Gianfranco Lauri

Sustained improvement in functional capacity after removal of body fluid with isolated ultrafiltration in chronic cardiac insufficiency: Failure of furosemide to provide the same result

OBJECTIVES This study was designed to investigate whether a subclinical accumulation of fluid in the lung interstitium associated with moderate congestive heart failure interferes with the patients functional capacity, and whether furosemide treatment can promote reabsorption of the excessive fluid. BACKGROUND In patients with moderate congestive heart failure, pulmonary overhydration may be detected by chest roentgenography even if therapy is optimized to keep the urinary output normal and to prevent weight gain and dependent edema formation. Removal of the overhydration may help define its significance. METHODS Patients, whose regimens of digoxin, oral furosemide, and angiotensin-converting enzyme (ACE) inhibitor therapy were kept constant, were randomly allocated to receive ultrafiltration (8 cases) or an intravenous bolus of supplemental furosemide (mean dose: 248 mg; 8 cases). The amount of body fluid removed with each method approximated 1600 mL. Functional performance was assessed with cardiopulmonary exercise tests. RESULTS Soon after fluid withdrawal by either method, the filling pressures of the two ventricles and body weight were reduced and plasma renin activity, norepinephrine, and aldosterone were augmented. After furosemide administration, hormone levels remained elevated for the next 4 days, and during this period, patients had positive water metabolism, recovery of the elevated ventricular filling pressures, and re-occurrence of lung congestion with no improvement in functional capacity. After ultrafiltration, levels of renin, norepinephrine, and aldosterone fell to below control values within the first 48 hours and water metabolism was equilibrated at a new set point (less fluid intake and diuresis without weight gain). The favorable circulatory and ventilatory adjustments consequent to the reabsorption of lung water improved the functional capacity of these patients. That may also have restored the lungs ability to clear norepinephrine, thus restraining its facilitation of renin release. The improvement continued 3 months after the procedure. CONCLUSIONS In patients with congestive heart failure the set point of fluid balance is altered in spite of oral furosemide therapy; supplemental intravenous furosemide does not shift the set point, at least not when combined with ACE inhibition. Excessive, although asymptomatic, lung water limits the functional capacity of the patient.

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

Circulatory response to fluid overload removal by extracorporeal ultrafiltration in refractory congestive heart failure

OBJECTIVES The goal of this study was to investigate the hemodynamic and circulatory adjustments to extracorporeal ultrafiltration (UF) in refractory congestive heart failure (rCHF). BACKGROUND In rCHF, UF allows clinical improvement and restores diuretic efficacy. However, in the course of a UF session, patients are exposed to rapid variations of body fluid composition so that, as fluid is withdrawn from the intravascular compartment, hypotension or even shock could occur. METHODS In 24 patients with rCHF undergoing UF, we measured, after every liter of plasma water removed, hemodynamics, blood gas analysis (in both systemic and pulmonary arteries), plasma volume changes (PV) and plasma refilling rate (PRR). The PV and PRR were calculated by considering hematocrit and ultrafiltrate volume. RESULTS In all patients, UF was performed safely, without side effects or hemodynamic instability (ultrafiltrate = 4,880 +/- 896 ml). Mean right atrial, pulmonary artery and wedge pressures progressively reduced during the procedure. Cardiac output increased at the end of the procedure and, to a greater extent, 24 h later, in relation to the increase of stroke volume. Heart rate and systemic vascular resistance did not increase, and other peripheral biochemical parameters did not worsen during UF. Intravascular volume remained stable throughout the entire duration of the procedure, indicating that a proportional volume of fluid was refilled from the congested parenchyma. CONCLUSIONS In patients with rCHF, subtraction of plasma water by UF is associated with hemodynamic improvement. Fluid refilling from the overhydrated interstitium is the major compensatory mechanism for intravascular fluid removal, and hypotension does not occur when plasma refilling rate is adequate to prevent hypovolemia.

Interrelation of humoral factors, hemodynamics, and fluid and salt metabolism in congestive heart failure: Effects of extracorporeal ultrafiltration

PURPOSE We investigated the mechanisms involved in the regulation of salt and water metabolism in patients with congestive heart failure (CHF). Extracorporeal ultrafiltration was utilized as a nonpharmacologic method for withdrawal of body fluid. PATIENTS, METHODS, AND RESULTS In 32 consecutive patients with CHF (New York Heart Association functional class II to IV) and different degrees of water retention, 24-hour diuresis and natriuresis were inversely best correlated with the combination of circulating renin, aldosterone, norepinephrine, and renal perfusion pressure (RPP, mean aortic pressure minus mean right atrial pressure). Fluid withdrawal (600 to 5,000 mL) at a rate of 500 mL/h, until right atrial pressure decreased to 50% of baseline, caused variable humoral, circulatory, and diuretic effects that were mainly related to the extent of fluid retention. In fact, in 10 patients (Group 1) with overhydration refractory to drug therapy and with urinary output less than 1,000 mL/24 h (mean, 370 mL), soon after the procedure, plasma renin (-39%), aldosterone (-50%), and norepinephrine (-47%) were reduced and RPP was increased (+16%), and in the subsequent 24 hours, diuresis was increased by 493%; in 9 patients (Group 2) whose baseline urinary output exceeded 1,000 mL/24 h (mean, 1,785 mL), renin increased by 40%, norepinephrine, aldosterone, and RPP each decreased by 12%, and diuresis remained unchanged; in 13 patients (Group 3) with a daily urinary excretion as in Group 2 and without overhydration, RPP decreased (-7%), renin (+196%), aldosterone (+170%), and norepinephrine (+52%) increased, and diuresis decreased by 45%. There was an overall correlation (p < 0.0001) between the combination of changes in these circulatory and hormonal variables and changes in diuresis and natriuresis with ultrafiltration. CONCLUSIONS It appears that in CHF, (1) retention of sodium and water results from an interaction of hormonal and hemodynamic (primarily RPP) alterations that may exert a reciprocal positive feedback; (2) depending on the presence and severity of fluid retention, the response to withdrawal of body fluid may vary from neurohumoral activation and restriction of diuresis to neurohumoral depression and extreme potentiation of salt and water excretion; (3) refractory CHF requires the interruption of the humoral-hemodynamic vicious circle, and ultrafiltration is able to accomplish that.

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.

Lung-heart interaction as a substrate for the improvement in exercise capacity after body fluid volume depletion in moderate congestive heart failure

We investigated exercise capacity after fluid depletion in patients with moderate congestive heart failure (CHF). Twenty-one patients underwent ultrafiltration (mean volume +/- SEM: 1,770 +/- 135 ml). Echocardiography, tests of pulmonary function, and a cardiopulmonary exercise test with hemodynamic and esophageal pressure monitoring were performed before ultrafiltration and 3 months later. Tests without invasive measurements were repeated 4 and 30 days after ultrafiltration. Twenty-one control patients followed the same protocol but did not have ultrafiltration. Patients who underwent ultrafiltration and increased their oxygen consumption at peak exercise (peak VO2) by > 10% at the 3-month evaluation (group A1, n = 9) were separated from those who did not (group A2, n = 8); 3 patients did not complete the follow-up. Four days after the procedure, peak VO2 had risen from 17.3 +/- 0.8 to 19.3 +/- 0.9 ml/min/kg in group A1, and from 11.9 +/- 0.7 to 14.1 +/- 0.7 ml/min/kg in group A2 (p < 0.01). Plasma norepinephrine and pulmonary function were consistent with a greater severity of the syndrome in group A2. At 3 months in group A1, the relations of filling pressure to cardiac index of the right and left ventricles were shifted upward; the esophageal pressure swing (differences between end-expiratory and end-inspiratory pressure) for a given tidal volume was lower; the peak exercise dynamic lung compliance had increased from 0.10 +/- 0.05 to 0.14 +/- 0.03 L/mm Hg (p < 0.01). None of these changes were detected in group A2 and control patients.(ABSTRACT TRUNCATED AT 250 WORDS)

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.

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.

Usefulness of excitable gap and pattern of resetting in atrial flutter for determining reentry circuit location

Clinical and experimental data show that type I atrial flutter is due to a reentry mechanism with an excitable gap. To define the location of the reentry circuit of atrial flutter, width of excitable gap, poststimulation cycle and pattern of reset after premature stimulus were analyzed in 18 patients during atrial flutter at multiple atrial sites (high, lateral, posterior and septal right atrium, and coronary sinus). The pattern of reset was defined as flat or increasing whether the return cycle remained unchanged or prolonged with increasing prematurity. Shorter values of the excitable gap were found at the coronary sinus (33 +/- 8 ms) and high right atrium (30 +/- 10 ms) than at the posterior (43 +/- 9 ms) or septal right atrium (45 +/- 11 ms). Intermediate values (36 +/- 8 ms) were measured at the lateral right atrium. Poststimulation cycle, corrected for atrial flutter cycle length, was shorter in the posterior (6 +/- 7 ms) and septal right atrium (5 +/- 7 ms) than in the coronary sinus (35 +/- 9 ms), and the high (23 +/- 10 ms) and lateral right atrium (15 +/- 9 ms). A flat pattern of resetting occurred more frequently at the septal (18 of 18 patients) and posterior right atrium (15 of 18) than at the lateral (8 of 18) and high right atrium (2 of 17), and was never observed at the coronary sinus. Atrial flutter was successfully terminated by overdrive atrial pacing in 15 of 18 patients, and termination was more easily obtained from the septal and posterior right atrium.(ABSTRACT TRUNCATED AT 250 WORDS)