic kidneys. In long-term studies GFR further and significantly increased, to 37.8 +/- 3.2 mL/min in the former group, whereas it stabilized in the latter group (46.0 +/- 3.6 mL/min). In patients with fibromuscular stenosis these changes in GFR were associated with clear-cut reductions in blood pressure (BP), PRA, and AII; these decrements also occurred in patients with atherosclerotic stenosis but to a much lesser extent. We also found that in short- and long-term studies the percent of PTRA-induced increments of GFR in the poststenotic kidneys were inversely correlated with the baseline values of GFR. In addition, the absolute and percent increments of GFR were positively correlated with the basal levels of AII. Thus the time course of the improvement in GFR after angioplasty may differ in kidneys, depending on the etiology of the stenosis, in that in those with fibromuscular stenosis it was entirely apparent within a few days whereas in those with atherosclerotic stenosis it required several months to be fully expressed. Also, it appears that the more compromised kidneys are those that benefit most from the dilatation and that AII levels are useful indicators of the possibility that the stenotic kidney will have a favorable functional outcome in terms of restoration of renal blood flow.

Incidence and Relevance of Acute Kidney Injury in Patients Hospitalized With Acute Coronary Syndromes

Acute kidney injury (AKI) occurs frequently in patients with acute coronary syndromes (ACS) and is associated with adverse short- and long-term outcomes. To date, however, no standardized definition of AKI has been used for patients with ACS. As a result, information on its true incidence and the clinical and prognostic relevance according to the severity of renal function deterioration are still lacking. We retrospectively studied 3,210 patients with ACS. AKI was identified on the basis of the changes in serum creatinine during hospitalization according to the AKI Network criteria. Overall, 409 patients (13%) developed AKI: 262 (64%) had stage 1, 25 (6%) stage 2, and 122 (30%) stage 3 AKI. In-hospital mortality was greater in patients with AKI than in those without AKI (21% vs 1%; p <0.001). The adjusted risk of death increased with increasing AKI severity. Compared to no AKI, the adjusted odds ratio for death was 3.5 (95% confidence interval 1.79 to 6.83) with stage 1 AKI and 31.2 (95% confidence interval 16.96 to 57.45) with stage 2 to 3 AKI. A significant parallel increase in major adverse cardiac events was also observed comparing patients without AKI and those with stage 2 to 3 AKI. In conclusion, in patients with ACS, AKI is a frequent complication, and the graded increase of its severity, as assessed using the AKI Network classification, is associated with a progressive increased risk of in-hospital morbidity and mortality.

Effects of exposure to high altitude on plasma endothelin-1 levels in normal subjects

Objective: To assess whether the hypoxia associated with exposure to high altitude affects plasma endothelin-1 levels, and whether changes in endothelin-1 are related to those in systemic and pulmonary blood pressure. Design: Eight normal subjects ascended Mount Everest to an altitude of 5050 m within a period of 8 days (study 1) and 10 ascended Mount Rosa in the Italian Alps to an altitude of 4559 m within 2 days (study 2). In study 1 systemic blood pressure, heart rate, haematocrit, haemoglobin oxygen saturation (evaluated by percutaneous oximetry) and venous plasma endothelin-1 were measured several times during the ascent, and twice more during the time spent at high altitude. In study 2 the same parameters as well as systolic pulmonary pressure by echocardiography were evaluated on the second day of resting at 4559 m. In both studies, data obtained during the expeditions were compared with those collected from the same subjects at sea level. Results: In study 1 plasma endothelin-1 increased progressively up to 4240 m (from 1.8±0.1 pg/ml at sea level to 2.7±0.2pg/ml) and decreased slightly thereafter; these increments were directly related to the decrements in percutaneous oxygen saturation, which, at that altitude, fell from 98.6±0.2% at sea level to 80.8±0.4%. Blood pressure and haematocrit also rose in response to exposure to high altitude but these changes were not related to changes in endothelin-1. In study 2 the increments in plasma endothelin-1 were similar to those observed in study 1 and the changes again correlated with changes in oxygen saturation as well as with those in systolic pulmonary pressure. On average, systolic pulmonary pressure increased from 19 ± 1 to 26±1.9mmHg, whereas systemic blood pressure and haematocrit were unchanged. Conclusion: Exposure to high altitude is associated with consistent increases in plasma endothelin-1. This is probably the result of augmented secretion of the peptide in response to hypoxia and may contribute to the physiological adaptation of the pulmonary circulation to this condition.

Continuous veno-venous hemofiltration for the treatment of contrast-induced acute renal failure after percutaneous coronary interventions

Acute renal failure (ARF) requiring hemodialysis after percutaneous coronary interventions (PCI) is a serious complication with poor prognosis. Hemodialysis‐induced hypotension may have deleterious cardiovascular effects, especially in high‐risk patients. Ultrafiltrate removal and simultaneous fluid replacement with a solution similar to plasma for high‐volume controlled hydration can be obtained with hemodynamic stability by continuous veno‐venous hemofiltration (CVVH). We prospectively assessed the safety and effectiveness of percutaneous CVVH (Y‐shaped double‐lumen catheter, circuit originating from and terminating in the femoral vein) in 33 consecutive patients (23 men and 10 women; mean age, 69 ± 9 years) who, after PCI, developed oligo‐anuric ARF, associated in 20 of them with congestive heart failure. All patients received a concomitant infusion of furosemide (500–1,000 mg/day) and dopamine (2 μg/kg/min). During CVVH, the average fluid volume replacement and body fluid net reduction were 1,000 ± 247 and 75 ± 48 ml/hr, respectively. Treatment with CVVH continued for 4.7 ± 2.7 days and corrected fluid overload in all cases. No patient experienced systemic hypotension or hypovolemia. Diuresis recovered in 32 (97%) patients, who showed a parallel improvement of renal function parameters. One patient required chronic dialysis. In‐hospital and 1‐year mortality was 9.1% and 27.3%, respectively. In conclusion, our data indicate that CVVH is a safe and effective therapy of radiocontrast‐induced ARF following PCI. It temporarily replaces renal function without deleterious cardiovascular effects, allowing the kidney to recover from the nephrotoxic injury. However, despite promising early results, large randomized trials are required to define the role of CVVH in ARF after PCI. Cathet Cardiovasc Intervent 2003;58:59–64.

Superiority of acceleration and acceleration time over pulsatility and resistance indices as screening tests for renal artery stenosis

Objective To compare the accuracy of four echo-Doppler-derived velocimetric indices (pulsatility and resistance indices, acceleration and acceleration time) in detecting renal artery stenosis in hypertensive patients. Patients and methods In 73 hospitalized patients with moderate-to-severe hypertension, 18 of whom had normal renal arteries and 55 renal artery stenosis (50-95%) either atherosclerotic (30 cases, five bilateral) or fibromuscular dysplasia (25 cases, two bilateral), we measured the four velocimetric indices using the lateral abdominal approach and sampling Doppler waveforms distally to the stenosis. The diagnostic accuracy of each index was calculated using as cut-off limit the ideal threshold determined with the receiver-operating characteristic curves. Results On average all of the indices were altered significantly in arteries with stenosis of both aetiologies with respect to normal arteries, the alterations of pulsatility and resistance indices being, however, less pronounced than those of acceleration and acceleration time, particularly in atherosclerotic stenosis. With the cut-off limits of 0.93, 0.59 and 7.4 m/s2 and 60 ms, respectively, for pulsatility and resistance indices, acceleration and acceleration time, their diagnostic accuracies were 80, 73, 93 and 92%. In stenotic arteries, only the acceleration time was correlated with the degree of arterial narrowing, whereas, in normal arteries, only pulsatility and resistance indices were directly correlated with the age of patients. Conclusions Acceleration and acceleration time are more accurate indices than pulsatility and resistance to screen for renal artery stenosis, probably because their alterations are less attenuated by the counterbalancing effects of age and of atherosclerosis.