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Safety of an intravenous second generation contrast agent in patients with severe left ventricular dysfunction
  1. Department of Cardiovascular Medicine
  2. Northwick Park Hospital and Institute of Medical Research
  3. Harrow, Middlesex HA1 3UJ, UK
  4. roxy.senior{at}

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Contrast echocardiography has been used to opacify the left ventricular cavity, delineate endocardial borders, and assess myocardial perfusion. Since capillary integrity is essential for myocardial viability, the presence of contrast in dysfunctional myocardial segments may be used as indirect evidence of preserved viability in patients with left ventricular dysfunction.1It has been shown that 50–60% of patients with severe left ventricular dysfunction and coronary artery disease have evidence of myocardial viability, and the demonstration of viable myocardium in these patients has profound therapeutic and prognostic implications.2 The recent development of second generation contrast agents that can be administered intravenously has enhanced the applicability of contrast echocardiography. Contrast agents transit the pulmonary capillary circulation after intravenous administration. They could theoretically have adverse effects on pulmonary vascular resistance and oxygen saturation.3 It has also been suggested that a high pulmonary vascular impedance could hinder the pulmonary transit of contrast agents, thereby compromising efficacy. Sonovue (Bracco, Spa, Milan, Italy) is an aqueous suspension of phospholipid encapsulated sulfur hexafluoride microbubbles, developed as an intravenous contrast agent for echocardiography.4Although the safety of transpulmonary contrast agents has been previously established in human studies, it has not been specifically examined in patients with severe left ventricular dysfunction where the technique is likely to be increasingly used to determine myocardial viability.

Thus, the purpose of this study was to determine the cardiopulmonary and haemodynamic effects of bolus doses of Sonovue in patients with severe left ventricular dysfunction and congestive cardiac failure, and the ability of this agent to opacify the myocardium in presence of pulmonary hypertension. This was performed as a single centre, randomised, placebo controlled study where patients were randomised to receive either two boluses of 2 ml and 4 ml of Sonovue and matching placebo, given alternately at intervals of at least 15 minutes (active group), or matching doses of placebo only (control group). Haemodynamic parameters were measured by pulmonary artery catheterisation. Myocardial opacification was assessed by two dimensional (cross sectional) echocardiography using intermittent harmonic imaging, to ensure effective pulmonary transit of Sonovue in the presence of pulmonary hypertension. Approval of the hospital ethics committee was obtained.

All haemodynamic parameters were recorded at 5, 4, 3, 2, and 1 minute(s) before the first administration of the study agent and again at 30 seconds, 2, 4, 6, 10 minutes after administration. Oxygen saturation was monitored throughout using fingertip pulse-oximeter. Twelve lead ECGs were recorded 10 minutes before the first injection, and at 10 minutes and 1 hour after the final injection of the study agent. Local tolerability (local heat and pain) was evaluated immediately and at 5 minutes after each injection of the study agent. Patients were monitored throughout the study for any adverse symptoms and specifically for signs and symptoms of worsening heart failure. Echocardiography was performed using standard four and two chamber views at baseline and during each injection of study agent, starting before the administration of each dose and continuing until the end of the contrast effect. Second harmonic imaging was performed using broad bandwidth transducer (2–4 MHz). Images were acquired intermittently during the systole of each cardiac cycle by triggering on the T wave of the ECG, and stored on super VHS videotapes for off-line analysis. In each view left ventricle was divided into five segments and myocardial contrast activity was scored (0 = absent, 1 = weak, 2 = good).

Of the 19 patients recruited into the study, 18 were male. Thirteen and six patients were randomised to the active and control groups, respectively. Twelve and seven patients were in New York Heart Association (NYHA) functional class II and class III, respectively. The mean (SD) left ventricular ejection fraction of patients in the Sonovue and placebo groups was 30 (8)% and 24 (5)%, respectively (p = NS). Thirteen patients were known to have coronary artery disease and 10 had previous myocardial infarction. All patients received the full cumulative dose of 6 ml of the study agent in the predetermined sequence and were evaluable for safety.

Eleven patients in the active and five patients in the control group had pulmonary artery hypertension at baseline, defined as a systolic pulmonary artery pressure greater than 30  mm Hg or diastolic pulmonary artery pressure greater than 15 mm Hg. The changes in these parameters from baseline were short lasting and not significantly different following administration of either Sonovue or placebo. The peak changes from baseline in mean right atrial pressure, mean pulmonary artery pressure, mean pulmonary capillary wedge pressure, systemic vascular resistance, and pulmonary vascular resistance are shown in fig 1. Baseline cardiac output was 5 (1) l/min. The changes in all these parameters from baseline were not significantly different between Sonovue and placebo groups. Oxygen saturation was maintained within normal limits in all patients throughout the period of monitoring. Of the 13 patients in the active group, one with a history of chronic renal impairment and hypertension experienced a transient worsening in renal function which improved to pre-study levels at one week. No patient had deterioration in symptoms or developed worsening signs of cardiac decompensation.

Figure 1

The mean deviation from baseline of the haemodynamic parameters (A) and systemic and pulmonary vascular resistance (B) measured after administration of Sonovue and placebo. RAP, right atrial pressure; mPAP, mean pulmonary arterial pressure; PCWP, pulmonary capillary wedge pressure; SVR, systemic vascular resistance; PVR, pulmonary vascular resistance.

Myocardial perfusion was visualised in all patients who received Sonovue. Contrast activity was detectable in all 13 patients with the 2 ml dose and in 12 patients with the 4 ml dose. In one patient technical problems precluded image acquisition after the 4 ml dose, but myocardial perfusion was visualised after the 2 ml dose. As expected, no myocardial opacification was seen after the placebo injections in any patient. Intraobserver concordance for normal versus abnormal myocardial opacification was 92% (κ = 0.78).

This study represents the first evaluation of the safety of a second generation contrast agent, Sonovue, for echocardiography in this specific population of patients with severe left ventricular dysfunction and pulmonary artery hypertension. The administration of a cumulative dose of 6 ml of Sonovue as two bolus doses of 4 ml and 2 ml did not result in significant changes in clinical, ECG, laboratory or haemodynamic parameters compared to placebo. This was equally true for patients with and without pulmonary hypertension at baseline. The lack of any significant change in pulmonary arterial pressure, capillary wedge pressures, and oxygen saturation suggests that the administration of this agent is not associated with any worsening of left ventricular function. However, further data on the use of Sonovue in patients with impaired renal function needs to be collected before conclusions can be drawn about its safety in such patients. Bolus doses of 2 ml and 4 ml produced adequate myocardial opacification even in patients with pulmonary artery hypertension. This is contrary to previous suggestions that a high pulmonary vascular impedance in patients with elevated pulmonary arterial pressures may affect the pulmonary transit of contrast agents.

However, cardiac output, which is another important determinant of myocardial opacification, was normal in our group of patients.

In conclusion, Sonovue is a second generation echocardiographic contrast agent that does not appear to produce adverse cardiopulmonary haemodynamic effects in patients with left ventricular dysfunction and pulmonary arterial hypertension. Furthermore, its efficacy is not compromised by the presence of pulmonary arterial hypertension.